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Fu-Li Zhu,1,2 Ting Huang,3 Zi-Li Lv,4 Gang Liang,5 Zhen Yao,2 Lian-Cheng Lan,2 Abdul Qadir,2 Xiu-Qi Chen,2 Qing-Wen Shan2 1Department of Pediatrics, the First College of Clinical Medical Science, China Three Gorges University, Yichang Central People’s Hospital, Yichang, Hubei, 443000, People’s Republic of China; 2Department of Pediatrics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 3Guangxi Key Laboratory of Aquatic Genetic Breeding and Healthy Aquaculture, Guangxi Academy of Fishery Science, Nanning, Guangxi, 530021, People’s Republic of China; 4Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China; 5Department of Pathophysiology, School of Basic Medical Sciences of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Qing-Wen Shan; Xiu-Qi Chen, Department of Pediatrics, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, People’s Republic of China, Email shanqw333@163.com; chenxiuqi@gxmu.edu.cnPurpose: To investigate the intestinal inflammatory response and the abundance of intestinal bacteria in rats with high-fat diet (HFD)-induced nonalcoholic fatty liver disease (NAFLD) and assess the intervention effects of taurine (TAU).Methods: Forty male Sprague-Dawley rats were randomly divided into five groups: group I, normal diet and normal saline gavage; group II, normal diet and TAU gavage; group III, HFD and normal saline gavage; group IV, HFD and TAU gavage (from the 1st week); group V, HFD and TAU gavage (from the 10th week). At the end of the 16th week, all the animals were sacrificed. Body weight, liver weight, liver function, and serum lipid levels were measured. The histopathologies of the liver and ileum were observed. The mRNA and protein expression levels of interleukin 17 (IL-17) and IL-10 in the ileum were detected by reverse transcription quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Three types of bacteria were detected in intestinal feces using the 16S rDNA qPCR method.Results: The ileal IL-17 level in group III was significantly higher than those in the other four groups (P < 0.01). The ileal IL-10 mRNA levels in group IV was significantly higher than those in groups III and V (P < 0.05), and IL-10 protein MOD levels in group III was significantly lower than those in the other four groups (P < 0.01). The numbers of Lactobacillus in group III were significantly lower than those in the other four groups (P < 0.01 or P < 0.05). The numbers of Bifidobacteria in groups IV and V were significantly increased compared with that in group III (P < 0.05).Conclusion: TAU may down-regulate the expression of IL-17, up-regulate the expression of IL-10 and regulate the intestinal flora, and alleviate the liver and intestinal damage in rats with HFD-induced NAFLD.Keywords: taurine, non-alcoholic fatty liver disease, interleukin 17, interleukin 10, intestinal barrier, gut microbiota

Hui-Fen Wang, Chun-You Wang, Xiao-Fang Zhou, Xiang-Fen Deng, Hui Huang, Juan Wang, Xue-Qin Chen, Zhi-Fang Zhai Department of Dermatology, the First Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Zhi-Fang Zhai, Department of Dermatology, the First Affiliated Hospital of Army Medical University, Gaotanyan Street No. 30, Shapignba District, Chongqing, 400038, People’s Republic of China, +86 023 6876 6338, Email zhaizf1004@163.comPurpose: The aim is to investigate the application value of dermoscopy combined with reflectance confocal microscopy (RCM) in assessing vitiligo disease activity and treatment response.Patients and Methods: We enrolled 279 patients with vitiligo and evaluated the disease activity by Vitiligo Disease Activity (VIDA) score, dermoscopy, RCM and dermoscopy combined with RCM respectively. The sensitivity and specificity of different assessment techniques were compared with VIDA score by the differences and consistency. The different characteristics of dermoscopy and RCM with different treatment responses were also analyzed.Results: The results showed that the sensitivity and specificity of dermoscopy combined RCM were higher than RCM or dermoscopy alone (P values less than 0.05). In the repigmentation process, leukotrichia, pigment network absent and perilesional hyperpigmentation under dermoscopy at the baseline suggested a poor treatment response, while the incompletely disappearing pigment rings under RCM and perifollicular hyperpigmentation under dermoscopy indicated a good treatment response. We also found the proportion of patients with telangiectasia, increased pigment at the lesions and around the hair follicles was significantly higher in the good treatment response group than that in the poor one by dermoscopy (χ 2 = 4.423, 32.471, 4.348, P = 0.035 0.000, 0.037) and by RCM the proportion of patients with both increased pigment granules and dendritic melanocytes in the good treatment response group was higher than that in the poor one (χ 2 = 38.215, 5.283, P = 0.000, 0.022, respectively).Conclusion: With the higher sensitivity and specificity than dermoscopy or RCM alone, a combination of dermoscopy and RCM may be a new more accurate measure to assess the vitiligo disease activity and the treatment response.Keywords: vitiligo, dermoscopy, reflectance confocal microscopy, the disease activity, the treatment response

