Silencing BMAL1 promotes M1/M2 polarization through the LDHA/lactate axis to promote GBM sensitivity to bevacizumab.

OBJECTIVE: Glioblastoma (GBM) has poor clinical prognosis due to limited treatment options. In addition, the current treatment regimens for GBM may only slightly prolong patient survival. The aim of this study was to assess the role of BMAL1 in the immune microenvironment and drug resistance of GBM. METHODS: GBM cell lines with stable BMAL1 knockdown or LDHA overexpression were constructed, and functionally characterized by the CCK8, EdU incorporation, and transwell assays. In vivo GBM model was established in C57BL/6J mice. Flow cytometry, ELISA, immunofluorescence, and RT-qPCR were performed to detect macrophage polarization. Lactate production, pathological changes, and the expression of glycolytic proteins were analyzed by HE staining, immunohistochemistry, biochemical assays, and Western blotting. RESULTS: BMAL1 silencing inhibited the malignant characteristics, lactate production, and expression of glycolytic proteins in GBM cells, and these changes were abrogated by overexpression of LDHA or exogenous lactate supplementation. Furthermore, BMAL1 knockdown induced M1 polarization of macrophages, and inhibited M2 polarization and angiogenesis in GBM cells in conditioned media. Overexpression of LDHA or presence of exogenous lactate inhibited BMAL1-induced M1 polarization and angiogenesis. Finally, BMAL1 silencing and bevacizumab synergistically inhibited glycolysis, angiogenesis and M2 polarization, and promoted M1 polarization in vivo, thereby suppressing GBM growth. CONCLUSION: BMAL1 silencing can sensitize GBM cells to bevacizumab by promoting M1/M2 polarization through the LDHA/lactate axis.

Inter-individual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors - a genome-wide association study: results from PanCareLIFE.

OBJECTIVE: We aimed to discover new variants associated with low ovarian reserve after gonadotoxic treatment among adult female childhood cancer survivors using a genome-wide association study approach. DESIGN: Genome-wide association study. SUBJECTS: A discovery cohort of adult female childhood cancer survivors, from the pan-European PanCareLIFE cohort (n=743; median age: 25.8 years), excluding those who received bilateral ovarian irradiation, bilateral oophorectomy, central nerve system or total body irradiation, or stem cell transplantation. Replication was attempted in the USA-based St. Jude Lifetime Cohort (n=391; median age: 31.3 years). EXPOSURE: Female childhood cancer survivors are at risk of therapy-related gonadal impairment. Alkylating agents are well-established risk factors, and the inter-individual variability in gonadotoxicity may be explained by genetic polymorphisms. Data were collected in real-life conditions and cyclophosphamide equivalent dose was used to quantify alkylation agent exposure. INTERVENTION: No intervention was performed. MAIN OUTCOME MEASURE: Anti-Müllerian hormone (AMH) levels served as a proxy for ovarian function and findings were combined in a meta-analysis. RESULTS: Three genome-wide significant (<5.0x10-8) and 16 genome-wide suggestive (<5.0x10-6) loci were associated with log-transformed AMH levels, adjusted for cyclophosphamide equivalent dose of alkylating agents, age at diagnosis, and age at study in the PanCareLIFE cohort. Based on effect allele frequency (EAF) (>0.01 if not genome-wide significant), p-value (<5.0×10-6), and biological relevance, 15 SNPs were selected for replication. None of the SNPs were statistically significantly associated with AMH levels. A meta-analysis indicated that rs78861946 was associated at borderline genome-wide statistical significance (Reference/effect allele: C/T; EAF: 0.04, Beta (SE): -0.484 (0.091), p-value= 9.39×10-8). CONCLUSION: This study found no genetic variants associated with a lower ovarian reserve after gonadotoxic treatment, as the findings of this GWAS were not statistically significant replicated in the replication cohort. Suggestive evidence for potential importance of one variant is briefly discussed, but the lack of statistical significance calls for larger cohort sizes. As the population of childhood cancer survivors is increasing, large-scale and systematic research is needed to identify genetic variants that could aid predictive risk models of gonadotoxicity and as well as fertility preservation options for childhood cancer survivors.

The Emerging Role of ADAM 12 Regulates Epithelial-mesenchymal Transition by Activating the Wnt/ß-catenin Signaling Pathway in Colorectal Cancer.

