Metformin Use beyond Diabetes: Reducing Cardiovascular Events in the Healthy Elderly

As the global ageing population rises, there is increasing interest and demand for research evaluating anti-ageing strategies. One such strategy involves investigating a drug that may have additional mechanisms and pathways of action to combat ageing - metformin. This common glucose-lowering agent for diabetes has been safe, effective and globally affordable for over 60 years. Research into the use of metformin and its beneficial influence on healthy ageing is currently emerging. Although metformin’s effect on clinical ageing outcomes may be speculative, findings from studies into cellular and animal models and from observational and pilot human studies support its potential beneficial effects on ageing. Ageing has a significant impact on the cardiovascular system and is the leading non-modifiable risk factor for Cardiovascular Disease (CVD). The incidence and prevalence of CVD increases with advancing age, and CVD is the leading cause of death for populations over 65 years of age. However, most CVD prevention research has focused on development of interventions that target “traditional” CV risk factors such as hypertension, hypercholesterolaemia and diabetes. Metformin has been proposed to be an “anti-ageing” drug, based on preclinical experiments with lower-order organisms and numerous retrospective data on beneficial health outcomes for patients with type 2 diabetes. At present, randomised clinical trials to evaluate metformin’s clinical impact on healthy ageing are limited. Here, we review the role of metformin and its potential to reduce cardiovascular events in the healthy elderly

First-in-human phase I/II ICONIC trial of the ICOS agonist vopratelimab alone and with nivolumab: ICOS-high CD4 T-cell populations and predictors of response

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633

Factors impacting participation in research during the COVID-19 pandemic: results from a survey of patients in the ophthalmology outpatient department

BACKGROUND: Understanding public and patient attitudes to clinical research is paramount to successful recruitment. The COVID-19 pandemic has led to additional hurdles in achieving this. Our aim is to understand the current factors and attitudes towards clinical trial participation in order to assist in recruitment to clinical trials. METHODS: We conducted face-to-face interviews with patients in the outpatient department at a tertiary eye hospital facilitated by a 32-item questionnaire developed by the research team. Patient characteristics were correlated with their responses, in addition to qualitative thematic text analysis. RESULTS: A total of 53 patients were interviewed. Forty per cent indicated that they would be willing to participate in clinical research in the current climate. General motivating factors for involvement in research included personal gain, altruism and contribution to innovation. Factors limiting participation included concerns regarding own safety, inconvenience, accessibility and lack of benefit. 22.6% of participants felt that the COVID-19 pandemic has changed their outlook on research. These were categorised into positive (increased awareness of the importance and need for research, altruism) and negative (increased anxiety, need to minimise exposure to the hospital environment) influences. CONCLUSIONS: Factors influencing patients' decisions to participate in trials are similar to those observed prior to COVID-19 but with an increased focus on the environment the research is conducted in. The COVID-19 pandemic has had positive and negative impacts on patient attitudes towards research. Trial design, with a particular focus on setting and safety measures, in reassuring patients is increasingly important

Vesuvianite From Pajsberg, Sweden, and the Role of Be In the Vesuvianite Structure

Vesuvianite from Pajsberg, Sweden contains about one atom of Mn, based on 50 cations per formula unit, and small amounts of Be, B, and As. Optical absorption analysis suggests that the Mn is predominantly or entirely trivalent. Crystal-structure analysis indicates that Mn is housed at the general octahedral site Y3, which exhibits only minor distortion from ideal octahedral symmetry. Arsenic is housed at Y2 and Z2, and the formula derived from electron microprobe and LA-ICP-MS analyses suggests minor substitution of Al for Si, also at Z2. Beryllium and B are at T1, between the edge-sharing trimers Y3Y2Y3, as is the case for B in the boron-dominant vesuvianite species wiluite. The total content at T1 is interpreted as 0.82Be, 0.34B, and 0.037Fe^(3+)

First-In-Human Phase I Study of a Next-Generation, Oral, TGFβ Receptor 1 Inhibitor, LY3200882, in Patients with Advanced Cancer

Càncer avançat; Factor de creixement transformador betaAdvanced Cancer; Transforming Growth Factor betaCáncer avanzado; Factor de crecimiento transformador betaPurpose: A novel, selective, next-generation transforming growth factor beta (TGFβ) receptor type-1 small molecule inhibitor, LY3200882, demonstrated promising preclinical data. This first-in-human trial evaluated safety, tolerability, recommended phase II dose (RP2D), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of LY3200882 as monotherapy or with other anticancer agents in patients with advanced cancer. Patients and Methods: This phase I multicenter study of oral LY3200882 (NCT02937272) comprised dose escalation, monotherapy expansion in grade 4 glioma, and combination therapy in solid tumors (LY3200882 and PD-L1 inhibitor LY3300054), pancreatic cancer (LY3200882, gemcitabine, and nab-paclitaxel), and head and neck squamous cell cancer (LY3200882, cisplatin, and radiation). Results: Overall, 139 patients with advanced cancer were treated. The majority (93.5%) of patients experienced ≥1 treatment-emergent adverse events (TEAE), with 39.6% LY3200882-related. Grade 3 LY3200882-related toxicities were only observed in combination therapy arms. One patient in the pancreatic cancer arm experienced cardiovascular toxicity. The LY3200882 monotherapy RP2Ds were established in two schedules: 50 mg twice a day 2-weeks-on/2-weeks-off and 35 mg twice a day 3-weeks-on/1-week-off. Four patients with grade 4 glioma had durable Revised Assessment in Neuro Oncology (RANO) partial responses (PR) with LY3200882 monotherapy (n = 3) or LY3200882-LY3300054 combination therapy (n = 1). In treatment-naïve patients with advanced pancreatic cancer, 6 of 12 patients achieved Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 PR and 3 of 12 patients demonstrated stable disease, for an overall 75% disease-control rate with the combination of LY3200882, gemcitabine, and nab-paclitaxel. Conclusions: LY3200882 as monotherapy and combination therapy was safe and well tolerated with preliminary antitumor activity observed in pancreatic cancer. Further studies to evaluate the efficacy of LY3200882 with gemcitabine and nab-paclitaxel in advanced pancreatic cancer are warranted

