Treating Cancer Through Metastasis Neutralization and Possible Activation

While cancer in any form is potentially dangerous to a patent, it is widely acknowledged that only a small percentage of primary tumors are threatening to the life of a patient in the interim. A vast majority of cancer patient deaths occur due to cancer metastasis. Metastasis is a complex pathway of molecular interactions that produce an end result that involves the departure of a group of tumor cells from the primary tumor into the bloodstream and eventual invasion into other tissues resulting in the formation of additional tumors. Not surprisingly the process is governed by a number of complex pathways that are not fully understood. Despite this lack of knowledge regarding metastasis, is it clear that one of the best strategies for addressing cancer would be to create a therapeutic regimen that would prevent metastasis from occurring in the first place allowing physicians ample time to eradicate the primary tumor with no legitimate threat of reoccurrence.

Of the agents thought to be involved in cancer metastasis chemokine receptor CXCR4 is a promising agent of study and potential therapeutic target. Chemokines are a group of low molecular weight cytokines that induce chemotaxis, most of the time as chemoattractants, largely in leukocytes, endothelial and epithelial cells.1 Chemokines are commonly classified into CC, XC, CXC or CX3C designations based on the positioning of their respective conserved cysteine residues.1 One of the key normal functions of chemotaxis is to facilitate the movement of pro-inflammatory cells to the site of inflammation, including immune cells, normally after some form of injury. CXCR4 is an attractive target because of both strong anecdotal and experimental evidence regarding its overall expression and role in tumor malignancy and metastasis.1-5

CXCR4 functions as a G protein-coupled receptor (GPCR) that principally binds stromal cell-derived factor 1 (SDF-1), which is also known as CXCL12. With regards to cancer, CXCR4 plays a significant role in directional migration though activation of actin polymerization6,7 as well as invasion and adhesion, which influence the overall level of aggression for a tumor. There is also some evidence suggesting that CXCR4 plays a role in angiogenesis as well.4,5

CXCR4 can undergo four major changes to influence its functionality: homo or heterodimerization (with CCR2, CCR5, CXCR7 or CD4), phosphorylation, glycosylation, or sulfation.8-14 Unfortunately limited information is known about functional changes associated with dimerization in cancer for almost all studies involving CXCR4 dimerization relate to HIV, but it is thought that such changes enhance CXCL12 binding. It is also believed that dimerization typically occurs internally before CXCR4 is expressed on the cell surface, typically as oligomers. This oligomeric structure persists in the plasma membrane.14

Phosphorylation occurs principally at serine residue number 339 (Ser339) after exposure to either CXCL12, epidermal growth factor (EGF), or phorbol ester and it is believed that phosphorylation may also occur to a much smaller extent at Ser324, Ser325, and Ser330.12 Phosphorylation is important for increasing the probability of receptor internalization and secondary messenger activation. On a side note mono-ubiquitination occurs at Lys327, Lys331 or Lys333.13 Glycosylation of human born CXCR4 only appears to occur at Asn11 and seems to serve no unique function other than stabilizing CXCL12 binding (lack of glycosylation reduces binding efficiency).1

Sulfation, which takes place primarily at Tyr21 and does not appear to occur on two other potential sites (Tyr7 and Tyr12),15 may the most interesting modification regarding CXCL12 binding probability and functionality.16 When CXCL12 binds to CXCR4 there is a specific site interaction between sulfated Tyr21 on CXCR4 and Arg47 on CXCL12.15 One of the reasons that sulfation appears important is that one study demonstrated that while highly metastatic NPC cells and non-metastatic NPC cells expressed similar levels of CXCR4, both via mRNA and protein, only high levels of sulfinated CXCR4 resulted in high metastatic potential.17

While there are a number of tyrosine sulfation pathways, with regards to CXCR4 one of the more prominent interactions involves the action of the latent membrane protein 1 (LMP1). While LMP1 concentration changes are not universal to CXCR4 activity increases, LMP1 interacts with EGF receptors, which is thought to be one of the early steps in inducing Tyrosylprotein sulfotransferase-1 (TPST-1) dependent tyrosine sulfation of CXCR4.15 However, there is the lingering question of whether sulfation is the chicken or the egg, is it a chief agent in how CXCR4 activation influences the potency of cancer or is it a result of that activation?

CXCR4 activation also significantly increases the overall expression of matrix metalloproteinases (MMP), especially MMP-2, MMP-3, MMP-7 and MMP-9.18,19 One of the major triggers for this action could involve the activated CXCR4 guiding Bone marrow-derived cells (BMDCs) to their pre-metastatic niche, which then triggers BMDCs to initiate the release various metastatic positive elements including various MMPs most notably MMP-7 and MMP-9.20,21 CXCR4 is also involved in the homing of cells into the endosteal HSC,22 which facilitates the expression of SUMO-specific protease 1 that regulates MMP-9 as well.23

As stated above one of the key steps in metastasis is the proteolytic degradation of the extracellular matrix (ECM) in which various MMPs are critical agents. Initially MMPs were thought to be degenerative proteases that were limited to cleaving matrix components, but that role has expanded to include the release of growth factors and other bioactive peptides localized at cleaved extracellular matrices.24-26 While there are up to 26 known MMPs (MMP-1, MMP-2, MMP-3, …) only a few have demonstrated significant roles in both cancer growth and cancer metastasis. Of these select few MMPs that play a prominent role in cancer, MMP-3 and MMP-7 appear to be the most important.

MMP-7, (a.k.a. matrilysin) is the smallest MMP and is commonly expressed in epithelial tumor cells instead of interstitial cells27 and has numerous substrates in the ECM namely collagen fibers, laminin, gelatin, proteoglycan and elastin, etc.28,29 MMP-7 is commonly over-expressed in various types of cancer including, but not limited to non-small cell lung, pancreatic, oral squamous cell carcinoma, colorectal, prostate, stomach and papillary thyroid carcinoma.28,30-34 In addition to its ECM degradation role, MMP-7 can also breakdown cell surface proteins, which aids cancer cell proliferation through the regulation of apoptosis and angiogenesis as well as help evade immune system detection.34-36

Furthermore, as mentioned above, MMP-7 is thought to increase expression of MMP-2 and MMP-9 to aid in ECM degradation and other pro-cancer actions.37,38 Finally not surprisingly MMP-7 levels increase in response to decreased blood glucose levels for this increase is tied to a low quality or deteriorating principal environment for the tumor, which should trigger elements responsible for assisting metastasis like MMP-7. However, while MMP-7 appears to be the most active MMP in most cancers, its activation may only be a downstream event caused by MMP-3.

An early action taken by a member of the MMP family typically involves MMP-3 cleaving decorin, releasing growth factor-beta and cleaving transforming growth-factor-alpha (TGF-a), which activates the MAP-kinase pathway.39 This activation can later activate MMP-7, which as previously mentioned leads to the activation of MMP-2 and MMP-9.40 In addition to activating other MMPs like -2, -7 and -9, MMP-3 can also promote genomic instability and epithelial–mesenchymal transition (EMT) through the activation of Rac1b, which stimulates both the production and release of intercellular mitochondrial superoxide.41,42 MMP-3 appears to be the dominant expression route for Rac1b.41

Due to the important role MMPs play in inducing both metastasis and possible anti-apoptosis protection, a number of researchers have thought of MMP inhibition as a promising treatment option. However, clinical trials investigating the viability of MMP inhibitors, commonly known as tissue inhibitors of metalloproteinases or TIMPs, have not proven successful.43 One of the major theories behind this failure is that during tumor development MMPs have different roles depending on tumor progression and the other molecules present in the tumor microenvironment. Some information has demonstrated anti-tumor effects for certain MMPs, most notably MMP-3, MMP-8, MMP-9, MMP-12, and a newer MMP, MMP-26, which may be a natural protectorate MMP.43-47

Clearly this dual behavior makes targeting MMPs directly difficult for therapeutic reasons, as demonstrated clinically, thus it could be more important to focus on important MMP triggers like CXCR4, which appear to activate MMPs during a time when their interaction with the tumor microenvironment will produce a net negative for the patient.

