Postmortem communication.

The phenomenon of near death and dying experiences has been both of popular interest and of scientific speculation. However, the reality of mental perception at the point of death is currently a subjective experience and has not been formally evaluated. While postmortem gene expression, even in humans, has been evaluated, restoration of postmortem brain activity has heretofore only been attempted in animal models, at the molecular and cellular levels.

Immunotherapy and Cannabis: A Harmful Drug Interaction or Reefer Madness?

A retrospective (N = 140) and a prospective (N = 102) observational Israeli study by Bar-Sela and colleagues about cannabis potentially adversely impacting the response to immunotherapy have together been cited 202 times, including by clinical practice guidelines. There have also been concerns on PubPeer outlining irregularities and unverifiable information in their statistics and numerous errors in calculating percentages. This reanalysis attempted to verify the data analysis while including non-parametric statistics.

Too much of a good thing? Teamwork in medical education.

Teams and the promotion of teamwork for both faculty and for students can be key components of integrated curriculum and 'flipped classroom' active learning approaches for medical education. The benefits of teams and teamwork are presented to faculty and students, sometimes indoctrination, but the costs of the team approach, balanced against the purported benefits, are typically not discussed. This unbalanced presentation creates the need for a statement of a contrarian view.

Hypothesis: Cancer Hormesis and Its Potential for Cancer Therapeutics.

Primary tumors can inhibit the growth of secondary lesions, particularly metastases, in a phenomenon termed "concomitant resistance". Several mechanisms have been proposed for this effect, each supported by experimental data. In this paper, we hypothesize that concomitant resistance is a form of hormesis, a biphasic dose response in which a stimulus has a positive and/or stimulatory effect at low dosages and a negative, inhibitory, and/or toxic effect at higher dosages.

Evaluating the medical curriculum: Bias, problems, solutions.

Medical school curriculums have increasingly shifted to an integrated curriculum and have been replacing lecture with 'flipped classroom' approaches. Analyses of the benefits of the integrated curriculum and flipped classroom model typically report enhanced student performance. However, the question is whether institutional self-evaluation of curricular success is biased to demonstrate success that may not objectively exist and/or whether such biased data are presented during Liaison Committee on Medical Education (LCME) site visits.

Hypothesis: functional age and onset of autosomal dominant genetic prion disease.

Autosomal dominant diseases typically have an age-related onset. Here, I focus on genetic prion disease (gPrD), caused by various mutations in the PRNP gene. While gPrD typically occurs at or after middle age, there can be considerable variability in the specific age of onset.

Oncogenic and Receptor-Mediated Wnt Signaling Influence the Sensitivity of Colonic Cells to Butyrate.

Deregulated Wnt signaling is responsible for most cases of colorectal cancer (CRC). Dietary fiber is protective against CRC and this activity is likely mediated by butyrate, a breakdown product of dietary fiber that hyperactivates Wnt signaling, repressing CRC proliferation and inducing apoptosis. Receptor-mediated Wnt signaling and oncogenic Wnt signaling, which is typically initiated by mutation in more downstream elements of the pathway, activate non-overlapping patterns of gene expression.

Hypothesis: Mutations and Immunosurveillance in Obesity-Associated Colorectal Cancer.

Tumorigenesis typically requires the accumulation of several driver gene mutations; therefore, there is a mutation threshold for the completion of the neoplastic process. Obesity increases the risk of cancer, and we have proposed that one mechanism whereby obesity raises the risk of microsatellite stable (MSS) colon cancer is by decreasing the mutation threshold. Therefore, obese MSS colon cancer patients should exhibit fewer driver gene mutations compared to normal body-mass index (BMI) patients.

Multifactorial causation of early onset colorectal cancer.

The multiple-hit hypothesis of cancer, including colorectal cancer (CRC), states that neoplastic development requires a sequence of mutations and epigenetic changes in driver genes. We have previously proposed that obesity increases CRC risk by supporting neoplastic development through adipokine-induced signaling, and this proliferative signaling substitutes for specific driver gene mutations. In support of this hypothesis, analyses of The Cancer Genome Atlas (TCGA) mutation data have revealed that obese patients with microsatellite stable CRC exhibit fewer driver gene mutations than CRC patients with normal body mass index.