Xiao-Qi Chen,&ast; Yun-Xia Zhao,&ast; Chuan-Lei Zhang, Xin-Ting Wang, Xin Zhang, Xi Chen, Chang-Wei Yuan, Qing Zhao, Xin-Ju Chen Department of Gastroenterology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xin-Ju Chen, Department of Gastroenterology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, No. 19, Renmin Road, Jinshui District, Zhengzhou, Henan, 450000, People’s Republic of China, Tel +86-13700867158, Email chxj888@163.comPurpose: Anlotinib, a novel multi-target tyrosine kinase inhibitor, has shown encouraging antitumor effects in advanced hepatocellular carcinoma (HCC). This study evaluated the effectiveness and safety of anlotinib with or without programmed death-1 (PD-1) blockades for patients with advanced primary HCC in a real-world setting in China.Patients and Methods: Between July 2019 and May 2021, 27 patients with advanced primary HCC who received at least 2 cycles of anlotinib were included in this retrospective study. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.Results: Of the 27 patients, ORR and DCR were 25.93% and 74.07%, respectively. The median follow-up time was 6.27 months (range: 1.30– 17.40) with a median PFS and OS of 3.29 months (95% CI: 1.31– 15.47) and 6.21 months (95% CI: 2.23– 15.87), respectively. A total of 14 patients received anlotinib and PD-1 blockade combination therapy, and 13 received anlotinib monotherapy. No significant differences were observed in ORR (28.57 vs 23.08%), DCR (71.43 vs 76.92%), PFS (3.38 [95% CI: 2.66– 13.14] vs 11.86 months [95% CI: 4.27– 15.93]) and OS (4.90 [95% CI: 2.56– 13.60] vs 11.04 months [95% CI: 1.31– 17.18]) between the two groups (all p> 0.05). Treatment-related AEs were reported in 88.89% of patients. Grade 3 AE was bleeding, which occurred in 3 patients (11.11%).Conclusion: Anlotinib yielded a promising efficacy and manageable safety in patients with advanced primary HCC irrespective of whether patients received PD-1 blockades, indicating that anlotinib might be a promising treatment option for this patient population.Keywords: anlotinib, objective response rate, PD-1 blockades, primary hepatocellular carcinoma

Qi-Yong Zhang,* Xiao-Qin Chen,* Xiong-Chang Liu, De-Ming Wu Department of Gastroenterology, The First People’s Hospital of Lanzhou, Lanzhou City, Gansu 730050, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiao-Qin Chen Department of GastroenterologyThe First People’s Hospital of Lanzhou City, Number 1 Wu Jia Yuan West Road, Lanzhou, Gansu 730050, People’s Republic of ChinaTel +86 931 233 7286Email cxq1967@163.comBackground: Abnormal expression of protein kinase membrane associated tyrosine/threonine 1 (PKMYT1) is closely associated with multiple types of cancers. In the present study, we examined the roles of PKMYT1 in gastric cancer (GC) progression.Methods: We examined the expression status of PKMYT1 in GC tissues and cell lines. Meanwhile, short hairpin RNA (shRNA) was used to inhibit the endogenous expression of PKMYT1 in GC cells. Then we analyzed the effect of PKMYT1 on the malignant biological behavior of GC cells by in vitro and in vivo experiments.Results: The findings showed high PKMYT1 expressions in GC tissues as well as a positive correlation between PKMYT1 expression and prognosis of patients with GC. Additional findings also revealed that PKMYT1 silencing significantly enhanced apoptosis and inhibited GC cell proliferation. In vivo, the silence of PKMYT1 inhibits tumor growth. Further analysis showed that the increase in PKMYT1 expressions led to malignant biological behavior through activation of the MAPK signaling pathway.Conclusion: Our data suggested that PKMYT1 promotes cell proliferation and apoptosis resistance in GC cells by activating the MAPK signaling pathway, making it a potential therapeutic target for GC.Keywords: gastric cancer, PKMYT1, prognosis, proliferation, apoptosis, MAPK pathway

