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In solid tumors, the exhaustion of natural killer (NK) cells and cytotoxic T cells in the immunosuppressive tumor microenvironment poses challenges for effective tumor control. Conventional humanized mouse models of hepatocellular carcinoma patient-derived xenografts (HCC-PDX) encounter limitations in NK cell infiltration, hindering studies on NK cell immunobiology. Here, we introduce an improved humanized mouse model with restored NK cell reconstitution and infiltration in HCC-PDX, coupled with single-cell RNA sequencing (scRNA-seq) to identify potential anti-HCC treatments. A single administration of adeno-associated virus carrying human interleukin-15 reinstated persistent NK cell reconstitution and infiltration in HCC-PDX in humanized mice. scRNA-seq revealed NK cell and T cell subpopulations with heightened PDCD1 and TIGIT levels. Notably, combination therapy with anti-PD-1 and anti-TIGIT antibodies alleviated HCC burden in humanized mice, demonstrating NK cell-dependent efficacy. Bulk-RNA sequencing analysis also revealed significant alterations in the tumor transcriptome that may contribute to further resistance after combination therapy, warranting further investigations. As an emerging strategy, ongoing clinical trials with anti-PD-1 and anti-TIGIT antibodies provide limited data. The improved humanized mouse HCC-PDX model not only sheds light on the pivotal role of NK cells but also serves as a robust platform for evaluating safety and anti-tumor efficacy of combination therapies and other potential regimens, complementing clinical insights., Competing Interests: Declaration of interests Q.C. is the scientific cofounder of two biotech companies., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aim: Hyperhomocysteine has been recognized as an independent risk factor of multiple diseases, including several eye diseases. In this study, we aim to investigate whether increased homocysteine (Hcy) is related to cataracts, and to explore whether dysregulation of mTOR-mediated autophagy and connexin expression are underlying mechanisms., Method: We first developed a method of liquid chromatography tandem mass spectrometry to accurately measure serum concentrations of Hcy in 287 cataract patients and 334 healthy controls. Next, we treated human lens epithelial (HLC-B3) cells with Hcy at different concentrations and durations, and then analyzed expression of autophagy-related markers and connexins, as well as phosphorylated mTOR (p-mTOR) in these cells by Western blotting. Formation of autophagic vacuoles and intracellular Ca 2+ in the Hcy-treated cells were observed by fluorescence microscopy. Further, we performed a rescue experiment in the Hcy-treated HLC-B3 cells by pre-incubation with rapamycin, an mTOR inhibitor., Results: The serum levels of Hcy in patients with cataracts were significantly increased compared to those in healthy controls. In cultured HLC-B3 cells, expression of autophagy related markers (LC3B and Beclin1) and connexins (Cx43 and Cx50) was inhibited by Hcy treatment in a dose- and duration-dependent manner. Accumulation of Ca 2+ in the Hcy-treated lens epithelial cells was observed as a consequence of reduced connexin expression. Meanwhile, expression of p-mTOR increased, representing up-regulation of the mTOR pathway. Importantly, inhibition of autophagy and connexin expression due to hyperhomocysteine was rescued via mTOR suppression by pretreatment with rapamycin in HLC-B3 cells., Conclusion: Our results demonstrate that hyperhomocysteine might promote cataract development through two mTOR-mediated pathways in the lens epithelial cells: 1) dysregulation of autophagy and 2) accumulation of intracellular calcium via decreased connexin expression., 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.The funders played no role in the study design, data collection, or analyses, the decision to publish, or manuscript preparation., (Copyright © 2024. Published by Elsevier B.V.)

Patients with tissue inflammation or injury often experience aberrant mechanical pain hypersensitivity, one of leading symptoms in clinic. Despite this, the molecular mechanisms underlying mechanical distortion are poorly understood. Canonical transient receptor potential (TRPC) channels confer sensitivity to mechanical stimulation. TRPC3 and TRPC6 proteins, coassembling as heterotetrameric channels, are highly expressed in sensory neurons. However, how these channels mediate mechanical pain hypersensitivity has remained elusive. It is shown that in mice and human, TRPC3 and TRPC6 are upregulated in DRG and spinal dorsal horn under pathological states. Double knockout of TRPC3/6 blunts mechanical pain hypersensitivity, largely by decreasing nociceptor hyperexcitability and spinal synaptic potentiation via presynaptic mechanism. In corroboration with this, nociceptor-specific ablation of TRPC3/6 produces comparable pain relief. Mechanistic analysis reveals that upon peripheral inflammation, TRPC3/6 in primary sensory neurons get recruited via released bradykinin acting on B1/B2 receptors, facilitating BDNF secretion from spinal nociceptor terminals, which in turn potentiates synaptic transmission through TRPC3/6 and eventually results in mechanical pain hypersensitivity. Antagonizing TRPC3/6 in DRG relieves mechanical pain hypersensitivity in mice and nociceptor hyperexcitability in human. Thus, TRPC3/6 in nociceptors is crucially involved in pain plasticity and constitutes a promising therapeutic target against mechanical pain hypersensitivity with minor side effects., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Backgrounds: Habitual substance use, i. e., alcohol, tobacco and betel nut, has been found with an increased risk of metabolic syndrome (MetS) in the general population, whereas the association remains unclear in physically fit military personnel. This study aimed to investigate the combination of these substances use and their associations with new-onset MetS in the military., Methods: A total of 2,890 military men and women, aged 18-39 years, without MetS were obtained from the cardiorespiratory fitness and health in eastern armed forces study (CHIEF) in Taiwan and followed for incident MetS from baseline (2014) through the end of 2020. Incident MetS event was defined by the International Diabetes Federation guideline and confirmed in the annual health examinations. A self-report was used to assess the alcohol, tobacco and betel nut use status (active vs. former/never). Multivariable Cox regression model was performed to determine the association with adjustments for sex, age, body mass index and physical activity at baseline., Results: At baseline, there were 279 active betel nut chewers (9.7%), 991 active smokers (34.3%) and 1,159 active alcohol consumers (40.1%). During a mean follow-up of 6.0 years, 673 incident MetS (23.3%) were observed. As compared to no substance users, only one substance, and two and three substances users had a greater risk of incident MetS [hazard ratios (HRs) and 95% confidence intervals: 1.27 (1.06-1.54), 1.38 (1.12-1.69) and 1.78 (1.37-2.32), respectively]. In subgroup analyses, the risk of incident MetS in two and three substances users was significantly greater in those free of baseline low high-density lipoprotein [HRs: 1.54 (1.21-1.95) and 2.57 (1.92-3.46), respectively], as compared to their counterparts (both p for interactions <0.05)., Conclusion: A dose-response association of more substances use for new-onset MetS was noted in military personnel. This finding suggests that the combined alcohol, tobacco and betel nut use may play a role in the development of MetS. Further study is required to establish causation and to investigate the potential benefits of substance use cessation in reducing the risk of MetS., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Liu, Hsu, Lin, Tsai, Chang, Liu and Lin.)

