Murine cytotoxic CD4+ T cells in the tumor microenvironment are at a hyper-maturation stage of Th1 CD4+ T cells sustained by IL-12.

The roles of tumor-infiltrating CD4+Foxp3- T cells are not well characterized due to their plasticity of differentiation, and varying levels of activation or exhaustion. To further clarify this issue, we used a model featuring subcutaneous murine colon cancer and analyzed the dynamic changes of phenotype and function of the tumor-associated CD4+ T-cell response. We found that, even at a late stage of tumor growth, the tumor-infiltrating CD4+Foxp3- T cells still expressed effector molecules, inflammatory cytokines and molecules that are expressed at reduced levels in exhausted cells. We used microarrays to examine the gene-expression profiles of different subsets of CD4+ T cells and revealed that the tumor-infiltrating CD4+Foxp3- T cells expressed not only type 1 helper (Th1) cytokines, but also cytolytic granules such as those encoded by Gzmb and Prf1. In contrast to CD4+ regulatory T cells, these cells exclusively co-expressed natural killer receptor markers and cytolytic molecules as shown by flow-cytometry studies. We used an ex vivo killing assay and proved that they could directly suppress CT26 tumor cells through granzyme B and perforin. Finally, we used pathway analysis and ex vivo stimulation to confirm that the CD4+Foxp3- T cells expressed higher levels of IL12rb1 genes and were activated by the IL-12/IL-27 pathway. In conclusion, this work finds that, in late-stage tumors, the tumor-infiltrating lymphocyte population of CD4+ cells harbored a sustained, hyper-maturated Th1 status with cytotoxic function supported by IL-12.

The Influencing Factors of Implementation in Emergency Medical Service Systems - A Scoping Review.

OBJECTIVES: Emergency medical services (EMS) provide health care in situations with limited time and resources. Challenges arise when introducing novel medications, treatments, or technologies or modifying existing practices in these settings. Effective implementation strategies are pivotal for their success. This study aims to identify and categorize potential facilitators and barriers in the implementation of prehospital EMS through a review of relevant research articles.METHODS: We searched PubMed and EMbase to identify studies published before December 2023, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for our search strategy and scoping review. We included original articles written in English that report on the factors that influence the implementation in prehospital settings. We extracted and categorized the factors into different themes.RESULTS: Out of the 371 retrieved papers, we selected 19 (5%) for inclusion in this review. We extracted 46 influencing factors from the selected articles and categorized them into ten themes: (1) Outer system, (2) Inner system, (3) Practitioner characteristics, (4) Resources, (5) Communication and collaboration, (6) Patient factors, (7) Intervention characteristics, (8) De-implementation of prior practices, (9) Logistical issues, and (10) Quality improvement.CONCLUSIONS: This study examined the literature on EMS implementation factors and proposed a 10-theme EMS model framework. Key factors include training/education, equipment/tools, communication with hospitals, and practitioners' attitudes.

Development, implementation, and evaluation of entrustable professional activities (EPAs) for medical radiation technologists in Taiwan: a nationwide experience.

BACKGROUND: Competency-based medical education (CBME) is an outcomes-oriented approach focused on developing competencies that translate into clinical practice. Entrustable professional activities (EPAs) bridge competency assessment and clinical performance by delineating essential day-to-day activities that can be entrusted to trainees. EPAs have been widely adopted internationally, but not yet implemented for medical radiation professionals in Taiwan. MATERIALS AND METHODS: A nationwide consensus process engaged 97 experts in radiation technology education representing diagnostic radiography, radiation therapy, and nuclear medicine. Preliminary EPAs were developed through the focus group discussion and the modified Delphi method. The validity of these EPAs was evaluated using the QUEPA and EQual tools. RESULTS: Through iterative consensus building, six core EPAs with 18 component observable practice activities (OPAs) in total were developed, encompassing routines specific to each radiation technology specialty. QUEPA and EQual questionnaire data verified these EPAs were valid, and of high quality for clinical teaching and evaluation. CONCLUSION: The consensus development of tailored EPAs enables rigorous competency assessment during medical radiation technology education in Taiwan. Further expansion of EPAs and training of clinical staff could potentially enhance care quality by producing competent professionals.

More than one way to say I love you: An Internet-based intervention for training flexible thinking in romantic relationships.

