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Objectives: Breast cancer is the leading cause of female cancer mortality in Armenia. The government is considering covering breast cancer screening, but prevailing attitudes towards it are unknown. This cross-sectional study assessed Armenian women's awareness and perceptions of breast cancer screening., Methods: We administered a validated telephone survey to women ages 35-65 registered in Yerevan's polyclinic system between 2019-2021, assessing sociodemographic characteristics, breast cancer exposure and screening attitudes, using an adapted Champion's Health Belief Model Scale (CHBMS). We analyzed the association, unadjusted and adjusted, between sociodemographic characteristics, screening exposure, and CHBMS scores., Results: 170 women completed surveys. Most (82.9%) were aware of screening, 48.5% knew someone with breast cancer, but only 42.5% had undergone screening, predominantly without their physician's recommendation (63.2%). Despite elevated awareness, 76.2% had never discussed screening with their provider. Barriers included cost and mistreatment concerns. Education consistently predicted prior screening and most CHBMS scores., Conclusion: Armenian women are highly exposed to breast cancer, but knowledge and prior screening primarily emanate from non-physician sources. Results highlighted the influence of education, patient-provider relationships, and healthcare costs, underscoring the importance of multi-level interventions., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Tupper, Ghukasyan, Bayburtyan, Hovhannisyan and Shekherdimian.)

Purpose: Stimulator of interferon genes (STING) agonists are currently in development for treatment of solid tumors, including pancreatic ductal adenocarcinoma (PDAC). Response rates to STING agonists alone have been promising yet modest, and combination therapies will likely be required to elicit their full potency. We sought to identify combination therapies and mechanisms that augment the tumor cell-intrinsic effect of therapeutically relevant STING agonists apart from their known effects on tumor immunity., Experimental Design: We screened 430 kinase inhibitors to identify synergistic effectors of tumor cell death with diABZI, an intravenously administered and systemically available STING agonist. We deciphered the mechanisms of synergy with STING agonism that cause tumor cell death in vitro and tumor regression in vivo., Results: We found that MEK inhibitors caused the greatest synergy with diABZI and that this effect was most pronounced in cells with high STING expression. MEK inhibition enhanced the ability of STING agonism to induce type I IFN-dependent cell death in vitro and tumor regression in vivo. We parsed NFκB-dependent and NFκB-independent mechanisms that mediate STING-driven type I IFN production and show that MEK signaling inhibits this effect by suppressing NFκB activation., Conclusions: Our results highlight the cytotoxic effects of STING agonism on PDAC cells that are independent of tumor immunity and that these therapeutic benefits of STING agonism can be synergistically enhanced by MEK inhibition., (©2023 American Association for Cancer Research.)

Background or Purpose: The role of extended lymphadenectomy as part of resection for lymph node (LN)-positive gastrointestinal (GI) malignancies remains controversial with no clear clinical guidance. The purpose of this retrospective study is to determine whether the number of LNs examined as part of GI malignancy resections affects overall survival (OS) among patients with node-positive esophageal, gastric, pancreatic, and colon cancers., Methods: Participants with LN-positive GI cancers who were diagnosed between 2004 and 2015 and underwent oncologic resections were selected from National Cancer Database (NCDB). The primary predictor was the number of examined LNs categorized in tertiles. The effect on OS was measured by hazard ratio (HR) derived from multivariate Cox regression analyses., Results: From 2004 to 2015, 1877, 10,086, 18,193, and 102,500 patients with LN-positive esophageal, gastric, pancreatic, and colon adenocarcinomas who did not receive neoadjuvant treatment and underwent oncologic tumor resection were registered in the NCDB. Using multivariate Cox proportional hazard modeling, greater LNs examined in surgically resected LN-positive GI cancers were found to be associated with increased OS for all histologies. This association was the strongest (as compared to the lowest tertile) for gastric cancer (middle tertile: HR = 0.91, 95% CI, 0.86-0.96, p = 0.001; highest tertile: HR = 0.73, 95% CI, 0.69-0.78, p < 0.001), followed by colon (highest tertile: HR = 0.86, 95% CI, 0.84-0.88, p < 0.001), esophageal (highest tertile: HR = 0.83, 95% CI, 0.72-0.95, p = 0.01), and pancreatic (highest tertile: HR = 0.93, 95% CI, 0.89-0.98, p = 0.002) cancers., Discussion and Conclusion: In patients with surgically resected node-positive GI malignancies who did not receive neoadjuvant systemic therapy, a higher number of examined LNs is associated with increased OS. This association is the strongest for gastric cancer, followed by colon, esophageal, and pancreatic cancers respectively., (© 2023. The Society for Surgery of the Alimentary Tract.)