Background and Objectives : Peripheral arterial stiffness (PAS), assessed by brachial-ankle pulse wave velocity (baPWV), is an independent biomarker of cardiovascular diseases (CVD) in patients on maintenance hemodialysis (HD). Malondialdehyde-modified low-density lipoprotein (MDA-LDL), an oxidative stress marker, has been linked to atherosclerosis and CVD. However, the association between serum MDA-LDL and PAS among HD patients has not been fully elucidated. This study aimed to examine the association of serum MDA-LDL with PAS in HD patients and to identify the optimal cutoff value of serum MDA-LDL for predicting PAS. Materials and Methods : A cross-sectional study was conducted in 100 HD patients. Serum MDA-LDL was quantified using an enzyme-linked immunosorbent assay (ELISA), and baPWV was measured using a volume plethysmographic device. Patients were divided into the PAS group (baPWV > 18.0 m/s) and the non-PAS group (baPWV ≤ 18.0 m/s). The associations of baPWV and other clinical and biochemical parameters with serum MDA-LDL were assessed by multivariable logistic regression analyses. A receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cutoff value of serum MDA-LDL for predicting PAS. Results : In multivariable logistic regression analysis, higher serum MDA-LDL, older age, and higher serum C-reactive protein [odds ratios (ORs) and 95% confidence intervals: 1.014 (1.004-1.025), 1.044 (1.004-1.085) and 3.697 (1.149-11.893)] were significantly associated with PAS. In the ROC curve analysis, the optimal cutoff value of MDA-LDL for predicting PAS was 80.91 mg/dL, with a sensitivity of 79.25% and a specificity of 59.57%. Conclusions : Greater serum MDA-LDL levels, particularly ≥80.91 mg/dL, were independently associated with PAS in HD patients. The findings suggest that oxidative stress plays a crucial role in the pathogenesis of PAS, and targeting MDA-LDL may be a potential therapeutic strategy for reducing cardiovascular risk in HD patients.

Aim: The study aimed to examine the association of obesity phenotypes with dental calculus., Background: Obesity has been recognized as a risk factor for kidney and gallbladder stones formation and periodontitis., Objective: We have investigated the association between obesity, metabolic risk factors, and dental calculus, which is a sequela following periodontitis., Methods: This study included 5,281 military members, aged 19-45 years, without antihypertensive medications in Taiwan. Obesity was defined as body mass index ≥27.5 kg/m 2 , and metabolic syndrome (MetS) was defined according to the modified ATP III criteria. Supragingival calculus in any teeth, except for impacted teeth and the third molar, was the outcome of interest. Multiple linear regression analysis with adjustments for age, sex, toxic substance use, brushing teeth frequency, and blood leukocyte counts, was used to determine the association of obesity with dental calculus numbers. Multiple logistic regression analysis was used to assess the association between obesity with or without MetS and the presence of any dental calculus., Results: BMI was positively correlated to dental calculus numbers [β and confidence intervals (CI) = 0.023 (0.014, 0.032)]. Compared to the obesity(-)/MetS(-) group, there were dosedependent associations for the obesity(-)/MetS(+), obesity(+)/MetS(-), and obesity(+)/MetS(+) groups with the presence of any dental calculus [odds ratios (ORs): 1.08 (0.76, 1.53), 1.31 (1.08, 1.58), and 1.51 (1.20, 1.90), respectively]. Of the metabolic risk factors, abdominal obesity and hypertension were independently associated with dental calculus [ORs: 1.33 (1.13, 1.55) and 1.30 (1.11, 1.52), respectively]., Conclusion: This study suggests general obesity as an independent risk factor for dental calculus formation, and MetS, particularly the components of abdominal obesity, and hypertension may also increase the prevalence of dental calculus. Diet control and regular exercise might be preventive measures for the development of both obesity and dental calculus., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)