Knockdown of PIK3R6 impedes the onset and advancement of clear cell renal cell carcinoma.

In this research, we investigated the role of PIK3R6, a regulatory subunit of PI3Kγ, known for its tumor-promoting properties, in clear cell renal cell carcinoma (CCRCC). Utilizing the UALCAN website, we found PIK3R6 upregulated in CCRCC, correlating with lower survival rates. We compared PIK3R6 expression in CCRCC tumor tissues and adjacent normal tissues using immunohistochemistry. Post RNA interference-induced knockdown of PIK3R6 in 786-O and ACHN cell lines, we performed CCK-8, colony formation, Edu staining, flow cytometry, wound healing, and transwell assays. Results showed that PIK3R6 silencing reduced cell proliferation, migration, and invasion, and induced G0/G1 phase arrest and apoptosis. Molecular analysis revealed decreased CDK4, Cyclin D1, N-cadherin, Vimentin, Bcl-2, p-PI3K and p-AKT, with increased cleaved caspase-3, Bax, and E-cadherin levels in CCRCC cells. Moreover, inhibiting PIK3R6 hindered tumor growth. These findings suggest a significant role for PIK3R6 in CCRCC cell proliferation and metastasis, presenting it as a potential therapeutic target.

Investigation of epidemiological and clinical characteristics of people infected with SARS-CoV-2 during the second pandemic of COVID-19 in Chengdu, China.

Objective: This study investigated the epidemiological and clinical characteristics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infected patients during the second pandemic of COVID-19 (coronavirus disease of 2019) in Chengdu, China. Furthermore, the differences between first infection and re-infection cases were also compared and analyzed to provide evidence for better prevention and control of SARS-CoV-2 re-infection. Methods: An anonymous questionnaire survey was conducted using an online platform (wjx.cn) between May 20, 2023 to September 12, 2023. Results: This investigation included 62.94% females and 32.97% of them were 18-30 years old. Furthermore, 7.19-17.18% of the participants either did not receive vaccination at all or only received full vaccination, respectively. Moreover, 577 (57.64%) participants were exposed to cluster infection. The clinical manifestations of these patients were mainly mild to moderate; 78.18% of participants had a fever for 1-3 days, while 37.84% indicated a full course of disease for 4-6 days. In addition, 40.66% of the participants had re-infection and 72.97% indicated their first infection approximately five months before. The clinical symptoms of the first SARS-CoV-2 infection were moderate to severe, while re-infection indicated mild to moderate symptoms (the severity of symptoms other than diarrhea and conjunctival congestion had statistically significant differences) (p < 0.05). Moreover, 70.53 and 59.21% of first and re-infection cases had fever durations of 3-5 and 0-2 days, respectively. Whereas 47.91 and 46.40% of first and re-infection cases had a disease course of 7-9 and 4-6 days. Conclusion: The SARS-CoV-2 infected individuals in Chengdu, China, during the second pandemic of COVID-19 had mild clinical symptoms and a short course of disease. Furthermore, compared with the first infection, re-infection cases had mild symptoms, low incidences of complications, short fever duration, and course of disease.

Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRß/CLDN1 pathway.

Adhesion after tendon injury, which can result in limb movement disorders, is a common clinical complication; however, effective treatment methods are lacking. Hyaluronic acid hydrogels are a new biomedical material used to prevent tendon adhesion owing to their good biocompatibility. In addition, potential drugs that inhibit adhesion formation have gradually been discovered. The anti-adhesion effects of a combination of loaded drugs into hydrogels have become an emerging trend. However, current drug delivery systems usually lack specific regulation of drug release, and the effectiveness of drugs for treating tendon adhesions is mostly flawed. In this study, we identified a new drug, imatinib mesylate (IM), that prevents tendon adhesion and explored its related molecular pathways. In addition, we designed a pH-responsive sustained-release hydrogel for delivery. Using the metal-organic framework ZIF-8 as a drug carrier, we achieved controlled drug release to increase the effective drug dose at the peak of adhesion formation to achieve better therapeutic effects. The results showed that IM blocked the formation of peritendon adhesions by inhibiting the PDGFRß/ERK/STAT3/CLDN1 pathway. Furthermore, the hydrogel with ZIF-8 exhibited better physical properties and drug release curves than the hydrogel loaded only with drugs, showing better prevention and treatment effects on tendon adhesion.