Yan-Hua Zheng,1 Yue-Yun Ma,2 Yi Ding,3 Xie-Qun Chen,1 Guang-Xun Gao1 1Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China; 2Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China; 3Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China Abstract: Invasive fungal infections especially in immunocompromised patients represent a dominating cause of mortality. The most commonly used antifungal agents can be divided into three broad categories, including triazoles, echinocandins and polyenes. Antifungal resistance is on the increase, posing a growing threat to the stewardship of immunocompromised patients with fungal infections. The paucity of currently available antifungals leads to the rapid emergence of drug resistance and thus aggravates the refractoriness of invasive fungal infections. Therefore, deep exploration into mechanisms of drug resistance and search for new antifungal targets are required. This review highlights the therapeutic strategies targeting Hsp90, calcineurin, trehalose biosynthesis and sphingolipids biosynthesis, in an attempt to provide clinical evidence for overcoming drug resistance and to form the rationale for combination therapy of conventional antifungals and agents with novel mechanisms of action. What’s more, this review also gives a concise introduction of three new-fashioned antifungals, including carboxymethyl chitosan, silver nanoparticles and chromogranin A-N46. Keywords: carboxymethyl chitosan, chromogranin A-N46, Hsp90, calcineurin, trehalose, sphingolipids

Hua Wang,1–3,* Liang Wang,1–3,* Yue Lu,1–3 Xiaoqin Chen,1–3 Qirong Geng,1–3 Weida Wang,1–3 Zhongjun Xia1–3 1Department of Hematological Oncology, 2State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, 3Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, People’s Republic of China *These authors contributed equally to this work Abstract: Bortezomib has significantly increased the response rates in multiple myeloma (MM), but optimal bortezomib-based regimens for initial MM therapy have not yet been defined. We retrospectively compared the outcomes of 128 patients newly diagnosed with symptomatic MM who received either bortezomib combined with dexamethasone (PD) or three-drug combinations of PD with liposomal doxorubicin (PAD) or thalidomide (PTD). The overall response rate (ORR), very good partial response (VGPR) rate, and complete remission CR/near-complete remission (nCR) results were better for the PAD and PTD regimens than for the PD group. Three-year overall survival (OS) was 80.1%, 72.5%, and 61.8% with PAD, PTD, and PD regimens, respectively. The 3-year OS rate of PAD and PTD was significantly higher than that of PD (80.1% vs 61.8%, P=0.024; 72.5% vs 61.8%, P=0.035), but the difference was not statistically significant between PAD and PTD (80.1% vs 72.5%, P=0.843). Similarly, the PAD and PTD regimens resulted in significantly superior 3-year progression-free survival (PFS) rates. The patients in the PTD arm were more frequently observed with grade 1–3 peripheral neuropathy (PN), compared to those in the PAD and PD groups, especially grade 2–3 PN. PN developed less frequently without sacrificing the efficacy when bortezomib was administered subcutaneously rather than intravenously. Our experience suggests that the three-drug combinations PAD and PTD produce a better outcome than PD, especially with respect to PAD, with fewer adverse events. Keywords: multiple myeloma, bortezomib, prognostic factors, peripheral neuropathy, subcutaneous

We present a novel approach to induce charge density waves (CDWs) in metallic MA 2 Z 4 materials, resembling the behavior observed in transition metal dichalcogenides (TMDCs). This method leverages the intercalating architecture to maintain the same crystal field and Fermi surface topologies. Our investigation reveals that CDW instability in these materials arises from electron-phonon coupling (EPC) between the d band and longitudinal acoustic (LA) phonons, mirroring TMDC's behavior. By combining α-MA 2 Z 4 with 1 H -MX 2 materials in a predictive CDW phase diagram using critical EPC constants, we demonstrate the feasibility of extending CDW across material families with comparable crystal fields and reveal the crucial role in CDW instability of the competition between ionic charge transfer and electron correlation. We further uncover a strain-induced Mott transition in β 2 -NbGe 2 N 4 monolayer featuring star-of-David patterns. This work highlights the potential of intercalating architecture to engineer CDW materials, expanding our understanding of CDW instability and correlation physics.

