Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

Characterization of a Novel Monoclonal Antibody with High Affinity and Specificity against Aflatoxins: A Discovery from Rosetta Antibody-Ligand Computational Simulation.

Aflatoxin B1 (AFB1) accumulates in crops, where it poses a threat to human health. To detect AFB1, anti-AFB1 monoclonal antibodies have been developed and are widely used. While the sensitivity and specificity of these antibodies have been extensively studied, information regarding the atomic-level docking of AFB1 (and its derivatives) with these antibodies is limited. Such information is crucial for understanding the key interactions that are required for high affinity and specificity in aflatoxin binding. First, a 3D comparative model of anti-AFB1 antibody (Ab-4B5G6) was predicted from the sequence using RosettaAntibody. We then utilized RosettaLigand to dock AFB1 onto ten homology models, producing a total of 10,000 binding modes. Interestingly, the best-scoring mode predicted strong interactions involving four sites within the heavy chain: ALA33, ASN52, HIS95, and TRP99. Importantly, these strong binding interactions exclusively involve the variable domain of the heavy chain. The best-scoring mode with AFB1 was also obtained through AF multimer combined with RosettaLigand, and two interactions at TRP and HIS were consistent with those found by Rosetta antibody-ligand computational simulation. The role of tryptophan in π interactions in antibodies was confirmed through mutation experiments, and the resulting mutant (W99A) exhibited a >1000-fold reduction in binding affinity for AFB1 and analogs, indicating the effect of tryptophan on the stability of CDR-H3 region. Additionally, we evaluated the binding of two glycolic acid-derived molecular derivatives (with impaired hydrogen bonding potential), and these derivatives (AFB2-GA and AFG2-GA) demonstrated a very weak binding affinity for Ab-4B5G6. The heavy chain was successfully isolated, and its sensitivity and specificity were consistent with those of the intact antibody. The homology models of variable heavy (VH) single-domain antibodies were established by RosettaAntibody, and the docking analysis revealed the same residues, including Ala, His, and Trp. Compared to the potential binding mode of fragment variable (FV) region, the results from a model of VH indicated that there are seven models involved in hydrophobic interaction with TYR32, which is usually referred to as polar amino acid and has both hydrophobic and hydrophilic features depending on the circumstances. Our work encompasses the entire process of Rosetta antibody-ligand computational simulation, highlighting the significance of variable heavy domain structural design in enhancing molecular interactions.

Sirt1 m6A modification-evoked Leydig cell senescence promotes Cd-induced testosterone decline.

Diminished testosterone levels have been documented as a key factor in numerous male health disorders. Both human and animal studies have consistently demonstrated that cadmium (Cd), a pervasive environmental heavy metal, results in decreased testosterone levels. However, the exact mechanism through which Cd interferes with testosterone synthesis remains incompletely elucidated. This research sought to examine the impact of cellular senescence on Cd-suppressed testosterone synthesis. We also investigated the related m6A modification mechanism. The results demonstrated that Cd (100 mg/L) led to a decrease in testosterone levels, along with downregulated expression of testosterone synthase in C57BL/6 N male mice. Furthermore, Cd significantly increased ß-galactosidase staining intensity, senescence-related proteins, and senescence-related secretory phenotypes in mouse testicular Leydig cells. Subsequent investigations revealed that Cd decreased the mRNA and protein levels of NAD-dependent deacetylase Sirtuin-1 (SIRT1) in Leydig cells. Mechanistically, mice treated with resveratrol (50 mg/kg), a specific SIRT1 activator, mitigated Leydig cell senescence and reversed Cd-reduced testosterone levels in mouse testes. These effects were also restored by SIRT1 overexpression in Leydig cells. Additionally, we found that Cd increased the level of methyltransferase enzyme METTL3 and Sirt1 m6A modification in Leydig cells. Mettl3 siRNA effectively restored Cd-enhanced Sirt1 m6A level and reversed Cd-downregulated Sirt1 mRNA expression in Leydig cells. Overall, our findings suggest that Cd exposure inhibits testosterone synthesis via Sirt1 m6A modification-mediated senescence in mouse testes. These results offer an experimental basis for investigating the causes and potential treatments of hypotestosteronemia induced by environmental factors.