OBJECTIVE: The objective of this study is to investigate the expression and regulatory mechanisms of A disintegrin and metalloproteinase domain 12 (ADAM12) in colorectal cancer (CRC) tissues and cells. METHODS: Download and analyze the expression levels of ADAM12 in the TCGA and GSE68468 datasets. Collect paraffin-preserved specimens from the Chongqing University Jiangjin Hospital from April 2017 to December 2019 and detect the expression of ADAM12 through immunohistochemistry. Cell experiments were conducted using colorectal cancer cell lines (SW480, HCT116), and cells with high expression of ADAM12 were selected for silencing experiments, and cell proliferation ability using CCK-8, and migration ability of cells in each group using scratch assay and Transwell invasion assay. The EMT markers (E-cadherin, N-cadherin, Vimentin, Twist) and the Wnt/ß-catenin markers (ß-catenin, GSK-3ß, p-GSK-3ß, C-MYC, MMP-7) were detected using western blot. We construct a nude mouse CRC tumor model and validate the effect of ADAM12 on EMT and Wnt/ß-catenin through immunohistochemistry and Western blot. RESULTS: Bioinformatics showed that increased expression of ADAM12 was strongly correlated with patient prognosis. Immunohistochemistry showed that elevated ADAM12 was associated with vascular invasion (p < 0.05), neurological invasion (p < 0.01), lymph node metastasis (p < 0.01), and TNM staging (p < 0.001). Experiments on cell function revealed that the ADAM12 overexpression group augmented CRC cells' proliferation and migration. After overexpression of ADAM12, the expression of N-cadherin, Vimentin, and Twist increased, while the expression of E-cadherin decreased (p < 0.01). The expression of Proteins related to Wnt/ß-catenin: ß-catenin, p-GSK-3 ß, C-MYC and MMP-7 increased (p < 0.01), and Wnt/ß-catenin inhibitor MSAB can counteract the effect of ADAM12 on EMT in CRC cells. The subcutaneous tumor formation experiment results in nude mice showed that ADAM12 promoted tumor growth and induced EMT compared to the control group. CONCLUSION: ADAM12 overexpression through the Wnt/ß-catenin signal axis controls the EMT of CRC to promote invasion and metastasis.

Simultaneous cholecystectomy for asymptomatic gallstones during elective colorectal cancer surgery.

BACKGROUND: Asymptomatic gallstones are commonly detected using preoperative imaging in patients with colorectal cancer (CRC), but its management remains a topic of debate. METHODS: Clinicopathologic characteristics of patients who had asymptomatic gallstones presenting during the colorectal procedure were retrospectively reviewed. Medical records, including postoperative morbidity, mortality, and long-term gallstone-related diseases, were assessed. RESULTS: Of 134 patients with CRC having asymptomatic gallstones, 89 underwent elective colorectal surgery only (observation group), and 45 underwent elective colorectal surgery with simultaneous cholecystectomy (cholecystectomy group). After propensity score matching (PSM), the complications were similar in the 2 groups. During the follow-up period, biliary complications were noted in 11 patients (12.4%) in the observation group within 2 years after the initial CRC surgery, but no case was found in the cholecystectomy group. After PSM, the incidence of long-term biliary complications remained significantly higher in the observation group than in the cholecystectomy group (26.5% vs 0.0%; P < .01). Multivariable logistic regression analysis identified female gender, old age (≥65 years old), and small multiple gallstones as independent risk factors for the development of long-term gallstone-related diseases in patients from the observation group. CONCLUSION: Simultaneous prophylactic cholecystectomy during prepared, elective CRC surgery did not increase postoperative morbidity or mortality but decreased the risk of subsequent gallstone-related complications. Hence, simultaneous cholecystectomy might be a preferred therapeutic option for patients with CRC having asymptomatic gallstones in cases of elective surgery, especially for older patients (≥65 years old), female patients, and those with small multiple calculi.

Discovery of the Clinical Candidate Sonrotoclax (BGB-11417), a Highly Potent and Selective Inhibitor for Both WT and G101V Mutant Bcl-2.

