Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

SRPK1 Promotes Glioma Proliferation, Migration, and Invasion through Activation of Wnt/ß-Catenin and JAK-2/STAT-3 Signaling Pathways.

Currently, the treatment of gliomas still relies primarily on surgery and radiochemotherapy. Although there are various drugs available, including temozolomide, the overall therapeutic effect is unsatisfactory, and the prognosis remains poor. Therefore, the in-depth study of the mechanism of glioma development and a search for new therapeutic targets are the keys to improving the therapeutic treatment of gliomas and improving the prognosis of patients. Immunohistochemistry is used to detect the expression of relevant molecules in tissues, qPCR and Western blot are used to detect the mRNA and protein expression of relevant molecules, CCK-8 (Cell Counting Kit-8) is used to assess cell viability and proliferation capacity, Transwell is used to evaluate cell migration and invasion ability, and RNA transcriptome sequencing is used to identify the most influential pathways. SRPK1 (SRSF protein kinase 1) is highly expressed in gliomas but is not expressed in normal tissues. Its expression is positively correlated with the grades of gliomas and negatively correlated with prognosis. SRPK1 significantly promotes the occurrence and development of gliomas. Knocking down SRPK1 leads to a significant decrease in the proliferation, migration, and invasion abilities of gliomas. Loss of SRPK1 expression induces G2/M phase arrest and mitotic catastrophe, leading to apoptosis in cells. Overexpression of SRPK1 activates the Wnt/ß-catenin (wingless-int1/ß-catenin) and JAK-2/STAT-3 (Janus kinase 2/signal transducer and activator of transcription 3) signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Overexpression of SRPK1 rescues the reduced cell proliferation, migration, and invasion abilities caused by the silencing of ß-catenin or JAK-2. A stable shRNA-LN229 cell line was constructed, and using a nude mouse model, it was found that stable knockout of SRPK1 significantly reduced the tumorigenic ability of glioma cells, as evidenced by a significant decrease in the subcutaneous tumor volume and weight in nude mice. We have demonstrated that SRPK1 is highly expressed in gliomas. Overexpression of SRPK1 activates the Wnt/ß-catenin and JAK-2/STAT-3 signaling pathways, promoting the proliferation, migration, and invasion of gliomas. Silencing SRPK1-related signaling pathways may provide potential therapeutic options for glioma patients.

Synthesis, biological activities and mechanism studies of 1,3,4-oxadiazole analogues of petiolide A as anticancer agents.

In order to develop new natural product-based anticancer agents, a series of 1,3,4-oxadiazole analogues based on petiolide A were prepared and evaluated for their anticancer activities by MTT method. The structures of all analogues were characterized by various spectral analyses, and B9 was further confirmed by X-ray crystallography. Among all the synthesized compounds, B1 displayed the most promising growth inhibitory effect on colon cancer cells (HCT116) with the IC50 value of 8.53 µM. Flow cytometric analysis exhibited that B1 arrested the cell cycle at G2 phase and induced apoptosis. Additionally, network pharmacology analysis calculated that B1 might target several key proteins, including AKT serine/threonine kinase 1 (AKT1), SRC proto-oncogene, non-receptor tyrosine kinase (SRC) and epidermal growth factor receptor (EGFR). Furthermore, molecular docking study indicated that B1 had potentially high binding affinity to these three target proteins. Given these results, analogue B1 could be deeply developed as potential anticancer agents.

Clinical characteristics of congenital heart defects in mild congenital anorectal malformation: single-centre experience.

OBJECTIVE: To analyze the clinical characteristics and types of congenital heart defect (CHD) in mild congenital anorectal malformation (CARM), namely the rectoperineal and rectovestibular fistulas. METHODS: The retrospective study of 183 patients with mild CARM was conducted with assessments of demographic information, color Doppler echocardiography results, and follow-up data. We performed an analysis of the clinical characteristics of CHD, grouping them based on sex and type of mild CARM. RESULTS: Of the 183 patients, rectoperineal fistula occurred in 133 patients (72.7%), while the frequency of CHD was 79.8% (146/183). Ventricular septal defects (VSDs) occur more frequently in patients with rectoperineal fistula compared to those with rectovestibular fistula (1.5% vs. 10%), while the opposite trend was observed for patent ductus arteriosus (PDAs) (39.8% vs. 22.0%). Additionally, males presented higher frequency of PDA (42.7% vs. 26.4%) and self-healing (6 months: 87.2% vs. 42.6%; 12 months: 91.0% vs. 63.2%) than females. However, males had a lower rate of undergoing cardiac surgery (6.4% vs. 17.6%) and a younger median diagnosis age (1 day vs. 9 days). CONCLUSION: Our study indicates that there is a necessity for meticulous cardiac assessment and follow-up in neonates diagnosed with mild CARM.