OBJECTIVES: This study developed and pilot-tested an adaptation of Cognitive Bias Modification (CBM) to target two aspects of relational flexibility in couples: the ability to generate alternative perspectives, and the ability to respond nondefensively when alternative partner perspectives are raised within challenging relationship situations (referred to as flexibility in partner perspectives). METHODS: CBM-FlexC training materials were developed in Phase 1, and expert users (N = 4) and end-point users (N = 7) provided qualitative feedback. Feasibility and preliminary efficacy of CBM-FlexC were evaluated in Phase 2, using an online sample of distressed couples (N = 18). Using a multiple baseline design, participants completed three baseline assessments, six CBM-FlexC sessions over 2 weeks, and a 1-month follow-up. RESULTS: CBM-FlexC training resulted in greater flexibility in partner perspectives, relationship satisfaction, and general psychological flexibility compared to baseline, and improvements were maintained 1-month after training when using mixed-effects models. However, analyses of reliable change (based on graphical inspection and the Reliable Change Index) indicated that most participants did not experience reliable improvement in flexibility in partner perspectives, or relationship satisfaction. CONCLUSION: This pilot study provides some positive signals regarding the potential efficacy of CBM-FlexC, while pointing to the need for further development to strengthen its effects.

Hesperetin promotes longevity and delays aging via activation of Cisd2 in naturally aged mice.

BACKGROUND: The human CISD2 gene is located within a longevity region mapped on chromosome 4q. In mice, Cisd2 levels decrease during natural aging and genetic studies have shown that a high level of Cisd2 prolongs mouse lifespan and healthspan. Here, we evaluate the feasibility of using a Cisd2 activator as an effective way of delaying aging. METHODS: Hesperetin was identified as a promising Cisd2 activator by herb compound library screening. Hesperetin has no detectable toxicity based on in vitro and in vivo models. Naturally aged mice fed dietary hesperetin were used to investigate the effect of this Cisd2 activator on lifespan prolongation and the amelioration of age-related structural defects and functional decline. Tissue-specific Cisd2 knockout mice were used to study the Cisd2-dependent anti-aging effects of hesperetin. RNA sequencing was used to explore the biological effects of hesperetin on aging. RESULTS: Three discoveries are pinpointed. Firstly, hesperetin, a promising Cisd2 activator, when orally administered late in life, enhances Cisd2 expression and prolongs healthspan in old mice. Secondly, hesperetin functions mainly in a Cisd2-dependent manner to ameliorate age-related metabolic decline, body composition changes, glucose dysregulation, and organ senescence. Finally, a youthful transcriptome pattern is regained after hesperetin treatment during old age. CONCLUSIONS: Our findings indicate that a Cisd2 activator, hesperetin, represents a promising and broadly effective translational approach to slowing down aging and promoting longevity via the activation of Cisd2.

Cisd2 is essential to delaying cardiac aging and to maintaining heart functions.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2) is pivotal to mitochondrial integrity and intracellular Ca2+ homeostasis. In the heart of Cisd2 knockout mice, Cisd2 deficiency causes intercalated disc defects and leads to degeneration of the mitochondria and sarcomeres, thereby impairing its electromechanical functioning. Furthermore, Cisd2 deficiency disrupts Ca2+ homeostasis via dysregulation of sarco/endoplasmic reticulum Ca2+-ATPase (Serca2a) activity, resulting in an increased level of basal cytosolic Ca2+ and mitochondrial Ca2+ overload in cardiomyocytes. Most strikingly, in Cisd2 transgenic mice, a persistently high level of Cisd2 is sufficient to delay cardiac aging and attenuate age-related structural defects and functional decline. In addition, it results in a younger cardiac transcriptome pattern during old age. Our findings indicate that Cisd2 plays an essential role in cardiac aging and in the heart's electromechanical functioning. They highlight Cisd2 as a novel drug target when developing therapies to delay cardiac aging and ameliorate age-related cardiac dysfunction.

Construction of simple and sensitive pancreatitis related microRNA detection strategy via self-priming triggered cascade signal amplification.

Pancreatic diseases, such as pancreatitis and pancreatic cancer, remain the most threatening gastrointestinal diseases with a high mortality due to atypical symptoms. MicroRNA plays crucial roles in regulating metastasis and cell proliferation of pancreatic cancer, constituting important biomarkers for the early diagnosis of pancreatic cancers. Herein, we develop a sensitive and simple exosomal miRNA detection method with only a dual-hairpin-probe. In detail, the dual-hairpin-probe is constructed through combination of two functional sections for both target miRNA identification and signal amplification. With only one probe, the method possesses the capability to avoid interferences from concentration changes of other probes, and exhibits a higher stability which is demonstrated through the obtained low coefficients of variation (CV) of 6.73%. With let-7a as detection target, the LOD of the established method is determined to be 243 aM, while maintaining a high discriminating capability towards let-7a homogenous miRNAs.

