Study on significance of pillar dimensions on stability of caverns in rocks with high overburden.

The present study aims to examine the influence of pillar widths on the stability of caverns. Case study considering two caverns viz. Powerhouse Cavern (PHC) and Transformerhall Cavern (TC), in a major hydro-electric project in the eastern Himalayas is considered. 2D and 3D numerical analysis was carried out for w/B ratios 1.5 and 3.0 respectively. Primary aspects like major principal stress and development of plastic zone were investigated for the two pillar widths. An optimum pillar width was observed that resulted in reduced stress acting along the cavern periphery, a better stress distribution, and no overlap of plastic zones between the caverns. Further, the optimum pillar width resulted in a better stress-redistribution with progress of excavation and the in-situ stress became constant at an earlier stage of excavation. Observations from comparative analysis revealed that a pillar width nearly equal to the largest dimension or twice the width of the larger of the caverns in the group resulted in a better stability and hence can be considered as the optimum width. Furthermore, the analysis suggests that along the pillar width, maximum stress was observed at mid-height, and it is more in the vicinity of the face of the caverns.

Childhood cancer mutagenesis caused by transposase-derived PGBD5.

Genomic rearrangements are a hallmark of most childhood tumors, including medulloblastoma, one of the most common brain tumors in children, but their causes remain largely unknown. Here, we show that PiggyBac transposable element derived 5 (Pgbd5) promotes tumor development in multiple developmentally accurate mouse models of Sonic Hedgehog (SHH) medulloblastoma. Most Pgbd5-deficient mice do not develop tumors, while maintaining normal cerebellar development. Ectopic activation of SHH signaling is sufficient to enforce cerebellar granule cell progenitor-like cell states, which exhibit Pgbd5-dependent expression of distinct DNA repair and neurodevelopmental factors. Mouse medulloblastomas expressing Pgbd5 have increased numbers of somatic structural DNA rearrangements, some of which carry PGBD5-specific sequences at their breakpoints. Similar sequence breakpoints recurrently affect somatic DNA rearrangements of known tumor suppressors and oncogenes in medulloblastomas in 329 children. This identifies PGBD5 as a medulloblastoma mutator and provides a genetic mechanism for the generation of oncogenic DNA rearrangements in childhood cancer.

Case report: A novel biallelic FTO variant causing multisystem anomalies with severe epilepsy, widening the spectrum of FTO syndrome.

The fat mass and obesity-associated gene (FTO) codes for a DNA/RNA demethylase. Pathological variants in this gene are rare, with only three reports in the literature, all with mutations in the catalytic domain. We report the first biallelic human variant in fat mass and obesity-associated gene (c.287G>C, p.Arg96Pro/R96P) outside the catalytic site, causing numerous abnormalities across multiple organ systems, affecting respiratory, cardiovascular, and neurological function. Biochemical assays of cells with the patient's variant were performed to further quantify the effect of the variant on function. Loss-of-function resulting from the patient's R96P missense variant was demonstrated with in vitro biochemical characterization of demethylase activity, resulting in a 90% reduction in function of the fat mass and obesity-associated protein compared to wild-type. Our findings demonstrate a novel fat mass and obesity-associated gene non-catalytic site variant with a unique patient phenotype of bilateral multifocal epilepsy and multisystem congenital anomalies.

P-selectin-targeted nanocarriers induce active crossing of the blood-brain barrier via caveolin-1-dependent transcytosis.

Medulloblastoma is the most common malignant paediatric brain tumour, with ~30% mediated by Sonic hedgehog signalling. Vismodegib-mediated inhibition of the Sonic hedgehog effector Smoothened inhibits tumour growth but causes growth plate fusion at effective doses. Here, we report a nanotherapeutic approach targeting endothelial tumour vasculature to enhance blood-brain barrier crossing. We use fucoidan-based nanocarriers targeting endothelial P-selectin to induce caveolin-1-dependent transcytosis and thus nanocarrier transport into the brain tumour microenvironment in a selective and active manner, the efficiency of which is increased by radiation treatment. In a Sonic hedgehog medulloblastoma animal model, fucoidan-based nanoparticles encapsulating vismodegib exhibit a striking efficacy and marked reduced bone toxicity and drug exposure to healthy brain tissue. Overall, these findings demonstrate a potent strategy for targeted intracranial pharmacodelivery that overcomes the restrictive blood-brain barrier to achieve enhanced tumour-selective penetration and has therapeutic implications for diseases within the central nervous system.

