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Background and objective: Patients with intermediate-risk non–muscle-invasive bladder cancer (IR NMIBC) have a high risk of recurrence and need effective therapies to reduce the risk of disease recurrence or progression. This phase 1b study (NCT02720367) assessed the safety and tolerability of TAR-200, an intravesical drug delivery system, in participants with IR NMIBC. Methods: Participants with recurrent IR NMIBC were eligible. Participants received either two 7-d or two 21-d TAR-200 dosing cycles over a 4–6-wk period in a marker lesion/ablation design. TAR-200 was placed in the window between the cystoscopy showing recurrent papillary disease and the subsequent complete transurethral resection of the bladder tumour. The primary endpoint was TAR-200 safety. The secondary endpoints included TAR-200 tolerability, pharmacokinetics, and preliminary efficacy. Key findings and limitations: Twelve participants received TAR-200 treatment. No TAR-200–related serious or grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred. Nine participants had grade ≤ 2 TAR-200–related TEAEs, with urgency, dysuria, and haematuria being most common. Two participants refused a second dosing cycle due to urinary urgency and frequency. Insertion and removal of TAR-200 was successful in all cases. Plasma gemcitabine concentrations remained below the lower limit of detection. Five participants (42%) had complete response (CR): four had pathological CR and one had CR based on visual assessment. Conclusions and clinical implications: TAR-200 appears to be safe and well tolerated, with encouraging preliminary efficacy in participants with IR NMIBC. This study lays the groundwork for the multiple phase 2 and 3 global studies that are currently on-going for TAR-200. Patient summary: In this study, researchers evaluated the safety of the novel drug delivery system TAR-200 in participants with intermediate-risk non-muscle-invasive bladder cancer. They concluded that TAR-200 was safe and well tolerated with promising antitumour activity.

Thermal plasma is one of the upcoming powerful tools used for materials processing. It covers a wide range of technological applications such as synthesis of various refractory ceramic materials, metals and alloys, deposition of coatings, high temperature processing of materials as well as disintegration of waste materials. Representative technologically important material systems viz rare earth hexaboride (e.g. GdB6) and carbonaceous materials are focus of the present manuscript. Both the material systems have been processed using DC thermal plasma route and characterized thoroughly for structural, morphological, surface properties using XRD, TEM, XPS respectively. Morphology of GdB6 has been tailored by varying plasma parameters during synthesis. Further, these GdB6 powder were investigated for electron emission performance using Field Electron Emission and maximum current density of 0.5 mA/cm2 was noted for the nanocrystalline GdB6 sample. Feasibility of thermal plasmas for production of nanocrystalline GdB6 and processing of a bio-waste to obtain technologically important carbonaceous materials has also been explored.

Background and Aims: Irritable bowel syndrome (IBS) is characterized by abdominal pain and changes in bowel habits. Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are poorly absorbed short-chain carbohydrates that may drive commensal microbial gas production, promoting abdominal pain in IBS. Low-FODMAP diet can result in symptomatic improvement in 50%–80% of IBS patients. However, this diet is not meant to be sustained long term, with concern for downstream nutrition and microbial issues. In this study, we evaluate the function of a targeted FODMAP enzymatic digestion food supplement FODMAP enzymatic digestion (FODZYME) containing a fructan-hydrolase enzyme (with significant inulinase activity) in a simulated gastrointestinal environment. Methods: Using SHIME (Simulator of the Human Intestinal Microbial Ecosystem), a multi-compartment simulator of the human gut, FODZYME dose finding assay in modeled gastrointestinal conditions assessed enzymatic ability to hydrolyze 3 g of inulin. Full intestinal modeling assessing digestion of inulin, absorption of fructose, gas production, and other measures of commensal microbial behavior was completed using 1.125 g of FODZYME. Results: After 30 minutes, 90% of the inulin was converted to fructose by 1.125 g of FODZYME. Doubling dosage showed no significant improvement in conversion, whereas a half dose decreased performance to 77.2%. Seventy percent of released fructose was absorbed during simulated small intestinal transit, with a corresponding decrease in microbial gas production, and a small decrease in butyrate and short-chain fatty acid production. Conclusion: FODZYME specifically breaks down inulin in representative gastrointestinal conditions, resulting in decreased gas production while substantially preserving short-chain fatty acid and butyrate production in the model colon. Our results suggest dietary supplementation with FODZYME would decrease intestinal FODMAP burden and gas production.