The approval of venetoclax, a B-cell lymphoma-2 (Bcl-2) selective inhibitor, for the treatment of chronic lymphocytic leukemia demonstrated that the antiapoptotic protein Bcl-2 is a druggable target for B-cell malignancies. However, venetoclax's limited potency cannot produce a strong, durable clinical benefit in other Bcl-2-mediated malignancies (e.g., diffuse large B-cell lymphomas) and multiple recurrent Bcl-2 mutations (e.g., G101V) have been reported to mediate resistance to venetoclax after long-term treatment. Herein, we described novel Bcl-2 inhibitors with increased potency for both wild-type (WT) and mutant Bcl-2. Comprehensive structure optimization led to the clinical candidate BGB-11417 (compound 12e, sonrotoclax), which exhibits strong in vitro and in vivo inhibitory activity against both WT Bcl-2 and the G101V mutant, as well as excellent selectivity over Bcl-xL without obvious cytochrome P450 inhibition. Currently, BGB-11417 is undergoing phase II/III clinical assessments as monotherapy and combination treatment.

Characteristics, sources, and health risks of volatile organic compounds in different functional regions of Shenyang.

The concentration of 56 volatile organic compounds (VOCs) in the ambient air of Shenyang was continuously monitored at four sites in 2021. The characteristics, sources, secondary pollution potential and health risks of VOCs in different functional regions of Shenyang were discussed. The results indicate that the concentration of VOCs in industrial regions was significantly higher than that in non-industrial regions, with a mean of 41.09 ±â€¯69.82 parts per billion volumes (ppbv) compared to 19.99 ±â€¯17.86 ppbv (commercial & residential region in urban fringe), 27.51 ±â€¯28.81 ppbv (educational & scenic region) and 29.71 ±â€¯23.97 ppbv (commercial & residential region in urban center). The positive matrix factorization (PMF) model was utilized to assign the sources of VOCs in Shenyang, and six factors were recognized: gasoline vehicles (34.8 %), diesel vehicles (28.3 %), combustion (11.4 %), biogenic emissions (9.7 %), industrial processes (8.2 %), and fuel evaporation (7.7 %). The results of the reactivity evaluation indicated that the ozone (O3) formation potential (OFP) was primarily influenced by industrial processes (29.2 %), diesel vehicles (25.7 %), biogenic emissions (17.0 %). These three factors were also the top three contributors to secondary organic aerosol formation potential (SOAP), accounting for 44.2 %, 9.4 % and 30.3 %, respectively. At the all four sites, the non-carcinogenic and carcinogenic risks of VOCs ranged from 1.6 × 10-2 to 3.8 × 10-2 and from 2.3 × 10-6 to 3.3 × 10-6, respectively. And the main risks can be attributed to emissions from industrial processes and gasoline vehicles. These findings suggested to strengthen the control of vehicle emissions throughout all regions in Shenyang and industrial processes emissions in industrial regions.

Spin-Phonon Coupling in Iron-Doped Ultrathin Bismuth Halide Perovskite Derivatives.

Spin in semiconductors facilitates magnetically controlled optoelectronic and spintronic devices. In metal halide perovskites (MHPs), doping magnetic ions is proven to be a simple and efficient approach to introducing a spin magnetic momentum. In this work, we present a facile metal ion doping protocol through the vapor-phase metal halide insertion reaction to the chemical vapor deposition (CVD)-grown ultrathin Cs3BiBr6 perovskites. The Fe-doped bismuth halide (Fe:CBBr) perovskites demonstrate that the iron spins are successfully incorporated into the lattice, as revealed by the spin-phonon coupling below the critical temperature Tc around 50 K observed through temperature-dependent Raman spectroscopy. Furthermore, the phonons exhibit significant softening under an applied magnetic field, possibly originating from magnetostriction and spin exchange interaction. The spin-phonon coupling in Fe:CBBr potentially provides an efficient way to tune the spin and lattice parameters for halide perovskite-based spintronics.

Quercetin attenuates inflammation in rosacea by directly targeting p65 and ICAM-1.