With the fourth highest breast cancer mortality rate in the world, breast cancer prevention and early detection is a priority for Armenia. The Ministry of Health recently initiated efforts to expand access to breast cancer screening. However, little is known about the population's understanding and perception of breast cancer screening programs. This cross-sectional telephone-based study sought to develop and validate an Eastern Armenian language version of the Champion's Health Belief Model Scale (CHBMS) for future use. The English-language CHBMS survey was first rigorously translated by two Armenian nationals and evaluated for face validity. Telephone surveys were then administered to randomly-selected women of approximately screening age (35-65 years) with no prior history of breast cancer living in Armenia's capital between 2019-2020 (n = 103). The translated survey's psychometric properties were evaluated, examining (1) content equivalence, (2) test-retest reliability and (3) internal consistency. Content equivalence and test-retest reliability of the Armenian CHBMS were characterized using correlational analysis with Pearson's coefficient ranging from 0.76-0.97 (p<0.001) and 0.72-0.97 (p<0.001), respectively, for all five CHBMS domains. The translated survey's internal consistency was comparable to the original English-language CHBMS with a Cronbach's alpha greater than 0.7 for all five domains (0.75-0.94 (p<0.001). The translated Eastern Armenian version of CHBMS is a valid, internally-consistent, and reliable research tool that is ready for imminent use among screening-age women to investigate breast cancer perceptions and beliefs as the Armenian government seeks to expand screening access., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Tupper et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Type I interferons (IFNs) are critical effectors of emerging cancer immunotherapies designed to activate pattern recognition receptors (PRRs). A challenge in the clinical translation of these agents is the lack of noninvasive pharmacodynamic biomarkers that indicate increased intratumoral IFN signaling following PRR activation. Positron emission tomography (PET) imaging enables the visualization of tissue metabolic activity, but whether IFN signaling-induced alterations in tumor cell metabolism can be detected using PET has not been investigated. We found that IFN signaling augments pancreatic ductal adenocarcinoma (PDAC) cell nucleotide metabolism via transcriptional induction of metabolism-associated genes including thymidine phosphorylase (TYMP). TYMP catalyzes the first step in the catabolism of thymidine, which competitively inhibits intratumoral accumulation of the nucleoside analog PET probe 3'-deoxy-3'-[ 18 F]fluorothymidine ([ 18 F]FLT). Accordingly, IFN treatment up-regulates cancer cell [ 18 F]FLT uptake in the presence of thymidine, and this effect is dependent upon TYMP expression. In vivo, genetic activation of stimulator of interferon genes (STING), a PRR highly expressed in PDAC, enhances the [ 18 F]FLT avidity of xenograft tumors. Additionally, small molecule STING agonists trigger IFN signaling-dependent TYMP expression in PDAC cells and increase tumor [ 18 F]FLT uptake in vivo following systemic treatment. These findings indicate that [ 18 F]FLT accumulation in tumors is sensitive to IFN signaling and that [ 18 F]FLT PET may serve as a pharmacodynamic biomarker for STING agonist-based therapies in PDAC and possibly other malignancies characterized by elevated STING expression., Competing Interests: Competing interest statement: C.G.R. and J. Czernin are cofounders of Sofie Biosciences and the Trethera Corporation. They and the University of California hold equity in Sofie Biosciences and the Trethera Corporation. T.R.D. is an executive board member and holds equity in the Trethera Corporation.

Emerging evidence suggests that intratumoral interferon (IFN) signaling can trigger targetable vulnerabilities. A hallmark of pancreatic ductal adenocarcinoma (PDAC) is its extensively reprogrammed metabolic network, in which nicotinamide adenine dinucleotide (NAD) and its reduced form, NADH, are critical cofactors. Here, we show that IFN signaling, present in a subset of PDAC tumors, substantially lowers NAD(H) levels through up-regulating the expression of NAD-consuming enzymes PARP9, PARP10, and PARP14. Their individual contributions to this mechanism in PDAC have not been previously delineated. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the NAD salvage pathway, a dominant source of NAD in cancer cells. We found that IFN-induced NAD consumption increased dependence upon NAMPT for its role in recycling NAM to salvage NAD pools, thus sensitizing PDAC cells to pharmacologic NAMPT inhibition. Their combination decreased PDAC cell proliferation and invasion in vitro and suppressed orthotopic tumor growth and liver metastases in vivo., Competing Interests: Competing interest statement: C.G.R. is a cofounder of Sofie Biosciences and Trethera Corporation. He and the University of California (UC) hold equity in Sofie Biosciences and Trethera Corporation. The intellectual property developed by C.G.R. and licensed by UC to Sofie Biosciences and Trethera Corporation was not used in this study.

