Exploring the mechanism of andrographolide in the treatment of gastric cancer through network pharmacology and molecular docking.

Gastric cancer has emerged as a key challenge in oncology research as a malignant tumour with advanced stage detection. Apart from surgical management, a pharmacotherapeutic approach to stomach cancer treatment is an appealing option to consider. Andrographolide has been shown to have anticancer and chemosensitizer properties in a variety of solid tumors, including stomach cancer but the exact molecular mechanism is skeptical. In this study, we identified and validated pharmacological mechanism involved in the treatment of GC with integrated approach of network pharmacology and molecular docking. The targets of andrographolide and GC were obtained from databases. The intersected targets between andrographolide and GC-related genes were used to construct protein-protein interaction (PPI) network. Furthermore, mechanism of action of the targets was predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Finally, these results were validated by molecular docking experiments, mRNA and protein expression level. A total of 197 targets were obtained for andrographolide treating GC. Functional enrichment analysis revealed that the target genes were exerted promising therapeutic effects on GC by HIF-1 and PI3K-Akt signaling pathway. The possible mechanism of action is by inactivation of HIF-1 signaling pathway which is dependent on the inhibition of upstream PI3K-AKT pathway. The PPI network identified SRC, AKT1, TP53, STAT3, PIK3CA, MAPK1, MAPK3, VEGFA, JUN and HSP90AA1 as potential hub targets. In addition, these results were further validated with molecular docking experiments. Survival analysis indicated that the expression levels of the hub genes were significantly associated with the clinical prognosis of GC. This study provided a novel approach to reveal the therapeutic mechanisms of andrographolide on GC, making future clinical application of andrographolide in the treatment of GC.

Reciprocal interplay between asporin and decorin: Implications in gastric cancer prognosis.

Effective patient prognosis necessitates identification of novel tumor promoting drivers of gastric cancer (GC) which contribute to worsened conditions by analysing TCGA-gastric adenocarcinoma dataset. Small leucine-rich proteoglycans, asporin (ASPN) and decorin (DCN), play overlapping roles in development and diseases; however, the mechanisms underlying their interplay remain elusive. Here, we investigated the complex interplay of asporin, decorin and their interaction with TGFß in GC tumor and corresponding normal tissues. The mRNA levels, protein expressions and cellular localizations of ASPN and DCN were analyzed using real-time PCR, western blot and immunohistochemistry, respectively. The protein-protein interaction was predicted by in-silico interaction analysis and validated by co-immunoprecipitation assay. The correlations between ASPN and EMT proteins, VEGF and collagen were achieved using western blot analysis. A significant increase in expression of ASPN in tumor tissue vs. normal tissue was observed in both TCGA and our patient cohort. DCN, an effective inhibitor of the TGFß pathway, was negatively correlated with stages of GC. Co-immunoprecipitation demonstrated that DCN binds with TGFß, in normal gastric epithelium, whereas in GC, ASPN preferentially binds TGFß. Possible activation of the canonical TGFß pathway by phosphorylation of SMAD2 in tumor tissues suggests its role as an intracellular tumor promoter. Furthermore, tissues expressing ASPN showed unregulated EMT signalling. Our study uncovers ASPN as a GC-promoting gene and DCN as tumor suppressor, suggesting that ASPN can act as a prognostic marker in GC. For the first time, we describe the physical interaction of TGFß with ASPN in GC and DCN with TGFß in GC and normal gastric epithelium respectively. This study suggests that prevention of ASPN-TGFß interaction or overexpression of DCN could serve as promising therapeutic strategies for GC patients.

Role of Preoperative Ureteric Stenting in Optimization of Patients with Retroperitoneal Tumors Associated with Obstructive Uropathy.

