Applicability of the FDA-approved Immunohistochemical Panel for Identification of MMRd Phenotype in Uterine Endometrioid Carcinoma.

Recently, the US Food and Drug Administration (FDA) approved the Ventana MMR RxDx Panel as the first immunohistochemical companion diagnostic test for identification of tumors with mismatch repair (MMR) status. The aim of this study was to investigate the accuracy of this test in comparison with polymerase chain reaction (PCR)-based microsatellite instability (MSI) analysis. We assessed the MMR/MSI concordance rate in 140 cases of endometrioid carcinoma. MMR status was evaluated by immunohistochemistry (MMR-IHC), and MSI status was evaluated by PCR-based analysis (MSI-PCR). Potential molecular mechanisms responsible for MSH6 staining variations were also analyzed. Immunohistochemistry showed that 34 tumors (24.3%) were MMRd; these included 26 with combined MLH1/PMS2 loss, 2 with combined MSH2/MSH6 loss, and 6 with isolated MSH6 loss. Heterogeneous MSH6 loss was found in 10 tumors and was recognized only in tumors with combined MLH1/PMS2 loss. Eight of 10 tumors with heterogeneous MSH6 loss harbored MSH6 C8 tract instability, suggesting a secondary somatic event after MLH1/PMS2 loss. MSI-PCR revealed that 102 tumors were MSS, 4 were MSI-low, and 34 were MSI-high. Consequently, MMR-IHC and MSI-PCR showed perfect concordance (kappa=0.080, P <0.0001). However, 10 of the 34 MSI-high tumors, including the 6 tumors with isolated MSH6 loss, showed only minimal microsatellite shift by MSI-PCR, which may have been erroneously interpreted as MSS or MSI-low. On the basis of these findings, we consider that the FDA-approved immunohistochemical panel can detect MMR variations consistently and is more accurate than MSI-PCR for determining the applicability of immune checkpoint inhibitors for treatment of endometrioid carcinomas.

Activation of CTNNB1 by deubiquitinase UCHL3-mediated stabilization facilitates bladder cancer progression.

BACKGROUND: The catenin beta 1 gene (CTNNB1) plays a crucial role in the malignant progression of various cancers. Recent studies have suggested that CTNNB1 hyperactivation is closely related to the occurrence and development of bladder cancer (BCa). As a member of the deubiquitinating enzyme (DUB) family, ubiquitin C-terminal hydrolase L3 (UCHL3) is abnormally expressed in various cancers. In this study, we discovered that UCHL3 is a novel oncogene in bladder cancer, suggesting it is a promising target against bladder cancer. METHODS: We utilized CRISPR‒Cas9 technology to construct cell lines with UCHL3 stably overexpressed or knocked out. The successful overexpression or knockout of UCHL3 was determined using Western blotting. Then, we performed CCK-8, colony formation, soft agar and Transwell migration assays to determine the impact of the UCHL3 gene on cell phenotype. RNA-seq was performed with UCHL3-depleted T24 cells (established via CRISPR-Cas9-mediated genomic editing). We analyzed differences in WNT pathway gene expression in wild-type and UCHL3-deficient T24 cell lines using a heatmap and by gene set enrichment analysis (GSEA). Then, we validated the effect of UCHL3 on the Wnt pathway using a dual fluorescence reporter. We then analyzed the underlying mechanisms involved using Western blots, co-IP, and immunofluorescence results. We also conducted nude mouse tumor formation experiments. Moreover, conditional UCHL3-knockout mice and bladder cancer model mice were established for research. RESULTS: We found that the overexpression of UCHL3 boosted bladder cancer cell proliferation, invasion and migration, while the depletion of UCHL3 in bladder cancer cells delayed tumor tumorigenesis in vitro and in vivo. UCHL3 was highly associated with the Wnt signaling pathway and triggered the activation of the Wnt signaling pathway, which showed that its functions depend on its deubiquitination activity. Notably, Uchl3-deficient mice were less susceptible to bladder tumorigenesis. Additionally, UCHL3 was highly expressed in bladder cancer cells and associated with indicators of advanced clinicopathology. CONCLUSION: In summary, we found that UCHL3 is amplified in bladder cancer and functions as a tumor promoter that enhances proliferation and migration of tumor cells in vitro and bladder tumorigenesis and progression in vivo. Furthermore, we revealed that UCHL3 stabilizes CTNNB1 expression, resulting in the activation of the oncogenic Wnt signaling pathway. Therefore, our findings strongly suggest that UCHL3 is a promising therapeutic target for bladder cancer.

