Analysis of low-density lipoprotein receptor gene mutations in a family with familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common monogenic autosomal dominant disorder, primarily mainly caused by pathogenic mutations in the low-density lipoprotein receptor (LDLR) gene. Through phenotypic-genetic linkage analysis, two LDLR pathogenic mutations were identified in FH families: c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr). MATERIALS AND METHODS: Whole exome sequencing was conducted on the proband with familial hypercholesterolemia to identify the target gene and screen for potential pathogenic mutations. The suspicious responsible mutation sites in 14 family members were analyzed using Sanger sequencing to assess genotype-phenotype correlations. Mutant and wild type plasmids were constructed and transfected into HEK293T cells to evaluate LDLR mRNA and protein expression. In parallel, bioinformatics tools were employed to predict structural and functional changes in the mutant LDLR. RESULTS: Immunofluorescence analysis revealed no significant difference in the intracellular localization of the p.Gly343Ser mutation, whereas protein expression of the p.Ala627Thr mutation was decreased and predominantly localized in the cytoplasm. Western blotting has showed that protein expression levels of the mutant variants were markedly declined in both cell lysates and supernatants. Enzyme linked immunosorbent assay has demonstrated that LDLR protein levels in the supernatant of cell culture medium was not significant different from those of the wild-type group. However, LDLR protein levels in the cell lysate of both the Gly343Ser and Ala627Thr variants groups were significantly lower than those in the wild-type group. Bioinformatic predictions further suggested that these mutations may affect post-translational modifications of the protein, providing additional insight into the mechanisms underlying the observed reduction in protein expression. CONCLUSIONS: In this study, we identified two heterozygous pathogenic variants in the LDLR gene, c.G1027A (p.Gly343Ser) and c.G1879A (p.Ala627Thr), in a family with familial hypercholesterolemia. We also conducted preliminary investigations into the mechanisms by which these mutations contribute to disease pathology.

Identification of a Novel ECM Remodeling Macrophage Subset in AKI to CKD Transition by Integrative Spatial and Single-Cell Analysis.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single-cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI-to-CKD model of unilateral ischemia-reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co-localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro-repair subsets, whereas infiltrating monocyte-derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling-associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin-like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI-to-CKD transition, which could be a potential therapeutic target for preventing CKD development.

A rare concurrence of acute tubular necrosis and chronic glomerular sclerosis in a patient with wasp stings.

Wasp venom injections from wasp stings can damage several organs, most commonly the kidneys. Despite literature evidence, wasp sting-induced acute kidney injury (AKI) is rare and involves complex pathophysiological processes. While acute tubular necrosis (ATN) is the most prevalent histological result of wasp sting-induced AKI, uncommon combinations of chronic renal lesions have been described, alerting us to the patient's underlying illness. We report a 55-year-old hypertensive patient with unknown renal function who got AKI following multiple wasp stings. His renal function had not improved after continuous hemodialysis and plasma exchange; therefore, a kidney biopsy was performed. The pathology revealed that in addition to ATN, his kidney's distinguishing feature was a mix of chronic interstitial renal disease and chronic glomerulosclerosis. We think that his current renal pathological results were caused by hypertension in addition to wasp venom.

[Corrigendum] The role of IGFBP­5 in mediating the anti­proliferation effect of tetrandrine in human colon cancer cells.

Following the publication of the above article, a concerned reader drew to the authors' attention that, among Figs. 1D, 2A and 4B, certain of the control western blots had been re­used in different blots. The authors have retrieved and re­examined their original data, and were able to identify the correct control western blots where the data had been inadvertently duplicated in the affected original figures. The revised versions of Figs. 2 and 4, now featuring the correct control western blots, are shown in the subsequent two pages. The authors regret that the data in question featured in the original article had been re­used, and thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 46: 1205­1213, 2015; DOI: 10.3892/ijo.2014.2800].