CXCR4 also can activate the P110-beta isoform of PI3K resulting in the eventual synthesis of phosphatidylinositol (3,4,5)-triphosphate, which leads to the phosphorylation of protein kinase B/Akt and mTOR pathways most notably activation of p70S6K and 4E binding protein 1.7,48,49 Not surprisingly mTOR inhibitor, rapamycin, reduces the extent of p70S6K and 4E binding protein 1 activation in a CXCL12/CXCR4 environment.7,19,50 Furthermore CXCR4 also activates elements in the Src family of protein tyrosine kinases, which aid the activation of focal adhesion elements like Crk, paxillin, and tyrosine kinase/Pyk2.51

For a long time CXCR4 was thought to be a unique target for CXCL12 until CXCR7 was identified, potentially complicating the role of CXCR4. Similar to CXCR4, CXCR7 is expressed at a much higher rate in malignant cancer cells versus normal cells and binds CXCL12 with high affinity.10,52 However, despite the significant similarities between CXCR4 and CXCR7, CXCR7 does not appear to play a meaningful role in cancer development or metastasis.53,54 The role of CXCR7 appears to involve the migration of primordial germ cells or interneurons.55 Its increased expression simply may be the result of dramatically increased levels of CXCL12 in the localized environment. Interestingly enough CXCR7 may prove to be a possible therapeutic element as an indirect natural CXCL12 competitive inhibitor of sorts for every CXCL12 molecule that binds to CXCR7 is no longer available to bind to CXCR4.

Earlier it was mentioned that CXCR4 might have a relationship in tumor growth and/or angiogenesis. If true, then this result is complicated because cancer growth at established tumor sites is more rapid in the absence of CXCR4 rather than its presence.53 Therefore, it may be that while CXCR4 assists growth immediately after invasion, its continued presence becomes detrimental for the tumor because it helps induce metastasis, thereby diverting resources like recruited and differentiated endothelial cells or progenitors from the original tumor towards elements that will be involved in the metastasis or even the attraction of metastatic elements already in the bloodstream.

CXCR4 also appears to interact with another potential important factor in cancer metastasis, macrophage migration inhibitory factor (MIF). MIF is a pro-inflammatory cytokine that plays an important role in inflammation and immune response and is expressed at a higher than normal rate during numerous cancer stages like cell proliferation, angiogenesis and anti-tumor immune interaction.56-58 High MIF concentrations have also been associated with poor outcomes in lymphoma, melanoma and colon cancer.59,60 CXCR4 interacts with MIF through the formation of a MIF receptor complex with CD74, which further enhances MIF-stimulated AKT activation.61

There is some thought that when MIF lacks its traditional activation pathway it requires caspase-1 activity for proper secretion.62 Also Golgi-associated protein p115 may be essential for the transport of MIF from the perinuclear ring to the plasma membrane and then out of the cell.63 In addition to aiding metastasis, MIF is also thought to apply some level of apoptosis resistance to cancer cells, favoring those with androgen-dependency over those with androgen-independence, but that resistance may be tied to CXCR4 interaction.64

With CXCR4 having its “fingerprints” over a number of pro-cancer processes, fortunately an additional element that makes it an attractive therapeutic target is its natural role in the body. In non-cancerous tissue CXCR4 is expressed on hematopoietic cells like CD34+ HSC, B-lymphocytes, neutrophils, monocytes, macrophages, and microglia, etc.65 CXCR4 or CXCL12 knockouts in mice result in impaired hematopoiesis through reduced hematopoietic stem cell (HSC) trafficking, which results in heart and brain defects as well as vascularization commonly producing embryonic death;66 in adults CXCR4 is important in HSC homing for the bone marrow microenvironment and lymphocyte trafficking.65 However, most of the time CXCR4 expression in normal cells is low, unless the body has been recently injured. Therefore, treatments that limit CXCL12/CXCR4 pathway activation should result in limited negative side effects for healthy non-injured individuals.

Another potential benefit from CXCR4 inhibition could involve reducing the probability of chemotherapy agent resistance, including Docetaxel (DTX) resistance. Some research suggests that the CXCL12-CXCR4 pathway interacts with p21-activated kinase 4 (PAK4)-induced LIM domain kinase 1 (LIMK1) via phosphorylation to reduce the ability of DTX to destabilize microtubules, which typically results in cell cycle arrest during the G2/M phase.67 Basically CXCR4 activation provides additional protection against cell death for tumors when exposed to DTX. This result suggests that LIMK1 could have a role similar to microtubule-associated protein (MAP) depending on whether or not it is phosphorylated. Therefore, this chemotherapy resistant pathway has two principal inhibition targets in CXCR4 or PAK4 to negatively influence prospective chemo resistance.

Existing potential therapies involving CXCR4 have focused largely on inhibiting the binding capacity of CXCR4 most notably either through the use of AMD3100, a specific CXCR4 antagonist, or synthetic peptide TM4.14,68,69 AD3100 (a.k.a. (Plerixafor) is a small molecule with two cyclam rings connected by a phenylene linker that have nitrogens on each ring that have charge-charge interactions with carboxylate groups on CXCR4, which inhibits CXCL12 binding.70-72

Plerixafor is most commonly used as a pre-treatment element for chemotherapy where, as mentioned, CXCR4 disruption reduces the probability of hematopoietic stem cells homing to bone marrow, thus it increases their circulation in the blood stream allowing for their collection for transplantation after chemotherapy regimens.73,74 Plerixafor has also proven promising as an anti-cancer treatment via its ability to reduce cancer cell chemotherapy resistance by either neutralizing the CXCL12-CXCR4 pathway or reducing the physical attachment of various micro-environment critical cells, similar to what is expected for a CXCR4 inhibitor.

An interesting side effect in plerixafor treatment is that surface expression of CXCR4 increases both in vitro and in vivo.65 One possible explanation for this outcome could be that principal signals that induce CXCR4 expression continue while plerixafor prevents CXCL12 from binding CXCR4; CXCL12 binding leads to internalization and activation of secondary pathways. When there is no CXCL12 binding there is no CXCR4 internalization, but the pathways governing CXCR4 expression towards the cell surface continue, thus explaining the overall increase in CXCR4 expression. If this tendency is accurate then long-term treatment with plerixafor alone may not be beneficial because the increased surface expression will substitute for the CXCR4 “removed” by plerixafor interaction. Basically plerixafor works well alone in the short-term, but may not work well alone in the long-term, which may be the same fate of all substrate based CXCR4 inhibitors.

Apart from preventing metastasis, treating the primary tumor is also an important task, especially when surgical options are unavailable. One promising potential therapeutic agent that can influence both primary tumors and metastasis is salinomycin (SAL), which has demonstrated effective ability to kill cancer via a perceived mixture of apoptotic and autophagic cell death in breast, prostrate, brain, blood, liver, pancreatic and lung cancers with no immediate lethal toxicity.75-77 Initially it was reported that SAL was toxic to certain neuronal cells (dorsal root ganglion in mice) at 1 uM, but this toxicity was neutralized when paired with factors that inhibited mitochondrial Na+/K+ exchangers with no resultant change in cancer cell cytotoxicity.78,79

One of the chief advantages of SAL in treating cancer is that it uses a different methodology apart from more common chemotherapy drugs like Doxorubicin, Cisplatin, Gemcitabine, Temozolamide, Tratsuzumab, Imatinib, etc.75,80-82 SAL has a preference for targeting cancer stem cells (CSCs), which reduces the probability of cancer reoccurrence after its primary removal.75 CSCs are important to address in treatment because they are commonly thought of as another element responsible for driving the core of cancer metastasis after responding to various signal triggers as well as driving cancer recurrence after the primary tumor is eliminated due to their ability to more frequently resist anti-cancer therapies. Thus, addressing CSCs, either directly or indirectly, is a critical part to addressing both cancer itself as well as its metastasis.

Another interesting behavioral aspect of SAL is amplified effectiveness under hypoxia or starvation conditions. This result makes sense on two different levels: first, it is thought that a means in which SAL triggers cell death is through damage to the mitochondria, in part to being a potassium ionophore, promoting hyperpolarization in the mitochondria, which decreases ATP availability and triggers caspase-3, 8 and 9, a consequence worsened by starvation conditions.76,83 Second, its effectiveness against CSCs is enhanced by the reaction of the tumor to hypoxia. In hypoxia the primary tumor will begin to focus an effort to metastasize due to the negative environment that currently exists; one step in this process requires the recruitment and creation of CSCs which reduce resource availability for the primary tumor, yet those CSCs are more effectively eliminated by SAL versus the cells that comprise the primary tumor.