The Effects of circ_000558/miR-1225-5p/ARL4C on Regulating the Proliferation of Renal Cell Carcinoma Cells.

Renal cell carcinoma (RCC) is one of the top ten tumors over the world. RCC is not sensitive to radiotherapy and chemotherapy. Therefore, it is necessary to find new targets for the treatment. CircRNAs are a special type of noncoding RNAs, which play important roles in many types of cancer. In this study, we found circ_000558 was upregulated in RCC cells, and it elevated the proliferation ability of RCC cells. The relationship between miR-1225-5p and circ_000558 or ARL4C was predicted via circBank and circular RNA interactome and confirmed by dual-luciferase reporter assay. Then, the effects of circ_000558/miR-1225-5p/ARL4C on RCC cell proliferation and apoptosis were assessed by CCK-8 assay. The results revealed that the knockdown of ARL4C significantly reduced RCC cell proliferation and overexpression of circ_000558 could significantly induce RCC cell proliferation after miR-1225-5p treatment further promoted the inhibitory ability of ARL4C knockdown. Overall, our study suggested that circ_000558/miR-1225-5p/ARL4C network was related to the RCC cell proliferation. This finding could provide new targets for the treatment and prognosis of RCC.

Sncg, Mybpc1, and Parm1 Classify subpopulations of VIP-expressing interneurons in layers 2/3 of the somatosensory cortex.

Neocortical vasoactive intestinal polypeptide-expressing (VIP+) interneurons display highly diverse morpho-electrophysiological and molecular properties. To begin to understand the function of VIP+ interneurons in cortical circuits, they must be clearly and comprehensively classified into distinct subpopulations based on specific molecular markers. Here, we utilized patch-clamp RT-PCR (Patch-PCR) to simultaneously obtain the morpho-electric properties and mRNA profiles of 155 VIP+ interneurons in layers 2 and 3 (L2/3) of the mouse somatosensory cortex. Using an unsupervised clustering method, we identified 3 electrophysiological types (E-types) and 2 morphological types (M-types) of VIP+ interneurons. Joint clustering based on the combined electrophysiological and morphological features resulted in 3 morpho-electric types (ME-types). More importantly, we found these 3 ME-types expressed distinct marker genes: ~94% of Sncg+ cells were ME-type 1, 100% of Mybpc1+ cells were ME-type 2, and ~78% of Parm1+ were ME-type 3. By clarifying the properties of subpopulations of cortical L2/3 VIP+ interneurons, this study establishes a basis for future investigations aiming to elucidate their physiological roles.

Effects of Intraoperative Opioid Administration on Postoperative Pain and Pain Threshold: A Randomized Controlled Study.

Fentanyl and short-acting remifentanil are often used in combination. We evaluated the effect of intraoperative opioid administration on postoperative pain and pain thresholds when the two drugs were used. Patients who underwent gynecological laparoscopic surgery were randomly assigned into two groups (15 patients each) to receive either sufficient (group A) or minimum (group B) fentanyl (maximum estimated effect site concentration: A: 7.86 ng/mL, B: 1.5 ng/mL). The estimated effect site concentration at the end of surgery was adjusted to the same level (1 ng/mL). Patients in both groups also received continuous intravenous remifentanil during surgery. The primary outcome was the pressure pain threshold, as evaluated by a pressure algometer 3 h postoperatively. The pressure pain threshold at 3 h postoperatively was 51.1% (95% CI: [44.4-57.8]) in group A and 56.6% [49.5-63.6] in group B, assuming a preoperative value of 100% (p = 0.298). There were no significant differences in pressure pain threshold and numeric rating scale scores between the groups after surgery. The pain threshold decreased significantly in both groups at 3 h postoperatively compared to preoperative values, and recovered at 24 h. Co-administration of both opioids caused hyperalgesia regardless of fentanyl dose.

