LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.

Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca2+) flux and Ca2+-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically, CamK-A activates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.

Single-cell transcriptomic analysis reveals that the APP-CD74 axis promotes immunosuppression and progression of testicular tumors.

Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra-tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single-cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease-free survival. Further analysis identified that APP-CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra-tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Anti-tumor activity of niclosamide-mediated oxidative stress against acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a heterogeneous clonal disease originated from B- or T-cell lymphoid precursor cells. ALL is often refractory or relapses after treatment. Novel treatments are anxiously needed in order to achieve a better response and prolonged overall survival in ALL patients. In the present study, we aimed at examining the anti-tumor effect of niclosamide on ALL. We investigated the effects of niclosamide on the proliferation and apoptosis in vitro, the growth of ALL cells in xenografted NCG mice. The results showed that niclosamide treatment potently inhibited the growth of ALL cells and induced apoptosis via elevating the levels of reactive oxygen species (ROS) and activating TP53. These findings suggest that niclosamide may be a promisingly potential agent for ALL therapy.

In vitro and in vivo study of antibacterial and anti-encrustation coating on ureteric stents.

OBJECTIVES: To investigate the ability of propolis-coated ureteric stents to solve complications, especially urinary tract infections (UTIs) and crusting, in patients with long-term indwelling ureteric stents through antimicrobial and anti-calculus activities. MATERIALS AND METHODS: Polyurethane (PU) ureteric stents were immersed in the ethanol extract of propolis (EEP), a well-known antimicrobial honeybee product, and subjected to chemical, hydrophilic, and seismic tests. The antimicrobial activity of the EEP coating was then examined by in vitro investigation. Proteus mirabilis infection was induced in rats within uncoated and EEP-coated groups, and the infection, stone formation, and inflammation were monitored at various time points. RESULTS: The characterisation results showed that the hydrophilicity and stability of the EEP surface improved. In vitro tests revealed that the EEP coating was biocompatible, could eliminate >90% of bacteria biofilms attached to the stent and could maintain bacteriostatic properties for up to 3 months. The in vivo experiment revealed that the EEP-coating significantly reduced the amount of bacteria, stones, and salt deposits on the surface of the ureteric stents and decreased inflammation in the host tissue. CONCLUSIONS: Compared with clinically used PU stents, EEP-coated ureteric stents could better mitigate infections and prevent encrustation. Thus, this study demonstrated that propolis is a promising natural dressing material for ureteric stents.

Migraine, chronic kidney disease and kidney function: observational and genetic analyses.

Epidemiological studies demonstrate an association between migraine and chronic kidney disease (CKD), while the genetic basis underlying the phenotypic association has not been investigated. We aimed to help avoid unnecessary interventions in individuals with migraine through the investigation of phenotypic and genetic relationships underlying migraine, CKD, and kidney function. We first evaluated phenotypic associations using observational data from UK Biobank (N = 255,896). We then investigated genetic relationships leveraging genomic data in European ancestry for migraine (Ncase/Ncontrol = 48,975/540,381), CKD (Ncase/Ncontrol = 41,395/439,303), and two traits of kidney function (estimated glomerular filtration rate [eGFR, N = 567,460] and urinary albumin-to-creatinine ratio [UACR, N = 547,361]). Observational analyses suggested no significant association of migraine with the risk of CKD (HR = 1.13, 95% CI = 0.85-1.50). While we did not find any global genetic correlation in general, we identified four specific genomic regions showing significant for migraine with eGFR. Cross-trait meta-analysis identified one candidate causal variant (rs1047891) underlying migraine, CKD, and kidney function. Transcriptome-wide association study detected 28 shared expression-trait associations between migraine and kidney function. Mendelian randomization analysis suggested no causal effect of migraine on CKD (OR = 1.03, 95% CI = 0.98-1.09; P = 0.28). Despite a putative causal effect of migraine on an increased level of UACR (log-scale-beta = 0.02, 95% CI = 0.01-0.04; P = 1.92 × 10-3), it attenuated to null when accounting for both correlated and uncorrelated pleiotropy. Our work does not find evidence supporting a causal association between migraine and CKD. However, our study highlights significant biological pleiotropy between migraine and kidney function. The value of a migraine prophylactic treatment for reducing future CKD in people with migraine is likely limited.