Frequency of lymph node metastases at different neck levels in patients with oral squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Currently, neck dissection is a standard treatment for the majority of oral squamous cell carcinoma (OSCC) patients. However, the procedure can lead to a series of complications, significantly reducing patient quality of life and even affecting the antitumor immune response in patients undergoing immunotherapy. Therefore, in the era of precision surgery, gaining a deeper understanding of the patterns of lymph node metastasis (LNM) in OSCC is crucial. MATERIALS AND METHODS: Literature searches were performed on PubMed, Embase, Web of Science, Cochrane Library, WANFANGDATA and China National Knowledge Infrastructure (CNKI) (inception to April 10, 2024). In addition, a manual searching was conducted in Scopus, Google Scholar, and Education Resources Information Center (ERIC). We included observational studies that evaluated the frequency of LNM in OSCC patients. Systematic review and a random effects model meta-analysis were performed. RESULTS: The search identified 4694 articles, of which 17 studies included in our study. We calculated the frequency of LNM according to the data reported in the articles. Frequency of LNM=number of patients with positive lymph node / number of patients with OSCC. The frequency of LNM was 12% in level I (95%CI: 0.11 to 0.15, I2=38.01%), 20% in level II (95%CI: 0.17 to 0.22, I2=47.71%), 10% in level III (95%CI: 0.08 to 0.12, I2=49.10%), 2% in level VI (95%CI: 0.01 to 0.03, I2=27.58%), 1% in level V (95%CI: 0.00 to 0.01, I2=11.37%). CONCLUSION: The frequency of LNM is consistent with the "cascade theory" and appears to be no significant difference from different primary sites. The frequency of LNM were low in levels I-III and were very low in level IV-V which implicated that more conservative treatments may be considered for OSCC in the future. This study will help clinicians better determine the extent of surgery and preserve lymph nodes during neck dissection.

Adjuvants for cancer mRNA vaccines in the era of nanotechnology: strategies, applications, and future directions.

Research into mRNA vaccines is advancing rapidly, with proven efficacy against coronavirus disease 2019 and promising therapeutic potential against a variety of solid tumors. Adjuvants, critical components of mRNA vaccines, significantly enhance vaccine effectiveness and are integral to numerous mRNA vaccine formulations. However, the development and selection of adjuvant platforms are still in their nascent stages, and the mechanisms of many adjuvants remain poorly understood. Additionally, the immunostimulatory capabilities of certain novel drug delivery systems (DDS) challenge the traditional definition of adjuvants, suggesting that a revision of this concept is necessary. This review offers a comprehensive exploration of the mechanisms and applications of adjuvants and self-adjuvant DDS. It thoroughly addresses existing issues mentioned above and details three main challenges of immune-related adverse event, unclear mechanisms, and unsatisfactory outcomes in old age group in the design and practical application of cancer mRNA vaccine adjuvants. Ultimately, this review proposes three optimization strategies which consists of exploring the mechanisms of adjuvant, optimizing DDS, and improving route of administration to improve effectiveness and application of adjuvants and self-adjuvant DDS.

METTL3 aggravates cell damage induced by Streptococcus pneumoniae via the NEAT1/CTCF/MUC19 axis.

Disruption of the alveolar barrier can trigger acute lung injury. This study elucidated the association of methyltransferase-like 3 (METTL3) with Streptococcus pneumoniae (SP)-induced apoptosis and inflammatory injury of alveolar epithelial cells (AECs). AECs were cultured and then infected with SP. Furthermore, the expression of METTL3, interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), long noncoding RNA nuclear paraspeckle assembly transcript 1 (NEAT1), mucin 19 (MUC19), N6-methyladenosine (m6A), and NEAT1 after m6A modification were detected by qRT-PCR, Western blot, and enzyme-linked immunosorbent, m6A quantification, and methylated RNA immunoprecipitation-qPCR analyses, respectively. Moreover, the subcellular localization of NEAT1 was analyzed by nuclear/cytosol fractionation assay, and the binding between NEAT1 and CCCTC-binding factor (CTCF) was also analyzed. The results of this investigation revealed that SP-induced apoptosis and inflammatory injury in AECs and upregulated METTL3 expression. In addition, the downregulation of METTL3 alleviated apoptosis and inflammatory injury in AECs. METTL3-mediated m6A modification increased NEAT1 and promoted its binding with CTCF to facilitate MUC19 transcription. NEAT1 or MUC19 overexpression disrupted their protective role of silencing METTL3 in AECs, thereby increasing apoptosis and inflammatory injury. In conclusion, this is the first study to suggest that METTL3 aggravates SP-induced cell damage via the NEAT1/CTCF/MUC19 axis.