No Racial Disparities Observed Using Point-of-Care Genetic Counseling and Testing for Endometrial and Ovarian Cancer in a Diverse Patient Population: A Retrospective Cohort Study.

We investigated genetic counseling and testing rates for patients with gynecologic malignancy at a tertiary care center with a large minority population. Our retrospective cohort included newly diagnosed epithelial ovarian, fallopian tube, peritoneal, or endometrial cancer patients between January 2014 and June 2022. For endometrial cancer, 373 patients were identified. A total of 207 (55%) patients were screened using mismatch repair immunohistochemistry (MMR IHC). A total of 82 (40%) had MMR deficiencies on IHC. Of these, 63 (77%) received genetic counseling. A total of 62 (98%) underwent genetic testing, and ultimately, 7 (11%) were diagnosed with Lynch syndrome (LS). The overall rate of LS was 1.9%. MMR IHC testing increased steadily, reaching 100% in 2022. For ovarian cancer, 144 patients were identified. A total of 104 (72%) patients received genetic counseling, and 99 (95%) underwent genetic testing. Rates were not influenced by race, ethnicity, insurance type, or family history of cancer. They were significantly different by cancer stage (p < 0.01). The proportion of patients who received genetic counseling increased from 47% in 2015 to 100% in 2022 (p < 0.01). Most counseling was performed by a gynecologic oncologist (93%) as opposed to a genetic counselor (6.7%). Overall, 12 (8.3%) patients were BRCA+. High rates of counseling and testing were observed with few disparities.

Antiadhesion Biomaterials in Tendon Repair: Application Status and Future Prospect.

The healing process after tendon injury is often accompanied by the formation of peritendinous adhesion, contributing to limb dysfunction and exerting detrimental effects on the individuals, as well as the development of society and economy. With the continuous development of material science, as well as the augmented understanding of tendon healing and the mechanism of peritendinous adhesion formation, materials used for the fabrication of barrier membranes against peritendinous adhesion emerge endlessly. In this article, based on the analysis of the mechanism of adhesion formation, we first review the commonly used natural and synthetic materials, along with their corresponding fabrication strategies, in order to furnish valuable insights for the future optimization and development of antiperitendinous adhesion barrier membranes. This article also discusses the interaction between antiadhesion materials and cells for ameliorating peritendinous adhesion.

Cytokine expression in subjects with Mycobacterium avium ssp. paratuberculosis positive blood cultures and a meta-analysis of cytokine expression in Crohn's disease.

Objectives: 1) Culture Mycobacterium avium ssp. paratuberculosis (MAP)from blood, 2) assess infection persistence, 3) determine Crohn's disease (CD) cytokine expression, 4) compare CD cytokine expression to tuberculosis, and 5) perform a meta-analysis of cytokine expression in CD. Methods: The Temple University/Abilene Christian University (TU/ACU) study had a prospective case control design with 201 subjects including 61 CD patients and 140 non-CD controls. The culture methods included MGIT, TiKa and Pozzato broths, and were deemed MAP positive, if IS900 PCR positive. A phage amplification assay was also performed to detect MAP. Cytokine analysis of the TU/ACU samples was performed using Simple Plex cytokine reagents on the Ella ELISA system. Statistical analyses were done after log transformation using the R software package. The meta-analysis combined three studies. Results: Most subjects had MAP positive blood cultures by one or more methods in 3 laboratories. In our cytokine study comparing CD to non-CD controls, IL-17, IFNγ and TNFα were significantly increased in CD, but IL-2, IL-5, IL-10 and GM-CSF were not increased. In the meta-analysis, IL-6, IL-8 and IL-12 were significantly increased in the CD patients. Conclusion: Most subjects in our sample had MAP infection and 8 of 9 subjects remained MAP positive one year later indicating persistent infection. While not identical, cytokine expression patterns in MAP culture positive CD patients in the TU/ACU study showed similarities (increased IL-17, IFNγ and TNFα) to patterns of patients with Tuberculosis in other studies, indicating the possibilities of similar mechanisms of pathogen infection and potential strategies for treatment.