Safety and efficacy of double plasma molecular adsorption system with sequential low-volume plasma exchange in intermediate-stage hepatitis B virus-related acute-on-chronic liver failure.

Current evidence suggests that the mortality rate of intermediate-stage hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) remains high. We aimed to investigate the safety and efficacy of double plasma molecular adsorption system (DPMAS) with sequential low-volume plasma exchange (LPE) treatment in intermediate-stage HBV-related ACLF. This prospective study recruited intermediate-stage HBV-related ACLF patients and was registered on ClinicalTrials.gov (NCT04597164). Eligible patients were randomly divided into a trial group and a control group. Patients in both groups received comprehensive medical treatment. Patients in the trial group further received DPMAS with sequential LPE. Data were recorded from baseline to Week 12. Fifty patients with intermediate-stage HBV-related ACLF were included in this study. The incidence of bleeding events and allergic reactions in the trial group was 12% and 4%, respectively, with no other treatment-related adverse events. The levels of total bilirubin and prothrombin time-international normalized ratio, and model for end-stage liver disease scores after each session of DPMAS with sequential LPE were significantly lower than those before treatment (all p < 0.05). The 12-week cumulative liver transplantation-free survival rates in the trial and control groups were 52% and 24%, respectively (p = 0.041). The 12-week cumulative overall survival rates in the trial and control groups were 64% and 36%, respectively (p = 0.048). The Kaplan-Meier survival analysis revealed significant differences in liver transplantation-free survival (p = 0.047) and overall survival (p = 0.038) between the trial and control groups. Cox regression analysis indicated that blood urea nitrogen (p = 0.038), DPMAS with sequential LPE (p = 0.048), and Chinese Group on the Study of Severe Hepatitis B-ACLF II score (p < 0.001) were significant risk factors for mortality. DPMAS with sequential LPE treatment is safe and effective for patients with intermediate-stage HBV-related ACLF.

Limited clinical role of blood eosinophil levels in early life atopic disease: A mother-child cohort study.

BACKGROUND: Blood eosinophil count is a well-established biomarker of atopic diseases in older children and adults. However, its predictive role for atopic diseases in preschool children is not well established. OBJECTIVE: To investigate the association between blood eosinophil count in children and development of atopic diseases up to age 6 years. METHODS: We investigated blood eosinophil count at age 18 months and 6 years in relation to recurrent wheeze/asthma, atopic dermatitis, allergic rhinitis, and allergic sensitization during the first 6 years of life in the two Copenhagen Prospective Studies on Asthma in Childhood cohorts (n = 1111). Blood eosinophil count was investigated in association with remission of existing atopic disease, current atopic disease, and later development of atopic disease. RESULTS: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis, while blood eosinophil count at age 6 years was associated with increased occurrence of current wheezing/asthma (OR = 1.1; 1.04-1.16, p = .0005), atopic dermatitis (OR = 1.06; 1.01-1.1, p = .02), and allergic rhinitis (OR = 1.11; 1.05-1.18, p = .0002). Blood eosinophil count at 18 months did not predict persistence or development of recurrent wheeze/asthma or atopic dermatitis at age 6 years. CONCLUSION: Blood eosinophil count at 18 months was not associated with current wheezing/asthma or atopic dermatitis and did not predict persistence or development of disease. This implies a limited clinical role of blood eosinophil levels in early-life atopic disease and questions the clinical value of blood eosinophil counts measured in toddlers as a predictive biomarker for subsequent atopic disease in early childhood.

A visible-light-mediated cascade reaction of quinoxalin-2(1H)-ones, alkenes, and sulfinic acids.