AIMS: Rosacea is an inflammatory skin disease with immune and vascular dysfunction. Although there are multiple treatment strategies for rosacea, the clinical outcomes are unsatisfactory. MAIN METHODS: Combining transcriptome data and the Connectivity Map database quercetin was identified as a novel candidate for rosacea. Next, the therapeutic efficacy of quercetin was substantiated through proteomic analyses, in vivo experiments, and in vitro assays. Additionally, the utilization of DARTS, molecular docking and experimental verification revealed the therapeutic mechanisms of quercetin. KEY FINDINGS: Treatment with quercetin resulted in the following effects: (i) it effectively ameliorated rosacea-like features by reducing immune infiltration and angiogenesis; (ii) it suppressed the expression of inflammatory mediators in HaCaT cells and HDMECs; (iii) it interacted with p65 and ICAM-1 directly, and this interaction resulted in the repression of NF-κB signal and ICAM-1 expression in rosacea. SIGNIFICANCE: We show for the first time that quercetin interacted with p65 and ICAM-1 directly to alleviated inflammatory and vascular dysfunction, suggesting quercetin is a novel, promising therapeutic candidate for rosacea.

St. Jude Survivorship Portal: sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors.

Childhood cancer survivorship studies generate comprehensive datasets comprising demographic, diagnosis, treatment, outcome, and genomic data from survivors. To broadly share this data, we created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing pediatric cancer survivorship data. Over 1,600 phenotypic variables and 400 million genetic variants from over 7,700 childhood cancer survivors can be explored on this free, open-access portal. Summary statistics of variables are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be customized and/or divided into groups for comparative analysis. Users can also seamlessly perform cumulative incidence and regression analyses on the stored survivorship data. Using the portal, we explored the ototoxic effects of platinum-based chemotherapy, uncovered a novel association between mental health, age, and limb amputation, and discovered a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry.

Comparison of the prognostic effect of pyrotinib plus trastuzumab and chemotherapy different lines therapy in HER2-positive advanced breast cancer.

This study aimed to compare the efficacy of pyrotinib, trastuzumab combined with chemotherapy with different lines therapy in human epidermal growth factor receptor 2- (HER2-) positive advanced breast cancer (ABC) and analyze the factors affecting the prognosis. A total of 84 patients with median age of 49 year-old. The mPFS of patients receiving first-line pyrotinib plus trastuzumab and chemotherapy was the longest (11 months) compared with second- and third line patients (p = 0.106). The objective response rate (ORR) and disease control rate (DCR) of the total population were 33.3% and 82.1% respectively. Subgroup analysis suggested that using pyrotinib plus trastuzumab and Albumin-bound paclitaxel was not inferior to combine with Vinorelbine in regards of PFS. Histological grade (OR: 0.233[0.069 ∼ 0.781], p = 0.018) and tumor location (OR: 0.286[0.087 ∼ 0.942], p = 0.040) were independent factors influencing the ORR. Multivariate cox analysis showed that Ki-67 was independently associated with increased risk of progression (HR: 1.843[1.044-3.254], p = 0.035). The most common adverse events were diarrhea (17.9%) and neutropenia (11.9%). In the first-, second- and third-line treatment, pyrotinib plus trastuzumab and chemotherapy is effective and safe. Pyrotinib and trastuzumab combined with Albumin-bound paclitaxel may be a potential ideal treatment plan for HER2-positive advanced breast cancer.

Alkaloids from Zanthoxylum nitidum and their anti-proliferative activity against A549 cells by regulating the EGFR/AKT/mTOR pathway.

Zanthoxylum nitidum is frequently used as a traditional Chinese medicine and food supplement. Our previous study revealed that its constituent compounds were able to inhibit cancer cell proliferation. In our continuous exploration of bioactive compounds in Z. nitidum, we isolated ten alkaloids (1-10), including one new natural compound (1), and nine known alkaloids (2-10), from an ethanolic extract of the whole plant. The chemical structures were elucidated based on a combination of comprehensive NMR and HRESIMS analyses. Compounds 5, 8 and 10 exhibited significant antiproliferative effects against A549 cancer cell lines. We further elucidated the underlying molecular mechanisms of the antiproliferative activity of compound 8 in A549 human lung cancer cells. Compound 8 was found to induce cell cycle arrest in the G0/G1 phase via p53 activation and CDK4/6 suppression. Compound 8 also effectively inhibited cell migration through the modulation of the epithelial-mesenchymal transition (EMT), as indicated by the expression of biomarkers, such as N-cadherin downregulation and E-cadherin upregulation. Compound 8 significantly suppressed the activation of the EGFR/AKT/mTOR signalling pathway in A549 cells. These results indicate that alkaloid 8 from Z. nitidum has potential to be a lead antiproliferative compound in cancer cells.