Transient Receptor Potential Channel 1 Potentially Serves as a Biomarker Indicating T/TNM Stages and Predicting Long-Term Prognosis in Patients With Renal Cell Carcinoma.

Background: Transient receptor potential channel 1 (TRPC1) regulates the progression of several cancers, but its clinical implication in renal cell carcinoma (RCC) has not been explored yet. This study aimed to investigate the correlation of TRPC1 with clinical characteristics and prognosis in patients with RCC. Methods: Totally, 177 patients with primary RCC who received surgical resection were retrospectively screened. Their tumor and paired adjacent tissue specimens were retrieved to assess TRPC1 mRNA expression using RT-qPCR and TRPC1 protein expression using immunohistochemistry (IHC). Results: Both TRPC1 IHC score and TRPC1 mRNA expression were elevated in RCC tissue than in adjacent tissue (both P < 0.001). Meanwhile, both TRPC1 IHC score and TRPC1 mRNA expression in tumor were associated with higher T stage (both P = 0.02) and TNM stage (P = 0.009, P = 0.003, respectively). However, no correlation was found in tumor TRPC1 IHC score or TRPC1 mRNA expression with other tumor properties (all P > 0.05). Besides, the 3-, 5-, and 7-year overall survival (OS) were 81.4, 68.6, and 60.2%, respectively in patients with high tumor TRPC1 protein, while they were 89.3, 82.7, and 76.7%, respectively in patients with low tumor TRPC1 protein. High (vs. low) TRPC1 protein in the tumor was associated with shorter OS (P = 0.017), while high (vs. low) TRPC1 mRNA in the tumor was not correlated with OS (P = 0.144). By the forward stepwise method, TRPC1 protein expression independently predicted poor OS (P = 0.01, hazard ratio = 2.052). Conclusion: TRPC1 serves as a potential biomarker reflecting tumor features and long-term survival profile in patients with RCC.

Prevalence of tobacco dependence and associated factors in China: Findings from nationwide China Health Literacy Survey during 2018-19.

Background: Tobacco dependence is the key barrier to successful smoking cessation. However, little is known about its prevalence, sociodemographic characteristics and determinants. We aimed to estimate the prevalence, associated factors and burden of tobacco dependence in China. Methods: During 2018-2019, the nationally representative 2018 China Health Literacy Survey (2018 CHLS) invited 87,708 participants to participate using a multistage stratified sampling method from 31 provinces (or equivalent) in mainland China, and 84,839 participants aged 20-69 with valid data were included in the analysis. We diagnosed tobacco dependence based on international criteria (ICD-10, DSM-4) and tailored to Chinese population according to China Clinical Guideline for Tobacco Cessation (2015 version). The prevalence of tobacco dependence was estimated overall and by sociodemographic factors. The Logistic regression was conducted to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tobacco dependence and success of smoking cessation (being ex-smokers), with different levels of adjustment. These were used to estimate the total number of adults who were tobacco dependent in China. Findings: In China, the estimated prevalence of current smoking was 25.1%, significantly higher in men than in women (47.6% vs 1.9%). The prevalence of current smoking varied approximately 3-fold (12.9% to 37.9%) across 31 provinces of China. Among general population aged 20-69 years, the prevalence of tobacco dependence was 13.1% (95% CI:12.2-14.1). Among current smokers, the prevalence of tobacco dependence was 49.7% (46.5-52.9%), with no difference between men and women (49.7% vs 50.8%). The prevalence of tobacco dependence was associated significantly with smoking intensity, defined by pack-years (1.62 [1.54-1.70] per 10 pack-years), cigarettes smoked per day (2.01 [1.78, 2.27] per 10 cigarettes), and smoking starting age (0.93 [0.90, 0.97] per 5 years). Given smoking intensity, the prevalence of tobacco dependence also varied by age, gender, certain socioeconomic status and regions. Compared with those without tobacco dependence, ever smokers with tobacco dependence were less likely to be ex-smokers (2.88, 2.59-3.21). In China, 183.5 (170.4-197.4) million adults (177.5 million were men) were tobacco dependent in 2018. Interpretation: In China, tobacco dependence is highly prevalent, with approximately half of current smokers being addictive, highlighting the need for coordinated effort to improve awareness, diagnosis and treatment of tobacco dependence. Funding: Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine (CAMS 2021-I2M-1-010), National Key R&D Program of China (grant no 2017YFC1309400), and National Natural Science Foundation of China (grant no 81720108001). Note: Chinese translation of abstract is available in appendix section.

