Promising first-line immuno-combination therapies for unresectable hepatocellular carcinoma: A cost-effectiveness analysis.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death all over the world, and brings a heavy social economic burden especially in China. Several immuno-combination therapies have shown promising efficacy in the first-line treatment of unresectable HCC and are widely used in clinical practice. Nevertheless, which combination is the most affordable one is unknown. Our study assessed the cost-effectiveness of the immuno-combinations as first-line treatment for patients with unresectable HCC from the perspective of Chinese payers. METHODS: A Markov model was built according to five multicenter, phase III, open-label, randomized trials (Himalaya, IMbrave150, ORIENT-32, CARES-310, LEAP-002) to investigate the cost-effectiveness of tremelimumab plus durvalumab (STRIDE), atezolizumab plus bevacizumab (A + B), sintilimab plus bevacizumab biosimilar (IBI305) (S + B), camrelizumab plus rivoceranib (C + R), and pembrolizumab plus lenvatinib (P + L). Three disease states were included: progression free survival (PFS), progressive disease (PD) as well as death. Medical costs were searched from West China Hospital, published literatures or the Red Book. Cost-effectiveness ratios (CERs) and incremental cost-effectiveness ratios (ICERs) were evaluated to compare costs among different combinations. Sensitivity analyses were performed to assess the robust of the model. RESULTS: The total cost and quality-adjusted life years (QALYs) of C + R, S + B, P + L, A + B and STRIDE were $12,109.27 and 0.91, $26,961.60 and 1.12, $55,382.53 and 0.83, $70,985.06 and 0.90, $84,589.01 and 0.73, respectively, resulting in the most cost-effective strategy of C + R with CER of $13,306.89 per QALY followed by S + B with CER of $24,072.86 per QALY. Compared with C + R, the ICER of S + B strategy was $70,725.38 per QALY, which would become the most cost-effective when the willing-to-pay threshold exceeded $73,500/QALY. In the subgroup analysis, with the application of Asia results in Leap-002 trial, the model results were the same as global data. In the sensitivity analysis, with the variation of parameters, the results were robust. CONCLUSION: As one of the promising immuno-combination therapies in the first-line systemic treatment of HCC, camrelizumab plus rivoceranib demonstrated the potential to be the most cost-effective strategy, which warranted further studies to best inform the real-world clinical practices.

Current concepts of the crosstalk between lncRNA and E2F1: shedding light on the cancer therapy.

Long noncoding RNAs (lncRNAs) constitute a distinctive subset of RNA molecules with limited protein-coding potential, which exert crucial impacts on various biological activities. In the context of cancer, dysregulated lncRNAs function as essential regulators that affect tumor initiation and malignant progression. These lncRNAs serve as competitive endogenous RNAs (ceRNAs) through sponging microRNAs and regulating the expression of targeted genes. Moreover, they also directly bind to RNA-binding proteins, which can be integrated into a complex mechanistic network. E2F1, an extensively studied transcription factor, mediates multiple malignant behaviors by regulating cell cycle progression, tumor metastasis, and therapeutic response. Emerging evidence suggests that lncRNAs play a pivotal role in regulating the E2F1 pathway. This review aims to elucidate the intricate gene regulatory programs between lncRNAs and E2F1 in cancer progression. We elaborate on distinct mechanistic networks involved in cancer progression, emphasizing the potential of the lncRNAs/E2F1 axes as promising targets for cancer therapy. Additionally, we provide novel perspectives on current evidence, limitations, and future directions for targeting lncRNAs in human cancers. Fully deciphering the intricate network of lncRNA/E2F1-mediated regulatory mechanisms in cancer could facilitate the translation of current findings into clinical course, such efforts ultimately significantly improve the clinical prognosis of cancer patients.

Highly oxidized intraplate basalts and deep carbon storage.

