No thick carbon dioxide atmosphere on the rocky exoplanet TRAPPIST-1 c.

Seven rocky planets orbit the nearby dwarf star TRAPPIST-1, providing a unique opportunity to search for atmospheres on small planets outside the Solar System1. Thanks to the recent launch of the James Webb Space Telescope (JWST), possible atmospheric constituents such as carbon dioxide (CO2) are now detectable2,3. Recent JWST observations of the innermost planet TRAPPIST-1 b showed that it is most probably a bare rock without any CO2 in its atmosphere4. Here we report the detection of thermal emission from the dayside of TRAPPIST-1 c with the Mid-Infrared Instrument (MIRI) on JWST at 15 µm. We measure a planet-to-star flux ratio of fp/f⁎ = 421 ± 94 parts per million (ppm), which corresponds to an inferred dayside brightness temperature of 380 ± 31 K. This high dayside temperature disfavours a thick, CO2-rich atmosphere on the planet. The data rule out cloud-free O2/CO2 mixtures with surface pressures ranging from 10 bar (with 10 ppm CO2) to 0.1 bar (pure CO2). A Venus-analogue atmosphere with sulfuric acid clouds is also disfavoured at 2.6σ confidence. Thinner atmospheres or bare-rock surfaces are consistent with our measured planet-to-star flux ratio. The absence of a thick, CO2-rich atmosphere on TRAPPIST-1 c suggests a relatively volatile-poor formation history, with less than [Formula: see text] Earth oceans of water. If all planets in the system formed in the same way, this would indicate a limited reservoir of volatiles for the potentially habitable planets in the system.

Genomic stratification based on microenvironment immune types and PD-L1 for tailoring therapeutic strategies in bladder cancer.

BACKGROUND: The tumour microenvironment (TME) not only plays a role during tumour progression and metastasis but also profoundly influences treatment efficacy. Environment-mediated drug resistance is a result of crosstalk between tumour cells and stroma. The presence of a "stromal exhaustion" response is suggested by the T cell exhaustion signature and PD-L1 expression. The prognostic role of PD-L1 in bladder cancer has been investigated in previous studies, but the results remain inconclusive. For a more comprehensive study, we discuss potential strategies to improve effectiveness in patients with various TME statuses and PD-L1 expression levels. METHODS: We estimated the prognostic role of PD-L1 using immunohistochemistry and identified four immune subtypes according to the type of stromal immune modulation and PD-L1 expression status. RESULTS: Patients in the PD-L1-low-exhausted group had the worst prognosis and showed the worst antigen-presenting cell (APC) immunosuppression status. The PD-L1-low-exhausted group showed the highest amount of infiltration by macrophage M2 cells, naïve B cells and resting mast cells. The TMB and the effectiveness of anti-PD-1 treatment were significantly increased in the PD-L1-high expression groups compared with the PD-L1-low expression groups. In the PD-L1-high groups, patients who underwent chemotherapy exhibited better overall survival rates than patients who did not undergo chemotherapy, whereas there was no significant difference in the PD-L1-low groups. We performed gene set enrichment analysis (GSEA) to explore the critical pathways that were active in the PD-L1-low-exhausted group, including the myogenesis, epithelial-mesenchymal transition and adipogenesis pathways. Copy number variations (CNVs) were related to the expression levels of differentially expressed genes upregulated in the PD-L1-low-exhausted group, including LCNL1, FBP1 and RASL11B. In addition, RASL11B played a role in predicting overall survival according to The Cancer Genome Atlas data, and this finding was validated in the PD-L1-low-exhausted group in the Gene Expression Omnibus database (GEO). CONCLUSION: The immune environment of tumours plays an important role in the therapeutic response rate, and defining the immune groups plays a critical role in predicting disease outcome and strategy effectiveness.

Identification of an immune classification for cervical cancer and integrative analysis of multiomics data.

BACKGROUND: To understand the molecular mechanisms of the antitumour response, we analysed the immune landscape of cervical cancer to identify novel immune molecular classes. METHODS: We established a stable immune molecular classification using a nonnegative matrix factorization algorithm and validated the correlation in two validation sets of 249 samples. RESULTS: Approximately 78% of cervical cancers (CCs) (228/293) were identified to show significant enrichment in immune cells (e.g., CD8 T cells and macrophages), a type I IFN response, enhanced cytolytic activity and high PDCD1, and these CCs were referred to as the "immune class". We further identified two subtypes of the immune class: active immune and exhausted subtypes. Although the active immune subtype was characterized by enrichment of IFN signatures and better survival, the exhausted subtype expressed activated stroma, a wound healing signature, enhanced M2 macrophages and absence of CD8 T cells and the TGF-ß response signature. Integrative analysis of multiomics data identified EGFR, JUN, MYC, FN1 and SERPINE1 as key modulators of the tumour immune microenvironment and potential targets for combination therapies which was validated in two validation sets. CONCLUSIONS: Our study introduces a novel immune classification that might predict ideal candidates to receive immunotherapy or specific combination therapies.