Background and Objectives: To systematically investigate the association between the dietary inflammatory index (DII) and gestational diabetes mellitus (GDM), with a focus on the role of BMI in this relationship., Methods and Study Design: A comprehensive search was conducted in PubMed, Embase, Web of Science, The Cochrane Library, Medline, CINAHL Complete, Chinese Periodical Full-text Database, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Wanfang Database for rele-vant observational studies published up to August 2023. The quality of the included studies was assessed using the Newcastle-Ottawa Scale. The pooled effect size was calculated using a random-effects model. Sub-group and meta-regression analyses were performed to explore potential sources of heterogeneity., Results: The study included 54,058 participants from 10 studies. Pregnant women with a higher DII, indicating a pro-inflammatory diet, had a significantly increased risk of GDM compared to those with a lower DII, indicating an anti-inflammatory diet (pooled OR: 1.17, 95% CI: 1.01-1.36; I²=70%, p <0.001). Subgroup analyses revealed a stronger association in normal weight stratification (OR: 1.25, 95%CI: 1.04-1.51), case-control studies (OR: 1.45, 95%CI: 1.03-2.05), Asia (OR: 1.26, 95%CI: 1.10-1.43), Europe (OR: 1.27, 95%CI: 1.09-1.48), 3-day dietary record as a dietary assessment tool (OR: 1.30, 95%CI: 1.16-1.46), physical activity adjustment (OR: 1.28, 95%CI: 1.13-1.46), and energy intake adjustment (OR: 1.33, 95%CI: 1.19-1.48). Meta-regression analysis confirmed that geographical region significantly influenced heterogeneity between studies (p <0.05)., Conclusions: An elevated DII is independently linked to a higher risk of GDM, especially in women of normal weight., Competing Interests: The authors declare no conflict of interest

Recently, the sortilin receptor (SORT1) was found to be preferentially over-expressed on the surface of many cancer cells, which makes SORT1 a novel anticancer target. The SORT1 binding proprietary peptide TH19P01 could achieve the SORT1-mediated cancer cell binding and subsequent internalization. Inspired by the peptide-drug conjugate (PDC) strategy, the TH19P01-camptothecin (CPT) conjugates were designed, efficiently synthesized, and evaluated for their anticancer potential in this study. The water solubility, in vitro anticancer activity, time-kill kinetics, cellular uptake, anti-migration activity, and hemolysis effects were systematically estimated. Besides, in order to monitor the release of CPT from conjugates in real-time, the CPT/Dnp-based "turn on" hybrid peptide was designed, which indicted that CPT could be sustainably released from the hybrid peptide in both human serum and cancer cellular environments. Strikingly, compared with free CPT, the water solubility, cellular uptake, and selectivity towards cancer cells of hybrid peptide LYJ-2 have all been significantly enhanced. Moreover, unlike free CPT or TH19P01, LYJ-2 exhibited selective anti-proliferative and anti-migration effects against SORT1-positive MDA-MB-231 cells. Collectively, this study not only established efficient strategies to improve the solubility and anticancer potential of chemotherapeutic agent CPT, but also provided important references for the future development of TH19P01 based PDCs targeting SORT1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lymph node metastasis (LNM) is a common invasive feature of hepatocellular carcinoma (HCC) associated with poor clinical outcomes. Through microarray profiling and bioinformatic analyses, we identified the circ-0044539-miR-29a-3p-VEGFA axis as a potential key factor in the progression of HCC LNM. In HCC cells and nude mice, circ-0044539 downregulation or miR-29a-3p upregulation was associated with small tumor size, PI3K-AKT-mTOR pathway inactivation, and downregulation of the key LNM factors (HIF-1α and CXCR4). Furthermore, circ-0044539 was also responsible for exosomal miR-29a-3p secretion. Exosomal miR-29a-3p was then observed to migrate to the LNs and downregulate High-mobility group box transcription factor 1 (Hbp1) in Polymorphonuclear Myeloid-derived suppressor cells (PMN-MDSCs), inducing the formation of a microenvironment suitable for tumor colonization. Overall, circ-0044539 promotes HCC cell LNM abilities and induces an immune-suppressive environment in LNs through exosomes, highlighting its potential as a target for HCC LNM and HCC immunotherapy., (© 2024. The Author(s).)

Tunable luminescence-assisted information storage and encryption holds increasing significance in today's society. A promising approach to incorporating the benefits of both organic long persistent luminescent (LPL) materials and rare-earth (RE) luminescence lies in utilizing organic host materials to sensitize RE luminescence, as well as hydrogen-bonded organic framework (HOF) phosphorescence Förster resonance energy transfer to RE compound luminescence. This work introduces a one-pot, in situ pyrolytic condensation method, achieved through high-temperature melting calcination, to synthesize lanthanide ion-doped HOF materials. This method circumvents the drawback of molecular triplet energy annihilation, enabling the creation of organic LPL materials with RE characteristics. The HOF material serves as the host, exhibiting blue phosphorescence and cyan LPL. By fine-tuning the doping amount, the composite material U-Tb-100 achieves green LPL with a luminescent quantum yield of 56.4%, and an LPL duration of approximately 2-3 s, demonstrating tunable persistence. Single-crystal X-ray diffraction, spectral analysis, and theoretical calculation unveil that U-Tb-100 exhibits exceptional quantum yield and long-lived luminescence primarily due to the efficient sensitization of U monomer to RE ions and the PRET process between U and RE complexes. This ingenious strategy not only expands the repertoire of HOF materials but also facilitates the design of multifunctional LPL materials., (© 2024 Wiley‐VCH GmbH.)