Post-synthetic Rhodium (III) Complexes in Covalent Organic Frameworks for Photothermal Heterogeneous C-H Activation.

Although photocatalytic C-H activation has been realized by using heterogeneous catalysts, most of them require high-temperature conditions to provide the energy required for C-H bond breakage. The catalysts with photothermal conversion properties can catalyze this reaction efficiently at room temperature, but so far, these catalysts have been rarely developed. Here, we construct bifunctional catalysts Rh-COF-316 and -318 to combine photosensitive covalent organic frameworks (COFs) and transition-metal catalytic moiety using a post-synthetic approach. The Rh-COF enable the heterogeneous C-H activation reaction by photothermal conversion for the first time, and exhibit excellent yields (up to 98 %) and broad scope of substrates in [4+2] annulation at room temperature, while maintaining the high stability and recyclability. Significantly, this work is the highest yield reported so far in porous materials catalyzing C(sp2)-C(sp2) formation at room temperature. The excellent performances can be attributed to the COF-316, which enhances the photothermal effect (ΔT=50.9 °C), thus accelerating C-H bond activation and the exchange of catalyst with substrates.

Recyclable fabrication of hollow N-doped amorphous carbon nanospindles with abundant short-range curved carbon fragments as bifunctional anode for lithium/sodium ion storage.

A recyclable hard-template method is proposed to exploit spindle-shaped hollow nitrogen-doped amorphous carbon (h-NAC) with a large number of short-range curved carbon fragments as anodes for lithium/sodium ion batteries (LIBs/SIBs). Besides providing adsorption sites due to the high existence of oxygen-containing functional groups (CO and COOH), the heavily exposed edge regions also provide a favorable storage environment with high adsorption energy for Li+/Na+ due to their short-range curved structure. Importantly, the etching solution of hard templates can be recycled to generate the FeOOH nanospindles as a precursor through a simple chemical titration, which supplies a new idea for the green preparation of hollow materials. The h-NAC electrode is proven to be bifunctional for storing lithium and sodium ions, displaying favorable rate capability (255 mAh g-1 and 106 mAh g-1 at 5 A g-1 for LIBs and SIBs, respectively). After 1000 cycles at 1 A g-1, the reproducible capacities of the LIBs and SIBs kept 496 mAh g-1 and 181 mAh g-1, respectively.

Highly efficient conversion of mouse fibroblasts into functional hepatic cells under chemical induction.

Previous studies have shown that hepatocyte-like cells can be generated from fibroblasts using either lineage-specific transcription factors or chemical induction methods. However, these methods have their own deficiencies that restrict the therapeutic applications of such induced hepatocytes. In this study, we present a transgene-free, highly efficient chemical-induced direct reprogramming approach to generate hepatocyte-like cells from mouse embryonic fibroblasts (MEFs). Using a small molecule cocktail (SMC) as an inducer, MEFs can be directly reprogrammed into hepatocyte-like cells, bypassing pluripotent and immature hepatoblast intermediate stages. These chemical-induced hepatocyte-like cells (ciHeps) closely resemble mature primary hepatocytes in terms of morphology, biological behavior, gene expression patterns, marker expression levels, and hepatic functions. Furthermore, transplanted ciHeps can integrate into the liver, promote liver regeneration, and improve survival rates in mice with acute liver damage. ciHeps can also ameliorate liver fibrosis caused by chronic injuries and enhance liver function. Notably, ciHeps exhibit no tumorigenic potential either in vitro or in vivo. Mechanistically, SMC-induced mesenchymal-to-epithelial transition and suppression of SNAI1 contribute to the fate conversion of fibroblasts into ciHeps. These results indicate that this transgene-free, chemical-induced direct reprogramming technique has the potential to serve as a valuable means of producing alternative hepatocytes for both research and therapeutic purposes. Additionally, this method also sheds light on the direct reprogramming of other cell types under chemical induction.

Type H vessels: functions in bone development and diseases.