Chronic Sleep Deprivation Impairs Visual Functions via Oxidative Damage in Mice.

Sleep deprivation (SD) is a global public health burden, and has a detrimental role in the nervous system. Retina is an important part of the central nervous system; however, whether SD affects retinal structures and functions remains largely unknown. Herein, chronic SD mouse model indicated that loss of sleep for 4 months could result in reductions in the visual functions, but without obvious morphologic changes of the retina. Ultrastructural analysis by transmission electron microscope revealed the deterioration of mitochondria, which was accompanied with the decrease of multiple mitochondrial proteins in the retina. Mechanistically, oxidative stress was provoked by chronic SD, which could be ameliorated after rest, and thus restore retinal homeostasis. Moreover, the supplementation of two antioxidants, α-lipoic acid and N-acetyl-l-cysteine, could reduce retinal reactive oxygen species, repair damaged mitochondria, and, as a result, improve the retinal functions. Overall, this work demonstrated the essential roles of sleep in maintaining the integrity and health of the retina. More importantly, it points towards supplementation of antioxidants as an effective intervention strategy for people experiencing sleep shortages.

CP41, a novel curcumin analogue, induces apoptosis in endometrial cancer cells by activating the H3F3A/ proteasome-MAPK signaling pathway and enhancing oxidative stress.

AIMS: Curcumin is a natural compound and has good antitumor properties, but its clinical use is limited by its low bioavailability. We constructed the derivative CP41 (3,5-bis(2-chlorobenzylidene)-1-piperidin-4-one) by enhancing the bioavailability of curcumin while retaining its antitumor properties. MAIN METHODS: CCK-8 (Cell Counting Kit-8) was used to detect the effect of CP41 on cell proliferation; Western blotting, immunofluorescence, immunoprecipitation, quantitative PCR and enzyme-linked immunosorbent assay were used to evaluate the expression of subcutaneous tumor-related molecules in cells and mice. KEY FINDINGS: Our results showed that CP41 inhibited the proliferation of endometrial cancer cells by suppressing the proliferation of AN3CA and HEC-1-B cells. We found that CP41 significantly increased H3F3A and inhibited proteasome activity, which activated MAPK signaling and led to apoptosis. Further experiments showed that H3F3A is a potential target of CP41. Correlation analysis showed that H3F3A was positively correlated with the sensitivity to chemotherapeutic agents in endometrial cancer. CP41 significantly induced reactive oxygen species (ROS) levels and activated endoplasmic reticulum stress, which led to apoptosis. The safety profile of CP41 was also evaluated, and CP41 did not cause significant drug toxicity in mice. SIGNIFICANCE: CP41 showed stronger antitumor potency than curcumin, and its antitumor activity may be achieved by inducing ROS and activating H3F3A-mediated apoptosis.

Lymphoma-related intussusception in children: diagnostic challenges and clinical characteristics.

Intussusception is a common cause of acute abdominal pain in children and the most frequent cause of intestinal obstruction in infants. Although often idiopathic, it can stem from conditions like lymphoma. This study delves into lymphoma-related intussusception in children, aiming to enhance early detection and management. A retrospective review encompassed children admitted from 2012 to 2023 with intussusception due to intestinal lymphoma. Demographic, clinical, and imaging data were meticulously extracted and analyzed. The study included 31 children in the lymphoma-related intussusception group. Contrasted with non-lymphoma-related cases, the patients of lymphoma-related intussusception were notably older (median age: 87 months vs. 18.5 months), predominantly male, and demonstrated protracted abdominal pain. Ultrasound unveiled mesenteric lymph node enlargement and distinct intra-abdominal masses; enema reduction success rates were notably diminished. Detecting lymphoma-related intussusception remains intricate. Age, prolonged symptoms, and distinctive ultrasound findings can arouse suspicion. Timely surgical intervention, based on preoperative imaging, proves pivotal for accurate diagnosis. CONCLUSION:  Swift identification of lymphoma-related intussusception, distinguished by unique clinical and ultrasound features, is imperative for timely intervention and treatment. Further research is warranted to refine diagnostic approaches. WHAT IS KNOWN: • Intussusception in pediatric patients can be caused by a wide spectrum of underlying diseases including lymphoma. • Early Identifying the exact underlying cause of intussusception is crucial for tailored therapy, however often challenging and time-consuming. WHAT IS NEW: • Lymphoma-related intussusception may present with increased abdominal fluid accumulation, intestinal obstruction, and a higher likelihood of failed reduction during enema procedures. • For high-risk children, repeated ultrasound examinations or further investigations may be necessary to confirm the diagnosis.