Pulse pressure variation guided goal-direct fluid therapy decreases postoperative complications in elderly patients undergoing laparoscopic radical resection of colorectal cancer: a randomized controlled trial.

OBJECTIVE: The use of goal-directed fluid therapy (GDFT) has been shown to reduce complications and improve prognosis in high-risk abdominal surgery patients. However, the utilization of pulse pressure variation (PPV) guided GDFT in laparoscopic surgery remains a subject of debate. We hypothesized that utilizing PPV guidance for GDFT would optimize short-term prognosis in elderly patients undergoing laparoscopic radical resection for colorectal cancer compared to conventional fluid therapy. METHODS: Elderly patients undergoing laparoscopic radical resection of colorectal cancer were randomized to receive either PPV guided GDFT or conventional fluid therapy and explore whether PPV guided GDFT can optimize the short-term prognosis of elderly patients undergoing laparoscopic radical resection of colorectal cancer compared with conventional fluid therapy. RESULTS: The incidence of complications was significantly lower in the PPV group compared to the control group (32.8% vs. 57.1%, P = .009). Additionally, the PPV group had a lower occurrence of gastrointestinal dysfunction (19.0% vs. 39.3%, P = .017) and postoperative pneumonia (8.6% vs. 23.2%, P = .033) than the control group. CONCLUSION: Utilizing PPV as a monitoring index for GDFT can improve short-term prognosis in elderly patients undergoing laparoscopic radical resection of colorectal cancer. REGISTRATION NUMBER: ChiCTR2300067361; date of registration: January 5, 2023.

Distinctive Craniofacial and Oral Anomalies in MN1 C-terminal Truncation Syndrome.

MN1 C-terminal truncation (MCTT) syndrome was first reported in 2020 and only 28 patients have been recorded to date. Since MCTT syndrome is a newly defined and rare syndrome with many clinical features, the present study reviewed the manifestations and management of oral and dental anomalies. Gene variants of MCTT syndrome and their positive phenotypes were summarised. The phenotypes of variants in two exons differed from each other mainly in the craniomaxillofacial region, including brain MRI abnormalities and palatal morphology. Pathogenic mechanisms, especially in craniofacial and oral anomalies, were discussed. Appropriate treatments in the stomatology and respiratory departments could improve the symptoms of MCTT syndrome. The different sites of MN1 gene variants may influence the clinical symptoms and there may be racial differences in MCTT syndrome. We recommend oral and pulmonary evaluations for the multidisciplinary treatment of MCTT syndrome.

Revelation of the discrepancy of volatile compounds in fig (Ficus carica) via gas chromatography ion-mobility spectrometry.

The volatile compounds of fig (Ficus carica) are influenced by various factors. To explore the composition and difference of volatile compounds among figs, gas chromatography ion mobility spectrometry (GC-IMS) was used to study the volatiles of figs from various regions, diverse cultivars, and after treatment with different drying methods. Aldehydes were the main volatile compounds in Bojihong from Shandong, while esters, ketones, and alcohols were the main volatile compounds in Bojihong from Sichuan and Guangdong. The volatiles of Branswick and Banane were similar, but differed significantly from those of Bojihong. Drying had the most significant effect on fig volatiles, which greatly reduced the content of benzaldehyde, (E)-2-hexenal, 2-methylbutanal aldehydes, lost the content of esters such as isoamyl acetate, butyl acetate, ethyl butyrate, and generated some ketones and ethers. The results showed that Bojihong from Shandong was more suitable for the processing of subsequent fig drying products.

