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Crude oil is a vital energy source for industrialised and developing countries. Both investors who trade crude oil derivatives and firms that use oil as raw material for production monitor oil supply and demand. Disruption in the flow of oil in the commodity markets, therefore, leads to oil price volatility that affects major economies worldwide. Often, geopolitical and natural conditions could adversely impact the oil price and the financial markets react to such fluctuations in oil prices. This paper analyses the effects of oil price changes on sectorial stock returns in India. Using daily returns of S&P BSE Sensex, S&P BSE Oil & Gas and S&P BSE-Auto sectoral indices from January 2000 to March 2020, we examined the impact of Brent crude oil price fluctuations on the two major sectorial stock indices and overall market index. The results of the Granger causality test show significant results on S&P BSE-Sensex and S&P BSE-Oil and Gas Index Returns except S&P BSE-Auto Index Returns. Further for contemporaneous association between the oil price changes and sectorial returns, we operationalised the simple regression analysis. The results from the regression analysis show statistically significant impact of crude oil price fluctuations on the sectorial returns. [ABSTRACT FROM AUTHOR]

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial. CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort. [ABSTRACT FROM AUTHOR]

CAMILLA is a basket trial (NCT03539822) evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Herein, are the phase II colorectal cohort results. 29 patients were evaluable. 100% had confirmed pMMR/MSS tumors. Primary endpoint was met with ORR of 27.6% (95% CI 12.7-47.2%). Secondary endpoints of 4-month PFS rate was 44.83% (95% CI 26.5-64.3%); and median OS was 9.1 months (95% CI 5.8-20.2). Grade≥3 TRAE occurred in 39%. In post-hoc analysis of patients with RAS wild type tumors, ORR was 50% and median PFS and OS were 6.3 and 21.5 months respectively. Exploratory spatial transcriptomic profiling of pretreatment tumors showed upregulation of VEGF and MET signaling, increased extracellular matrix activity and preexisting anti-tumor immune responses coexisting with immune suppressive features like T cell migration barriers in responders versus non-responders. Cabozantinib plus durvalumab demonstrated anti-tumor activity, manageable toxicity, and have led to the activation of the phase III STELLAR-303 trial. CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort. [ABSTRACT FROM AUTHOR]

High grade serous ovarian carcinoma (HGSOC) accounts for ~ 70% of ovarian cancer cases. Non-invasive, highly specific blood-based tests for pre-symptomatic screening in women are crucial to reducing the mortality associated with this disease. Since most HGSOCs typically arise from the fallopian tubes (FT), our biomarker search focused on proteins found on the surface of extracellular vesicles (EVs) released by both FT and HGSOC tissue explants and representative cell lines. Using mass spectrometry, 985 EV proteins (exo-proteins) were identified that comprised the FT/HGSOC EV core proteome. Transmembrane exo-proteins were prioritized because these could serve as antigens for capture and/or detection. With a nano-engineered microfluidic platform, six newly discovered exo-proteins (ACSL4, IGSF8, ITGA2, ITGA5, ITGB3, MYOF) plus a known HGSOC associated protein, FOLR1 exhibited classification performance ranging from 85 to 98% in a case–control study using plasma samples representative of early (including stage IA/B) and late stage (stage III) HGSOCs. Furthermore, by a linear combination of IGSF8 and ITGA5 based on logistic regression analysis, we achieved a sensitivity of 80% with 99.8% specificity and a positive predictive value of 13.8%. Importantly, these exo-proteins also can accurately discriminate between ovarian and 12 types of cancers commonly diagnosed in women. Our studies demonstrate that these lineage-associated exo-biomarkers can detect ovarian cancer with high specificity and sensitivity early and potentially while localized to the FT when patient outcomes are more favorable. [ABSTRACT FROM AUTHOR]

Simple Summary: Ewing sarcoma (EWS) is a rare pediatric sarcoma affecting children and adolescents, with median diagnosis around the age of 15. Despite an intensive therapeutic regimen, including chemotherapy, surgery/radiation patients with recurrent (10–15%) and metastatic disease (<30%) have poor overall survival rates. Moreover, standard chemotherapy is intense and is often associated with systemic toxicity and secondary malignancies. Hence, it is critical to find new treatments to improve outcomes in EWS patients. We identified a combination of mitotic inhibitors targeting KIF11 (SB-743921) and AURKA (VIC-1911) that are effective in inhibiting EWS tumor growth at physiologically relevant nanomolar doses. This drug combination inhibited EWS cell viability in vitro by promoting cell cycle arrest followed by cell death. In vivo, this treatment regimen led to significantly delayed tumor growth and improved overall survival in xenograft EWS mouse models. Overall, these preclinical data provide encouragement to consider a future clinical trial for patients with this deadly disease. Ewing sarcoma (EWS) is an aggressive pediatric malignancy of the bone and soft tissues in need of novel therapeutic options. To identify potential therapeutic targets, we focused on essential biological pathways that are upregulated by EWS-FLI1, the primary oncogenic driver of EWS, including mitotic proteins such as Aurora kinase A (AURKA) and kinesin family member 15 (KIF15) and its binding partner, targeting protein for Xklp2 (TPX2). KIF15/TPX2 cooperates with KIF11, a key mitotic kinesin essential for mitotic spindle orientation. Given the lack of clinical-grade KIF15/TPX2 inhibitors, we chose to target KIF11 (using SB-743921) in combination with AURKA (using VIC-1911) given that phosphorylation of KIF15S1169 by Aurora A is required for its targeting to the spindle. In vitro, the drug combination demonstrated strong synergy (Bliss score ≥ 10) at nanomolar doses. Colony formation assay revealed significant reduction in plating efficiency (1–3%) and increased percentage accumulation of cells in the G2/M phase with the combination treatment (45–52%) upon cell cycle analysis, indicating mitotic arrest. In vivo studies in EWS xenograft mouse models showed significant tumor reduction and overall effectiveness: drug combination vs. vehicle control (p ≤ 0.01), SB-743921 (p ≤ 0.01) and VIC-1911 (p ≤ 0.05). Kaplan–Meier curves demonstrated superior overall survival with the combination compared to vehicle or monotherapy arms (p ≤ 0.0001). [ABSTRACT FROM AUTHOR]

