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Abstract Background Resveratrol has demonstrated its ability to regulate BRCA1 gene expression in breast cancer cells, and previous studies have established the binding of MBD proteins to BRCA1 gene promoter regions. However, the molecular mechanism underlying these interactions remains to be elucidated. The aimed to evaluate the impact of MBD proteins on the regulation of BRCA1, BRCA2, and p16 genes and their consequential effects on breast cancer cells. Methods Efficacy of resveratrol was assessed using the MTT assay. Binding interactions were investigated through EMSA, ChIP, & MeIP assay. Expression analyses of MBD genes and proteins were conducted using qRT-PCR and western blotting, respectively. Functional assays, including clonogenic, migratory, and sphere formation assays were used to assess cancer cells’ colony-forming, metastatic, and tumor-forming abilities. The cytotoxicity of resveratrol on cancer cells was also tested using an apoptosis assay. Results The study determined an IC50 of 30µM for resveratrol. MBD proteins were found to bind to the BRCA1 gene promoter. Resveratrol exhibited regulatory effects on MBD gene expression, subsequently impacting BRCA1 gene expression and protein levels. Higher concentrations of resveratrol resulted in reduced colony and sphere formation, decreases migration of cancer cells, and an increases number of apoptotic cells in breast cancer cells. Impact Identification of MBD2-BRCA1 axis indicates their significant role in the induction of apoptosis and reduction of metastasis and proliferation in breast cancer cells. Further therapy can be designed to target these MBD proteins and resveratrol could be used along with other anticancer drugs to target breast cancer. Conclusions In conclusion MBD2 protein interact to the BRCA1 gene promoter, and resveratrol modulates MBD2 gene expression, which in turn regulates BRCA1 gene expression, and inhibits cell proliferation, migration, and induces apoptosis in ER+, PR+ & Triple negative breast cancer cells.

Background and Aims: Immune checkpoint inhibitor therapy causes numerous immune-related adverse events, including autoimmune pancreatic injury (AIPI), which results in rapid organ atrophy. We profiled the clinico-radiological features, short-term natural history, and response to steroids of AIPI. Methods: We retrospectively reviewed medical records of 229/11,165 (2.1%) adult patients with AIPI. One hundred and ten out of 229 (48%) had abdominal computerized tomography (CT) scan at lipase elevation; data of 110 without pancreatic metastases were analyzed. We analyzed serial CT-based pancreas volumetry data in 48 patients with AIPI (32 with normal CT and 16 with pancreatitis on CT at lipase elevation). We examined impact of steroids on pain and disease course. Results: In AIPI (n = 229), median lipase elevation was 4x upper limit of normal (range: 3–40x). The injury was more often asymptomatic than painful (143/229 (62%) vs 86/229 (38%), P < .000). Majority (83/110 (75%) had normal CT, often in painless vs painful disease: 51/57 (90%) vs 32/53 (60%), P < .001) 25% had interstitial pancreatitis. On serial pancreas volumetry, marked volume (cc) loss occurred 1 year after vs 3 months before lipase elevation in both normal CT (median 81.6 vs 61.3, P = .00) and pancreatitis on CT groups (91.8 vs 60.5, P = .00), ≥20% volume loss occurred in 47% vs 73%, respectively (P = .08). Steroids, when used did not mitigate pain, biochemical relapse, pancreas volume loss or 1-year diabetes incidence (7.2%). Conclusion: Autoimmune pancreatic injury (AIPI) is uniquely characterized by painless lipase elevation, normal pancreas on CT and rapid pancreatic volume loss on follow-up. Steroids do not appear to have a role in management.