[Using Biochar and Iron-calcium Material to Remediate Paddy Soil Contaminated by Cadmium and Arsenic].

In this study, iron-calcium material (FC) and hickory-cattail biochar (BC) were applied to prepare composite material (BF), which was used to repair the combined pollution of cadmium and arsenic in paddy soil to reduce the content of cadmium (Cd) and arsenic (As) in rice grain. Soil pore water, rhizosphere soil, bulk soil, rice plants, and root iron plaque samples were collected during the growth period of rice in a pot experiment to explore the effects and mechanism of FC, BC, and BF on the bioavailability of Cd and As in paddy soil and their contents in plants. The results showed that biochar could significantly (P < 0.05) increase the pH value of bulk soil (0.55-0.66 units) and rhizosphere soil (0.28-0.36 units) and elevate the soil dissolved organic carbon (DOC) content. FC material could significantly (P < 0.05) reduce the pH of bulk soil (0.14-0.27 units) and rhizosphere soil (0.38-0.41 units), as well as the soil DOC content. Iron-calcium materials and composite could simultaneously reduce the contents of available Cd and As in soil pore water, rhizosphere soil, and bulk soil, whereas biochar could reduce the content of Cd but increase the content of As. Among them, a 1% addition of composite had the best effect. The available Cd and As in soil decreased by 41.8%-48.2% and 6.1%-10.1%, respectively. Biochar, iron-calcium materials, and composites improved plant biomass (dry weight of root, stem, leaf, and grain). For example, the dry weights of rice grains under these treatments were higher (48.5%-184.0%) than that of CK, as was the root iron plaque content (7.5%-13.6%). Compared with that in the CK, biochar could effectively reduce the Cd content in rice grain by 21.0%-26.1%. Iron-calcium material and composite could simultaneously reduce the Cd and As contents in rice grain. Among them, the BF treatment had the best effect on the reduction of Cd and As in rice grain, with a decrease of 36.9%-42.0% and 40.4%-44.4%, respectively. The Cd and As contents in rice grain were lower than the national standard values (GB 2762-2017).

Electroacupuncture alleviates ciliary muscle cell apoptosis in lens-induced myopic guinea pigs through inhibiting the mitochondrial signaling pathway.

AIM: To investigate the effect of electroacupuncture (EA) on the mitochondria-dependent apoptotic signaling pathway in the ciliary muscle of guinea pigs with negative lens-induced myopia (LIM). METHODS: Guinea pigs were randomly divided into normal control (NC) group, LIM group, LIM+SHAM acupoint (LIM+SHAM) group, and LIM+EA group. Animals in the NC group received no intervention, while those in other three groups were covered with -6.0 diopter (D) lenses on right eyes. Meanwhile, animals in the LIM+EA group received EA at Hegu (LI4) combined with Taiyang (EX-HN5) acupoints, while those in the LIM+SHAM group were treated at sham points. After treatments for 1, 2, and 4wk, morphological changes in ciliary muscles were observed with hematoxylin and eosin (H&E) staining and nick end labeling (TUNEL), and the expression of the mitochondrial apoptotic signaling pathway-related molecules in ciliary muscles was measured by real-time quantitative polymerase chain reaction (qPCR) and Western blot. Additionally, the adenosine triphosphate (ATP) contents were also determined in ciliary muscles. RESULTS: Axial length increased significantly in the LIM and LIM+SHAM groups and decreased in the LIM+EA group. The ciliary muscle fibers were broken and destroyed in both LIM and LIM+SHAM groups, whereas those in the LIM+EA group improved significantly. TUNEL assay showed the number of apoptotic cells increased in the LIM and LIM+SHAM groups, whereas reduced in the LIM+EA group. ATP contents showed a significant decrease in the LIM and LIM+SHAM groups, whereas increased after EA treatment. Compared with the NC group, the dynamin-related protein 1 (DRP1), Caspase3, and apoptotic protease activator 1 (APAF1) levels were significantly increased in the LIM group and decreased in the LIM+EA group. CONCLUSION: The results provide evidence of EA inhibiting the development of myopia by regulating the mitochondrial apoptotic signaling pathway.