Hypothesis: Sam68 and Pygo2 mediate cell type-specific effects of the modulation of CBP-Wnt and p300-Wnt activities in Colorectal Cancer Cells.

The preventive activity of dietary fiber against colorectal cancer (CRC) may be in part mediated by the fermentation product of fiber, butyrate, a histone deacetylase inhibitor (HDACi) that induces CRC cell growth arrest and apoptosis. This action of butyrate, and other HDACis, is in part due to the hyperactivation of the deregulated Wnt activity found in the relevant CRC cell lines. The histone acetylases CBP and p300 interact with beta-catenin; and the relative levels of CBP-Wnt vs.

Further analysis of p300 in mediating effects of Butyrate in Colorectal Cancer Cells.

Butyrate, a product of dietary fiber, hyperactivates Wnt signaling in colorectal cancer (CRC) cells; this activity of butyrate is causally associated with the induction of apoptosis, and the repression of proliferation, in these cells. However, CRC can develop despite a high fiber diet; hence, butyrate resistance likely occurs during colonic neoplasia. To evaluate the mechanisms of butyrate resistance, HCT-116 CRC cells were previously made resistant to butyrate (HCT-R cell line); I observed that butyrate resistance in HCT-R cells is accompanied by repressed Wnt hyperactivation.

Hypothesis: Retinoblastoma protein inactivation mediates effects of histone deacetylase inhibitor-induced Wnt hyperactivation in colorectal cancer cells.

Butyrate, a product of dietary fiber and a histone deacetylase inhibitor, induces apoptosis of colorectal cancer cells; this effect of butyrate is in part mediated by its ability to hyperactivate Wnt signaling, and may in part explain the preventive action of dietary fiber against colorectal cancer. However, the mechanisms by which Wnt hyperactivation promotes apoptosis are unknown. Inactivation of the retinoblastoma tumor suppressor occurs in some cancers and can lead to context-dependent cell proliferation or cell death/apoptosis.

A Quantitative and Narrative Evaluation of Goodman and Gilman's Pharmacological Basis of Therapeutics.

Goodman and Gilman's (PBT) has been a cornerstone in the education of pharmacists, physicians, and pharmacologists for decades. The objectives of this study were to describe and evaluate the 13 edition of PBT on bases including: (1) author characteristics; (2) recency of citations; (3) conflict of interest (CoI) disclosure; (4) expert evaluation of chapters. Contributors' (N = 115) sex, professional degrees, and presence of undisclosed potential CoI-as reported by the Center for Medicare and Medicaid's Open Payments (2013-2017)-were examined.

Postmortem vs. neoplastic gene expression: Clues to cancer development and therapy.

Organismal death does not immediately end gene expression. Studies of postmortem gene expression in zebrafish and mice and in the myocardium, liver, prostate, pericardial fluid, and blood of human cadavers have identified genes whose expression is increased after organismal death. Cancer can be considered a form of "un-death" since excessively proliferating cells are typically unusually resistant to apoptosis (programmed cell death), and are subject to strong selective pressure for "uncontrolled life.

Secondary Bile Acids and Short Chain Fatty Acids in the Colon: A Focus on Colonic Microbiome, Cell Proliferation, Inflammation, and Cancer.

Secondary bile acids (BAs) and short chain fatty acids (SCFAs), two major types of bacterial metabolites in the colon, cause opposing effects on colonic inflammation at chronically high physiological levels. Primary BAs play critical roles in cholesterol metabolism, lipid digestion, and host⁻microbe interaction. Although BAs are reabsorbed via enterohepatic circulation, primary BAs serve as substrates for bacterial biotransformation to secondary BAs in the colon.

Amlexanox and UPF1 Modulate Wnt Signaling and Apoptosis in HCT-116 Colorectal Cancer Cells.

Deregulated Wnt signaling initiates most cases of colorectal cancer (CRC). Butyrate, a product of dietary fiber, hyperactivates Wnt signaling, resulting in induction of CRC cell apoptosis, which may in part explain the protective action of fiber. Nonsense mediated decay (NMD) of mRNAs containing premature stop codons (PTCs) affects tumorigenesis and upregulates Wnt signaling in human embryonic stem cells.