Transcranial alternating current stimulation (tACS) may modulate neuronal oscillations by applying sinusoidal alternating current, thereby alleviating associated symptoms in schizophrenia. Considering its possible utility in schizophrenia, we reviewed the literature for tACS protocols administered in schizophrenia and their findings. A scoping review was conducted following the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline in databases and clinical trial registers. The search resulted in 59 publications. After excluding review articles unrelated to tACS, trials without published results or not involving patients with schizophrenia, 14 studies were included. Among the included studies/case reports only 5 were randomized controlled therapeutic trials. The studies investigated the utility of tACS for clinical and neurobiological outcomes. All studies reported good tolerability with only transient mild side effects. It was administered mostly during the working memory task (such as computerized n-back task, dual back task, and computerized digit symbol substitution task) for schizophrenia patients with cognitive deficits and during resting state while targeting positive symptoms. A possible reduction in hallucinations and delusions using alpha tACS, and improvement in negative and cognitive deficits with theta and gamma tACS were reported. Nevertheless, one of the randomized controlled trials targeting hallucinations was negative and rigorous large-sample studies are lacking for other domains. The current evidence for tACS in schizophrenia is preliminary though promising. In future, more sham controlled randomized trials assessing the effect of tACS on various domains are needed to substantiate these early findings. [ABSTRACT FROM AUTHOR]

There is a high clinical unmet need to improve outcomes for pancreatic ductal adenocarcinoma (PDAC) patients, either with the discovery of new therapies or biomarkers that can track response to treatment more efficiently than imaging. We report an innovative approach that will generate renewed interest in using circulating tumor cells (CTCs) to monitor treatment efficacy, which, in this case, used PDAC patients receiving an exploratory new therapy, poly ADP-ribose polymerase inhibitor (PARPi)—niraparib—as a case study. CTCs were enumerated from whole blood using a microfluidic approach that affinity captures epithelial and mesenchymal CTCs using anti-EpCAM and anti-FAPα monoclonal antibodies, respectively. These antibodies were poised on the surface of two separate microfluidic devices to discretely capture each subpopulation for interrogation. The isolated CTCs were enumerated using immunophenotyping to produce a numerical ratio consisting of the number of mesenchymal to epithelial CTCs (denoted "Φ"), which was used as an indicator of response to therapy, as determined using computed tomography (CT). A decreasing value of Φ during treatment was indicative of tumor response to the PARPi and was observed in 88% of the enrolled patients (n = 31). Changes in Φ during longitudinal testing were a better predictor of treatment response than the current standard CA19-9. We were able to differentiate between responders and non-responders using ΔΦ (p = 0.0093) with higher confidence than CA19-9 (p = 0.033). For CA19-9 non-producers, ΔΦ correctly predicted the outcome in 72% of the PDAC patients. Sequencing of the gDNA extracted from affinity-selected CTC subpopulations provided information that could be used for patient enrollment into the clinical trial based on their tumor mutational status in DNA repair genes. [ABSTRACT FROM AUTHOR]

The human fallopian tube epithelium (hFTE) is the site of fertilization, early embryo development, and the origin of most high-grade serous ovarian cancers (HGSOCs). Little is known about the content and functions of hFTE-derived small extracellular vesicles (sEVs) due to the limitations of biomaterials and proper culture methods. We have established a microfluidic platform to culture hFTE for EV collection with adequate yield for mass spectrometry-based proteomic profiling, and reported 295 common hFTE sEV proteins for the first time. These proteins are associated with exocytosis, neutrophil degranulation, and wound healing, and some are crucial for fertilization processes. In addition, by correlating sEV protein profiles with hFTE tissue transcripts characterized using GeoMx® Cancer Transcriptome Atlas, spatial transcriptomics analysis revealed cell-type-specific transcripts of hFTE that encode sEVs proteins, among which, FLNA, TUBB, JUP, and FLNC were differentially expressed in secretory cells, the precursor cells for HGSOC. Our study provides insights into the establishment of the baseline proteomic profile of sEVs derived from hFTE tissue, and its correlation with hFTE lineage-specific transcripts, which can be used to evaluate whether the fallopian tube shifts its sEV cargo during ovarian cancer carcinogenesis and the role of sEV proteins in fallopian tube reproductive functions. [ABSTRACT FROM AUTHOR]

