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Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of cancer chemotherapy that can often limit treatment options for cancer patients or have life-long neurodegenerative consequences that reduce the patient’s quality of life. CIPN is caused by the detrimental actions of various chemotherapeutic agents on peripheral axons. Currently, there are no approved preventative measures or treatment options for CIPN, highlighting the need for the discovery of novel therapeutics and improving our understanding of disease mechanisms. In this study, we utilized human-induced pluripotent stem cell (hiPSC)-derived motor neurons as a platform to mimic axonal damage after treatment with vincristine, a chemotherapeutic used for the treatment of breast cancers, osteosarcomas, and leukemia. We screened a total of 1902 small molecules for neuroprotective properties in rescuing vincristine-induced axon growth deficits. From our primary screen, we identified 38 hit compounds that were subjected to secondary dose response screens. Six compounds showed favorable pharmacological profiles – AZD7762, A-674563, Blebbistatin, Glesatinib, KW-2449, and Pelitinib, all novel neuroprotectants against vincristine toxicity to neurons. In addition, four of these six compounds also showed efficacy against vincristine-induced growth arrest in human iPSC-derived sensory neurons. In this study, we utilized high-throughput screening of a large library of compounds in a therapeutically relevant assay. We identified several novel compounds that are efficacious in protecting different neuronal subtypes from the toxicity induced by a common chemotherapeutic agent, vincristine which could have therapeutic potential in the clinic.

Glycine N -methyltransferase (GNMT) is a tumor suppressor for HCC. It is down-regulated in HCC, but the mechanism is not fully understood. MicroRNA-224 (miR-224) acts as an onco-miR in HCC. This study is the first to investigate miR-224 targeting the coding region of GNMT transcript. The GNMT-MT plasmid containing a miR-224 binding site silent mutation of the GNMT coding sequence can escape the suppression of miR-224 in HEK293T cells. Expression of both exogenous and endogenous GNMT was suppressed by miR-224, while miR-224 inhibitor enhanced GNMT expression. miR-224 counteracts the effects of GNMT on the reduction of cell proliferation and tumor growth. The levels of miR-224 and GNMT mRNA showed a significant inverse relationship in tumor specimens from HCC patients. Utilizing CCl4-treated hepatoma cells and mice as a cell damage of inflammatory or liver injury model, we observed that the decreased expression levels of GNMT were accompanied with the elevated expression levels of miR-224 in hepatoma cells and mouse liver. Finally, hepatic AAV-mediated GNMT also reduced CCl4-induced miR-224 expression and liver fibrosis. These results indicated that AAV-mediated GNMT has potential liver protection activity. miR-224 can target the GNMT mRNA coding sequence and plays an important role in GNMT suppression during liver tumorigenesis.

Aim Adolescents in low-and-middle-income countries (LMICs) are facing numerous developmental, sexual and reproductive health (SRH) challenges including exposure to multidimensional violence. Gender-based violence (GBV) specifically intimate partner violence (IPV) are both highly prevalent in LMICs and are strongly linked with poor SRH outcomes. However, GBV and IPV interventions have not yet been adequately integrated in SRH due to individual, social, cultural, service, and resource barriers. To promote long-term SRH, a more holistic approach that integrates GBV and IPV, and adolescent development needs is imperative. Digital health has the potential to address multiple service setup, provision, and addressing access barriers through designing and providing integrated SRH care. However, there are no guidelines for an integrated digital SRH and development promotion for adolescents in LMICs. Methods An umbrella review was conducted to synthesize evidence in three inter-related areas of digital health intervention literature: (i) SRH, (ii) GBV specifically IPV as a subset, and (iii) adolescent development and health promotion. We first synthesize findings for each area of research, then further analyze the implications and opportunities to inform approaches to develop an integrated intervention that can holistically address multiple SRH needs of adolescents in LMICs. Articles published in English, between 2010 and 2020, and from PubMed were included. Results Seventeen review articles met our review inclusion criterion. Our primary finding is that application of digital health strategies for adolescent SRH promotion is highly feasible and acceptable. Although effectiveness evidence is insufficient to make strong recommendations for interventions and best practices suggestions, some user-centered design guidelines have been proposed for web-based health information and health application design for adolescent use. Additionally, several digital health strategies have also been identified that can be used to further develop integrated GBV-IPV-SRH-informed services to improve adolescent health outcomes. We generated several recommendations and strategies to guide future digital based SRH promotion research from our review. Conclusions Rigorous research that focuses on intervention effectiveness testing using a combination of digital health strategies and standardized albeit contextualized outcome measures would be important. Methodological improvement such as adoption of longitudinal experimental design will be crucial in generating evidence-based intervention and practice guidelines for adolescents in LMICs.