Association between dietary flavonoid intake and depressive symptoms: A cross-sectional research.

OBJECTIVE: To investigate the relationship between dietary flavonoid intake and depression symptoms in American adults. METHODS: Data sets were obtained from the National Health and Nutrition Examination Survey (NHANES) 2007-2008, 2009-2010, and 2017-2018 survey cycles. Both males and females aged 18 years and older with complete information about dietary flavonoid intake (isoflavones, anthocyanidins, flavan-3-ols, flavanones, flavones, and flavonols), depression symptoms, and covariates were included. Logistic regression models were conducted to calculate the odds ratio (OR) of single dietary flavonoid subclass intake on depression, and the restricted cubic spline (RCS) models were utilized to explore the corresponding dose-response relationships. Additionally, we implemented the weighted quantile sum (WQS) regression and quantile g-computation (qgcomp) models to estimate the mixed effects of six flavonoid subclasses and identify the predominant types. RESULTS: After multivariable adjustments, people with higher consumption of flavanones (OR: 0.68, 95% CI: 0.52-0.90, p = 0.008), flavones (OR: 0.63, 95% CI: 0.46-0.87, p = 0.007), flavonols (OR: 0.66, 95% CI: 0.49-0.89, p = 0.008), and total flavonoids (OR: 0.69, 95% CI: 0.50-0.95, p = 0.024) had lower odds of depression symptoms. Meanwhile, significant dose-response relationships were supported by the RCS models. However, no obvious associations between isoflavones, anthocyanidins, flavan-3-ols, and the odds of suffering from depression symptoms were found by the logistic regression models and RCS models. As for the mixed effect, the WQS and qgcomp models both demonstrated that the mixture of six flavonoid subclasses was inversely related to the odds ratios of depression symptoms, and flavones, flavanones, and anthocyanidins were the top 3 contributors. CONCLUSION: Our study implied dietary flavonoid intake was associated with the decreased probability of depression symptoms in U.S. adults, among which flavones, flavanones, and anthocyanidins may occupy the predominant roles.

CircRNF10 triggers a positive feedback loop to facilitate progression of glioblastoma via redeploying the ferroptosis defense in GSCs.

BACKGROUND: Glioma exhibit heterogeneous susceptibility for targeted ferroptosis. How circRNAs alterations in glioma promote iron metabolism and ferroptosis defense remains unclarified. METHODS: The highly enriched circRNAs in glioblastoma (GBM) were obtained through analysis of sequencing datasets. Quantitative real-time PCR (qRT-PCR) was used to determine the expression of circRNF10 in glioma and normal brain tissue. Both gain-of-function and loss-of-function studies were used to assess the effects of circRNF10 on ferroptosis using in vitro and in vivo assays. The hypothesis that ZBTB48 promotes ferroptosis defense was established using bioinformatics analysis and functional assays. RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to examine the interaction between circRNF10 and target proteins including ZBTB48, MKRN3 and IGF2BP3. The posttranslational modification mechanism of ZBTB48 was verified using coimmunoprecipitation (co-IP) and ubiquitination assays. The transcription activation of HSPB1 and IGF2BP3 by ZBTB48 was confirmed through luciferase reporter gene and chromatin immunoprecipitation (ChIP) assays. The stabilizing effect of IGF2BP3 on circRNF10 was explored by actinomycin D assay. Finally, a series of in vivo experiments were performed to explore the influences of circRNF10 on the glioma progression. RESULTS: A novel circular RNA, hsa_circ_0028912 (named circRNF10), which is significantly upregulated in glioblastoma tissues and correlated with patients' poor prognosis. Through integrated analysis of the circRNA-proteins interaction datasets and sequencing results, we reveal ZBTB48 as a transcriptional factor binding with circRNF10, notably promoting upregulation of HSPB1 and IGF2BP3 expression to remodel iron metabolism and facilitates the launch of a circRNF10/ZBTB48/IGF2BP3 positive feedback loop in GSCs. Additionally, circRNF10 can competitively bind to MKRN3 and block E3 ubiquitin ligase activity to enhance ZBTB48 expression. Consequently, circRNF10-overexpressed glioma stem cells (GSCs) display lower Fe2+ accumulation, selectively priming tumors for ferroptosis evading. CONCLUSION: Our research presents abnormal circRNAs expression causing a molecular and metabolic change of glioma, which we leverage to discover a therapeutically exploitable vulnerability to target ferroptosis.