MIT CAACB Risk Assessment Case Study: Assessing Virus Cross-Contamination Risk between Two Simultaneous Processes in an Open Biomanufacturing Facility.

Some members of MIT's Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) previously published content on the "Quality Risk Management in the Context of Viral Contamination", which described tools, procedures, and methodologies for assessing and managing the risk of a potential virus contamination in cell culture processes. To address the growing industry interest in moving manufacturing toward open ballrooms with functionally closed systems and to demonstrate how the ideas of risk management can be leveraged to perform a risk assessment, CAACB conducted a case study exercise of these new manufacturing modalities. In the case study exercise, a cross-functional team composed of personnel from many of CAACB's industry membership collaboratively assessed the risks of viral cross-contamination between a human and non-human host cell system in an open manufacturing facility. This open manufacturing facility had no walls to provide architectural separation of two processes occurring simultaneously, specifically a recombinant protein perfusion cell culture process using the human cell line, HEK-293 (Process 1) and a downstream postviral filtration unit operation (Process 2) of a recombinant protein produced in CHO cells. This viral risk assessment focused on cross-contamination of the Process 2 filtration unit operation after the Process 1 perfusion bioreactor was contaminated with a virus that went undetected. The workflow for quality risk management that is recommended by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) was followed, which included identifying and mapping the manufacturing process, defining the risk question, risk evaluation, and risk control. The case study includes a completed Failure Mode and Effects Analysis (FMEA) to provide descriptions of the specific risks and corresponding recommended risk reduction actions.

Effect of Multi-Walled Carbon Nanotubes and Carbon Fiber Reinforcements on the Mechanical and Tribological Behavior of Hybrid Mg-AZ91D Nanocomposites.

Magnesium matrix composites are extensively used in automotive and structural applications due to their low density, high strength, and wear-resistant properties. To reach the scope of industry needs, research is carried out regarding enhancing the mechanical and tribological behavior of the magnesium composites by reinforcing the nano-sized reinforcements. In the present work, research has been carried out to enhance the properties of the magnesium AZ91D hybrid composite by reinforcing carbon fibers (CFs) and multi-walled carbon nanotubes (MWCNTs) with varying weight percentages (AZ91D + 0.5% CF's + 0.5% MWCNT and AZ91D + 0.75% CF's + 0.75% MWCNT, respectively). The experimental tests were carried out to evaluate the mechanical and tribological behavior of the composites. The test results showed that the addition of CF and MWCNT reinforcements improved the hybrid Mg composite's hardness, tensile strength, and impact strength compared to the base Mg matrix. The AZ91D + 0.75% CF's + 0.75% MWCNT hybrid composite showed a 19%, 35%, and 66% increased hardness, tensile strength, and impact strength, respectively, compared to the base Mg AZ91D. The wear test results also showed the improved wear resistance of the Mg composite compared to the base matrix. The enhanced wear resistance of the composite is due to the addition of hard MWCNT and CF reinforcements. The wear rate of the AZ91D + 0.75%CF's + 0.75% MWCNT composite for a load of 30 N at a sliding distance of 1500 m is lower as compared to the base matrix. The SEM micrographs of the worn surfaces revealed the existence of abrasive wear. The improved mechanical and tribological behavior of the magnesium composite is also due to the homogeneous distribution of the hard reinforcement particles along the grain boundaries.

A tumor suppressor role for EZH2 in diffuse midline glioma pathogenesis.

Pediatric high-grade gliomas, specifically diffuse midline gliomas, account for only 20% of clinical cases but are 100% fatal. A majority of the DMG cases are characterized by the signature K27M mutation in histone H3. The H3K27M mutation opposes the function of enhancer of zeste homolog 2 (EZH2), the methyltransferase enzyme of the polycomb repressor complex 2. However, the role of EZH2 in DMG pathogenesis is unclear. In this study, we demonstrate a tumor suppressor function for EZH2 using Ezh2 loss- and gain-of-function studies in H3WT DMG mouse models. Genetic ablation of Ezh2 increased cell proliferation and tumor grade while expression of an Ezh2 gain-of-function mutation significantly reduced tumor incidence and increased tumor latency. Transcriptomic analysis revealed that Ezh2 deletion upregulates an inflammatory response with upregulation of immunoproteasome genes such as Psmb8, Psmb9, and Psmb10. Ezh2 gain-of-function resulted in enrichment of the oxidative phosphorylation/mitochondrial metabolic pathway namely the isocitrate dehydrogenase Idh1/2/3 genes. Pharmacological inhibition of EZH2 augmented neural progenitor cell proliferation, supporting the tumor suppressive role of EZH2. In vivo 7-day treatment of H3K27M DMG tumor bearing mice with an EZH2 inhibitor, Tazemetostat, did not alter proliferation or significantly impact survival. Together our results suggest that EZH2 has a tumor suppressor function in DMG and warrants caution in clinical translation of EZH2 inhibitors to treat patients with DMG.