Quantum biology and human carcinogenesis.

Quantum-mediated effects have been observed in biological systems. We have previously discussed basis-dependent quantum selection as a mechanism for directed adaptive mutation, a process in which selective pressure specifically induces mutation in those genes involved in the adaptive response. Tumor progression in cancer easily lends itself to the adaptive evolutionary perspective, as the Darwinian combination of heritable variations together with selection of the better proliferating variants are believed to play a major role in multistep carcinogenesis.

Hypothesis: Cancer Is a Disease of Evolved Trade-Offs Between Neoplastic Virulence and Transmission.

Virulence is defined as the ability of a pathogen to cause morbidity and/or mortality in infected hosts. The relationship between virulence and transmissibility is complex; natural selection may promote decreased virulence to enhance host mobility and increase the probability for transmission, or transmissibility may be enhanced by increased virulence, leading to higher pathogen load and, in some cases, superior evasion from host defenses. An evolutionary trade-off exists between the ability of pathogens to maintain opportunities for long-term transmission via suppressed virulence and increased short-term transmission via enhanced virulence.

Hypothesis: Induction of biomarkers for detection of colonic neoplasms.

The signing of the National Cancer Act of 1971 by President Nixon marked the beginning of our war on cancer. More than 45 years later, the war is still going steady, with the enemy being almost as strong as in 1971. Furthermore, the increasing rates of obesity not only among adults, but among children and adolescents, are the likely cause for the 30-year trend of colon cancer (CC) becoming a disease of the younger population in the U.

p300 Knockout Promotes Butyrate Resistance.

Dietary fiber is linked to a reduced risk of colorectal cancer (CRC), and this protective activity is likely due to its fermentation product, butyrate. Dependent upon the hyperactivation of Wnt signaling, butyrate represses CRC cell growth and induces apoptosis. However, resistance to butyrate activity may allow for CRC development even in the context of relatively high fiber intake.

ZEB1 Mediates Drug Resistance and EMT in p300-Deficient CRC.

We discuss the hypothesis that ZEB1-Wnt-p300 signaling integrates epithelial to mesenchymal transition (EMT) and resistance to histone deacetylase inhibitors (HDACis) in colorectal cancer (CRC) cells. The HDACi butyrate, derived from dietary fiber, has been linked to CRC prevention, and other HDACis have been proposed as therapeutic agents against CRC. We have previously discussed that resistance to butyrate likely contributes to colonic carcinogenesis, and we have demonstrated that butyrate resistance leads to cross-resistance to cancer therapeutic HDACis.

Effects of propolis and gamma-cyclodextrin on intestinal neoplasia in normal weight and obese mice.

Obesity is associated with colorectal cancer (CRC). This effect might be attributed to adipokine-supported signaling. We have established that propolis suppresses survival signaling in CRC cells in vitro; therefore, we ascertained the ability of a propolis supplement to modulate intestinal neoplastic development in C57BL/6J-ApcMin/+/J mice in the lean and obese state.

In Hyperthermia Increased ERK and WNT Signaling Suppress Colorectal Cancer Cell Growth.

Although neoplastic cells exhibit relatively higher sensitivity to hyperthermia than normal cells, hyperthermia has had variable success as an anti-cancer therapy. This variable outcome might be due to the fact that cancer cells themselves have differential degrees of sensitivity to high temperature. We hypothesized that the varying sensitivity of colorectal cancer (CRC) cells to hyperthermia depends upon the differential induction of survival pathways.

Determination of the Role of CBP- and p300-Mediated Wnt Signaling on Colonic Cells.

Background: The Wnt signaling pathway, mediated through active beta-catenin, is responsible for initiating the majority of cases of human colorectal cancer (CRC), and we have previously shown that hyperactivation of this pathway by histone deacetylase inhibitors (HDACis), such as butyrate, can induce the death of CRC cells. An important cellular switch that mediates the effects of Wnt-signaling activation is variation in the association between beta-catenin and the transcriptional coactivators cAMP response element binding (CREB) binding protein (CBP) and p300. Association of CBP with beta-catenin is thought to activate a set of genes linked to cell proliferation, while the p300-mediated Wnt genetic program is believed to promote cell differentiation.