Does Microbiome Contribute to Longevity? Compositional and Functional Differences in Gut Microbiota in Chinese Long-Living (>90 Years) and Elderly (65-74 Years) Adults.

The study of longevity and its determinants has been revitalized with the rise of microbiome scholarship. The gut microbiota have been established to play essential protective, metabolic, and physiological roles in human health and disease. The gut dysbiosis has been identified as an important factor contributing to the development of multiple diseases. Accordingly, it is reasonable to hypothesize that the gut microbiota of long-living individuals have healthy antiaging-associated gut microbes, which, by extension, might provide specific molecular targets for antiaging treatments and interventions. In the present study, we compared the gut microbiota of Chinese individuals in two different age groups, long-living adults (aged over 90 years) and elderly adults (aged 65-74 years) who were free of major diseases. We found significantly lower relative abundances of bacteria in the genera Sutterella and Megamonas in the long-living individuals. Furthermore, we established that while biological processes such as autophagy (GO:0006914) and telomere maintenance through semiconservative replication (GO:0032201) were enhanced in the long-living group, response to lipopolysaccharide (GO:0032496), nicotinamide adenine dinucleotide oxidation (GO:0006116), and S-adenosyl methionine metabolism (GO:0046500) were weakened. Moreover, the two groups were found to differ with respect to amino acid metabolism. We suggest that these compositional and functional differences in the gut microbiota may potentially be associated with mechanisms that contribute to determining longevity or aging.

Curcumin Induces Autophagy-mediated Ferroptosis by Targeting the PI3K/AKT/mTOR Signaling Pathway in Gastric Cancer.

As a very common malignancy of the digestive system, the incidence and mortality rates of gastric cancer (GC) are increasing year by year. The critical role of ferroptosis in cancer development has been well-documented. The polyphenol compound curcumin shows prominent anti-tumor effects in multiple cancer types, including GC. However, whether curcumin participates in GC tumorigenesis by regulating ferroptosis remains unknown. Gastric cancer cells AGS and HGC-27 were treated with curcumin (0, 10, and 20 µM). Cell viability and death were evaluated through CCK-8 and LDH release assays. LC3B expression in cells was estimated through immunofluorescence staining. Intracellular ferrous iron (Fe2+), GSH, MDA, and lipid ROS levels were assessed by corresponding assay kits. The cellular levels of autophagy markers (ATG5, ATG7, Beclin 1, and LC3B), ferroptosis markers (ACSL4, SLC7A11, and GPX4), and phosphorylated (p)-PI3K, p-AKT, and p-mTOR were determined through western blotting. Curcumin attenuated cell viability but stimulated cell death in GC cells. Curcumin enhanced autophagy in GC cells, as demonstrated by the increased levels of ATG5, ATG7, Beclin 1, and LC3B. Besides, curcumin upregulated iron, MDA, GSH, and ACSL4 levels while downregulated lipid ROS, SLC7A11, and GPX4 levels, suggesting its stimulation on ferroptosis in GC cells. Curcumin decreased p-PI3K, p-AKT, and p-mTOR levels in cells. Importantly, the ferroptosis inhibitor ferrostatin-1 overturned the impacts of curcumin on GC cell viability, death, and ferroptosis. Curcumin suppresses GC development by inducing autophagy-mediated ferroptosis by inactivating the PI3K/AKT/mTOR signaling.

Erratum: [Corrigendum] ACSM3 suppresses proliferation and induces apoptosis and cell cycle arrest in acute myeloid leukemia cells via the regulation of IGF2BP2.

[This corrects the article DOI: 10.3892/etm.2023.11876.].

Solution State-Like Reactivity of a Flexible Crystalline Werner-Type Metal Complex.