Effect of glutamine on the systemic innate immune response in broiler chickens challenged with Salmonella pullorum.

BACKGROUND: The objective of this study was to evaluate the effects of glutamine on the growth performance and systemic innate immune response in broiler chickens challenged with Salmonella pullorum. A total of 600 one-day-old Arbor Acres broiler chickens were assigned randomly to 6 dietary treatments with 10 replicates for a 21-day feeding experiment. The experimental treatments were as follows: the control treatment (birds fed the basal diet), the Gln1 treatment, and the Gln 2 treatment (birds fed the basal diet supplemented with 0.5%, and 1.0% Glutamine, respectively). At 3 d of age, half of the birds from each treatment were challenged oral gavage with 2.0 × 104 CFU/mL of S. pullorum suspension (1.0 mL per bird) or an equivalent amount of sterile saline alone, which served as a control. RESULTS: The results showed that S. pullorum infection had adverse effects on the average daily feed intake, average daily gain, and feed conversion ratio of broiler chickens compared with those of the CON treatment on d 7, decreased the spleen and bursa of fabricius relative weights (except on d 21), serum immunoglobulin A (IgA),immunoglobulin G (IgG), and immunoglobulin M (IgM) concentrations, and spleen melanoma differentiation-associated gene 5 (MDA5) and laboratory of genetics and physiology gene 2 (LGP2) mRNA expression levels, and increased the mRNA expression levels of spleen Nodinitib-1 (NOD1), Toll-like receptors 2,4 (TLR2, TLR4), DNA-dependent activator of IFN-regulatory factors (DAI), mitochondrial antiviral-signaling protein (MAVS), P50, P65, and RelB on d 4, 7, 14, and 21. Supplementation with Gln improved the relative weights of the spleen and bursa of Fabricius (except on d 21), increased the serum IgA, IgG, and IgM concentrations and the mRNA expression levels of spleen MDA5 and LGP2, and decreased the mRNA expression levels of spleen NOD1, TLR2, TLR4, DAI, MAVS, P50, P65, and RelB of S. pullorum-challenged broiler chickens. CONCLUSION: These results indicate that Gln might stimulate the systemic innate immune responses of the spleen in broiler chickens challenged with S. pullorum.

Real-world tobacco cessation practice in China: findings from the prospective, nationwide multicenter China National Tobacco Cessation Cohort Study (CNTCCS).

Background: Tobacco cessation is proven to be the most effective and cost-effective strategy for smokers to reduce their risk of smoking-related disease and premature death. Providing effective, efficient, safe, and patient-centred tobacco cessation treatment to reach those who need them is a significant challenge. To date, only a few nationwide studies in China have assessed the overall clinical care practice and treatment outcome of tobacco cessation. Methods: This a prospective, nationwide, multicenter, cohort study covering all Eastern China, Northwest China, Central China, North China, Southwest China, Northeast China, and South China. Participants who were current smokers aged 18-85 years attending clinic for smoking cessation were included. All the participants were treated with 3-month cessation treatment and followed up for 3 months. Data were collected prospectively using online system. The primary outcome was 7-day point abstinence rate at 24 weeks, validated biochemically by an expired carbon monoxide level of less than 10 ppm. The participants lost to follow-up or not providing validation were included as non-abstainers. Findings: A representative sample of 3557 participants were recruited and 2943 participants were included into this analysis. These participants had mean age of 53.05 years, and 94.8% were males, with 75.8% showing symptoms of tobacco dependence. A total of 965 (32.8%) participants were treated with Bupropion + behavioural counselling, followed by 935 (31.8%) with behavioural counselling, 778 (26.4%) with Varenicline + behavioural counselling, 135 (4.6%) with alternative treatments + behavioural counselling, and 130 (4.4%) with nicotine replacement therapy (NRT) + behavioural counselling. After 3-month treatment and 3-month follow-up, 21.74% of the participants quit smoking at 24 weeks. In the multivariable-adjusted analyses, quitting smoking was significantly associated with female, higher socioeconomic status, poor health condition, different treatment received, and less smoking intensity. The tobacco cessation treatment varied widely across different areas of China. In particular, the areas with higher usage of cessation medication were associated with better cessation treatment outcome. Interpretation: The CNTCCS is the first large-scale nationwide cohort study of smoking cessation in China. Rich data collected from this prospective cohort study provided the opportunity to evaluate the clinical practice of tobacco cessation treatment in China. Funding: Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS 2021-I2M-1-010), Heilongjiang Provincial Science and Technology Key Program (2022ZXJ03C02), and National Key R&D Program of China (grant no. 2017YFC1309400).

