Agonists and Inhibitors of the cGAS-STING Pathway.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or DNA binding ability of cGAS. Meanwhile, non-CDN compounds and cGAS agonists are also gaining attention. The omnipresence of the cGAS-STING pathway in vivo indicates that its overactivation could lead to undesired inflammatory responses and autoimmune diseases, which underscores the necessity of developing both agonists and inhibitors of the cGAS-STING pathway. This review describes the molecular traits and roles of the cGAS-STING pathway and summarizes the development of cGAS-STING agonists and inhibitors. The information is supposed to be conducive to the design of novel drugs for targeting the cGAS-STING pathway.

Reduced inhibitory synaptic transmission onto striatopallidal neurons may underlie aging-related motor skill deficits.

Human beings are living longer than ever before and aging is accompanied by an increased incidence of motor deficits, including those associated with the neurodegenerative conditions, Parkinson's disease (PD) and Huntington's disease (HD). However, the biological correlates underlying this epidemiological finding, especially the functional basis at the synapse level, have been elusive. This study reveals that motor skill performance examined via rotarod, beam walking and pole tests is impaired in aged mice. This study, via electrophysiology recordings, further identifies an aging-related reduction in the efficacy of inhibitory synaptic transmission onto dorsolateral striatum (DLS) indirect-pathway medium spiny neurons (iMSNs), i.e., a disinhibition effect on DLS iMSNs. In addition, pharmacologically enhancing the activity of DLS iMSNs by infusing an adenosine A2A receptor (A2AR) agonist, which presumably mimics the disinhibition effect, impairs motor skill performance in young mice, simulating the behavior in aged naïve mice. Conversely, pharmacologically suppressing the activity of DLS iMSNs by infusing an A2AR antagonist, in order to offset the disinhibition effect, restores motor skill performance in aged mice, mimicking the behavior in young naïve mice. In conclusion, this study identifies a functional inhibitory synaptic plasticity in DLS iMSNs that likely contributes to the aging-related motor skill deficits, which would potentially serve as a striatal synaptic basis underlying age being a prominent risk factor for neurodegenerative motor deficits.

Fighting bacteria with bacteria: A biocompatible living hydrogel patch for combating bacterial infections and promoting wound healing.

Bacterial infections are among the most critical global health challenges that seriously threaten the security of human. To address this issue, a biocompatible engineered living hydrogel patch was developed by co-embedding engineered photothermal bacteria (EM), photosensitizer (porphyrin) and reactive oxygen species amplifier (laccase) in a protein hydrogel. Remarkably, the genetice engineered bacteria can express melanin granules in vivo and this allows them to exhibit photothermal response upon being exposed to NIR-II laser (1064 nm) irradiation. Besides, electrostatically adhered tetramethylpyridinium porphyrin (TMPyP) on the bacterial surface and encapsulated laccase (Lac) in protein gel can generate highly toxic singlet oxygen (1O2) and hydroxyl radical (·OH) in the presence of visible light and lignin, respectively. Interestingly, the engineered bacteria hydrogel patch (EMTL@Gel) was successfully applied in synergistic photothermal, photodynamic and chemodynamic therapy, in which it was able to efficiently treat bacterial infection in mouse wounds and enhance wound healing. This work demonstrates the concept of "fighting bacteria with bacteria" combining bacterial engineering and material engineering into an engineered living hydrogel path that can synergistically boost the therapeutic outcome. STATEMENT OF SIGNIFICANCE: Genetically engineered bacteria produce melanin granules in vivo, exhibiting remarkable photothermal properties. These bacteria, along with a photosensitizer (TMPyP) and a reactive oxygen species amplifier (laccase), are incorporated into a biocompatible protein hydrogel patch. Under visible light, the patch generates toxic singlet oxygen (1O2) and hydroxyl radical (·OH), demonstrates outstanding synergistic effects in photothermal, photodynamic, and chemodynamic therapy, effectively treating bacterial infections and promoting wound healing in mice.

Preoperative prediction of perineural invasion of rectal cancer based on a magnetic resonance imaging radiomics model: A dual-center study.