Type H vessels are specialized blood vessels found in the bone marrow that are closely associated with osteogenic activity. They are characterized by high expression of endomucin and CD31. Type H vessels form in the cancellous bone area during long bone development to provide adequate nutritional support for cells near the growth plate. They also influence the proliferation and differentiation of osteoprogenitors and osteoclasts in a paracrine manner, thereby creating a suitable microenvironment to facilitate new bone formation. Because of the close relationship between type H vessels and osteogenic activity, it has been found that type H vessels play a role in the physiological and pathological processes of bone diseases such as fracture healing, osteoporosis, osteoarthritis, osteonecrosis, and tumor bone metastasis. Moreover, experimental treatments targeting type H vessels can improve the outcomes of these diseases. Here, we reviewed the molecular mechanisms related to type H vessels and their associated osteogenic activities, which are helpful in further understanding the role of type H vessels in bone metabolism and will provide a theoretical basis and ideas for comprehending bone diseases from the vascular perspective.

PC3T: a signature-driven predictor of chemical compounds for cellular transition.

Cellular transitions hold great promise in translational medicine research. However, therapeutic applications are limited by the low efficiency and safety concerns of using transcription factors. Small molecules provide a temporal and highly tunable approach to overcome these issues. Here, we present PC3T, a computational framework to enrich molecules that induce desired cellular transitions, and PC3T was able to consistently enrich small molecules that had been experimentally validated in both bulk and single-cell datasets. We then predicted small molecule reprogramming of fibroblasts into hepatic progenitor-like cells (HPLCs). The converted cells exhibited epithelial cell-like morphology and HPLC-like gene expression pattern. Hepatic functions were also observed, such as glycogen storage and lipid accumulation. Finally, we collected and manually curated a cell state transition resource containing 224 time-course gene expression datasets and 153 cell types. Our framework, together with the data resource, is freely available at http://pc3t.idrug.net.cn/ . We believe that PC3T is a powerful tool to promote chemical-induced cell state transitions.

Effectiveness of sublingual immunotherapy with house dust mite drops in asthmatic children at different ages.

Background: Respiratory allergies in children, such as asthma and rhinitis, are becoming progressively common every year. Recent studies found that pediatric patients with asthma receiving regular medication and specific immunotherapy (SIT) had improved therapeutic outcomes in a wide age range. However, there are few studies that have examined the effectiveness of SIT treatment in children with allergic asthma at different ages in terms of the degree of asthma control, improvements in lung function, and changes in exhaled nitric oxide (FeNO). Method: A total of 200 asthmatic pediatric patients who had been receiving regular treatment for at least a year were split into the observation and the control groups, which depended on whether sublingual immunotherapy was added based on conventional treatment medicines. The children who were divided by an age cut-off of 6 years old in these two groups were compared before and after therapy based on the exhaled levels of FeNO, pulmonary function, visual analog scale, medication scores, daytime and nighttime ratings of asthma symptom, and rhinitis symptom scores. Results: Before treatment, there was no significant difference between the observation group and the control group in various indicators of the patients under 6 years old; and in the older children (6-16 years old) group, the scores of FVC, FEV1, and FEF25 in the observation group were significantly lower than those in the control group (P < 0.05). The FEF75, FEF50, FEF25, and MMEF75/MMEF25 indexes in the observation group were significantly higher than those in the control group after treatment (P < 0.05), but there was no statistical significance in other indexes (P > 0.05). The scores of ACT, FEF75, FEF50, MMEF72/MMEF25, and FeNO in the observation group were all higher than those in the control group after treatment (P < 0.05), and the differences in other indexes were not statistically significant (P > 0.05). Between the young-age group and the elder group, there was no significant difference in all indexes in the observation group before and after treatment (P > 0.05). Conclusion: Children with asthma of all ages can considerably benefit from sublingual immunotherapy. Specifically, younger patients showed greater tendency on the improvement of small airway resistance, whereas school-age children with asthma significantly improved their small airway resistance as well as their asthma control and inflammation alleviation.

Investigating the role of E-commerce marketing capabilities to achieve the strategic performance of tourism firms.