Deep carbon cycle is crucial for mantle dynamics and maintaining Earth's habitability. Recycled carbonates are a strong oxidant in mantle carbon-iron redox reactions, leading to the formation of highly oxidized mantle domains and deep carbon storage. Here we report high Fe3+/∑Fe values in Cenozoic intraplate basalts from eastern China, which are correlated with geochemical and isotopic compositions that point to a common role of carbonated melt with recycled carbonate signatures. We propose that the source of these highly oxidized basalts has been oxidized by carbonated melts derived from the stagnant subducted slab in the mantle transition zone. Diamonds formed during the carbon-iron redox reaction were separated from the melt due to density differences. This would leave a large amount of carbon (about four times of preindustrial atmospheric carbon budget) stored in the deep mantle and isolated from global carbon cycle. As such, the amounts of subducted slabs stagnated at mantle transition zone can be an important factor regulating the climate.

[Comparison of Carbon Emissions from Traditional Treatment and Source Separation Treatment of Rural Domestic Sewage].

Based on the carbon emission accounting method for domestic sewage, combined with the current situation of rural domestic sewage treatment, the carbon emissions of traditional schemes and source separation schemes under the three scenarios of single household, multi-household, and pipeline treatments were calculated. The results showed that the net carbon emissions （calculated as CO2） of the single household, multi-household, and pipeline treatment traditional schemes were 1.21, 3.37, and 2.69 kg·m-3, respectively. The net carbon emissions （calculated as CO2） of the single household, multi-household, and pipeline treatments in source separation schemes were -0.50, -0.04, and -0.54 kg·m-3, respectively, achieving zero or even negative carbon emissions. The direct and indirect carbon emissions of the source separation scheme were lower than those of the traditional scheme under all three scenarios. The carbon compensation measures in the source separation scheme mainly came from the land use of urine after storage and treatment. By separating blackwater from graywater at the source, the Source Separation Program achieved resource utilization of highly concentrated pollutants in blackwater, reducing emissions while generating significant carbon offsets. Therefore, efforts should be made to promote the separation and treatment of rural domestic sewage sources, improve the utilization rate of rural domestic sewage resources, and achieve green and low-carbon development of rural domestic sewage treatment.

RREB1-mediated SUMOylation enhancement promotes chemoresistance partially by transcriptionally upregulating UBC9 in colorectal cancer.

Chemoresistance is a main cause of chemotherapy failure and tumor recurrence. The effects of global protein SUMOylation on chemoresistance in colorectal cancer (CRC) remains to be investigated. Herein, we have proposed that the elevated SUMO2/3-modified proteins confer 5-fluorouracil (5-FU) chemoresistance acquisition in CRC. The SUMOylation levels of global proteins in CRC cell lines were elevated compared with normal colon cell line NCM460. 5-FU treatment obviously reduced SUMOylation of global proteins in 5-FU-sensitive CRC cells including HT29, HCT116 and HCT-8. However, in 5-FU-resistant HCT-8/5-FU cells, the expression level of SUMO2/3-modified proteins was increased under 5-FU exposure in a concentration-dependent manner. 5-FU treatment combined with SUMOylation inhibitor ML-792 significantly increased the sensitivity of 5-FU-resistant cells to 5-FU and reduced colony formation numbers in HCT-8/5-FU cells. And UBC9-mediated SUMOylation elevation contributes to 5-FU resistance in HCT116 cells. Moreover, we also identified RREB1 as a regulator of SUMOylation profiling of global cellular proteins via directly binding to the promoter of UBC9. Overexpression of RREB1 promoted 5-FU resistance in CRC, which was partially abolished by treatment of inhibitor ML-792. In conclusion, RREB1-enhanced protein SUMOylation contributes to 5-FU resistance acquisition in CRC.

Caregiving risk perception characteristics and associated factors among informal caregivers of functionally dependent elderly individuals at home: a qualitative study.