BACKGROUND: Perineural invasion (PNI) has been used as an important pathological indicator and independent prognostic factor for patients with rectal cancer (RC). Preoperative prediction of PNI status is helpful for individualized treatment of RC. Recently, several radiomics studies have been used to predict the PNI status in RC, demonstrating a good predictive effect, but the results lacked generalizability. The preoperative prediction of PNI status is still challenging and needs further study. AIM: To establish and validate an optimal radiomics model for predicting PNI status preoperatively in RC patients. METHODS: This retrospective study enrolled 244 postoperative patients with pathologically confirmed RC from two independent centers. The patients underwent pre-operative high-resolution magnetic resonance imaging (MRI) between May 2019 and August 2022. Quantitative radiomics features were extracted and selected from oblique axial T2-weighted imaging (T2WI) and contrast-enhanced T1WI (T1CE) sequences. The radiomics signatures were constructed using logistic regression analysis and the predictive potential of various sequences was compared (T2WI, T1CE and T2WI + T1CE fusion sequences). A clinical-radiomics (CR) model was established by combining the radiomics features and clinical risk factors. The internal and external validation groups were used to validate the proposed models. The area under the receiver operating characteristic curve (AUC), DeLong test, net reclassification improvement (NRI), integrated discrimination improvement (IDI), calibration curve, and decision curve analysis (DCA) were used to evaluate the model performance. RESULTS: Among the radiomics models, the T2WI + T1CE fusion sequences model showed the best predictive performance, in the training and internal validation groups, the AUCs of the fusion sequence model were 0.839 [95% confidence interval (CI): 0.757-0.921] and 0.787 (95%CI: 0.650-0.923), which were higher than those of the T2WI and T1CE sequence models. The CR model constructed by combining clinical risk factors had the best predictive performance. In the training and internal and external validation groups, the AUCs of the CR model were 0.889 (95%CI: 0.824-0.954), 0.889 (95%CI: 0.803-0.976) and 0.894 (95%CI: 0.814-0.974). Delong test, NRI, and IDI showed that the CR model had significant differences from other models (P < 0.05). Calibration curves demonstrated good agreement, and DCA revealed significant benefits of the CR model. CONCLUSION: The CR model based on preoperative MRI radiomics features and clinical risk factors can preoperatively predict the PNI status of RC noninvasively, which facilitates individualized treatment of RC patients.

Liquid-Liquid Phase Separation-Mediated Photocatalytic Subcellular Hybrid System for Highly Efficient Hydrogen Production.

Plant chloroplasts have a highly compartmentalized interior, essential for executing photocatalytic functions. However, the construction of a photocatalytic reaction compartment similar to chloroplasts in inorganic-biological hybrid systems (IBS) has not been reported. Drawing inspiration from the compartmentalized chloroplast and the phenomenon of liquid-liquid phase separation, herein, a new strategy is first developed for constructing a photocatalytic subcellular hybrid system through liquid-liquid phase separation technology in living cells. Photosensitizers and in vivo expressed hydrogenases are designed to coassemble within the cell to create subcellular compartments for synergetic photocatalysis. This compartmentalization facilitates efficient electron transfer and light energy utilization, resulting in highly effective H2 production. The subcellular compartments hybrid system (HM/IBSCS) exhibits a nearly 87-fold increase in H2 production compared to the bare bacteria/hybrid system. Furthermore, the intracellular compartments of the photocatalytic reactor enhance the system's stability obviously, with the bacteria maintaining approximately 81% of their H2 production activity even after undergoing five cycles of photocatalytic hydrogen production. The research brings forward visionary prospects for the field of semi-artificial photosynthesis, offering new possibilities for advancements in areas such as renewable energy, biomanufacturing, and genetic engineering.

Dimethyl fumarate covalently modifies Cys673 of NLRP3 to exert anti-inflammatory effects.