Introduction: This study aims to explore the relationships between strategic performance, e-commerce marketing capabilities (ECMCs), the Internet of Things (IoT) and customer engagement. This study examines the direct association between ECMC and strategic performance. Current research also explores the customer engagement mediation between ECMC and strategic performance (SP). Furthermore, our study investigates the IoT moderation between ECMC and SP. Methods: We test our research hypotheses using data collected in the tourism sector in the context of digital commerce. The questionnaire is used to collect data through random sampling, and these data are useful as a basis for future research. By adding e-commerce capabilities, we show firms how to become more efficient and improve their strategic performance. Moreover, this study, by incorporating the findings of the existing literature, provides a strong foundation for studying the impact of ECMCs and customer engagement on strategic performance as well as the mediating role of e-trust. Results: The results can be useful for managers who conduct digital business internationally, as they need to understand the importance of ECMCs. In fact, the adaptation of ECMCs to the organization enhances customer engagement and helps to improve strategic performance. Discussion: The approach used in this study is in line with previous theoretical analyses and shows emerging patterns in international digital businesses. Moreover, this study adds insights to the e-commerce research by linking different dimensions to reach an in-depth understanding of each item that is affected by ECMCs.

Pharmacokinetics and Bioequivalence of Fudosteine in Healthy Chinese Volunteers Under Fasting and Fed Conditions: A 4-Way Replicate Crossover Study.

The bioequivalence of a generic fudosteine tablet vs a brand-named fudosteine tablet under fasting and fed conditions was evaluated in this study. This randomized, open-label, single-dose, 4-way replicate, crossover, bioequivalence study included 64 healthy Chinese subjects (fasting cohort, n = 32; fed cohort, n = 32) who were assigned to receive a single 200-mg dose of generic or brand-named fudosteine. Blood samples were collected before dosing and up to 24 hours after dosing. The plasma concentrations of fudosteine were analyzed by high-performance liquid chromatography-tandem mass spectrometry. Safety was monitored. There were no significant differences in maximum plasma concentration (Cmax ), area under the plasma concentration-time curve (AUC) from time 0 to time t (AUC0-t ), or AUC from time 0 to infinity (AUC0-∞ ) between the test and reference formulations. However, food showed a significant effect on Cmax , AUC0-t , and AUC0-∞ for both generic and brand-named fudosteine. The 90%CIs of the test/reference ratios of Cmax , AUC0-t, and AUC0-∞ were within the range of 80% to 125% under both fasting and fed conditions. No serious adverse events were reported. The bioequivalence between generic and brand-named fudosteine under fasting and fed conditions was demonstrated. Both of them had good tolerance for healthy Chinese volunteers. In addition, food delayed the absorption of fudosteine, so taking this medicine before meals might be an optimized option.

Discovering a Multi-Component Combination against Vascular Dementia from Danshen-Honghua Herbal Pair by Spectrum-Effect Relationship Analysis.

The Danshen-Honghua (DH) herbal pair exhibits a synergistic effect in protecting the cerebrovascular system from ischemia/reperfusion injury, but the therapeutic effect on vascular dementia (VaD) has not been clarified, and the main active ingredient group has not been clarified. In this work, the chemical constituents in DH herbal pair extract were characterized by UHPLC-QTOF MS, and a total of 72 compounds were identified. Moreover, the DH herbal pair alleviated phenylhydrazine (PHZ)-induced thrombosis and improved bisphenol F (BPF)- and ponatinib-induced brain injury in zebrafish. Furthermore, the spectrum-effect relationship between the fingerprint of the DH herbal pair and the antithrombotic and neuroprotective efficacy was analyzed, and 11 chemical components were screened out as the multi-component combination (MCC) against VaD. Among them, the two compounds with the highest content were salvianolic acid B (17.31 ± 0.20 mg/g) and hydroxysafflor yellow A (15.85 ± 0.19 mg/g). Finally, we combined these 11 candidate compounds as the MCC and found that it could improve thrombosis and neuronal injury in three zebrafish models and rat bilateral common carotid artery occlusion (BCCAO) model, which had similar efficacy compared to the DH herbal pair. This study provides research ideas for the treatment of VaD and the clinical application of the DH herbal pair.

Muscone and (+)-Borneol Cooperatively Strengthen CREB Induction of Claudin 5 in IL-1ß-Induced Endothelium Injury.