BACKGROUND: This study explored risk perception characteristics and influencing factors among informal caregivers of functionally dependent elderly individuals at home, aiming to improve caregivers' caregiving risk perception and coping abilities and ultimately enhance the quality of life for these individuals. METHODS: We used purposive sampling to select 22 informal caregivers from a community in Zhengzhou City, Henan Province, China, between March and September 2023 and conducted face-to-face semi-structured in-depth interviews. The data were analyzed using Colaizzi's seven-step analysis method. RESULTS: We extracted two themes, caregiving risk perception characteristics and caregiving risk perception associated factors, and eight sub-themes, perceived risk possibility, perceived risk anticipation, perceived severity of consequences, past caregiving experiences, health literacy, psychological status, caregiving burden, and family social support. CONCLUSION: There were differences in how informal caregivers perceived the risks associated with caring for functionally dependent elderly individuals at home, which various factors could influence. It was essential to provide training that covered the knowledge and skills needed for caregiving, improve caregivers' awareness of safety risks, and establish a correct perception of caregiving risks. The government must construct and refine a comprehensive framework for caregiver respite services. Simultaneously, healthcare professionals should proactively undertake health education endeavors to augment the recognition of care safety risks among informal caregivers, thereby cultivating an accurate awareness of care risk perception.

The superior mesenteric artery angle in diagnosis of nutcracker syndrome: a systematic review and meta-analysis.

PURPOSE: Nutcracker syndrome (NCS) can be caused by narrowness of the superior mesenteric artery (SMA) angle. Nevertheless, the cut-off value of the SMA angle is controversial and variable. Therefore, the present study evaluated the optimal SMA angle to maximize diagnostic performance for NCS diagnosis by conducting a meta-analysis. METHODS: We comprehensively searched the English literature related to the diagnosis of NCS from the perspective of SMA (from the date of database inception to June 2022). The accuracy of an SMA angle less than 41° in the diagnosis of NCS was evaluated by calculating the pooled sensitivity (SEN), pooled specificity (SPE), positive likelihood ratio (LR+), negative likelihood ratio (LR-), summary receiver operating characteristic (SROC) curve and area under the curve (AUC) value. The I2 test and meta-regression analysis were used to assess heterogeneity and sources of heterogeneity, respectively. Publication bias was assessed using Deeks' funnel plot asymmetry test. RESULTS: Six studies (526 patients) met the inclusion criteria. SEN and SPE were 0.94 (95% confidence interval (CI) 0.80-0.99) and 0.85 (95% CI 0.65-0.94), respectively. The LR + value was 6.0, and the LR- value was 0.07, revealing that SMA angles less than 41° exhibited an excellent ability to help confirm or exclude NCS. Additionally, SROC curves showed that the AUC of SMA angles less than 41° for the diagnosis of NCS was 0.96, indicating that SMA angles less than 41° have good efficacy for helping to diagnose NCS. CONCLUSION: This study explored the diagnostic efficacy of the cut-off value of the SMA angle by meta-analysis. According to the high SPE and SEN results, SMA angles less than 41° have good efficacy in facilitating NCS diagnosis.

Extremely Large Anomalous Hall Conductivity and Unusual Axial Diamagnetism in a Quasi-1D Dirac Material La3MgBi5.

Anomalous Hall effect (AHE), one of the most important electronic transport phenomena, generally appears in ferromagnetic materials but is rare in materials without magnetic elements. Here, a study of La3MgBi5 is presented, whose band structure carries multitype Dirac fermions. Although magnetic elements are absent in La3MgBi5, the signals of AHE can be observed. In particular, the anomalous Hall conductivity is extremely large, reaching 42,356 Ω-1 cm-1 with an anomalous Hall angle of 8.8%, the largest one that has been observed in the current AHE systems. The AHE is suggested to originate from the combination of skew scattering and Berry curvature. Another unique property discovered in La3MgBi5 is the axial diamagnetism. The diamagnetism is significantly enhanced and dominates the magnetization in the axial directions, which is the result of the restricted motion of the Dirac fermion at the Fermi level. These findings not only establish La3MgBi5 as a suitable platform to study AHE and quantum transport but also indicate the great potential of 315-type Bi-based materials for exploring novel physical properties.

Fuzheng Huayu recipe inhibits bleomycin-induced pulmonary fibrosis in rats by inhibiting M2 polarization of macrophages via the oxidative phosphorylation pathway.