Trypanosomiasis is one of the neglected tropical diseases which curtails the productivity of the victim and causes mortality in extreme cases. Non-availability of vaccines, low therapeutic index of trypanocidal drugs and development of resistance lead to the need for research focused on developing alternative treatment options against this disease. The aim of the current work is to use computer-assisted drug discovery techniques to examine the anti-trypanosomal action of bufadienolides, which are commonly detected in the skin secretions of toads. A library of 16 compounds from the bufadienolides family was tested for toxicity and docked against the Trypanosoma brucei hydrolase. The oral bioavailability and good suitability of the compounds for transdermal delivery was also indicated by the ADMET study. The findings based on molecular docking and dynamics simulation along with toxicity assessment showed that three compounds, marinobufagin, resibufogenin and resibufaginol, have the lowest toxicity and maximum binding energy against Trypanosoma brucei hydrolase. According to the results obtained by molecular docking interactions between drugs and target proteins are observed and contain a number of hydrogen bonds near the residues in the active pocket of the enzyme. The results of this study contribute to the understanding of the SAR of bufadienolides and provide a foundation for further research and drug development efforts. The computational analysis, including the density functional theory study, the knowledge of inhibitory mechanisms and aids in the design and optimization of novel anti-trypanosomal drugs.

Background: Triple negative Breast tumor (TNBC) is an aggressive tumor with sparse data worldwide. Methods: We analyzed non-metastatic TNBC from 2013 to 2019 for demographics, practice patterns, and survival by the Kaplan Meir method. Prognostic factors for OS and DFS were evaluated using Cox Proportional Hazard model estimator for univariate and multivariable analysis after checking for collinearity among the variables. Results: There were 1297 patients with median age of 38 years; 41 (33.3%) among 123 tested were BRCA-positives. Among these 593 (45.7%) had stage III disease, 1279 (98.6%) were grade III, 165 (13.0%) had peri-nodal extension (PNE), 212 (16.0%) lympho-vascular invasion (LVI), and 21 (1.6%) were metaplastic; 1256 (96.8%) received chemotherapy including 820 (63.2%) neoadjuvant with 306 (40.0%) pCR. Grade ≥3 toxicities occurred in 155 (12.4%) including two deaths and 3 s-primaries. 1234 (95.2%) underwent surgery [722 (55.7%) breast conservations] and 1034 (79.7%) received radiotherapy.At a median follow-up of 54 months, median disease-free (DFS) was 92.2 months and overall survival (OS) was not reached. 5-year estimated DFS and OS was 65.9% and 80.3%. There were 259 (20.0%) failures; predominantly distant (204, 15.7%) - lung (51%), liver (31.8%).In multivariate analysis presence of LVI (HR-2.00, p-0.003), PNE (HR-2.09 p-0.003), older age (HR-1.03, p-0.002) and stage III disease (HR-4.89, p-0.027), were associated with poor OS. Conclusion: Relatively large contemporary data of non-metastatic TNBC confirms aggressive biology and predominant advanced stage presentation which adversely affects outcomes. The data strongly indicate the unmet need for early detection to optimize care.

Background: Young (≤40 years) breast cancers (YBC) are uncommon, inadequately represented in trials and have unique concerns and merit studying. Methods: The YBC treated with a curative intent between 2015 and 2016 at our institute were analysed. Results: There were 1228 patients with a median age of 36 (12–40) years; 38 (3.1%) had Stage I, 455 (37.1%) - II, 692 (56.3%) –III, and remaining 43 (3.5%) Stage IV (oligo-metastatic) disease; 927 (75.5%) were node positive; 422 (34.4%) were Triple negatives (TNBC), 331 (27%) were HER-2 positive. There were 549 (48.2%) breast conservations and 591 (51.8%) mastectomies of which 62 (10.4%) underwent breast reconstruction. 1143 women received chemotherapy, 617 (53.9%) received as neoadjuvant and 142 (23.1%) had pathological complete response; 934 (81.9%) received adjuvant radiotherapy. At the median follow-up of 48 (0–131) months, 5-year overall and disease-free survival was 79.6% (76.8–82.5) and 59.1% (55.8–62.6). For stage I, II, III and IV, the 5-year overall-survival was 100%, 86.7% (82.8–90.6), 77.3% (73.4–81.2), 69.7% (52.5–86.9) and disease-free survival was 94% (85.9–100), 65.9% (60.3–71.5), 55% (50.5–59.5), and 29.6% (14–45.2) respectively. On multivariate analysis, TNBC and HER-2+ subgroups had poorer survival (p = 0.0035). 25 patients had BRCA mutations with a 5-year DFS of 65.1% (95% CI:43.6–86.6). Fertility preservation was administered in 104 (8.5%) patients; seven women conceived and 5 had live births. Significant postmenopausal symptoms were present in 153 (13%) patients. Conclusion: More than half of the YBC in India were diagnosed at an advanced stage with aggressive features leading to suboptimal outcomes. Awareness via national registry and early diagnosis is highly warranted. Menopausal symptoms and fertility issues are prevalent and demand special focus.