Topological insulating states in 2-dimensional (2D) materials are ideal systems to study different types of quantized response signals due to their in gap metallic states. Very recently, the quantum spin Hall effect was discovered in monolayer TaIrTe 4 via the observation of quantized longitudinal conductance that rarely exists in other 2D topological insulators. The nontrivial Z 2 topological charges can exist at both charge neutrality point and the van Hove singularity point with correlation-effect-induced bandgap. On the basis of this model 2D material, we studied the switch of quantized signals between longitudinal conductance and transversal Hall conductance via tuning external magnetic field. In Z 2 topological phase of monolayer TaIrTe 4 , the zero Chern number can be understood as 1 - 1 = 0 from the double band inversion from spin-up and spin-down channels. After applying a magnetic field perpendicular to the plane, the Zeeman split changes the band order for one branch of the band inversion from spin-up and spin-down channels, along with a sign charge of the Berry phase. Then, the net Chern number of 1 - 1 = 0 is tuned to 1 + 1 = 2 or -1 - 1 = -2 depending on the orientation of the magnetic field. The quantized signal not only provides another effective method for the verification of topological state in monolayer TaIrTe 4 but also offers a strategy for the utilization of the new quantum topological states based on switchable quantized responses., Competing Interests: Author contributions: Y.S. conceived the project. Y.S. designed the research with the help of X.-Q.C. J.W.L. wrote the programs for the calculation based on Wannier basis. J.W.L., X.Y.L. and J.Z. performed the calculations. Y.S. and X.-Q.C. supervised the project. T.Y.Y. and P.T.L. participated in discussions. Y.S. and J.W.L. wrote the manuscript with inputs from other authors. All authors comments on the manuscript., (Copyright © 2024 Junwen Lai et al.)

Background: Not all eligible breast cancer (BC) patients could afford the expensive test of 21-gene recurrence score (RS) assay. This study aimed to identify clinicopathological factors associated with high-risk RS and examine whether these factors correlate with the benefit of chemotherapy., Research Design and Methods: Patients diagnosed with early-stage BC, node-negative, and estrogen receptor-positive disease were identified from the Surveillance, Epidemiology, and End Results Oncotype DX database., Result: We included 74,605 patients. Those with higher grade ( p  < 0.001) and progesterone receptor-negative (PR Neg) ( p  < 0.001) had the highest odds of a high-risk RS. Among them, 3.2%, 10.1%, 39.1%, 18.6%, 41.6%, and 80.1% had high-risk RS tumors in PR-positive (PR Pos)/well-differentiated (G1), PR Pos/moderately differentiated (G2), PR Pos/poorly and/or undifferentiated (G3), PR Neg/G1, PR Neg/G2, and PR Neg/G3 groups, respectively. Receipt of chemotherapy was associated with improved breast cancer-specific survival ( p  = 0.010) and overall survival ( p  < 0.001) in high-risk RS cohort. However, there were no survival benefits from chemotherapy in patients with PR Neg/G3 disease and other groups after stratification by grade and PR status (all p  ≥ 0.05)., Conclusion: Our study aids in refining patient selection for the RS testing, which is crucial given its economic implications. However, 21-gene RS remains pivotal for treatment decision-making.

Background: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients., Methods: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded., Results: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217)., Conclusions: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration., Trial Registration: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892., (© 2024. The Author(s).)