Simple Summary: About 40% of people diagnosed with cancer are eligible for treatment with checkpoint inhibitors (CPIs). Little research has been conducted to understand whether CPIs affect cognitive function. Most research that has been conducted included patients who received both CPIs and chemotherapy. This pilot study was conducted with patients receiving CPIs as their first line of cancer treatment. This study's purpose was to show the feasibility of recruiting, retaining, and assessing older adult patients with cancer starting first line CPI treatment and provide early evidence of the impact of CPI on cognitive function. Approximately 40% of patients with cancer are eligible for check-point inhibitor (CPI) therapy. Little research has examined the potential cognitive impact of CPIs. First-line CPI therapy offers a unique research opportunity without chemotherapy-related confounders. The purpose of this prospective, observational pilot was to (1) demonstrate the feasibility of prospective recruitment, retention, and neurocognitive assessment for older adults receiving first-line CPI(s) and (2) provide preliminary evidence of changes in cognitive function associated with CPI(s). Patients receiving first-line CPI(s) (CPI Group) were assessed at baseline (n = 20) and 6 months (n = 13) for self-report of cognitive function and neurocognitive test performance. Results were compared to age-matched controls without cognitive impairment assessed annually by the Alzheimer's Disease Research Center (ADRC). Plasma biomarkers were measured at baseline and 6 months for the CPI Group. Estimated differences for CPI Group scores prior to initiating CPIs (baseline) trended to lower performance on the Montreal Cognitive Assessment-Blind (MOCA-Blind) test compared to the ADRC controls (p = 0.066). Controlling for age, the CPI Group's 6-months MOCA-Blind performance was lower than the ADRC control group's 12-months performance (p = 0.011). No significant differences in biomarkers were detected between baseline and 6 months, although significant correlations were noted for biomarker change and cognitive performance at 6 months. IFNγ, IL-1β, IL-2, FGF2, and VEGF were inversely associated with Craft Story Recall performance (p < 0.05), e.g., higher levels correlated with poorer memory performance. Higher IGF-1 and VEGF correlated with better letter-number sequencing and digit-span backwards performance, respectively. Unexpected inverse correlation was noted between IL-1α and Oral Trail-Making Test B completion time. CPI(s) may have a negative impact on some neurocognitive domains and warrant further investigation. A multi-site study design may be crucial to fully powering prospective investigation of the cognitive impact of CPIs. Establishment of a multi-site observational registry from collaborating cancer centers and ADRCs is recommended. [ABSTRACT FROM AUTHOR]

Objective: Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic EWS-ETS chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing. Importantly, small extracellular vesicles (sEVs), including those frequently referred to as exosomes have been shown to be highly enriched with tumor-derived small RNAs such as miRNAs. We hypothesized that ESFT-specific sEVs are enriched with certain miRNAs which could be utilized toward an exo-miRNA biomarker signature specific to this disease. Methods: We performed miRNAseq to compare both the exo-derived and cell-derived miRNA content from 8 ESFT, 2 osteosarcoma, 2 non-cancerous cell lines, and pediatric plasma samples. Results: We found that sEVs derived from ESFT cells contained nearly 2-fold more number of unique individual miRNAs as compared to non-ESFT samples. Quantitative analysis of the differential enrichment of sEV miRNAs resulted in the identification of 62 sEV-miRNAs (exo-miRNAs) with significant (P <.05) enrichment variation between ESFT and non-ESFT sEV samples. To determine if we could utilize this miRNA signature to diagnose ESFT patients via a liquid biopsy, we analyzed the RNA content of total circulating sEVs isolated from 500 µL plasma from 5 pediatric ESFT patients, 2 pediatric osteosarcoma patients, 2 pediatric rhabdomyosarcoma patients, and 4 non-cancer pediatric controls. Pearson's clustering of 60 of the 62 candidate exo-miRNAs correctly identified 80% (4 of 5) of pathology confirmed ESFT patients. Importantly, RNAseq analysis of tumor tissue from the 1 outlier, revealed a previously uncharacterized EWS-FLI1 translocation. Conclusions: Taken together, these findings support the development and validation of an exo-miRNA-based liquid biopsy to aid in the diagnosis and monitoring of ESFT. [ABSTRACT FROM AUTHOR]

Radiation-induced loss of the hematopoietic stem cell progenitor population compromises bone marrow regeneration and development of mature blood cells. Failure to rescue bone marrow functions results in fatal consequences from hematopoietic injury, systemic infections, and sepsis. So far, bone marrow transplant is the only effective option, which partially minimizes radiation-induced hematopoietic toxicities. However, a bone marrow transplant will require HLA matching, which will not be feasible in large casualty settings such as a nuclear accident or an act of terrorism. In this study we demonstrated that human peripheral blood mononuclear cell-derived myeloid committed progenitor cells can mitigate radiation-induced bone marrow toxicity and improve survival in mice. These cells can rescue the recipient's hematopoietic stem cells from radiation toxicity even when administered up to 24 h after radiation exposure and can be subjected to allogenic transplant without GVHD development. Transplanted cells deliver sEVs enriched with regenerative and immune-modulatory paracrine signals to mitigate radiation-induced hematopoietic toxicity. This provides a natural polypharmacy solution against a complex injury process. In summary, myeloid committed progenitor cells can be prepared from blood cells as an off-the-shelf alternative to invasive bone marrow harvesting and can be administered in an allogenic setting to mitigate hematopoietic acute radiation syndrome. [ABSTRACT FROM AUTHOR]

Background and Purpose: Emerging studies have shown that gut-derived endotoxins might play a role in intestinal and systemic inflammation. Although the significance of intestinal permeability in modulating the pathogenesis of Schizophrenia (SCZ) is recognized, not much data on the specific role of intestinal permeability biomarkers, viz., zonulin, lipopolysaccharide-binding protein (LBP), and intestinal alkaline phosphatase (IAP) in SCZ is available. Therefore, we measured the plasma levels of zonulin, LBP, and IAP and its correlation with neutrophil-to-lymphocyte ratio (NLR); a marker of systemic inflammation in patients with SCZ. Methods: We recruited 60 individuals, patients with SCZ (n = 40) and healthy controls (n = 20), from a large tertiary neuropsychiatry center. Plasma levels of zonulin, IAP, and LBP were quantified by enzyme-linked immunosorbent assay. Results: Plasma levels of both LBP and zonulin were significantly increased (P <0.05), whereas the IAP levels (P <0.05) were significantly decreased in patients with SCZ compared to healthy controls. Pearson correlation analysis revealed that zonulin and LBP had a significant positive correlation with NLR, and IAP negatively correlated with NLR. Individuals with SCZ had higher independent odds of zonulin [odds ratio (OR): 10.32, 95% CI: 1.85–57.12], LBP [OR: 1.039, 95% CI: 1.02–1.07], and IAP [OR: 0.643, 95% CI: 0.471–0.879], even after adjusting for potential confounders. Conclusion: Our study demonstrates an association of zonulin, LBP, and IAP in Asian Indian SCZ patients and correlates with NLR. Our results indicate that low-grade inflammation induced by metabolic endotoxemia might be implicated in the pathoetiology of SCZ. [ABSTRACT FROM AUTHOR]