Benzene ring bisphenol A substitutes potently inhibit human, rat, and mouse gonadal 3ß-hydroxysteroid dehydrogenases: Structure-activity relationship and in silico docking analysis.

Bisphenol A (BPA) is a chemical used in the production of certain plastics and resins. Recent research has found that BPA can inhibit the activity of 3ß-hydroxysteroid dehydrogenase/Δ5,4-isomerases (3ß-HSDs). Whether benzene ring BPA substitutes can inhibit human, rat, and mouse gonadal 3ß-HSDs, the structure-activity relationship and the underlying mechanism remain unclear. In this study, we compared 6 benzene ring BPA substitutes to BPA in the inhibition of human, rat, and mouse gonadal 3ß-HSDs and conducted structure-activity relationship and in silico docking analysis. The inhibitory activity (IC50) of human 3ß-HSD2 in KGN cells ranged from about 0.02 µM for bisphenol H to 8.75 µM for BPA, that of rat 3ß-HSD1 in testicular microsomes ranged from 0.099 µM for bisphenol H to 31.32 µM for BPA, and that of mouse 3ß-HSD6 ranged from 0.021 µM for BPH to ineffectiveness for 100 µM BPA. These compounds acted as mixed inhibitors with LogP inversely correlated with IC50 and ΔG positively correlated with IC50 value. Docking analysis showed that these compounds bind to the steroid active site of the 3ß-HSD enzymes. In conclusion, some benzene ring BPA substitutes potently inhibit gonadal 3ß-HSD in various species, and lipophilicity and binding affinity determine their inhibitory strength.

Case Report: Successful treatment of advanced hepatocarcinoma with the PD-1 inhibitor Camrelizumab.

Primary liver cancer is characterized by closely related with chronic liver inflammation, thereby reversing hypoxic immunosuppressive microenvironment of tumor cell growth by immunotherapy drug is a potentially effective strategy. Camrelizumab is an anti-PD-1 antibody being developed by Jiangsu Hengrui Pharmaceuticals Co., Ltd. We reported a case of an adult critical Chinese patient with primary hepatocellular carcinoma and lung metastasis completely responding to Camrelizumab, most of the lesions were stable and no new lesions occurred after 1-year treatment, which provides us to reconsider the therapeutic effect of Camrelizumab on such patients. Camrelizumab had a safety profile for the patient in our case report, except for the occurrence of RCCEP. This case provides the evidence of the effective antitumor activity and manageable toxicities of Camrelizumab for patients with advanced hepatocellular carcinoma, which was the first application as far as we know.

Weekend warrior physical activity pattern is associated with lower depression risk: Findings from NHANES 2007-2018.

OBJECTIVE: This study aimed to explore the association between weekend warrior physical activity (PA) pattern and depression risk in American adults. METHODS: Data of adults (n = 21,125) from NHANES 2007-2018 were used. Adults were categorized into 4 PA patterns (inactive, insufficiently active, weekend warrior, and regularly active) by self-reported PA levels. Participant characteristics in different groups were tested using the Rao & Scott adjusted χ2 test. Multivariate logistic regression models with adjustment for demographics data, behavioral factors and health condition were used to explore the association between PA patterns and depression risk. Finally, interaction analyses were conducted to test if the associations differ by gender, age, race, education level, income level and marital status. RESULTS: Multivariate logistic regression models showed that insufficiently active, weekend warrior and regularly active adults had 31% (OR: 0.69, 95%CI:0.54-0.88), 57% (OR: 0.43, 95%CI:0.25-0.74) and 54% (OR: 0.46, 95%CI:0.39-0.54) reduced depression risk when compared with inactive adults, respectively. When compared with regularly active adults, inactive (OR: 2.188, 95%CI:1.842-2.600) and insufficiently active (OR: 1.505, 95%CI:1.159-1.955) adults had elevated depression risk, but no significant difference was found between weekend warrior (OR: 0.949, 95%CI:0.538-1.675) and regularly active adults. Moreover, the associations did not differ by demographic variables. CONCLUSIONS: This study showed that adults who engaged in either regularly active pattern or weekend warrior pattern, experienced lower risk of depression compared to inactive adults. Weekend warrior and regularly active patterns showed similar benefits for lowering depression risk in adults, encouraging adults to take up PA in limited sessions.