Fuzheng Huayu recipe (FZHYR) is a Chinese patent medicine for the treatment of fibrosis. The effects of FZHYR on pulmonary fibrosis and macrophage polarization were investigated in vitro. FZHYR inhibited pulmonary inflammation and fibrosis and M2 polarization of macrophages in bleomycin-induced pulmonary fibrosis (BPF) of rat model. Differentially expressed genes were screened by high-throughput mRNA sequencing and GSEA showed that oxidative phosphorylation (OXPHOS) was correlated with BPF. FZHYR inhibited expressions of Ndufa2 and Ndufa6 in lung tissues of BPF rats. These findings suggest that OXPHOS pathway serves as a possible target for pulmonary fibrosis therapy by FZHYR.

Neoantigens in cancer immunotherapy: focusing on alternative splicing.

Alternative splicing (AS) functions as a crucial program in transcriptional modulation, leading to proteomic diversity and functional alterations of proteins. These splicing actions induce various neoantigens that hold prognostic significance and contribute to various aspects of cancer progression, including immune responses against cancer. The advent of immunotherapy has remarkably revolutionized tumor therapy. In this regard, AS-derived neoantigens are potent targets for cancer vaccines and chimeric antigen receptor (CAR) T cell therapies. In this review, we outline that AS-derived neoantigens serve as promising immunotherapeutic targets and guide immunotherapy strategies. This evidence contributes to a deeper comprehension of the complexity of proteomic diversity and provides novel perspectives and techniques for precision medicine in immunotherapy. Moreover, we underscore the obstacles that are awaited to be addressed for this novel approach to become clinically applicable.

[Plankton Community Stability and Drive Factor Identification Guizhou Plateau Reservoir].

In order to understand the stability of the zooplankton and phytoplankton communities in the Guizhou plateau reservoir environment, the process of reservoir water quality change affecting the stability of plankton was studied. The changes in the plankton community and water quality in three different nutrient reservoirs （Huaxi Reservoir, Goupitan Reservoir, and Hailong Reservoir） were studied from October 2020 to August 2021. The stability of the zooplankton and phytoplankton communities was studied using time-lag analysis （TLA）. Variance decomposition analysis （VPA） was used to explore the response of the two communities to environmental changes. The driving factors of plankton community changes in reservoirs were also revealed. The results showed that Huaxi Reservoir and Goupitan Reservoir were mesotrophic reservoirs, and Hailong Reservoir was a eutrophic reservoir. The average comprehensive nutrition indices of the three reservoirs were 44.07, 44.68, and 50.25. A total of 51 species of zooplankton rotifers, 39 species of rotifers, three species of copepods, and nine species of cladocera were identified. Among them, the abundance of rotifers was the highest, accounting for 85.96%. A total of seven phyla and 73 species of phytoplankton were identified, including 16 species in the phylum Cyanophyta, 32 species in the phylum Chlorophyta, 16 species in the phylum Diatoma, three species in the phylum Chlorophyta, four species in the phylum Euglenophyta, and one species each in the phyla Cryptophyta and Chrysophyta. Among them, the abundance of cyanobacteria and diatoms was the highest, accounting for 66.2% and 27.35%, respectively. The median absolute deviation （MAD） of the Bray-Curtis distance of zooplankton and phytoplankton community in the three reservoirs were 0.67 and 0.65 in Huaxi Reservoir, 0.80 and 0.69 in Goupitan Reservoir, and 0.85 and 0.47 in Hailong Reservoir, respectively. The larger the value, the greater the variation in the community. The absolute value of the slope of zooplankton was greater than that of phytoplankton in the TLA results, and the absolute values of the slopes were 0.018 and 0.004, respectively. The larger the absolute value of the slope, the faster the community variability. The zooplankton community in the three reservoirs was less stable than the phytoplankton community and more sensitive to environmental changes, and the degree of variation was greater. The higher the degree of eutrophication of the reservoir, the more obvious this phenomenon. VPA showed that the changes in plankton communities in Huaxi Reservoir and Hailong Reservoir were mainly influenced by water temperature and eutrophication factors. The changes in planktonic community in Goupitan Reservoir were mainly influenced by water temperature and chemical factors. The driving factors of Huaxi Reservoir were water temperature, TP, permanganate index, and SD. The driving factors of Goupitan Reservoir were water temperature, NO3-- N, and pH. The driving factors of Hailong Reservoir were water temperature and TP. Nutrients and water temperature were the main factors affecting the stability of plankton communities in reservoirs.

IGF-1 inhibits inflammation and accelerates angiogenesis via Ras/PI3K/IKK/NF-κB signaling pathways to promote wound healing.

Exogenous insulin-like growth factor-1 (IGF-1) has been reported to promote wound healing through regulation of vascular endothelial cells (VECs). Despite the existing studies of IGF-1 on VEC and its role in angiogenesis, the mechanisms regarding anti-inflammatory and angiogenetic effects of IGF-1 remain unclear. In this study, we investigated the wound-healing process and the related signaling pathway of IGF-1 using an inflammation model induced by IFN-γ. The results demonstrated that IGF-1 can increase cell proliferation, suppress inflammation in VECs, and promote angiogenesis. In vivo studies further confirmed that IGF-1 can reduce inflammation, enhance vascular regeneration, and improve re-epithelialization and collagen deposition in acute wounds. Importantly, the Ras/PI3K/IKK/NF-κB signaling pathways was identified as the mechanisms through which IGF-1 exerts its anti-inflammatory and pro-angiogenic effects. These findings contribute to the understanding of IGF-1's role in wound healing and may have implications for the development of new wound treatment approaches.

HMGA1 promotes the progression of esophageal squamous cell carcinoma by elevating TKT-mediated upregulation of pentose phosphate pathway.

Esophageal squamous cell carcinoma (ESCC) possesses a poor prognosis and treatment outcome. Dysregulated metabolism contributes to unrestricted growth of multiple cancers. However, abnormal metabolism, such as highly activated pentose phosphate pathway (PPP) in the progression of ESCC remains largely unknown. Herein, we report that high-mobility group AT-hook 1 (HMGA1), a structural transcriptional factor involved in chromatin remodeling, promoted the development of ESCC by upregulating the PPP. We found that HMGA1 was highly expressed in ESCC. Elevated HMGA1 promoted the malignant phenotype of ESCC cells. Conditional knockout of HMGA1 markedly reduced 4-nitroquinoline-1-oxide (4NQO)-induced esophageal tumorigenesis in mice. Through the metabolomic analysis and the validation assay, we found that HMGA1 upregulated the non-oxidative PPP. With the transcriptome sequencing, we identified that HMGA1 upregulated the expression of transketolase (TKT), which catalyzes the reversible reaction in non-oxidative PPP to exchange metabolites with glycolytic pathway. HMGA1 knockdown suppressed the PPP by downregulating TKT, resulting in the reduction of nucleotides in ESCC cells. Overexpression of HMGA1 upregulated PPP and promoted the survival of ESCC cells by activating TKT. We further characterized that HMGA1 promoted the transcription of TKT by interacting with and enhancing the binding of transcription factor SP1 to the promoter of TKT. Therapeutics targeting TKT with an inhibitor, oxythiamine, reduced HMGA1-induced ESCC cell proliferation and tumor growth. Together, in this study, we identified a new role of HMGA1 in ESCCs by upregulating TKT-mediated activation of PPP. Our results provided a new insight into the role of HMGA1/TKT/PPP in ESCC tumorigenesis and targeted therapy.

Matrix Protein of Vesicular Stomatitis Virus Targets the Mitochondria, Reprograms Glucose Metabolism, and Sensitizes to 2-Deoxyglucose in Glioblastoma.

A potential therapeutic approach for cancer treatment is target oxidative phosphorylation and glycolysis simultaneously. The matrix protein of vesicular stomatitis virus (VSV MP) can target the surface of mitochondria, causing morphological changes that may be associated with mitochondrial dysfunction and oxidative phosphorylation inhibition. Previous research has shown that mitochondrial abnormalities can direct glucose metabolism toward glycolysis. Thus, after treatment with VSV MP, glycolysis inhibition is necessary to completely block glucose metabolism and eradicate cancer. Here, to inhibit glycolysis, the 2-deoxy-D-glucose (2-DG), a synthetic glucose analog was used to combine with VSV MP to treat cancer. This study aims to determine how VSV MP affects the glucose bioenergetic metabolism of cancer cells and to evaluate the synergistic effect of 2-DG when combined with VSV. Our results indicated that in U87 and C6 glioblastoma cell lines, VSV MP caused mitochondrial membrane potential loss, cytochrome c release, and glucose bioenergetics metabolism reprogramming. When combined with 2-DG, VSV MP synergistically aggravated cell viability, apoptosis, and G2/M phase arrest. Meanwhile, the combination therapy exacerbated ATP depletion, activated AMPK, and inhibited mammalian target of rapamycin signaling pathways. In addition, 2-DG treatment alone induced autophagy in glioblastoma cells; however, VSV MP inhibited the autophagy induced by 2-DG in combined treatment and finally contributed to the enhanced cytotoxic effect of the combination strategy in U87 and C6 cancer cells. In the orthotopic U87 glioblastoma model and subcutaneous C6 glioblastoma model, the combined treatment led to significant tumor regression and prolonged survival. A potent therapeutic approach for treating glioblastoma may be found in the combination of VSV MP and glycolytic inhibitors.

The causal effect of atopic dermatitis on lung cancer: A Mendelian randomization study.

BACKGROUND: Growing evidence has shown that atopic dermatitis (AD) may decrease lung cancer (LC) risk. However, the causality between the two diseases is inconsistent and controversial. Therefore, we explored the causal relationship between AD and different histological subtypes of LC by using the Mendelian randomization (MR) method. MATERIALS AND METHODS: We conducted the MR study based on summary statistics from the genome-wide association studies (GWAS) of AD (10,788 cases and 30,047 controls) and LC (29,266 cases and 56,450 controls). Instrumental variables (IVs) were obtained after removing SNPs associated with potential confounders. We employed inverse-variance weighted (IVW), MR-Egger, and weighted median methods to pool estimates, and performed a comprehensive sensitivity analysis. RESULTS: The results of the IVW method suggested that AD may decrease the risk of developing lung adenocarcinoma (LUAD) (OR = 0.91, 95% CI: 0.85-0.97, P = 0.007). Moreover, no causality was identified between AD and overall LC (OR = 0.96, 95% CI: 0.91-1.01, P = 0.101), lung squamous cell carcinoma (LUSC) (OR = 1.04, 95% CI: 0.96-1.036, P = 0.324), and small cell lung carcinoma (SCLC) (OR = 0.95, 95% CI: 0.82-1.10, P = 0.512). A comprehensive sensitivity test showed the robustness of our results. CONCLUSION: The present study indicates that AD may decrease the risk of LUAD in the European population, which needs additional investigations to identify the potential molecular mechanisms.

The effect of BMI on survival outcome of breast cancer patients: a systematic review and meta-analysis.