In the light of the growing importance of Corporate Governance (CG) in academic and industrial research, the present paper aims to answer the question: Does corporate governance impact Firm Performance and Firm Risk? Multivariate regression analysis was conducted on three models to answer the question, with firm performance and firm risk being the dependent variables. Different CG mechanisms (Board Composition, Board Size, Frequency of Meetings and Audit Committee) were considered as independent variables. The results of the regression analysis postulate that board composition, frequency of meetings and audit committee significantly impact the firm performance i.e., Return on Assets (ROA) and Profit Margin (PM). Board composition was also found to have a significant impact on firm risk where we used Beta as a proxy measure. Overall, the objective of the study was met, as all the three models showcase significant results. The present study provides important insights into fair CG practice, with scope for future research. [ABSTRACT FROM AUTHOR]

Objective: Ewing Sarcoma Family of Tumors (ESFT) are a highly aggressive pediatric bone and soft tissue malignancy with poor outcomes in the refractory and recurrent setting. Over 90% of Ewing Sarcoma (ES) tumors are driven by the pathognomonic EWS-ETS chimeric transcripts and their corresponding oncoproteins. It has been suggested that the EWS-ETS oncogenic action can mediate microRNA (miRNA) processing. Importantly, small extracellular vesicles (sEVs), including those frequently referred to as exosomes have been shown to be highly enriched with tumor-derived small RNAs such as miRNAs. We hypothesized that ESFT-specific sEVs are enriched with certain miRNAs which could be utilized toward an exo-miRNA biomarker signature specific to this disease. Methods: We performed miRNAseq to compare both the exo-derived and cell-derived miRNA content from 8 ESFT, 2 osteosarcoma, 2 noncancerous cell lines, and pediatric plasma samples. Results: We found that sEVs derived from ESFT cells contained nearly 2-fold more number of unique individual miRNAs as compared to non-ESFT samples. Quantitative analysis of the differential enrichment of sEV miRNAs resulted in the identification of 62 sEV-miRNAs (exo-miRNAs) with significant (P < .05) enrichment variation between ESFT and non-ESFT sEV samples. To determine if we could utilize this miRNA signature to diagnose ESFT patients via a liquid biopsy, we analyzed the RNA content of total circulating sEVs isolated from 500 µL plasma from 5 pediatric ESFT patients, 2 pediatric osteosarcoma patients, 2 pediatric rhabdomyosarcoma patients, and 4 non-cancer pediatric controls. Pearson's clustering of 60 of the 62 candidate exo-miRNAs correctly identified 80% (4 of 5) of pathology confirmed ESFT patients. Importantly, RNAseq analysis of tumor tissue from the 1 outlier, revealed a previously uncharacterized EWS-FLI1 translocation. Conclusions: Taken together, these findings support the development and validation of an exo-miRNA-based liquid biopsy to aid in the diagnosis and monitoring of ESFT. [ABSTRACT FROM AUTHOR]

In light of the growing importance of mutual fund investment in academic and industrial research, the paper aims at answering a question of paramount importance, i.e. Does recategorization affect mutual fund investment? An unmatched sample t-test was conducted to compare the pre- and post-categorization among the large, mid, and small-cap firms based on three variables: liquidity, volatility, and returns. The results of the t-test postulate that the liquidity of large-cap firms and returns of the small-cap firms were significantly different for both periods of study. In contrast, all other variables remain indifferent across both periods. Overall, the study contributes to the literature and practice by providing meaningful pre- and post-categorization insights. The study provides important insights for mutual fund managers to understand the correct effect of re-categorization on market efficiency. The study provides transparency for future research in the field of mutual fund investment. [ABSTRACT FROM AUTHOR]

Economic empowerment and sustainable livelihood of small and marginal farmers have become a major challenge in India. The NSS survey report indicated that around 40% of farmers are willing to quit farming and seek other means of economic survival. The ease of agricultural credit for the financially weak farmers can significantly help them to sustain. This study aims to understand the relationship between the financial position of organic and conventional farmers and their accessibility to agricultural loans. The primary data from 400 farmers has been collected from organic and convention farmers. To address the objectives, a Binomial logistic regression model has been used to examine the impact of financial position in accessing agricultural credit. The study revealed that educated, large-scale, and financially sound farmers benefited more from financial institutions, whereas economically deprived small and marginal farmers were unable to access agricultural credit due to illiteracy, lack of awareness, and lengthy documentation. The study suggests that generalization of loan waived should be avoided. Further, the required documents for availing agricultural credit for the economically weak and uneducated small and marginal farmers need to be simplified that could minimize the non-institutional sources of loan. [ABSTRACT FROM AUTHOR]

Bimaxillary protrusion is one of the commonly seen skeletal deformity in Indian population. This skeletal condition is typically characterized by proclined and protruding anterior teeth with everted lips. If this condition is associated with macroglossia or any parafunctional habits like tongue thrusting or thumb sucking, an anterior open bite is often found. Minor discrepancies can be managed by orthodontic treatment alone by extracting all first premolars and retracting the anterior segment. But in severe skeletal cases, orthognathic surgery along with pre-and post-surgical orthodontics is the best option to get the ideal result. This article describes the case of a female patient with bimaxillary protrusion. The patient had a convex profile, anterior open bite, and incompetent lips. Chin had a relative deficiency with hyperactive mentalis muscle. On patients’ consent and willingness for a shorter course of the treatment period, surgery first approach was planned. Within seven months of the total treatment period, a remarkable change in facial profile and a pleasing anterior occlusion was achieved. [ABSTRACT FROM AUTHOR]