Circadian clock disruption attenuated growth hormone(GH)-mediated signalling.

The circadian molecular clock is an internal time-keeping system, which regulates various physiological processes through the generation of approximately 24-hour circadian rhythms. BMAL1 (brain and muscle arnt-like 1) is a core component of the circadian clock. Previous studies have shown that the circadian clock correlates with rhythmic secretion of endocrine hormone (such as growth hormone, GH). Currently, the effect of circadian clock on the GH-mediated biological activities is not fully understood. In this work, we used BMAL1 gene knockout mice (BMAL-/- mice) model to explore the effect of circadian clock dysfunction on GH's activities, and the results from in vivo and in vitro experiments showed that GH-induced signaling is down-regulated. In vivo, GH/GHR-mediated tyrosine phosphorylation of signaling molecules (such as the Janus kinase-signal transducer and activator of transcription, JAK-STAT) in BMAL-/- mice was significantly lower compared to control mice. In vitro, GH/GHR-mediated signaling in the hepatocytes from BMAL-/- mice is decreased compared to hepatocytes from control mice. Furthermore, we explore the mechanism by which GH/GHR-mediated signalling is down-regulated in BMAL-/- mice, and results indicated that the expression levels of negative regulators of cytokine signaling (such as the suppressor of cytokine signaling (SOCS) and protein phosphatase) were increased, which may be one of the factors that cause the GH signaling downregulation. In summary, our results show that the circadian clock affects the biological activities of GH. This finding lays the foundation for future investigations into the relationship between the circadian clock and biological activities of GH.

Acute sleep deprivation leads to growth hormone (GH) resistance in rats.

Sleep is an essential physiological process that is required by all higher animals. Sleep has many important physiological functions. Previous studies have focused on the relationship between sleep and growth hormone secretion patterns. However, to date, whether sleep affects the biological activities of GH remains unclear. Here, we investigated this issue by evaluating the growth hormone receptor (GHR)-mediated intracellular signalling pathway in a sleep-deprived rat model. The results showed that GH's signalling ability is decreased in an acute sleep deprivation rat model. JAK2-STAT signalling was decreased significantly compared to that in control rats. We further analysed the possible molecular mechanism of GH signal inhibition in sleep-deprived rats. The results showed that the protein expression levels of SOCS3 (suppressors of cytokine signalling 3, which functions as the negative regulatory molecule of GH's signalling) increased; however, other negative regulatory proteins, such as protein phosphatase (PTP1B), did not change. In addition, acute sleep deprivation results in a significant increase in serum FFA (free fatty acid) level, which is also one of the factors contributing to GH inhibition. These findings suggest that GH signal resistance may be caused by a combination of factors. This study could serve as an important reference for related studies on the effect of sleep deprivation on endocrine systems.

Gene signatures based on therapy responsiveness provide guidance for combined radiotherapy and chemotherapy for lower grade glioma.

For a long time, the guidance for adjuvant chemoradiotherapy for lower grade glioma (LGG) lacks instructions on the application timing and order of radiotherapy (RT) and chemotherapy. We, therefore, aimed to develop indicators to distinguish between the different beneficiaries of RT and chemotherapy, which would provide more accurate guidance for combined chemoradiotherapy. By analysing 942 primary LGG samples from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases, we trained and validated two gene signatures (Rscore and Cscore) that independently predicted the responsiveness to RT and chemotherapy (Rscore AUC = 0.84, Cscore AUC = 0.79) and performed better than a previous signature. When the two scores were combined, we divided patients into four groups with different prognosis after adjuvant chemoradiotherapy: RSCS (RT-sensitive and chemotherapy-sensitive), RSCR (RT-sensitive and chemotherapy-resistant), RRCS (RT-resistant and chemotherapy-sensitive) and RRCR (RT-resistant and chemotherapy-resistant). The order and dose of RT and chemotherapy can be adjusted more precisely based on this patient stratification. We further found that the RRCR group exhibited a microenvironment with significantly increased T cell inflammation. In silico analyses predicted that patients in the RRCR group would show a stronger response to checkpoint blockade immunotherapy than other patients.

Impact of adaptive intensity-modulated radiotherapy on the neutrophil-to-lymphocyte ratio in patients with nasopharyngeal carcinoma.