Flexible crystalline solids exhibit unique properties in response to external stimuli like heat and light. However, challenges exist in developing crystalline solids that have similar degrees of flexibility as in solution. Herein, we report the preparation of the new flexible crystalline metal complex [Cd(CF3SO3)2(4-spy)4] (4-spy=4-styrylpyridine), which contains photoreactive 4-spy ligand. Unlike traditional solids, this metal complex displays solution state-like [2+2] photocycloaddition reactivity. Specifically, UV irradiation of the crystalline material leads to formation of the same diverse array of dimers and cis isomer that are generated by photoreaction in the solution state. In addition, the photoresponsive flexibility of the solid leads to a photosalient effect and photo-induced formation of pores. The origin of the solution state-like photoreactivity of the solid is related to properties of the Cd(II) cation and fluorinated CF3SO3 anion, and the multi-orientational arrangement of the 4-spy ligands.

Photoinduced π-Bond breakage causing dynamic closing-opening shell transition of Z-type Diphenylmaleonitriles molecules.

Organic molecules with dynamic covalent-bonding characteristics have attracted much attention for their important role in constructing stimulus-responsive smart materials. However, it is difficult to realize sensitive and reversible covalent bond cleavage/formation through external stimuli in the aggregated state of molecules. Herein, a series of 2,3-diphenylmaleonitriles (DPMNs) with photoinduced π-bond cleavage properties have been designed and synthesized to construct the dynamic covalent bond materials. The cis-form 2,3-diphenylmaleonitriles (Z-DPMNs) exhibit significant photochromism in both solid and solution states under ultraviolet light and visible light. The photochromism stems from the photoinduced π-bond splitting of Z-DPMNs, resulting in a transition from the closed-shell to open-shell structure. Moreover, the twisted structure and molecular stacking of Z-DPMNs, the push-pull electron effect of substituents, and the external factors including temperature and solvent polarity have important effects on the dynamic conversion of π-bonds. Based on the sensitive and reversible optical performance transformation, Z-DPMNs can be applied as safety ink in anti-counterfeiting, information encryption and storage systems. This work not only provides an approach for constructing dynamic covalent bonds but also greatly enriches stimulus-responsive materials.

Two-stage solid-state fermentation to increase the nutrient value of corn processing waste and explore its efficacy as a feed protein source.

Corn gluten meal-corn husk mixes (CCM) are an inexpensive and readily available agricultural by-product. This study explores a novel technique by converting CCM into high-value livestock feed protein sources through fermentation with Aspergillus niger AAX and Lactobacillus fermentum LLS, aiming to sustainably meet future global protein needs. The process of fermentation significantly altered the structural composition of high molecular weight proteins, zein, and dietary fibers. This transformation resulted in a marked elevation in the concentrations of peptides, free amino acids, and polyphenols. The acidic environment produced during fermentation prevented lipid oxidation in CCM, thereby extending its storability. After fermentation, the content of anti-nutritional factors decreased, while its antioxidant capacity increased. In vitro simulated digestion suggested that fermentation improved the digestibility of CCM protein. In vivo animal experiments showed that fermented CCM (FCCM) promoted growth and gut health in chicks. This study provides new insights into the utilization of CCM.

Plin4 exacerbates cadmium-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

Strong evidence indicates that environmental stressors are the risk factors for male testosterone deficiency (TD). However, the mechanisms of environmental stress-induced TD remain unclear. Based on our all-cause male reproductive cohort, we found that serum ferrous iron (Fe2⁺) levels were elevated in TD donors. Then, we explored the role and mechanism of ferroptosis in environmental stress-reduced testosterone levels through in vivo and in vitro models. Data demonstrated that ferroptosis and lipid droplet deposition were observed in environmental stress-exposed testicular Leydig cells. Pretreatment with ferrostatin-1 (Fer-1), a specific ferroptosis inhibitor, markedly mitigated environmental stress-reduced testosterone levels. Through screening of core genes involved in lipid droplets formation, it was found that environmental stress significantly increased the levels of perilipins 4 (PLIN4) protein and mRNA in testicular Leydig cells. Further experiments showed that Plin4 siRNA reversed environmental stress-induced lipid droplet deposition and ferroptosis in Leydig cells. Additionally, environmental stress increased the levels of METTL3, METTL14, and total RNA m6A in testicular Leydig cells. Mechanistically, S-adenosylhomocysteine, an inhibitor of METTL3 and METTL14 heterodimer activity, restored the abnormal levels of Plin4, Fe2⁺ and testosterone in environmental stress-treated Leydig cells. Collectively, these results suggest that Plin4 exacerbates environmental stress-decreased testosterone level via inducing ferroptosis in testicular Leydig cells.