Advancement in deep learning is mapping to every field of life and applying it to almost all research problems. Numerous Deep Convolutional Neural Network (DCNN) architectures are being proposed, giving different results based on the depth and value of hyperparameters. The entire development of such DCNN architectures from scratch needs a lot of effort, and such architectures may not be used for other applications than the one they are structured for. Transfer learning is a way to modify these pre-trained networks to make them suitable for newer diverse applications. This paper attempts to empirically assess the performance and suitability of existing pre-trained DCNN architectures for human face liveness detection. Due to the advent of ambient computing for contactless identification of humans using their biometric traits, human face liveness detection proves to be an important research area. Six pre-trained DCNN models, alias VGG16, VGG19, DensNet121, Xception, MobileNet, and InceptionV3, are considered for empirical assessment in human face liveness detection. The method is explored using two face liveness detection datasets - NUAA and Replay-Attack. Face Liveness Accuracy, and Half Total Error Rate (HTER) are considered prime performance evaluation metrics. At a learning rate of 10−4, the VGG19 network with scenario “Original VGG” gives the highest face liveness detection accuracy, which is the outcome of current research.

Background: Pregnancy associated breast cancer (PABC) is a rare entity and defined as breast cancer diagnosed during pregnancy or one-year post-partum. There is sparse data especially from low and middle-income countries (LMIC) and merits exploration. Methods: The study (2013–2020) evaluated demographics, treatment patterns and outcomes of PABC. Results: There were 104 patients, median age of 31 years; 43 (41%) had triple-negative disease, 31(29.8%) had hormone-receptor (HR) positive and HER2 negative, 14 (13.5%) had HER2-positive and HR negative and 16(15.4%) had triple positive disease. 101(97%) had IDC grade III tumors and 74% had delayed diagnosis. 72% presented with early stage (24, EBC) or locally advanced breast cancer (53, LABC) and received either neoadjuvant (n = 49) or adjuvant (n = 26) chemotherapy and surgery. Trastuzumab, tamoxifen, and radiotherapy were administered post-delivery. At a median follow up of 27 (IQR:19–35) months, the estimated 3-year event-free survival (EFS) for EBC and LABC was 82% (95% CI: 65.2–100) and 56% (95% CI: 42–75.6%) and for metastatic 24% (95% CI: 10.1%–58.5%) respectively.Of the 104 patients, 34 were diagnosed antepartum (AP) and 15 had termination, 2 had preterm and 16 had full-term deliveries(FTDs). Among postpartum cohort (n = 70), 2 had termination, 1 had preterm, 67 had FTDs. 83(including 17 from AP) children from both cohorts were experiencing normal milestones. Conclusion: Data from the first Indian PABC registry showed that the majority had delayed diagnosis and aggressive features(TNBC, higher grade). Treatment was feasible in majority and stage matched outcomes were comparable to non-PABCs.

