Fecal concentrations of cortisol, testosterone, and progesterone in cotton-top tamarins hosted in different zoological parks: Relationship among physiological data, environmental conditions and behavioral patterns

The aim of this investigation was to study the welfare of three captive groups of cotton-top tamarins housed in different zoological parks. Ethological observations were conducted over one year. In addition, fecal samples were collected and the concentrations of glucocorticoids, androgens, and progestagens were measured. Within each group, no significant differences in fecal cortisol concentrations were found between subjects. The fecal concentrations of testosterone and progesterone significantly differed depending on the sex and the age of the animals. A significant association was found among hormone concentrations, exhibit dimension, and group composition. A highly significant correlation was uncovered between all hormones considered and the space available for each subject. Significant differences in behavioral patterns were observed among groups, including social-individual, affiliative-aggressive, and anogenital-suprapubic scent marking. Correlations between hormone measurements and behaviors were detected. In conclusion, this study confirmed the associations between some behaviors exhibited by these nonhuman primates and both cortisol and testosterone; these data also highlight the role played by progesterone in these behaviors

Pterostilbene Promotes Mean Lifespan in Both Male and Female Drosophila Melanogaster Modulating Different Proteins in the Two Sexes

Aging is a multifactorial phenomenon characterized by degenerative processes closely connected to oxidative damage and chronic inflammation. Recently, many studies have shown that natural bioactive compounds are useful in delaying the aging process. In this work, we studied the effects of an in vivo supplementation of the stilbenoid pterostilbene on lifespan extension in Drosophila melanogaster. We found that the average lifespan of flies of both sexes was increased by pterostilbene supplementation with a higher effect in females. The expression of longevity related genes (Sir2, Foxo, and Notch) was increased in both sexes but with different patterns. Pterostilbene counteracted oxidative stress induced by ethanol and paraquat and up-regulated the antioxidant enzymes Ho e Trxr-1 in male but not in female flies. On the other hand, pterostilbene decreased the inflammatory mediators dome and egr only in female flies. Proteomic analysis revealed that pterostilbene modulates 113 proteins in male flies and only 9 in females. Only one of these proteins was modulated by pterostilbene in both sexes: vacuolar H[+] ATPase 68 kDa subunit 2 (Vha68-2) that was strongly down-regulated. These findings suggest a potential role of pterostilbene in increasing lifespan both in male and female flies by mechanisms that seem to be different in the two sexes, highlighting the need to conduct nutraceutical supplementation studies on males and females separately in order to give more reliable results

Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis

A preclinical evaluation of pemetrexed and irinotecan combination as second-line chemotherapy in pancreatic cancer

Gemcitabine (GEM)-based chemotherapy is regarded as the standard treatment of pancreatic adenocarcinoma, but yields a very limited disease control. Very few studies have investigated salvage chemotherapy after failure of GEM or GEM-containing chemotherapy and preclinical studies attempting to widen the therapeutic armamentarium, not including GEM, are warranted. MIA PaCa2, CFPAC-1 and Capan-1 pancreatic cancer cell lines were treated with GEM, fluouracil (5-FU), docetaxel (DCT), oxaliplatin (OXP), irinotecan (CPT-11), pemetrexed (PMX) and raltitrexed (RTX) as single agent. Pemetrexed, inducing apoptosis with IC50s under the Cmax in the three lines tested, appeared the most effective drug as single agent. Based on these results, schedule- and concentration-dependent drug interactions (assessed using the combination index) of PMX/GEM, PMX/DCT and PMX–CPT-11 were evaluated. The combinatory study clearly indicated the PMX and CPT-11 combination as the most active against pancreatic cancer. To confirm the efficacy of PMX–CPT-11 combination, we extended the study to a panel of 10 pancreatic cancer cell lines using clinically relevant concentrations (PMX 10 μM; CPT-11 1 μm). In eight of 10 lines, the PMX–CPT-11 treatment significantly reduced cell recovery and increased both the subG1 and caspase 3/7 fraction. After a 5-day wash out period, an increased fraction of subG1 and caspase3/7 persisted in PMX–CPT-11-pretreated cell lines and a significant reduction in the clonogenicity capacity was evident. Finally, in vivo, the PMX/CPT-11 combination showed the ability to inhibit xenograft tumours growth as second-line therapy after GEM treatment. The PMX and CPT-11 combination displays a strong schedule-independent synergistic cytotoxic activity against pancreatic cancer, providing experimental basis for its clinical testing as salvage chemotherapy in pancreatic cancer patients

Lost in translation: Returning germline genetic results in genome-scale cancer research

Background: The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods: We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium-high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results: A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion: Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors1,2, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies