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Supplemental material, sj-docx-2-tam-10.1177_17588359221126149 for Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial by Maria-Pilar Barretina-Ginesta, Bradley J. Monk, Sileny Han, Bhavana Pothuri, Annika Auranen, Dana M. Chase, Domenica Lorusso, Charles Anderson, Sophie Abadie-Lacourtoisie, Noelle Cloven, Elena I. Braicu, Amnon Amit, Andrés Redondo, Ruchit Shah, Nehemiah Kebede, Carol Hawkes, Divya Gupta, Tatia Woodward, David M. O’Malley and Antonio González-Martín in Therapeutic Advances in Medical Oncology

Supplemental material, sj-docx-1-tam-10.1177_17588359221126149 for Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial by Maria-Pilar Barretina-Ginesta, Bradley J. Monk, Sileny Han, Bhavana Pothuri, Annika Auranen, Dana M. Chase, Domenica Lorusso, Charles Anderson, Sophie Abadie-Lacourtoisie, Noelle Cloven, Elena I. Braicu, Amnon Amit, Andrés Redondo, Ruchit Shah, Nehemiah Kebede, Carol Hawkes, Divya Gupta, Tatia Woodward, David M. O’Malley and Antonio González-Martín in Therapeutic Advances in Medical Oncology

The β-lactam antibiotics are the most effective medicines for treating bacterial infections. Resistance to them, particularly through the production of β-lactamases, which can hydrolyse all kinds of β-lactams, poses a threat to their continued use. The synthesised flavone and coumarin based isoxazole derivatives have the potential to be used as broad-spectrum inhibitors of the mechanistically different serine-(SBL) and metallo-β-lactamases (MBL). The synthesised compounds were discovered as potent β-lactamase inhibitors using molecular docking and in silico pharmacokinetic analysis. We studied the binding of chemically synthesised inhibitors to clinically significant β-lactamases of class A, B, and C using biophysical and biochemical approaches, and computational analyses. These molecules follow Lipinski’s rule of five and have acceptable solubility, permeability, and oral bioavailability. These molecules were found to be non-toxic and non-carcinogenic. MIC results suggest that these molecules restore the antibiotic efficacy against class A, B, and C β-lactamases. Kinetics data showed that these molecules reduce the catalytic efficiency of clinically relevant class A, B, and C β-lactamases. Fluorescence study showed significant interaction between these flavone-/coumarin-based isoxazole derivatives and class A/B/ C β-lactamases. This study showed promising effect of these new generation compounds as broad spectrum β-lactamase inhibitors of both SBLs and MBLs. Communicated by Ramaswamy H. Sarma

Supplemental material, sj-docx-2-tam-10.1177_17588359221126149 for Quality-adjusted time without symptoms of disease or toxicity and quality-adjusted progression-free survival with niraparib maintenance in first-line ovarian cancer in the PRIMA trial by Maria-Pilar Barretina-Ginesta, Bradley J. Monk, Sileny Han, Bhavana Pothuri, Annika Auranen, Dana M. Chase, Domenica Lorusso, Charles Anderson, Sophie Abadie-Lacourtoisie, Noelle Cloven, Elena I. Braicu, Amnon Amit, Andrés Redondo, Ruchit Shah, Nehemiah Kebede, Carol Hawkes, Divya Gupta, Tatia Woodward, David M. O’Malley and Antonio González-Martín in Therapeutic Advances in Medical Oncology

Ultraviolet (UV) exposure to the skin causes photo-damage and acts as the primary etiological agent in photo-carcinogenesis. UV-B exposure induces cellular damage and is the major factor challenging skin homeostasis. Autophagy allows the fundamental adaptation of cells to metabolic and oxidative stress. Cellular dysfunction has been observed in aged tissues and in toxic insults to cells undergoing stress. Conversely, promising anti-aging strategies aimed at inhibiting the mTOR pathway have been found to significantly improve the aging-related disorders. Recently, autophagy has been found to positively regulate skin homeostasis by enhancing DNA damage recognition. Here, we investigated the geno-protective roles of autophagy in UV-B-exposed primary human dermal fibroblasts (HDFs). We found that UV-B irradiation to HDFs impairs the autophagy response in a time- and intensity-independent manner. However, improving autophagy levels in HDFs with pharmacological activators regulates the UV-B-induced cellular stress by decreasing the induction of DNA photo-adducts, promoting the DNA repair process, alleviating oxidative and ER stress responses, and regulating the expression levels of key cell cycle regulatory proteins. Autophagy also prevents HDFs from UV-B-induced nuclear damage as is evident in TUNEL assay and Acridine Orange/Ethidium Bromide co-staining. Salubrinal (an eIF2α phosphatase inhibitor) relieves ER stress response in cells and also significantly alleviates DNA damage and promotes the repair process in UV-B-exposed HDFs. P62-silenced HDFs show enhanced DNA damage response and also disturb the tumor suppressor PTEN/pAKT signaling axis in UV-B-exposed HDFs whereas Atg7-silenced HDFs reveal an unexpected consequence by decreasing the UV-B-induced DNA damage. Taken together, these results suggest that interventional autophagy offers significant protection against UV-B radiation-induced photo-damage and holds great promise in devising it as a suitable therapeutic strategy against skin pathological disorders.