The ability of SAL to “cooperative” with other anti-cancer drugs directly is questionable for most of the benefit from co-therapy between SAL and given drug x appears indirect.84 This result is somewhat interesting because there is some evidence to suggest that SAL can also function as an efflux pump inhibitor, which is commonly operated by a p-glycoprotein;85-87 efflux pumps increase the ability of cancer cells to remove chemotherapy agents before the inducement of cell death, so inhibiting them would increase tumor susceptibility to these chemotherapy agents. However, Metformin (METF), which is though to lower circulating insulin levels and stimulate AMPK-mediated suppression of mTOR, along with having some anti-cancer properties in thyroid, prostate, gastric, breast and glioblastoma,88-90 seems to have some form of direct enhancing cooperative relationship with SAL.84

This combination activity results in the “unspecific” inhibition of EGFR and HER2/HER3 leading to reduced concentrations of AKT and ERK1/2 via an unknown mechanism.84 However, it seems appropriate to suggest that based on SAL activity when acting alone that this “inhibition” is born from a reduction in available receptors due to cancer cell or associated cell death.

Another mechanism for inducing cancer death that includes SAL interaction is autophagy. In its most basic form autophagy involves the “self-digestion” of intracellular elements via the vacuolar lysosomal degradation pathway to recycle cytoplasmic constituents.91 Autophagy is typically used to prevent the accumulation of damaged proteins and organelles, largely born from cell damage due to outside agents; for cancer it would be anti-cancer drugs. This process also reduces the production potential of reactive oxygen species (ROS) that negatively impact cell survival.

There is reason to believe that SAL can interfere with autophagy in cancer cells by inhibiting lysosomal activity driven by cathepsins.85 Interestingly enough this activity occurs without impacting the lysosomal compartment.85 This aspect of SAL interaction is not surprising due to structural similarities with both nigericin and monensin, which have similar behavior as anti-porters themselves, but the lack of change in pH of the lysosomes from SAL treatment belies a different pathway.

Also the behavior of SAL runs contrast to ATG7 expression where ATG7 acts as a protectorate of sorts ensuring the proper functionality of autophagy. For breast cancer cells and more than likely other forms of cancer, aldehyde dehydrogenase 1 positive cells (ALDH+) promote autophagy.85,92 Thus, SAL directly works against ALDH as well as competes to “thwart” ATG7 autophagy protection. Therefore, ATG7 in some instances is able to neutralize the dual ability of SAL to kill cancer cells via induction of apoptosis while inhibiting autophagy inhibition. Therefore, inhibiting the activity of ATG7 may provide a useful co-therapy with SAL to significantly neutralize the ability of cancer cells to build resistance to SAL-related apoptotic activity.

Another popular method of action for SAL against cancerous agents is thought to be its interaction with Wnt signaling and its relation to b-catenin. The interaction between Wnt and b-catenin begins when Wnt binds to frizzled (Fzd) receptor and then that complex binds to lipoprotein receptor-related protein 5 or 6 (LRP5/6) co-receptors leading to a ternary complex that typically exists at the cell surface.93 The presence of this complex can trigger phosphorylation of either LRP leading to the recruitment of axin, which then undergoes endocytosis.93 The end result of this entire process is the breakdown or inactivation of the Adenomatous polyposis coli (APC)-Axin complex, which is responsible for b-catenin elimination.

This processes is important because b-catenin accumulation leads to its nuclear translocation and can even increase expression of Wnt genes via those tumors located at the invasive front, which have more interaction with growth factors and cytokines including hepatocyte growth factor.94 This interaction may even create a positive feedback loop of sorts.94,95 This nuclear translocation of b-catenin is thought to play some role in tumor cells experiencing cell-cycle arrest and EMTs via the loss of E-cadherin expression creating some form of cancer stem cell, with increased migration/metastasis potential.96,97

SAL interferes with the Wnt pathway by degrading the LRP6 protein and possibly LRP5 protein, which obviously reduces the probability that they form a complex with Wnt and are later phosphorylated activating the complex.85 LRP protein importance is further supported by a level of suppression in breast cancer tumor growth after treatment with a LRP antagonist, Mesoderm development (Mesd).98,99

However, SAL is not a cure-all when it comes to this supposed pro-cancer pathway, for Wnt and its associated complex is not the only significant destruction inhibition interaction experienced by b-catenin. Expression of platelet-derived growth factors (PDGF) can induce the tyrosine phosphorylation of p68 via c-Abl kinase.100 After phosphorylation p68 can bind b-catenin and inhibit GSK3b mediated phosphorylation reducing the probability that it is eliminated, thereby increasing the probability of b-catenin nuclear location.100 It is also thought that EGF and TGF-b can induce p68 phosphorylation via receptor tyrosine kinases.100,101

Another possible strategy to deal with LRP protein complex interaction involves the inhibition of vacuolar H+-adenosine triphosphatase using an agent like archazolid.102 LRP6 phosphorylation and internalization appears to require V-ATPase. The general role of V-ATPase is transport of both intracellular and extracellular organelles near the plasma membrane. Not surprisingly it also pumps protons leading to the acidification of vesicles, which promotes endocytosis.103

Another element in cancer development that has garnered attention for metastasis is the role of carcinoma-associated fibroblasts (CAFs). Tumor invasion is heavily influenced by the tumor microenvironment, especially the types of non-tumor cells. Various types of fibroblast recruitment lead to the production of soluble factors and extra-cellular matrix (ECM) remodeling usually through actin changes and cell migration born from MMPs, Rho targeted via ubiquitination and SUMO pathways104 as well as global DNA hypomethylation and recruitment of mesenchymal stromal cells; these changes increase the viability of future invasion.105-108

The cancer stroma is typically populated by various concentrations of fibroblastic cell groups that make up CAFs and are commonly divided into myofibroblast (MFs) and non-myofibroblast populations (non-MFs).105 MF populations have received much more attention than non-MF populations more than likely due to the diversity of the non-MF populations. It is thought that CAFs differ significantly from normal fibroblasts and myoblasts, but there is little information regarding the extent of these differences.105,109

CAFs are heavily involved in various pro-cancer pathways like tumor necrosis factor alpha (TNFa), IL-1 and IL-6,105,110,111 which lead to promoting invasion, immune suppression and angiogenesis through the secretion of SDF-1, TGF-b, hepatocyte growth factor (HGF), PDGFs, or vascular endothelial growth factors (VEGFs) principally driven by FSP-1- or PDGF receptor alpha-positive stromal fibroblasts.112-116

Not surprisingly if CAFs are thought to play a role in all of these pro-cancer processes, targeting them would prove useful for developing effective therapies. A number of proposals have been made regarding PDGF receptor inhibitors, SUMO inhibitors, Met receptor inhibitors or HGF inhibitors; however, on its face it is difficult to envision how to effectively target the “right” CAFs due to the widely diverse population of cells within the stroma. Interestingly enough some possibly contradictory research could prove some insight.

As mentioned above CAFs in the stroma are typically defined as either MF or non-MF, but both of these groups can be activated and/or transformed as well. One particular group to question is activated non-transformed MFs, which express alpha-smooth muscle actin (a-SMA). There are some that believe that these cells have “anti-cancer” activity instead of “pro-cancer” activity. Support for this mindset comes from studies of early and late stages of pancreatic cancer outcomes, clinical correlation between high a-SMA levels and improved survival on a general level, and studies of resected tumors.117-120 Also there is some question to whether or not a-SMA positive MF cells increase hyaluronic acid concentration.121 The anti-cancer attributes of MFs appear to stem from aiding both innate and adaptive immune response via increased fibrosis.117

Whether or not these MFs are pro-cancer or anti-cancer elements is important to deduce because anti-cancer therapies tend to kill indiscriminately around the principal tumor and its microenvironment, including a-SMA positive MFs. If these particular MFs are anti-cancer then these drugs are inherently less effective because while they are killing cancerous elements they are also killing anti-cancer elements.

The final possible important element to CAFs and their role in cancer is their ability to produce exosomes. For example in breast cancer CAFs secrete Cd81+ exosomes that can induce the planar cell polarity (PCP) signaling pathway targeting Wnt and influencing the polarity of carcinoma cells.122 Internalization of these exosomes also promotes Wnt11-PCP induction via autocrine through Frizzled receptor signaling leading to increased probability of pulmonary metastases.112 Targeting these exosomes may be a valid therapeutic strategy for reducing cancer potency.

