Kennedyclark8796

BACKGROUND Acute lymphocytic leukemia (ALL) is a common blood cancer which induces high mortality in children. Bromodomains and extra-terminal (BET) protein inhibitors, such as JQ1 and ARV-825, are promising cancer therapeutic agents that can be used by targeting c-Myc. A recent work reported that JQ1 effectively attenuates ALL in vitro by suppressing cell proliferation and accelerating apoptosis. The purpose of this research was to probe into the potential mechanism of how JQ1 inhibits ALL cell proliferation in vitro. MATERIAL AND METHODS Cell viability of ALL cells were measured by CTG after treatment by JQ1. Cell cycle analysis was done by EdU and PI staining. Cell apoptosis was assessed by Annexin V/PI staining. Glycolysis was detected using Seahorse and LC-MS kits. The expression of glycolytic rate-limiting enzymes was assessed by RNA-seq, qRT-PCR, and Western blot. RESULTS JQ1 suppressed cell proliferation by arresting the cell cycle and inducing the apoptosis of acute lymphocytic leukemia cells. JQ1 inhibited cell proliferation of B-ALL cells by restraining glycolysis. Conversely, the cell cycle block of B-ALL cells induced by JQ1 was partially abolished after pretreatment with 2-Deoxy-D-glucose (2-DG), an inhibitor of glycolysis. Furthermore, JQ1 restrained the glycolysis of B-ALL cell lines by remarkably downregulating the rate-limiting enzymes of glycolysis, such as hexokinase 2, phosphofructokinase, and lactate dehydrogenase A. Moreover, the cell cycle arrest was reversed in B-ALL cells with overexpressed c-Myc treated by JQ1, which is involved in the enhancement of glycolysis. CONCLUSIONS The BET inhibitor JQ1 suppresses the proliferation of ALL by inhibiting c-Myc-mediated glycolysis, thus providing a new strategy for the treatment of ALL.The development of clinical applications has led to a perpetual increase in the demand for mesenchymal stem cells (MSCs). However, the ex vivo expansion of MSCs while maintaining their stemness and differentiation potential remains an immense challenge. MSCs require high cell density for their intercellular communication and specific physico-chemical cues from the surrounding environment for spheroid formation in order to maintain their stemness. Inadequacy of the traditional in vitro cell culture method (tissue culture plastic surface) to fulfill any of these special requirements is responsible for inducing the loss of stem cell properties of the MSCs over time. In this study, we propose that glucosaminoglycan (GAG) mimicking ultrafine nanofibers could support the spheroid culture for in vitro human MSC expansion. The geometrical and biochemical properties of nanofibers provide biomimicking cues to MSCs, as well as enhance cell-cell interactions and stimulate spheroid formation in MSCs, which subsequently result in increased cell proliferation, enhanced expression of stem cell markers and maintenance of their multilineage differentiation potential. Furthermore, close monitoring of the behavior of MSCs on nanofibers serves as the key to understand their mode of action in niche formation. Interestingly, GAG mimicking substrate stimulated MSCs for long-distance intercellular communication via 'tunneling tubes', their subsequent migration and niche formation. cisdiamminedichloroplatinumII These kinds of cellular interactions over long distances have rarely been observed in MSCs to provide better insight for future studies on MSC niche. Furthermore, PCL-CHT nanofibers were observed to be as conducive to use as tissue culture polystyrene for stem cell expansion. Overall, these polymeric nanofibers provide a more relevant, convenient and more suitable substrate than the conventional monolayer culture for in vitro MSC expansion.BACKGROUND Natural resource extraction projects offer both opportunities and risks for sustainable development and health in host communities. Often, however, the health of the community suffers. Health impact assessment (HIA) can mitigate the risks and promote the benefits of development but is not routinely done in the developing regions that could benefit the most. OBJECTIVE Our study aims to investigate health and health determinants in regions affected by extractive industries in Burkina Faso, Ghana, Mozambique, and Tanzania. The evidence generated in our study will inform a policy dialogue on how HIA can be promoted as a regulatory approach as part of the larger research initiative called the HIA4SD (Health impact assessment for sustainable development) project. METHODS The study is a concurrent triangulation, mixed methods, multi-stage, multi-focus project that specifically addresses the topics of governance and policy, social determinants of health, health economics, health systems, maternal and childteractions of resource extraction projects with their host communities requires an integrative approach drawing on many methodologies under the HIA umbrella. By using complementary data sources to address the question of population health in project areas from several angles, bias and missing data will be reduced, generating high-quality evidence to aid countries in moving toward sustainable development. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) DERR1-10.2196/17138. ©Andrea Farnham, Hermínio Cossa, Dominik Dietler, Rebecca Engebretsen, Andrea Leuenberger, Isaac Lyatuu, Belinda Nimako, Hyacinthe R Zabre, Fritz Brugger, Mirko S Winkler. Originally published in JMIR Research Protocols (http//www.researchprotocols.org), 08.04.2020.BACKGROUND Advances in biologic treatments have led to a new therapeutic frontier for moderate-to-severe psoriasis. Nevertheless, the efficacy of anti-TNFα decreases with time, requiring adjustments to maintain valuable Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) responses. OBJECTIVES To evaluate the efficacy and safety of adalimumab dose escalation (40 mg, subcutaneous, once a week for 24 weeks) in psoriatic adult patients with secondary loss of response (PASI ≥50 to ≤75 or PASI≥75 and DLQI ≥5). MATERIALS AND METHODS A multicentre, observational study involving different Italian third-level referral centres for psoriasis enrolled a total of 64 adult patients with moderate-to-severe psoriasis who were treated with adalimumab and experienced a secondary loss of response. Primary end-points were PASI> 75 or PASI ≥50 to ≤ 75 with DLQI ≤ 5, and the secondary end-point was the ability to maintain a therapeutic response, resuming adalimumab every other week. RESULTS At Week 16 and Week 24, 29/64 (45.3%) and 35/64 (54.6%) responded based on PASI, and mean DLQI was 4.9 and 4.09, respectively. At Week 36 and Week 48, 45.3% and 28.1% patients achieved the second end-point, respectively. No adverse events were recorded except for one patient with recurrent tonsillitis. CONCLUSION Adalimumab escalation could be considered in cases with loss of response before switching to alternative biologic therapy.BACKGROUND The management of keratinocyte carcinoma (KC) and actinic keratosis (AK) as well as the number of dermatologists differ across the Bavarian counties in Germany. OBJECTIVES To determine regions with low utilization rates of dermatological care and a high medical need due to AK and KC burden. MATERIALS AND METHODS A cross-sectional study of 2,483 people was carried out during the Munich Oktoberfest in September 2016. Participants from urban, semi-urban and rural areas completed a questionnaire and received a medical examination on site by dermatologists. RESULTS The rate of previous skin cancer screening and previous treatment by dermatologists ranged from 18.8% to 58.6% and from 34.3% to 75.4% for all regions, respectively. Over 60% of people living in the environs or rural areas would consult a dermatologist first if they found a visible skin condition. Thus, people living in urban areas were twice as likely as people living in rural areas to consult a dermatologist first (odds ratio = 2.16; 95% CI 1.38-3.39). link2 Comparing the three different locations, dermatologists detected the highest AK burden among people living in rural areas (27.3% of the participants) and the highest KC burden among people living in urban areas (3.4% of the participants). CONCLUSION In rural areas, a high AK burden coupled with a low utilization rate of dermatological care was observed. To effectively address these problems, a broader implementation of alternative medical resources, such as teledermatology, might improve access to health care.The recent pandemic associated with SARS-CoV-2, a virus of the Coronaviridae family, has resulted in an unprecedented number of infected people. The highly contagious nature of this virus makes it imperative for us to identify promising inhibitors from pre-existing antiviral drugs. Two druggable targets, namely 3C-like proteinase (3CLpro) and 2'-O-ribose methyltransferase (2'-O-MTase) were selected in this study due to their indispensable nature in the viral life cycle. 3CLpro is a cysteine protease responsible for the proteolysis of replicase polyproteins resulting in the formation of various functional proteins, whereas 2'-O-MTase methylates the ribose 2'-O position of the first and second nucleotide of viral mRNA, which sequesters it from the host immune system. The selected drug target proteins were screened against an in-house library of 123 antiviral drugs. Two promising drug molecules were identified for each protein based on their estimated free energy of binding (ΔG), the orientation of drug molecules in the active site and the interacting residues. The selected protein-drug complexes were then subjected to MD simulation, which consists of various structural parameters to equivalently reflect their physiological state. From the virtual screening results, two drug molecules were selected for each drug target protein [Paritaprevir (ΔG = -9.8 kcal/mol) & Raltegravir (ΔG = -7.8 kcal/mol) for 3CLpro and Dolutegravir (ΔG = -9.4 kcal/mol) and Bictegravir (ΔG = -8.4 kcal/mol) for 2'-OMTase]. After the extensive computational analysis, we proposed that Raltegravir, Paritaprevir, Bictegravir and Dolutegravir are excellent lead candidates for these crucial proteins and they could become potential therapeutic drugs against SARS-CoV-2. Communicated by Ramaswamy H. Sarma.Carbonic anhydrase IX (hCAIX) is a membrane-spanning metalloenzyme, encoded by CA9 gene, which can lead to various carcinomas if upregulated. Due to its overexpression in many cancer tissues, hCAIX has become a promising target for developing anticancer therapeutics. Furthermore, several classes of small-molecules have shown to inhibit the hCAIX expression. In this study, therefore, we screened (n = 42) plant-derived compounds to identify the most potent hCAIX inhibitors and to understand their interactions with hCAIX and drug candidacy through in silico approaches. link3 Among all, only 3 compounds (i.e., fraxoside, scopolin, and xanthone,) provided higher binding affinity towards hCAIX protein as compared to the native ligand. In standard docking, scopolin showed -4.97 kcal/mol of binding energy with hCAIX while control ligand provided -4.45 kcal/mol. In precise docking, the highest binding affinity was found for fraxoside (-7.67 kcal/mol) as compared to -3.04 kcal/mol of the control. The Gibbs free energy (ΔG) of these potent leads was also consistent and in support of the docking studies.