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by excessive intracellular fat deposition in the hepatocytes, and the development is exacerbated by gut microbiota and bile acids metabolism disorders. Ilex hainanensis Merr. is a traditional medicine of the Zhuang nationality, historically esteemed for its efficacy in lowering blood pressure and lipid levels. This study aimed to investigate the pharmacodynamic effects in NAFLD mice and impacts on gut microbiota and bile acids (BAs) metabolism of I. hainanensis extract (IHA). 16 compounds were identified from IHA by HPLC-DAD-MS analysis. IHA significantly reduced body weight indexs, alanine transaminase (ALT) and aspartate transaminase (AST) activities, improved dyslipidemia and insulin resistance (IR), and effectively ameliorated hepatic steatosis in HFD-induced NAFLD mice. IHA also altered gut microbiota composition, particularly enhancing the abundance of bacteria involved in BAs metabolism, as well as augmented BAs synthesis in the liver and increased fecal excretion. In conclusion, our findings suggest that IHA holds promise in improving NAFLD conditions and modulating gut microbiota and BAs metabolism. These insights contribute to a deeper understanding of the mechanisms underlying IHA-mediated alleviation of lipid accumulation in NAFLD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To analyze the clinicopathological features of prostate cancers with BRCA2 pathogenic mutations, and the association between BRCA2 pathogenic mutation and clinicopathological characteristics. Patient survivals were also examined. Methods: Clinicopathological data of 249 prostate cancer patients who underwent genetic testing in West China Hospital of Sichuan University, Chengdu, China from June 2014 to August 2021 were collected. A retrospective analysis of histopathological morphology, clinicopathological characteristics, and patient survivals was conducted. Results: The genetic testing in the 249 prostate cancer patients showed a pathogenic mutation of DNA damage repair gene (DRG) in 73 cases (73/249, 29.3%), including 22 cases (8.8%) with BRCA2 pathogenic mutation and 51 cases with pathogenic mutations of other DRG. Among the 22 patients with BRCA2 pathogenic mutation, 14 patients (5.6%) harbored germline mutations and 8 patients (3.2%) somatic mutations. Their ages ranged from 48 to 91 years, with a median of 67 years. Seventeen patients (77.3%) had distant metastasis, including 16 cases with bone metastasis and 1 case with multiple metastases. Thirteen patients (59.1%) were castration-resistant prostate cancer. The histological type was mainly classical prostatic acinar adenocarcinoma, including 16 cases (72.7%) with intraductal carcinoma of the prostate (IDC-P). Six cases (27.3%) showed focal neuroendocrine differentiation. Perineural/vascular invasion and extraprostatic extension were seen in 11 cases (50.0%) and 8 cases (36.4%), respectively. The Gleason scores of 19 patients (86.4%) were≥8. IDC-P was more commonly found in patients with BRCA2 germline pathogenic mutation than those with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation ( P =0.002). With a total follow-up time of 189 months, the median overall survival (OS) was 132.3 months. Patients with DRG pathogenic mutation had shorter OS than those with no-DRG pathogenic mutation ( P =0.040). The OS of patients with BRCA2 germline pathogenic mutation did not significantly differ from that of patients with BRCA2 somatic pathogenic mutation, other DRG pathogenic mutation or no-DRG pathogenic mutation ( P =0.216). Conclusions: The presence of BRCA2 gene pathogenic mutation is common in the prostate cancers with high Gleason grade, advanced clinical stage, and castration resistance. IDC-P is more commonly noted in cases with BRCA2 germline pathogenic mutation than those without. Patients with DRG pathogenic mutation have shorter OS than those with no-DRG pathogenic mutation, but there is no significant association between BRCA2 pathogenic mutations and OS.

Background: Persistent infection with high-risk human papillomavirus (HR-HPV) plays a key role in the onset of cervical cancer. This study was designed to examine the epidemiological trends and genotype distribution of HPV from 2014 to 2023 in the plateau region of Southwest China., Methods: The findings could offer valuable insights for clinical screening of cervical cancer and the formulation of HPV vaccination policies. This retrospective study analyzed 66,000 women who received HPV-DNA testing at the First People's Hospital of Qujing, Yunnan, China, between 2014 and 2023. The cohort consisted of 33,512 outpatients, 3,816 inpatients, and 28,672 individuals undergoing health examinations. Cervical cells were collected for DNA extraction, and PCR amplification along with Luminex xMAP technology were used to detect 27 HPV genotypes. The data analysis was conducted using GraphPad Prism and IBM SPSS Statistics 27 software., Results: The overall HPV infection rate at the First People's Hospital of Qujing declined from 24.92% in 2014 to 16.29% in 2023, averaging 16.02%. Specific infection rates were 18.50% among outpatients, 12.97% among inpatients, and 13.53% for health examination attendees. The predominant high-risk HPV genotypes identified were HPV52 (2.61%), HPV16 (2.06%), HPV58 (1.81%), HPV53 (1.55%), and HPV39 (1.09%). Meanwhile, the most frequent low-risk HPV genotypes were HPV6 (1.30%), HPV61 (1.21%), and HPV11 (0.85%). In HPV-positive cases, the distribution of single, double, triple, and quadruple or more infections were 79.90%, 15.17%, 3.59%, and 1.33%, respectively. The proportions of pure LR-HPV, pure HR-HPV, and mixed infections were 22.16%, 67.82%, and 10.02%, respectively. Age-specific analysis revealed a bimodal distribution of HPV infection, with the infection rate rapidly decreasing from 44.02% in the ≤ 19 age group to 19.55% in the 20-29 age group and 13.84% in the 30-39 age group, followed by a gradual increase to 14.64% in the 40-49 age group, 16.65% in the 50-59 age group, and 22.98% in the ≥ 60 age group. The coverage rates of the three available vaccines are all below 50%. The results of this study indicated a declining trend in HPV prevalence in the plateau region of Southwest China over the period from 2014 to 2023, especially in the reduction of genotypes targeted by vaccines., Conclusion: There were significant variations in the genotypes prevalent among different age groups, years, and patient sources within the same region. The underwhelming vaccination rates emphasize the critical need for developing either a multivalent vaccine or a personalized vaccine that targets the HPV genotypes common in the Chinese population. Furthermore, vaccinating adolescents to curb HPV infection and ensuring regular cervical cancer screenings for postmenopausal women are crucial steps., (© 2024. The Author(s).)