As mentioned above directly targeting CAFs via therapies may be difficult, but one potential candidate could be TNF receptor associated factor 6 (TRAF6). At least for squamous cell carcinoma (SCC), TRAF6 plays a role in enabling nuclear factor kappa beta (NF-kB) signaling to activate a number of downstream pathways for CAFs, like Akt, Src-family kinases, IKK, IL-1beta and p38 and can regulate the formation of Cdc42-dependent F-actin microspikes.105,107,123 While the role of Cdc-42 is exactly unclear, TNFa plays a large role in promoting invasion in SCC and TRAF6 plays a significant role in producing sufficient TNFa concentration. The reduction of either one of these pathways significantly reduces cancer invasion, possibly due to the K63 ubiquitin ligase activation associated with TRAF6.124

The final issue when addressing cancer metastasis is developing a strategy to promote delivery of the anti-cancer agents to increase the probability of positive action, especially through ensuring proximity action. A reason behind this strategy is that some agents, like the rather useful SAL, demonstrate low quality aqueous solubility, which restricts their ability to be injected through a more standard IV strategy.125 Not surprisingly nanoparticles have become the most attractive vessel for transporting anti-cancer agents to cancer sites.

Overall nanoparticles are advantageous due to their low to non-immunogenic activity reducing complications and increasing their lifespan in the bloodstream, their natural and generally safe biodegradability and biocompatibility and their general design flexibility for producing the right type of particle for the given job. For example some nanoparticle structures use polypeptides with elastin and hydrophilic properties in effort to produce immune-tolerant elements. These elements are commonly referenced with the acronym, iTEP.126 However, nanoparticles need a form of “navigation” system to reach the appropriate target. The two most common targeting strategies are the use of antibodies or the use of aptamers.

Antibody targeting in some respects is the “old reliable” while aptamer targeting is somewhat new. Aptamers are comprised either of oligonucleic acid (DNA or RNA) or a peptide that are able to bind a specific target molecule. The major advantages of aptamers are their molecular specificity, their lack of immunogenicity, and their low molecular weights. These two latter advantages along with ease of production have further increased the popularity of aptamers versus antibodies regarding therapeutic targeting strategies including those dealing with cancer. A number of aptamers have already been developed for use in cancer treatment.127,128

Regardless of navigation methodology, the drug delivery vessel must have the right navigation point. One molecule that has drawn interest for potential cancer targeting ability is hyaluronic acid (HA). HA typically binds to CD44, a receptor commonly over-expressed on numerous types of tumors.129 Furthermore HA is frequently broken down by tumor cells by hyaluronidases (Hyals), which is widely thought to experience concentration increases in various cancers including prostate, bladder, colorectal, brain and breast due to the presence of increased low weight HA fragments found in these tumors versus normal cells.130-133

The general process of HA catabolism involves binding to CD44 resulting in its breakdown into smaller elements by Hyal-2 while still on the cell surface forming what is known as a caveolae. This caveolae eventually becomes an endosome that fuses with lysosomes resulting in the further degradation of HA fragments into tetrasaccharides by Hyal-1.134,135 Based on this process one could theorize that a self-assembled nanoparticle comprised of HA would serve as an effective means of drug delivery to the tumor site both tracking and through its degradation, a belief that has been supported with early empirical results.129

In addition to HA, it is widely thought that cluster of differentiation 133 (CD133) is a positive stem cell marker for both normal and cancerous tissue and is thought to be a critical agent in identifying CSCs. For example it is common for CD133+ cancer cells to form mammospheres that can initiate tumor growth in non-tumor cells. Due to the importance of CD133 expressing cells, an RNA aptamer (A15) has already been developed that binds to CD133 for use as a “tracking” marker of sorts and some groups have already explored the idea of using A15 as a drug delivery targeting agent.136

However, it must be noted that while CD133 expressing cells appear to be the most important in the CSC pool, tumors do produce CSCs that express other surface receptors while not expressing CD133. For example in osteosarcoma, CD133, CD117 and Stro-1 are all considered to be legitimate CSC markers.48 Additionally there is some evidence to support the idea that CSCs can convert to non-CSCs and back again.137 Therefore, while targeting CD133 is clearly an appropriate strategy for treating CSCs, it may not be the only targeting strategy necessary to eliminate CSCs.

The type of nanoparticle is only part of the issue involving drug delivery. Another important element is whether or not the principal drug should have other elements encapsulated with it to increase efficacy. For example SAL delivery involves a charged hydrophobic drug trapped inside a hydrophobic core of micelle-like nanoparticle; these interacting charges can increase destabilization potential, leading to ineffective drug application, which has been seen in past studies.125,126 Therefore, this charge interaction needs to be neutralized.

An early candidate for cooperation with SAL stability was N,N-dimethyloctadecylamine (DMOA) due to its similar hydrophobic nature, yet positive charge which is obviously counter to the negative charge of SAL. Unfortunately DMOA proved too toxic for this role.126 Fortunately it has a less toxic analogue in N,N-dimethylhexylamine. However, this reduced toxicity comes at the price of reduced hydrophobic strength due to a shorter hydrocarbon chain.126 Thus, researchers have added alpha-tocopherol as a second hydrophobic agent to enhance internal hydrophobicity to increase stability, which appears to work well.126

In the end while metastasis is still a process with a number of question marks associated with its occurrence and action there does appear to be certain elements that have important roles in its successful occurrence and function regardless of these question marks. First, it is quite clear that any therapy will have to involve some form of drug cocktail to cover multiple metastasis pathways including treatment of the principal tumor via either drugs or surgery. With this strategy in mind one interesting combination would involve the use of SAL in HA nanoparticles, some form of CXCR4 inhibitor, something like Plerixafor should be sufficient when not applied by itself, and a standard chemotherapy drug like Docetaxel.

Another possible addition to this cocktail could be an anti-angiogenesis drug. In recent treatment history anti-angiogenesis drugs have had a negative history of being useful anti-cancer agents despite the sound theoretical reasoning that reducing growth resources should reduce cancer growth potential. The failure of anti-angiogenesis drugs more than likely occurred due to the induced hypoxia environment increasing rates of metastasis. However, this increased metastasis may be a benefit when the anti-angiogenesis drug is used in combination with a CXCR4 inhibitor and/or SAL, which could speed cancer death by eliminating the metastatic elements versus attempting to eliminate the principal tumor. Of course this combination and the possible positive outcome is only theoretical, without appropriate empirical evidence the addition of an anti-angiogenesis agent may not provide a benefit, similar to how it functions currently.

While promising gains have been made in recent years in immunotherapy-based techniques to combat cancer, it is important to acknowledge that overall there is no magic bullet, but the above potential cocktail should be able to overlap the important negative cancerous element of both primary tumor elimination through multiple destruction pathways and metastasis neutralization via elimination of CSCs as well as the major pathways the drive the preparation and activation of metastasis itself. This method alone or in combination with a proven effective immunotherapy technique could provide a legitimate anti-cancer therapy for various stages of cancer development.



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Does Criticism of Oscar Nominations Ring Hollow?

With the conclusion of the 2016 Oscar nominations and the lack of any black individuals in any of the major categories the black populous has commenced with their criticism of such an outcome with social media tags like #OscarsSoWhite or calling the Oscars “the White BET Awards”. Unfortunately almost all of this criticism represents a significant problem in society, not because one may disagree with the nomination results, but instead because the criticism is sound bite in nature without any substance behind it.

Overall there are two principal motivations behind criticizing these nominations. First, certain individuals feel that the Oscars missed an opportunity to promote diversity by not having black nominees (or other minorities, but it is unlikely that most in the black community care about the nomination of a non-black minority). The underlying motivation of this argument is that every year the Oscars should nominate at least one black individual, i.e. basically there should be a “diversity” quota.

Congratulations to anyone with this belief for you are a racist. You believe that someone should receive different treatment based on the color of that individual’s skin. Oscar nominations do not fall under the umbrella of “affirmative action” because acting, directing or writing performances are not significantly hindered by potential detriments from possible racism in the upbringing or the acquisition of the role for once you have the role those issues become irrelevant. To argue otherwise would be akin to saying Wrestler A in the U.S. Olympic Trials should start with a 2-point advantage over Wrestler B due to the background of Wrestler A. College admissions and employment opportunities are much more complex and need deeper analysis versus a direct merit based analysis like an Oscar nomination.

So now that the ridiculous idea that the Oscars need diversity for the sake of diversity has been revealed as what it is, a racist based quota system, it is time to address the second and actual legitimate criticizing motivation, the idea of the snub. Unfortunately for individuals supporting a particular person or movie for an Oscars, almost every year there are more deserving candidates than there are nominations; therefore, clearly a number of deserving individuals will not be nominated. Where is the criticism from the black community about the lack of nominations for Steve Carell (Big Short), Michael Keaton (Spotlight) or Johnny Depp (Black Mass) or does their lack of nominations not matter because they are white?