The increasing global adoption of Electric Vehicles (EVs) necessitates a greater supply of electricity for charging these cars. The popularity of EVs is also driven by their minimal maintenance requirements, enhanced performance, and eco-friendly nature. However, the expanding usage of EVs poses challenges to the distribution system's efficiency, thereby impacting its reliability. Consequently, ensuring the precise placement of electric vehicle charging stations (EVCS) becomes crucial for maintaining a dependable infrastructure. Solar and wind-based Renewable Distributed Generations (RDGs), Distribution STATic COMPensator (DSTATCOM), and Battery Energy Storage System (BESS) have become an important part of a Radial Distribution System (RDS) for mitigating the impact of EVCS as environmental sensitivity has grown and technology has advanced. Improper placement and sizing of components in can significantly impact the performance of a RDS. This research proposes a unique approach utilizing the Slime Mould Algorithm (SMA) and other optimization algorithms to identify the optimum positioning and sizing of RDG/DSTATCOM/EVCS/BESS within the RDS. The presented approach's efficacy is showcased by employing it on two commonly used IEEE RDSs: specifically, the 33-bus and 69-bus systems. The main objective of this research is to address actual power loss in these systems, subsequently enhancing voltage stability and bus voltage profiles. Findings from the test cases demonstrate that optimizing with the SMA algorithm produces more precise results in mitigating real power loss, enhancing bus voltage levels, and improving overall system stability when compared to existing algorithms.

AbstractElastomers are the class of materials that are widely used in a variety of industrial, commercial, and consumer applications due to their unique mechanical properties, including high elasticity, high flexibility, and high resilience. However, there are many challenges in machining of elastomers such as poor surface finish, build up of heat, degradation of elastomers, etc. To overcome these challenges, cryogenic cooling assistance has been introduced as a means of improving the machinability of elastomers. This paper presents a soft computing approach for optimizing the surface roughness and cutting force during turning of elastomers under different lubrication conditions. Three types of elastomers, namely Nitrile Rubber (NBR), Polyurethane Rubber (PU), and Neoprene Rubber (CR), are studied, and a cryogenic fluid delivery system is employed to improve the machining process. Taguchi’s L27 array is used to vary the input parameters, and a Back-Propagation Artificial Neural Network (BPANN) model is developed to predict the cutting force and surface roughness. The cutting force and surface roughness are analyzed under different cooling conditions, cutting speeds, feeds, and depths of cut for various elastomers. The results show that changes in cutting conditions significantly affect the cutting force and that the type of lubrication used affects the cutting force by altering the material’s physical properties. Cutting force is significantly influenced by cutting conditions, and NBR requires the highest cutting force compared to PU and CR. Further, at a cutting speed of 55 m/min, a feed of 0.11 mm/rev, and a depth of cut of 0.25 mm, the cutting force for NBR (85.1 N), while for PU (75.1 N) and CR (80.3 N), respectively. Finally, with LN2 lubrication conditions, the Cutting Force decreased by 45% and Surface Roughness decreased by 16.9%. This study provides insights into the factors affecting the elastomer machining process, which can be useful for optimizing the machining process parameters and improving machining efficiency.

AbstractDespite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. In response to the maturity of AI, Kenner Family Research Fund conducted the 2020 AI and Early Detection of Pancreatic Cancer Virtual Summit (www.pdac-virtualsummit.org) in conjunction with the American Pancreatic Association, with a focus on the potential of AI to advance early detection efforts in this disease. This comprehensive presummit article was prepared based on information provided by each of the interdisciplinary participants on one of the 5 following topics: Progress, Problems, and Prospects for Early Detection; AI and Machine Learning; AI and Pancreatic Cancer-Current Efforts; Collaborative Opportunities; and Moving Forward-Reflections from Government, Industry, and Advocacy. The outcome from the robust Summit conversations, to be presented in a future white paper, indicate that significant progress must be the result of strategic collaboration among investigators and institutions from multidisciplinary backgrounds, supported by committed funders.

