CVD phenotyping in oncologic disorders: cardio-miRNAs as a potential target to improve individual outcomes in revers cardio-oncology.

With the increase of aging population and prevalence of obesity, the incidence of cardiovascular disease (CVD) and cancer has also presented an increasing tendency. These two different diseases, which share some common risk factors. Relevant studies in the field of reversing Cardio-Oncology have shown that the phenotype of CVD has a significant adverse effect on tumor prognosis, which is mainly manifested by a positive correlation between CVD and malignant progression of concomitant tumors. This distal crosstalk and the link between different diseases makes us aware of the importance of diagnosis, prediction, management and personalized treatment of systemic diseases. The circulatory system bridges the interaction between CVD and cancer, which suggests that we need to fully consider the systemic and holistic characteristics of these two diseases in the process of clinical treatment. The circulating exosome-miRNAs has been intrinsically associated with CVD -related regulation, which has become one of the focuses on clinical and basic research (as biomarker). The changes in the expression profiles of cardiovascular disease-associated miRNAs (Cardio-miRNAs) may adversely affect concomitant tumors. In this article, we sorted and screened CVD and tumor-related miRNA data based on literature, then summarized their commonalities and characteristics (several important pathways), and further discussed the conclusions of Cardio-Oncology related experimental studies. We take a holistic approach to considering CVD as a risk factor for tumor malignancy, which provides an in-depth analysis of the various regulatory mechanisms or pathways involved in the dual attribute miRNAs (Cardio-/Onco-miRNAs). These mechanisms will be key to revealing the systemic effects of CVD on tumors and highlight the holistic nature of different diseases. Therefore, the Cardio-miRNAs should be given great attention from researchers in the field of CVD and tumors, which might become new targets for tumor treatment. Meanwhile, based on the principles of precision medicine (such as the predictive preventive personalized medicine, 3PM) and reverse Cardio-oncology to better improve individual outcomes, we should consider developing personalized medicine and systemic therapy for cancer from the perspective of protecting cardiovascular function.

Bone-derived PDGF-BB drives brain vascular calcification in male mice.

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRß (p-PDGFRß) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRß/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.

APPL1 Is a Prognostic Biomarker and Correlated with Treg Cell Infiltration via Oxygen-Consuming Metabolism in Renal Clear Cell Carcinoma.

Kidney renal clear cell carcinoma (KIRC) is one of the most hazardous tumors in the urinary system. The regulation of oxygen consumption in renal clear cell carcinoma is a consequence of adaptive reprogramming of oxidative metabolism in tumor cells. APPL1 is a signaling adaptor involved in cell survival, oxidative stress, inflammation, and energy metabolism. However, the correlation of APPL1 with regulatory T cell (Treg) infiltration and prognostic value in KIRC remain unclear. In this study, we comprehensively predicted the potential function and prognostic value of APPL1 in KIRC. For KIRC patients, relatively low expression of APPL1 was associated with high degree of metastasis, pathological stage, and shorter overall time or poor prognosis. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that low expression of APPL1 may be adapted to the malignant progression of tumors via affecting oxygen-consuming metabolism. In addition, the expression level of APPL1 was negatively correlated with Treg cell infiltration and chemotherapy sensitivity, which indicated that APPL1 may regulate the tumor immune infiltration and chemotherapy resistance by decrease oxygen-consuming metabolic process in KIRC. Therefore, APPL1 may become one of the important prognostic factors, and it may serve as a candidate prognostic biomarker in KIRC.

Pulsed electromagnetic fields for the management of knee osteoarthritis: multicentre, randomised, controlled, non-inferiority trial protocol.