Modified recurrent equation-based cubic spline interpolation for missing data recovery in phasor measurement unit (PMU) [version 3; peer review: 2 approved, 1 not approved]

Background Smart grid systems require high-quality Phasor Measurement Unit (PMU) data for proper operation, control, and decision-making. Missing PMU data may lead to improper actions or even blackouts. While the conventional cubic interpolation methods based on the solution of a set of linear equations to solve for the cubic spline coefficients have been applied by many researchers for interpolation of missing data, the computational complexity increases non-linearly with increasing data size. Methods In this work, a modified recurrent equation-based cubic spline interpolation procedure for recovering missing PMU data is proposed. The recurrent equation-based method makes the computations of spline constants simpler. Using PMU data from the State Load Despatch Center (SLDC) in Madhya Pradesh, India, a comparison of the root mean square error (RMSE) values and time of calculation (ToC) is calculated for both methods. Results The modified recurrent relation method could retrieve missing values 10 times faster when compared to the conventional cubic interpolation method based on the solution of a set of linear equations. The RMSE values have shown the proposed method is effective even for special cases of missing values (edges, continuous missing values). Conclusions The proposed method can retrieve any number of missing values at any location using observed data with a minimal number of calculations

Diarrheagenic pathogens in adults attending a hospital in Singapore.

BACKGROUND: Singapore's diarrhoeal notification system is based on specific pathogens. Official data may thus be skewed towards notifiable diseases. Limited information is available on the profiles of aetiological agents responsible for acute gastroenteritis (AGE) cases, especially among the adult population. To understand the frequency and distribution of potential causative agents of diarrheal disease in Singapore, we screened adults' stool samples collected from a large public hospital. METHODS: The stool samples were screened for 18 diarrheagenic pathogens using a combination of commercial multiplex polymerase chain reaction (PCR), in-house singleplex PCR and immunochromatographic assays. One hundred adult faecal samples that were collected from October 2013 to January 2014 for routine diagnostic purposes and submitted for culture at Tan Tock Seng Hospital, Singapore were used. RESULTS: Pathogens were detected in 32% of the samples. The predominant organisms encountered were norovirus genogroup II (11%), Aeromonas spp. (9%) and Campylobacter spp. (5%). One sample was positive for both verocytotoxigenic E. coli (VTEC) and E. coli O157:H7. Two other samples were positive for VTEC only, and one other sample was positive for E. coli O157:H7 only. Astrovirus, C. perfringens, Shigella spp. and toxigenic C. difficile were each detected in 2% of the samples. Cryptosporidium parvum, Giardia lamblia, group A rotavirus, Salmonella spp. and Vibrio spp. were each detected in 1% of the samples. No L. monocytogenes, Y. enterocolitica, enteric adenovirus, or norovirus genogroup I were detected. CONCLUSION: Our preliminary findings suggest that pathogens causing non-notifiable diseases might have contributed considerably to the adult hospitalised AGE cases. However, as the samples were from an adult hospital, the data obtained may not be representative of the whole community. Thus, a larger study to collect clinical samples and risk exposure data from primary healthcare clinics and children hospital is planned for, to gain a more holistic perspective on the epidemiology of AGE in Singapore. A larger study may also offer valuable insights for improving the approach of microbiological surveillance of food, as well as strategizing inspection efforts along the food supply chain by public health authorities

The mTOR Pathway Independent Function of NPRL2 in the Regulation of S-Phase DNA Damage Response

https://openworks.mdanderson.org/sumexp22/1070/thumbnail.jp

Increased upconversion performance for thin film solar cells: A trimolecular composition

Photochemical upconversion based on triplet-triplet annihilation (TTA-UC) is employed to enhance the short-circuit currents generated by two varieties of thin-film solar cells, a hydrogenated amorphous silicon (a-Si:H) solar cell and a dye-sensitized solar cell (DSC). TTA-UC is exploited to harvest transmitted sub-bandgap photons, combine their energies and re-radiate upconverted photons back towards the solar cells. In the present study we employ a dual-emitter TTA-UC system which allows for significantly improved UC quantum yields as compared to the previously used single-emitter TTA systems. In doing so we achieve record photo-current enhancement values for both the a-Si:H device and the DSC, surpassing 10-3 mA cm-2 sun-2 for the first time for a TTA-UC system and marking a record for upconversion-enhanced solar cells in general. We discuss pertinent challenges of the TTA-UC technology which need to be addressed in order to achieve its viable device application