Retroperitoneal tumors can cause ureteric obstruction leading to obstructive uropathy. Early preoperative ureteric stenting helps to improve renal function and also helps in identifying ureters and prevent ureteric injury during surgery. This study was aimed at assessing the outcome of preoperative stenting in optimizing such patients. A total of 24 cases were enrolled. Of these, 15 patients who had obstructive uropathy were taken for ureteric stenting preoperatively and other 9 patients have undergone surgery without stenting. Twelve patients were stented successfully but 3 patients could not be stented (underwent percutaneous nephrostomy). All 24 patients underwent laparotomy, and of the 12 stented patients, 11 underwent successful resection and one had unresectable tumor. The patient's serum creatinine was assessed initially and then twice after stenting (48 h and 5 days). Serum creatinine was also estimated 24 h after excision of the tumor. In the successfully stented and operated patients, mean initial creatinine was 7.85. The mean creatinine at 48 h and 5 days after stenting was 4.29 and 1.19 respectively. The mean creatinine 24 h after resection of the tumor was 1.04. Of the non-stented patients, 3 had ureteric injury during surgery. We conclude that preoperative ureteric stenting is helpful for optimization of patients with retroperitoneal tumors with obstructive uropathy.

Comparison of emergency department trauma triage performance of clinicians and clinical prediction models: a cohort study in India.

OBJECTIVE: The aim of this study was to evaluate and compare the abilities of clinicians and clinical prediction models to accurately triage emergency department (ED) trauma patients. We compared the decisions made by clinicians with the Revised Trauma Score (RTS), the Glasgow Coma Scale, Age and Systolic Blood Pressure (GAP) score, the Kampala Trauma Score (KTS) and the Gerdin et al model. DESIGN: Prospective cohort study. SETTING: Three hospitals in urban India. PARTICIPANTS: In total, 7697 adult patients who presented to participating hospitals with a history of trauma were approached for enrolment. The final study sample included 5155 patients. The majority (4023, 78.0%) were male. MAIN OUTCOME MEASURE: The patient outcome was mortality within 30 days of arrival at the participating hospital. A grid search was used to identify model cut-off values. Clinicians and categorised models were evaluated and compared using the area under the receiver operating characteristics curve (AUROCC) and net reclassification improvement in non-survivors (NRI+) and survivors (NRI-) separately. RESULTS: The differences in AUROCC between each categorised model and the clinicians were 0.016 (95% CI -0.014 to 0.045) for RTS, 0.019 (95% CI -0.007 to 0.058) for GAP, 0.054 (95% CI 0.033 to 0.077) for KTS and -0.007 (95% CI -0.035 to 0.03) for Gerdin et al. The NRI+ for each model were -0.235 (-0.37 to -0.116), 0.17 (-0.042 to 0.405), 0.55 (0.47 to 0.65) and 0.22 (0.11 to 0.717), respectively. The NRI- were 0.385 (0.348 to 0.4), -0.059 (-0.476 to -0.005), -0.162 (-0.18 to -0.146) and 0.039 (-0.229 to 0.06), respectively. CONCLUSION: The findings of this study suggest that there are no substantial differences in discrimination and net reclassification improvement between clinicians and all four clinical prediction models when using 30-day mortality as the outcome of ED trauma triage in adult patients. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02838459).

Prevalence of a definitive airway in patients with severe traumatic brain injury received at four urban public university hospitals in India: a cohort study.

AIM: To estimate the proportion of patients arriving with a Glasgow Coma Scale (GCS) less than 9 who had a definitive airway placed prior to arrival. METHODS: We conducted a retrospective analysis of the data from a multicentre, prospective observational research project entitled Towards Improved Trauma Care Outcomes in India. Adults aged ≥18 years with an isolated traumatic brain injury (TBI) who were transferred from another hospital to the emergency department of the participating hospital with a GCS less than 9 were included. Our outcome was a definitive airway, defined as either intubation or surgical airway, placed prior to arrival at a participating centre. RESULTS: The total number of patients eligible for this study was 1499. The median age was 40 years and 84% were male. Road traffic injuries and falls comprised 88% of the causes of isolated TBI. The number of patients with GCS<9 who had a definitive airway placed before reaching the participating centres was 229. Thus, the proportion was 0.15 (95% CI 0.13 to 0.17). The proportions of patients with a definitive airway who arrived after 24 hours (19%) were approximately double the proportion of patients who arrived within 6 hours (10%) after injury to the definitive care centre. CONCLUSION: The rates of definitive airway placement are poor in adults with an isolated TBI who have been transferred from another health facility to tertiary care centres in India.

