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Poking palpebral conjunctiva evoked upper-eyelid retraction during ophthalmic surgery. Iatrogenic eyelid ptosis occurred if eyelid branch of lachrymal nerve was sectioned. Mesencephalic trigeminal nucleus (Vme) neurons were labeled when tracer injected into lachrymal nerve innervating eyelid Mueller’s muscle. Masseter afferent Vme neurons projecting to oculomotor nucleus (III) was observed in toad and rat, which helps amphibians to stare prey when they open mouth widely to prey. We hypothesized single Vme neurons may have peripheral collaterals to both eyelid and masseter muscles. WGA-594 was injected into upper eyelid, and WGA-488 was simultaneously delivered into ipsilateral masseter muscle in the same rat. Then, double labeled Vme neurons were found under both conventional and confocal microscope. Meanwhile, contact of WGA-594 positive eyelid afferent Vme neurons with WGA-488 labeled masseter afferent ones were observed sometimes. Combined with our previous observation of oculomotor projection Vme neurons, we thought WGA-594/488 double labeled Vme cells, at least some of them, are oculomotor projecting ones. Contact between eyelid and masseter afferent Vme neurons are supposed to be electrotonically coupled, based on a line of previous studies. If exogenous or genetic factors make these Vme neurons misinterpret masseter input as eyelid afferent signals, these Vme neurons might feedforward massages to eyelid retractor motoneurons in the III. Besides, oculomotor projecting Vme neurons might be co-fired by adjacent masseter afferent Vme neurons through electrotonic coupling once the masseter muscle is activated. In these cases, Marcus Gunn Syndrome might occur. This finding leads to a new hypothesis for the Syndrome.

The options for first-line treatment of advanced oesophageal squamous cell carcinoma are scarce, and the outcomes remain poor. The anti-PD-1 antibody, tislelizumab, has shown antitumour activity in previously treated patients with advanced oesophageal squamous cell carcinoma. We report interim analysis results from the RATIONALE-306 study, which aimed to assess tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma. This global, randomised, double-blind, parallel-arm, placebo-controlled, phase 3 study was conducted at 162 medical centres across Asia, Europe, Oceania, and North America. Patients (aged ≥18 years) with unresectable, locally advanced, recurrent or metastatic oesophageal squamous cell carcinoma (regardless of PD-L1 expression), Eastern Cooperative Oncology Group performance status of 0–1, and measurable or evaluable disease per Response Evaluation Criteria in Solid Tumours (version 1.1) were recruited. Patients were randomly assigned (1:1), using permuted block randomisation (block size of four) and stratified by investigator-chosen chemotherapy, region, and previous definitive therapy, to tislelizumab 200 mg or placebo intravenously every 3 weeks on day 1, together with an investigator-chosen chemotherapy doublet, comprising a platinum agent (cisplatin 60–80 mg/m2 intravenously on day 1 or oxaliplatin 130 mg/m2 intravenously on day 1) plus a fluoropyrimidine (fluorouracil [750–800 mg/m2 intravenously on days 1–5] or capecitabine [1000 mg/m2 orally twice daily on days 1–14]) or paclitaxel (175 mg/m2 intravenously on day 1). Treatment was continued until disease progression or unacceptable toxicity. Investigators, patients, and sponsor staff or designees were masked to treatment. The primary endpoint was overall survival. The efficacy analysis was done in the intention-to-treat population (ie, all randomly assigned patients) and safety was assessed in all patients who received at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03783442. Between Dec 12, 2018, and Nov 24, 2020, 869 patients were screened, of whom 649 were randomly assigned to tislelizumab plus chemotherapy (n=326) or placebo plus chemotherapy (n=323). Median age was 64·0 years (IQR 59·0–69·0), 563 (87%) of 649 participants were male, 86 (13%) were female, 486 (75%) were Asian, and 155 (24%) were White. 324 (99%) of 326 patients in the tislelizumab group and 321 (99%) of 323 in the placebo group received at least one dose of the study drug. As of data cutoff (Feb 28, 2022), median follow-up was 16·3 months (IQR 8·6–21·8) in the tislelizumab group and 9·8 months (IQR 5·8–19·0) in the placebo group, and 196 (60%) of 326 patients in the tislelizumab group versus 226 (70%) of 323 in the placebo group had died. Median overall survival in the tislelizumab group was 17·2 months (95% CI 15·8–20·1) and in the placebo group was 10·6 months (9·3–12·1; stratified hazard ratio 0·66 [95% CI 0·54–0·80]; one-sided p<0·0001). 313 (97%) of 324 patients in the tislelizumab group and 309 (96%) of 321 in the placebo group had treatment-related treatment-emergent adverse events. The most common grade 3 or 4 treatment-related treatment-emergent adverse events were decreased neutrophil count (99 [31%] in the tislelizumab group vs 105 [33%] in the placebo group), decreased white blood cell count (35 [11%] vs 50 [16%]), and anaemia (47 [15%] vs 41 [13%]). Six deaths in the tislelizumab group (gastrointestinal and upper gastrointestinal haemorrhage [n=2], myocarditis [n=1], pulmonary tuberculosis [n=1], electrolyte imbalance [n=1], and respiratory failure [n=1]) and four deaths in the placebo group (pneumonia [n=1], septic shock [n=1], and unspecified death [n=2]) were determined to be treatment-related. Tislelizumab plus chemotherapy as a first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy. Given that the interim analysis met its superiority boundary for the primary endpoint, as confirmed by the independent data monitoring committee, this Article represents the primary study analysis. BeiGene.

Background Osteoporosis and kidney stones share several common pathophysiological risk factors, and their association is well-established. However, previous studies have primarily focused on environmental mediators, such as diet, and the precise mechanism linking these two conditions remains unclear. Methods The relationship between osteoporosis and kidney stones was analyzed using weighted multivariate logistic regression, employing data from five cycles of the National Health and Nutrition Examination Survey (NHANES) from 2007–2010, 2013–2014, and 2017–2020. Gene expression data from the Gene Expression Omnibus (GEO) microarray database were integrated with machine learning techniques to identify key genes involved in both osteoporosis and kidney stones. Common targets were then identified through the Comparative Toxicogenomics Database (CTD) and GeneCards. GMFA enrichment analysis was performed to identify shared biological pathways. Additionally, drug prediction and molecular docking were employed to further investigate the pharmacological relevance of these targets. Results Analysis of the NHANES database confirmed a strong association between osteoporosis and kidney stones. Weighted multivariate logistic regression showed that osteoporosis (OR: 1.41; 95% CI 1.11–1.79; P  < 0.001) and bone loss (OR: 1.24; 95% CI 1.08–1.43; P  < 0.001) were significantly correlated with an increased risk of kidney stones. Three hub genes—WNT1, AKT1, and TNF—were identified through various analytical methods. GMFA revealed that the mTOR signaling pathway is a key shared pathway. Molecular docking studies further confirmed the pharmacological relevance of these targets, demonstrating strong binding affinity between drugs and the proteins involved, consistent with previous findings. Conclusion Bone loss is associated with an increased risk of kidney stones. Targeting the mTOR signaling pathway may offer a potential therapeutic approach for treating both osteoporosis and kidney stones.

This randomized, open-label, multi-center phase 2 study (NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemotherapy in patients with esophageal squamous cell carcinoma after first-line chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with efficacy. The median OS in the sintilimab group was significantly improved compared with the chemotherapy group (median OS 7.2 vs.6.2 months; P  = 0.032; HR = 0.70; 95% CI, 0.50–0.97). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1%). Patients with high T-cell receptor (TCR) clonality and low molecular tumor burden index (mTBI) showed the longest median OS (15.0 months). Patients with NLR < 3 at 6 weeks post-treatment had a significantly prolonged median OS (16.6 months) compared with NLR ≥ 3. The results demonstrate a significant improvement in OS of sintilimab compared to chemotherapy as second-line treatment for advanced or metastatic ESCC. Patients with advanced esophageal cancer have poor prognosis and limited treatment options. This randomized, phase II trial compares the efficacy and safety of the anti-PD-1 antibody sintilimab versus chemotherapy in Chinese patients with esophageal squamous cell carcinoma after first-line therapy

Due to rapid urbanization and the implementation of ecological civilization construction in China, many industrial factories have been closed or relocated. Therefore, numbers of contaminated sites were generated with contaminated soils which may pose a risk to receptors living nearby. This study presented a spatial health risk assessment and hierarchical risk management policy making for mercury (Hg) in soils from a typical contaminated site in the Hunan Province, central China. Compared with the second class value (0.3 mg/kg) of the Chinese Environmental Quality Standard for Soils, the mean concentrations of Hg in the three soil depths exceeded the second class value. The non-carcinogenic risk of Hg probably posed adverse health effects in 41, 30 and 36 % of the surface soil, the moderate soil and subsoil, respectively, under a sensitive land scenario. The non-carcinogenic risk temporarily posed no adverse health effects in most areas under an insensitive land scenario except for the area around sampling site S29. Spatially, the central, southwest and northeast parts of the contaminated land under a sensitive land scenario should be regarded as the priority regions. For non-carcinogenic effects, the exposure pathways that resulted in the higher levels of exposure risk were ingestion and inhalation of vapors, followed by dermal contact and inhalation of particles. A risk-based integrated risk management policy including the hierarchical risk control values for different soil depths and the calculated remediation earthwork was proposed with consideration of the cost-benefit effect for the related decision-makers.

The physicochemical properties and the contents of metals (Cu, Zn, Pb, Cd, Cr, and Fe) in 51 road dust samples from Xiandao District (XDD) were investigated. Enrichment factor ( EF ), multivariate statistics, geostatistics, and health risk assessment model were adopted to study the spatial pollution pattern and to identify the priority pollutants and regions of concern and sources of studied metals. The mean EF s revealed the following order: Cd > Zn ≈ Pb ≈ Cu > Cr. For non-carcinogenic effects, the exposure pathway which resulted in the highest levels of exposure risk for children and adults was ingestion, followed by dermal contact and inhalation. Hazard index ( HI ) values for the studied metals at each site were within the safe level of 1 except maximum HI Cr (1.08) for children. The carcinogenic risk ( CR ) for Cd and Cr at each site was within the acceptable risk level (1E-06) except CR Cr (1.08E-06) for children in the road intersection between the Changchang highway and the Yuelin highway. Cr was identified as the priority pollutant followed by Pb and Cd with consideration of the local population distribution. Spatially, northwest and northeast of XDD were regarded as the priority regions of concern. Results based on the proposed integrated source identification method indicated that Pb was probably sourced from traffic-related sources, Cd was associated with the dust organic material mainly originated from industrial sources, and Cr was mainly derived from both sources.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a tumor microenvironment (TME) composed of a dense extracellular matrix, cancer-associated fibroblasts (CAFs), vasculature, neural elements, and immune cell populations. This complex network promotes tumor proliferation, invasion, metastasis, and resistance to immunotherapy and chemotherapy. The microenvironmental characteristics of the various PDAC subtypes are discussed in this review. And we examines the role of cancer cells in the TME, highlighting their ability to manipulate stromal components to serve as collaborators in tumor progression. Furthermore, we explored the formation mechanism of the immunosuppressive microenvironment in PDAC, paying attention on Inflammation and intrinsic genetic alterations, the regulatory effect of metabolic reprogramming, the contribution of CAFs and the role of immune cells in cancer cell metastasis. This review shows the role of soluble molecules and exosomes in facilitating PDAC progression and immune evasion within the microenvironment. In conclusion, we outline the novel therapeutic strategies that focus on the interaction between cancer cells and their microenvironment, with the objective of offering new insights for future precision medical interventions.

Colorectal cancer (CRC) is one of the most lethal cancers of the digestive system. The tumor microenvironment (TME) plays a central role in the initiation and development of CRC. However, little is known about the modulation mechanism of the TME in CRC. In our study, we attempted to identify a biomarker related to the TME modulation that could serve as a potential prognostic biomarker for CRC. We identified differentially expressed genes between the ImmuneScore high/low and StromalScore high/low groups. Using univariate COX regression analysis and hub gene analysis (cytoHubba), SLC11A1 was identified as the only candidate gene for subsequent analysis. CIBERSORT, EPIC, MCPcounter, and immunogenic cell death were performed to evaluate the effect of SLC11A1 on the TME. We also collected samples and performed Real-time quantitative PCR to verify the expression levels of SLC11A1 in CRC and adjacent normal tissues. The IMvigor210 cohort, TIDE score, and immunophenoscore (IPS) were used to analyze the association between SLC11A1 and immunotherapy efficacy. SLC11A1 was highly expressed in CRC tissues compared with its expression in normal colorectal tissues and was associated with poor prognosis and advanced clinicopathological stages. Gene set enrichment analysis showed that TGF-β pathways, JAK-STAT pathways, and angiogenesis were significantly enriched in the high-SLC11A1 group. Single-cell analysis validated the correlation between SLC11A1 and the TME. Using CIBERSORT, EPIC, and MCPcounter algorithms, we found that there was more macrophage and fibroblast infiltration in the SLC11A1 high-expression group. Meanwhile, high-SLC11A1 patients had lower IPS scores, higher TIDE scores, and fewer immunotherapy benefits than those of low-SLC11A1 patients. In conclusion, SLC11A1 plays a crucial role in the TME and could serve as a potential biomarker for poor prognosis and immunotherapy efficacy in CRC.

