Microbial peptides activate tumour-infiltrating lymphocytes in glioblastoma.

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors1,2. Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4+ T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches.

Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank.

BACKGROUND: Peripheral glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are sensitive markers of neuroinflammation and neuronal damage. Previous studies with highly selected participants have shown that peripheral GFAP and NfL levels are elevated in the pre-clinical phase of Alzheimer's disease (AD) and dementia. However, the predictive value of GFAP and NfL for dementia requires more evidence from population-based cohorts. METHODS: This was a prospective cohort study to evaluate UK Biobank participants enrolled from 2006 to 2010 using plasma GFAP and NfL measurements measured by Olink Target Platform and prospectively followed up for dementia diagnosis. Primary outcome was the risk of clinical diagnosed dementia. Secondary outcomes were cognition. Linear regression was used to assess the associations between peripheral GFAP and NfL with cognition. Cox proportional hazard models with cross-validations were used to estimate associations between elevated GFAP and NfL with risk of dementia. All models were adjusted for covariates. RESULTS: A subsample of 48,542 participants in the UK Biobank with peripheral GFAP and NfL measurements were evaluated. With an average follow-up of 13.18 ± 2.42 years, 1312 new all-cause dementia cases were identified. Peripheral GFAP and NfL increased up to 15 years before dementia diagnosis was made. After strictly adjusting for confounders, increment in NfL was found to be associated with decreased numeric memory and prolonged reaction time. A greater annualized rate of change in GFAP was significantly associated with faster global cognitive decline. Elevation of GFAP (hazard ratio (HR) ranges from 2.25 to 3.15) and NfL (HR ranges from 1.98 to 4.23) increased the risk for several types of dementia. GFAP and NfL significantly improved the predictive values for dementia using previous models (area under the curve (AUC) ranges from 0.80 to 0.89, C-index ranges from 0.86 to 0.91). The AD genetic risk score and number of APOE*E4 alleles strongly correlated with GFAP and NfL levels. CONCLUSIONS: These results suggest that peripheral GFAP and NfL are potential biomarkers for the early diagnosis of dementia. In addition, anti-inflammatory therapies in the initial stages of dementia may have potential benefits.

Accumulation of γδT cells in the decidua is promoted by RANKL which upregulates ICAM-1 via NF-κB.

In brief: The mechanism underlying the accumulation of γδT cells in the decidua, which helps maintain maternal-fetal immunotolerance in early pregnancy, is unknown. This study reveals that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. Abstract: Decidual γδT (dγδT) cells help maintain maternal-fetal immunotolerance in early pregnancy. However, the mechanism underlying the accumulation of γδT cells in the decidua is unknown. Previous work showed that RANKL upregulated intercellular adhesion molecule 1 (ICAM-1) in decidual stromal cells (DSCs), and Rankl knockout mice had limited dγδT cell populations. In this study, we measured the expression levels of RANKL/RANK and ICAM-1 in DSCs, in addition to the integrins of ICAM-1 on dγδT cells, and the number of dγδT cells from patients with recurrent spontaneous abortion (RSA) and normal pregnant women in the first trimester. RSA patients showed significantly decreased RANKL/RANK and ICAM-1/CD11a signaling in decidua, and a decreased percentage of dγδT cells, which was positively correlated with DSC-derived RANKL and ICAM-1. Next, an in vitro adhesion experiment showed that the enhanced attraction of human DSCs to dγδT cells after RANKL overexpression was almost completely aborted by anti-ICAM-1. Furthermore, Rankl knockout mice showed a significant reduction in NF-κB activity compared with wild-type controls. Finally, we applied a selective NF-κB inhibitor named PDTC to validate the role of NF-κB in RANKL-mediated ICAM-1 upregulation. Taken together, our data show that DSC-derived RANKL upregulates ICAM-1 expression via the NF-κB pathway to enable γδT cell accumulation in the early decidua. A reduction in RANKL/ICAM-1 signaling in DSCs may result in insufficient accumulation of γδT cells in decidua and, in turn, RSA.

Effect of aromatase inhibitors for preventing ovarian hyperstimulation syndrome in infertile patients undergoing in vitro fertilization: a systematic review and meta-analysis.

PURPOSE: To summarize the findings of relevant randomized controlled trials (RCTs) and conduct a meta-analysis to investigate the potential effect of aromatase inhibitors on preventing moderate to severe ovarian hyperstimulation syndrome (OHSS) in infertile women undergoing in vitro fertilization (IVF). METHODS: We searched for relevant RCTs in electronic databases, including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov (from inception to August 2023). In addition, we manually searched the related reviews and reference lists of included studies for further relevant studies. We included RCTs where aromatase inhibitors prescribed either during controlled ovarian stimulation (COS) or in early luteal phase. The meta-analysis was performed using RevMan 5.4.1 software. The primary outcome was the incidence of moderate to severe OHSS. A descriptive analysis was conducted in cases where a meta-analysis was not feasible due to heterogeneity or lack of comparable data. RESULTS: 2858 records were retrieved and 12 RCTs were finally included. Letrozole was administered in the treatment group during COS in seven RCTs, whereas in the early luteal phase in five RCTs. Compared with the control group, the risk of moderate to severe OHSS significantly reduced by 55% in the letrozole group (RR 0.45, 95% CI 0.32 to 0.64, I2 = 0%, 5 RCTs, 494 patients). Moreover, serum estradiol (E2) levels on hCG trigger day significantly decreased with the administration of letrozole during COS (MD -847.23, 95% CI -1398.00 to -296.47, I2 = 93%, 5 RCTs, 374 patients). And serum E2 levels on the 4th, 5th and 7th to 10th day after hCG trigger were also significantly lower than those in the control group when letrozole was administered in the early luteal phase. CONCLUSIONS: Patients with high risk of OHSS probably benefit from letrozole, which has been revealed to reduce the incidence of moderate to severe OHSS by this systematic review. However, the very limited number of participants and the quality of the included studies does not allow to recommend letrozole for the prevention of severe OHSS.

Ultrasound-guided percutaneous radiofrequency ablation versus surgery for solitary T1N0M0 papillary thyroid carcinoma in the danger triangle.

OBJECTIVES: To compare the safety and efficiency of ultrasound-guided percutaneous radiofrequency ablation (RFA) and surgical resection (SR) for thyroid papillary carcinoma (PTC) in the danger triangle area. METHODS: The clinical data of 298 patients who underwent either percutaneous RFA or SR for PTC in the thyroid danger triangle at our hospital between January 2018 and April 2020 were retrospectively analyzed. Propensity score matching is employed to regulate for confounding factors. All patients undergoing ablation were treated using a strategy that combined sufficient paratracheal fluid isolation with a low-power, short electrode. Disease progression was analyzed in patients with T1N0M0 PTC (T1a and T1b) employed in Kaplan‒Meier curves. Treatment parameters and the rates of local recurrence, distant metastasis, and complications are recorded and compared. RESULTS: Of 182 eligible patients who were included, 91 were in the RFA (age 44.84 ± 13.19; 71 females; 77 T1a) and 91 were in the SR (age 47.36 ± 11.05; 68 females; 69 T1a). The average treatment time, length of hospital stays, blood loss volume, and scar length are substantially less in the RFA than in the SR. Major complications as well as postoperative permanent recurrent laryngeal nerve injury and postoperative transient parathyroid dysfunction occurred only in the SR, with a substantial distinction between the two groups (p < 0.05). There is no substantial distinction in the disease progression between RFA and SR treatment of T1N0M0 PTC. CONCLUSION: RFA is as effective as surgery for PTC in the danger triangle area in the short term, with faster recovery and fewer complications. CLINICAL RELEVANCE STATEMENT: Radiofrequency ablation has a clinical efficacy comparable to surgery in the treatment of papillary thyroid carcinoma in the danger triangle area in the short term with the advantages of faster recovery and fewer complications when compared with surgery. KEY POINTS: Use of radiofrequency ablation (RFA) in the thyroid danger triangle is still controversial. RFA and surgery groups showed no difference in disease progressions, and no major complications occurred with RFA. Radiofrequency ablation offers a new option for papillary thyroid carcinoma patients in the danger triangle.

Radiofrequency ablation for solitary T1N0M0 papillary thyroid carcinoma in the danger triangle area: a preliminary analysis.

OBJECTIVES: To evaluate the feasibility, efficacy, and safety of radiofrequency ablation (RFA) for solitary T1N0M0 papillary thyroid carcinoma (PTC) in the danger triangle area. METHODS: 94 participants (mean age 44.45 ± 13.08; 73 females) with solitary T1N0M0 PTC in the danger triangle area who underwent percutaneous RFA at the hospital from January 2018 to April 2020 were retrospectively analyzed. Key ablation procedures included sufficient paratracheal fluid isolation, low-power, and short active tip (5 mm working electrode). Tumor size changes at different time points after RFA, technical success rates, tumor disappearance, disease progression, and complications were recorded and compared. RESULTS: Contrast-enhanced ultrasonography revealed that complete tumor ablation was performed with a 100% success rate in these patients. Post-ablation, the maximum diameter and volume of the ablation zone increased at the first and third month (p < 0.001), followed by a gradual decrease in size, without significant difference by the 6th month. The tumor disappearance rate was 76.59% (72/94), with higher rates in the T1a group compared to the T1b group (80% [64/80] VS57.1% [8/14], p < 0.001). There were no local recurrences. The incidence of new lesions and LNM was 3.2% (3/94), limited to the T1a subgroup. Further ablation was successfully applied to all new lesions and LMN. Mild voice changes were the only complication, with a rate of 3.2% (3/94), resolved within 4 months after RFA. CONCLUSIONS: Sufficient paratracheal fluid isolation combined with a low-power, short active tip radiofrequency ablation strategy is a safe and effective method for treating solitary T1N0M0 PTC in the danger triangle area.

The 'danger triangle' area comprises the dorsal edge of the thyroid gland, the lateral tracheal wall, and the anterior edge of the esophageal wall. When PTC tumors are present within the danger triangle, there is only limited space available for ablation. Furthermore, the proximity of the tumor with the esophagus, trachea, and thyroid capsule can complicate technical treatment success, potentially increasing the chance of local tumor recurrence and nerve injury. Therefore, the most effective approach for managing PTC lesions within the danger triangle remains undetermined. The goal of this study was to clarify the viability of ultrasound-guided RFA as a means of managing solitary T1N0M0 PTC tumors within the danger triangle area, providing a foundation for future clinical decision-making efforts.

Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Brain structural and functional connectivity alterations are associated with fatigue in neuromyelitis optica spectrum disorder.

BACKGROUND: Many patients with neurological disorders experience chronic fatigue, but the neural mechanisms involved are unclear. OBJECTIVE: Here we investigated whether the brain structural and functional connectivity alterations were involved in fatigue related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: This prospective pilot study used structural and resting-state functional brain magnetic resonance imaging to compare total cortical thickness, cortical surface area, deep gray matter volume and functional connectivity (FC) between 33 patients with NMOSD and 20 healthy controls (HCs). Patients were subgrouped as low fatigue (LF) and high fatigue (HF). RESULTS: HF patients scored higher on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression than LF patients and HCs. The two patient subgroups and HC group did not differ significantly in cortical thickness, cortical surface area and volumes of the bilateral caudate nucleus, bilateral putamen, bilateral amygdala, bilateral hippocampus, bilateral thalamus proper or right nucleus accumbens (p > 0.05). However, after correcting for age, sex, years of education, anxiety and depression, HF patients showed larger left pallidum than HCs (0.1573 ± 0.0214 vs 0.1372 ± 0.0145, p = 0.009). Meanwhile, both LF patients (0.0377 ± 0.0052 vs 0.0417 ± 0.0052, p = 0.009) and HF patients (0.0361 ± 0.0071 vs 0.0417 ± 0.0052, p = 0.013) showed smaller left nucleus accumbens than HCs.. Compared with LF patients, HF patients showed significantly decreased FC between the left pallidum and bilateral cerebellar posterior lobes. CONCLUSIONS: This was the first evidence linking structural and functional alterations in the brain to fatigue in NMOSD, and in the future, long term follow-up was necessary.

The novel quinolizidine derivate IMB-HDC inhibits STAT5a phosphorylation at 694 and 780 and promotes DNA breakage and cell apoptosis via blocking STAT5a nuclear translocation.

Sophoridine is a quinolizidine natural product and the exploration of its derivatives has been carried out, and the potent anticancer compound IMB-HDC was acquired. Although previous studies have revealed that some sophoridine derivatives could induce DNA breakage, the underlying mechanisms of inhibition of DNA damage repair (ATR inactivation) and the apoptosis independent of p53, have not been elucidated. Our research reveals a novel DNA response mechanism different from general DNA-damaging agents, and that sophoridine derivate inhibits the phosphorylation of Tyr694 and Ser780 of STAT5a to induce the lessened shuttle from the cytoplasm to the nucleus, and leads to the decreased nuclear STAT5a and subsequently inhibits the expression of STAT5a target gene RAD51 that contributes to the checkpoint activation, thus inhibiting ATR activation. Meanwhile, IMB-HDC that induced the diminished expression of STAT5a target gene contributes to proliferation and leads to apoptosis. More importantly, we give the first evidence that promoting the effect of Tyr694 phosphorylation on nuclear location and subsequent STAT5a target gene transcription depends on Ser780 increased or unchanged phosphorylation and was not correlated with Ser726 phosphorylation.

Cell Wall Modification Based on Combination Reagents to Improve Dimensional Stability of Wood with High Efficiency.

Although γ-methacryloxypropyltrimethoxysilane (MPS) was proved to be an effective reagent for improving the dimensional stability of wood, a bottleneck in ASE value (around 50%) existed. The reason was that MPS with low polarity opened few hydrogen bonds in the amorphous region of cellulose, while these hydrogen bonds could be reopened by water. Therefore, citric acid (CA) is chosen to cooperate with MPS to further enhance the dimensional stability of wood. In this paper, MPS and CA were used to modify wood individually (MW and CW) or with different combinations, that is, one-step modification (M/CW) and two-step modification with MPS first (M-CW) or CA first (C-MW). CA and MPS concentrations were optimized at 5 wt%. The ASE value for M/CW was only 25.74% at a weight percent gain (WPG) of 6.43%, which was only 0.6 times to MW or 0.7 times to CW. For M-CW, the ASE value gradually decreased with the soaking cycles, from 65.64% at a WPG of 9.05% to 51.20%. The C-MW had the best dimensional stability, with the ASE value 75.35% at a WPG of 11.50%. Although it decreased during the first soaking cycle, it stabilized at 62.20% at last. SEM and EDS images showed that the polymer mainly distributed in cell walls and few in cell lumen in C-MW. Thus, the enhanced dimensional stability of C-MW could be explained by CA opening the hydrogen bonds in the amorphous region of cellulose first, which provided more binding sites for MPS.

Plasma Exosomes in Insulin Resistant Obesity Exacerbate Progression of Triple Negative Breast Cancer.

Breast cancer, the most common cancer among women worldwide, continues to pose significant public health challenges. Among the subtypes of breast cancer, triple-negative breast cancer (TNBC) is particularly aggressive and difficult to treat due to the absence of receptors for estrogen, progesterone, or human epidermal growth factor receptor 2, rendering TNBC refractory to conventional targeted therapies. Emerging research underscores the exacerbating role of metabolic disorders, such as type 2 diabetes and obesity, on TNBC aggressiveness. Here, we investigate the critical cellular and molecular factors underlying this link. We explore the pivotal role of circulating plasma exosomes in modulating the tumor microenvironment and enhancing TNBC aggressiveness. We find that plasma exosomes from diet-induced obesity mice induce epithelial- mesenchymal transition features in TNBC cells, leading to increased migration in vitro and enhanced metastasis in vivo . We build on our previous reports demonstrating that plasma exosomes from obese, diabetic patients, and exosomes from insulin-resistant 3T3-L1 adipocytes, upregulate key transcriptional signatures of epithelial- mesenchymal transition in breast cancer. Bioinformatic analysis reveals that TNBC cells exhibit higher expression and activation of proteins related to the Rho-GTPase cascade, particularly the small Ras-related protein Rac1. Our approach suggests novel therapeutic targets and exosomal biomarkers, ultimately to improve prognosis for TNBC patients with co-morbid metabolic disorders.

Insulin Resistance Increases TNBC Aggressiveness and Brain Metastasis via Adipocyte-derived Exosomes.

Patients with triple negative breast cancer (TNBC) and comorbid Type 2 Diabetes (T2D), characterized by insulin resistance of adipose tissue, have higher risk of metastasis and shorter survival. Adipocytes are the main non-malignant cells of the breast tumor microenvironment (TME). However, adipocyte metabolism is usually ignored in oncology and mechanisms that couple T2D to TNBC outcomes are poorly understood. Here we hypothesized that exosomes, small vesicles secreted by TME breast adipocytes, drive epithelial-to-mesenchymal transition (EMT) and metastasis in TNBC via miRNAs. Exosomes were purified from conditioned media of 3T3-L1 mature adipocytes, either insulin-sensitive (IS) or insulin-resistant (IR). Murine 4T1 cells, a TNBC model, were treated with exosomes in vitro (72h). EMT, proliferation and angiogenesis were elevated in IR vs. control and IS. Brain metastases showed more mesenchymal morphology and EMT enrichment in the IR group. MiR-145a-3p is highly differentially expressed between IS and IR, and potentially regulates metastasis. Significance: IR adipocyte exosomes modify TME, increase EMT and promote metastasis to distant organs, likely through miRNA pathways. We suggest metabolic diseases such as T2D reshape the TME, promoting metastasis and decreasing survival. Therefore, TNBC patients with T2D should be closely monitored for metastasis, with metabolic medications considered.

Unveiling the neural mechanisms of acute aerobic exercise on inhibitory control among young adults with obesity: Insights from an ERP study.

Obesity has become a prominent public health concern worldwide and is associated with adverse cognitive function. Exercise, particularly aerobic exercise, is known to benefit for weight loss and cognitive function. However, whether acute aerobic exercise could yield benefits to obese individuals and the precise brain mechanisms of action remain poorly understood. The study aimed to investigate whether acute aerobic exercise could improve inhibitory control among obese individuals and what neuroelectric mechanisms are implicated. A 3 (session: control, low-intensity exercise, moderate-intensity exercise) × 2 (congruency: congruent, incongruent) within-subject design was conducted. 18 obese young male adults underwent three sessions of 30-min interventions in a counterbalanced order seperated by five days: moderate-intensity aerobic exercise (MIE), low-intensity aerobic exercise (LIE) and a control session (a sedentary period of seated rest). The Flanker task and EEG recordings (N2 and P3 amplitude) were investigated following exercise and the control treatment. Results showed that the N2 amplitude following MIE was larger than the control session, whereas a larger N2 and reduced congruent P3 amplitude was observed following MIE than LIE. However, no main effect of the session was found for reaction time and accuracy, but a significant main effect of congruency was observed. These findings suggest acute moderate-intensity aerobic exercise may modulate brain activity through enhanced recruitment of attentional resources for cognitive control and conflict monitoring in adults with obesity.

The crosstalk within the breast tumor microenvironment in type II diabetes: Implications for cancer disparities.

Obesity-driven (type 2) diabetes (T2D), the most common metabolic disorder, both increases the incidence of all molecular subtypes of breast cancer and decreases survival in postmenopausal women. Despite this clear link, T2D and the associated dysfunction of diverse tissues is often not considered during the standard of care practices in oncology and, moreover, is treated as exclusion criteria for many emerging clinical trials. These guidelines have caused the biological mechanisms that associate T2D and breast cancer to be understudied. Recently, it has been illustrated that the breast tumor microenvironment (TME) composition and architecture, specifically the surrounding cellular and extracellular structures, dictate tumor progression and are directly relevant for clinical outcomes. In addition to the epithelial cancer cell fraction, the breast TME is predominantly made up of cancer-associated fibroblasts, adipocytes, and is often infiltrated by immune cells. During T2D, signal transduction among these cell types is aberrant, resulting in a dysfunctional breast TME that communicates with nearby cancer cells to promote oncogenic processes, cancer stem-like cell formation, pro-metastatic behavior and increase the risk of recurrence. As these cells are non-malignant, despite their signaling abnormalities, data concerning their function is never captured in DNA mutational databases, thus we have limited insight into mechanism from publicly available datasets. We suggest that abnormal adipocyte and immune cell exhaustion within the breast TME in patients with obesity and metabolic disease may elicit greater transcriptional plasticity and cellular heterogeneity within the expanding population of malignant epithelial cells, compared to the breast TME of a non-obese, metabolically normal patient. These challenges are particularly relevant to cancer disparities settings where the fraction of patients seen within the breast medical oncology practice also present with co-morbid obesity and metabolic disease. Within this review, we characterize the changes to the breast TME during T2D and raise urgent molecular, cellular and translational questions that warrant further study, considering the growing prevalence of T2D worldwide.

Effects of pregnancy on neuromyelitis optica spectrum disorder and predictors of related attacks.

OBJECTIVE: Our study aimed to investigate the influence of pregnancy on the course of neuromyelitis optica spectrum disorders (NMOSD) and to explore the independent predictors of pregnancy-related attacks. METHODS: We performed a retrospective study of patients with NMOSD based on the Wingerchuk 2006 or the revised Wingerchuk 2015 criteria. Demographic, clinical, and pregnancy data were recorded. We compared the annualized relapse rate (ARR) before, during, and after pregnancy. The Expanded Disability Status Scale (EDSS) score was used to assess the degree of disability. Multivariate Cox proportional hazards models were used to identify the independent risk factors that predict pregnancy-related attacks. RESULTS: There were 202 informative pregnancies following symptom onset in 112 women with NMOSD. The ARR in the first-trimester postpartum period (1.44 ± 2.04) was higher than that before pregnancy (0.23 ± 0.48; p < 0.001) and during pregnancy. The EDSS score increased from 1.40 ± 1.38 before pregnancy to 1.99 ± 1.78 postpartum (p = 0.004). Multivariate Cox proportional hazards models indicated that increased disease activity 1 year before conception (HR = 1.79, 95% CI 1.09-2.92, p = 0.021) and lack of immunotherapy during pregnancy and the postpartum period (HR = 5.25, 95% CI 1.91-14.42, p = 0.001) were independent risk factors that predicted pregnancy-related attacks. INTERPRETATION: The postpartum period is a particularly high-risk time for the onset and relapse of NMOSD. Pregnancy exerted detrimental effects on the disease courses of NMOSD. Immunotherapy during pregnancy and the postpartum period might be recommended to decrease the risk of pregnancy-related attacks. Larger-scale prospective studies are warranted to confirm our findings.

Impact of maternal gestational weight gain in twin pregnancies on early childhood obesity risk: A longitudinal birth cohort study.

Objectives: To investigate the impact of gestational weight gain (GWG) on the body mass index-for-age z score (BAZ) and obesity risk among twin offspring. Methods: This study included 263 women who were pregnant with twins and their offspring. Maternal GWG was measured in each trimester, and infant weight and length were measured at 6, 12, and 24 months. Results: Total GWG was positively correlated with offspring birthweight and BAZ at 6, 12 and 24 months [adjusted ß 0.013 (95% CI: 0.008-0.019), 0.028 (95% CI: 0.005-0.050), 0.033 (95% CI: 0.010-0.056) and 0.025 (95% CI: 0.004-0.047), respectively]. Excessive total GWG was related to an increased relative risk (RR) of large for gestational age (LGA) and overweight at 6 and 12 months. Only the second trimester gestational weight gain rate (GWGR) was positively correlated with birthweight (adjusted ß 0.380, 95% CI: 0.256-0.504), and RRs of 6.818 (95% CI: 1.568-29.642) and 2.852 (95% CI: 1.466-5.548) were found for LGA and overweight at 12 months, respectively. Conclusions: Total GWG and the second trimester GWGR were correlated with BAZ and overweight/obesity risk in twin offspring; the impact was obvious in the first year of life and gradually disappeared over time. Clinical trial registration: ChiCTR-OOC-16008203, Registered on 1 April 2016 at the Chinese Clinical Trial Registry.

Reactive Oxygen Species are Essential for Placental Angiogenesis During Early Gestation.

Background: Preeclampsia (PE) is associated with insufficient placental perfusion attributed to maldevelopment of the placental vasculature. Reactive oxygen species (ROS) are implicated in angiogenesis, but their regulatory effects and mechanisms in placental vascular development remain unclear. Methods: Placental oxidative stress was determined throughout gestation by measuring 4-hydroxynonenal (4HNE) and malondialdehyde (MDA). The antioxidant MitoQ was administered to pregnant mice from GDs 7.5 to 11.5; placental morphology and angiogenesis pathways were examined on GDs 11.5 and 18.5. Moreover, we established a mouse mFlt-1-induced PE model and assessed blood pressure, urine protein levels, and placental vascular development on GDs 11.5 and 18.5. Human umbilical vein endothelial cells (HUVECs) were treated with various H2O2 concentrations to evaluate cell viability, intracellular ROS levels, and tube formation capability. MitoQ, an AKT inhibitor and an ERK1/2 inhibitor were applied to validate the ROS-mediated mechanism regulating placental angiogenesis. Results: First-trimester placentas presented significantly higher MDA and 4HNE levels. MitoQ significantly reduced the blood vessel density and angiogenesis pathway activity in the placenta on GDs 11.5 and 18.5. Serum sFlt-1 levels were elevated, and we observed poor placental angiogenesis and PE-like symptoms in cases with mFlt-1 overexpression. Moderate H2O2 treatment promoted HUVEC proliferation and angiogenesis, whereas these improvements were abolished by MitoQ, AKT inhibitor, or ERK1/2 inhibitor treatment. Conclusions: Moderate ROS levels are essential for placental angiogenesis; diminishing ROS with potent antioxidants during placentation decreases placental angiogenesis and increases PE risk. Therefore, antioxidant therapy should be considered carefully for normal pregnant women during early gestation.

ER-phagy in the Occurrence and Development of Cancer.

As an organelle, the endoplasmic reticulum (ER) is closely related to protein synthesis and modification. When physiological or pathological stimuli induce disorders of ER function, misfolded proteins trigger ER-phagy, which is beneficial for restoring cell homeostasis or promoting cell apoptosis. As a double-edged sword, ER-phagy actively participates in various stages of development and progression in tumor cells, regulating tumorigenesis and maintaining tumor cell homeostasis. Through the unfolded protein response (UPR), the B cell lymphoma 2 (BCL-2) protein family, the Caspase signaling pathway, and others, ER-phagy plays an initiating role in tumor occurrence, migration, stemness, and proliferation. At the same time, many vital proteins strongly associated with ER-phagy, such as family with sequence similarity 134 member B (FAM134B), translocation protein SEC62 (SEC62), and C/EBP-homologous protein (CHOP), can produce a marked effect in many complex environments, which ultimately lead to entirely different tumor fates. Our article comprehensively focused on introducing the relationship and interaction between ER-phagy and cancers, as well as their molecular mechanism and regulatory pathways. Via these analyses, we tried to clarify the possibility of ER-phagy as a potential target for cancer therapy and provide ideas for further research.

Novel plasma exosome biomarkers for prostate cancer progression in co-morbid metabolic disease.

Comorbid Type 2 diabetes (T2D), a metabolic complication of obesity, associates with worse cancer outcomes for prostate, breast, head and neck, colorectal and several other solid tumors. However, the molecular mechanisms remain poorly understood. Emerging evidence shows that exosomes carry miRNAs in blood that encode the metabolic status of originating tissues and deliver their cargo to target tissues to modulate expression of critical genes. Exosomal communication potentially connects abnormal metabolism to cancer progression. Here, we hypothesized that T2D plasma exosomes induce epithelial-mesenchymal transition (EMT) and immune checkpoints in prostate cancer cells. We demonstrate that plasma exosomes from subjects with T2D induce EMT features in prostate cancer cells and upregulate the checkpoint genes CD274 and CD155. We demonstrate that specific exosomal miRNAs that are differentially abundant in plasma of T2D adults compared to nondiabetic controls (miR374a-5p, miR-93-5p and let-7b-3p) are delivered to cancer cells, thereby regulating critical target genes. We build on our previous reports showing BRD4 controls migration and dissemination of castration-resistant prostate cancer, and transcription of key EMT genes, to show that T2D exosomes require BRD4 to drive EMT and immune ligand expression. We validate our findings with gene set enrichment analysis of human prostate tumor tissue in TGCA genomic data. These results suggest novel, non-invasive approaches to evaluate and potentially block progression of prostate and other cancers in patients with comorbid T2D.

The novel ER stress inducer Sec C triggers apoptosis by sulfating ER cysteine residues and degrading YAP via ER stress in pancreatic cancer cells.

Pancreatic adenocarcinoma (PAAD) is one of the most lethal malignancies. Although gemcitabine (GEM) is a standard treatment for PAAD, resistance limits its application and therapy. Secoemestrin C (Sec C) is a natural compound from the endophytic fungus Emericella, and its anticancer activity has not been investigated since it was isolated. Our research is the first to indicate that Sec C is a broad-spectrum anticancer agent and could exhibit potently similar anticancer activity both in GEM-resistant and GEM-sensitive PAAD cells. Interestingly, Sec C exerted a rapid growth-inhibiting effect (80% death at 6 h), which might be beneficial for patients who need rapid tumor shrinkage before surgery. Liquid chromatography/mass spectrometry and N-acetyl-l-cysteine (NAC) reverse assays show that Sec C sulfates cysteines to disrupt disulfide-bonds formation in endoplasmic reticulum (ER) proteins to cause protein misfolding, leading to ER stress and disorder of lipid biosynthesis. Microarray data and subsequent assays show that ER stress-mediated ER-associated degradation (ERAD) ubiquitinates and downregulates YAP to enhance ER stress via destruction complex (YAP-Axin-GSK-ßTrCP), which also elucidates a unique degrading style for YAP. Potent anticancer activity in GEM-resistant cells and low toxicity make Sec C a promising anti-PAAD candidate.