Association of Interleukin-1 beta and tumor necrosis factor-alpha genetic polymorphisms with gastric cancer in India.

Interleukin 1 beta (IL-1ß) and Tumor necrosis factor alpha (TNF-α) are key inflammatory cytokines whose polymorphisms have been correlated with increased susceptibility to gastric cancer (GC). Since geographical and racial differences exist in cancer rates, our study was aimed to evaluate the first possible association of polymorphisms in these genes with GC risk in West Bengal, India. Polymorphisms in IL-1ß and TNF-α genes were genotyped in 120 GC patients and 135 healthy individuals. Combined effect of the SNPs in both genes with GC risk was determined through allele dosage analysis (ADA) and the survival data were analyzed by Log Rank Test. The study results revealed that IL-1ß rs1143627: T > C, rs16944: C > T (p = 0.001;OR = 1.85; 95% CI 1.30-2.63) and rs1143633: G > A (p < 0.0001; OR = 2.53; 95% CI 1.67-3.83) and TNF-α rs1800630: C > A, rs1799964: T > C (p < 0.0001; OR = 2.31; 95% CI 1.54-3.46) polymorphisms significantly contributed toward GC risk. Moreover, ADA showed that carriage of 7 "effective" risk alleles conferred a risk of almost 10-fold in comparison to individuals carrying less than 3 "effective" risk alleles. Our survival analysis also indicated a significant association between IL-1ß rs1143627: T > C and rs16944: C > T and patient survivability. The presence of H. pylori enhanced the risk in individuals with IL-1ß rs1143627:CC and rs16944:TT genotypes. Further, meta-analysis revealed significant association of IL-1ß rs1143627: T > C (p = 0.026; OR = 4.165; 95% CI 1.18-14.65) and rs16944: C > T (p = 0.01; OR = 5.49; 95% CI 1.48-20.37) in presence of H. pylori with gastric cancer in Asian population though no significant difference (p > 0.05) was found when compared to absence of H. pylori Environ. Mol. Mutagen. 59:653-667, 2018. © 2018 Wiley Periodicals, Inc.

Assessment of the predictive value of the International Classification of Diseases Injury Severity Score for trauma mortality in urban India.

BACKGROUND: Trauma is the cause of 1.2 million deaths in India annually. Injury severity scores play an important role in trauma research and care because these scores enable the adjustment of trauma severity when comparing mortality outcomes. The generalizability of the International Classification of Diseases Injury Severity Score (ICISS) between different populations is not fully known, and the validity of the ICISS has not been assessed in the Indian context. The aim of this study was to assess the predictive performances of three international versions of the ICISS, derived from data from Australia, New Zealand and pooled data from seven different high-income countries, in trauma patients admitted to four public hospitals in urban India. MATERIAL AND METHODS: We used patient data from an Indian cohort of 16,047 trauma patients. The patients were assigned an ICISS based on International Classification of Diseases codes using survival risk ratios from publicly available data sets from Australia and New Zealand and with pooled data from seven different high-income countries. Predicted mortality based on the ICISS was compared with observed patient mortality, and the predictive performance was assessed in terms of discrimination and calibration. RESULTS: Discrimination and calibration did not reach the threshold for predictive performance in any of the ICISS versions used. The threshold value used was 0.8 for discrimination, which was not significantly different from one for the calibration slope and not significantly different from zero for the calibration intercept. CONCLUSIONS: None of the international versions of the ICISS adequately predicted mortality within the study population, indicating the need for an ICISS version specifically adapted to the Indian context.