Curcumin derivative NL01 induces ferroptosis in ovarian cancer cells via HCAR1/MCT1 signaling.

OBJECTIVE: Curcumin has been shown to have anti-tumor proliferative properties, but its clinical application is limited by its low bioavailability, etc. Derivatives of curcumin have been developed and tested to improve its therapeutic efficacy. Derivative NL01 could induce ferroptosis through the HCAR1/MCT1 pathway. METHOD: CCK-8 was used to detect curcumin and derivative IC50, crystalline violet staining was used to detect the proliferation inhibition effect of NL01 in ovarian cancer, western blot and qPCR were used to detect downstream related molecular expression changes, Transwell and survival curve assays were used to detect malignant phenotypic. RESULTS: NL01 inhibited cell growth of Anglne and HO8910PM ovarian cancer cells by 13 times more potent than curcumin and induced ferroptosis of these two cells. we found that NL01 was able to reduce the expression of HCAR1/MCT1 and activate the AMPK signaling pathway, which in turn induced cellular ferroptosis via SREBP1 pathway. Knock-down HCAR1 expression revealed similar phenotype and pathway alterations to NL01 treatment. HCAR1 overexpression promoted a malignant phenotype and resistance to cisplatin in both cancer cells, whereas knockdown of HCAR1 showed the opposite phenotype. Subcutaneous transplantation tumor experiments in nude mice also showed that NL01 induced iron death and inhibited ovarian cancer proliferation. Further study showed that NL01 promoted the downregulation of GPX4 expression, which is related to ferroptosis, and that addition of ferrostatin-1 partially reversed NL01-mediated inhibition of the growth of two cell lines. CONCLUSION: NL01 exhibits better anti-tumor growth properties than curcumin, and NL01 induces ferroptosis in ovarian cancer cells.

Hydroxide-Mediated SNAr Rearrangement for Synthesis of Novel Depside Derivatives Containing Diaryl Ether Skeleton as Antitumor Agents.

A simple and efficient hydroxide-mediated SNAr rearrangement was reported to synthesize new depside derivatives containing the diaryl ether skeleton from the natural product barbatic acid. The prepared compounds were determined using 1H NMR, 13C NMR, HRMS, and X-ray crystallographic analysis and were also screened in vitro for cytotoxicity against three cancer cell lines and one normal cell line. The evaluation results showed that compound 3b possessed the best antiproliferative activity against liver cancer HepG2 cell line and low toxicity, which made it worth further study.

Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis.