Efficacy and safety of fibrin sealant application in patients undergoing thyroidectomy: a systematic review and meta-analysis.

Various studies have focused on the application of fibrin sealants (FS) in thyroid surgery. Utilizing a meta-analysis, this systematic review analyzed the findings of recent randomized controlled trials on the safety and efficacy of FS in patients who underwent thyroidectomy. The Cochrane Library, Web of Science, Embase, PubMed, and Medline databases were searched for relevant studies, without any language restrictions. Seven randomized controlled trials were included in the originally identified 69 studies. Overall, 652 patients received FS during thyroid surgery; their outcomes were compared with those of conventionally treated patients. The primary outcomes were total volume of wound drainage, length of hospitalization, and operative time. Significant differences were observed in the total volume of wound drainage (mean deviation (MD): -29.75, 95% confidence interval (CI): -55.39 to -4.11, P = 0.02), length of hospitalization (MD: -0.84, 95% CI: -1.02 to -0.66, P < 0.00001), and surgery duration (MD: -7.60, 95% CI: -14.75 to -0.45, P = 0.04). Secondary outcomes were seroma and hypoparathyroidism development. The risk of hypoparathyroidism did not differ between the FS and conventional groups (I = 0%, relative risk = 1.31, P = 0.38). Analysis of "seroma formation that required invasive treatment" indicated that FS showed some benefit (I2 = 8%, relative risk 0.44, P = 0.15). Heterogeneity among the different trials limited their conclusions. The meta-analysis showed that although FS use did not significantly reduce seroma or hypoparathyroidism incidence in patients after thyroidectomy, it significantly reduced the total drainage volume, length of hospitalization, and duration of surgery.

Changes metabolic hormones and trace elements in CSF in active smokers indicate oxidative damage to brain cells.

OBJECTIVE: This study aimed to reveal associations between metabolic hormones in cerebral spinal fluid (CSF) and cigarette smoking-induced weight gain and to explore the underlying mechanism. METHODS: A total of 156 adult men were included in active smokers and nonsmokers. In addition to demographic information and body mass index (BMI), plasma levels of ApoA1 and ApoB, high-density lipoprotein (HDL), low-density lipoprotein (LDL), cholesterol (CHO), triglyceride (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in the participants were measured. Moreover, the metabolic hormones adiponectin, fibroblast growth factor 21 (FGF21), ghrelin, leptin, and orexin A, plus the trace elements of iron and zinc in CSF were assessed. RESULTS: Compared to non-smokers, active smokers showed higher BMI, elevated CSF levels of FGF21, Zn and Fe, but decreased levels of metabolic hormones adiponectin, ghrelin, leptin, and orexin A. Negative correlations existed between CSF FGF21 and ghrelin, between CSF Zn and ghrelin, as well as between CSF Fe and orexin A in active smokers. Furthermore, elevated CSF FGF21 and Zn predicted ghrelin level decrease in the smokers. CONCLUSION: These data relate the smoking-induced weight gain to its neurotoxic effect on the neurons that synthesize the metabolic hormones of adiponectin, ghrelin, leptin, or orexin A in the brain via disrupting mitochondrial function and causing oxidative stress in the neurons.

Robotic Actuation-Mediated Quantitative Mechanogenetics for Noninvasive and On-Demand Cancer Therapy.

Cell mechanotransduction signals are important targets for physical therapy. However, current physiotherapy heavily relies on ultrasound, which is generated by high-power equipment or amplified by auxiliary drugs, potentially causing undesired side effects. To address current limitations, a robotic actuation-mediated therapy is developed that utilizes gentle mechanical loads to activate mechanosensitive ion channels. The resulting calcium influx precisely regulated the expression of recombinant tumor suppressor protein and death-associated protein kinase, leading to programmed apoptosis of cancer cell line through caspase-dependent pathway. In stark contrast to traditional gene therapy, the complete elimination of early- and middle-stage tumors (volume ≤ 100 mm3) and significant growth inhibition of late-stage tumor (500 mm3) are realized in tumor-bearing mice by transfecting mechanogenetic circuits and treating daily with quantitative robotic actuation in a form of 5 min treatment over the course of 14 days. Thus, this massage-derived therapy represents a quantitative strategy for cancer treatment.