If one feels that Idris Elba (Beasts of No Nation), Will Smith (Concussion), Ryan Coogler (Creed director), etc. should have been nominated then one must articulate the rationality behind why a nomination was deserved. Also one must go further and then discuss why nominee x did not deserve his/her nomination, thus it would have been appropriate for one of the above individuals to have taken nominee x’s place. Failing to conduct such an analysis simply places one in the first criticism motivation camp, i.e. you are a racist, because you fail to produce a rational argument to counter the decision of the nomination committee beyond “there should be a black person simply for faux diversity reasons”.

Now some individuals could contend a flaw in the nominations because out of all of the possible worthy contenders, there were no black nominees? While on its face this argument may seem convincing, the chief problem is that it fails to take into consideration the demographical participation rate of both overall contenders and those who would be deemed worthy contenders. The black participation rate is rather low in the movie industry on both counts; for example of the worthy nominees for Best Actor (most likely the strongest category for blacks to receive a nomination) just the sheer math lists the worthy black participation rate at no more than 20%, thus significantly reducing the probability of receiving a nomination.

The above argument would have much more merit if the black participation rate were higher. For example if the NBA All-Star team selection was carried out by a committee of individuals and both teams were selected without any black participants, then one would have a much stronger argument for racial motivations behind the selection because of both the number of available black participants and their overall quality. However, in the movie business the participation rate hardly matches that seen in the NBA.

Some could counter-argue that the low participation rate implies racism in the movie business, but such an argument is difficult to make because of simple natural demographics. A number people, including many individuals in the black populous, seem to forget that black individuals only make up approximately 13% of the U.S. population. So it is not unreasonable for a number of fields to have similar participation rates because the overall population is low to begin with as well as the pool of individuals with sufficient talent to sufficient participate and even excel in these fields (which is similar as a percentage for all demographics not just blacks).

Overall if one wants to criticize the Oscar nominations then make sure to do so using rational analysis regarding why candidate x should have been nominated over nominee y. That way your criticism will at least have a measurable element to judge its validity. Otherwise, if one forgoes this type or similar rational analysis one is simply acknowledging that he/she is a racist.

Should the United States adopt a different system from the current Opt-In system for organ procurement?

One of the more acknowledged problems in healthcare that receives some attention yet little is actually done about is the lack of available organs for transplant. Based on recent data at least 114,000 people in the United States are waiting for an organ transplant that will significantly increase their remaining lifespan.1,2 Unfortunately most of those waiting will die before receiving that desired organ due to the dramatic gap between the available supply of organs for transplant and those waiting for one.

To understand and appreciate the extent of this gap according to the Scientific Registry of Transplant Recipients (SRTR) between 2000 and 2009 the annual number of deceased organ donors (the most viable for most types of transplants) in the U.S. increased from 5,985 to 8,022 whereas the number of individuals waiting for a transplant increased from 74,635 to 111,027.3 In the first half of 2010s there was not significant deviation from this trend. Note that this increase in the waiting list occurred despite an increase in organ transplants. In either absolute numbers or relative percent change, there is an increasing gap between available organs and those who need them. While various aspects of biological research are working to create an environment where new organs can be grown in a lab with low rejection probabilities, thus significantly mitigating this supply problem, such a reality still appears to be a long way off. Therefore, should changes be made to the current organ donation system to speed the closure of this gap and save lives?

While each state has their own laws on organ donation the general model has always followed the Uniform Anatomical Gift Act (UAGA), which was first passed in 1968 and amended in both 1987 and 2006. UAGAs are created by the National Conference of Commissioners on Uniform State Laws (NCCUSL) as a means to create uniformity among states on various laws where uniformity makes sense due to a lack of special circumstances; however in the end states have the option to adopt, decline, or simply use the act as a skeleton for their own laws. The original 1968 UAGA established the general goal of organ donation as a system based on altruism through voluntarism due to the opt-in nature of the program and created legislative guidelines for donation of fetal organs and tissues.4

In 1987 the UAGA experienced two significant changes among other smaller changes: first it was amended to forbid persons from “knowingly, for valuable consideration, purchase or sell a part for transplantation or therapy, if removal of the part is intended to occur after the death of the decedent.” Second, a narrow form of presumed consent was added whereby a medical examiner could remove any needed organs or tissue in the absence of any objection by the decedent or decedent’s next of kin.5 This presumed consent addition was not unique for numerous states already had similar types of regulations in their organ donation laws mostly concerning cornea removal.

In 2006 the UAGA was further revised to remove the presumed consent regulations largely due to a number of lawsuits filed against those measures.6,7 Almost all states followed the pattern of the UAGA by either officially enacting its recommendations or making changes to their own state laws to flow in close proximity with its recommendations including the removal their own presumed consent regulations as well, with only a few states retaining very restrictive guidelines concerning cornea removal.6

As noted above while the idea of characterizing organ donation as an altruistic gesture is certainly a nice idea in theory, especially when 90+% of people support organ donation and 70+% of polled individuals would consider being an organ donor; in reality when only about 42% of U.S. adults are registered organ donors when lives are on the line, clearly theory and reality are in conflict.1,2

The difference between those who claim to be interested in being a donor and those who actually are donors suggest some significant problems with the opt-in system. One of the major issues appears to be physicians adhering to the wishes of next of kin to not harvest organs even though the decedent was an organ donor; a decision that makes no sense. Also there can be problems with organ procurement agents obtaining referrals from donors.7 A lack of public campaigning to raise awareness regarding the organ shortfall and the benefits of organ donation has also played a role in the lower than expected donor rates. Finally another less fixable problem is the psychological reluctance of most individuals to contemplate death and plan appropriately for it. This “kicking the can” strategy concerning death typically creates numerous problems when handling end of life decisions, including issues involving organ donation. So, if these are the problems associated with the opt-in system, what are other options that could increase the number of individuals willing to donate?

One way to close the gap and improve donation rates is to provide an incentive for individuals to be “altruistic” (the irony of having to provide incentives for individuals to be altruistic is somewhat hilarious). However, with the sale of organs illegal, incentives must be creative in a sense, but also be of significant value. Israel and Singapore are two countries that utilize a low-cost incentive program that involves influencing organ allocation. In the U.S. a national waiting list is maintained where transplant candidates are ranked largely based their overall health (how long they have left to live without the organ) and when their name was placed on the list. However, in the determination of who receives an organ there is no “bonus” to those who are donors. The priority rule or preferred donation system used by Israel and Singapore provides some level of preference to future donors over those who do not plan to be future donors.

For example in Israel potential organ recipients are rated on a multiple point scale and whether or not they are planning to be a donor is also part of that criteria.8 Additional consideration can be gained if a direct family member of a potential recipient has signed a donor card or has already donated in the past be it as a live non-designated donor or a deceased donor.8 In Israel this program largely arose from the perceived repugnant behavior that a number of individuals were willing to accept an organ transplant, but would never be willing to donate an organ even after death. For Israel this program, as well as other supplemental small incentive programs, dramatically increased the rate of organ donations, especially in its early years of its adoption 2011 and 2012.9

While the initial logic associated with the priority rule program appears sound, for it makes sense that future organ donors should receive some level of priority over those who do not plan to donate, there are some important issues. The first problem is the system in Israel is not legally binding in that an individual can agree to become a donor, but back out later. This type of system creates problems on both fronts because instituting a rule that once a person has agreed to be a donor then that individual can never withdraw from being a donor would see an immediate court challenge that would probably result in the elimination of such a condition. However, if the system remains as such one can simply declare donor intentions when it is advantageous and withdraw when it is no longer advantageous making a mockery of the system. One way to address this issue may be instituting a time limit where no benefits are acquired until an individual has declared donor intentions for at least x number of years, thus at least eliminating individuals who join solely for selfish short-term reasons.

The second problem is such a system raises potential moral questions when non-medical elements outside of time are introduced into the organ selection process. While on its face such a system appears to have a “tit-for-tat” characteristic, it would not be hard for one to produce a potential slippery slope argument. A common argument would be that the individual who agrees to become a donor is receiving some form of preferential treatment because he/she is offering something of value to the organ bank, replacing the used organ as well as offering others. Some could argue that in this environment how is it justified for an alcoholic poor person to receive a liver over a philanthropic millionaire? The millionaire provides dramatically more benefit to society if he/she survives over the alcoholic. While this argument should be irrelevant because the priority rule system only addresses organ donation specifically… sometimes certain parties just need a small window of opportunity to change a system significantly and the United States does not have a quality track record for societal fairness.