Serum miRNAs are available clinical samples for cancer screening. Identifying early serum markers in lung cancer (LC) is essential for patients' early diagnosis and clinical treatment. Expression data of serum miRNAs of lung adenocarcinoma (LUAD) patients and healthy individuals were downloaded from the Gene Expression Omnibus (GEO). These data were normalized and subjected to differential expression analysis to obtain differentially expressed miRNAs (DEmiRNAs). The DEmiRNAs were subsequently subjected to ReliefF feature selection, and subsets closely related to cancer were screened as candidate feature miRNAs. Thereafter, a Gaussian Naive Bayes (NB), Support Vector Machine (SVM), and Random Forest (RF) classifier were constructed based on these candidate feature miRNAs. Then the best diagnostic signature was constructed through NB combined with incremental feature selection (IFS). Thereafter, these samples were subjected to principal component analysis (PCA) based on miRNAs with optimal predictive performance. Finally, the peripheral serum miRNAs of 64 LUAD patients and 59 normal individuals were extracted for qRT-PCR analysis to validate the performance of the diagnostic model in respect of clinical detection. Finally, according to area under the curve (AUC) and accuracy values, the NB classifier composed of miR-5100 and miR-663a manifested the most outstanding diagnostic performance. The PCA results also revealed that the 2-miRNA diagnostic signature could effectively distinguish cancer patients from healthy individuals. Finally, qRT-PCR results of clinical serum samples revealed that miR-5100 and miR-663a expression in tumor samples was remarkably higher than that in normal samples. The AUC of the 2-miRNA diagnostic signature was 0.968. In summary, we identified markers (miR-5100 and miR-663a) in serum for early LUAD screening, providing ideas for developing early LUAD diagnostic models.

Objectives: Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS-AD. How the increased APP gene dose acts and which APP products are responsible for DS-AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of γ-secretase modulators that promote γ-site cleavages by the γ-secretase complex, resulting in lower levels of the Aβ42 and Aβ40 peptides., Methods: Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10 mg/kg/weekday of BPN15606 (a potent and novel pyridazine-containing γ-secretase modulators). Treatment started at 3 months-of-age and lasted for 4 months., Results: Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of Aβ40 and Aβ42 in the cortex and hippocampus; it had no effect on full-length APP or its C-terminal fragments in either 2 N or Ts65Dn mice. Importantly, the levels of total amyloid-β were not impacted, pointing to BPN15606-mediated enhancement of processivity of γ-secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits., Interpretation: Our findings point to the involvement of increased levels of Aβ42 and/or Aβ40 in contributing to several molecular and cognitive traits associated with DS-AD. They speak to increased dosage of the APP gene acting through heightened levels of Aβ42 and/or Aβ40 as supporting pathogenesis. These findings further the interest in the potential use of γ-secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390-404., (© 2024 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Outside of pregnancy, intuitive eating (IE) is associated with lower body weight, blood glucose, and higher positive mood. However, little was known about the relationship between IE and anxiety-depression in the GDM population. Thus, this study aimed to investigate the association of IE with anxiety and depression, pregnancy weight and pregnancy blood glucose in the first and second GDM visit., Methods: Data from 310 pregnant women with GDM from the Fujian Maternal and Child Health Hospital Trial (Approval Number: 2020Y9133) were analyzed. IE was assessed using the Intuitive Eating Scale-2 subscales of Eating for Physiological Reasons rather than Emotional Reasons (EPR), Relying on Hunger and Satiety Cues (RHSC) and Body-Food Choice Consistency (B-FCC). Observations included weight, body mass index (BMI), fasting plasma glucose (FPG) and 2-h postprandial blood glucose; the Hospital Anxiety and Depression Scale (HADS) was used to assess the level of anxiety and depression in pregnant women with GDM. Linear regression analysis was used to assess the correlation between IE and anxiety, depression, pregnancy blood glucose and weight., Results: The cross-sectional analysis showed that the EPR eating behavior was negatively correlated with anxiety and depression, and the B-FCC eating behavior was negatively correlated with depression at both the first and second GDM visit; in addition, the B-FCC eating behavior was associated with lower BMI in the third trimester (all p < 0.05). In longitudinal analyses, the EPR eating behavior in the first visit for GDM predicted lower levels of anxiety and depression in the second GDM visit, whereas the RHSC eating behavior in the first visit for GDM was associated with lower FPG in the second GDM visit (all p < 0.01)., Conclusion: These results suggest that practicing intuitive eating may be beneficial and that higher intuitive eating adherence can lead to lower levels of anxiety and depression and more ideal gestational weight and blood glucose values., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Gao, Zheng, Chen, Jiang, Liao, Pan, Zou and Liu.)