The rise in atmospheric [CO2] is associated with increasing air temperature. However, studies on plant responses to interactive effects of [CO2] and temperature are limited, particularly for leaf structural attributes. In this study, Eucalyptus saligna plants were grown in sun-lit glasshouses differing in [CO2] (290, 400, and 650 µmol mol–1) and temperature (26 °C and 30 °C). Leaf anatomy and chloroplast parameters were assessed with three-dimensional confocal microscopy, and the interactive effects of [CO2] and temperature were quantified. The relative influence of leaf structural attributes and chemical properties on the variation of leaf mass per area (LMA) and photosynthesis within these climate regimes was also determined. Leaf thickness and mesophyll size increased in higher [CO2] but decreased at the warmer temperature; no treatment interaction was observed. In pre-industrial [CO2], warming reduced chloroplast diameter without altering chloroplast number per cell, but the opposite pattern (reduced chloroplast number per cell and unchanged chloroplast diameter) was observed in both current and projected [CO2]. The variation of LMA was primarily explained by total non-structural carbohydrate (TNC) concentration rather than leaf thickness. Leaf photosynthetic capacity (light- and [CO2]-saturated rate at 28 °C) and light-saturated photosynthesis (under growth [CO2] and temperature) were primarily determined by leaf nitrogen contents, while secondarily affected by chloroplast gas exchange surface area and chloroplast number per cell, respectively. In conclusion, leaf structural attributes are less important than TNC and nitrogen in affecting LMA and photosynthesis responses to the studied climate regimes, indicating that leaf structural attributes have limited capacity to adjust these functional traits in a changing climate.

Background TMPRSS2-ERG gene rearrangement, the most common E26 transformation specific (ETS) gene fusion within prostate cancer, is known to contribute to the pathogenesis of this disease and carries diagnostic annotations for prostate cancer patients clinically. The ERG rearrangement status in prostatic adenocarcinoma currently cannot be reliably identified from histologic features on H&E-stained slides alone and hence requires ancillary studies such as immunohistochemistry (IHC), fluorescent in situ hybridization (FISH) or next generation sequencing (NGS) for identification. Methods Objective We accordingly sought to develop a deep learning-based algorithm to identify ERG rearrangement status in prostatic adenocarcinoma based on digitized slides of H&E morphology alone. Design Setting, and Participants: Whole slide images from 392 in-house and TCGA cases were employed and annotated using QuPath. Image patches of 224 × 224 pixel were exported at 10 ×, 20 ×, and 40 × for input into a deep learning model based on MobileNetV2 convolutional neural network architecture pre-trained on ImageNet. A separate model was trained for each magnification. Training and test datasets consisted of 261 cases and 131 cases, respectively. The output of the model included a prediction of ERG-positive (ERG rearranged) or ERG-negative (ERG not rearranged) status for each input patch. Outcome measurements and statistical analysis: Various accuracy measurements including area under the curve (AUC) of the receiver operating characteristic (ROC) curves were used to evaluate the deep learning model. Results and Limitations All models showed similar ROC curves with AUC results ranging between 0.82 and 0.85. The sensitivity and specificity of these models were 75.0% and 83.1% (20 × model), respectively. Conclusions A deep learning-based model can successfully predict ERG rearrangement status in the majority of prostatic adenocarcinomas utilizing only H&E-stained digital slides. Such an artificial intelligence-based model can eliminate the need for using extra tumor tissue to perform ancillary studies in order to assess for ERG gene rearrangement in prostatic adenocarcinoma.

There is currently a crucial need for improved diagnostic techniques and targeted treatment methods for Alzheimer’s disease (AD), a disease which impacts millions of elderly individuals each year. Metabolomic analysis has been proposed as a potential methodology to better investigate and understand the progression of this disease. In this report, we present our AD metabolomics results measured with high resolution magic angle spinning (HRMAS) nuclear magnetic resonance (NMR) on human blood plasma samples obtained from AD and non-AD subjects. Our study centers on developments of AD and non-AD metabolomics differentiating models with procedures of quality assurance (QA) and quality control (QC) through pooled samples. Our findings suggest that analysis of blood plasma samples using HRMAS NMR has the potential to differentiate between diseased and healthy subjects, which has important clinical implications for future improvements in AD diagnosis methodologies.