A survey of resident physicians' perceptions of competency-based education in standardized resident training in China: a preliminary study.

BACKGROUND: Understanding resident physicians' perceptions of competency-based medical education(CBME) may help improve approaches for implementing such education in standardized resident training (SRT). We conducted surveys of residents in China to identify their perceptions of CBME and determine the degree to which such education impacts their career plans. METHODS: Questionnaire contained a total of 24 questions, which were answered using multiple choice or yes/no, was distributed to residents who were undergoing SRT, regardless of specialty, at 7 accredited training bases located across six provinces of China. The survey aimed to investigate residents' reasons for participating in SRT, perceptions of CBME, interest in receiving CBME-associated courses, and attitudes towards CBME. RESULTS: Overall, 441 residents completed the questionnaire.17.7% (78/441) responded "no clear objective" before the participated in SRT. Only 3.9% (17/441) fully understood the objectives, training contents, and assessment system of the current "competency-based" standardized training program for residents in China. Residents ranked clinical skills and patient care, interpersonal communication, and professionalism, as the three most important competencies. Most were interested in the CBME residency programs. 90.7% felt that implementing CBME could help them clarify their professional direction and improve their career planning. CONCLUSION: Residents had positive perceptions of the incorporation of CBME into SRT. Administrators, educational leaders, and clinical faculty should seek to further publicize and increase the popularity of CBME.

Chronic Ca2+/Calmodulin-Dependent Protein Kinase II Inhibition Rescues Advanced Heart Failure.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is upregulated in congestive heart failure (CHF), contributing to electrical, structural, and functional remodeling. CaMKII inhibition is known to improve CHF, but its direct cardiac effects in CHF remain unclear. We hypothesized that CaMKII inhibition improves cardiomyocyte function, [Ca2+]i regulation, and ß-adrenergic reserve, thus improving advanced CHF. In a 16-week study, we compared plasma neurohormonal levels and left ventricular (LV)- and myocyte-functional and calcium transient ([Ca2+]iT) responses in male Sprague-Dawley rats (10/group) with CHF induced by isoproterenol (170 mg/kg sq for 2 days). In rats with CHF, we studied the effects of the CaMKII inhibitor KN-93 or its inactive analog KN-92 (n = 4) (70 µg/kg per day, mini-pump) for 4 weeks. Compared with controls, isoproterenol-treated rats had severe CHF with 5-fold-increased plasma norepinephrine and about 50% decreases in ejection fraction (EF) and LV contractility [slope of LV end-systolic pressure-LV end-systolic volume relation (EES)] but increased time constant of LV relaxation (τ). They also showed significantly reduced myocyte contraction [maximum rate of myocyte shortening (dL/dtmax)], relaxation (dL/dtmax), and [Ca2+]iT Isoproterenol superfusion caused significantly fewer increases in dL/dtmax and [Ca2+]iT KN-93 treatment prevented plasma norepinephrine elevation, with increased basal and acute isoproterenol-stimulated increases in EF and EES and decreased τ in CHF. KN-93 treatment preserved normal myocyte contraction, relaxation, [Ca2+]iT, and ß-adrenergic reserve, whereas KN-92 treatment failed to improve LV and myocyte function, and plasma norepinephrine remained high in CHF. Thus, chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system, restoring normal LV and cardiomyocyte basal and ß-adrenergic-stimulated contraction, relaxation, and [Ca2+]iT, thereby playing a rescue role in advanced CHF. SIGNIFICANCE STATEMENT: We investigated the therapeutic efficacy of late initiation of chronic Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibition on progression of advanced congestive heart failure (CHF). Chronic CaMKII inhibition prevented CHF-induced activation of the sympathetic nervous system and restored normal intrinsic cardiomyocyte basal and ß-adrenergic receptor-stimulated relaxation, contraction, and [Ca2+]i regulation, leading to reversal of CHF progression. These data provide new evidence that CaMKII inhibition is able and sufficient to rescue a failing heart, and thus cardiac CaMKII inhibition is a promising target for improving CHF treatment.

Upregulation of Cisd2 attenuates Alzheimer's-related neuronal loss in mice.

CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid ß (Aß) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aß-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Association of hypertension and incident diabetes in Chinese adults: a retrospective cohort study using propensity-score matching.