CTSV (cathepsin V) promotes bladder cancer progression by increasing NF-κB activity.

Chronic inflammation is positively associated with the development of urinary bladder cancer. However, its detailed regulatory mechanism remains elusive. The quantitative real-time polymerase chain reaction was used to measure mRNA levels of relative genes. The protein levels were monitored by western blotting. Cell proliferation and viability were evaluated by the cell counting Kit 8 (CCK8) and colony formation assays, respectively. The dual-luciferase reporter assay was performed to assay the transcriptional activity. In vivo experiments were implemented in nude mice as well. The TCGA database analysis suggested that the aberrant expression of cathepsin V (CTSV) was related to a poor outcome in bladder cancer patients. CTSV boosted the inflammation reaction, which facilitated the development of bladder cancer. The overexpression of CTSV increased the proliferation and viability of bladder cancer cells. On the contrary, the deletion of CTSV significantly inhibited the proliferation and viability of bladder cancer cells. The tumor repression resulting from CTSV deficiency in vitro was also verified in vivo. Moreover, multiple cancer-associated luciferase screening showed that the overexpression of CTSV triggered the inflammatory signaling pathway, which could be restored by introducing the NF-κB inhibitor. CTSV is upregulated and promotes proliferation through the NF-κB pathway in bladder cancer and may be a potential target in inflammation-associated bladder cancer.

Long non-coding RNA MEG8 induced by PLAG1 promotes clear cell renal cell carcinoma through the miR-495-3p/G3BP1 axis.

Clear cell renal cell carcinoma (ccRCC) is recognized as one of the most lethal malignancies among the urological system, with constantly increasing mortality. While the molecular mechanisms underlying ccRCC progression are still poorly understood, the molecular and functional role of lncRNA in multiple diseases has been well demonstrated. In this study, we hypothesized that lncRNA MEG8 might participate in ccRCC development. At first, we found that MEG8 expression was increased in ccRCC tumor tissues and cells. Next, we demonstrated that MEG8 knockdown suppressed cell viability, migration, and invasion in vitro and inhibited tumor growth in vivo. Subsequently, we utilized bioinformatics analysis, ChIP, and luciferase assays, and we found that PLAG1 could transcriptionally regulate MEG8 in ccRCC cells. Furthermore, MEG8 promoted G3BP1 expression to aggravate ccRCC tumorigenic properties through sponging miR-495-3p. Our study identified a novel PLAG1/MEG8/miR-495-3p/G3BP1 network in ccRCC development, which might be a promising direction for developing new diagnoses or therapeutic agents for ccRCC.

Association between intention to call EMS in stroke patients and level of hospital classification and emergency medical service usage among stroke patients in China.

INTRODUCTION: Different categories of hospitals in China have varying levels of patient education. Stroke recognition and emergency medical services (EMS) usage in patients appears to be closely associated with patient education in hospital. This study aimed to explore the effect of hospital classification in China on a patient's ability to recognise stroke symptoms and the likelihood of using the EMS. MATERIAL AND METHODS: A cross-sectional, community-based study was conducted from January to May 2017, and 1,426 residents who had previously been hospitalised were analysed. The patients involved in the study were from 69 administrative areas in China. Multivariable logistic regression models were developed separately for primary, secondary, and tertiary hospitals to identify the associations between hospital grades and patient stroke recognition or the prospects of them using the EMS. RESULTS: Among the 1,426 patients studied, 725 had been admitted to tertiary hospitals, 448 to secondary hospitals, and 253 to primary hospitals. According to univariate analysis, tertiary hospital patients were more likely to use the EMS than patients in primary and secondary hospitals. The difference therein was still significant after full adjustment. CONCLUSIONS: Patients in tertiary hospitals were significantly more likely to use the EMS promptly compared to patients in primary or secondary hospitals. Therefore, patient education on timely EMS usage at stroke onset should be enhanced in primary and secondary hospitals in China.

[Effect of Bo's abdominal acupuncture as adjunctive therapy on rheumatoid arthritis and ESR, RF and CRP levels].

OBJECTIVE: To explore the therapeutic effect on rheumatoid arthritis treated with Bo's abdominal acupuncture for "guiding qi to the source" plus "opening four gates on the abdomen" and the relevant effect mechanism. METHODS: A total of 104 patients with rheumatoid arthritis were randomized into and an observation group (52 cases, 1 case dropped off) and a control group (52 cases, 3 cases dropped off). In the control group, methotrexate tablets were prescribed for oral administration, 5 mg each time, once a week. In the observation group, on the base of the treatment as the control group, Bo's abdominal acupuncture was combined. The acupoints included Zhongwan (CV 12), Xiawan (CV 10), Guanyuan (CV 4), Qihai (CV 6), Huaroumen (ST 24), Wailing (ST 26), etc. The treatment was given once every two days, 3 times weekly. Totally 12 weeks were required in the two groups. Before and after treatment, the score of TCM symptoms (including joint pain, the range of motion, joint swelling and morning stiffness), and the levels of erythrocyte sedimentation rate (ESR), rheumatoid factor (RF) and C-reactive protein (CRP) were observed and the clinical therapeutic effect was assessed in the two groups. RESULTS: After treatment, the total effective rate was 88.2% (45/51) in the observation group, higher than 73.5% (36/49) in the control group (P<0.05). The score of each TCM symptom and the total scores after treatment were all lower than those before treatment in the two groups (P<0.05), and these scores in the observation group were lower than the control group (P<0.05). After treatment, the levels of ESR, RF and CRP were all lower than those before treatment in the two groups (P<0.05), while the levels of those indexes in the observation group were lower than the control group (P<0.05). CONCLUSION: Bo's abdominal acupuncture for "guiding qi to the source" plus "opening four gates on the abdomen" as the adjunctive therapy effectively relieves the clinical symptoms in the patients with rheumatoid arthritis, which is related to the reduction of ESR, RF and CRP in mechanism.

Impact of regional differences in stroke symptom awareness and low-income status on seeking emergency medical service in China.

BACKGROUND: Unawareness of stroke symptoms and low income are two barriers that affect the seeking of emergency medical service (EMS). This study aimed to assess the effect of unawareness and low income on seeking EMS and to investigate the regional distribution of the unawareness and low-income status and their associations with failing to call EMS in China. METHODS: A total of 187,723 samples from the China National Stroke Screening Survey was interviewed cross-sectionally. Four status of awareness and annual income were identified: unaware and low-income, unaware-only, low-income-only, and aware and regular income. The outcomes were whether they intended to call EMS or not. The regional distribution of each status and their associations with not calling EMS were presented. RESULTS: The status of unaware and low-income, unaware-only, and low-income-only accounted for 6.3% (11,806/187,673), 11.9% (22,241/187,673), and 21.5% (40,289/187,673) of the total sample, respectively. Not calling EMS was significantly associated with the status of unaware and low-income (odds ratio [OR]: 3.21, 95% confidence interval [CI]: 3.07-3.35), unaware-only (OR: 2.38, 95% CI: 2.31-2.46), and low-income-only (OR: 1.67, 95% CI: 1.63-1.71), compared with the aware and regular income status. The Midwest regions had higher percentages of people in the unaware and low-income status; the East, South, and Central had higher percentages of unaware-only status; the North and Northeast regions had a higher percentage of low-income-only status, compared with other regions. CONCLUSION: The existence of the regional difference in unawareness and low income justifies the specific stroke education strategies for the targeted regions and population.

Construction of the National Brain Tumor Registry of China for better management and more efficient use of data: a protocol.

INTRODUCTION: Brain tumours encompass a complex group of intracranial tumours that mostly affect young adults and children, with a high incidence rate and poor prognosis. It remains impossible to systematically collect data on patients with brain tumours in China and difficult to perform in-depth analysis on the status of brain tumours, medical outcomes or other important medical issues through a multicentre clinical study. This study describes the first nation-wide data platform including the entire spectrum of brain tumour entities, which will allow better management and more efficient application of patient data in China. METHODS AND ANALYSIS: The National Brain Tumor Registry of China (NBTRC) is a registry of real-word clinical data on brain tumours. It is established and managed by the China National Clinical Research Center for Neurological Diseases and administered by its scientific and executive committees. The 54 participating hospitals of the NBTRC are located in 27 provinces/municipalities, performing more than 40 000 brain tumour surgeries per year. The data consist of in-hospital medical records, images and follow-up information after discharge. Data can be uploaded in three ways: the web portal, remote physical servers and offline software. The data quality control scheme is seven-dimensional. Each participating hospital could focus on a single pathology subtype and public subtypes of brain tumour for which they expect to conduct related multicentre clinical research. The standardised workflow to conduct clinical research is based on the benefit-sharing mechanism. Data collection will be conducted continuously from 1 February 2019 to 31 January 2024. ETHICS AND DISSEMINATION: Informed consent will be obtained from all participants. Consent for the adolescents' participation will be also obtained from their guardians via written consent. The results will be published in professional journals, in both Chinese and English. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1900021096).

Downregulated exosomal microRNA-148b-3p in cancer associated fibroblasts enhance chemosensitivity of bladder cancer cells by downregulating the Wnt/ß-catenin pathway and upregulating PTEN.

OBJECTIVE: Exosomes derived from cancer-associated fibroblasts (CAFs) are known as important drivers of tumor progression. Previously, microRNA (miR)-148b-3p has been found to be upregulated in bladder cancers as well as in body fluids (blood, urine) of bladder cancer patients. Here, we aimed to explore the role of CAF-derived exosome miR-148b-3p in bladder cancer progression and chemosensitivity. METHODS: Transwell, MTT, flow cytometry and colony formation assays were applied to assess the effects of CAF-derived exosomes on bladder cancer cell metastasis, epithelial-mesenchymal transition (EMT) and chemosensitivity. A dual luciferase reporter assay was employed to evaluate the targeting relationship between miR-148b-3p and PTEN. Gain- and loss- of function assays were conducted to explore the roles of miR-148b-3p and PTEN in the behavior of bladder cancer cells. The role of PTEN in the metastasis, EMT and chemosensitivity of bladder cancer cells was assessed both in vivo and in vitro. RESULTS: We found that CAF-derived exosomes promoted the metastasis, EMT and drug resistance of bladder cancer cells. We also found that CAF-derived exosomes could directly transport miR-148b-3p into bladder cancer cells. In a xenograft mouse model we found that CAF-derived exosomes increased miR-148b-3p expression levels and promoted tumor proliferation, metastasis and drug resistance. PTEN was validated as a target of miR-148b-3p. Concordantly, we found that PTEN overexpression inhibited EMT, metastasis and chemoresistance in bladder cancer cells, reversing the tumor promoting effects of miR-148b-3p via the Wnt/ß-catenin pathway. CONCLUSIONS: Our results suggest that miR-148b-3p downregulation in CAF-derived exosomes, thereby inhibiting the Wnt/ß-catenin pathway and promoting PTEN expression, may offer potential opportunities for bladder cancer treatment.