The NLRP3 inflammasome plays a pivotal role in various chronic inflammation-driven human diseases. However, no drugs specifically targeting NLRP3 inflammasome have been approved by the Food and Drug Administration (FDA) of the United States. In our current study, we showed that dimethyl fumarate (DMF) efficiently suppressed the activation of the NLRP3 inflammasome induced by multiple agonists and covalently modified Cys673 of NLRP3, thereby impeding the interaction between NLRP3 and NEK7. The inhibitory effect of DMF was nullified by anaplerosis of the Cys673 mutant (but not the wild-type) NLRP3 in Nlrp3-/- THP-1 cells. In vivo experiments, DMF demonstrated protective effects in the dextran sodium sulfate (DSS)-induced ulcerative colitis of WT mice, but not in Nlrp3-/- mice. In summary, our study identified DMF as a direct covalent inhibitor of NLRP3 and a potential candidate for the treatment of NLRP3 inflammasome-mediated diseases.

E3 ubiquitin ligase CHIP interacts with transferrin receptor 1 for degradation and promotes cell proliferation through inhibiting ferroptosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the major form of liver malignancy with high incidence and mortality. Identifying novel biomarkers and understanding regulatory mechanisms underlying the development and progression of HCC are critical for improving diagnosis, treatment and patient outcomes. Carboxyl terminus of Hsc-70-interacting protein (CHIP) is a well-described U-box-type E3 ubiquitin ligase which promotes the ubiquitination and degradation of numerous tumor-associated proteins. Recent studies have shown that CHIP can play as a tumor-suppressor gene or an oncogene in different kinds of malignancies. To date, the function and mechanism of CHIP in hepatocellular carcinoma remains largely unknown. Based on TCGA data, we found that compared with high CHIP expression, the overall survival of HCC patients with low expression of CHIP was better. In addition, CHIP overexpression markedly enhanced HCC cell proliferation and colony formation. Conversely, knockdown of CHIP restrained the proliferation and colony formation of HCC cells. Meanwhile, knockdown of CHIP decreased mitochondrial cristae or ruptured outer mitochondrial membrane, promoted the accumulation of Fe2+ and ferroptosis of HCC cells. Further research for the first time confirmed that CHIP interacts and degrades transferrin receptor 1 (TfR1) by ubiquitin-proteasome pathway, which leads to the inhibition of ferroptosis and promotes the proliferation of HCC cells. The analysis of proteomics data from CPTAC revealed a negative correlation between CHIP and TfR1 protein expression levels in HCC. These findings indicate that CHIP acts as a negative modulator of ferroptosis and functions as an oncogene in HCC.

In Vivo Fluorescent Labeling of Foam Cell-Derived Extracellular Vesicles as Circulating Biomarkers for In Vitro Detection of Atherosclerosis.

Real-time monitoring of the development of atherosclerosis (AS) is key to the management of cardiovascular disease (CVD). However, existing laboratory approaches lack sensitivity and specificity, mostly due to the dearth of reliable AS biomarkers. Herein, we developed an in vivo fluorescent labeling strategy that allows specific staining of the foam cell-derived extracellular vesicles (EVs) in atherosclerotic plaques, which are released into the blood as circulating biomarkers for in vitro detection of AS. This strategy relies on a self-assembled nanoprobe that could recognize foam cells specifically, where the probe is degraded by the intracellular HClO to produce a trifluoromethyl-bearing boron-dipyrromethene fluorophore (termed B-CF3), a lipophilic dye that can be transferred to the exosomal membranes. These circulating B-CF3-stained EVs can be detected directly on a fluorescence spectrometer or microplate reader without resorting to any sophisticated analytical method. This liquid-biopsy format enables early detection and real-time differentiation of lesion vulnerability during AS progression, facilitating effective CVD management.

Analysis of physical activity and prescription opioid use among US adults: a cross-sectional study.