The third problem is such a system could be unconstitutional on the grounds that it would violate equal protection in that government could provide an organ to one individual over another based on non-medical factors. For a violation of equal protection it must be determined that the groups being compared are similarly situated otherwise government or another agency can apply different standards as long as those standards are not discriminatory.10 It is unknown how a court would rule in this case because providing a benefit only based on the notion that the receiver made a non-binding declaration of donation would require the court to determine the intent of the parties and whether that intent makes other groups distinguishable, which could potentially open a nasty can of legal worms.7 Any “perks” for donor kin would be an instant no-go because granting a benefit to someone simply on the basis of relation is inherently discriminatory.

The fourth and final major issue is would religious objections to organ donations cause problems for such a system in a discriminatory fashion? Initially it appears that religious objections should not cause a significant problem because discriminatory intent requires that the principal purpose of creating a law in the eyes of its creators be to produce discrimination; if the law is neutral and indirect discrimination is simply derived from its enforcement then no legal discrimination exists. This general legal structure was noted in Personnel Administrator of Massachusetts v. Feeney.11 However, while religious objections should not be a problem, religion can make these types of things more complicated.

Overall these potential issues do raise the question of the true value of changing the existing opt-in system to a priority rule donation system. So if a priority rule system is not preferred what other options remain? Another possible system for donor expansion removes the passivity from the opt-in system while maintaining its spirit, the mandated choice system.

Execution of the mandated choice system is rather straight-forward; when individuals over the age of 18 acquire or renew their driver’s license they are asked whether or not they wish to be an organ donor. This system attempts to maintain the altruistic characteristic of organ donation while eliminating the obligation of the potential donor to initiate the process to become a donor. Such a system has been utilized in both Texas and Virginia before other systems replaced them and is currently operating in Illinois, Colorado and California.12 Of course there are certain conditions that must be followed outside of simply asking “Do you want to be an organ donor.”

For example the American Medical Association has noted that in the mandated choice system the asked individual must be properly informed regarding the elements that are involved in organ donation to ensure that the individual understands the procedure and can be regarded as meeting the principles of informed consent.13 Also some might argue that a mandated choice system is not constitutional on First Amendment grounds in that an individual has the right not to speak and asking the question of organ donation without providing a means to simply not answer without consequence would be unlawful.

Realistically the First Amendment argument more than likely fails if the question embodying the mandated choice system is asked in a neutral manner with no legitimate attempt to favor a particular decision. With this condition in mind the question medium would more than likely have to be paper for one could interpret certain pressures upon an individual when asked verbally whether or not they want to be an organ donor. Such pressures are commonly associated with “being put on the spot”, which can favor a yes response over a no response, especially with a moral issue like organ donation and being asked by a government official (DMV employee). The question itself should simply ask “Would you like to make your organs available for transplant into other parties after your death?” or something similar, just a neutral question with no positive or negative overtones.

The success level of mandated choice programs have varied over time for both Texas and Virginia eventually overturned their programs because of strong negative reaction from the public including an increase in donation rejection in Texas up to 80%.14 Whereas in Illinois organ donation participants have increased to 60%.7 It is difficult to reconcile these two results. The best potential explanation may simply be political in the context of how individuals view government involvement in society. Both Texas and Virginia lean more conservatively and some may simply be offended that government even asks in the first place while the more liberal leaning Illinois is not offended by such behavior. Overall if this is the case then it is difficult to see how a mandate choice program would make significant in-roads towards increasing organ donation rates as potential increases in some places may be offset by other potential decreases in others.

The final major option to increase organ donation rates would be to simply return to the presumed consent days (i.e. Opt-Out over Opt-In), yet expand the program to include all organs not simply corneas or John/Jane Does. Clearly to ensure significant positive changes this presumed consent program would have to be hard/strong (after death if the individual did not opt-out then next of kin have no say in the issue of organ donation) versus soft/weak (next of kin can still reject organ donation for the deceased). Not surprisingly such a change could produce strong objections from some individuals for presumed consent/opt-out would in essence redefine the rule of who owns a deceased’s organs from next of kin to the government. Others would argue that such a policy poses a direct attack on individual liberty, autonomy and privacy by restricting freedom of choice, the very factors that some believe grant acceptability to an opt-in system.

The notion that an individual loses liberty, autonomy and privacy in an opt-out system is basically ridiculous. In short there is no threat to these elements in such a system because the individual has sufficient opportunity to declare their intentions to not be an organ donor while still alive. Once an individual dies the rights associated with liberty, autonomy, privacy, etc. are heavily handicapped, thus eliminating any meaningful violations in this circumstance.

Any minor opposition on the grounds that legislating altruism is not a responsibility of the government is a non-starter because the issue of establishing an opt-out system over the current opt-in system is a matter of public health due to the significant gap between available organs and individual need, not altruism and again there is no violation of personal autonomy because the individual is dead, thus the individual no longer possesses the capacity for autonomy.

Also some could argue that soft/weak presumed consent provide respect for the decedent’s relatives who are more than likely grieving the loss by allowing them to preserve the state of the loved one. However, there is a notion of hypocrisy in this idea for individuals in a presumed consent system can opt-out, thus why is it alright that the wishes of the next of kin supercede the wishes of the decedent if the decedent never opted out? Any “psychological” detriment born by the next of kin due to a hard/strong presumed consent system is the fault of their own selfishness and/or arrogance, not the system.

A more relevant issue is the question of next of kin property rights. Although it may sound grizzly, when an individual dies the body and its contents (in a sense) basically become property of the next of kin, especially with relation to burial rights. Some next of kin could challenge a presumed consent system on the grounds that it interferes with property rights or even religious services. However, in case of previous presumed consent laws, courts almost always side against such claims. For example in Tillman v. Detroit Receiving Hosp, a Michigan court ruled that the state’s presumed consent law for cornea extraction did not violate the privacy right of the decedent or her next of kin and the cornea removal did not constitute sufficient mutilation to void such action.15

However, one could argue that this case only involved cornea extraction not the extraction of numerous and various other organs, which would occur in a more thorough presumed consent system. While there certainly would be more incisions made in the individual, the individual would receive the appropriate remediation treatment through stitches and if properly dressed should have no significant mutilation or ascetical issues apart from an individual who simply had corneas removed.

Moreover pertaining to the issue of next of kin property, government should be able to utilize eminent domain to support the acquisition of the decedent’s organs. Eminent domain is the power of government to take private property for public use and while it commonly refers to land, it should also be applicable in a presumed consent environment when the individual did not choose to opt-out as a donor. Clearly in the case of a presumed consent environment the government would exert authority for the organs, but not the body, unless legally required.

How could the government manage the Takings Clause of the Fifth Amendment in such a scenario? Overall one could simply validate the acquisition of the organs under the “public use” requirement, for the organs are certainly going to be used for a “public purpose” through the increase of deceased organ donation rates resulting in more lives saved. From a standpoint of organ value, if one wanted to, realistically no monetary compensation could be expected. For the next of kin, who would own the organs, have a product with ephemeral functionality and due to the fact that one cannot legally sell an organ, a monetary value of zero dollars.

The ephemeral nature of organ functionality is important because it cannot be argued that the organs may have monetary value later due to a change in the law, thus compensation would be required to satisfy this potential future value. Therefore just compensation or “fair market value” is simply zero dollars. This reality is helpful because it avoid questions regarding organ value in the context of the various associated parties like the government, the next of kin or a potential recipient. However, while it can be argued that technically the government would not have to pay any monetary sum to the next of kin for the acquisition of the organs, it stands to reason that the government could make a small good-faith gesture tied to addressing funeral costs (i.e. 200-500 dollars).

A final initial question regarding a presumed consent system would be whether or not it actually increases the number of available organs. Official literature can be somewhat murky on this issue for some studies find that when controlling outside factors presumed consent does increase organ donations rates significantly,16,17 but others suggest that the casual link is not appropriate due to the level of heterogeneity that exists in transplantation systems throughout the world.19

The chief problem with analyzing existing systems is the lack of strong data regarding hard/strong presumed consent. Of the more studied presumed consent systems in Europe (Austria, Belgium, France, Italy, Norway, Spain and Sweden), only Austria typically sees genuine practice as a hard/strong presumed consent system whereas the others are either soft/weak or physicians almost default to a soft/weak system for various reasons.12 Unfortunately most soft/weak systems have few differences from an opt-in system, thus identifying any significant differences becomes quite difficult limiting the value of the analysis.