PURPOSE: Nutritional status and haematological parameters are related to the prognosis of patients treated with radiotherapy, but the correlation between adaptive radiotherapy (ART) and haematological indicators has never been reported. This study explores the influence of ART on the change in haematological indicators and provides a theoretical basis for the use of ART in patients with nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: We retrospectively analysed 122 patients with NPC from January 2014 to December 2015. Patients in two treatment groups were matched using the propensity score matching method at a ratio of 1:1. The data were analysed with the Kaplan-Meier method, log-rank tests, regression analyses and paired t tests. RESULTS: Significant differences were detected for changes in the neutrophil-to-lymphocyte ratio (ΔNLR), circulating lymphocyte count (ΔCLC), circulating platelet count (ΔCPC), and circulating neutrophil granulocyte count (ΔCNC) during radiotherapy (P = 0.002, P < 0.001, and P = 0.036, respectively) between the ART and non-ART groups. Differences in acute radiation injury to the parotid glands (PGs) (P < 0.001), skin (P < 0.001), and oral structures (P < 0.001), Δweight (kg) (P = 0.025), and Δweight (%) (P = 0.030) were also significant between the two groups. According to univariate and multivariate analyses, ART (R = 0.531, P = 0.004), skin-related side effects (R = 0.328, P = 0.020), and clinical stage (R = -0.689, P < 0.001) are influencing factors for the ΔNLR in patients. ART is also the influencing factor for the ΔCLC (R = 2.108, P < 0.001) and the only factor affecting the ΔCPC (R = 0.121, P = 0.035). Based on subgroup analyses, for stage T1-2N0-3 disease, ΔCLC was higher in patients in the ART group than in patients in the non-ART group (P < 0.001, P = 0.003, and P = 0.003). CONCLUSION: ART ameliorates changes in haematological indexes (ΔNLR, ΔCLC, and ΔCPC) and reduces side effects to the skin and PGs and weight loss during radiotherapy in patients with NPC, and patients with stage T1-2 disease experience a greater benefit.

Deconvolution and network analysis of IDH-mutant lower grade glioma predict recurrence and indicate therapeutic targets.

Aim: IDH-mutant lower grade glioma (LGG) has been proven to have a good prognosis. However, its high recurrence rate has become a major therapeutic difficulty. Materials & methods: We combined epigenomic deconvolution and a network analysis on The Cancer Genome Atlas IDH-mutant LGG data. Results: Cell type compositions between recurrent and primary gliomas are significantly different, and the key cell type that determines the prognosis and recurrence risk was identified. A scoring model consisting of four gene expression levels predicts the recurrence risk (area under the receiver operating characteristic curve = 0.84). Transcription factor PPAR-α explains the difference between recurrent and primary gliomas. A cell cycle-related module controls prognosis in recurrent tumors. Conclusion: Comprehensive deconvolution and network analysis predict the recurrence risk and reveal therapeutic targets for recurrent IDH-mutant LGG.

Genomic stratification based on radiosensitivity and PD-L1 for tailoring therapeutic strategies in cervical cancer.

Aim: We performed an immunogenomic analysis to help identify a model for the cervical cancer therapeutic module. Patients & methods: Patients were divided into groups according to radiosensitivity and PD-L1 expression status. Results: The PD-L1-low-radioresistant (RR) group indicated worse overall survival under radiotherapy. In addition, the PD-L1-low-RR group showed the lowest immunophenoscore and predicted poor response to anti-PD-1 treatment. Differentially expressed genes associated with the PD-L1-low-RR group were found to play a role in the immune response pathways. FGF19 and PLA2G5 were validated to be upregulated in the PD-L1-low-RR group in the Gene Expression Omnibus database, which predicted the overall survival in the The Cancer Genome Atlas. Conclusion: It will be important to test radiosensitivity and PD-L1 stratification to predict the response to strategies in cervical cancer patients.

Interleukin-6 production mediated by the IRE1-XBP1 pathway confers radioresistance in human papillomavirus-negative oropharyngeal carcinoma.