BACKGROUND: Reliable quantification of the relationship between hypertension and diabetes risk is limited, especially among Chinese people. We aimed to investigate the association between hypertension and the risk of diabetes in a large cohort of the Chinese population. METHODS: This was a retrospective propensity score-matched cohort study among 211,809 Chinese adults without diabetes at baseline between 2010 and 2016. The target independent and dependent variable were hypertension at baseline and incident diabetes during follow-up respectively. The propensity score matching using a non-parsimonious multivariable logistic regression was conducted to balance the confounders between 28,711 hypertensive patients and 28,711 non-hypertensive participants. The doubly robust estimation method was used to investigate the association between hypertension and diabetes. RESULTS: In the propensity-score matching cohort, diabetes risk increased by 11.0% among hypertensive patients (HR = 1.110, 95% confidence interval (CI): 1.031-1.195, P = 0.00539). And diabetes risk dropped to 8.3% among hypertensive subjects after adjusting for the propensity score (HR = 1.083, 95%CI: 1.006-1.166, P = 0.03367). Compared to non-hypertensive participants with low propensity score, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity score (HR = 3.646, 95%CI: 2.635-5.045, P < 0.0001). CONCLUSION: Hypertension was associated with an 11.0% increase in the risk of developing diabetes in Chinese adults. And the figure dropped to 8.3% after adjusting the propensity score. Additionally, compared to non-hypertensive participants with low propensity scores, the risk of incident diabetes increased by 2.646 times among hypertensive patients with high propensity scores.

Strategies on locations of public access defibrillator: A systematic review.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a critical condition with poor outcomes. Although the survival rate increases in those who undergo defibrillation, the utility of on-time defibrillation among bystanders remained low. An evaluation of the deployment strategy for public access defibrillators (PADs) is necessary to increase their use and accessibility. This study was to conduct a systematic review for deployment strategies of PADs. METHODS: Two authors independently searched for articles published before October 2019 from PubMed, Embase, Web of Science, and Cochrane Library. An independent librarian provided the search strategy and assisted the literature research. We included articles that were focused on the main topic, but excluded those which were missing results or that used an unclear definition. The qualitative outcomes were the utility and OHCA coverage of PADs. We performed a qualitative analysis across the studies, but a quantitative analysis was not available due to the studies' heterogeneity in design and variety of outcomes. RESULTS: We eventually included 15 studies. Three strategies were presented: guidelines-based, grid-based, and landmark-based. The guidelines-based deployment was common fit for OHCA events. The grid-based method increased the use of bystander defibrillation 3-fold, and 30-day survival doubled. The top 3 landmarks in the landmark-based strategy were offices (18.6%), schools (13.3%), and sports facilities (12.9%). Utility of PADs might increase if we optimize PAD location by mathematical modeling and evaluation feedback. CONCLUSION: Three deployment strategies were presented. Although the optimal method could not be fully identified, a more efficient PAD deployment could benefit the population in terms of OHCA coverage and survival among patients with OHCA.

Meta-Analysis of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

BACKGROUND: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF); However, the prognostic impact of AF on HFpEF patients has not been fully elucidated. METHODS: A literature search of the PubMed and EMBASE databases on literature published through April 2019 was undertaken. Combined hazard ratio (HR) estimates and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, depending on the heterogeneity. Subgroup analyses, sensitivity analysis and meta-regression analyses were also performed. RESULTS: Fourteen (14) eligible studies with 1,948,923 patients with HFpEF were included in the analysis. Atrial fibrillation was associated with an 11% increased risk of all-cause mortality in patients with HFpEF (HR 1.11, 95% CI 1.09-1.12). Sensitivity analysis confirmed the stability of the results. The stratification of studies by controlled or uncontrolled confounding factors affected the final estimate (confounder-controlled HR 1.21, 95% CI 1.12-1.30; confounder-uncontrolled HR 1.13, 95% CI 0.96-1.31). In addition, AF was an independent predictor of hospitalisation for heart failure (HR 1.32, 95% CI 1.15-1.52), cardiovascular death (HR 1.38, 95% CI 1.01-1.89) and stroke (HR 1.87, 95% CI 1.54-2.27). CONCLUSIONS: Atrial fibrillation was associated with worse clinical outcomes in patients with HFpEF. Further investigation is required to see whether AF is the primary offender in these patients or merely a bystander to worse diastolic function.

Catalytic pyrolysis of linear low-density polyethylene using recycled coal ash: Kinetic study and environmental evaluation.