The application of real-time indocyanine green fluorescence cholangiography in laparoscopic living donor left lateral sectionectomy.

Background: The judgment of the division point of the bile duct has always been one of the difficulties of laparoscopic left lateral sectionectomy (LLLS). The purpose of this study was to assess the effects of indocyanine green (ICG) fluorescence cholangiography during LLLS on the occurrence of biliary complications in both donors and recipients. The optimal dose and injection time of ICG were also investigated. Methods: This is a retrospective cohort study. From October 2016 to December 2022, the clinical data of 103 donors who underwent LLLS and relevant recipients were retrospectively analyzed. According to whether ICG fluorescence cholangiography was used, they were divided into a non-ICG group (n=46) and an ICG group (n=57). Biliary complications were observed and the optimal dose and injection time of ICG were explored. Results: Three donors in the non-ICG group suffered from bile leakage. Four grafts had multiple bile duct openings and biliary complications were observed in the relevant recipients who received these grafts in the non-ICG group. Two recipients had bile leakage, and the other two had biliary stenosis. There was no biliary complications both in donors and recipients in the ICG group. The fluorescence intensity of the liver was 108.1±17.6 at a dose of 0.004 mg/kg 90 minutes after injection, significantly weaker than that at 0.05 mg/kg 30 minutes (200.3±17.6, P=0.001) and 90 minutes after injection (140.2±15.4, P=0.001). The fluorescence intensity contrast value at a dose of 0.004 mg/kg was stronger than that at 0.05 mg/kg, both measured 90 minutes after injection (0.098±0.032 vs. 0.078±0.022, P=0.021). Conclusions: ICG fluorescence cholangiography is safe and feasible in LLLS. It reduces biliary complications in both donors and recipients. The optimal ICG dose was 0.004 mg/kg, and 90 minutes after injection was the best observation time. ICG fluorescence cholangiography is recommended for routine use in LLLS.

Retrospective analysis of molecular characteristics, risk factors, and outcomes in carbapenem-resistant Klebsiella pneumoniae bloodstream infections.

BACKGROUND: Klebsiella pneumoniae (KP) is the second most prevalent Gram-negative bacterium causing bloodstream infections (BSIs). In recent years, the management of BSIs caused by KP has become increasingly complex due to the emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP). Although numerous studies have explored the risk factors for the development of CRKP-BSIs, the mortality of patients with KP-BSIs, and the molecular epidemiological characteristics of CRKP, the variability in data across different populations, countries, and hospitals has led to inconsistent conclusions. In this single-center retrospective observational study, we utilized logistic regression analyses to identify independent risk factors for CRKP-BSIs and factors associated with mortality in KP-BSI patients. Furthermore, a risk factor-based prediction model was developed. CRKP isolates underwent whole-genome sequencing (WGS), followed by an evaluation of microbiological characteristics, including antimicrobial resistance and virulence genes, as well as epidemiological characteristics and phylogenetic analysis. RESULTS: Our study included a total of 134 patients with KP-BSIs, comprising 50 individuals infected with CRKP and 84 with carbapenem-susceptible Klebsiella pneumoniae (CSKP). The independent risk factors for CRKP-BSIs were identified as gastric catheterization (OR = 9.143; CI = 1.357-61.618; P = 0.023), prior ICU hospitalization (OR = 4.642; CI = 1.312-16.422; P = 0.017), and detection of CRKP in non-blood sites (OR = 8.112; CI = 2.130-30.894; P = 0.002). Multivariate analysis revealed that microbiologic eradication after 6 days (OR = 3.569; CI = 1.119-11.387; P = 0.032), high Pitt bacteremia score (OR = 1.609; CI = 1.226-2.111; P = 0.001), and inappropriate empirical treatment after BSIs (OR = 6.756; CI = 1.922-23.753; P = 0.003) were independent risk factors for the 28-day mortality in KP-BSIs. The prediction model confirmed that microbiologic eradication after 6.5 days and a Pitt bacteremia score of 4.5 or higher were significant predictors of the 28-day mortality. Bioinformatics analysis identified ST11 as the predominant CRKP sequence type, with blaKPC-2 as the most prevalent gene variant. CRKP stains carried multiple plasmid-mediated resistance genes along with some virulence genes. Phylogenetic analysis indicated the presence of nosocomial transmission of ST11 CRKP within the ICU. CONCLUSIONS: The analysis of risk factors for developing CRKP-BSIs and the association between KP-BSIs and 28-day mortality, along with the development of a risk factor-based prediction model and the characterization of CRKP strains, enhances clinicians' understanding of the pathogens responsible for BSIs. This understanding may help in the timely administration of antibiotic therapy for patients with suspected KP-BSIs, potentially improving outcomes.

IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.

Calcium ions (Ca2+) regulate cell proliferation and differentiation and participate in various physiological activities of cells. The calcium transfer protein inositol 1,4,5-triphosphate receptor (IP3R), located between the endoplasmic reticulum (ER) and mitochondria, plays an important role in regulating Ca2+ levels. However, the mechanism by which IP3R1 affects porcine meiotic progression and embryonic development remains unclear. We established a model in porcine oocytes using siRNA-mediated knockdown of IP3R1 to investigate the effects of IP3R1 on porcine oocyte meiotic progression and embryonic development. The results indicated that a decrease in IP3R1 expression significantly enhanced the interaction between the ER and mitochondria. Additionally, the interaction between the ER and the mitochondrial Ca2+ ([Ca2+]m) transport network protein IP3R1-GRP75-VDAC1 was disrupted. The results of the Duolink II in situ proximity ligation assay (PLA) revealed a weakened pairwise interaction between IP3R1-GRP75 and VDAC1 and a significantly increased interaction between GRP75 and VDAC1 after IP3R1 interference, resulting in the accumulation of large amounts of [Ca2+]m. These changes led to mitochondrial oxidative stress, increased the levels of reactive oxygen species (ROS) and reduced ATP production, which hindered the maturation and late development of porcine oocytes and induced apoptosis. Nevertheless, after treat with [Ca2+]m chelating agent ruthenium red (RR) or ROS scavenger N-acetylcysteine (NAC), the oocytes developmental abnormalities, oxidative stress and apoptosis caused by Ca2+ overload were improved. In conclusion, our results indicated IP3R1 is required for meiotic progression and embryonic development by regulating mitochondrial calcium and oxidative damage.

Hydrogen inhibition of wet AlLi alloy dust collector systems using a composite green biopolymer inhibitor based on chitosan/sodium alginate: Experimental and theoretical studies.

Aluminum­lithium (AlLi) alloy polishing and grinding processes in wet dust collector systems could cause hydrogen fire and explosion. From the fundamental perspective of preventing hydrogen explosions, a safe, nontoxic, and sustainable modified green hydrogen inhibitor based on chitosan (CS) and sodium alginate (SA) was developed in this study and was used as a hydrogen evolution inhibitor for the processing of waste dust from AlLi alloys. The structure and elemental distribution of the synthesized material were characterized through characterization experiments. Hydrogen evolution experiments and a hydrolysis kinetic model were used to explore the inhibitory effect of modified CS/SA on AlLi alloy dust, and the results revealed that the inhibitory concentration of the hydrogen explosion lower limit was 0.40 wt%, with an inhibition efficiency of 91.93 %, indicating an 11.88-61.44 % improvement over that of CS and SA. As the inhibitor concentration increased and the temperature decreased, the hydrogen inhibition effect increased. Characterization experiments and density functional theory showed that CS/SA primarily formed a dense physical protective barrier on the dust surface through chemical adsorption and complexation reactions, interrupting the hydrogen evolution reaction between the metal and water. This study introduces a novel green modified hydrogen inhibitor that fundamentally addresses hydrogen generation and explosion.