Both mesenchymal stem cells (MSCs) and their corresponding small extracellular vesicles (sEVs, commonly referred to as exosomes) share similar immunomodulatory properties that are potentially beneficial for the treatment of acute graft versus host disease (aGvHD). We report that clinical grade Wharton's Jelly‐derived MSCs (WJMSCs) secrete sEVs enriched in programmed death‐ligand 1 (PD‐L1), an essential ligand for an inhibitory immune checkpoint. A rapid increase in circulating sEV‐associated PD‐L1 was observed in patients with aGvHD and was directly associated with the infusion time of clinical grade WJMSCs. In addition, in vitro inhibitory antibody mediated blocking of sEV‐associated PD‐L1 restored T cell activation (TCA), suggesting a functional inhibitory role of sEVs‐PD‐L1. PD‐L1‐deficient sEVs isolated from WJMSCs following CRISPR‐Cas9 gene editing fail to inhibit TCA. Furthermore, we found that PD‐L1 is essential for WJMSC‐derived sEVs to modulate T cell receptors (TCRs). Our study reveals an important mechanism by which therapeutic WJMSCs modulate TCR‐mediated TCA through sEVs or sEV‐carried immune checkpoints. In addition, our clinical data suggest that sEV‐associated PD‐L1 may be not only useful in predicting the outcomes from WJMSC clinical administration, but also in developing cell‐independent therapy for aGvHD patients. [ABSTRACT FROM AUTHOR]

Purpose: Paracrine interactions with the stromal environment, including fibroblasts, may be important in the pathogenesis of ovarian cancer. Here, we evaluated the effect of conditioned media derived from ovarian fibroblasts (fibroblast-CMs) and their major cytokines on the growth of ovarian cancer cells, as well as the involvement of mitogen-activated protein kinases (MAPKs) and AKT in mediating this effect. Methods: Ovarian cancer cells were cultured in serum-free media (SF), or conditioned media of fibroblasts derived from normal ovary (CM1) and ovarian tumor tissue (CM2). Cell proliferation was measured by MTT assay. Phosphorylation of MAPKs and AKT was evaluated by Western blotting. Specific inhibitors of MAPKs and AKT were used to evaluate their respective involvement in mediating increased cell growth. Cytokine levels in fibroblast-CMs were measured using Luminex assays. Immunohistochemical staining was conducted for CXCL1, CXCR2 and phosphorylated p38 in primary ovarian tumors. Results: CM1 and CM2 significantly increased the growth of ovarian cancer cells relative to SF. In OVCAR3 and OVCAR4 cells, p38 phosphorylation was strongly induced by fibroblast-CMs, and pre-treatment with a p38 inhibitor prevented the growth increase induced by fibroblast-CMs. Fibroblasts secreted high levels of IL-6, IL-8, MCP1 and CXCL1. Treatment with only CXCL1 (1 μg/ml) increased cell growth and p38 phosphorylation. Treatment with a CXCR2 inhibitor effectively prevented p38 activation and cell growth induced by fibroblast-CMs. High expression of both CXCL1 and CXCR2 correlated with high expression of phosphorylated p38 in primary ovarian tumors. Conclusions: From our data, we conclude that CXCL1 is a key factor derived from ovarian fibroblasts that is responsible for increased ovarian cancer cell growth in part through p38 activation. Phosphorylated p38 can be used as a biomarker to predict CXCL1-CXCR2 interaction in vivo. [ABSTRACT FROM AUTHOR]

In most of the cases of space infections are secondary to an odontogenic infection. In space infection, spread occurs through the fascial plane because of the degradation of connective tissue by action of different enzymes produced by microorganisms. Different factors like age, nutritional status of the host, host defense, virulence of the microorganism play an important role in the spread of the infection. Sometimes it may take the fetal course if not treated on time because of its local and systemic complications. It should be treated as an emergency condition to prevent its rapid progression leading to fatal outcome. Here the case report describes an old lady suffering from fascial space infection and treated by incision and drainage. Incomplete removal of any odontogenic infection may cause the recurrence of the infection or infection that may spread to fascial spaces. [ABSTRACT FROM AUTHOR]

Objective: Evaluation of presentable tumor size in oral squamous cell carcinoma was the objective of the study. Patients and Method: The study sample comprised of ninety-eight biopsies diagnosed as oral squamous cell carcinoma presented to dental college from 2015 to 2020. Result and analysis of presentable tumor size when reported. Results: Male to female ratio was 2.5:1. Among the 295 diagnosed OSCC cases presentable tumor sizes when reported, most of the cases were T2 (42.37%) followed by T1 (18.3%), T3 (11.86%), and T4 (6.1%). Conclusions: Oral squamous cell carcinoma is one of the major health problems in India. Strategies must be made to improve the present scenario of health care service, where Government-run health care centres are burdened with ever-increasing patient pool, and to avail treatment in such centres is always a compromise with time and health. Oral health and cancer awareness programs should be undertaken for prevention, early diagnosis, and management of the affected population. Regular long-term follow-up is also necessary for these cases to avoid the recurrence of the disease and a better quality of life. [ABSTRACT FROM AUTHOR]

Violence is one of the primary sources of facial injury. It forms a big part of emergency care and trauma and differs from each because of the physical, psychosocial and economic relations. Trauma from pointed arms happens less frequently affecting the head and neck region, most commonly affecting males. Facial injury: 83 percent comprises of bone fracture, 66 percent of lacerations & 53 percent comprises of hematomas. [ABSTRACT FROM AUTHOR]