BACKGROUND: Opioid crisis has become a global concern, but whether physical activity (PA) can effectively reduce prescription opioid use remains unclear. The study aimed to examine the relationship of different domains of PA (e.g., occupation-related PA [OPA], transportation-related PA [TPA], leisure-time PA [LTPA]) with prescription opioid use and duration of prescription opioid use. METHODS: This cross-sectional study was conducted on 27,943 participants aged ≥ 18 years from National Health and Nutrition Examination Survey (NHANES, 2007- March 2020). We examined the relationship of different domains of PA with prescription opioid use and duration of prescription opioid use using multivariable logistic regression. Stratified analysis and a series of sensitivity analysis were used to elevate robustness. All analyses were conducted using appropriate sampling weights. RESULTS: Of the 27,943 participants, the mean age was 45.10 years, with 14,018 [weighted, 50.0%] females and 11,045 [weighted, 66.0%] non-Hispanic White. After multivariable adjustment, inverse associations between PA and prescription opioid use were observed for sufficient (≥ 150 min/week) total PA (OR,0.68 95%CI [0.56-0.81]), TPA (OR,0.73 95%CI [0.58-0.92]), and LTPA (OR,0.60 95%CI [0.48-0.75]) compared with insufficient PA(< 150 min/week), but not for sufficient OPA (OR,0.93 95%CI [0.79-1.10]). In addition, the associations were dose-responsive, participants had 22-40%, 27-36%, and 26-47% lower odds of using prescription opioids depending on the duration of total PA, TPA, and LTPA, respectively. Nevertheless, the impact of PA on prescription opioid use varied by duration of opioid use. Sufficient total PA was associated with elevated odds of short-term use of prescription opioids (< 90 days). Comparatively, sufficient total PA, TPA, and LTPA had different beneficial effects on reducing long-term use of prescription opioids (≥ 90 days) depending on the strength of opioids. CONCLUSIONS: This study demonstrated sufficient total PA, TPA, and LTPA were inversely associated with prescription opioid use and varied depending on the duration and strength of prescription opioid use. These findings highlight PA can provide policy guidance to address opioid crisis.

Single-layer semiconductor-decorated flexible 2D protein nanosheets by engineered anchoring for efficient photocatalytic hydrogen production.

Protein self-assembly can be accurately manipulated to form ordered nanostructures through various supramolecular forces. This strategy is expected to make significant breakthroughs in the field of new biomimetic functional materials. Specifically, the construction of photocatalytic systems on two-dimensional (2D) flexible protein nanosheets meets a great challenge. We introduce a synthetic methodology for creating single-layer semiconductor-decorated protein 2D materials under mild conditions with enhanced light-driven hydrogen production. This approach employs a bioengineered green fluorescent protein (E4P) with the addition of a Cd-binding peptide, enabling precise control of the assembly of CdS quantum dots (QDs) on the protein's surface. Consequently, we obtained 4.3 nm-thin single-layer 2D protein nanosheets with substantial surface areas ideal for accommodating CdS QDs. By orthogonal incorporation of metal-binding peptides and supramolecular coordination, significantly enhancing the overall photocatalytic efficiency. Our findings demonstrate the potential for stable and efficient hydrogen production, highlighting the adaptability and biocompatibility of protein scaffolds for photocatalysis.

Magnetic resonance imaging-guided radiofrequency ablation of breast cancer: a current state of the art review.

With a gradual increase in breast cancer incidence and mortality rates and an urgent need to improve patient prognosis and cosmetology, magnetic resonance imaging (MRI)-guided radiofrequency ablation (RFA) therapy has attracted wide attention as a new treatment method for breast cancer. MRI-RFA results in a higher complete ablation rate and extremely low recurrence and complication rates. Thus, it may be used as an independent treatment for breast cancer or adjuvant to breast-conserving surgery to reduce the extent of breast resection. Furthermore, with MRI guidance, accurate control of RFA can be achieved, and breast cancer treatment can enter a new stage of minimally invasive, safe, and comprehensive therapy. With progress in MR thermometry technology, the applications of MRI are expected to broaden.

Association between secondhand smoke exposure and severe headaches or migraine in never-smoking adults.

