Enhancing Natural Killer and CD8 + T Cell-Mediated Anticancer Cytotoxicity and Proliferation of CD8 + T Cells with HLA-E Monospecific Monoclonal Antibodies

Cytotoxic NK/CD8+ T cells interact with MHC-I ligands on tumor cells through either activating or inhibiting receptors. One of the inhibitory receptors is CD94/NKG2A. The NK/CD8+ T cell cytotoxic capability is lost when tumor-associated human leukocyte antigen, HLA-E, binds the CD94/NKG2A receptor, resulting in tumor progression and reduced survival. Failure of cancer patients to respond to natural killer (NK) cell therapies could be due to HLA-E overexpression in tumor tissues. Preventing the inhibitory receptor-ligand interaction by either receptor- or ligand-specific monoclonal antibodies (mAbs) is an innovative passive immunotherapeutic strategy for cancer. Since receptors and ligands can be monomeric or homo- or heterodimeric proteins, the efficacy of mAbs may rely on their ability to distinguish monospecific (private) functional epitopes from nonfunctional common (public) epitopes. We developed monospecific anti-HLA-E mAbs (e.g., TFL-033) that recognize only HLA-E-specific epitopes, but not epitopes shared with other HLA class-I loci as occurs with currently available polyreactive anti-HLA-E mAbs. Interestingly the amino acid sequences in the α1 and α2 helices of HLA-E, critical for the recognition of the mAb TFL-033, are strikingly the same sequences recognized by the CD94/NKG2A inhibitory receptors on NK/CD8+ cells. Such monospecific mAbs can block the CD94/NKG2A interaction with HLA-E to restore NK cell and CD8+ anticancer cell cytotoxicity. Furthermore, the HLA-E monospecific mAbs significantly promoted the proliferation of the CD4-/CD8+ T cells. These monospecific mAbs are also invaluable for the specific demonstration of HLA-E on tumor biopsies, potentially indicating those tumors most likely to respond to such therapy. Thus, they can be used to enhance passive immunotherapy once phased preclinical studies and clinical trials are completed. On principle, we postulate that NK cell passive immunotherapy should capitalize on both of these features of monospecific HLA-E mAbs, that is, the specific determination HLA-E expression on a particular tumor and the enhancement of NK cell/CD8+ cytotoxicity if HLA-E positive

Analisis Asupan Makanan Dan Estimasi Risiko Kesehatan Penduduk Di Kawasan Pertambangan Emas Tradisional - Gunung Pongkor, Kabupaten Bogor, Provinsi Jawa Barat

Traditional gold mining activities can increase the concentration of mineral contaminants enter into the environment and into the food chain. In artisanal gold mining Gunung Pongkor, Bogor Regency, arsenic has been detected in food samples from local production. Intake rate of arsenic into human body can cause effects that are non-carcinogenic and carcinogenic. The aim of this study is to assess the risk estimates due to arsenic exposure in food samples, the health effect, and also to formulate risk management. This study was using data from Riset Khusus Pencemaran Lingkungan 2012 organized by National Institute of Health Research and Development, Ministry of Health. The results showed that non-carcinogen risk level (RQ) are 28,55 and lifetime excess cancer risk (ECR) are 5,49 x10-3. This levels are unacceptable (RQ>1 and ECR>10-4). Highly consumption of rice everyday and also high level arsenic contaminant in rice are the major of relative contributor sources. Potential health effects, especially skin lesions (keratosis and hyperpigmentation,) has occurred. Risk management options need to be done were decreasing exposure level and reducing consumption of local food products

Molecular Simulations of the Ribosome and Associated Translation Factors

The ribosome is a macromolecular complex which is responsible for protein synthesis in all living cells according to their transcribed genetic information. Using X-ray crystallography and, more recently, cryo-electron microscopy (cryo-EM), the structure of the ribosome was resolved at atomic resolution in many functional and conformational states. Molecular dynamics simulations have added information on dynamics and energetics to the available structural information, thereby have bridged the gap to the kinetics obtained from single-molecule and bulk experiments. Here, we review recent computational studies that brought notable insights into ribosomal structure and function.Comment: 11 pages, 3 figures, to be published in Current Opinion in Structural Biolog

Detecting multiple, simultaneous talkers through localising speech recorded by ad-hoc microphone arrays

This paper proposes a novel approach to detecting multiple, simultaneous talkers in multi-party meetings using localisation of active speech sources recorded with an ad-hoc microphone array. Cues indicating the relative distance between sources and microphones are derived from speech signals and room impulse responses recorded by each of the microphones distributed at unknown locations within a room. Multiple active sources are localised by analysing a surface formed from these cues and derived at different locations within the room. The number of localised active sources per each frame or utterance is then counted to estimate when multiple sources are active. The proposed approach does not require prior information about the number and locations of sources or microphones. Synchronisation between microphones is also not required. A meeting scenario with competing speakers is simulated and results show that simultaneously active sources can be detected with an average accuracy of 75% and the number of active sources counted accurately 65% of the time

Trends in use of e-cigarette device types and heated tobacco products from 2016 to 2020 in England

This study examined use trends of e-cigarette devices types, heated tobacco products (HTPs) and e-liquid nicotine concentrations in England from 2016 to 2020. Data were from a representative repeat cross-sectional survey of adults aged 16 or older. Bayesian logistic regression was used to estimate proportions and 95% credible intervals (CrIs). Of 75,355 participants, 5.3% (weighted = 5.5%) were currently using e-cigarettes or HTPs, with the majority (98.7%) using e-cigarettes. Among e-cigarette users, 53.7% (CrI 52.0–55.1%) used tank devices, 23.7% (22.4–25.1%) mods, 17.3% (16.1–18.4%) pods, and 5.4% (4.7–6.2%) disposables. Tanks were the most widely used device type throughout 2016–2020. Mods were second until 2020, when pods overtook them. Among all e-cigarette/HTP users, prevalence of HTP use remains rare (3.4% in 2016 versus 4.2% in 2020), whereas JUUL use has risen from 3.4% in 2018 to 11.8% in 2020. Across all years, nicotine concentrations of ≤ 6 mg/ml were most widely (41.0%; 39.4–42.4%) and ≥ 20 mg/ml least widely used (4.1%; 3.4–4.9%). Among e-cigarette/HTP users, ex-smokers were more likely than current smokers to use mod and tank e-cigarettes, but less likely to use pods, disposables, JUUL and HTPs. In conclusion, despite growing popularity of pods and HTPs worldwide, refillable tank e-cigarettes remain the most widely used device type in England