Interestingly enough the studies focus so much on potential confusion associated with multiple factors in the donation environment that they discard simple logic in that under a strong presumed consent system everyone who does not opt-out will become a donor upon death, thus it stands to reason that donation rates would significantly increase on two counts of logic. First, no one who has opted-in should opt-out, thus theoretically the worst a presumed consent system does is break-even. Second, studies have shown that most of the time people often choose the assigned default option, among various instances, possibly due to a lack of strong feelings or a lack of desire to spending the resources and time required to change the option.19-22

In the end among the three major donation methods, beyond opt-in, that could potentially increase the number of available organs for transplant, all three have their positives and negatives. Priority rule systems incentivize the donation process, but have numerous holes in how this incentive is effectively applied and could have a number of potential constitutional issues associated with their application. Mandated response systems are able to effectively transfer the initiation of the donation process from the individual to the government significantly eliminating situations of ignorance to the existence and operation of the donation system. However, there are questions to how effective such a system is in actually increasing the available number of organs for donation. Presumed consent systems increase the available number of organs as well as do not appear to have any obvious legal issues, but must address elements of methodological opposition largely brought on by government paranoia and contempt in some camps as witnessed by the failure to establish such a system in New York, Illinois, and Colorado.

Overall it appears that a presumed consent program is the best option for quickly increasing the total number of available organs for transplant, but pursuit of this strategy must involve a strong commitment to establishing such a system over the personal objections of a number of individuals despite the ability to opt-out.


Citations –

1. 2012 National Donor Designation Report Card by the Donate Life America: http://donatelife.net/2012-national-donor-designation-report-card-released/

2. 2013 National Donor Designation Report Card by the Donate Life America:
http://donatelife.net/2013-national-donor-designation-report-card-released/

3. Scientific Registry of Transplant Recipients 2012: http://srtr.transplant.hrsa.gov/annual_reports/2012/Default.aspx

4. Uniform Anatomical Gift Act (1968). http://www.uniformlaws.org/shared/docs/anatomical_gift/uaga%201968_scan.pdf

5.Revised Uniform Anatomical Gift Act (1987). http://www.uniformlaws.org/shared/docs/anatomical_gift/uaga87.pdf

6. Revised Uniform Anatomical Gift Act (2006).
http://www.uniformlaws.org/shared/docs/anatomical_gift/uaga_final_aug09.pdf

7. August, J. “Modern Models of Organ Donation: Challenging Increases of Federal Power to Save Lives.” 394 Hastings Constitutional Law Quarterly Vol. 40:2 393-422.

8. Lavee, J. “A New Law for Allocation of Donor Organs in Israel.” The Lancet. 2010. 375(9720):1131-1133.

9. Even, D. “Dramatic Increase in Organ Transplants Recorded in Israel in 2011.” Haaretz. Jan. 12, 2012. http://www.haaretz.com/dramatic-increase-in-organ-transplants-recorded-in-israel-in-2011-1.406824

10. Vacco v. Quill, 521 U.S. 793, 799. 1997.

11. Personnel Adm’r of Massachusetts v. Feeney, 442 U.S. 256. 1979.

12. Rodriguez, S. “No Means No, But Silence Means Yes? The Policy and Constitutionality of the Recent State Proposals for Opt-Out Organ Donation Laws.” FIU Law Review. 7:149-186.

13. AMA Recommendation. Opinion 2.155 – Presumed Consent and Mandated Choice for Organs from Deceased Donors. American Medical Association. http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion2155.page?

14. Siminoff, L, and Mercer, M. “Public Policy, Public Opinion, and Consent for Organ Donation.” Camb Q Healthc Ethics. 2001. 10(4):377-86.

15. Tillman v. Detroit Receiving Hosp., 360 N.W.2d 275, 277. 1984.

16. Hawley, Z, Li, D, and Schnier, K. “Increasing Organ Donation via Changes in the Default Choice or Allocation Rule.” Journal of Health Economics. 2013. 32.6:1117-1129.

17. Abadie, A, and Gay, S. “The Impact of Presumed Consent Legislation on Cadaceric Organ Donation: A Cross-Country Study. Journal of Health Economics. 2006. 25.4:599-620.

18. Boyarsky, B, et Al. “Potential Limitations of Presumed Consent Legislation.” Transplantation. 2012. 93.2:136-140.

19. Samuelson, W, and Zeckhauser, R. “Status Quo Bias in Decision Making.” Journal of Risk and Uncertainty. 1988. 1(1):57-59.

20. Madrian, B, and Shea, D. “The Power of Suggestion: Inertia in 401(k) Participation and Savings Behavior.” Quarterly Journal of Economics. 116(4): 1149-1187.

21. Johnson E, and Goldstein, D. “Defaults and Donation Decisions.” Transplantation. 2004. 78(12): 1713-1716.

22. Gäbel, H. “Donor and Non-Donor Registries in Europe.” Stockholm, Sweden: on behalf of the committee of experts on the Organizational Aspects of Co-operation in Organ Transplantation of the Council of Europe. 2002.

What are Mars Analogue Missions Really Studying?

While various parties argue back and forth about whether humanity has progressed far enough technologically to colonize Mars, technology alone will not determine the success of such a venture. Interpersonal relationships and how the first colonists are able to work together to augment their strengths and mitigate their weaknesses will also be an incredibly important element in producing success. With this in mind NASA and other space-based organizations have undertaken occasional training experiments or analogue missions in an attempt to simulate a mission to Mars. These missions typically take place in specific locations in Hawaii or Antarctica, which are suitable for simulating Martian environment as far as Earth can simulate Mars; however, do these analogue missions have the appropriate goals and tasks for the participating individuals to properly simulate a Martian colonization party?

The major goal of these simulation experiments is to access how different individuals interact with each other over a fixed continuous time period in a confined space, simulating conditions in both travel to Mars and after landing, in effort to understand and predict potential positive and negative behavior among the colonizing party. However, the environment these individuals are commonly thrust into is not similar to that which will be faced by the initial colonists. While the inside habitat-outside habitat transition is properly simulated through the use of space suits, the activities of the participants within the habitat are more focused on specific scientific studies, not on building and developing the operational structure of the shelter. In short these experiments focus too much on simulating a developed Martian habitat versus a developing one.

For example one of the first major issues for a Martian colonization mission is that there is little to no food growth on site. The first colonists will bring a significant amount of food with them when first traveling to Mars, but almost every expert is in agreement that the development of some means to grow sufficient amounts of food on Mars will have to occur soon after arrival for it is too costly to continue to re-supply from Earth. Unfortunately these simulations experiments do not appear to be modeling this critical element for Mars colonization. This lack of planning is a missed opportunity because there are questions to what is the most effective way to grow food on Mars and various simulations starting from scratch could produce important information to determining which method would be the most successful in a real colonization mission. Every scientist and engineer knows that laboratory simulations/conclusions and in-field simulation/conclusions can differ radically.

One of the sub-questions on this issue is what type of food growth system would be optimal for Martian colonization both in the interim and for expansion. Various options, such as hydroponics, aquaponics, aeroponics, cultivating Martian soil, etc. exist and analogue missions would be an effective means to produce higher quality costs, effort and efficiency estimates of these system, both alone and in cooperation with each other, apart from ISS analysis and laboratory hypotheses. Aeroponics is NASA’s leader in the “clubhouse”, but would it work well as the initial on-site food provider for the first Martian colony?

Furthermore due to the significant reduction in gravity on Mars, colonists will have to engage in a rigorous exercise program to reduce the potency of negative physiological effects associated with the loss of this gravity. Simulating the necessary exercise in these analogue missions cannot help study how it influences health on Mars due to the lack of similar gravity, but it can help study how such levels of vigorous exercise would influence energy levels and food consumption along with interpersonal relationships. Unfortunately this potentially valuable information is not acquired in these simulations because the participants are not instructed to exercise in such a way.

Another important connective element that is lacking in these simulations, due in large part to the lack of these above elements, is the changes in stress that would accompany this behavior and these goals. While it is not ethical to emulate the life threatening conditions that failure would bring, general failure to complete necessary tasks would create tension and stress through challenges to the pride of the individuals involved, thus would better emulate real Martian colonization conditions. In these moments of stress, potential problems within the group dynamics can be identified that would not exist when stress levels were not increased leading to a better understanding of how to manage failures in the real colonizing party.

In the end analogue missions are important for various reasons and while human factor elements are certainly important to study and general simulation research strategies have their place, there needs to be more simulations that mimic what colonists will experience when first landing on Mars to better create a methodology regarding how to maximize success for the Martian colonization mission. Overall without expanding the scope of analogue missions to reflect the realities of Martian colonization, one wonders what the point of conducting these missions in the first place actually is, for they are certainly not preparing colonists for the most important part of the colonization, establishing the environment and behaviors to increase the probability of long-term survival.