The Armenian highlands encompasses rugged and environmentally diverse landscapes and is characterized by a mosaic of distinct ecological niches and large temperature gradients. Strong seasonal fluctuations in resource availability along topographic gradients likely prompted Pleistocene hominin groups to adapt by adjusting their mobility strategies. However, the role that elevated landscapes played in hunter-gatherer settlement systems during the Late Pleistocene (Middle Palaeolithic [MP]) remains poorly understood. At 1640 m above sea level, the MP site of Kalavan 2 (Armenia) is ideally positioned for testing hypotheses involving elevation-dependent seasonal mobility and subsistence strategies. Renewed excavations at Kalavan 2 exposed three main occupation horizons and ten additional low densities lithic and faunal assemblages. The results provide a new chronological, stratigraphical, and paleoenvironmental framework for hominin behaviors between ca. 60 to 45 ka. The evidence presented suggests that the stratified occupations at Kalavan 2 locale were repeated ephemerally most likely related to hunting in a high-elevation within the mountainous steppe landscape., Competing Interests: The authors have declared that no competing interests exist.

Unplanned returns after ambulatory surgery pose a burden to patients and health care providers alike. We hypothesized that a postoperative phone call by a physician would decrease avoidable returns to urgent care (UC) or the emergency department (ED) in the week after anorectal (AR), laparoscopic cholecystectomy (LC), inguinal hernia repair (IHR), and umbilical hernia repair (UHR) operations. A retrospective analysis from 1/2011 to 12/2015 across 14 Kaiser hospitals was conducted to determine baseline UC/ED return rates of patients pre-call. Between 10/2017 and 06/2019, physicians placed phone calls to patients within postoperative days (PODs) 1-4. The cohorts were compared using chi-squared analysis with significance determined at P < .05. In total, 276 patients received a call, with the majority placed on PODs 1-3. There were no statistically significant differences in return rates between the pre- and post-call groups. All of the AR, 50.0% of LC, 66.7% of IHR, and 50.0% of UHR patients returned prior to phone call placement. Our data indicate that a physician phone call does not help in decreasing UC/ED returns. However, it is noteworthy that many of the returns occurred pre-call placement. Future directions should be aimed at placing earlier postoperative phone calls.

Functional lysosomes mediate autophagy and macropinocytosis for nutrient acquisition. Pancreatic ductal adenocarcinoma (PDAC) tumors exhibit high basal lysosomal activity, and inhibition of lysosome function suppresses PDAC cell proliferation and tumor growth. However, the codependencies induced by lysosomal inhibition in PDAC have not been systematically explored. We performed a comprehensive pharmacological inhibition screen of the protein kinome and found that replication stress response (RSR) inhibitors were synthetically lethal with chloroquine (CQ) in PDAC cells. CQ treatment reduced de novo nucleotide biosynthesis and induced replication stress. We found that CQ treatment caused mitochondrial dysfunction and depletion of aspartate, an essential precursor for de novo nucleotide synthesis, as an underlying mechanism. Supplementation with aspartate partially rescued the phenotypes induced by CQ. The synergy of CQ and the RSR inhibitor VE-822 was comprehensively validated in both 2D and 3D cultures of PDAC cell lines, a heterotypic spheroid culture with cancer-associated fibroblasts, and in vivo xenograft and syngeneic PDAC mouse models. These results indicate a codependency on functional lysosomes and RSR in PDAC and support the translational potential of the combination of CQ and RSR inhibitors., Competing Interests: The authors declare no conflict of interest.

Background: Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted., Methods: A single-arm study in 111 consecutive patients undergoing pancreatic resection April 2015-October 2016 was conducted. Beginning immediately before surgery, patients received 900 μg subcutaneous pasireotide twice daily for up to seven days. Fistula rates were compared to 168 historical controls from July 2013 to March 2015. The primary outcome was Grade B/C fistula, as defined by the International Study Group on Pancreatic Fistula (ISGPF)., Results: There were no significant differences between the pasireotide group and historical controls in demographics, comorbidities, operation type, malignancy, gland texture, or pancreatic duct size. Pasireotide did not reduce fistula rate (15.5% control versus 17.1% pasireotide, p = 0.72). In subgroup analyses of pancreaticoduodenectomy or distal pancreatectomy, or patients with soft gland texture and/or small duct size, there was no decrease in fistulas. Thirty-nine patients (38%) experienced dose-limiting nausea., Conclusions: In an appropriately-powered, single-institution prospective study, pasireotide was not validated as a preventive measure for pancreatic fistula., (Copyright © 2017 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