OBJECTIVE: The main goal of the present research is to explore the potential link of body mass index (BMI) with different survival metrics in breast cancer patients. Our aim is to offer the latest and most thorough meta-analysis, assessing the strength and reliability of the connection that BMI has with prognostic indicators in this disease. PATIENTS AND METHODS: As of January 2024, we conducted a systematic literature search across PubMed, Embase, Web of Science, and the Cochrane Library databases. Our search aimed to identify studies examining BMI as an exposure factor, with breast cancer patients constituting the study population, and utilizing adjusted hazard ratio (HR) as the data type of interest. RESULTS: The evidence synthesis incorporated a total of 61 eligible articles involving 201,006 patients. Being underweight posed a risk factor for overall survival (OS) in breast cancer patients compared to normal weight (HR 1.15, 95% CI 0.98-1.35; P = 0.08). Overweight or obesity, in comparison to normal weight, was a risk factor for OS (HR 1.18, 95% CI 1.14-1.23; P < 0.00001), disease-free survival (DFS) (HR 1.11, 95% CI 1.08-1.13; P < 0.00001), relapse-free survival (RFS) (HR 1.14, 95% CI 1.06-1.22; P = 0.03), and breast cancer-specific survival (BCSS) (HR 1.18, 95% CI 1.11-1.26; P < 0.00001), but not for progression-free survival (PFS) (HR 0.91, 95% CI 0.76-1.10; P = 0.33). Notably, in subgroup analyses, overweight patients achieved prolonged PFS (HR 0.80, 95% CI 0.64-0.99; P = 0.04), and compared to the obese population, the overweight cohort exhibited a significant difference in OS (HR 1.11, 95% CI 1.05-1.16; P < 0.00001) and DFS (HR 1.06, 95% CI 1.03-1.10; P = 0.0004), with a considerably stronger association. Furthermore, compared to HER- patients, HER + patients exhibited a greater predictive value for OS (HR 1.23, 95% CI 1.10-1.37; P = 0.0004), RFS (HR 1.30, 95% CI 1.03-1.64; P < 0.00001), and DFS (HR 1.10, 95% CI 1.03-1.17; P = 0.003). CONCLUSIONS: The results of our meta-analysis reveal a notable association between BMI and various survival measures in breast cancer prognosis. These findings provide a solid basis for predicting breast cancer outcomes and implementing more effective therapeutic approaches.

Maternal smoking cessation in the first trimester still poses an increased risk of attention-deficit/hyperactivity disorder and learning disability in offspring.

Background: Studies have found maternal smoking during pregnancy was linked to attention-deficit/hyperactivity disorder (ADHD) risk. It is unclear if maternal smoking cessation during pregnancy lowers ADHD and learning disability (LD) risk in offspring. This study aimed to explore the associations between maternal smoking cessation during pregnancy and ADHD and LD risk in offspring. Methods: Data from the National Health and Nutrition Examination Survey 1999-2004 (8,068 participants) were used. Logistic regression was used to analyze the associations between maternal smoking and smoking cessation during pregnancy and ADHD and LD risk in offspring. Results: Compared to non-smokers' offspring, maternal smoking during pregnancy increased the risk of ADHD (odds ratios [OR] = 2.07, 95% confidence interval [CI]: 1.67-2.56) and LD (OR = 1.93, 95% CI: 1.61-2.31) in offspring, even if mothers quit smoking later (ORADHD = 1.91, 95%CIADHD: 1.38-2.65, ORLD = 1.65, 95%CILD: 1.24-2.19). Further analysis of the timing of initiation of smoking cessation during pregnancy revealed that, compared to non-smokers' offspring, maternal quitting smoking in the first trimester still posed an increased risk of ADHD (OR = 1.72, 95% CI: 1.41-2.61) and LD (OR = 1.52, 95% CI: 1.06-2.17) in offspring. Maternal quitting smoking in the second or third trimester also had a significantly increased risk of ADHD (OR = 2.13, 95% CI: 1.26-3.61) and LD (OR = 1.82, 95% CI: 1.16-2.87) in offspring. Furthermore, maternal smoking but never quitting during pregnancy had the highest risk of ADHD (OR = 2.17, 95% CI: 1.69-2.79) and LD (OR = 2.10, 95% CI: 1.70-2.58) in offspring. Interestingly, a trend toward a gradual increase in the risk-adjusted OR for ADHD and LD risk was observed among the three groups: maternal quitting smoking in the first trimester, maternal quitting smoking in the second or third trimester, and maternal smoking but never quitting. Conclusion: Maternal smoking cessation in the first trimester still poses an increased risk of ADHD and LD in offspring. Furthermore, it seems that the later the mothers quit smoking during pregnancy, the higher the risk of ADHD and LD in their offspring. Therefore, early intervention of maternal smoking in preconception and prenatal care is vital for offspring neurodevelopment.

Treponema pallidum protein Tp0136 promotes angiogenesis to facilitate the dissemination of Treponema pallidum.