Cutaneous photodamage is incited via exposure of ultraviolet-B (UV-B) radiation to skin, characterized by the manifestation of oxidative stress, inflammation, collagen degradation and apoptosis which translates to external aging signs such as wrinkle formation and leathery skin appearance. Meanwhile, it increases cellular susceptibility to photocarcinogenesis. Several studies have accumulated evidence regarding the usage of natural agents in reversing the clinical signs of photoaging as well as preventing photo-toxicity at molecular level. In this study, we have explored the therapeutic potential of natural agent Trigonelline (TG) against UV-B radiation mediated skin photodamage. Various parameters modulated by the exposure of UV-B radiation were investigated in human skin cells and chronic photodamage mice model (Balb/c). We found that TG alleviates UV-B radiation induced photodamage in human skin cells and Balb/c skin mice. TG treatment in UV-B irradiated skin cells abates UV-B radiation mediated phototoxicity, oxidative stress, inflammation and apoptosis. At molecular level, we observed TG treatment significantly prevents the reactive oxygen species (ROS) generation and lipid peroxidation, restores collagen synthesis and matrix metalloproteinase (MMPs) levels. The in vitro findings were replicated in the in vivo model. We found that the TG acts potentially via modulation of ROS-MAPKs-NF-κB axis. Collectively, we propose that TG acts antagonistically against UV-B mediated skin damage and has strong potential to be developed as a therapeutic and cosmetical agent against photodamage disorders.

We introduce Blockene, a blockchain that reduces resource usage at member nodes by orders of magnitude, requiring only a smartphone to participate in block validation and consensus. Despite being lightweight, Blockene provides a high throughput of transactions and scales to a large number of participants. Blockene consumes negligible battery and data in smartphones, enabling millions of users to participate in the blockchain without incentives, to secure transactions with their collective honesty. Blockene achieves these properties with a novel split-trust design based on delegating storage and gossip to untrusted nodes. We show, with a prototype implementation, that Blockene provides throughput of 1045 transactions/sec, and runs with very low resource usage on smartphones, pointing to a new paradigm for building secure, decentralized applications., Comment: A version of this paper (without the appendix) will appear in OSDI 2020

Objective This prospective randomised double-blind study was conducted to compare the effect of intravenous (IV) with intraperitoneal (IP) administration of clonidine with respect to analgesic efficacy and side effects. Methods A total of 60 American Society of Anaesthesiologists (ASA) physical status class I and II patients, aged 35–60 years, undergoing total abdominal hysterectomy, were randomly divided into 2 groups. Standard general anaesthesia technique was used. All the patients in group IV received 3 μg kg−1 of IV clonidine after resection of the uterus along with 0.25% bupivacaine (20 mL intraperitoneally and 10 mL as wound infiltration), whereas patients in group IP received 10 mL of normal saline intravenously and 3 μg kg−1 of clonidine mixed with 0.25% bupivacaine (20 mL intraperitoneally and 10 mL as wound infiltration). Postoperative analgesia was provided with IV diclofenac every 8 hours and IV fentanyl (1 μg kg−1) on demand. Pain at rest, opioid consumption, level of sedation and severity of nausea were recorded for 24 hours. The heart rate (HR) and blood pressure (BP) were recorded at an interval of 15 minutes for 2 hours followed by routine hourly monitoring. Results Both the groups were found to be similar with respect to demography and ASA physical status. The maximum pain was felt at 6 hours in both the groups. The mean visual analogue scale score at 6 hours (p=0.47) was comparable. However, patients in group IV had significantly higher sedation (p

TPS6101 Background: Despite surgery and CT (paclitaxel + carboplatin ± bevacizumab [bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3 or 4 OC. Niraparib is a poly (ADP-ribose) polymerase (PARP) inhibitor that has recently demonstrated efficacy in 1L therapy. Dostarlimab (TSR-042) is an anti-programmed death (PD)-1 humanized monoclonal antibody that has shown clinical activity as monotherapy in early phase trials. The currently enrolling ENGOT-OV44/FIRST study will compare efficacy and safety of CT + dostarlimab + niraparib ± bev (Arm 3) vs CT + niraparib ± bev (Arm 2). Methods: Eligible pts are ≥18 years of age, with FIGO stage 3 or 4 non-mucinous epithelial OC, ECOG performance status < 2, and tumor tissue available for PD-1 ligand (PD-L1) testing. After cycle 1 of CT, pts are stratified by concurrent bev use, BRCA mutation/homologous recombination repair status, and disease burden, then randomized 1:2 into trial Arms 2 and 3 (Table). Dostarlimab is administered at 500 mg IV Q3W during the CT period, then 1000 mg IV Q6W during the maintenance period. Niraparib dosing is 200 mg PO QD for pts with baseline bodyweight (BW) < 77 kg and/or platelet count (PC) < 150,000/µL, or 300 mg QD for pts with baseline BW ≥77 kg and PC ≥150,000/µL. The dual primary endpoints are PFS, based on investigator assessment per RECIST v1.1, in both PD-L1+ and all patients. Initially the study enrolled pts to Arm 1. This arm was discontinued following positive results from the PRIMA/ENGOT-OV26/GOG-3012 and PAOLA-1/ENGOT-OV25 studies. This allows investigators to offer the current standard of care to all patients. Clinical trial information: NCT03602859, EUDRACT 2018-000413-20. [Table: see text]