Catalytic pyrolysis offers a sustainable route to convert plastic wastes into fuel. We investigated the catalytic performance of coal ash (fly and bottom ash) at blending ratio of 5 wt%, and 15 wt% during pyrolysis of linear low-density polyethylene (LLDPE). The influence on activation energy and oil was characterized via thermogravimetric analyzer (TGA) and gas chromatography-mass spectrometry (GC-MS). Results have shown that 15 wt% bottom ash exhibited higher catalytic activity. The activation energy estimated by Coats-Redfern method decreased from 458.7 kJ·mol-1 to 437.8 kJ·mol-1, while the alicyclic hydrocarbon yield increased from 5.97% to 32.09%. This implies that CaO, which is abundant in bottom ash, could promote the conversion of LLDPE. Furthermore, a cradle-to-factory gate life cycle assessment was performed to investigate three scenarios (non-catalytic pyrolysis, 15 wt% fly ash, and 15 wt% bottom ash) of LLDPE conversion strategies via a normalization and weighting approach. It was found that LLDPE pyrolysis with 15 wt% bottom ash also showed the lowest normalized score of 2.83, implying the lowest environmental impact. This work has demonstrated that the recycling of coal ash, particularly bottom ash, as catalysts for LLDPE pyrolysis is effective.

Synthesis, structure-activity relationship studies and evaluation of a TLR 3/8/9 agonist and its analogues.

A comprehensive SAR study of a putative TLR 3/8/9 agonist was conducted. Despite the excitement surrounding the potential of the first small molecule TLR3 agonist with a compound that additionally displayed agonist activity for TLR8 and TLR9, compound 1 displayed disappointing activity in our hands, failing to match the potency (EC50) reported and displaying only a low efficacy for the extent of stimulated NF-κB activation and release. The evaluation of >75 analogs of 1, many of which constitute minor modifications in the structure, failed to identify any that displayed significant activity and none that exceeded the modest activity found for 1.

Site-specific mortality in native joint septic arthritis: a national population study.

OBJECTIVE: This national cohort study investigated the incidence, site-specific mortality and prognostic factors of native septic arthritis (SA). METHODS: Tapping Taiwan's National Health Insurance Research Database, we identified inpatients with newly diagnosed SA between 1998 and 2012. They were categorized by site of infection and followed to calculate 30-day, 90-day and 1-year mortality. Predictors of mortality were calculated using Cox models. RESULTS: A total of 31 491 patients were identified as having SA, the most common site of infection being the knee (50.1%), followed by the hip (14.4%), other sites (26.8%), the shoulder (5.5%) and multiple sites (1.2%). Knee joint involvement was the most common site for all subgroups. Incidence increased from 9.8/105 in 1998 to 13.3/105 in 2012. The 30-day, 90-day and 1-year mortality rates were 4.3, 8.6 and 16.4% respectively. Predictors for mortality were hip infection, shoulder infection, multiple-site infection, being male, age ≥65 years old and comorbidities. We derived a mortality scoring model over age/SA site/comorbidity, and age ≥65 years old had the greatest risk contribution to mortality. No matter whether 1-month, 3-month or 1-year mortality was being considered, patients with the higher risk scores had the higher mortality rates (P < 0.0001). CONCLUSION: SA is an emerging infectious disease with a rising incidence, long duration of hospital stay and high mortality rate. The most common affected joint was knee for all subgroups. Patients aged ≥65 years old had a high SA incidence and the greatest risk contribution.

Synthesis and Biological Evaluation of a Carbamate-Containing Tubulysin Antibody-Drug Conjugate.

Antibody-drug conjugates (ADCs) use antibodies to deliver cytotoxic payloads directly into tumor cells via specifically binding to the target cell surface antigens. ADCs can enhance the anti-tumor effects of antibodies, and increase the delivery of cytotoxic payloads to cancer cells with a better therapeutic index. An ADC was prepared with a potent carbamate-containing tubulysin analogue attached to an anti-mesothelin antibody via a Cit-Val dipeptide linker. An aniline functionality in the tubulysin analogue was created to provide a site of linker attachment via an amide bond that would be stable in systemic circulation. Upon ADC internalization into antigen-positive cancer cells, the Cit-Val dipeptide linker was cleaved by lysosomal proteases, and the drug was released inside the tumor cells. The naturally occurring acetate of tubulysin was modified to a carbamate to reduce acetate hydrolysis of the ADC in circulation and to increase the hydrophilicity of the drug. The ADC bearing the monoclonal anti-mesothelin antibody and the carbamate-containing tubulysin was highly potent and immunologically specific to H226 human lung carcinoma cells in vitro, and efficacious at well-tolerated doses in a mesothelin-positive OVCAR3 ovarian cancer xenograft mouse model.