Background & aimsObservational studies of predominantly white populations have found new-onset diabetes to be associated with increased risk of pancreatic cancer. We sought to determine whether this relationship applies to other races or ethnicities and to identify metabolic profiles associated with increased risk of pancreatic cancer.MethodsWe conducted a population-based cohort study of Asian, black, Hispanic and white patients from Kaiser Permanente Southern California from 2006 through 2016 (n = 1,499,627). Patients with diabetes were identified based on glucose and hemoglobin A1c (HbA1c) measurements. We used Cox regression to assess the relationship between diabetes status and duration and pancreatic cancer. For patients with recent diagnoses of diabetes (1 year or less) we compared longitudinal changes in glucose, HbA1c, and weight, from time of diabetes diagnosis through 3 years prior to the diagnosis, in patients with vs without pancreatic cancer.ResultsWe identified 2,002 incident cases of pancreatic cancer from nearly 7.5 million person-years of follow-up. Compared to patients without diabetes, individuals who received a recent diagnosis of diabetes had an almost 7-fold increase in risk of pancreatic cancer (relative risk, 6.91; 95% CI, 5.76-8.30). Among patients with a recent diagnosis of diabetes, those who developed pancreatic cancer had more rapid increases in levels of glucose (Δslope: cases, 37.47 mg/dL vs non-cases, 27.68 mg/dL) and HbA1c (Δslope: cases, 1.39% vs non-cases, 0.86%) in the month preceding the diagnosis of diabetes, and subtle weight loss in the prior years (slope: cases -0.18 kg/interval vs non-cases 0.33 kg/interval). These longitudinal changes in markers of metabolism were stronger for specific race and ethnic groups.ConclusionsIn a study of a large ethnically diverse population, we found risk of pancreatic cancer to be increased among patients with a diagnosis of diabetes in the past year among different races and ethnicities. Weight loss and rapid development of poor glycemic control were associated with increased risk of pancreatic cancer in multiple races.

Introduction:To compare the three-dimensional conformal radiotherapy (3DCRT), dynamic conformal arc therapy (DCA), and volumetric modulated arc therapy (VMAT) in stereotactic body radiation therapy (SBRT) of liver cases using 6MV and 10 MV flattened beam (FB) and flattening filter-free beam (FFFB).Material and Methods:Twenty liver SBRT patients were selected. The dose prescription was 40 Gy delivered in 5 fractions. 3DCRT, DCA and VMAT planning was performed using 6 MV FB, 6 MV FFFB, 10 MV FB and 10 MV FFFB. Planning target volume (PTV) coverage, organs at risk (OARs) doses, monitor units (MU), and beam on time (BOT) were noted.Results:VMAT plan produces better PTV coverage in the D98% and D95% region. 6 MV and 10 MV VMAT FB and FFFB reduced the D700cc, V10Gy, and Dmean of the liver minus gross tumor volume region compared to 3DCRT and DCA plans. FFFB in combination with VMAT producing highly conformal plan (Conformit index=1.19), better conformity number (CN=0.85), and lowering Paddick gradient index (GIpad=3.29) in comparison to 3DCRT and DCA. The FFFB needs higher monitor units to achieve the plan in all the techniques. FFFB reduces the BOT, body-PTV mean dose in the non-tumour volume.Conclusion: VMAT combined with FFFB will produce a highly conformal plan, spare the OAR’s, deliver fast and dose fall off in the body-PTV region is more as compared to 3DCRT and DCA. The VMAT will more advantage to treat the multiple lesions simultaneously and reducing the intra-fraction motion error in liver SBRT.

Introduction Intervention and educational approaches ranging from oral language only to oral language combined with various forms of sign language have evolved. The aim of this study was to understand the choices of language for the deaf/ hearing impaired child for communication by the parents using a survey questionnaire. The objectives were to adapt the questionnaire given by to obtain the information about the choices of communication mode and the process of selection. Materials and Methods Participants included in this study were parents of hearing impaired and deaf children in Bengaluru. Modified and shortlisted 31 questions given to ten teachers of deaf and sign language users for content validation and those suggestions were incorporated. Questionnaire was provided to parents of hearing impaired and deaf children. Results Study showed majority were fitted with devices to help their hearing – hearing aid and cochlear implant and joined oral school for education. Age of Intervention was early only in small number of children. Sign language as a mode of communication was reported in only 20.3% and 59.3% reportedly not used sign language at all. The families that used sign language reported the reason for the choice being ease of use. Regardless of competence of children in oral language, majority of parent’s aspiration was oral language, followed by sign and oral language. Choosing sign language as a primary communication mode is seen in minority of parents. The survey also showed though children are in oral school, mode communication is not always oral. Peer group interaction and interaction with family members require sign and actions-gestures along with oral language. Conclusion The study emphasized the importance of learning oral language and sign language for deaf and hearing-impaired children. Parental concerns revolved around educational opportunities of deaf/ hearing impaired child population may be reduced.