OBJECTIVE: The study aimed to examine the relationship between secondhand smoke (SHS) exposure and severe headaches or migraine in never-smoking adults verified by serum cotinine. BACKGROUND: Current evidence about the association between self-reported SHS exposure and headaches or migraine is limited and contradictory. An important issue lies in the lack of actual SHS exposure assessment through biomarkers. METHODS: We conducted a cross-sectional study on 4560 never-smoking adults from the National Health and Nutrition Examination Survey (NHANES), 1999-2004. The SHS exposure was evaluated by measuring serum cotinine concentrations. The information regarding severe headaches or migraine was based on self-reporting. RESULTS: The overall prevalence rate of severe headaches or migraine was 20% (919/4560). After adjusting for relevant covariates, we found that heavy SHS exposure (serum cotinine at 1 to 10 ng/mL) was positively associated with severe headaches or migraine (OR: 2.02, 95% CI [1.19, 3.43]); however, no significant association was found between low SHS exposure (serum cotinine at 0.05 to 0.99 ng/mL) and severe headaches or migraine (OR: 1.15, 95% CI [0.91, 1.47]). Restricted cubic spline analysis showed that the natural logarithm of serum cotinine had a linear relationship with severe headaches or migraine (p = 0.335 for nonlinearity). Stratified analysis indicated that individuals with a BMI of <25 (p < 0.001 for interaction) and sedentary activity (p = 0.016 for interaction) modified the relationship between SHS exposure and severe headaches and migraine. Even after altering the definition of SHS exposure, excluding drugs that might affect the metabolism of serum cotinine, and multiple imputation, our sensitivity analysis results remained stable. CONCLUSIONS: The study demonstrated that heavy SHS exposure (serum cotinine at 1 to 10 ng/mL) had a significant positive association with severe headaches or migraine in never-smoking adults. Prospective studies are necessary to verify this relationship in the future.

Music Therapy in Pediatric Asthma: A Short Review.

Music therapy (MT) is a common modality that performs a complementary and integrative role along with standard treatments for many pediatric diseases. This article briefly reviewed the effects of MT on children aged 5-11 years old and adolescents with asthma from previous studies, specified its functional target towards asthma symptoms, and sorted out the design and investigation of selected research. Medline/PubMed, Embase, SportDis-cus, Cochrane Library, Teacher Reference Centre, Web of Science, Academic Search Complete, PsycARTICLES, and Scopus were queried for experimental and observational studies published between 1990 and 2021. Then, researchers showed that MT lessened patients' asthma symptoms, improved medication compliance, pulmonary function, and quality of life, and helped children and their parents manage anxiety and depression. This article may serve as a reference for clinical research for pediatric asthma therapies and lay the foundation for future research on MT and its clinical practice.

Dietary exposure to sulfamethazine alters fish intestinal homeostasis and promotes resistance gene transfer.

The present study was undertaken to explore the effects of sulfamethazine (SMZ) dietary exposure on the enrichment of the intestine microbial structure, and antibiotic resistance gene (ARGs) transmission in marine medaka, with respect to antibiotic dose, duration, and sex. In male fish, a dietary exposure of 10 µg/L SMZ led to a heightened SMZ enrichment in the intestine, whereas metabolite (N-SMZ) levels were elevated at a higher exposure concentration (100 µg/L). Conversely, female fish exhibited stable levels of accumulation and metabolic rates across the exposure period. The composition of intestinal microorganisms revealed that exposure duration exerted a greater impact on the abundance and diversity of gut microbes, and microbial responses to SMZ varied across exposure time points. The expansion of Bacteroidetes and Ruegeria likely stimulated SMZ metabolism and contributed to the more balanced level of SMZ and N-SMZ observed in females. In males, short-term SMZ stress resulted in a disruption of intestinal homeostasis, while the rise in the abundance of the Fusobacteria and Propionigeniuma suggested a potential enhancement in intestinal anti-inflammatory capacity over time. Overall, female medaka exhibited greater adaptability to SMZ, and males appear to experience prolonged effects due to SMZ. A total of 11 ARGs and 5 mobile genetic elements (MGEs) were identified. Ruegeria is the main carrier of two types of MGEs (IS1247, ISSm2-Xanthob), and may serve as an indicator of ARG transmission. Therefore, it is rational to consider some fish breeding areas in natural waters as potential "reservoirs" of antibiotic resistance. This research will provide a valuable reference for the transmission of drug resistance along the food chain.