Introduction: The aim of treating mandibular fracture is to recover the anatomic structure and function with special caution in restoring the occlusion. Champy's miniplate fixation has been the most commonly usedprocedure amongst the various treatment modalities available. The 3-dimensional (3D) plating is fairly new for treating mandibular fractures. Aim: This research was performed to equate the effectiveness, flexibility, and rigidity of 3-dimensional plates with that of 2 mm titanium miniplates in anterior mandibular fracture surgical management. Material and Method: The study was conducted on a singlepatient with anterior mandibular fracture (Right parasymphysisregion). The patient's preoperative, intraoperative, and postoperative clinical and radiological findings were recorded in a proforma. Results: The timerequired to adapt and fix the miniplates were slightly more than3-D plates and results were significant. Skeletaland occlusal stability was maintained. Conclusion: the 3-dimensional plate is as effective as conventional miniplates in the treatment of anterior mandibular fractures. Its the ease of use and reduced working hours that are advantages over traditional miniplates. [ABSTRACT FROM AUTHOR]

Optimal post-operative care has a multidisciplinary group of healthcare professionals and a patient oriented approach in order to avoid any post-operative complications & enables a rapid return to normal health. In the last 10 years, there has been an enhanced recovery after surgery, various implementation of programs over the world to reduce any complications and length of stay challenging the models of intra operative care. Various aspects of intra operative care have consensus guidelines without any controversy, while others like perioperative fluid management therapy remains contentious. [ABSTRACT FROM AUTHOR]

Verucous carcinoma is unusual variant of squamous cell carcinoma which is locally invasive and local recurrence may also common. In this type of carcinoma distance metastasis occur rarely so the prognosis is also good for them. They generally occur in the head neck region and possibility of transformation of these lesions into squamous cell carcinoma is high, for which prognosis become worst. Here in this article we discuss about a case who primarily diagnosed with verrucous carcinoma on right lateral border of tongue and undergone surgery for the same. Recovery was also uneventful but within 4 months of time again he developed a lesion on the right lateral border of the tongue. The clinical and histopathological study of the lesion suggestive of squamous cell carcinoma (early invasive). For the same we decided for aggressive treatment plan to prevent further spread of the lesion. Patient undergone right side hemiglossectomy along with SOHND on right side and reconstruction of the tongue with radial forearm free flap which proved to be functionally helpful for the patient. [ABSTRACT FROM AUTHOR]

Purpose: We examined associations of inflammation with breast density, a marker of breast cancer risk, among female Chinese immigrants and explored whether associations varied by neighborhood environment.Methods: Assessments of serum C-reactive protein (CRP), soluble tumor necrosis factor receptor 2 (sTNFR2), and breast density were performed among 401 Chinese immigrants across the Philadelphia region. Participant addresses were geocoded, with the majority residing in areas representing traditional urban enclaves (i.e., Chinatown and South Philadelphia) or an emerging enclave with a smaller, but rapidly growing Chinese immigrant population (i.e., the Near Northeast). The remainder was classified as residing in non-enclaves.Results: In multivariable adjusted regression models, CRP was inversely associated with dense breast area (p = 0.01). Levels of sTNFR2 were also inversely associated with dense breast area, but these associations varied by neighborhood (interaction p = 0.01); specifically, inverse associations were observed among women residing in the emerging enclave (p = 0.03), but not other neighborhoods.Conclusions: Among Chinese immigrant women, aggregate analyses that do not take neighborhood context into consideration can mask potential variations in association of inflammatory markers with breast density. Future studies should consider how neighborhood contextual factors may contribute to differential risk pathways. [ABSTRACT FROM AUTHOR]

The radicular (periapical cyst) is the second most common pulpo-periapical lesion arising from cell rests of malassez. Mainly associated with non- vital teeth with necrotic pulp. A case of large bilateral radicular cyst located in the maxilla of a 35-year-old female patient was reported in the dept. of oral surgery, institute of dental sciences, Bhubaneswar. Patient complained of swelling in upper front tooth region. On radiographic examination a well circumscribed radiolucency was seen. Incisional biopsy was taken previously suggestive of periapical cyst. Bilateral cyst was enucleated under general anesthesia and extraction of all root stumps were done. The enucleated specimen sent of H/P study. [ABSTRACT FROM AUTHOR]

Introduction: Maxillofacial trauma is in querulous expansion by clinical and biomechanical studies in order to enhance the well-established techniques and to utilize new materials to reduce immobilization period and enhancement of the rigid fixation.23 The principle of axial compression for better adaptation of fracture segments, with the advantage of increased stability and early function, is a promising means of avoiding the bulky rigid plates used previously.21Since 1984 the cannulated Herbert Bone Screw (HBS) proves to be a successful mean of fracture fixation in various fields of orthopaedic surgery, nonetheless with no sufficient evidence about its performance in the maxillofacial trauma field.23 Objectives: Purpose of this study was to evaluate clinically and radiographically the performance of Herbert Bone Screw in the treatment of anterior mandibular oblique fractures. Materials & Method: Three Patients with non-comminuted oblique anterior mandibular fracture who had reported to the dept. of OMFS, Institute of Dental Sciences, Siksha 'o' Anusandhan University (Deemed to be University) following RTA were treated using Herbert bone screw. Clinical follow up was conducted after one week, four weeks, six weeks and twelve weeks for postoperative occlusion, inter-fragmentary mobility, pain and isodensity values on panoramic radiographs. Results: By the end of the follow up period, all cases showed normal occlusal and good stability, a decrease in level of pain intensity and an uneventful wound healing with no records of developed infection. Mean bone density after twelve weeks showed a statistically significant. Conclusion: Fixation of anterior mandible fracture using this technique can achieve good stability and appropriate compression. [ABSTRACT FROM AUTHOR]

Platelet-rich fibrin (PRF), a second-generation platelet concentrate, has shown to be superior to PRP. It was first developed in France. PRF allows one to obtain fibrin membranes enriched with platelets and GF after starting from an anticoagulant-free blood harvest. Recently, studies have demonstrated that the PRF membrane has a very significant slow sustained release of many key GF for at least 1 week and up to 28 days, which means that PRF could release GF with its own biological scaffold for wound healing process. The aim of this case report is to describe two cases of radicular cysts in the maxillary anterior region that were individually managed, depending on the underlying etiology, by using an interdisciplinary approach including nonsurgical restorative and endodontic therapy followed by surgical eneucleation of the cyst followed by apicocectomy and placement of PRF. [ABSTRACT FROM AUTHOR]

