Geometry-Sensitive Protrusion Growth Directs Confined Cell Migration.

The migratory dynamics of cells can be influenced by the complex microenvironment through which they move. It remains unclear how the motility machinery of confined cells responds and adapts to their microenvironment. Here, we propose a biophysical mechanism for a geometry-dependent coupling between cellular protrusions and the nucleus that leads to directed migration. We apply our model to geometry-guided cell migration to obtain insights into the origin of directed migration on asymmetric adhesive micropatterns and the polarization enhancement of cells observed under strong confinement. Remarkably, for cells that can choose between channels of different size, our model predicts an intricate dependence for cellular decision making as a function of the two channel widths, which we confirm experimentally.

Developments in pancreatic cancer surgery.

Pancreatic cancer surgery, with one of the worst prognoses in oncology, is a challenge to the surgical community. Centralization of pancreatic surgery has led to the foundation of high-volume centers, thereby greatly facilitating the successful performance of more radical approaches. This review spotlights on recent advances in surgical approaches to pancreatic cancer and the risks and benefits of vascular reconstruction to improve resectability. Surgery being the only modality to achieve cure, multivisceral and vascular resections are being incorporated to improve dismal operability rates of < 10%. Great leaps have been made in neoadjuvant and adjuvant treatment, as targeted and specific chemotherapeutic agents are being continually added. The concept of borderline and locally advanced pancreatic tumors and the use of neoadjuvant chemorad has extended the indications of oncological resection in such tumors. Venous resections are being routinely performed so as to facilitate en bloc removal of tumors, while arterial resections, owing to the increased morbidity and mortality, are offered to highly selective cases. New techniques like the triangle operation and periarterial divestment have opened new viable surgical options. Although laparoscopic approach is time consuming, it offers reduced operative blood loss and a shortened hospital stay at specialized centers. Robotic surgery may produce better results in patients needing vascular resection and reconstruction, but the expenses involved and limited availability are major deterrents. Advanced techniques of surgical resection and vessel reconstruction provide a repository for curative-intent surgery in borderline resectable and locally advanced pancreatic cancer.

cyjShiny: A cytoscape.js R Shiny Widget for network visualization and analysis.

cyjShiny is an open-source R package that allows users to embed network visualization into Shiny apps and R Markdown documents. cyjShiny (https://github.com/cytoscape/cyjShiny) builds on the cytoscape.js Javascript graph library. Additionally, the package provides helper functions to convert common R data representations (e.g., data.frame) into forms compatible with cytoscape.js.

Impact of Covid-19 on gastrointestinal cancer surgery: A National Survey.

PURPOSE: To understand the actual impact of the Covid-19 pandemic and frame the future strategies, we conducted a pan India survey to study the impact on the surgical management of gastrointestinal cancers. METHODS: A national multicentre survey in the form of a questionnaire from 16 tertiary care gastrointestinal oncology centres across India was conducted from January 2019 to June 2021 that was divided into a 15-month pre-Covid era and a similar period of active Covid pandemic era. RESULTS: There was significant disruption of services; 13 (81%) centres worked as dedicated Covid care centres and 43% reported suspension of essential care for more than 6 months. In active Covid phase, there was a 14.5% decrease in registrations and proportion of decrease was highest in the centres from South zone (22%). There was decrease in resections across all organ systems; maximum reduction was noted in hepatic resections (33%) followed by oesophageal and gastric resections (31 and 25% respectively). There was minimal decrease in colorectal resections (5%). A total of 584 (7.1%) patients had either active Covid-19 infection or developed infection in the post-operative period or had recovered from Covid-19 infection. Only 3 (18%) centres reported higher morbidity, while the rest of the centres reported similar or lower morbidity rates when compared to pre-Covid phase; however, 6 (37%) centres reported slightly higher mortality in the active Covid phase. CONCLUSION: Covid-19 pandemic resulted in significant reduction in new cancer registrations and elective gastrointestinal cancer surgeries. Perioperative morbidity remained similar despite 7.1% perioperative Covid 19 exposure.

Genetic Susceptibility of DCC Gene in Gallbladder Cancer in Kashmir and Meta-Analysis.