Subcutaneous Basidiobolomycosis Treated Successfully with Oral Itraconazole: A Case Report.

Basidiobolomycosis is an opportunistic fungal infection with a high morbidity and mortality rate. It is known to cause invasive disease in immunocompromised persons but it may produce only cutaneous or subcutaneous infections in an immunocompetent patient. Treatment is difficult due to its fulminant course and lack of effective anti-fungal drugs. But here, we report a rare case of Basidiobolomycosis detected in an immunocompetent patient-without any debilitating illness, which showed a complete response to itraconazole 200 mg daily without any surgical intervention.

Serum Elemental Analysis of Type 2 Diabetes Patients Using SRXRF.

A total of 158 serum samples of newly diagnosed type 2 diabetes patients and control subjects were analyzed using Synchrotron Radiation X-ray Fluorescence (SRXRF) technique. The microprobe XRF beam line-16 of Indus-2 synchrotron radiation facility at Raja Ramanna Centre for Advanced Technology (RRCAT), Indore, India, was used to identify and quantify the elements K, Ca, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Br, Rb, Sr, and Pb. A significant decrease in the mean concentrations of K, Ca, Ti, Cr, Mn, Ni, Zn, and As and an increase in the concentrations of V, Fe, Co, Cu, Se, and Pb were observed in the serum samples of the patient group when compared to the control group. It is hypothesized that the observed alterations in the elemental concentrations might have led to ineffective uptake of insulin and have interfered with glucose homeostasis by either directly or indirectly causing oxidative stress.

Serum Human Epididymis Protein-4 (HE4) - A novel Approach to Differentiate Malignant Frombenign Breast Tumors.

BACKGROUND: The lack of sensitivity and specificity of existing diagnostic markers like Carbohydrate Antigen 15-3(CA15-3) and Carcinoembryonic antigen (CEA) in breast cancer stimulates the search for new biomarkers to improve diagnostic sensitivity especially in differentiating benign and malignant breast tumors. Expression of Human epididymal protein 4 (HE4) has been demonstrated in ductal carcinoma of the breast tissue. So we tried to evaluate serum HE4 levels as diagnostic marker in breast cancer patients and to comparatively assess serum HE4, CEA and CA15-3 in breast tumor patients both benign and malignant. METHODS: Total 90 female subjects were included in the study. We selected 30 breast cancer cases (Malignant group) and 30 benign breast lump cases (Benign group) based on histopathology report. And other 30 were age matched apparently healthy controls (Control group). HE4, CEA and CA15-3 were analysed in serum samples of all subjects by Electrochemiluminiscence immunoassay method. RESULTS: A significant difference in the median (IQR) of HE4 (pmol/l) was identified among malignant, benign and control groups {62.4(52.6-73.7) vs 49.3(39.8-57.4) vs 52.3(50.6-63.3) P=0.0009} respectively. The cutoff value for prediction of breast cancer was determined at >54.5 pmol/l for HE4, with a sensitivity of 73.3%, specificity of 65.3%, whereas cutoff value of CA 15-3 was >21.24 (U/ml) with a sensitivity of 56.7%, specificity of 74.5%. For CEA at cutoff value >0.99 (ng/ml) the sensitivity and specificity were 96.7 % and 62.7% respectively. AUC for HE4, CA15-3 and CEA were 0.725, 0.644 and 0.857 respectively. CONCLUSION: Our study demonstrated that serum levels of HE4 were significantly higher in malignant group compared to benign and control groups. There is no significant difference between HE4 levels between benign and control groups. These results indicate that HE4 appears as a useful and highly specific biomarker for breast cancer, which can differentiate between malignant and benign tumors.

Investigation of Mechanical and Physical Properties of Big Sheep Horn as an Alternative Biomaterial for Structural Applications.