A photocatalytic three-component cascade reaction of quinoxalin-2(1H)-ones, alkenes, and sulfinic acids under metal-, strong oxidant-, and external photocatalyst-free conditions was developed. The reaction was performed at room temperature using air as a green oxidant. Various sulfonated quinoxalin-2(1H)-ones were obtained in satisfactory yields with good functional group compatibility. The preliminary study showed that the current transformation was enabled by the formation of an electron donor-acceptor (EDA) complex between quinoxalin-2(1H)-ones and sulfinic acids.

The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial.

BACKGROUND: A recent sham-controlled clinical study has shown that low-intensity pulsed ultrasound twice per week can safely and effectively treat patients with mild-to-moderate erectile dysfunction (ED). However, large-scale clinical trials are needed to verify its efficacy and safety and determine a reasonable treatment interval. AIM: To study whether low-intensity pulsed ultrasound therapy thrice per week is non-inferior to twice per week in patients with mild-to-moderate ED. METHODS: A randomized, open-label, parallel-group, non-inferiority clinical trial was conducted in 7 hospitals in China. A total of 323 patients with mild-to-moderate ED were randomized (1:1) into thrice per week (3/W) and twice per week (2/W) groups. Low-intensity pulsed ultrasound was applied on each side of the penis for 16 sessions. OUTCOMES: The primary outcome was response rate using the minimal clinically important difference in the International Index of Erectile Function (IIEF-EF) score at week 12. Secondary outcomes included Erection Hardness Score (EHS), Sexual Encounter Profile, Global Assessment Question, and Self Esteem and Relationship Questionnaire. RESULTS: Response rates in 3/W and 2/W groups were 62.0% and 62.5%, respectively. Treatment effect in the 3/W group was noninferior to that of the 2/W group, with rate difference lower bound of -0.01% [95% confidence interval -0.11 to 0.10%] within the acceptable margin (-14.0%). No significant difference was found among secondary outcomes. IIEF-EF score showed a significant increase from baseline in the 3/W group (16.8 to 20.7) and 2/W group (17.8 to 21.7), and the percentage of patients with EHS ≥3 increased in the 3/W (54.9% to 84.0%) and 2/W (59.5% to 83.5%) groups. There was no significant difference in response rate between the 2 groups after controlling for strata factors and homogeneous tests. No treatment-related adverse events were reported. CLINICAL IMPLICATIONS: Low-intensity pulsed ultrasound therapy displays similar efficacy and safety for mild-to-moderate ED when administered thrice or twice per week for 16 sessions. This study provides two options to suit patients' needs. STRENGTHS & LIMITATIONS: This is a large-sample, randomized, controlled, noninferiority trial study. Short-term follow-up and mostly younger patients are the main limitations. CONCLUSION: Low-intensity pulsed ultrasound therapy thrice and twice per week showed equivalent therapeutic effects and safety for mild-to-moderate ED in a young and generally healthy population. This therapy warrants further investigation of its potential value in rehabilitation of ED. Chen, H., Li Z., Li X., et al. The Efficacy and Safety of Thrice vs Twice per Week Low-Intensity Pulsed Ultrasound Therapy for Erectile Dysfunction: A Randomized Clinical Trial. J Sex Med 2022;19:1536-1545.

Cu-Catalyzed alkylation-cyanation type difunctionalization of styrenes with aliphatic aldehydes and TMSCN via decarbonylation.

A copper-catalyzed decarbonylative alkylation-cyanation of styrene derivatives with aliphatic aldehydes and trimethylsilyl cyanide to provide chain elongated nitriles is reported. Using TBHP as an oxidant and free radical initiator, the reaction can smoothly convert abundant α-di-substituted, α-mono-substituted and linear aliphatic aldehydes into the corresponding 3°, 2° and 1° alkyl radicals to initiate the subsequent radical-type difunctionalization of various styrenes.

LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism.

The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes-associated protein (YAP). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNAs (lncRNAs) as attractive therapeutic targets, given their roles in modulating various cancer-related signaling pathways. In this study, we report that lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) is required for YAP-dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 attenuated YAP-dependent glycolysis and tumor growth. The expression levels of BCAR4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP-BCAR4-glycolysis axis for breast cancer treatment.

Alkylation of quinoxalin-2(1H)-ones using phosphonium ylides as alkylating reagents.