Nanotheranostics in cancer lymph node metastasis: The long road ahead.

Lymph node metastasis (LNM) significantly impacts the prognosis of cancer patients. Despite significant advancements in diagnostic techniques and treatment modalities, clinical challenges continue to persist in the realm of LNM. These include difficulties in early diagnosis, limited treatment efficacy, and potential side effects and injuries associated with treatment. Nanotheranostics, a field within nanotechnology, seamlessly integrates diagnostic and therapeutic functionalities. Its primary goal is to provide precise and effective disease diagnosis and treatment simultaneously. The development of nanotheranostics for LNM offers a promising solution for the stratified management of patients with LNM and promotes the advancement of personalized medicine. This review introduces the mechanisms of LNM and challenges in its diagnosis and treatment. Furthermore, it demonstrates the advantages and development potential of nanotheranostics, focuses on the challenges nanotheranostics face in its application, and provides an outlook on future trends. We consider nanotheranostics a promising strategy to improve clinical effectiveness and efficiency as well as the prognosis of cancer patients with LNM.

Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.

Calcineurin inhibitors or cyclophosphamide in the treatment of membranous nephropathy superimposed with FSGS lesions: a retrospective study from China.

BACKGROUND: Cyclophosphamide (CTX) and calcineurin inhibitors (CNIs) based regimens are recommended as immunosuppressive therapies for patients with idiopathic membranous nephropathy (IMN). Focal and segmental glomerular sclerosis (FSGS) lesions, which are common in membranous nephropathy (MN), are poor predictors of outcome. This study compared the differences of prognosis between two regimens in patients with IMN combined with FSGS lesions. METHODS: This retrospective study enrolled 108 patients with biopsy-proven IMN, accompanied with FSGS lesions, nephrotic syndrome and an estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 who were treated with CTX or CNIs. We used propensity score matching (PSM) for balancing the confounding variables. RESULTS: During follow-up, 10 patients (10/55 [18.2%]; nine males) in the CNIs group showed a 50% decline in eGFR; eight had a not otherwise specified variant. Patients initially treated with CNIs had a significantly higher risk of progression to the primary outcome and a lower probability of complete or total remission. The relapse rate was higher in patients who initially received CNIs- than in those who received CTX-based treatment. Before PSM, age and 24-h urine protein level differed significantly between the groups. The PSM model included data from 72 patients. Worse outcomes were also noted among patients who initially received CNIs than those who received CTX-based treatments after matching. CONCLUSIONS: Patients with MN combined with FSGS lesions have a higher risk of renal functional decline and a higher rate of relapse after CNIs than after CTX therapy.

Safety and Efficacy of Drug-Eluting Bead Transarterial Chemoembolization Combined with Lenvatinib and Anti-PD-1 Antibodies for Unresectable Hepatocellular Carcinoma: A Retrospective Analysis.