Polymorphisms in ADH1B and ALDH2 genes associated with the increased risk of gastric cancer in West Bengal, India.

BACKGROUND: Gastric cancer (GC) is one of the most frequently diagnosed digestive tract cancers and carries a high risk of mortality. Acetaldehyde (AA), a carcinogenic intermediate of ethanol metabolism contributes to the risk of GC. The accumulation of AA largely depends on the activity of the major metabolic enzymes, alcohol dehydrogenase and aldehyde dehydrogenase encoded by the ADH (ADH1 gene cluster: ADH1A, ADH1B and ADH1C) and ALDH2 genes, respectively. This study aimed to evaluate the association between genetic variants in these genes and GC risk in West Bengal, India. METHODS: We enrolled 105 GC patients (cases), and their corresponding sex, age and ethnicity was matched to 108 normal individuals (controls). Genotyping for ADH1A (rs1230025), ADH1B (rs3811802, rs1229982, rs1229984, rs6413413, rs4147536, rs2066702 and rs17033), ADH1C (rs698) and ALDH2 (rs886205, rs968529, rs16941667 and rs671) was performed using DNA sequencing and RFLP. RESULTS: Genotype and allele frequency analysis of these SNPs revealed that G allele of rs17033 is a risk allele (A vs G: OR = 3.67, 95% CI = 1.54-8.75, p = 0.002) for GC. Significant association was also observed between rs671 and incidence of GC (p = 0.003). Moreover, smokers having the Lys allele of rs671 had a 7-fold increased risk of acquiring the disease (OR = 7.58, 95% CI = 1.34-42.78, p = 0.009). CONCLUSION: In conclusion, rs17033 of ADH1B and rs671 of ALDH2 SNPs were associated with GC risk and smoking habit may further modify the effect of rs671. Conversely, rs4147536 of ADH1B might have a protective role in our study population. Additional studies with a larger patient population are needed to confirm our results.

Port-site infections by nontuberculous mycobacterium: A retrospective clinico-microbiological study.

BACKGROUND: Port-site infection (PSI) is a prevailing, chronic, nagging, treatment refractory complication of laparoscopic surgery (LS). It neutralizes the advantages of minimally invasive surgery and increases morbidity, treatment cost of patient, leading to loss of confidence on operating surgeon. PSIs are preventable with appropriate preoperative, intraoperative, and postoperative measures. Atypical mycobacterium is most commonly associated with nonhealing postlaparoscopic wound infections, causing outbreaks or sporadic cases worldwide. PURPOSE: We retrospectively studied the occurrence of nontuberculous mycobacterium (NTM) from PSIs following LS that did not respond to antibiotics used for pyogenic infections and having sterile routine aerobic cultures and their antimicrobial susceptibility pattern to guide proper management. METHODS: The study was done in a tertiary care hospital of Eastern India over a 1-year period which included PSI cases with delayed onset not responding to antibiotics, following different types of LS. Pus/discharge from 32 patients was collected and examined for isolation and identification of the causative agents. Gram stain and Ziehl-Neelsen staining methods were used for direct examination. Culture media included blood agar, Robertson's cooked meat broth, MacConkey agar, and Lowenstein-Jensen medium. Isolates from the cases were identified using biochemical tests or molecular methods and studied the antimicrobial susceptibility pattern by the standard microbiologic procedures. RESULTS: Mycobacterium abscessus (13) and Mycobacterium fortuitum (2) were isolated from 15 serosanguinous drainage obtained from 32 cases by routine microbiological techniques. All isolates analyzed for antimicrobial susceptibility pattern were highly sensitive to clarithromycin (93.3%), amikacin (93.3%), and imipenem (80%) but were variable to ciprofloxacin, ofloxacin, and linezolid. CONCLUSIONS: Our present study shows frequent association of NTM with laparoscopic port-site nonhealing chronic infection or wound dehiscence. Although direct microscopy can give us a clue to diagnosis, culture isolation is required for speciation and antimicrobial susceptibility testing, which helps formulate therapeutic regimen.