Dentigerous cyst which arises from dental follicle of unerrupted permanent tooth is 2nd most common cyst involving the maxillofacial region after radicular cyst. This type of cyst generally associated with unerrupted 3rd mandibular tooth. A case of a dentigerous cyst located in the mandible of a 36 year old woman was reported in Dept Of Omfs, Institute Of Dental Sciences, Siksha 'O' Anusandhan (Deemed To Be University), Bhubaneswar. The patient complaining swelling and discomfort in the left mandibular body region. on radiographic examination there was a well circumscribed radiolucent lesion associated with a impacted supernumerary tooth. lesion was excised under local anesthesia and specimen was sent for histopathological examination. Microscopic examination of the excised tissue showed it to be well-circumscribed with fibrous tissues, and the cystic space lined by keratinized epithelium. [ABSTRACT FROM AUTHOR]

Background: Several types of bone-plating systems have been evolved to provide proper fixation for the mandibular fractures and osteotomies. The main disadvantage of conventional miniplates system is that the plate must be perfectly adapted to the underlying bone to prevent alterations in the alignment of the segments and changes in the occlusal relationship. The introduction of locking miniplates reconstruction plating systems for the treatment of mandibular fractures and continuity defects has offered certain advantages over other plating systems. The locking miniplates function as internal fixators, achieving stability by locking the screws to the plates. The most advantage of locking screws/plates systems is that it becomes unnecessary for the plate to have intimate contact with the underlying bone, making plate adaptation easier. In this article we report a case of complete displaced mandibular right body and left Parasymphysis fracture, which was operated using locking miniplates. [ABSTRACT FROM AUTHOR]

Collaboration between firms is not a new concept, but the new thing that can be seen is that the collaborations have increased significantly during the past couple of decades, along with the increasing international competition. Moreover, the nature of collaboration has changed, shifting from peripheral interests to the very core functions of the corporation, and from equity to non-equity forms of collaboration. This paper essentially focuses on the legal framework governing the various aspects of a Joint Venture in India in brief, the methods of Joint Ventures, as well as RBI regulations on the topic. The research methodology adopted is largely analytical and descriptive. Reliance has been placed largely on various sources like articles and online articles. [ABSTRACT FROM AUTHOR]

Basal cell adenoma is a very rare monomorphic tumor of salivary gland that mainly involves the major salivary glands. Minor salivary gland involvement is a rare entity. A case of basal cell adenoma of heard palate of a 52-year-old woman was reported in Dept. Of OMFS, Institute of Dental Sciences, Siksha ‘O’ Anusandhan (Deemed to Be University), Bhubaneswar. The patient complains of swelling and discomfort during taking food and draining of pus from that swelling. On radiographic examination (on contrast enhanced computed tomography). Lesion was excised under local anesthesia and the excised tissue sent for histopathological study which reveals keratinized epithelium lined cystic space surrounded by fibrous capsule. [ABSTRACT FROM AUTHOR]

Background: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States (5 % of cancer deaths). The standard treatment for patients with advanced EOC is initial debulking surgery followed by carboplatin-paclitaxel combination chemotherapy. Unfortunately, with chemotherapy most patients relapse and die resulting in a five-year overall survival around 45 %. Thus, finding novel therapeutics for treating EOC is essential. Connectivity Mapping (CMAP) has been used widely in cancer drug discovery and generally has relied on cancer cell line gene expression and drug phenotype data. Therefore, we took a CMAP approach based on tumor information and clinical endpoints from high grade serous EOC patients. Methods: We determined tumor gene expression signatures (e.g., sets of genes) associated with time to recurrence (with and without adjustment for additional clinical covariates) among patients within TCGA (n = 407) and, separately, from the Mayo Clinic (n = 326). Each gene signature was inputted into CMAP software (Broad Institute) to determine a set of drugs for which our signature "matches" the "reference" signature, and drugs that overlapped between the CMAP analyses and the two studies were carried forward for validation studies involving drug screens on a set of 10 EOC cell lines. Results: Of the 11 drugs carried forward, five (mitoxantrone, podophyllotoxin, wortmannin, doxorubicin, and 17-AAG) were known a priori to be cytotoxics and were indeed shown to effect EOC cell viability. Conclusions: Future research is needed to investigate the use of these CMAP and similar analyses for determining combination therapies that might work synergistically to kill cancer cells and to apply this in silico bioinformatics approach using clinical outcomes to other cancer drug screening studies. [ABSTRACT FROM AUTHOR]

With trade and commerce increasing rapidly between nations, there has been a significant rise in disputes, leading to an urgent need for an effective and unified dispute resolution system which can sufficiently settle disagreements/issues among parties in dispute and which has to be arrived at keeping in mind the differences in laws of every nation, hence, immensely increasing the scope of private international law, or conflict of laws as called by different nations. Such urgency led to many conventions, one of most important being The New York Convention of 1958 (Convention on the Recognition and Enforcement of Foreign Arbitral Awards) and the UNCITRAL Model Law promulgated in 1985 and amended as recently as 2006 which has been the source for International Arbitration, the most widely used dispute resolution method for international commercial trade and transactions and many countries like India have also based their legislations on the rules of the UNCITRAL Model Law. Most European countries as well as India have ratified the New York Convention of 1958 (Convention on the Recognition and Enforcement of Foreign Arbitral Awards) for the purposes of International trade and commercial transactions therefore opening the gateway for international commercial transactions to take place among such convention countries easier. Further, the judiciary of concerned countries has also affirmed such ratification and the applicability of the Model Law laid down [ABSTRACT FROM AUTHOR]

Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity. [ABSTRACT FROM AUTHOR]

This article seeks to provide an insight on the international phenomenon of corruption, dealing with its existence, and whether compliance is higher with Anti-Corruption laws or with corruption itself, resulting in anti-corruption laws being much less effective than the legislators intended it to be and the reasons for increasing demand worldwide for new governance standards and higher compliance controls and other effective anti-corruption laws and policies in light of rapid increase in corruption every year. This article further deals with the diagnosis and measures to deal with the cause of corruption - the short-comings in anti-corruption law - the reasons why corporations are willing to face continuing legal risks and adverse publicity but still indulge in corrupt practices and the extent of negative impact the prevailing levels of corruption ultimately have on international business and trade. Strict compliance controls are being introduced with increasing enforcement of anti-corruption laws internationally and nations have also started to focus on individual and corporate liability in cases of violation of anti-corruption laws, for both government and private organisations. In this context of far-reaching developments, whether European and South-east Asian Countries like India and International Business Organisations can act in ignorance or buck up and accept this trend, slowly and steadily moving towards a less corrupt nation and International business projects - if not towards a totally corruption free one, keeping in mind the growth of international trade and Commerce and its sustainability. [ABSTRACT FROM AUTHOR]

Targeted therapies have been used to combat many tumor types; however, few have effectively improved the overall survival in women with epithelial ovarian cancer, begging for a better understanding of this deadly disease and identification of essential drivers of tumorigenesis that can be targeted effectively. Therefore, we used a loss-of-function screening approach to help identify molecular vulnerabilities that may represent key points of therapeutic intervention. We employed an unbiased high-throughput lethality screen using a 24,088 siRNA library targeting over 6,000 druggable genes and studied their effects on growth and/or survival of epithelial ovarian cancer (EOC) cell lines. The top 300 "hits" affecting the viability of A1847 cells were rescreened across additional EOC cell lines and non-tumorigenic, human immortalized ovarian epithelial cell lines. Fifty-three gene candidates were found to exhibit effects in all tumorigenic cell lines tested. Extensive validation of these hits refined the list to four high quality candidates (HSPA5, NDC80, NUF2, and PTN). Mechanistic studies show that silencing of three genes leads to increased apoptosis, while HSPA5 silencing appears to alter cell growth through G1 cell cycle arrest. Furthermore, two independent gene expression studies show that NDC80, NUF2 and PTN were significantly aberrantly overexpressed in serous adenocarcinomas. Overall, our functional genomics results integrated with the genomics data provide an important unbiased avenue towards the identification of prospective therapeutic targets for drug discovery, which is an urgent and unmet clinical need for ovarian cancer. [ABSTRACT FROM AUTHOR]

A subset of gastrointestinal stromal tumors (GISTs) lack gain-of-function mutations in c-KIT and PDGFRα. These so-called wild-type (WT) GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. We identified amplification of IGF1R in a SNP analysis of GIST and thus studied its potential as a therapeutic target in WT and mutant GIST. Expression of IGF1R and downstream effectors in clinical GIST samples was examined by using immunoblots and immunohistochemistry. The roles of IGF1R signaling in GIST and viability were analyzed by using NVP-AEW541, an inhibitor of IGF1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. IGF1R was strongly overexpressed, and IGF1R amplification was detected at a significantly higher frequency in WTGISTs, including a pediatric WT GIST, compared with mutant GISTs (P = 0.0173 and P = 0.01 63, respectively). Inhibition of IGF1R activity in vitro with NVP-AEW541 or down-regulation of expression with siIGF1R led to cytotoxicityand induced apoptosis in GIST cell lines via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Our results reveal that IGFIR is amplified and the protein is overexpressed in WT and pediatric GISTs. We also demonstrate that the aberrant expression of IGF1R may be associated with oncogenesis in WT GISTs and suggest an alternative and/or complementary therapeutic regimen in the clinical management of all GIST5, especially in a subset of tumors that respond less favorably to imatinib-based therapy. [ABSTRACT FROM AUTHOR]

Poliovirus protein 3CDpro possesses both proteinase and RNA binding activities, which are located in the 3Cpro domain of the protein. The RNA polymerase (3Dpol) domain of 3CDpro modulates these activities of the protein. We have recently shown that the level of 3CDpro in HeLa cell-free in vitro translation-RNA replication reactions is suboptimal for efficient virus production. However, the addition of either 3CDpro mRNA or of purified 3CDpro protein to in vitro reactions, programmed with viral RNA, results in a 100-fold increase in virus yield. Mutational analyses of 3CDpro indicated that RNA binding by the 3Cpro domain and the integrity of interface I in the 3Dpol domain of the protein are both required for function. The aim of these studies was to determine the exact step or steps at which 3CDpro enhances virus yield and to determine the mechanism by which this occurs. Our results suggest that the addition of extra 3CDpro to in vitro translation RNA-replication reactions results in a mild enhancement of both minus and plus strand RNA synthesis. By examining the viral particles formed in the in vitro reactions on sucrose gradients we determined that 3CDpro has only a slight stimulating effect on the synthesis of capsid precursors but it strikingly enhances the maturation of virus particles. Both the stimulation of RNA synthesis and the maturation of the virus particles are dependent on the presence of an intact RNA binding site within the 3Cpro domain of 3CDpro. In addition, the integrity of interface I in the 3Dpol domain of 3CDpro is required for efficient production of mature virus. Surprisingly, plus strand RNA synthesis and virus production in in vitro reactions, programmed with full-length transcript RNA, are not enhanced by the addition of extra 3CDpro. Our results indicate that the stimulation of RNA synthesis and virus maturation by 3CDpro in vitro is dependent on the presence of a VPg-linked RNA template. [ABSTRACT FROM AUTHOR]