Wanted: Reasonable and Intelligent Gun Policy

One thing that cannot be argued is that the number of gun deaths in the average year in the United States, including various mass shootings, has demonstrated that current gun policy does not work. The delusional idea harbored by some members of the National Rifle Association (NRA) that an effective means to address gun violence, which would involve weakening existing gun laws in effort to arm more “good guys” with firearms to combat the bad guys, demonstrates a genuine lack of intelligence and/or caring for the problem. While the specific intricacies of gun policy are better left to those with more experience, there are certain elements that appear to be “no-brainers” of sorts when producing effective and meaningful gun policy in effort to limit the number of violent gun-related deaths.

Clearly the lingering holes in the requirements for legally required background checks are unacceptable in any reasonable gun policy. Private sellers, i.e. individuals who “claim” they are not engaged in the business of selling guns, should be required just like all licensed federal dealers to perform background checks outside of legal gun transfers to other direct family members (i.e. father to son, sister to brother, etc.). The reason most arguments that private sellers should not be subjected to performing background checks fall flat is that a vast majority of these transfers occur at gun shows or online where it is much easier for individuals who know they would fail a background check to acquire a firearm. It is a matter of public safety first and foremost; also there is no “right” to sell a gun without any type of legal condition or restriction. Overall there is no rational argument against requiring a private dealer to conduct a background check.

Another reasonable step in the right direction would be the repel of the Tiahrt Amendments, which make it much more difficult for authorities to access and use gun trafficking data to pursue criminals and prevent criminal activity, especially via a dealer that is knowingly and willingly violating the law. Eliminating the Tiahrt Amendments would allow authorities to require dealers to conduct inventory of their stock (more than likely annual accounts would be appropriate) to increase the probability that unaccounted for inventory is detected much sooner than currently occurs. Also federal agencies will be able to maintain completed gun background checks for longer than 24 hours increasing the probability that authorities discover, arrest and convict straw purchasers (i.e. individuals who commonly purchase guns for individuals that would not pass a background check).

Hmm, all of these changes seem completely reasonable, especially the last one for a background check is not like DNA, authorities will not be able to utilize an existing background check to “set-up” someone as a criminal when they are not one, to think otherwise is to simply give in to paranoia. Furthermore allowing the ATF to create an electronic database of gun records that is easily searchable will dramatically increase the ability of proper authorities to manage and address gun-related issues more efficiently especially criminal activity. As long as this database is not made public there should be no issue with its existence. Just as a point of note, most of these issues were addressed in both The Fix Gun Checks Act of 2011 and The Fix Gun Checks Act of 2013.

Another good policy choice is to expand to the federal level the procedures and policies contained within the Maryland Firearms Safety Act of 2013. While this policy has numerous positive and practical elements, one of the most important is requiring certification for firearms training before legally being allowed to purchase a handgun. Note that with this expansion the law would be akin to policy associated with the National Minimum Drinking Age Acts in that states would not have to abide by the law, but they would not receive certain levels of federal funding if failing to do so. Therefore, if state x did not want to legal mandate that residents had to have firearm certification training before purchasing a gun it would be allowed, but state x would also not receive some significant percentage of federal aid.

Arguments against the policy of this bill both in Maryland and to any federal expansion of it range from the paranoid to the ridiculous. For example one argument against requiring gun training for the purchase of a weapon has been to analogize it to requiring an individual to have training in public speaking in order to speak in public. It is rather self-explanatory to why such an analogy is foolish. However, for the sake of completeness why is this “point of argument” ridiculous? The chief difference between guns and speech is an issue of public safety. A significant portion of gun use results in negative public health consequences, including death, whether or not the acquisition of the gun was legal versus both the assumption and the reality that almost no portion of speech is expected to or produces negative public health consequences.

Also like the 2nd Amendment, the 1st Amendment is not universal in its protection, in that not all speech is protected. For instance one cannot falsely yell fire in a crowded theater or other venue nor can an individual use speech to incite a group of individuals to “string up” some Jews, Blacks or Christians, etc. Furthermore the use of speech occurs at a far greater level than that of gun use, thus making it far more inconvenient for both society and individual functionality to require public speech course requirements versus gun training requirements.

One widely used argument in favor of gun training licenses have been a comparison to automobiles in that if one has to have a license to operate an automobile it makes sense that one should have to have a license to purchase a gun. Opponents have countered this analogy by stating that one does not need a driver’s license to purchase a car, thus one should not need a license to purchase a gun. On its face this counterargument seems to have value, until looking deeper. It breaks down rather quickly in the realm of practicality for almost no one purchases a car without the intention of it being driven, either by the buyer or someone else, and the same logic is applied to a gun, who spends hundreds of dollars on a gun without the prospect of using it at some point in the future? The only common instance where the purchase of either a car or gun is made without the prospect of using it is for collector purposes, which entails older models. It would not be difficult to create a hard cap on a date of purchase; i.e. all guns older than 1970 or some other year decades ago, which would not require a license.

Others would stubbornly avoid the issue of public health and practicality and argue that gun purchase is a right, but car purchase is not, thus the above analogy is irrelevant because Maryland policy violates the Constitution. The problem with this counter-argument is that firearm purchase is not a guaranteed universal right, the courts, both of conservative and liberal leaning, have ruled numerous times that government in all its forms can place reasonable restrictions on arms purchase and possession. Requiring the acquisition of a training license for the purchase of a particular type of firearm in a clear and transparent way, with no additional requirements beyond existing current training methods, does not produce an unreasonable burden for the purchase of a weapon, which is exactly what the Maryland and federal courts have ruled regarding the Maryland law.

One point of interest is why pro-gun individuals are so knee-jerk against even reasonable and intelligent gun policy? The best possible explanation appears to be simply “slippery slope paranoia”. They believe that giving any type of power to the government to restrict access to weaponry for private citizens will eventually lead to an environment where government restricts access to all weaponry.

Of course such a belief is incredibly foolish on two separate grounds. On legal grounds this belief fails because the Supreme Court ruling in District of Columbia v. Heller basically created a floor regarding what the government can do with respects to limiting private access to weapons. On non-legal grounds if a tyrannical government ever arose in the U.S., the idea that private citizens would be able to effectively fight against it (and the U.S. armed forces) without vast levels of support from foreign nations is laughable and utterly delusional, thus any “restrictions” on private firearm access established by this new tyrannical government would be irrelevant. Overall all slippery slope paranoia is doing for pro-gun individuals is making them indirectly responsible for more people dying due to gun violence.

The issue of creating a training course is not a significant hurdle because numerous training courses of varying degrees already exist. The only additional requirement beyond the standard training course would be the necessity of live fire training. Basically to purchase a gun the training course would require individuals to fire that type of firearm, given if it has a different firing capacity. For example firing a Beretta is significantly different from firing a type of shotgun, but not significantly different from firing a Desert Eagle. Basically individuals should actually know how to use the weapon they intend to purchase versus simply just “thinking” they know how to use it. For most training courses this live fire requirement is already addressed.

The length of time that a purchase license would last is an interesting question because too long and the general acquired skills that comprise the purpose behind gaining the license diminish, but too short and individuals may be pressured into purchase out of fear that the license will expire. Overall the total time period would be up to the states, but it stands to reason that between 1 to 5 years for license length would seem most appropriate. The issue of renewal is of limited importance because most individuals do not purchase a large amount of guns period, let alone over a long period of time; therefore there is little concern for any “annoyance” factor that may involve having to renew a license for a fourth gun purchase x years from the first purchase.

In the end anyone who cares about reasonable and effective gun policy, which should be almost everyone because continued gun violence does not serve a positive purpose for any law-abiding citizen, must realize that both closing background loopholes and ensuring that gun purchasers have proper training are important elements to accomplishing this goal. Some may argue that background checks are too slow and training is an inconvenience to buyers; however, purchasing a gun should not be a spontaneous action. Whether the gun will be used for hunting or self-protection, either motive is not short-term critical, but long-term thus the inability to acquire the gun immediately from the buyer on the same day does not produce a burdensome disadvantage opposed to the benefits background checks and training provide to society as a whole. Overall a certain portion of the population has to realize that some measures to ensure appropriate and responsible distribution of firearms will NOT result in the loss of any appropriate firearm access. Continuing to oppose such rudimentary and reasonable policy does nothing but increase the probability for more death.