Entropically driven melting of Cu-based 1D coordination polymers.

We investigated the melting behavior of four CPs with one-dimensional structures from a thermodynamic point-of-view. The difference in melting points depending on the crystal structures is observed. The interactions within the crystals were analyzed using DFT calculations. These analyses suggest that entropic terms dominate the melting points.

AWGC2023 cachexia consensus as a valuable tool for predicting prognosis and burden in Chinese patients with cancer.

BACKGROUND: The Asian Working Group for Cachexia (AWGC) proposed the first consensus report on diagnostic criteria for cachexia in Asians in 2023. However, the current consensus lacks cohort evidence to validate its effectiveness and practicality. We aimed to explore the value of the AWGC2023 criteria for predicting the prognosis and medical burden of patients with cancer through a retrospective post hoc cross-sectional analysis of the Investigation on Nutrition Status and its Clinical Outcome of Common Cancers (INSCOC) project in China. METHODS: Cox regression analyses were performed to assess the independent association between cachexia and long-term survival. We utilized C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), inflammatory burden index (IBI), albumin (ALB) and Glasgow prognostic score (GPS) as diagnostic markers for cachexia, designating them as CRP-based cachexia, NLR-based cachexia, IBI-based cachexia, ALB-based cachexia and GPS-based cachexia, respectively. Additionally, we diagnosed cachexia using body mass index (BMI) cutoff values of 18.5, 20, 21 and 22 kg/m2, respectively, and subsequently compared their prognostic predictive value through Harrell's concordance index (C-index). Logistic regression models were used to assess the association between cachexia and medical burden. RESULTS: A total of 5426 patients with cancer were enrolled in this study. Cox regression analysis confirmed that cachexia based on the AWGC2023 criteria was an independent predictor of long-term survival in patients with cancer. Patients with cachexia had significantly poorer long-term survival than patients without cachexia (66.4% vs. 49.7%, P < 0.001). Inflammatory biomarker-based cachexia was as an independent predictor of prognosis in patients with cancer, with inflammatory burden index (IBI)-based cachexia demonstrating the optimal prognostic discriminatory ability. The C-index indicated that cachexia based on BMI cutoff values of 18.5, 20, and 22 kg/m2 did not perform as well as a BMI cutoff value of 21 kg/m2. Logistic regression models revealed that using the AWGC2023 criteria, patients with cachexia had a 16.6% higher risk of prolonged hospitalization and a 16.0% higher risk of high medical expenses than patients without cachexia. CONCLUSION: The AWGC2023 criteria represent a valuable tool for predicting survival and medical burden among Chinese patients with cancer. Encouragement for further validation in other Asian populations is warranted for the AWGC2023 criteria.

Hybrid Integration of Wearable Devices for Physiological Monitoring.

Wearable devices can provide timely, user-friendly, non- or minimally invasive, and continuous monitoring of human health. Recently, multidisciplinary scientific communities have made significant progress regarding fully integrated wearable devices such as sweat wearable sensors, saliva sensors, and wound sensors. However, the translation of these wearables into markets has been slow due to several reasons associated with the poor system-level performance of integrated wearables. The wearability consideration for wearable devices compromises many properties of the wearables. Besides, the limited power capacity of wearables hinders continuous monitoring for extended duration. Furthermore, peak-power operations for intensive computations can quickly create thermal issues in the compact form factor that interfere with wearability and sensor operations. Moreover, wearable devices are constantly subjected to environmental, mechanical, chemical, and electrical interferences and variables that can invalidate the collected data. This generates the need for sophisticated data analytics to contextually identify, include, and exclude data points per multisensor fusion to enable accurate data interpretation. This review synthesizes the challenges surrounding the wearable device integration from three aspects in terms of hardware, energy, and data, focuses on a discussion about hybrid integration of wearable devices, and seeks to provide comprehensive guidance for designing fully functional and stable wearable devices.