A practical and efficient methodology for the construction of 3-alkylquinoxalinones through base promoted direct alkylation of quinoxalin-2(1H)-ones with phosphonium ylides as alkylating reagents under metal- and oxidant-free conditions was developed. Various 3-alkylquinoxalin-2(1H)-ones were easily obtained in good to excellent yields. Tentative mechanistic studies suggest that this reaction is likely to involve a nucleophilic addition-elimination process.

Selective recognition of DNA parallel G-quadruplexes by 3,8a-disubstituted indolizinones.

Owing to its potential biological relevance, DNA G-quadruplex has been considered as a prospective anti-cancer target. Some known G-quadruplex-interactive N-containing compounds with low cytotoxicity have become prospective anticancer drugs. Here we reported a new type of N-containing alkaloids 3,8a-disubstituted indolizinones, and investigated their substituent effects at 3- and 8a-positions in targeting to DNA c-myc G-quadruplex. And then we used 3-naphtyl-8a-(pyridin-2-yl) substrate I8 as an example, and investigated its ability in targeting to DNA parallel G-quadruplexes in vitro.

Effects of high-intensity interval training on adipose tissue lipolysis, inflammation, and metabolomics in aged rats.

High-intensity interval training (HIIT) is a time-efficient alternative to moderate-intensity continuous training (MICT) to improve metabolic health in older individuals. However, differences in adipose tissue metabolism between these two approaches are unclear. Here, we evaluated the effects of HIIT and MICT on metabolic phenotypes in aged rats. HIIT significantly decreased fat mass, increased percent lean mass, decreased fat-to-lean ratio, reduced serum high-sensitivity C-reactive protein, increased serum interleukin-10 levels, and decreased perirenal adipose tissue leptin compared with rats in the sedentary (SED) group. HIIT also increased pregnenolone, cortisol, and corticosterone in both adipose tissue and serum. Both exercise modalities enhanced hormone-sensitive lipase and adipose triglyceride lipase expression compared with the SED group and decreased palmitic acid, stearic acid, octadecadienoic acid, urea, 1-heptadecanol, and α-tocopherol. MICT was related to glycerolipid metabolism, whereas HIIT was related to steroid hormone biosynthesis. Overall, HIIT showed more favorable regulation of anti-inflammatory activity than MICT.

Suicide and associated psychosocial correlates among university students in Taiwan: A mixed-methods study.

BACKGROUND/PURPOSE: The trend of suicide rates among young adults has been increasing worldwide. The study aimed to identify the suicide risks and associated psychosocial factors in a large university in Taiwan. METHODS: This is a mixed-methods study using both questionnaire survey and two open-ended questions for the exploration of qualitative data. An online survey was conducted between two periods of the same semester in 2018 to collect different sources of stress and other suicide correlates. The measurement scales included the 9-item Concise Mental Health Checklist, the University Stress Screening Tool in Taiwan and the Chinese Maudsley Personality Inventory. The participants were required to fulfill two open-ended questions about stress experience and depressive symptoms in the previous month in the end of the questionnaire, which was analyzed using thematic analysis. RESULTS: A total of 857 university students were recruited (67.9% female participants). Over a quarter of participants were under poor mental health status and more than 60% experienced stressful events in the prior year. A higher suicide risk and neurotic trait was noticed compared to the general public. These results were consistent with the qualitative findings. CONCLUSION: While identifying several risk factors that cumulatively conduced to higher suicide risks, neuroticism served as a key element in the increased suicide risk among the university students. Suicide prevention strategies for university students should highlight stress management for those with neurotic trait and early suicide risk identification.

Fe-catalyzed Decarbonylative Alkylative Spirocyclization of N-Arylcinnamamides: Access to Alkylated 1-Azaspirocyclohexadienones.

For the convenient introduction of simple linear/branched alkyl groups into biologically important azaspirocyclohexadienones, a practical Fe-catalyzed decarbonylative cascade spiro-cyclization of N-aryl cinnamamides with aliphatic aldehydes to provide alkylated 1-azaspiro-cyclohexadienones was developed. Aliphatic aldehydes were oxidative decarbonylated into primary, secondary and tertiary alkyl radicals conveniently and allows for the subsequent cascade construction of dual C(sp3)-C(sp3) and C=O bonds via radical addition, spirocyclization and oxidation sequence.