Deleted in colorectal carcinoma (DCC) A > G (rs714) is the most widely studied SNP of tumor suppressor DCC gene found to be associated with increased risk of various cancers. Therefore, the aim of present case control study was to investigate the role of DCC A > G (rs714) in gallbladder cancer (GBC) in Kashmir and to conduct a meta-analysis of DCC A > G (rs714) polymorphism to demonstrate the more accurate strength of these associations. Genotyping was done by PCR/RFLP and confirmed by sequencing in 100 GBC cases, and 150 controls. We also performed a comprehensive meta-analysis of 2223 subjects (1118 cases and 1105 controls) to evaluate the association between DCC A > G (rs714) polymorphisms and cancer. In present case control study DCC A > G (rs714) genotypes did not modulate the GBC cancer risk. Meta-analysis results showed that DCC A > G (rs714) is associated with increased overall cancer risk. DCC A > G (rs714) polymorphism conferred significant risk for cancer in dominant model but in recessive model P-value was at borderline. DCC A > G (rs714) genotype was associated with increased risk of cancer in Asians and Kashmiri population whereas no such association was observed in Europeans. The evidence in this meta-analysis supports a modest involvement of DCC A > G (rs714) tumoursupressor pathway genes in cancer susceptibility.

Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer.

BACKGROUND: Pancreatic cancer (PC) is one of the deadliest malignancies with an alarming mortality rate. Despite significant advancement in diagnostics and therapeutics, early diagnosis remains elusive causing poor prognosis, marred by mutations and epigenetic modifications in key genes which contribute to disease progression. AIM: To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley. METHODS: A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9 (CA 19-9), tissue polypeptide specific antigen (TPS), carcinoembryonic antigen (CEA), vascular endothelial growth factor-A (VEGF-A), and epidermal growth factor receptor (EGFR). Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma (KRAS), Breast cancer type 2 (BRCA-2), and deleted in pancreatic cancer-4 (DPC-4) genes. However, epigenetic modifications (methylation of CpG islands) were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A (p16; CDKN2A), MutL homolog 1 (hMLH1), and Ras association domain-containing protein 1(RASSF1A) genes. RESULTS: We found significantly elevated levels of biological markers CA 19-9 (P ≤ 0.05), TPS (P ≤ 0.05), CEA (P ≤ 0.001), and VEGF (P ≤ 0.001). Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12 (16 subjects, P ≤ 0.05), and 13 (12 subjects, P ≤ 0.05). However, we did not find a mutation in DPC-4 (1203G > T) and BRCA-2 (617delT) genes. Furthermore, epigenetic modification revealed that CpG methylation in 21 (P ≤ 0.05) and 4 subjects in the promoter regions of the p16 and hMLH1 gene, respectively. CONCLUSION: In conclusion, CA 19-9, TPS, CEA, and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC. Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC. Additionally, methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.

Measurement-based care training curriculum in psychiatry residency programs: I: Description of the curriculum and demonstration of implementation.

BACKGROUND: Recent literature shows that most practicing psychiatrists do not receive training in measurement-based care (MBC). Among the primary barriers to MBC implementation are the lack of formal training and curriculums. We present the first comprehensive MBC curriculum for use in adult psychiatric practice, and describe how the curriculum is adapted and implemented in psychiatry residency training programs. METHODS: The Standard for Clinicians' Interview in Psychiatry (SCIP) was developed as a measurement-based care tool for clinicians' use. The SCIP is the only instrument that includes 18 reliable and validated clinician-rated scales covering most adult psychiatric disorders. The SCIP has simple, unified rules of measurement that apply to the 18 scales. The MBC curriculum includes 2 instruction manuals, 4 didactic lectures, and 12 videotaped interviews. We describe the annual learning and implementation of MBC curriculum in residency programs. RESULTS: The curriculum implementation at West Virginia University and Delaware Psychiatric Center began in 2019 and is ongoing. We present 3 case demonstrations of the implementation of MBC in clinical settings. CONCLUSIONS: Comprehensive implementation of MBC curriculum in residency programs has the potential to facilitate research and create a "culture" of MBC in future generations of psychiatrists.

The effectiveness of image-guided percutaneous catheter drainage in the management of acute pancreatitis-associated pancreatic collections.

PURPOSE: Acute pancreatitis is commonly complicated by the development of pancreatic collections (PCs). Symptomatic PCs warrant drainage, and the available options include percutaneous, endoscopic, and open surgical approaches. The study aimed to assess the therapeutic effectiveness and safety of image guided percutaneous catheter drainage (PCD) in the management of acute pancreatitis related PCs. MATERIAL AND METHODS: This was a single-centre prospective study covering a 4-year study period. Acute pancreatitisrelated PCs complicated by secondary infection or those producing symptoms due to pressure effect on surrounding structures were enrolled and underwent ultrasound or computed tomography (CT)-guided PCD. The patients were followed to assess the success of PCD (defined as clinical, radiological improvement, and the avoidance of surgery) and any PCD-related complications. RESULTS: The study included 60 patients (60% males) with a mean age of 43.1 ± 21.2 years. PCD recorded a success rate of 80% (16/20) for acute peripancreatic fluid collections (APFC) and pancreatic pseudocysts (PPs), 75% (12/16) for walled-off necrosis (WON), and 50% (12/24) for acute necrotic collections (ANCs). Post-PCD surgery (necrosectomy ± distal pancreatectomy) was needed in 50% of ANC and 25% of WON. Only 20% of APFCs/PPs patients required surgical/endoscopic treatment post-PCD. Minor procedure-related complications were seen in 4 (6.6%) patients. CONCLUSION: PCD is an effective, safe, and minimally invasive therapeutic modality with a good success rate in the management of infected/symptomatic PCs.