Gefitinib (an EGFR tyrosine kinase inhibitor) plus anlotinib (an multikinase inhibitor) for untreated, EGFR-mutated, advanced non-small cell lung cancer (FL-ALTER): a multicenter phase III trial.

Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1-14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48-0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Targeting Gsk3a reverses immune evasion to enhance immunotherapy in hepatocellular carcinoma.

BACKGROUND: Immune escape is an important feature of hepatocellular carcinoma (HCC). The overall response rate of immune checkpoint inhibitors (ICIs) in HCC is still limited. Revealing the immune regulation mechanisms and finding new immune targets are expected to further improve the efficacy of immunotherapy. Our study aims to use CRISPR screening mice models to identify potential targets that play a critical role in HCC immune evasion and further explore their value in improving immunotherapy. METHODS: We performed CRISPR screening in two mice models with different immune backgrounds (C57BL/6 and NPG mice) and identified the immunosuppressive gene Gsk3a as a candidate for further investigation. Flow cytometry was used to analyze the impact of Gsk3a on immune cell infiltration and T-cell function. RNA sequencing was used to identify the changes in neutrophil gene expression induced by Gsk3a and alterations in downstream molecules. The therapeutic value of the combination of Gsk3a inhibitors and anti-programmed cell death protein-1 (PD-1) antibody was also explored. RESULTS: Gsk3a, as an immune inhibitory target, significantly promoted tumor growth in immunocompetent mice rather than immune-deficient mice. Gsk3a inhibited cytotoxic T lymphocytes (CTLs) function by inducing neutrophil chemotaxis. Gsk3a promoted self-chemotaxis of neutrophil expression profiles and neutrophil extracellular traps (NETs) formation to block T-cell activity through leucine-rich α-2-glycoprotein 1 (LRG1). A significant synergistic effect was observed when Gsk3a inhibitor was in combination with anti-PD-1 antibody. CONCLUSIONS: We identified a potential HCC immune evasion target, Gsk3a, through CRISPR screening. Gsk3a induces neutrophil recruitment and NETs formation through the intermediate molecule LRG1, leading to the inhibition of CTLs function. Targeting Gsk3a can enhance CTLs function and improve the efficacy of ICIs.

Cr(VI) induced hepatocyte apoptosis through the CTH/H2S/Drp1 signaling pathway.

Hexavalent chromium [Cr(VI)] is a highly hazardous heavy metal with multiple toxic effects. Occupational studies indicate that its accumulation in humans can lead to liver damage. However, the exact mechanism underlying Cr(VI)-induced hepatotoxicity remains unknown. In this study, we explored the role of CTH/H2S/Drp1 pathway in Cr(VI)-induced oxidative stress, mitochondrial dysfunction, apoptosis, and liver injury. Our data showed that Cr(VI) triggered apoptosis, accompanied by H2S reduction, reactive oxygen species (ROS) accumulation, and mitochondrial dysfunction in both AML12 cells and mouse livers. Moreover, Cr(VI) reduced cystathionine γ-lyase (CTH) and dynamin related protein 1 (Drp1) S-sulfhydration levels, and elevated Drp1 phosphorylation levels at Serine 616, which promoted Drp1 mitochondrial translocation and Drp1-voltage-dependent anion channel 1 (VDAC1) interactions, ultimately leading to mitochondria-dependent apoptosis. Elevated hydrogen sulfide (H2S) levels eliminated Drp1 phosphorylation at Serine 616 by increasing Drp1 S-sulfhydration, thereby preventing Cr(VI)-induced Drp1-VDAC1 interaction and hepatotoxicity. These findings indicated that Cr(VI) induced mitochondrial apoptosis and hepatotoxicity by inhibiting CTH/H2S/Drp1 pathway and that targeting either CTH/H2S pathway or Drp1 S-sulfhydration could serve as a potential therapy for Cr(VI)-induced liver injury.