Background Despite depression's significant public health impact, efficient and accessible screening tools utilizing routine clinical indicators remain limited. This study aimed to develop and validate a practical depression risk prediction model based on commonly available biochemical markers, facilitating widespread early screening and timely intervention in general clinical settings. Methods We formulated a model for depression, scrutinizing an assortment of biochemical indicators and their bidirectional interrelationships with depression, employing data derived from the National Health and Nutrition Examination Survey (NHANES) and leveraging the Mendelian randomization (MR) approach, a method that utilizes genetic variants as instrumental proxies to ascertain causal nexus between risk determinants and diseases. Results Using NHANES data (training cohort: n = 27,327; validation cohort: n = 4383), we developed two prediction models through LASSO and multivariate logistic regression. Both models demonstrated comparable performance in terms of discrimination (ROC curves), calibration (slope and Hosmer‐Lemeshow test), Brier score, decision curve analysis, net reclassification improvement, and integrated discrimination improvement. Given the similar performance metrics and more parsimonious nature, Model 2, with 14 variables, was selected as the final model. MR analysis revealed bidirectional relationships between biomarkers and depression. Higher body mass index level was associated with increased depression risk (odds ratio [OR]: 1.061, p = 0.008). Depression itself showed significant associations with increased ALP (OR: 1.048, p = 0.010), decreased BUN (OR: 0.966, p = 0.032), and TB (OR: 0.963, p = 0.044) levels. Conclusions Model 2, selected for its predictive accuracy and streamlined complexity, presents a pragmatic instrument for large‐scale population screenings, facilitating timely intervention and therapeutic strategies. This study develops and validates a novel depression risk prediction model by integrating machine learning analysis of the National Health and Nutrition Examination Survey (NHANES) dataset with a two‐sample Mendelian Randomization (MR) approach. The work provides key evidence in three primary areas: the development of a parsimonious 14‐variable predictive model for large‐scale depression risk screening using routine biochemical and demographic markers; the identification of a causal relationship where higher body mass index (BMI) increases the risk of depression; and the elucidation of causal effects of depression on several biomarkers, including increased alkaline phosphatase (ALP) and decreased blood urea nitrogen (BUN) and total bilirubin (TB) levels.

Atypical hemolytic uremic syndrome (aHUS) is a rare thrombotic microangiopathy (TMA) caused by dysregulation of the complement system. It is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Owing to its diverse and nonspecific clinical manifestations, early diagnosis of the condition is challenging and typically requires excluding other TMA-related conditions, such as thrombotic thrombocytopenic purpura and hemolytic uremic syndrome caused by Escherichia coli infection. Accurate diagnosis relies on the recognition of typical TMA symptoms, laboratory testing, and the exclusion of other conditions. Treatments typically include plasma exchange, supportive care, and complement-targeted therapy. Eculizumab, a complement component 5 inhibitor, plays a crucial role in aHUS treatment in severe cases as well as when traditional interventions fail. In this case report, we described a female Han Chinese patient who developed aHUS following an upper respiratory tract infection, initially presented with intermittent seizures, and received treatment with eculizumab, plasma exchange, and hemodialysis. The patient ultimately remained dialysis-dependent; however, they achieved complete remission for other systemic complications of aHUS. We emphasized in this case report the importance of timely diagnosis and treatment of aHUS as well as the potential value of eculizumab in improving patient outcomes. Furthermore, successful treatment and follow-up results provide insights into the management of this rare disease, including long-term dialysis requirements and disease monitoring after remission. Thus, clinicians can better understand the clinical manifestations of aHUS and its associated diagnostic challenges, treatment strategies, and long-term management needs.