Reduced Activity of Glutamatergic Neurons in the Prelimbic Medial Prefrontal Cortex Underlies the Inherent Aging-Related Physiological Reduction in Social Dominance.

Human society is aging, and the percentage of the population of older adults is increasing at an unprecedented rate. It is increasingly appreciated that social behaviors change with aging. One such example is the possible aging-related reduction in dominance status. This change has been thought to underlie older adults' peculiar vulnerability to fraud, which has become a major challenge in the present aging society. However, whether this change is an inherent physiological process, and, if so, its underlying microscopic physiological mechanism, is not known. This study used groups of mice in a design that minimized effects that could confound any inherent process of dominance and verified that social dominance does inherently reduce with aging. This study further identified an aging-related microscopic functional alteration, that is, a reduction in the activity of glutamatergic pyramidal neurons in the prelimbic medial prefrontal cortex; and established that this reduction in neuronal activity serves as an intrinsic physiological mechanism underlying the macroscopic aging-related reduction in dominance. This study, by exploiting modern neurobiological techniques, sheds light on our understanding of human social behaviors during aging and may help develop strategies to counter related social challenges among the older adults population.

Formulation and Performance of Model Concrete in Reduced-Scale Physical Model Tests.

The utility of geotechnical centrifuge tests depends on how correctly they predict the physical and mechanical behaviour of concrete. In this study, a model concrete material that consisted of α-gypsum plaster, fine silica sand, and water was developed. An orthogonal test design was used to evaluate the effect of the mix proportion on the model concrete performance. The physical (i.e., flowability and bleeding rate) and mechanical (i.e., compressive and flexural strength) characteristics were considered as indices. Various mix ratios resulted in remarkable relative contributions to model concrete performance, and each raw material dosage exhibited positive or negative synergy. The water-plaster ratio (W/P) and aggregate-plaster ratio (A/P) strongly influenced the mechanical and physical characteristics, respectively. Multiple linear regression analysis (MLRA) was carried out to determine a forecast model for various small-scale test demands. Finally, the applicability and outlines of the presented forecasting method in proportioning design were evaluated by typical use of model concrete in small-scale model tests.

Incentive policy optimization of scientific and technological talents and low-carbon economy analysis from the perspective of public health.

In the face of multiple challenges in stabilizing economic growth, improving people's living quality, and limiting the total amount of CO2 emissions, firstly, this study analyzes the incentive and optimization policies of scientific and technological (S&T) talents from four aspects: incentive, cultivation, flow, and evaluation. Moreover, practical suggestions are put forward. Secondly, an optimization model of China's low-carbon economy (LCE) is implemented. The Matlab software can be adopted to solve the economic output of each department in the expected year and obtain the overall economic indicators for 2017 and 2022. Finally, the output influence and CO2 emission influence of each industry are analyzed. The research results are as follows. (1) From the viewpoint of public health (PH), the countermeasures and suggestions of the S&T talents policy mainly include four parts: building a complete S&T talents policy system, expanding the coverage group of the policy, strictly implementing the policy of evaluating S&T talents, and improving the guarantee mechanism of relevant talents introduction policy. (2) In 2017, the primary industry, agriculture, forestry, animal husbandry, and fishery, accounted for 5.33%; the secondary industry, the energy sector accounted for 72.04%, and the tertiary industry (service industry) accounted for 22.63%. In 2022, the primary, secondary, and tertiary industry accounted for 6.09%, 68.44%, and 25.47%. (3) From the perspective of the industrial influence coefficient, the coefficient of all sectors is stable during 2017-2022. From the standpoint of CO2 emission, China's total CO2 emission shows rapidly increasing trend during the same period. This study has vital practical significance and theoretical value for realizing the sustainable development (SH) and transformation of the LCE.

Targeting lysosomal HSP70 induces acid sphingomyelinase-mediated disturbance of lipid metabolism and leads to cell death in T cell malignancies.