Introduction: Rosai-Dorfman disease (RDD) is a rare, idiopathic, proliferative disorder of histiocytes usually involving head-neck lymph nodes. It can also involve extra nodal sites like skin, nasal sinuses, and soft tissue. It rarely affects the breast. Case presentation: We present three unusual case scenarios of breast RDD. One presented with breast lump, clinico-radiologically mimicking early breast cancer. The second case was thought to be de-novo metastatic breast cancer, but was found to have disseminated RDD of breast, lymph nodes and bones. The third patient was that of cervical lymphadenopathy in a breast cancer survivor masquerading as recurrence. In all 3, histopathology showing emperipolesis and immunohistochemical staining with S100 clinched the diagnosis. Discussion: The diagnosis of RDD is made by histopathology. The classic histological picture consists of a lymphoid rich associated infiltrate, atypical nuclei of the histiocytes and lack of fat necrosis or acute inflammatory cells. These histiocytes typically stain positive with S100 and CD168 on immunohistochemistry. Hence, an excision biopsy is often necessary, and mostly the only treatment needed. However, if the disease is disseminated or has massive lymphadenopathy, a course of oral steroids or chemotherapy is indicated. Conclusion: RDD of the breast usually has an indolent, benign, and non-aggressive course that requires minimum treatment. A high index of suspicion and accurate histopathological diagnosis is utmost important for proper management.

Nowadays, plants have been considered as powerful agents for treatment of disorders regarding to their traditional use. Plants have a special role in the treatment of various diseases in Ayurveda (Indian Traditional Medicine). Diabetes with their devastating outcomes has been discussed in Ayurveda as well. In the present study, a marketed polyherbal products (DBC & DMV), retrieved from Ayurveda, was purchased from market and its pharmacognostic standardization were performed. Quality control test for the Ayurveda tablets were performed as per Indian Pharmacopoeia. In addition to the dissolution studies for the poly herbal Ayurveda marketed formulations were assessed based on the phenolic content. Fingerprinting of phytochemical constituents of DBC & DMV was performed using spectroscopical (like IR and UV) and chromatographic techniques like HPTLC and TLC. The results showed that DBC & DMV was successfully passed quality control tests. Moreover, DBC & DMV exhibited different pharmacognostic behavior of all herbs present in the product. In addition, TLC, IR and HPTLC fingerprinting of DBC & DMV demonstrated the presence of several phenolic constituents corresponding to the poly herbs. Regarding to the role of phenolic compounds in diabetic process, DBC & DMV could be an appropriate candidate for diabetic with respect to its traditional use in Ayurveda formulation. Moreover, HPTLC fingerprinting could be utilized as an applicable method for quality control of the prepared formulation. Keywords: HPTLC fingerprinting, Ayurveda formulations, Dissolution studies, Standardisation, Spectroscopical evaluation

Low dose Methotrexate (MTX) therapy is considered a gold standard for Rheumatoid Arthritis (RA). Transdermal drug delivery is hypothesized as an alternative to conventional therapies to alleviate its adverse effects. In our study, MTX was entrapped in deformable liposomes and loaded in a hydroxyethyl cellulose gel. This system was evaluated by the Box Behnken statistical design for optimization. The effect of formulation variables on particle size, entrapment and ex vivo skin permeation was studied. The MTX nanogel was evaluated for its dermal toxicity (acute and repeat dose safety), in vivo biodistribution (using 125I radio-labelled MTX) and therapeutic efficacy (collagen induced arthritis [CIA] model). The optimized formulation demonstrated appreciable nanosize (110 ± 20 nm), drug entrapment (42 ± 1.9%) and high ex vivo transdermal flux (17.37 ± 1.5 μg/cm2/hr). In the dermal toxicity studies, nanogel formulation did not show any signs of irritation or toxicity, whereas in the biodistribution study, the MTX nanogel formulation depicted sustained systemic delivery up to 48 h with low accumulation in its organs of toxicity such as the liver, kidneys and gut. In the CIA model, the MTX nanogel significantly ameliorated hind paw swelling, reduced arthritic score, joint damage (histological, radiological examination) and attenuated the rise in serum cytokines such as TNF-ɑ and IL-6. In conclusion, the optimized MTX nanogel formulation displayed skin biocompatibility, sustained systemic delivery, safety as well as therapeutic efficacy.

Background: This phase 3, multi-center, open-label study evaluated the immunogenicity and safety of a quadrivalent meningococcal conjugate vaccine (MenACWY-CRM, Menveo®; Novartis Vaccines and Diagnostics S.r.l., Siena, Italy) in healthy Indian subjects aged 2–75 years, to provide data for licensure in India. Methods: A total of 180 subjects were enrolled (60 subjects 2–10 years, 60 subjects 11–18 years, and 60 subjects 19–75 years) and received one dose of MenACWY-CRM. Serum bactericidal activity with human complement (hSBA) was measured before and 1 month after vaccination. Adverse events were collected throughout the 29-day study period. Results: Percentages of subjects with post-vaccination hSBA ≥8 were 72%, 95%, 94%, and 90% for serogroups A, C, W, and Y, respectively. Geometric mean titers rose 7-fold to 42-fold against the four serogroups. Similar immune responses were observed for the age subgroups 2–10 years, 11–18 years, and 19–75 years. Seroresponse rates at 1 month following vaccination were 72%, 88%, 55%, and 71% for serogroups A, C, W, and Y, respectively. The vaccine was well tolerated with no safety concerns. Conclusion: A single dose of MenACWY-CRM induced a robust immune response against all four meningococcal serogroups and was well tolerated in an Indian population 2–75 years of age.