OBJECTIVES: Interstitial lung disease (ILD) is frequent in patients with rheumatoid arthritis (RA) and is a potentially life-threatening complication with significant morbidity and mortality. This meta-analysis aims to systematically determine the factors associated with the development of rheumatoid arthritis-related interstitial lung disease (RA-ILD). MATERIALS AND METHODS: All primary studies which reported the factors associated with of RA-ILD were eligible for the review except case reports. The Cochrane Library, PubMed, Embase, Web of Science, Chinese Biological Medicine Database (CBM), China National Knowledge Infrastructure (CNKI), and WANFANG electronic databases were searched through to December 30, 2022, for studies investigating the factors associated with RA-ILD. The methodological quality assessment of the eligible studies was performed using the Newcastle-Ottawa Scale (NOS). 2 reviewers extracted relevant data independently. Then, weighed mean differences (WMDs) or pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were obtained for the relationships between the factors and RA-ILD. The statistical meta-analysis, subgroup and sensitivity analyses were performed using the Review Manager 5.3, and publication bias with Egger's test were performed using the Stata12.0 software. RESULTS: A total of 22 articles were screened for a meta-analysis which involved 1887 RA-ILD patients and 8066 RA without ILD patients. Some identified factors that were associated with an increased risk of RA-ILD included male sex (OR = 1.92, 95% CI: 1.54-2.39; P < 0.00001), older age (WMD = 5.77 years, 95% CI: 3.50-8.04; P < 0.00001), longer duration of RA (WMD = 0.80 years, 95% CI 0.12-1.47; P = 0.02), older age at onset of RA (WMD = 6.41 years, 95% CI: 3.17-9.64; P = 0.0001), smoking (OR = 1.69, 95% CI: 1.30-2.18; P < 0.0001). Five factors of laboratory items associated with the development of RA-ILD were evaluated in the meta-analysis. Compared with RA without ILD patients, positive rheumatoid factor (RF) (OR = 1.72, 95% CI: 1.47-2.01; P < 0.00001) and positive anti-citrullinated protein antibodies (ACPA) (OR = 1.58, 95% CI: 1.31-1.90; P < 0.00001) increased the risk of RA-ILD. Meanwhile, RF titer (WMD = 183.62 (IU/mL), 95% CI: 66.94-300.30; P = 0.002) and ACPA titer (WMD = 194.18 (IU/mL), 95% CI: 115.89-272.47; P < 0.00001) were significantly associated with increased risk of RA-ILD. Elevated erythrocyte sedimentation rate (ESR) (WMD = 7.41 (mm/h), 95% CI: 2.21-12.61; P = 0.005) and C-reactive protein (CRP) (WMD = 4.98 (mg/L), 95% CI: 0.76-9.20; P = 0.02) were also significantly associated with the development of the RA-ILD, whereas antinuclear antibody (ANA) positive status was not significantly associated with increased risk of RA-ILD (OR = 1.27, 95% CI: 1.00-1.60; P = 0.05). CONCLUSIONS: This meta-analysis showed that male gender, older age, longer duration of RA, older age at onset of RA, smoking, positive RF, positive ACPA, elevated RF titer, elevated ACPA titer, higher ESR and higher CRP were associated with RA-ILD.

The association between pruritic dermatoses and inflammatory factors on sleep disorders: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES).

Pruritic dermatoses and sleep disorders have significant impacts on the health and quality of life of patients. Inflammatory conditions may lead to the sensation of itching. This study was to evaluate the association between pruritic dermatoses and inflammatory factors on sleep disorders. Data in the cross-sectional study were extracted from the National Health and Nutrition Examination Survey. The study population was divided into participants with and without sleep disorders. Pruritic dermatoses were assessed by the participant's self-report. Inflammatory factors included white blood cell count (WBC), lymphocyte count (LYM) and prognostic nutritional index (PNI). Logistic regression models were used with odds ratios and confidence intervals. The attributable proportion of interaction (AP) was utilized to assess the interaction between pruritic dermatoses and inflammatory factors on sleep disorders. Totally, 3,520 participants were included and 214 (6.08%) had sleep disorders. Pruritic dermatoses were associated with sleep disorders after adjusting for gender, age, race, marital status, body mass index, drinking, smoking, asthma, hay fever, allergy, depression and caffeine. LYM was associated with sleep disorders when inflammatory factors were divided by median. The interaction between participants without pruritic dermatoses and PNI < median on sleep disorders was observed compared to participants without pruritic dermatoses and PNI > median. Pruritic dermatoses were significantly associated with sleep disorders. We also found that a high level of PNI had an enhanced effect on the relationship between pruritic dermatoses and sleep disorders. Clinicians should focus on the potential sleep-related risks and changes in inflammatory factors in patients with pruritic dermatoses and intervene in time.

Naru-3 inhibits inflammation, synovial hyperplasia, and neovascularization in collagen-induced arthritis in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Naru-3 is a prescribed formulation based on the theory of Mongolian medicine for the treatment of rheumatoid arthritis (RA). Naru-3 consists of three medicinal agents: Aconitum kusnezoffii Reichb (caowu), Terminalia chebula Retz (hezi), and Piper longum L (biba). These medicinal agents are widely distributed in the Mongolian area of China and have been used to treat rheumatism for centuries. BACKGROUND: Mongolian medicine Naru-3 is commonly prescribed to treat RA, but its mechanism of action is unknown. METHODS: A rat collagen-induced arthritis (CIA) model was established to investigate the mechanism of Naru-3. Rats were treated with Naru-3, Etanercept (ETN), and sodium carboxymethylcellulose (CMC) for four weeks. After treatment was terminated, paw thickness, ankle diameter, and arthritis index (AI) were scored. Synovial hyperplasia was evaluated using hematoxylin and eosin (H&E) staining and two-dimensional ultrasonography. Synovitis and neovascularization were assayed using power Doppler imaging (PDI) and contrast-enhanced ultrasonography (CEUS). Levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1, and CD31 in the serum or synovium were detected using ELISA and immunohistochemistry analyses. RESULTS: Naru-3 and ETN alleviated the symptoms of CIA as evidenced by diminished paw thickness, ankle diameter, and AI scores. Mechanistically, Naru-3 inhibited synovial hyperplasia, synovitis, and neovascularization by diminishing systemic and local inflammation, as indicated by the relative expression of CD31, VEGF and IL-1 in the serumor synovium. After four weeks of treatment, no significant neovascularization was observed in the Naru-3 group, but neovascularization and synovitis occurred in the ETN group, as demonstrated by H&E staining, PDI, and CEUS examination. CONCLUSION: Naru-3 inhibited inflammation, synovial hyperplasia, and neovascularization and alleviates RA in our CIA rat model. No symptom recurrence was observed four weeks after drug treatment.