BACKGROUND: T cell malignancies proliferate vigorously, are highly dependent on lysosomal function, with limited therapeutic options. Deregulation of lysosomal structure and function has been confirmed to be a key role in the treatment of hematologic malignant disease. METHODS: Cell counting kit 8 and Annexin V/PI staining were used to assess the cell viability and apoptosis rate. Flow cytometry, liquid chromatography mass spectrometry, immunofluorescence and western blot were performed to detect the effect on lysosomes. Drug affinity responsive target stability, molecular docking and cellular thermal shift assay were employed to confirm the target protein of V8 on lysosomes. A xenograft model was constructed in NOD/SCID mice to assess the effect and mechanism. RESULTS: V8, a new lysosomotropic compound, could be rapidly trapped by lysosomes and accumulation in lysosomes, contributing to lysosomal-dependent cell death by evoking lysosomal membrane permeabilization (LMP), accompanied with disrupted lysosome and autophagic flux. Mechanistically, heat shock protein 70 (HSP70) was identified as the binding target of V8 in lysosome. As a downstream effect of targeting HSP70, enzymatic activity of acid sphingomyelinase (ASM) was inhibited, which induced disturbance of lipid metabolism, instability of lysosomal membrane, and leakage of cathepsin B and D, leading to LMP-mediated cell death. In vivo study showed V8 well controlled the growth of the tumour and confirmed lysosomal cell death induced by V8. CONCLUSIONS: Collectively, this study suggests targeting lysosomal HSP70-ASM axis by V8 illustrates the great value of drug therapy for T cell malignancies and the unlimited potential of lysosomal targeting for cancer therapy.

Association of maternal pre-pregnancy dietary intake with adverse maternal and neonatal outcomes: A systematic review and meta-analysis of prospective studies.

This study aimed to summarize the evidence regarding the effects of dietary intake before conception on pregnancy outcomes by performing a systematic review and meta-analysis of prospective studies. Electronic databases were searched from inception up to August 2021. Overall, 65 studies involving 831 798 participants were included and 38 studies were quantitatively pooled. With regard to maternal outcomes, pre-pregnancy intake of fried food, fast food, red and processed meat, heme iron and a low-carbohydrate dietary pattern was positively associated with the risk of gestational diabetes mellitus (GDM) (all P < 0.05). However, a high dietary fiber intake and folic acid supplementation were negatively associated with GDM risk (both P < 0.05). With regard to neonatal outcomes, maternal caffeine intake before pregnancy significantly increased the risk of spontaneous abortion, while folic acid supplementation had protective effects on total adverse neonatal outcomes, preterm birth, and small-for-gestational age (SGA, all P < 0.05). However, no significant associations were found between adverse pregnancy outcomes (i.e., GDM and SGA) and the pre-pregnancy dietary intake of sugar-sweetened beverages, potato, fish, and carbohydrates and the Healthy Eating Index. Our study suggests that maintaining a healthy diet before conception has significant beneficial effects on pregnancy outcomes.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1989658.

Association between Periodontitis and Aortic Calcification: A Cohort Study.

The present study investigated the association between the presence of periodontitis and aortic calcification (AC) risk among Chinese adults. A total of 6059 individuals who underwent regular health check-ups and received a diagnosis of periodontitis between 2009 and 2016 were included. The outcome was AC, assessed by a chest low-dose spiral CT scan. Cox proportional hazards regression analysis was used to assess the association between periodontitis and AC risk after adjusting for several confounders. After a median follow-up period of 2.3 years (interquartile range: 1.03-4.97 years), 843 cases of AC were identified, with 532 (12.13%) and 311 (18.59%) patients in the non-periodontitis group and periodontitis group, respectively. Multivariate analyses demonstrated that, compared with those without periodontitis, the hazard ratio and 95% confidence interval for AC risk in participants with periodontitis was 1.18 (1.02-1.36) (P = .025) in the fully adjusted model. Stratified analyses showed that the positive relationship between periodontitis and AC was more evident in males and participants <65 years of age (pinteraction = .005 and .004, respectively). Our results show that the presence of periodontitis was positively associated with AC among Chinese adults, especially among males and younger participants.