Claudin 5 is one of the major proteins of tight junctions and is responsible for cerebrovascular integrity and BBB function. Muscone and (+)-borneol is the major ingredient of moschus and borneolum, respectively, with antioxidative and anti-inflammatory activities. This study investigated whether muscone and (+)-borneol combination protected claudin 5 by targeting ROS-mediated IL-1ß accumulation. Muscone and (+)-borneol reduced cerebral infarct volume and cerebrovascular leakage with claudin 5 protection in mice after stroke, largely due to inhibiting ROS accumulation and inflammatory infiltrate of microglia. Muscone reduced ROS and then blocked the CaN/Erk1/2 pathway to decrease IL-1ß release, while (+)-borneol removed mitochondrial ROS and attenuated the SDH/Hif-1α pathway to inhibit IL-1ß transcription, thereby jointly reducing IL-1ß production. Accumulated IL-1ß disrupted cAMP/CREB activation and attenuated transcriptional regulation of claudin 5. Muscone and (+)-borneol combination cooperatively protected BBB function by blocking IL-1ß-mediated cAMP/CREB/claudin 5 cascades. Mutation of Ser133 site of CREB or knockdown of claudin 5 weakened the effects of muscone and (+)-borneol on upregulation of TEER value and downregulation of FITC-dextran permeability, suggesting that targeting CREB/claudin 5 was an important strategy to protect vascular integrity. This study provided ideas for the studies of synergistic protection against ischemic brain injury about the active ingredients of traditional Chinese medicines (TCMs).

Hollow nanospheres constructed by ultrafine few-layered MoS2 partially with amorphous fragments homogeneously incorporated in N-doped amorphous carbon for enhanced lithium storage performance.

The rational design of ultrathin and few-layered structures for three-dimensional MoS2 nanospheres is crucial for achieving attractive lithium-ion batteries (LIBs). Herein, hollow nanospheres constructed by ultrafine and few-layered MoS2 homogeneously incorporated in N-doped amorphous carbon (HUF-MoS2/NC) have been successfully synthesized as high-performance anode for LIBs. Using Mo-glycerol spheres as templates and dopamine hydrochloride as coordination ligands, hollow Mo-glycerol-polydopamine precursors are formed with Mo-containing groups which are surrounded by organic carbon species. Consequently, the MoS2 is confined to the nanoscale and grows partially amorphous fragments while being uniformly embedded in NC. This unique architecture can not only hinder the substantial restacking between MoS2 interlayers, offering more active sites, but also vastly enhance the electrical conductivity and relieve the mechanical stress ascribed to volume changes. As a result, the HUF-MoS2/NC composite anode exhibits excellent cyclic stability (980mAhg-1 after 300 cycles at 0.2Ag-1) and superior rate performance (498mAhg-1 at 5.0Ag-1) for LIBs.

Hydroxysafflor Yellow A Blocks HIF-1α Induction of NOX2 and Protects ZO-1 Protein in Cerebral Microvascular Endothelium.

Zonula occludens-1 (ZO-1) is a tight junction protein in the cerebrovascular endothelium, responsible for blood-brain barrier function. Hydroxysafflor yellow A (HSYA) is a major ingredient of safflower (Carthamus tinctorius L.) with antioxidative activity. This study investigated whether HSYA protected ZO-1 by targeting ROS-generating NADPH oxidases (NOXs). HSYA administration reduced cerebral vascular leakage with ZO-1 protection in mice after photothrombotic stroke, largely due to suppression of ROS-associated inflammation. In LPS-stimulated brain microvascular endothelial cells, HSYA increased the ratio of NAD+/NADH to restore Sirt1 induction, which bound to Von Hippel-Lindau to promote HIF-1αdegradation. NOX2 was the predominant isoform of NOXs in endothelial cells and HIF-1α transcriptionally upregulated p47phox and Nox2 subunits for the assembly of the NOX2 complex, but the signaling cascades were blocked by HSYA via HIF-1α inactivation. When oxidate stress impaired ZO-1 protein, HSYA attenuated carbonyl modification and prevented ZO-1 protein from 20S proteasomal degradation, eventually protecting endothelial integrity. In microvascular ZO-1 deficient mice, we further confirmed that HSYA protected cerebrovascular integrity and attenuated ischemic injury in a manner that was dependent on ZO-1 protection. HSYA blocked HIF-1α/NOX2 signaling cascades to protect ZO-1 stability, suggestive of a potential therapeutic strategy against ischemic brain injury.