[Silencing ERp29 promotes the invasiveness of human PCa cells in vitro: Molecular mechanisms].

OBJECTIVE: To analyz the correlation of the expression of ERp29 with the clinicopathological characteristics of PCa and investigate the effect of small interfering RNA (siRNA) silencing the ERp29 gene on the biological behavior of PCa LNCaP cells. METHODS: The expression of the ERp29 gene in the BPH and PCa tissues was detected by immunohistochemistry and that of the ERp29 protein in the PCa and adjacent normal tissues of 6 PCa patients determined by Western blot. Human LNCaP cells were transfected with siRNA using LipofectamineTM 2000, and the expressions of ERp29 mRNA and protein in the LNCaP cells detected by quantitative real-time PCR (qRT-PCR) and Western blot, respectively. The proliferation of the LNCaP cells was measured by MTT assay, their in vitro migration and invasiveness evaluated by the Transwell method, and the expressions of E-cadherin and Vimentin determined by qRT-PCR. RESULTS: The expression of ERp29 was significantly lower in the PCa than in the adjacent normal tissue (73.9% vs 91.9%， P < 0.05), with a significant correlation between the down-regulated ERp29 expression and metastasis (M) staging (P < 0.05). After transfection with siRNA, the LNCaP cells showed dramatically increased proliferation, migration and invasiveness (P < 0.05), and the expression of E-cadherin was markedly down-regulated while that of Vimentin up-regulated as compared with those in the normal control group (P < 0.05). CONCLUSIONS: The ERp29 gene may be a novel repressor of tumor metastasis. Silencing ERp29 can promote the invasiveness of human PCa cells in vitro by down-regulating the expression of E-cadherin and increasing epithelial-mesenchymal transition.

[Summary on international quality standards of Bupleuri Radix].

Bupleuri Radix is a traditional staple Chinese medicinal material which has a wide range of medicinal values. However, with the increase of the international trade of Bupleuri Radix, its quality and safety issues have attracted much attention. Therefore, the establishment of international standards for Bupleuri Radix has important practical significance. In view of this, based on our foundation work on the standardization of Chinese medicine and international standards, this review systematically collates the quality standards of the major countries(regions) in which Bupleuri Radix is used, including the origin, macroscopic characteristics, microscopic characteristics, determination of marker compounds and extrinsic harmful contaminants. The existing problems and suggestions are also discussed in this review, which may provide reference for the study of the quality standard of Bupleuri Radix.

A review of fibroblast growth factor 21 in diabetic cardiomyopathy.

FGF21 (fibroblast growth factor 21) is a regulator of metabolism and performs an important role in glucose and lipid metabolism and the maintenance of energy balance. FGF21 is principally expressed in the liver, but it can also be found in the pancreas, skeletal muscle, and adipose tissue. It is known that levels of serum FGF21 are significantly elevated in obese, insulin-resistant patients, and those with metabolic syndrome. Elevated levels of FGF21 in serum during the early stages of various metabolic diseases are considered a compensatory response by the organism. Therefore, FGF21 is considered a hormone in response to stress and an early diagnostic marker of disease. Diabetic cardiomyopathy is a special type of cardiac complication, characterized as a chronic myocardial disorder caused by diabetes. The pathological process includes increased oxidative stress, energy metabolism in myocardial cells, an inflammatory response, and myocardial cell apoptosis. A growing body of evidence suggests that FGF21 has the potential to be an effective drug for the treatment of diabetic cardiomyopathy. Here, we review recent progress on the characteristics of FGF21 in its protective role, especially in pathological processes such as suppressing apoptosis in the myocardium, reducing inflammation in cardiomyocytes, reducing oxidative stress, and promoting fatty acid oxidation. In addition, we explore the possibility that diabetic cardiomyopathy can be delayed through the application of FGF21, providing possible therapeutic targets of the disease.