Mitochondria and Calcium Homeostasis: Cisd2 as a Big Player in Cardiac Ageing.

The ageing of human populations has become a problem throughout the world. In this context, increasing the healthy lifespan of individuals has become an important target for medical research and governments. Cardiac disease remains the leading cause of morbidity and mortality in ageing populations and results in significant increases in healthcare costs. Although clinical and basic research have revealed many novel insights into the pathways that drive heart failure, the molecular mechanisms underlying cardiac ageing and age-related cardiac dysfunction are still not fully understood. In this review we summarize the most updated publications and discuss the central components that drive cardiac ageing. The following characters of mitochondria-related dysfunction have been identified during cardiac ageing: (a) disruption of the integrity of mitochondria-associated membrane (MAM) contact sites; (b) dysregulation of energy metabolism and dynamic flexibility; (c) dyshomeostasis of Ca2+ control; (d) disturbance to mitochondria-lysosomal crosstalk. Furthermore, Cisd2, a pro-longevity gene, is known to be mainly located in the endoplasmic reticulum (ER), mitochondria, and MAM. The expression level of Cisd2 decreases during cardiac ageing. Remarkably, a high level of Cisd2 delays cardiac ageing and ameliorates age-related cardiac dysfunction; this occurs by maintaining correct regulation of energy metabolism and allowing dynamic control of metabolic flexibility. Together, our previous studies and new evidence provided here highlight Cisd2 as a novel target for developing therapies to promote healthy ageing.

Radiosensitization of Hepatocellular Carcinoma through Targeting Radio-Associated MicroRNA.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide. For patients who are resistant to monotherapy, multimodal therapy is a basic oncologic principle that incorporates surgery, radiotherapy (RT), and chemotherapy providing survival benefits for patients with most types of cancer. Although liver has low tolerance for radiation, high-precision RT for local HCC minimizes the likelihood of radiation-induced liver disease (RILD) in noncancerous liver tissue. RT have several therapeutic benefits, including the down-staging of tumors to make them resectable and repression of metastasis. The DNA damage response (DDR) is a cellular response to irradiation (IR), including DNA repair of injured cells and induction of programmed cell death, thereby resulting in maintenance of cell homeostasis. Molecules that block the activity of proteins in DDR pathways have been found to enhance radiotherapeutic effects. These molecules include antibodies, kinase inhibitors, siRNAs and miRNAs. MicroRNAs (miRNAs) are short non-coding regulatory RNAs binding to the 3'-untranslated regions (3'-UTR) of the messenger RNAs (mRNAs) of target genes, regulating their translation and expression of proteins. Thus, miRNAs and their target genes constitute complicated interactive networks, which interact with other molecules during carcinogenesis. Due to their promising roles in carcinogenesis, miRNAs were shown to be the potential factors that mediated radiosensitivity and optimized outcomes of the combination of systemic therapy and radiotherapy.

Meta-Analysis of the Impact of Pre-Procedural Serum Albumin on Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement.

Pre-procedural serum albumin's impact on prognosis after transcatheter aortic valve replacement (TAVR) has been studied. Literature on the prognostic role of serum albumin in the survival of patients undergoing TAVR shows conflicting results. This meta-analysis was conducted to evaluate the impact of pre-procedural serum albumin on outcomes after TAVR. A comprehensive literature search of EMBASE, MEDLINE, and the Cochrane Library was undertaken through July 2019. The primary end points were 30-day and one-year all-cause mortality after TAVR. Risk ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effect model. Ten eligible studies with 8,236 patients were analyzed. Of the 8,236 patients undergoing TAVR, with a mean age of 83 years, 48.8% were men and were categorized into two groups according to low and normal serum albumin (cut-off value: 3.5 or 4 g/dL). Overall, low albumin was significantly associated with an approximately two-fold increase in 30-day all-cause mortality (HR, 2.09; 95% CI, 1.53-2.86) and a 61% increase risk for one-year mortality (HR, 1.61; 95% CI, 1.31-1.98) in patients after TAVR. Sensitivity analyses showed the results to be robust. The association of low albumin level with an increase in one-year mortality risk was not modified by study design, albumin cut-off value, Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), and study quality. In conclusion, low albumin levels were associated with poor prognosis in patients after TAVR. Pre-procedural albumin can be used as a simple tool related to prognosis after TAVR.