Application of bridging mesh repair in giant ventral incisional hernia.

Achieving ideal abdominal wall reconstruction in giant ventral incisional hernia has been a challenging for surgeons. This study aimed to verify the safety and efficacy of bridging repair by comparing it with primary fascial closure (PFC) repair in the treatment of giant ventral incisional hernia. We retrospectively analyzed the clinical data of 92 patients with giant ventral incisional hernia who underwent mesh repair at our medical institution from January 1, 2014 to December 31, 2020. Patients were divided into 2 groups: the bridging repair group with 40 patients in whom repair was completed using the bridging technique and the PFC group with 52 patients in whom primary fascial closure was achieved and all patients underwent mesh reinforcement during the operation. The main outcome measures were recurrence rate and morbidity, especially intra-abdominal hypertension (IAH). Follow-up time of both groups lasted at least 24 months after surgery. After a median of 46 months and 65 months of follow-up, respectively, in the two groups, bridging repair did not increase the long-term recurrence rate (2.56%) in the larger defect area group compared to the PFC group (1.96%). There were no significant differences in perioperative morbidity, IAH, incidence of postoperative chronic pain, and sensory impairment of the abdominal wall between both groups. The application of bridging surgery in the treatment of complex giant ventral incisional hernias is safe and effective and does not significantly increase the postoperative recurrence rate.

Hydrogen Sulfide Alleviates Oxidative Damage under Chilling Stress through Mitogen-Activated Protein Kinase in Tomato.

Tomato is the vegetable with the largest greenhouse area in China, and low temperature is one of the main factors affecting tomato growth, yield, and quality. Hydrogen sulfide (H2S) plays an important role in regulating plant chilling tolerance, but its downstream cascade reaction and mechanism remain unclear. Mitogen-activated protein kinases (MAPK/MPKs) are closely related to a variety of signaling substances in stress signal transmission. However, whether H2S is related to the MPK cascade pathway in response to low-temperature stress is rarely reported. In this study, NaHS treatment significantly decreased the electrolyte leakage (EL), superoxide anion (O2-) production rate, and hydrogen peroxide (H2O2) content of seedlings at low temperatures. In addition, the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) were obviously increased; and the photochemical efficiency of PSII (Fv/Fm) was enhanced with treatment with NaHS, indicating that NaHS improved the seedlings' cold tolerance by alleviating the degree of membrane lipid peroxidation and oxidative damage. However, H2S scavenger hypotaurine (HT) treatment showed the opposite effect. We found that H2S content, L-cysteine desulfhydrase (LCD) activity, and mRNA expression were increased by chilling stress but reduced by MPK inhibitor PD98059; PD98059 reversed the alleviating effect of H2S via increasing the EL and H2O2 contents. The expression levels of MPK1-MPK7 at low temperatures showed that SlMPK4 was significantly induced by exogenous NaHS and showed a trend of first increasing and then decreasing, while the expression level of SlMPK4 in HT-treated seedlings was lower than that of the control. After SlMPK4 was silenced by virus-induced gene silencing, the H2S-induced upregulation of C-repeat-Binding Factor (CBF1), inducer of CBF expression 1 (ICE1), respiratory burst oxidase homologs (RBOH1, RBOH2) at low temperatures disappeared, and tomato cold tolerance decreased. In conclusion, H2S improves the cold tolerance of tomato plants by increasing the activity of antioxidant enzymes and reducing reactive oxygen species (ROS) accumulation and membrane lipid peroxidation. MPK4 may act as a downstream signaling molecule in this process.

KDM4A-AS1 Promotes Cell Proliferation, Migration, and Invasion via the miR-4306/STX6 Axis in Hepatocellular Carcinoma.