Background: Drug-eluting bead transarterial chemoembolization (DEB-TACE) has good efficacy in the treatment of unresectable hepatocellular carcinoma (uHCC), with a relatively high objective response rate (ORR) compared to conventional transarterial chemoembolization (cTACE). This study aimed to evaluate the safety and medium-term clinical efficacy of DEB-TACE combined with lenvatinib (LEN) plus PD-1 inhibitors as a triple therapy for the treatment of uHCC. Methods: Data of patients with uHCC who received triple therapy of DEB-TACE combined with LEN plus PD-1 inhibitors from January 2019 to June 2021 were analyzed retrospectively. The study endpoints were ORR, progression-free survival (PFS), and treatment-related adverse events based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Results: Thirty-five patients were included in this study, with a median follow-up period of 15 months. The median cycle of DEB-TACE was 1, while that of all forms of TACE procedures per patient was 2. The median administration time of LEN was 7 months, and the median number of PD-1 inhibitor treatment was 4 cycles. The ORR based on mRECIST was 82.9%, disease control rate was 91.4%, and the median time to response was 7 weeks. Among these, the ORR of Barcelona Clinic Liver Cancer (BCLC) stage A reached 100%, while that of BCLC stages B and C reached 84.6% and 78.9%, respectively. The median PFS was 9 months; the mOS was not reached. Fourteen patients (40%) successfully underwent downstaging conversion and surgical resection, 32 patients (91.4%) experienced treatment-related adverse events, and no grade 5-related adverse reactions occurred. Conclusion: DEB-TACE combined with LEN and PD-1 inhibitors has a high ORR and surgical conversion rate in the treatment of uHCC tumors, and the toxicity and side effects were tolerable.

Ethanol extract of propolis regulates type 2 diabetes in mice via metabolism and gut microbiota.

ETHNOPHARMACOLOGICAL RELEVANCE: Propolis is a traditional natural medicine with various activities such as antioxidant and anti-inflammatory, immunomodulatory, anti-tumour, gastroenteritis treatment and prevention, anti-microbial and parasitic, as well as glucose regulation and anti-diabetes, and is expected to be an anti-diabetic candidate with few side effects, but the mechanism of action of propolis on type 2 diabetes mellitus (T2DM) has not been fully elucidated. AIM OF THE STUDY: The purpose of this study was to investigate the mechanism of the effect of ethanol extract of propolis (EEP) on the regulation of blood glucose in T2DM mice. MATERIALS AND METHODS: We studied the possible mechanism of EEP on T2DM using an animal model of T2DM induced by a combination of a high-fat diet and intraperitoneal injection of streptozotocin (STZ). The experiment was divided into four groups, namely, the normal group (HC), model group (T2DM), EEP and metformin group (MET). Biochemical indexes and cytokines were measured, and the differences of metabolites in the serum were compared by 1H-NMR. In addition, the diversity of intestinal flora in feces was studied by 16S rDNA amplicon sequencing. RESULTS: The results showed that following treatment with EEP and MET, the weight-loss trend of mice was alleviated, and the fasting blood glucose, insulin secretion level, insulin resistance index, C peptide level and oral glucose tolerance level decreased, whereas the insulin sensitivity index increased, thereby EEP effectively alleviated the occurrence of T2DM and insulin resistance. Compared with the T2DM group, the concentrations of pro-inflammatory cytokines interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) decreased significantly in EEP and MET groups, whereas the concentrations of anti-inflammatory cytokine interleukin-10 (IL-10) increased significantly. Metabolomics results revealed that EEP and MET regulate carbohydrate metabolism and restore amino acid and lipid metabolism. Correlation analysis of intestinal flora in mouse feces showed that compared with the HC group, harmful bacteria such as Bilophila, Eubacterium_ventriosum_group, Mucispirillum and Desulfovibrio were found in the T2DM group, whereas the abundance of beneficial bacteria such as Lactobacillus was significantly reduced. Parabacteroides, Akkermansia, Leuconostoc, and Alloprevotella were abundantly present in the EEP group; however, the MET group showed an increase in the genus Parasutterella, which could regulate energy metabolism and insulin sensitivity. CONCLUSIONS: The results showed that EEP and MET reduce fasting blood glucose in T2DM mice, followed by alleviating insulin resistance, improving the inflammatory reaction of mice, regulating the metabolism of mice, and affecting the steady state of gut microbiota. However, the overall therapeutic effect of EEP is better than that of MET.