INTRODUCTION: Pulsed electromagnetic field (PEMF) is an available treatment for knee osteoarthritis (KOA), which is the most common cause of pain and disability. Nonetheless, whether the clinical effects are like that of most used drugs is unclear. Thus, this study aims to determine the effect of PEMF on pain relief by comparing them with the positive drug (celecoxib). Furthermore, this clinical trial aims to evaluate the effect of PEMF on function and quality of life with a long-term follow-up. METHODS AND ANALYSIS: This two-armed, non-inferiority, randomised, controlled trial will be conducted in the outpatient physiatry/physiotherapy clinic or inpatient ward of 17 hospitals in China. A total of 428 individuals will be included who are more than 40 years of age with diagnosed KOA. The participants will be randomly allocated to the PEMF group: receiving a 6-week PEMF (15 Hz, 30 mT) at a frequency of 40 min per day, 5 days per week plus sham drug (n=214), or drug group: receiving a 6-week celecoxib 200 mg combined with sham PEMF (n=214). Clinical outcomes will be measured at baseline (T0), mid-term of intervention (T1), post-intervention (T2), 10, 18 and 30 weeks (T3-5) of follow-up after randomisation. The primary outcome will be the Western Ontario and McMaster Universities (WOMAC) pain index. The secondary outcomes will be WOMAC function and stiffness, pain measured by numerical rating score, quality of life, 6-minute walk test, pain catastrophising scale and responder index. ETHICS AND DISSEMINATION: The trial is performed following the Declaration of Helsinki. The study protocol and consent form have been approved by the Ethics Committee on Biomedical Research of West China Hospital of Sichuan University (#2021-220). All patients will give informed consent before participation and the trial is initiated after approval. Results of this trial will be disseminated through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2100052131.

Pulsed Electromagnetic Fields May Be Effective for the Management of Primary Osteoporosis: A Systematic Review and Meta-Analysis.

Little is known about the effect of pulsed electromagnetic fields (PEMFs) as an option for preventing osteoporosis. This study sought to investigate the effectiveness of PEMFs for the management of primary osteoporosis in older adults. We searched databases from the inception to date to target trials examining the effects of PEMFs compared to placebo or sham or other agents for the management of primary osteoporosis for a meta-analysis using random effects model. Eight trials including 411 participants were included. PEMFs was non-inferior to conventional pharmacological agents and exercise respectively in preventing the decline of Bone Mineral Density (BMD) at the lumbar (MD 8.76; CI -9.64 to 27.16 and MD 1.33; CI -2.73 to 5.39) and femur neck (MD 0.04; CI -1.09 to 1.16 and MD 1.50; CI -0.26 to 3.26), and significantly improving balance function measured by Berg Balance Scale (BBS) (MD 0.91; CI 0.32 to 1.49) and Timed Up and Go test (MD -3.61; CI -6.37 to -0.85), directly after intervention. The similar trends were observed in BMD and BBS at 12- and 24-weeks follow-up from baseline. PEMFs had positive effects non-inferior to first-line treatment on BMD and better over placebo on balance function in older adults with primary osteoporosis, but with moderate to very low certainty evidence and short-term follow-ups. There is a need for high-quality randomised controlled trials evaluating PEMFs for the management of primary osteoporosis.

Zebularine protects against blood-brain-barrier (BBB) disruption through increasing the expression of zona occludens-1 (ZO-1) and vascular endothelial (VE)-cadherin.

Blood-brain-barrier (BBB) disruption is an important pathological characteristic of ischemic stroke (IS) and mainly results from dysfunction of brain vascular endothelial cells and tight junctions. Zebularine is a novel inhibitor of DNA methyltransferase (DNMT). Here, we assessed its effects on BBB disruption in IS. Firstly, we reported that Zebularine maintained BBB integrity in middle cerebral artery occlusion (MCAO) mice by increasing the expressions of zona occludens-1 (ZO-1) and vascular endothelial (VE)-cadherin. Importantly, we found that Zebularine reduced the production of pro-inflammatory cytokines, attenuated brain edema, and improved neurological deficits. In in vitro experiments, the bEnd.3 brain endothelial cells were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R), and the protective effects of Zebularine were assessed. Our findings demonstrated that Zebularine prevented OGD/R-induced cytotoxicity by reducing the release of lactate dehydrogenase (LDH). Additionally, Zebularine protected bEnd.3 cells against OGD/R-induced hyper-permeability and reduction of trans-endothelial electrical resistance (TEER). Notably, we found that treatment with Zebularine activated the Adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway by increasing the phosphorylation of adenosine monophosphate-activated protein kinase α (AMPKα). Blockage of AMPKα using its specific inhibitor compound C abolished the beneficial effects of Zebularine in mitigating endothelial hyper-permeability by reducing the expressions of ZO-1 and VE-cadherin. These findings suggest that the protective effects of Zebularine against OGD/R-induced endothelial hyper-permeability are mediated by the activation of AMPKα. In conclusion, our study sheds light on the potential application of Zebularine in the treatment of IS.