With its well-preserved archaeological and environmental records, Aghitu-3 Cave permits us to examine the settlement patterns of the Upper Paleolithic (UP) people who inhabited the Armenian Highlands. We also test whether settlement of the region between ∼39-24,000 cal BP relates to environmental variability. The earliest evidence occurs in archaeological horizon (AH) VII from ∼39-36,000 cal BP during a mild, moist climatic phase. AH VI shows periodic occupation as warm, humid conditions prevailed from ∼36-32,000 cal BP. As the climate becomes cooler and drier at ∼32-29,000 cal BP (AH V-IV), evidence for occupation is minimal. However, as cooling continues, the deposits of AH III demonstrate that people used the site more intensively from ∼29-24,000 cal BP, leaving behind numerous stone artifacts, faunal remains, and complex combustion features. Despite the climatic fluctuations seen across this 15,000-year sequence, lithic technology remains attuned to one pattern: unidirectional reduction of small cores geared towards the production of bladelets for tool manufacture. Subsistence patterns also remain stable, focused on medium-sized prey such as ovids and caprids, as well as equids. AH III demonstrates an expansion of social networks to the northwest and southwest, as the transport distance of obsidian used to make stone artifacts increases. We also observe the addition of bone tools, including an eyed needle, and shell beads brought from the east, suggesting that these people manufactured complex clothing and wore ornaments. Remains of micromammals, birds, charcoal, pollen, and tephra relate the story of environmental variability. We hypothesize that UP behavior was linked to shifts in demographic pressures and climatic changes. Thus, by combining archaeological and environmental data, we gain a clearer picture about the first UP inhabitants of the Armenian Highlands., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Phosphoinositides serve as key membrane determinants for assembly of clathrin coat proteins that drive formation of clathrin-coated vesicles. At the trans -Golgi network (TGN), phosphatidylinositol 4-phosphate (PtdIns4P) plays important roles in recruitment of two major clathrin adaptors, Gga (Golgi-localized, gamma-adaptin ear homology, Arf-binding) proteins and the AP-1 (assembly protein-1) complex. The molecular mechanisms that mediate localization of phosphatidylinositol kinases responsible for synthesis of PtdIns4P at the TGN are not well characterized. We identify two motifs in the yeast phosphatidylinositol 4-kinase, Pik1, which are required for binding to the VHS domain of Gga2. Mutations in these motifs that inhibit Gga2-VHS binding resulted in reduced Pik1 localization and delayed accumulation of PtdIns4P and recruitment of AP-1 to the TGN. The Pik1 homolog in mammals, PI4KIIIβ, interacted preferentially with the VHS domain of GGA2 compared with VHS domains of GGA1 and GGA3. Depletion of GGA2, but not GGA1 or GGA3, specifically affected PI4KIIIβ localization. These results reveal a conserved role for Gga proteins in regulating phosphatidylinositol 4-kinase function at the TGN.

Although histone deacetylase inhibitors (HDACi) are a promising class of anti-cancer drugs, thus far, they have been unsuccessful in early phase clinical trials for pancreatic ductal adenocarcinoma (PDAC). One potential reason for their poor efficacy is the tumor stroma, where cancer-associated fibroblasts (CAFs) are a prominent cell type and a source of resistance to cancer therapies. Here, we demonstrate that stromal fibroblasts contribute to the poor efficacy of HDACi's in PDAC. HDACi-treated fibroblasts show increased biological aggressiveness and are characterized by increased secretion of pro-inflammatory tumor-supportive cytokines and chemokines. We find that HDAC2 binds to the enhancer and promoter regions of pro-inflammatory genes specifically in CAFs and in silico analysis identified AP-1 to be the most frequently associated transcription factor bound in these regions. Pharmacologic inhibition of pathways upstream of AP-1 suppresses the HDACi-induced inflammatory gene expression and tumor-supportive responses in fibroblasts. Our findings demonstrate that the combination of HDACi's with chemical inhibitors of the AP-1 signaling pathway attenuate the inflammatory phenotype of fibroblasts and may improve the efficacy of HDACi in PDAC and, potentially, in other solid tumors rich in stroma.

The open-air site of Kalavan 1 is located in the Aregunyats mountain chain (at 1640 m above sea level) on the northern bank of Lake Sevan. It is the first Upper Palaeolithic site excavated in Armenia. Led by an Armenian-French team, several excavations (2005-2009) have revealed a well preserved palaeosoil, dated to around 14,000 BP (years before present), containing fauna, lithic artefacts, as well as several hearths and activity areas that structure the settlement. The initial studies enable placement of the site in its environment and justify palaeoethnological analysis of the Epigravettian human groups of the Lesser Caucasus., (Copyright © 2013 Elsevier Ltd. All rights reserved.)