High blood pressure (BP) and type‐2 diabetes (T2DM) are forerunners of chronic kidney disease and left ventricular dysfunction. Home BP telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling risk stratification and personalized prevention. UPRIGHT‐HTM (NCT04299529) is an investigator‐initiated, multicenter, open‐label, randomized trial with blinded endpoint evaluation designed to assess the efficacy of HTM plus UPP (experimental group) over HTM alone (control group) in guiding treatment in asymptomatic patients, aged 55–75 years, with ≥5 cardiovascular risk factors. From screening onwards, HTM data can be freely accessed by all patients and their caregivers; UPP results are communicated early during follow‐up to patients and caregivers in the intervention group, but at trial closure in the control group. From May 2021 until January 2023, 235 patients were screened, of whom 53 were still progressing through the run‐in period and 144 were randomized. Both groups had similar characteristics, including average age (62.0 years) and the proportions of African Blacks (81.9%), White Europeans (16.7%), women 56.2%, home (31.2%), and office (50.0%) hypertension, T2DM (36.4%), micro‐albuminuria (29.4%), and ECG (9.7%) and echocardiographic (11.5%) left ventricular hypertrophy. Home and office BP were 128.8/79.2 mm Hg and 137.1/82.7 mm Hg, respectively, resulting in a prevalence of white‐coat, masked and sustained hypertension of 40.3%, 11.1%, and 25.7%. HTM persisted after randomization (48 681 readings up to 15 January 2023). In conclusion, results predominantly from low‐resource sub‐Saharan centers proved the feasibility of this multi‐ethnic trial. The COVID‐19 pandemic caused delays and differential recruitment rates across centers.

Nucleolar stress, characterized by loss of nucleolar integrity, has not been described in the cardiac context. In addition to ribosome biogenesis, nucleoli are critical for control of cell proliferation and stress responses. Our group previously demonstrated induction of the nucleolar protein nucleostemin (NS) in response to cardiac pathological insult. NS interacts with nucleophosmin (NPM), a marker of nucleolar stress with cytoprotective properties. The dynamic behavior of NS and NPM reveal that nucleolar disruption is an early event associated with stress response in cardiac cells. Rapid translocation of NS and NPM to the nucleoplasm and suppression of new preribosomal RNA synthesis occurs in both neonatal rat cardiomyocytes (NRCM) and cardiac progenitor cells (CPC) upon exposure to doxorubicin or actinomycin D. Silencing of NS significantly increases cell death resulting from doxorubicin treatment in CPC, whereas NPM knockdown alone induces cell death. Overexpression of either NS or NPM significantly decreases caspase 8 activity in cultured cardiomyocytes challenged with doxorubicin. The presence of altered nucleolar structures resulting from myocardial infarction in mice supports the model of nucleolar stress as a general response to pathological injury. Collectively, these findings serve as the initial description of myocardial nucleolar stress and establish the postulate that nucleoli acts as sensors of stress, regulating the cellular response to pathological insults.

High blood pressure (BP) and type‐2 diabetes (T2DM) are forerunners of chronic kidney disease and left ventricular dysfunction. Home BP telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling risk stratification and personalized prevention. UPRIGHT‐HTM (NCT04299529) is an investigator‐initiated, multicenter, open‐label, randomized trial with blinded endpoint evaluation designed to assess the efficacy of HTM plus UPP (experimental group) over HTM alone (control group) in guiding treatment in asymptomatic patients, aged 55–75 years, with ≥5 cardiovascular risk factors. From screening onwards, HTM data can be freely accessed by all patients and their caregivers; UPP results are communicated early during follow‐up to patients and caregivers in the intervention group, but at trial closure in the control group. From May 2021 until January 2023, 235 patients were screened, of whom 53 were still progressing through the run‐in period and 144 were randomized. Both groups had similar characteristics, including average age (62.0 years) and the proportions of African Blacks (81.9%), White Europeans (16.7%), women 56.2%, home (31.2%), and office (50.0%) hypertension, T2DM (36.4%), micro‐albuminuria (29.4%), and ECG (9.7%) and echocardiographic (11.5%) left ventricular hypertrophy. Home and office BP were 128.8/79.2 mm Hg and 137.1/82.7 mm Hg, respectively, resulting in a prevalence of white‐coat, masked and sustained hypertension of 40.3%, 11.1%, and 25.7%. HTM persisted after randomization (48 681 readings up to 15 January 2023). In conclusion, results predominantly from low‐resource sub‐Saharan centers proved the feasibility of this multi‐ethnic trial. The COVID‐19 pandemic caused delays and differential recruitment rates across centers.

Norcantharidin is the demethylated analog of cantharidin isolated from blister beetles (Mylabris phalerata Pall.). In this study, we evaluated whether norcantharidin exhibits anticancer effects against the human non-small cell lung cancer cell lines A549 (epidermal growth factor receptor (EGFR) mutation-negative) and PC9 (EGFR mutation-positive). Our results revealed that norcantharidin dose-dependently retards cell growth, arrests cell cycle at G2/M phase, reduces cell migration, and even induces apoptosis at the concentration of 100 μM. Moreover, we found that norcantharidin enhances the anticancer effects of gefitinib and cisplatin. Norcantharidin exhibited similar potency of anticancer effects against the two cell lines with different EGFR mutation status and did not affect EGF-induced EGFR phosphorylation, suggesting that the EGFR signaling may not be the target of norcantharidin. In conclusion, our results suggest that norcantharidin exhibits anticancer effects against non-small cell lung cancer cells in vitro and support its potential as a chemotherapeutic agent for treating non-small cell lung cancer.