Objectives: To compare color Doppler ultrasound and contrast-enhanced ultrasound (CEUS) in evaluating vascular invasion in pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: This retrospective study included 210 patients with PDAC who were evaluated by color Doppler ultrasound, CEUS, and contrast-enhanced computed tomography (CECT) at our institution between January 2017 and December 2020. Pathologic results were used as the gold standard in patients who underwent surgical and intraoperative exploration. For nonsurgical patients, CECT results were used as the reference standard. The vessels evaluated included those in the peripancreatic arterial system and venous system. The diagnostic performances of color Doppler ultrasound and CEUS for vascular invasion were compared., Results: In 51 patients who underwent surgery and intraoperative exploration, color Doppler ultrasound and CEUS differed only in assessing venous system invasion in patients with PDAC of the pancreatic body and tail, with the former being superior to the latter. In 159 nonsurgical patients, there was no difference between CEUS and color Doppler ultrasound in assessing superior mesenteric arteriovenous invasion. CEUS was superior to color Doppler ultrasound in evaluating the celiac artery and its branches, with an accuracy of up to 97.8% for some vessels. Color Doppler ultrasound was ideal for evaluating the splenic and portal veins., Conclusion: CEUS is more suitable for the evaluation of peripancreatic arteries than color Doppler. CEUS combined with color Doppler ultrasound can be used as a potential supplement to CECT and is also expected to be used to evaluate vascular invasion of PDAC after chemotherapy., Critical Relevance Statement: Contrast-enhanced US and color Doppler in the assessment of vascular invasion in pancreatic ductal adenocarcinoma have their respective advantages, through standardized ultrasound processes are expected to improve the efficiency of inspection., Key Points: Contrast-enhanced US has unique advantages in assessing pancreatic ductal adenocarcinoma invasion of the celiac artery. Doppler imaging is of high value in assessing venous system invasion. Standardization of ultrasound imaging procedures for pancreatic ductal adenocarcinoma is expected to improve efficiency., (© 2024. The Author(s).)

Retinitis pigmentosa (RP) is a group of genetic disorders characterized by progressive degeneration of photoreceptors and retinal pigment epithelium (RPE) cells. Its main clinical manifestations include night blindness and progressive loss of peripheral vision, making it a prevalent debilitating eye disease that significantly impacts patients' quality of life. RP exhibits significant phenotypic and genetic heterogeneity. For instance, numerous abnormal genes are implicated in RP, resulting in varying clinical presentations, disease progression rates, and pathological characteristics among different patients. Consequently, gene therapy for RP poses challenges due to these complexities. However, stem cells have garnered considerable attention in the field of RPE therapy since both RPE cells and photoreceptors can be derived from stem cells. In recent years, a large number of animal experiments and clinical trials based on stem cell transplantation attempts, especially cord blood mesenchymal stem cell (MSC) transplantation and bone marrow-derived MSC transplantation, have confirmed that stem cell therapy can effectively and safely improve the outer retinal function of the RP-affected eye. However, stem cell therapy also has certain limitations, such as the fact that RP patients may involve multiple types of retinal cytopathia, which brings great challenges to stem cell transplantation therapy, and further research is needed to solve various problems faced by this approach in the clinic. Through comprehensive analysis of the etiology and histopathological changes associated with RP, this study substantiates the efficacy and safety of stem cell therapy based on rigorous animal experimentation and clinical trials, while also highlighting the existing limitations that warrant further investigation., Competing Interests: Conflicts of Interest: Qi XY, None; Mi CH, None; Cao DR, None; Chen XQ, None; Zhang P, None., (International Journal of Ophthalmology Press.)

Objective: To study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV 17 gene variant., Case Presentation: A boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV 17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV 17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV 17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate., Conclusion: Hepatocerebral MDS patients without neurological symptoms may benefit from LT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wei, Chen, Huang, Shan and Tang.)