Human torpor: translating insights from nature into manned deep space expedition.

During a long-duration manned spaceflight mission, such as flying to Mars and beyond, all crew members will spend a long period in an independent spacecraft with closed-loop bioregenerative life-support systems. Saving resources and reducing medical risks, particularly in mental heath, are key technology gaps hampering human expedition into deep space. In the 1960s, several scientists proposed that an induced state of suppressed metabolism in humans, which mimics 'hibernation', could be an ideal solution to cope with many issues during spaceflight. In recent years, with the introduction of specific methods, it is becoming more feasible to induce an artificial hibernation-like state (synthetic torpor) in non-hibernating species. Natural torpor is a fascinating, yet enigmatic, physiological process in which metabolic rate (MR), body core temperature (Tb ) and behavioural activity are reduced to save energy during harsh seasonal conditions. It employs a complex central neural network to orchestrate a homeostatic state of hypometabolism, hypothermia and hypoactivity in response to environmental challenges. The anatomical and functional connections within the central nervous system (CNS) lie at the heart of controlling synthetic torpor. Although progress has been made, the precise mechanisms underlying the active regulation of the torpor-arousal transition, and their profound influence on neural function and behaviour, which are critical concerns for safe and reversible human torpor, remain poorly understood. In this review, we place particular emphasis on elaborating the central nervous mechanism orchestrating the torpor-arousal transition in both non-flying hibernating mammals and non-hibernating species, and aim to provide translational insights into long-duration manned spaceflight. In addition, identifying difficulties and challenges ahead will underscore important concerns in engineering synthetic torpor in humans. We believe that synthetic torpor may not be the only option for manned long-duration spaceflight, but it is the most achievable solution in the foreseeable future. Translating the available knowledge from natural torpor research will not only benefit manned spaceflight, but also many clinical settings attempting to manipulate energy metabolism and neurobehavioural functions.

Blocking Effect of Demethylzeylasteral on the Interaction between Human ACE2 Protein and SARS-CoV-2 RBD Protein Discovered Using SPR Technology.

The novel coronavirus disease (2019-nCoV) has been affecting global health since the end of 2019, and there is no sign that the epidemic is abating. Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. In this study, surface plasmon resonance (SPR) was used as the primary method to screen a library of 960 compounds. A compound 02B05 (demethylzeylasteral, CAS number: 107316-88-1) that had high affinities for S-RBD and ACE2 was discovered, and binding affinities (KD, µM) of 02B05-ACE2 and 02B05-S-RBD were 1.736 and 1.039 µM, respectively. The results of a competition experiment showed that 02B05 could effectively block the binding of S-RBD to ACE2 protein. Furthermore, pseudovirus infection assay revealed that 02B05 could inhibit entry of SARS-CoV-2 pseudovirus into 293T cells to a certain extent at nontoxic concentration. The compoundobtained in this study serve as references for the design of drugs which have potential in the treatment of COVID-19 and can thus accelerate the process of developing effective drugs to treat SARS-CoV-2 infections.

Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-ß signaling pathway.

Therapeutic failure in prostate cancer (PC) is believed to result from its unusually invasive and metastatic nature. Cancer-associated fibroblasts (CAFs) are essential in the tumor microenvironment. We intended to study the role of CAF-derived exosomes in the context of PC and the potential regulatory mechanism associated with miR-423-5p and GREM2. CAF-derived exosomes decreased the chemosensitivity of parental PC cells and enhanced the drug resistance of drug-resistant cells. PC-associated fibroblast-derived exosomes carrying miR-423-5p increased the resistance of PC to taxane by inhibiting GREM2 through the TGF-ß pathway. Inhibition of the TGF-ß pathway partially reversed the increased drug resistance in PC cells induced by CAF-derived exosomes. Inhibition of miR-423-5p enhanced the drug sensitivity of PC cells in vivo. We showed that CAF-secreted exosomal miR-423-5p promoted chemotherapy resistance in PC by targeting GREM2 through the TGF-ß pathway. This study may allow the development of novel approaches for PC.