Sonic Hedgehog Protein is Frequently Up-Regulated in Pancreatic Cancer Compared to Colorectal Cancer.

Sonic hedgehog (SHH) is a secreted protein which functions in autocrine or paracrine fashion on target cells to activate hedgehog (HH) signalling cascade responsible for growth and proliferation. This study is an attempt to understand the expression dynamics of SHH protein in colon, rectal and pancreatic cancers. Protein expression of SHH was studied by Western Blotting in the histologically confirmed colon, rectum and pancreatic cancer tissue samples along with their adjacent normal tissues. Only 31.4% (11 of 35) and 26.9% (7 of 26) of colon and rectal cancer cases respectively showed an increase in SHH expression in tumours compared to 72.7% (24 of 33) of the pancreatic cancer cases when compared with their adjacent normal tissues. Our results suggest that SHH may have a strong role in the predisposition of Pancreatic cancer and could possibly be used as a diagnostic or prognostic biomarker.

Role of Glutathione-S-Transferases in Gallbladder Cancer and Cholelithiasis Susceptibility and Meta-Analysis.

Glutathione-S-transferase T1 (GSTT1) and glutathione-S-transferase M1 (GSTM1) genes are associated with increase susceptibility to developing different types of cancers. The aim of present study was to investigate the role of genetic variants of GSTM1 and GSTT1 in gallbladder cancer (GBC) and cholelithiasis in Kashmir valley. Genotyping was done by multiplex polymerase chain reaction in 100 GBC, 100 cholelithiasis, and 150 controls adjusted by age and sex. We also performed a meta-analysis of published studies on GSTM1 and GSTT1 to evaluate the association between the GSTM1 and GSTT1 polymorphisms and GBC. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using random- or fixed-effects model. In the present study, no association was observed between GSTM1 null and GSTT1 null genotypes and GBC and cholelithiasis. Meta-analysis results showed that GSTM1 null genotype was associated with GBC risk (P = 0.042). Subgroup analysis by ethnicity showed that GSTM1 null (P = 0.024) and GSTT1 null genotype (P = 0.037) were significantly associated with risk of GBC in Asians. This is the first study to investigate the role of genetic variants of GSTM1 and GSTT1 in GBC in Kashmir valley and cholelithiasis in the world.

Dual Parasitization of the Biliary Tree: First Reported Case.

Cases of biliary ascariasis and hydatid cysts in liver and elsewhere are common in endemic areas and are routinely encountered in surgical outpatient departments. We describe the diagnosis and management of a unique case, who presented with manifestations of biliary ascariasis, but on further investigation was found to harbor ascarids as well as ruptured hydatids in his biliary passages. To our knowledge, this is the first reported case of simultaneous parasitization of common bile duct by ascarid and hydatid forms, resulting in obstruction of the biliary system. This report highlights the diversity of presentation and challenges in the management of such cases, when encountered in practice.

Nuclear localization and Overexpression of Smoothened in Pancreatic and Colorectal Cancers.

Smoothened (SMO) is a significant signalling protein which functions as a key transducer for the hedgehog signalling pathway, an important signalling mechanism with key roles in development and oncogenesis. The correlation of expression dynamics of SMO with pancreatic and colorectal cancer genesis has been known but with ambiguity. Therefore, in this study, we investigated messenger RNA (mRNA) and protein expression of SMO in pancreatic and colorectal cancers in our population and assessed relationship with various clinicopathological parameters. Surgically resected tumour and adjacent histologically normal tissues from 33 and 61 pancreatic and colorectal cancer patients were investigated in the present study. Expression of SMO was analysed by quantitative real-time polymerase chain reaction and immunohistochemistry. At mRNA level, SMO was overexpressed in 72.72% (24 of 33) and 50.81% (31 of 61) of the pancreatic and colorectal cancer cases as compared with their adjacent normal tissues. SMO immunohistochemical analysis revealed nuclear localization and overexpression was observed in 51.51% (17 of 33) and 40.98% (25 of 61) of pancreatic and colorectal cancer tissues. SMO overexpression was significantly associated with smoking, late-stage disease and lymph node metastasis in patients with Colorectal cancer. Our results showed that SMO is dysregulated in pancreatic and colorectal cancers and may be considered as a target in cancer therapeutics.