As a primary liver malignancy, hepatocellular carcinoma (HCC) is commonly induced by chronic liver disease and cirrhosis. Bioinformatics analysis reveals that long noncoding RNA KDM4A antisense RNA 1 (KDM4A-AS1) may be aberrantly expressed in HCC and its abnormal expression might influence prognosis in patients. We conducted this study to illustrate the functions and mechanism of KDM4A-AS1 in regulating HCC malignant cell behavior. KD-M4A-AS1, microRNA (miR)-4306 and messenger RNA syntaxin 6 (STX6) expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). HCC cell proliferation, apoptosis, migration, and invasion were measured by colony forming assays, flow cytometry, wound healing and Transwell assays. The interaction between genes was verified by RNA immunoprecipitation and luciferase reporter assays. Western blotting was performed to quantify protein expression of STX6 or apoptotic markers. KDM4A-AS1 was highly expressed in HCC cells and tissues. KDM4A-AS1 knockdown led to enhanced HCC cell apoptosis and suppressed HCC cell proliferation, migration, and invasion. MiR-4306 bound to and negatively regulated STX6. KDM4A-AS1 directly bound to miR-4306 and thus up-regulated STX6. STX6 overexpression reversed the inhibitory influence of KDM4A-AS1 depletion on HCC malignant behavior. KDM4A-AS1 promotes HCC cell migration, invasion, and growth by upregulating STX6 via miR-4306.

The effect of the interaction of sleep onset latency and age on ischemic stroke severity via inflammatory chemokines.

Objective: Prolonged sleep onset latency (PSOL) and age have been linked to ischemic stroke (IS) severity and the production of chemokines and inflammation, both of which contribute to IS development. This study aimed to explore the relationship between chemokines, inflammation, and the interplay between sleep onset latency (SOL) and age in influencing stroke severity. Methods: A cohort of 281 participants with mild to moderate IS was enrolled. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS), and SOL was recorded. Serum levels of macrophage inflammatory protein-1alpha (MIP-1α), macrophage inflammatory protein-1beta (MIP-1ß), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) were measured. Results: NIHSS scores of middle-aged participants with PSOL were significantly higher than those with normal sleep onset latency (NSOL) (p = 0.046). This difference was also observed when compared to both the elderly with NSOL (p = 0.022), and PSOL (p < 0.001). Among middle-aged adults with PSOL, MIP-1ß exhibited a protective effect on NIHSS scores (ß = -0.01, t = -2.11, p = 0.039, R2 = 0.13). MIP-1α demonstrated a protective effect on NIHSS scores in the elderly with NSOL (ß = -0.03, t = -2.27, p = 0.027, R2 = 0.12). Conclusion: This study reveals a hitherto undocumented association between PSOL and IS severity, along with the potential protective effects of MIP-1ß in mitigating stroke severity, especially among middle-aged patients.

Atezolizumab Plus Bevacizumab Combined with Transarterial Embolization Plus Hepatic Arterial Infusion Chemotherapy for Unresectable Hepatocellular Carcinoma with a Diameter >8 Cm: A Retrospective Study.

Purpose: Local in combination with systemic therapy might be an option for patients with advanced unresectable hepatocellular carcinoma (uHCC). This study examined the clinical benefits and adverse events (AEs) of first-line transarterial embolization (TAE) and hepatic arterial infusion chemotherapy (HAIC) combined with atezolizumab (Atezo) and bevacizumab (Bev) in patients with uHCC of a diameter larger than 8 cm. Patients and methods: This retrospective study included patients with uHCC of a diameter larger than 8 cm who were treated with first-line Atezo-Bev and TAE+HAIC at the First Affiliated Hospital of Sun Yat-Sen University between September 30, 2019, and September 30, 2022. Progression-free survival (PFS), overall survival (OS), tumor response according to mRECIST, and AEs were analyzed. Multivariable Cox analyses were performed to examine the factors associated with PFS. Results: Thirty patients were included. The objective response rate (ORR) was 74.4% (95% confidence interval [CI], 59.3%-89.5%), and the disease control rate (DCR) was 93.3% (95% CI, 85.4%-98.6%). The median follow-up was 11.4 (inter-quartile range [IQR], 5.5-17.9) months. The median PFS was 6.8 (95% CI, 2.6-11.1) months. The 3-, 6-, 9-, and 12-month survival rates were 86.2%, 82.5%, 68.6%, and 60%, respectively. The median OS was not estimated. Extrahepatic metastasis was independently associated with PFS (hazard ratio [HR]=3.468, 95% CI, 1.001-12.023). The most common AEs were fever (46.7%). Grade 4 AEs occurred one time as hematemesis but no 5 AEs were observed. Conclusion: Atezo-Bev combined with TAE and HAIC might benefit patients with uHCC of a diameter larger than 8 cm, with manageable AEs.