E6 associated protein is an E3 ubiquitin ligase encoded by the gene Ube3a. Deletion or loss of function of the maternally inherited allele of Ube3a leads to Angelman syndrome. In the present study, we show that maternal loss of Ube3a (Ube3am−/p+) in the mouse model leads to motor deficits that could be attributed to the dysfunction of the nigrostriatal pathway. The number of tyrosine hydroxylase positive neurons in the substantia nigra was significantly reduced in Ube3am−/p+ mice as compared to the wild type counterparts. The Ube3am−/p+ mice performed poorly in behavioural paradigms sensitive to nigrostriatal dysfunction. Even though the tyrosine hydroxylase staining was apparently the same in the striatum of both genotypes, the presynaptic and postsynaptic proteins were significantly reduced in Ube3am−/p+ mice. These findings suggest that the abnormality in the nigrostriatal pathway along with the cerebellum produces the observed motor dysfunctions in Ube3am−/p+ mice.

The eEF1 family of mammalian translation elongation factors is comprised of the two variants of eEF1A (eEF1A1 and eEF1A2), and the eEF1B complex. The latter consists of eEF1Bα, eEF1Bβ, and eEF1Bγ subunits. The two eEF1A variants have similar translation activity but may differ with respect to their secondary, “moonlighting” functions. This variability is underlined by the difference in the spatial organization of eEF1A1 and eEF1A2, and also possibly by the differences in their post-translational modifications. Here, we review the data on the spatial organization and post-translation modifications of eEF1A1 and eEF1A2, and provide examples of their involvement in various processes in addition to translation. We also describe the structural models of eEF1B subunits, their organization in the subcomplexes, and the trimeric model of the entire eEF1B complex. We discuss the functional consequences of such an assembly into a complex as well as the involvement of individual subunits in non-translational processes.

Translation elongation factor 1Bβ (eEF1Bβ) is a metazoan-specific protein involved into the macromolecular eEF1B complex, containing also eEF1Bα and eEF1Bγ subunits. Both eEF1Bα and eEF1Bβ ensure the guanine nucleotide exchange on eEF1A while eEF1Bγ is thought to have a structural role. The structures of the eEF1Bβ catalytic C-terminal domain and neighboring central acidic region are known while the structure of the protein-binding N-terminal domain remains unidentified which prevents clear understanding of architecture of the eEF1B complex. Here we show that the N-terminal domain comprising initial 77 amino acids of eEF1Bβ, eEF1Bβ(1-77), is a monomer in solution with increased hydrodynamic volume. This domain binds eEF1Bγ in equimolar ratio. The CD spectra reveal that the secondary structure of eEF1Bβ(1-77) consists predominantly of α-helices and a portion of disordered region. Very rapid hydrogen/deuterium exchange for all eEF1Bβ(1-77) peptides favors a flexible tertiary organization of eEF1Bβ(1-77). Computational modeling of eEF1Bβ(1-77) suggests several conformation states each composed of three α-helices connected by flexible linkers. Altogether, the data imply that the protein-binding domain of eEF1Bβ shows flexible spatial organization which may be needed for interaction with eEF1Bγ or other protein partners., (Copyright © 2018 Elsevier B.V. All rights reserved.)

An enhanced understanding of the cellular characteristics contributing to ongoing brain injury following intrapartum hypoxia-ischemia has resulted in the implementation of targeted neuroprotective strategies in the newborn period. This review briefly covers the pathogenesis of hypoxic-ischemic injury with an emphasis on reperfusion injury; the role of magnetic resonance imaging in the detection of such injury, and focuses on potential strategies both supportive and neuroprotective to prevent ongoing injury with a specific emphasis on modest hypothermia.