Association of DNA repair and xenobiotic pathway gene polymorphisms with genetic susceptibility to gastric cancer patients in West Bengal, India.

Gastric cancer is one of the most common malignancies in India. DNA repair gene or xenobiotic pathway gene polymorphisms have recently been shown to affect individual susceptibility to gastric cancer. Here, the possible interaction between common polymorphisms in X-ray repair cross complementing group I (XRCC1) gene and glutathione S-transferase (GST) genes (GSTM1, GSTT1 and GSTP1), smoking and alcohol consumption and overall survival in gastric cancer patients were evaluated. In this population-based case control study, 70 gastric cancer patients and 82 healthy controls were enrolled. The epidemiological data were collected by a standard questionnaire, and blood samples were collected from each individual. XRCC1 Arg194Trp, Arg280His and Arg399Gln polymorphisms were determined by polymerase chain reaction and direct DNA sequencing. GSTM1 and GSTT1 null polymorphisms and GSTP1 Ile105Val polymorphism were identified by multiplex polymerase chain reaction and restriction fragment length polymorphism (RFLP), respectively. The risk of gastric cancer was significantly elevated in individuals with XRCC1 Arg/Gln +Gln/Gln (p = 0.031; odds ratio = 2.32; 95 % confidence interval (CI) 1.07-5.06) and GSTP1 Val/Val genotype (p = 0.009; odds ratio = 8.64; 95 % CI 1.84-40.55). An elevated risk for GC was observed in smokers and alcohol consumers carrying GSTP1 Ile/Val +Val/Val genotype (p = 0.041; odds ratio = 3.71; 95 % CI 0.98-14.12; p = 0.002; odds ratio = 12.31; 95 % CI 1.71-88.59). These findings suggest that XRCC1 rs25487 and GSTP1 rs1695 can be considered as a risk factor associated with gastric cancer and might be used as a molecular marker for evaluating the susceptibility of the disease.

Traumatic transfers: calibration is adversely affected when prediction models are transferred between trauma care contexts in India and the United States.

OBJECTIVE: We evaluated the transferability of prediction models between trauma care contexts in India and the United States and explored updating methods to adjust such models for new contexts. STUDY DESIGN AND SETTINGS: Using a combination of prospective cohort and registry data from 3,728 patients of Towards Improved Trauma Care Outcomes in India (TITCO) and from 18,756 patients of the US National Trauma Data Bank (NTDB), we derived models in one context and validated them in the other, assessing them for discrimination and calibration using systolic blood pressure, heart rate, and Glasgow coma scale as candidate predictors. RESULTS: Early mortality was 8% in the TITCO and 1-2% in the NTDB samples. Both models discriminated well, but the TITCO model overestimated the risk of mortality in NTDB patients, and the NTDB model underestimated the risk in TITCO patients. CONCLUSION: Transferability was good in terms of discrimination but poor in terms of calibration. It was possible to improve this miscalibration by updating the models' intercept. This updating method could be used in samples with as few as 25 events.

A randomized controlled pilot study to compare capecitabine-oxaliplatin with 5-FU-leucovorin as neoadjuvant concurrent chemoradiation in locally advanced adenocarcinoma of rectum.