The discovery of NDM-1 and its variants has caused the emergence of antibiotic resistance in the community and hospital setting, causing major concern for health care across the globe. New Delhi Metallo-β-lactamase is known to hydrolyse almost all β-lactam antibiotics. Studies have shown the hydrolytic activates of NDM-1 and some of its variants, however a comparative study of these NDM variants has not been explored in detail. Hence, we proposed to check their catalytic activity by performing a comparative study between NDM-1 and its variants. The study was initiated to clone NDM variants (NDM-1, NDM-4, NDM-5, NDM-6 and NDM-7) followed by overexpression of the recombinant proteins to check their hydrolytic properties against β-lactam antibiotics. The minimum inhibitory concentration of carbapenems antibiotics for blaNDM-5 clone was found four fold increased, whereas no change was observed in the clones having other variants. The hydrolytic activity of carbapenem with NDM-5 variant was found to be augmented as per the kinetics parameter where Km was decreased and kcat, kcat/Km values increased as compared to the NDM-1. Molecular docking studies were employed to identify the variations in the binding ability among all NDM variants with imipenem or meropenem. Simulation studies at 100 ns showed a good stability of NDM-5 with imipenem and meropenem as compared to NDM-1. CD spectroscopy data revealed significant changes in the secondary structure of NDM variants. We conclude that NDM-5 showed higher hydrolytic activity as compared to other variants. This study provides a comparative analysis of the severity of NDM producing strains.

Interview guide. (DOCX 16 kb)

Industrial growth, urbanization and wrong agricultural practices are responsible for pollution and loss of environmental quality. Petro plastics, produced from mineral resources, are one of the most important materials, but the production process destructs the environment. Bio-based and biodegradable plastics can form the basis for environmentally preferable and sustainable alternative to current materials based exclusively on petroleum feed stocks. Bioplastic helps us to overcome the problem of pollution caused by synthetic plastics as they originate from renewable resources and are a new generation of plastics able to significantly reduce the environmental impact in terms of energy consumption and greenhouse effect. Polyhydroxyalkanoate (PHA) emerges as a potential candidate in a way to be used as a biopolymer material which not only possesses the characteristic similar to the traditional plastic, but it is also biodegradable in nature without any toxic production .A way to reduce the production cost is the use of alternative substrates, such as the agro industrial wastes. This review gives an overview of economical strategies to reduce production costs of PHA as well as its applications in various fields.

Augmented reality provides its user with additional information not available through the natural real-world environment. This additional information displayed to the user potentially poses a risk of perceptual and cognitive load and vision-based difficulties. The presence of real-world objects together with virtual augmenting information requires the user to repeatedly switch eye focus between the two in order to extract information from both environments. Switching eye focus may result in additional time on user tasks and lower task accuracy. Thus, one of the goals of this research was to understand the impact of switching eye focus between real-world and virtual information on user task performance. Secondly, focus depth, which is an important parameter and a depth cue, may affect the user's view of the augmented world. If focus depth is not adjusted properly, it may result in vision-based difficulties and reduce speed, accuracy, and comfort while using an augmented reality display. Thus, the second goal of this thesis was to study the effect of focus depth on task performance in augmented reality systems. In augmented reality environments, real-world and virtual information are found at different distances from the user. To focus at different depths, the user's eye needs to accommodate and converge, which may strain the eye and degrade performance on tasks. However, no research in augmented reality has explored this issue. Hence, the third goal of this thesis was to determine if distance of virtual information from the user impacts task performance. To accomplish these goals, a 3x3x3 within subjects design was used. The experimental task for the study required the user to repeatedly switch eye focus between the virtual text and real-world text. A monocular see-through head- mounted display was used for this research. Results of this study revealed that switching between real-world and virtual information in augmented reality is extremely difficult when information is displayed at optical infinity. Virtual information displayed at optical infinity may be unsuitable for tasks of the nature used in this research. There was no impact of focus depth on user task performance and hence it is preliminarily recommended that manufacturers of head-mounted displays may only need to make fixed focus depth displays; this clearly merits additional intensive research. Further, user task performance was better when focus depth, virtual information, and real-world information were all at the same distance from the user as compared to conditions when they were mismatched. Based on this result we recommend presenting virtual information at the same distance as real-world information of interest. Master of Science