Prevalence and pattern of growth abnormalities in children with extrahepatic portal vein obstruction: Response to shunt surgery.

OBJECTIVE: Growth retardation is common in children with extrahepatic portal vein obstruction (EHPVO) and growth hormone (GH) resistance may play a dominant role. The aim of this study was to ascertain growth parameters and growth-related hormones in children with EHPVO, comparing with controls and to study the response of shunt surgery on growth parameters. MATERIALS AND METHODS: The auxological and growth-related hormone profile (GH; insulin-like growth factor binding protein-3 [IGFBP-3] and IGF-1) of thirty children with EHPVO were compared with controls. The effect of shunt surgery on growth parameters in 12 children was also studied. RESULTS: The mean height standard deviation score (HSDS) of cases (-1.797 ± 1.146) was significantly lower than that of controls (-0.036 ± 0.796); the mean weight SDS of cases (-1.258 ± 0.743) was also lower than that of controls (-0.004 ± 0.533). The mean GH level of cases (5.00 ± 6.46 ng/ml) was significantly higher than that of controls (1.78 ± 2.04 ng/ml). The mean IGF-1 level of cases (100.25 ± 35.93 ng/ml) was significantly lower as compared to controls (233.53 ± 115.06 ng/ml) as was the mean IGFBP-3 level (2976.53 ± 1212.82 ng/ml in cases and 5183.28 ± 1531.28 ng/ml in controls). In 12 patients who underwent shunt surgery, growth parameters significantly improved. CONCLUSIONS: Marked decrease in weight and height SDSs associated with GH resistance is seen in children with EHPVO, which improves with shunt surgery.

Impact of centralization of pancreaticoduodenectomy coupled with fast track recovery protocol: a comparative study from India.

BACKGROUND: Fast track strategy in the management of patients undergoing intra-abdominal surgery of various types has emerged as a landmark approach to reduce surgical stress and accelerate recovery. This study was to evaluate the effect of fast track strategy on patients subjected to pancreaticoduodenectomy (PD) from an individual unit during transit from low to a high volume center. METHODS: A total of 142 PD patients who had been subjected to fast track strategy between June 2008 and September 2012 were compared with 46 patients who had received conventional surgery between January 2006 and May 2008. Comparative analysis was made of postoperative complications, postoperative recovery, length of hospital stay and patient readmission requirement. RESULTS: The patients subjected to fast track strategy had a faster recovery and a shorter hospital stay than those who were treated conventionally (7.8 vs 12.1 days). The intraoperative events like operative blood loss (417.9+/-83.8 vs 997.4+/-151.8 mL, P<0.001), blood transfused (a median of 0 vs 1 unit, P<0.001) and operative time taken (125 vs 245 minutes, P<0.001) were significantly lower in the fast track group. The frequency of pancreatic fistula (4.9% vs 13.0%) and delayed gastric emptying (7.0% vs 17.4%) was also significantly reduced with fast track treatment. Nevertheless, the readmission rate (11.3% vs 6.5%) was found relatively higher within the fast track group. However, increased readmission rates in this study seem to be independent of fast track protocol. CONCLUSIONS: This preliminary analysis suggests that the fast track approach might be beneficial to the well-being of the patients after PD, for it accelerates the immediate clinical recovery of patients and significantly shortens their length of hospital stay.

Pancreaticoduodenectomy: A study from India on the impact of evolution from a low to a high volume unit.

AIM: To analyse the impact of turning of our department from a low to a high volume provider of pancreaticoduodenectomy (PD) on surgical outcome. METHODS: A retrospective collection of data was done for patients who underwent PD. According to the number of PDs undertaken per year, we categorized the volume into low volume (< 10 PDs/year), medium volume (10-24 PDs/year) and high volume (> 25 PDs/year) groups. RESULTS: From 2002 to 2013, 200 patients underwent PD. The annual number of PD increased from 4 in 2002 to 34 in 2013. The mean operative time, operative blood loss and need for intraoperative blood transfusion decreased considerably over the volume categories (P < 0.001, P < 0.001 and P < 0.001, respectively). Increased procedural volume was associated with a lower morbidity (P = 0.021) and shorter length of hospital stay (P < 0.001). Similarly the rate of mortality dropped from 10% for the low volume group to 2.2% for the medium volume group and 0.0% for the high volume group (P = 0.007). CONCLUSION: The transformation from a low volume to a high volume provider of PD resulted in most favourable outcomes favouring the continued centralization of this high risk procedure.

Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study.

BACKGROUND: Although epidemiological studies have reported positive associations between circulating urate levels and cardiometabolic diseases, causality remains uncertain. OBJECTIVES: Through a Mendelian randomization approach, we assessed whether serum urate levels are causally relevant in type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), ischemic stroke, and heart failure (HF). METHODS: This study investigated 28 single nucleotide polymorphisms known to regulate serum urate levels in association with various vascular and nonvascular risk factors to assess pleiotropy. To limit genetic confounding, 14 single nucleotide polymorphisms exclusively associated with serum urate levels were used in a genetic risk score to assess associations with the following cardiometabolic diseases (cases/controls): T2DM (26,488/83,964), CHD (54,501/68,275), ischemic stroke (14,779/67,312), and HF (4,526/18,400). As a positive control, this study also investigated our genetic instrument in 3,151 gout cases and 68,350 controls. RESULTS: Serum urate levels, increased by 1 SD due to the genetic score, were not associated with T2DM, CHD, ischemic stroke, or HF. These results were in contrast with previous prospective studies that did observe increased risks of these 4 cardiometabolic diseases for an equivalent increase in circulating urate levels. However, a 1 SD increase in serum urate levels due to the genetic score was associated with increased risk of gout (odds ratio: 5.84; 95% confidence interval: 4.56 to 7.49), which was directionally consistent with previous observations. CONCLUSIONS: Evidence from this study does not support a causal role of circulating serum urate levels in T2DM, CHD, ischemic stroke, or HF. Decreasing serum urate levels may not translate into risk reductions for cardiometabolic conditions.

Omental flaps reduces complications after pancreaticoduodenectomy.

BACKGROUND: Major complications after pancreaticoduodenectomy are usually caused by a leaking pancreaticojejunal anastomosis. Omental flaps around various anastomoses were used to prevent the formation of fistula. METHODS: We reviewed 147 patients who had undergone pancreaticoduodenectomy between March 2006 and March 2012. The patients were divided into 2 groups according to the application of omental flaps around various anastomoses: group A (101 patients) who underwent omental wrapping procedure; group B (46 patients) who did not undergo the omental wrapping procedure. Perioperative data of the two groups were reviewed to assess the effectiveness of omental flap procedure in the prevention of pancreatic fistula and other complications. RESULTS: No differences were observed in the clinical characteristics between the 2 groups. The incidences of pancreatic fistula (4.0% vs 17.4%), post-pancreatectomy hemorrhage (0 vs 6.5%), biliary fistula (1.0% vs 13.0%), and delayed gastric emptying (4.0% vs 17.4%) were significantly less frequent in group A. The overall morbidity (18.8% vs 47.8%) and hospital stay (8.3 vs 9.6 days) were also significantly lower in group A than in group B. CONCLUSIONS: Omental flaps around various anastomoses after pancreaticoduodenectomy can reduce the incidences of pancreatic fistula, biliary fistula, post-pancreatectomy hemorrhage and delayed gastric emptying. This procedure is simple and effective to reduce the overall morbidity after pancreaticoduodenectomy.

The impact of early flow and brain oxygen crisis on the outcome of patients with severe traumatic brain injury.

BACKGROUND: Multimodality monitoring and goal-directed therapy may not prevent blood flow and brain oxygen (Flow/BrOx) crisis. We sought to determine the impact of these events on outcome in patients with severe traumatic brain injury (sTBI). METHODS: Twenty-four patients with sTBI were treated to maintain intracranial pressure (ICP) less than or equal to 20 mm Hg, cerebral perfusion pressure (CPP) greater than or equal to 60 mm Hg, brain oxygen greater than or equal to 20 mm Hg, and near infrared spectroscopy greater than or equal to 60%. Flow/BrOx crisis events were recorded. The 14-day predicted mortality was compared with actual mortality. RESULTS: Nonsurvivors had a significantly higher number of crisis events nonresponsive to treatment (P < .05). Mortality was 87.5% in patients with greater than or equal to 20 events versus 6.3% in patients with less than 20 events. The predicted mortality was 58%, whereas actual mortality was 33.3% (8/24), yielding a 42% reduction in mortality. CONCLUSIONS: A multimodality monitoring and goal-directed therapy may decrease mortality in sTBI. However, Flow/BrOx crisis events still occur and predict a poor outcome.