Marijuana use and post-transplant complications and non-compliance in liver transplant patients.

BACKGROUND: Liver transplant (LT) is a lifesaving treatment for patients with end stage liver disease. Historically, institutions across the United States have deemed active marijuana use as an exclusion criterion for listing. This study aims to investigate LT outcomes in patients with history of marijuana use prior to LT. METHODS: We performed a retrospective review of 111 patients who tested positive for marijuana on urine drug screen during initial LT evaluation between February 2016 and January 2021. 100 non-marijuana users who underwent LT were cross matched for control. Patient demographics, substance use history, and transplant decisions were recorded. Post-LT variables were also collected up to 1 year post surgery including postoperative infections, issues with non-compliance, and continued substance use. Chi-square analysis was used to assess the association between pre-transplant marijuana use and post-transplant complications. Logistics regression was implemented to measure associations amongst the entire cohort. RESULTS: From 111 marijuana users, 32 (29%) received a transplant. There was no statistical difference in post-LT outcomes between marijuana and non-marijuana users, including incidence of cardiac, respiratory, renal, psychiatric, or neurological complications, as well as readmission rates post-surgery. There were no statistically significant associations between marijuana use with post-transplant bacterial or fungal infections, medication non-compliance, or continued substance use (all p>0.05). Marijuana use was associated with pre-LT tobacco use (p = 0.020). CONCLUSIONS: Our data indicates that marijuana is not associated with increased risk of postoperative noncompliance, other organ complications, infections, or death. As a single factor, marijuana may not need to be a contraindication for LT.

Student leadership in medical school and its implications for health care and policy-making.

BACKGROUND: Approximately 5% of hospital chief executive officers are physicians, and that number is growing. Leadership is a vital skill for future physicians. METHODS: We conducted a narrative review of the literature on student leadership in medical school and its implications for health care and policy-making. RESULTS: Qualities a good leader should possess include accountability, empathy, positivity, teamwork, and organization. Leadership skills need to be taught to students in their formative pre-clinical years so they can build upon this foundation during their clinical and residency years. Leadership is a multifaceted quality because unlike other lessons, it cannot be measured on a scale or under the microscope; it is largely developed through practice. Furthermore, among physicians, psychiatrists are especially well-trained to serve in active leadership roles because psychiatry training emphasizes interpersonal dynamics and emotional intelligence, qualities that are vital to the skill set of an effective leader. CONCLUSIONS: Medical leadership is essential because physicians relate best to other physicians, and those adept in administrative skills can help bridge the gap between administration and clinicians. There is a need for teaching an evidence-based leadership curriculum and training techniques that will fill a recognized educational void in medical student education (as well as for residents and junior faculty).

Effect of P21-activated kinase 1 (PAK-1) inhibition on cancer cell growth, migration, and invasion.

P21-activated kinase-1 (PAK-1) is a serine/threonine kinase involved in multiple signaling pathways that mediate cellular functions such as cytoskeletal motility, cell proliferation, and survival. PAK-1 expression is altered in various cancers, including prostate and breast. Our recent studies showed that prostate cancer cells expressing higher levels of PAK-1 were resistant to the cytotoxic effects of the PAK-1 inhibitor, inhibitor targeting PAK-1 activation-3 (IPA-3), compared to those with lower expression. This study expanded these findings to other cancers (breast and melanoma) by testing the hypothesis that genetic and pharmacological inhibition of PAK-1 alters cell growth, migration, and invasion in prostate, breast, and skin cancer cell lines. We also tested the specificity of IPA-3 for PAK-1 and the hypothesis that gene silencing of PAK-1 altered the efficacy of sterically stabilized liposomes (SSL) containing IPA-3 (SSL-IPA-3). PAK-1 expression was identified in four different breast cancer cell lines, and in a melanoma cell line. The expression of PAK-1 correlated to the IC50 of IPA-3 as measured by MTT staining. PAK-1 inhibition using shRNA correlated with decreased cell migration and invasion in prostate cancer DU-145 and breast cancer MCF-7 cells. Decreased migration and invasion also correlated to decreased expression of E-cadherin and alterations in C-X-C Chemokine Receptor type 4 and Homing Cell Adhesion Molecule expression. PAK-1 inhibition increased the cytotoxicity of IPA-3, and the cytotoxicity of SSL-IPA-3 to levels comparable to that of free drug. These data demonstrate that both pharmacological and molecular inhibition of PAK-1 decreased growth in prostate, breast, and melanoma cancer cell lines, and increased the toxicity of IPA-3 and its liposomal formulation. These data also show the specificity of IPA-3 for PAK-1, are some of the first data suggesting that IPA-3 is a therapeutic treatment for breast cancer and melanoma, and demonstrate the efficacy of liposome-encapsulated IPA-3 in breast cancer cells.

ß-Arrestins Regulate Stem Cell-Like Phenotype and Response to Chemotherapy in Bladder Cancer.

ß-Arrestins are classic attenuators of G-protein-coupled receptor signaling. However, they have multiple roles in cellular physiology, including carcinogenesis. This work shows for the first time that ß-arrestins have prognostic significance for predicting metastasis and response to chemotherapy in bladder cancer. ß-Arrestin-1 (ARRB1) and ß-arrestin-2 (ARRB2) mRNA levels were measured by quantitative RT-PCR in two clinical specimen cohorts (n = 63 and 43). The role of ARRBs in regulating a stem cell-like phenotype and response to chemotherapy treatments was investigated. The consequence of forced expression of ARRBs on tumor growth and response to Gemcitabine in vivo were investigated using bladder tumor xenografts in nude mice. ARRB1 levels were significantly elevated and ARRB2 levels downregulated in cancer tissues compared with normal tissues. In multivariate analysis only ARRB2 was an independent predictor of metastasis, disease-specific-mortality, and failure to Gemcitabine + Cisplatin (G+C) chemotherapy; ∼80% sensitivity and specificity to predict clinical outcome. ARRBs were found to regulate stem cell characteristics in bladder cancer cells. Depletion of ARRB2 resulted in increased cancer stem cell markers but ARRB2 overexpression reduced expression of stem cell markers (CD44, ALDH2, and BMI-1), and increased sensitivity toward Gemcitabine. Overexpression of ARRB2 resulted in reduced tumor growth and increased response to Gemcitabine in tumor xenografts. CRISPR-Cas9-mediated gene-knockout of ARRB1 resulted in the reversal of this aggressive phenotype. ARRBs regulate cancer stem cell-like properties in bladder cancer and are potential prognostic indicators for tumor progression and chemotherapy response.