CONTEXT: Established as an adjuvant chemotherapy, CapeOX has recently been shown to have radiosensitizer property in a phase I and II studies, with appreciable downstaging and tolerable toxicities. AIMS: The study was designed to evaluate whether the capecitabine-oxaliplatin combination was superior to 5-fluorouracil (5-FU)-leucovorin as radiosensitizer for neoadjuvant chemoradiation in downstaging locally advanced rectal adenocarcinoma and to compare the toxicities between the two arms. SETTINGS AND DESIGN: Single institutional, double blinded, prospective, noncrossover, randomized control pilot study. SUBJECTS AND METHODS: In arm A (n = 21), patients received capecitabine (1,000 mg/m(2) daily) in twice dailydoseon days 1-14 and 25-38 and oxaliplatin (85 mg/m(2)) intravenous ( IV) over 2 h, on D1 and D29. In arm B (n = 21), patients received leucovorin (20 mg/m(2)) and 5-FU (350 mg/m(2)) from D1-5 and D29-33. Patient in both the arms received concurrent radiation (50.4 Gy in 28 #, in conventional fractionation of 1.8 Gy per fraction). Six to eight weeks after concurrent chemoradiation, patients underwent assessment and surgery with total mesorectal resection. Postoperatively, adjuvant chemotherapy with m-FOLFOX 6 of 4 months was given to all patients. STATISTICAL ANALYSIS USED: Chi-square test was used to compare categorical variables between the groups. RESULTS: Objective response rate (ORR) in arm A was 80.95% compared to arm B which had 66.66% (P = 0.3055). Pathological complete response (pCR) rate of arm A was comparable to arm B (23.8 vs 14.28%, P value = 0.6944). Surgery with R0 resection was possible in 80.95% cases of arm A compared to 66.66% cases of arm B (P = 0.4827). Grade III toxicities were quite comparable between two treatment arms. CONCLUSIONS: In terms of ORR, pCR rate, R0 resection, and toxicity profile; both the arms were comparable.

Predicting early mortality in adult trauma patients admitted to three public university hospitals in urban India: a prospective multicentre cohort study.

BACKGROUND: In India alone, more than one million people die yearly due to trauma. Identification of patients at risk of early mortality is crucial to guide clinical management and explain prognosis. Prediction models can support clinical judgement, but existing models have methodological limitations. The aim of this study was to derive a vital sign based prediction model for early mortality among adult trauma patients admitted to three public university hospitals in urban India. METHODS: We conducted a prospective cohort study of adult trauma patients admitted to three urban university hospitals in India between October 2013 and January 2014. The outcome measure was mortality within 24 hours. We used logistic regression with restricted cubic splines to derive our model. We assessed model performance in terms of discrimination, calibration, and optimism. RESULTS: A total of 1629 patients were included. Median age was 35, 80% were males. Mortality between admission and 24 hours was 6%. Our final model included systolic blood pressure, heart rate, and Glasgow coma scale. Our model displayed good discrimination, with an area under the receiver operating characteristics curve (AUROCC) of 0.85. Predicted mortality corresponded well with observed mortality, indicating good calibration. CONCLUSION: This study showed that routinely recorded systolic blood pressure, heart rate, and Glasgow coma scale predicted early hospital mortality in trauma patients admitted to three public university hospitals in urban India. Our model needs to be externally validated before it can be applied in the clinical setting.

Alveolar soft part sarcoma: a rare diagnosis.

Alveolar soft-part sarcoma (ASPS) is an extremely rare disease arising from connective tissues with a propensity for recurrence and metastasis. Clinically, it can be confused with hemangioma or arterio-venous malformations. Thus, a high index of suspicion and histopathological examination are required to make a definitive diagnosis. We report a case of recurrent ASPS in a young female with multiple sites involvement without any features of metastasis who has been treated with excision of the symptomatic lesions followed by chemotherapy.

Gossypiboma and surgeon- current medicolegal aspect - a review.

Gossypiboma or textiloma is referred to as a surgical gauze or towel inadvertently retained inside the body following surgery. It is an infrequent but avoidable surgical complication, which must be kept in mind in any postoperative patient who presents with pain, infection, or palpable mass. Gossypiboma, in the doctrine of res ipsa loquitur, proves that the surgeon is negligent. Moreover, it has medicolegal consequences including mental agony, humiliation, huge monetary compensation and imprisonment on the part of the surgeon and increased morbidity, mortality and financial loss on the part of the patient. Here we report two cases of gossypiboma and review its current medicolegal aspect in relation to the surgeon.