The incompletely eliminated Treponema pallidum (T. pallidum) during primary syphilis chancre infection can result in the progression of secondary, tertiary, or latent syphilis in individuals, suggesting that T. pallidum has successfully evaded the immune response and spread to distant sites. The mechanism underlying the dissemination of T. pallidum is unclear. Here, a syphilitic rabbit model dorsal-injected with recombinant Tp0136 protein or Tp0136 antibody subcutaneously was used to demonstrate the role of Tp0136 protein in promoting the dissemination of T. pallidum to the testis and angiogenesis in vivo; vascular endothelial cell line HMEC-1 was employed to display that Tp0136 protein enhances the angiogenesis. Furthermore, the three-dimensional microfluidic angiogenesis system showed that the angiogenesis would heighten vascular permeability. Then transcriptome sequencing analysis, in conjunction with cell-level validation, elucidated the critical role of the PI3K-AKT signaling pathway in the promotion of angiogenesis by Tp0136 protein, resulting in heightened permeability. These findings elucidate the strategy employed by T. pallidum in evading immune clearance.

Psoralen attenuates cigarette smoke extract-induced inflammation by modulating CD8+ T lymphocyte recruitment and chemokines via the JAK2/STAT1 signaling pathway.

Chronic obstructive pulmonary disease (COPD) is a respiratory inflammatory disease. Psoralen (PSO) is the main pharmacological component identified from Bu-Shen-Fang-Chuan formula which has been traditionally used in treatment of COPD, yet its efficacy in COPD inflammation were unreported. In this study, we aimed to elucidate the anti-inflammatory potential of PSO in COPD and unravel the underlying mechanisms, focusing on T lymphocyte recruitment and the modulation of chemokines, namely monokine induced by interferon-gamma (CXCL9), interferon inducible protein 10 (CXCL10), and interferon inducible T-Cell alpha chemoattractant (CXCL11). In vitro, RAW264.7 was stimulated by interferon (IFN)-γ + cigarette smoke extract (CSE) and were treated with PSO (2.5, 5, 10 µM), then the levels of chemokines and the activation of Janus kinase (JAK)/Signal transducer and activator of transcription 1 (STAT1) pathway were analyzed by real time PCR and western blot. In vivo, a murine model was established by intraperitoneal injection of CSE on day 1, 8, 15, and 22, then treated with PSO (10 mg/kg). Our experiments in vitro illustrated that PSO reduced the levels of CXCL9, CXCL10, and CXCL11, and decreased the protein phosphorylation levels of JAK2 and STAT1. Additionally, PSO effectively improved inflammatory infiltration and decreased the proportion of CD8+ T cells in CSE-exposed mice. Furthermore, PSO reduced the levels of CXCL9, CXCL10, and CXCL11 in bronchoalveolar lavage fluid (BALF) and lung tissue, and decreased the protein phosphorylation levels of JAK2 and STAT1. In conclusion, our results revealed the therapeutic potential of PSO for COPD inflammation, possibly mediated through the regulation of CD8+ T cell recruitment and chemokines via the JAK2/STAT1 signaling pathway.

Single-cell transcriptome sequencing partially revealed the changes of T cells in the early stage of aging kidney.

Aging is a gradual, inevitable physiologic process. The organ aging is related to the persistence of chronic inflammation, but the understanding of inflammatory state during renal aging is lacking currently. Single-cell transcriptome sequencing was performed on aging mouse kidney to reveal the molecular phenotype and composition changes of different cell types. In the early stage of aging, immune cells such as T, B cells and mononuclear macrophages increased in kidney. The molecular state of T cells in aging kidney changed and polarized. Among them, we identified a group of GZMK+ CD8 + T cells with high expression of Eomes, Pdcd1 and Ifng and a group of Il17a+ T cells with high expression of Il17a and Il23r. Moreover, the cytokines and inflammations can aggravate tissue damage eventually. Furthermore, we found the interaction between different types of epithelial cells and T cells increased during the renal aging. These results identify the changes of T cells in the early stage of aging kidney and suggest that GZMK+CD8+ T cells might be a potential target to ameliorate age-associated dysfunctions of kidney(Graphical Abstract).