This paper investigates the physical and mechanical properties of bighorns of Deccani breed sheep native from Karnataka, India. The exhaustive work comprises two cases. First, rehydrated (wet) and ambient (dry) conditions, and second, the horn coupons were selected for longitudinal and lateral (transverse) directions. More than seventy-two samples were subjected to a test for physical and mechanical property extraction. Further, twenty-four samples were subjected to physical property testing, which included density and moisture absorption tests. At the same time, mechanical testing included analysis of the stress state dependence with the horn keratin tested under tension, compression, and flexural loading. The mechanical properties include the elastic modulus, yield strength, ultimate strength, failure strain, compressive strength, flexural strength, flexural modulus, and hardness. The results showed anisotropy and depended highly on the presence of water content more than coupon orientation. Wet conditioned specimens had a significant loss in mechanical properties compared with dry specimens. The observed outcomes were shown at par with results for yield strength of 53.5 ± 6.5 MPa (which is better than its peers) and a maximum compressive stress of 557.7 ± 5 MPa (highest among peers). Young's modulus 6.5 ± 0.5 GPa and a density equivalent to a biopolymer of 1.2 g/cc are expected to be the lightest among its peers; flexural strength 168.75 MPa, with lowest failure strain percentage of 6.5 ± 0.5 and Rockwell hardness value of 60 HRB, seem best in the class of this category. Simulation study identified a suitable application area based on impact and fatigue analysis. Overall, the exhaustive experimental work provided many opportunities to use this new material in various diversified applications in the future.

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.

One-Dimensional NiSe-Se Hollow Nanotubular Architecture as a Binder-Free Cathode with Enhanced Redox Reactions for High-Performance Hybrid Supercapacitors.

Selenium-enriched nickel selenide (NiSe-Se) nanotubes supported on highly conductive nickel foam (NiSe-Se@Ni foam) were synthesized using chemical bath deposition with the aid of lithium chloride as a shape-directing agent. The uniformly grown NiSe-Se@Ni foam, with its large number of electroactive sites, facilitated rapid diffusion and charge transport. The NiSe-Se@Ni foam electrode exhibited a superior specific capacitance value of 2447.46 F g-1 at a current density value of 1 A g-1 in 1 M aqueous KOH electrolyte. Furthermore, a high-energy-density pouch-type hybrid supercapacitor (HSC) device was fabricated using the proposed NiSe-Se@Ni foam as the positive electrode, activated carbon on Ni foam as the negative electrode, and a filter paper separator soaked in 1 M KOH electrolyte solution. The HSC delivered a specific capacitance of 84.10 F g-1 at a current density of 4 mA cm-2 with an energy density of 29.90 W h kg-1 at a power density of 594.46 W kg-1 for an extended operating voltage window of 1.6 V. In addition, the HSC exhibited excellent cycling stability with a capacitance retention of 95.09% after 10,000 cycles, highlighting its excellent potential for use in the hands-on applications. The real-life practicality of the HSC was tested by using it to power a red light-emitting diode.

Rate of colorectal neoplasia in patients with Hodgkin lymphoma.

AIM: Survivors of Hodgkin lymphoma (HL) are at increased risk of breast, lung, thyroid, stomach, pancreatic and colon cancer. There is limited information on the utility of endoscopic screening for colon cancer. We aimed to describe the adenoma detection rate (ADR) in patients with HL to determine the appropriate timing of colonoscopy screening. METHOD: We retrospectively studied patients with HL who underwent colonoscopy between 2000 and 2017. RESULTS: A total of 251 patients underwent colonoscopy. Eighty (32%) patients had 151 colonic polyps. Thirty per cent of the polyps exhibited high-grade dysplasia, and invasive colon adenocarcinoma was found in 10 patients. Patients with the nodular sclerosing subtype of HL had a significantly lower ADR than others (P = 0.002). The ADR was 5% in patients younger than 35 years (n = 64), 23% in patients between 35 and 40 years of age (n = 22), 39% in patients between 40 and 50 years of age (n = 51) and 46% in patients older than 50 years (n = 114).

Using a Benefit-Risk Analysis Approach to Capture Regulatory Decision Making: Renal Cell Carcinoma.

Drug regulators such as the US Food and Drug Administration (FDA) make decisions about drug approvals based on benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision making about new drugs to treat renal cell carcinoma (RCC). Fifteen FDA decisions on RCC drugs based on clinical trials whose results were published from 2005 to 2018 were identified and analyzed. The benefits and risks of the new drug in each clinical trial were quantified relative to comparators (typically the control arm of the same clinical trial) to estimate whether the benefit-risk was positive or negative. A sensitivity analysis was demonstrated using pazopanib to explore the magnitude of uncertainty. FDA approval decision outcomes for the clinical trials assessed were consistent and logical using this benefit-risk framework.

