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In order to evaluate risk factors for germ cell cancers, we conducted a case-control study of 510 men with testicular cancer aged 15 to 79 years and 996 randomly selected age-matched controls in the provinces of British Columbia and Alberta, Canada. Subjects completed a mailed questionnaire providing data on education level, ethnic origin, medical history, smoking, occupation, and recreational and sports activity. The response rate among cases was 80.3 percent and among controls was 68.1 percent. After controlling for age and ethnic origin, undescended testis was associated positively with risk of testicular cancer (odds ratio [OR] = 3.5; 95 percent confidence interval [CI] = 2.2-5.7) as was inguinal hernia requiring surgery (OR = 2.0, CI = 1.3-2.9), and hydrocoele (OR = 2.6, CI = 1.4-5.1). Risk of testicular cancer increased with height, with subjects taller than 180 cm having a significantly increased risk compared with those 174 cm or less (OR = 1.5, CI = 1.1-2.1). A moderate to high level of recreational activity level was associated inversely with testicular cancer risk (OR = 0.6, CI = 0.5-0.8).

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Opioids are powerful analgesics acting via the human μ‐opiate receptor (hMOR). Opioid use is associated with adverse effects such as tolerance, addiction, respiratory depression, and constipation. Two synthetic opioids, AH‐7921 and U‐47700 that were developed in the 1970s but never marketed, have recently appeared on the illegal drug market and in forensic toxicology reports. These agents were initially characterized for their analgesic activity in rodents; however, their pharmacology at hMOR has not been delineated. Thus, we synthesized over 50 chemical analogs based on core AH‐7921 and U‐47700 structures to assess for their ability to couple to Gα i signaling and induce hMOR internalization. For both the AH‐7921 and U‐47700 analogs, the 3,4‐dichlorobenzoyl substituents were the most potent with comparable EC 50 values for inhibition of cAMP accumulation; 26.49 ± 11.2 nmol L −1 and 8.8 ± 4.9 nmol L −1 , respectively. Despite similar potencies for Gα i coupling, these two compounds had strikingly different hMOR internalization efficacies: U‐47700 (10 μmol L −1 ) induced ~25% hMOR internalization similar to DAMGO while AH‐7921 (10 μmol L −1 ) induced ~5% hMOR internalization similar to morphine. In addition, the R , R enantiomer of U‐47700 is significantly more potent than the S , S enantiomer at hMOR. In conclusion, these data suggest that U‐47700 and AH‐7921 analogs have high analgesic potential in humans, but with divergent receptor internalization profiles, suggesting that they may exhibit differences in clinical utility or abuse potential.

Stem cells (SCs) receive inductive cues from the surrounding microenvironment and cells. Limited molecular evidence has connected tissue-specific mesenchymal stem cells (MSCs) with mesenchymal transit amplifying cells (MTACs). Using mouse incisor as the model, we discover a population of MSCs neibouring to the MTACs and epithelial SCs. With Notch signaling as the key regulator, we disclose molecular proof and lineage tracing evidence showing the distinct MSCs contribute to incisor MTACs and the other mesenchymal cell lineages. MTACs can feedback and regulate the homeostasis and activation of CL-MSCs through Delta-like 1 homolog (Dlk1), which balances MSCs-MTACs number and the lineage differentiation. Dlk1 ’s function on SCs priming and self-renewal depends on its biological forms and its gene expression is under dynamic epigenetic control. Our findings can be validated in clinical samples and applied to accelerate tooth wound healing, providing an intriguing insight of how to direct SCs towards tissue regeneration.

The formation of a normal pancreas and the activation of insulin production are, in part, dependent on the expression and activation of the pancreatic duodenal homeobox gene 1 (PDX-1). The expression of PDX-1 also has been detected in various human pancreatic ductal adenocarcinoma (PDA) cell lines. This has made it possible to generate a cancer cell-specific gene expression system to treat human pancreatic cancer. In this study, we have developed a cell-specific cytotoxic model of PDA cells using the expression of herpes simplex virus thymidine kinase (TK) under the control of the rat insulin promoter (RIP-TK). We have shown that the cell-specific cytotoxicity in human PDA cells depends on the presence of PDX-1. Our results also demonstrate that in vivo PDA-specific cytotoxicity can be achieved with RIP-TK using an intraperitoneal liposomal gene delivery method followed by a short period of ganciclovir treatment in severe combined immunodeficient (SCID) mice. Furthermore, PDX-1 protein was found in all six freshly isolated human pancreas cancer specimens and two liver metastasis samples that were group-tested, suggesting the feasibility of using RIP-TK gene therapy in humans. This study may provide an alternative strategy for the future treatment of pancreatic cancer.

BACKGROUND: Nationally over 50% of physicians report symptoms of burnout. OBJECTIVE: To understand the perspectives of health system leaders and frontline physicians on contributors to physician burnout and strategies to improve wellbeing. DESIGN: We conducted in-depth interviews with health system leaders and frontline physicians at a large, predominantly fee-for-service, multispecialty group practice with approximately 1300 physicians. PARTICIPANTS: The 17 participants included 15 physicians, (12 Internal Medicine and Family Medicine physicians and 3 from other specialties), 11 individuals in leadership roles, and 11 women. APPROACH: Interviews included a review of factors associated with burnout at the organization, asking participants which factors they believed contributed to burnout, questions about experiences of burnout, and what specific changes would improve well-being. KEY RESULTS: All 17 participants agreed that organizational factors were key contributors to burnout, while only 9 mentioned the salience of individual factors: "It does not matter how resilient or positive you are, the work environment, especially in primary care will eventually be a problem." An increasing workload associated with the electronic health record (EHR) and a culture focused on productivity were cited as contributing to burnout, especially among physicians in Internal Medicine and Family Medicine (primary care) departments. Physicians in primary care, women, and leaders described multiple barriers to well-being. Participants described responding to increased workloads by reducing clinical work hours. Participants suggested reducing and compensating EHR work, expanding care teams/support staff, reducing use of metrics, providing more support to leaders, changing the business model, and increasing positivity and collegiality, as essential to improving well-being. CONCLUSION: Interviews reveal a variety of interacting factors contributing to physician burnout. Reducing clinical work hours has become a coping strategy. Changes recommended to improve physician well-being include increasing support staff, reducing EHR workload, changing revenue generation and compensation approaches, and shifting organizational culture to place more value on physician wellness.