Endoplasmic reticulum stress (ERS) plays a key role in the pathogenesis and development of tumors and protects tumor cells from radiation damage and drug-induced stress. We previously demonstrated that EGFR confers radioresistance in human papillomavirus (HPV)-negative human oropharyngeal carcinoma by activating ERS signaling through PERK and IRE1α. In addition, PERK confers radioresistance by activating the inflammatory cytokine NF-κB. However, the effect of IRE1 on radiosensitivity has not yet been fully elucidated. Here, we clarified that IRE1 overexpression was associated with poor outcome in HPV-negative patients treated with radiotherapy (P = 0.0001). In addition, a significantly higher percentage of radioresistant HPV-negative patients than radiosensitive HPV-negative patients exhibited high IRE expression (66.7% vs 27.8%, respectively; P = 0.001). Silencing IRE1 and XBP1 increased DNA double-strand break (DSB) and radiation-induced apoptosis, thereby increasing the radiosensitivity of HPV-negative oropharyngeal carcinoma cells. IRE1-XBP1 silencing also inhibited radiation-induced IL-6 expression at both the RNA and protein levels. The regulatory effect of IRE1-XBP1 silencing on DNA DSB-induced and radiation-induced apoptosis was inhibited by pretreatment with IL-6. These data indicate that IRE1 regulates radioresistance in HPV-negative oropharyngeal carcinoma through IL-6 activation, enhancing X-ray-induced DNA DSB and cell apoptosis.

Successful removal of multiple magnetic foreign bodies in the digestive tract of children by gastroscopy: Two case reports.

RATIONALE: Gastrointestinal foreign body (FB) is an emergency commonly encountered by the pediatric gastroenterology department. Management of their extraction requires knowledge and careful consideration of removal techniques. PATIENT CONCERNS: Two little girls swallowed multiple magnets that stuck together for >3 days, which was an indication for surgery. DIAGNOSIS: X-ray revealed dense shadows in the left abdomen. However, the abdominal examination revealed a soft abdomen without tenderness, rebound tenderness, or muscle rigidity. INTERVENTION: The multiple magnets were removed by endoscopy instead of surgery. OUTCOME: We conducted sufficient preoperative assessment and preparation. Eventually, we successfully removed the multiple magnets by endoscopy, and no perforation or fistula formation was observed. Surgery was avoided. LESSONS: Swallowing multiple magnets isn't a rare emergency in children. Physicians must be aware that surgery is not the only option even if multiple magnets are swallowed for >12 hours. Endoscopic removal can be considered if there is no obstruction, perforation, or fistula formation upon careful patient assessment. If endoscopic removal fails, surgical treatment should be performed as soon as possible to avoid serious complications.

PD-1 and PD-L1 Expression Predicts Radiosensitivity and Clinical Outcomes in Head and Neck Cancer and is Associated with HPV Infection.

Objectives: PD-1 and PD-L1 overexpression in malignant tumors in response to radiotherapy is correlated with a poor prognosis. Human papilloma virus (HPV) infection impacts intrinsic radiosensitivity of head and neck cancers (HNCs). Herein, this study aims to determine PD-1/PD-L1 expression differences in tumors with different HPV statuses and their prognostic value in patients with different radiosensitivity gene signatures to define the characteristics of patients who will benefit from radiotherapy combined with anti-PD-1/PD-L1 therapy. Material and methods: According to the identified gene signature related to radiosensitivity, 517 patients from the TCGA HNSCC cohort were selected and divided into the radioresistant (RR) group and radiosensitive (RS) group using a K-mean clustering algorithm. All data analyses were conducted using SPSS and GraphPad Prism. Results: PD-L1 expression is upregulated in tumor tissue (unpaired t test, P=0.0363; paired t test, P=0.0584) compared with normal tissue. PD-L1 was positively correlated with PD-1 expression (P<0.0001). The HPV/p16-positive group was significantly high PD-1 expression (P<0.0001). PD-L1 expression (P=0.0005) and PD-1 expression (P<0.0001) were significantly increased in the RS group compared with that in the RR group. In the patients who were treated with radiotherapy, the PD-1-high group was associated with better recurrence-free survival (RFS) (HR, 0.4892; 95% CI, 0.2357-1.015; P=0.023). Within the RR group, high PD-L1 expression was associated with reduced overall survival (OS) (HR, 2.196; 95% CI, 1.081-4.46; P=0.0108) compared with low PD-L1 expression. In the RR group, HPV/p16-negative patients with high PD-L1 expression exhibited reduced OS (HPV: HR, 2.334; 95% CI, 0.7828-6.961; P=0.0313; p16: HR,2.486; 95% CI, 0.8559-7.219; P=0.0192) compared with that of patients with low PD-L1 expression. In the PD-L1-high group, RR patients exhibited reduced OS (HR, 0.4858; 95% CI, 0.2136-1.105; P=0.0189) and RFS (HR, 0.4371; 95% CI, 0.1421-1.345; P=0.0231) compared with that of RS patients. Conclusion: Our findings demonstrated that high PD-1/PD-L1 expression was strongly related to radiosensitivity, and high PD-1 expression was significantly associated with HPV/p16-positive HNCs. Patients in the radioresistant group and patients in the HPV/p16-negative group with a radioresistant gene signature could benefit from the combination of radiotherapy and anti-PD-1/PD-L1 therapy.