Preparation of Platelet-rich Fibrin Membrane over Scaffold of Collagen Sheet, its Advantages over Compression Method: A Novel and Simple Technique.

INTRODUCTION: Platelet-rich fibrin (PRF) is compressed by using various tools to make platelet-rich fibrin membrane (PRFM). Preservation of platelets and plasma content of PRFM depends on the compression method used. To overcome limitations of compression method, we prepared PRFM over scaffold of collagen sheet without using any compression device. AIMS AND OBJECTIVE: To prepare PRFM without using any compression device over a scaffold of collagen sheet and to evaluate its efficacy in chronic nonhealing ulcer. MATERIALS AND METHODS: PRFM was prepared, with minor modification in Choukron's protocol, over a collagen sheet without using compression device. To study its efficacy and reproducibility, total 15 patients over 18 years of age with chronic, nonhealing ulcers of more than 3 months of various causes were included and patients with active wound infection were excluded. RESULTS: We were able to prepare and reproduce PRFM by our technique. It overcomes the limitations of compression method with comparable efficacy to compression method. Results obtained on comparison at week 0, 3, and 6, by paired t-test, were found to be statistically significant (P < 0.0001). CONCLUSION: Preparation of PRFM with the method described is easy and reproducible. Use of collagen sheet synergistically improved wound healing.

Prescription and Usage Pattern of Topical Corticosteroids among Out-patient Attendees with Dermatophyte Infections and Its Analysis: A Cross-sectional, Survey-based Study.

BACKGROUND: There is scarce scientific data on topical corticosteroids (TCS) prescription by non-dermatologists including registered medical practitioners, ayurvedic, homeopathic practitioners, and over-the-counter (OTC) use of TCS-containing creams. OBJECTIVE: The main objective of this study is to analyze the prescription and usage pattern of topical steroids among out-patient attendees with dermatophyte infection. To study health-seeking behavior of patients with dermatophyte infections. MATERIAL AND METHODS: An open, cross-sectional, duration-based study of 3 months. Inclusion criteria: Patients with dermatophytosis having a history of topical steroid application; either prescribed or purchased OTC and used themselves. Exclusion criteria: Patients who were not willing to give informed consent. Patient's data like socio-demographic profile, duration, frequency, site of application, contents of the topical cream used, prescriber information, and patients' desire to continue the use of topical steroids were recorded. RESULTS: Total of 18.40% (n = 503) patients were already using cream-containing TCS at the time of presentation to the tertiary dermatology care center. The study shows that almost half of the patients (48.90%) were using unprescribed TCS. Registered medical practitioners were the most common source of TCS creams prescription (59.92%) in the prescribed group, while 26.07% patients were prescribed TCS by dermatologists. Clobetasol propionate (47.91%), was most common steroid agent used. CONCLUSION: Patients are able to get "prescription-only" drugs as OTC products. Such OTC use of TCS puts patients at risk of steroid modified dermatophytosis and topical steroid damaged skin. Even dermatologists may be culprit in creating menace of steroid abuse.

Oral Antifungal Therapy: Emerging Culprits of Cutaneous Adverse Drug Reactions.

INTRODUCTION: Antifungals are one of the most widely used drugs in dermatology practice for dermatophytosis. Oral antifungal therapy against superficial dermatophytosis is generally associated with a low incidence of adverse events in an immunocompetent population. However, lately, cutaneous adverse drugs reactions (CADRs) have been reported with varying incidence rates in the patients on oral antifungal therapy with many uncommon morphological patterns. The present, observational study was conducted over a period of 4 months to report the cases which presented with antifungal therapy-associated CADRs. MATERIALS AND METHODS: It was an observational, prospective study carried out at a tertiary care center in Western India over a period of 4 months. All patients diagnosed with superficial dermatophytic infections (clinically and fungal hyphae seen on 10% potassium hydroxide mount) started on oral antifungal therapy, presenting with cutaneous manifestation other than the primary dermatophytosis were included. The incidence of CADRs due to oral antifungal agents and the percentage of each clinical type of the CADR observed was calculated. RESULTS: The incidence of CADRs due to antifungal drugs was 8.3 per 10,000 patients. In total, 35 cases were reported out of 4,208 cases of dermatophytosis. Terbinafine was the most common causative drug, accounting for nearly 83% of cases, followed by itraconazole for 14% cases, and griseofulvin for 2.8% of cases. CONCLUSION: The role of systemic antifungals must not be overlooked in any patient with a CADR and should be reported as a trend indicator.