Naturally derived cyanotoxins, cylindrospermopsin (CYN), and microcystin-LR (MC-LR) have shown hepatotoxic and nephrotoxic effects in several studies. The present study aimed to determine the possible nephrotoxicity of MC-LR and CYN on mammalian kidneys using male Wistar rats as an animal model. Potential nephrotoxicity was evaluated at different doses of CYN (0.175 µg.kg-1, 0.140 µg.kg-1, 0.105 µg.kg-1) and MC-LR (0.105 µg.kg-1, 0.070 µg.kg-1, 0.035 µg.kg-1) was observed. Water samples from dug wells contaminated with CYN (0.161 µg.kg-1) and MC-LR (0.091 µg.kg-1) from the Padaviya area in Anuradhapura, Sri Lanka were used as environmental samples. The control groups were treated with distilled water. The exposure time of rats to the toxin was 90 days. Evaluation of urinary creatinine, serum creatinine, and Kidney Injury Molecule-1 (KIM-1) were estimated using standard protocols. A significant increase in serum creatinine levels was observed in all CYN and MC-LR treated groups (p<0.05) after 7 and 42 days of exposure, respectively, compared to control. It was found a decrease of urine creatinine when rats were treated with different concentrations of CYN and MC-LR (p<0.05) after 7 days compared to the control. The highest KIM-1 concentrations were recorded at 0.175 µg.kg-1 of CYN and 0.105 µg.kg-1 of MC-LR. The concentrations of KIM-1 in the control groups for CYN-treated and MC-LRt-reated were not detected. Luminal protein, nuclear pyknosis, mild tubular epithelial swelling, vascular congestion, and interstitial inflammation in CYN and MC-LR treated groups were common. No predominant changes were observed in the control groups treated with CYN and MC-LR. The results of the present study confirm that the consumption of CYN and MCLR- contaminated water may lead to kidney injury in Wistar rats. [ABSTRACT FROM AUTHOR]

Background and Aims: Management of intraductal papillary mucinous neoplasms (IPMNs) relies on clinical and imaging features to select patients for either pancreatectomy or periodic image-based surveillance. We aimed to compare outcomes in patients with IPMNs who underwent surgery at diagnosis with those who underwent surgery after a period of surveillance and identify preoperative clinical and imaging features associated with advanced neoplasia. Methods: Patients with surgically resected IPMN (n = 450) were divided into 2 groups: “immediate surgery”: resection within 6 months of IPMN detection, and “surveillance surgery”: resection after surveillance >6 months. Survival was analyzed with Kaplan-Meier estimates and Cox proportional hazard models. Results: Pancreatic cancers in the surveillance surgery group (n = 135) was more frequently stage I compared with the immediate surgery group (9/13, 69.2% vs 41/110, 37.3%; P = .027). Among Fukuoka “worrisome features,” only main pancreatic duct dilation 5–9 mm (odds ratio [OR] = 3.12, 95% confidence interval [CI]: 1.72–5.68; P < .001) and serum CA 19-9≥ 35 U/mL (OR = 2.82, 95% CI: 1.31–6.06; P = .008) were significantly associated with advanced neoplasia. In addition, smoking history was associated with increased risk of advanced neoplasia (OR = 2.05, 95% CI: 1.23–3.43). Occurrence of future cancer was 16-fold higher in IPMN with high-grade dysplasia when compared with low-grade dysplasia (hazard ratio: 16.5; 95% CI: 4.19–64.7). Conclusion: Surveillance-detected pancreatic cancers in patients with IPMNs are more frequently stage I, and IPMN-HGD on surgical pathology is associated with significant risk of future pancreatic cancer. In addition to known “high-risk” features, main pancreatic duct dilation 5–9 mm, CA 19-9 elevation, and smoking history are significantly associated with advanced neoplasia.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis (CP) in the United States. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in CP. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of CP-controls, suspected CP, and definite CP. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid, and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of CP. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of CP.