Identification of a novel mutation in the FGF10 gene in a Chinese family with obvious congenital lacrimal duct dysplasia in lacrimo-auriculo-dento-digital syndrome.

AIM: To identify the pathogenic gene variant in a family with lacrimo-auriculo-dento-digital syndrome [LADD (MIM 149730)] showing congenital lacrimal duct dysplasia as the main clinical manifestation and lay the foundation for future research on the pathogenic gene. METHODS: Ophthalmological examinations, including slit-lamp biomicroscopy and lacrimal duct probing, and computed tomography dacryocystography (CT-DCG) were performed for all participants. The family pedigree was drawn, genetic features were analyzed, and the genomic DNA of the subjects was extracted. Pathogenic genes were screened via whole exome sequencing (WES) and confirmed using Sanger sequencing. RESULTS: Six patients belonged to this three-generation family, and their clinical manifestations included congenital nasolacrimal duct obstruction, congenital absence of lacrimal puncta and canaliculi, lacrimal fistulae, and limb deformities. This pattern indicates autosomal dominant inheritance. Diagnosis was based on the clinical characteristics of LADD syndrome, which presented in all the patients in this family. A novel frameshift mutation in the FGF10 gene (NM_004465.1), c.234dupC (p.Trp79Leus*15), was identified in all patients via WES. The variant was confirmed by Sanger sequencing and classified as a "pathogenic mutation" according to the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines. CONCLUSION: A novel frameshift mutation in the FGF10 gene is found in all patients. This finding helps this family with LADD syndrome receiving a more accurate clinical diagnosis and genetic counseling by extending the mutation range of the FGF10 gene.

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer.

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.

Efficacy of Laparoscopic Totally Extraperitoneal Repair for Inguinal Hernia.

Objective: To assess the treatment efficacy of laparoscopic totally extraperitoneal repair for inguinal hernia. Methods: Between November 2018 and May 2020, 130 patients with inguinal hernias diagnosed and treated in our hospital were randomly recruited and assigned to receive either tension-free hernia repair (control group) or laparoscopic totally extraperitoneal repair (study group) at the random method. All patients received routine care including external traditional Chinese medicine (TCM) application. Outcome measures included surgical indices, numeric rating scale (NRS) scores, infections, and postoperative complications. Results: Laparoscopic surgery is associated with a shorter operation duration, time-lapse before postoperative off-bed activity, and hospital stay, as well as less intraoperative hemorrhage volume compared to tension-free hernia repair in the control group. Patients in the study group had considerably lower NRS ratings after therapy than those in the control group. (P < 0.05). After treatment, the levels of blood cell count (WBC), C-reactive protein (CRP), and procalcitonin (PCT) in the study group were lower than those in the control group (P < 0.05). In the control group, there were 0 cases of hematoma, 3 cases of subcutaneous effusion, 4 cases of urinary retention, 5 cases of scrotal effusion, and 1 case of bladder injury. In the study group, there were 0 cases of hematoma, 1 case of subcutaneous fluid, 1 case of urinary retention, 0 cases of scrotal fluid, and 0 cases of bladder injury. Laparoscopic surgery resulted in a lower incidence of postoperative complications versus traditional surgery (P <0.05). Conclusion: Laparoscopic totally extraperitoneal repair for inguinal hernia improves the intraoperative indices, mitigates postoperative pain, and reduces the risks of infections and complications, with the advantages of short operation duration, less hemorrhage volume, and shorter hospital stay. It shows great potential for clinical promotion.