Frailty in middle-aged and older adult postoperative patients with gynecological malignancies structural equation modeling.

Background: Frailty and self-management are important determinants of quality of life in cancer patients. However, their synergistic effects and potential mechanisms on quality of life in middle-aged and older adult postoperative gynecologic malignancy patients have not been adequately studied. Objective: This cross-sectional study aimed to explore the relationship between frailty, self-management, and quality of life in middle-aged and older adult postoperative gynecologic malignancy patients. Methods: A cross-sectional study was conducted from January 2024 to April 2024 in three gynecological wards of a tertiary hospital in Wuxi. The study recruited 177 patients aged 45 years or older who underwent surgery for gynecologic malignancies (cervical, ovarian, and endometrial cancer). Data were collected using demographic and clinical characteristics, the Edmonton Frailty Scale, the Self-Management Competence Scale, and the EORTC Core Quality of Life Questionnaire. Structural equation modeling was used to explore the interactions between frailty, self-management, and quality of life. Results: The prevalence of frailty in middle-aged and older adult postoperative gynecologic malignancy patients was 39.5%, with a mean total self-management score of 125.81 ± 13.21 and a mean total quality of life score of 69.26 ± 10.88. The fit indices of the model indicated a good fit, and that frailty had multiple effects on quality of life; specifically, frailty could affect the quality of life directly or through self-management, i.e., self-management partially mediated frailty and quality of life. Conclusion: Self-management is a mediating variable between frailty and quality of life, suggesting that clinical workers can intervene in self-management skills to improve patient's quality of life and physical and mental health.

Serum Soluble Suppression of Tumorigenicity-2 Levels Predict Cardiovascular Events in Patients Undergoing Incident Peritoneal Dialysis: A Prospective Cohort Study.

INTRODUCTION: Biomarkers are urgently required to identify peritoneal dialysis (PD) patients at risk of cardiovascular (CV) events. This study aimed to investigate the predictive value of soluble suppression of tumorigenicity-2 (sST2) for CV events in patients undergoing incident PD. METHODS: In this prospective cohort study, incident PD patients were enrolled. Blood samples to measure sST2 levels were obtained before PD catheter implantation. The patients underwent a standard peritoneal equilibration test (PET) after initiation of PD for 4-6 weeks. The sST2 levels in both serum and dialysate were determined using enzyme-linked immunosorbent assay. CV events were recorded during the follow-up period. RESULTS: A total of 137 patients were enrolled. During the follow-up period of 17.3 months, 49 (35.76%) patients experienced CV events. When patients were dichotomized based on the median values and the calculated cutoff values of sST2, the higher sST2 group had 2.980- and 3.048-fold increased risks of CV events, respectively, when compared with the lower sST2 group. Moreover, the prognostic value of sST2 remained significant as a continuous variable (per 1 standard deviation increase, hazard ratio [HR] = 1.037, 95% confidence interval [CI] 1.010-1.066, p = 0.008). N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were found to indicate a higher risk only when dichotomized based on the calculated cutoff values. Furthermore, serum sST2 and NT-proBNP levels simultaneously above the calculated cutoff values were associated with a higher risk of CV events (HR = 3.398, 95% CI 1.813-6.367, p < 0.001). CONCLUSION: Baseline serum sST2 level is an independent predictor of the risk of CV events in patients receiving incident PD, and in combination with NT-proBNP level, it can provide a more accurate predictive value.

Clinical, Imaging Characteristics and Outcome of Intracerebral Hemorrhage Caused by Structural Vascular Lesions.

BACKGROUND: The objective of this study was to investigate the clinical, imaging, and outcome characteristics of intracerebral hemorrhage (ICH) caused by structural vascular lesions. METHODS: We retrospectively analyzed data from a prospective observational cohort study of patients with spontaneous ICH admitted to the First Affiliated Hospital of Chongqing Medical University between May 2016 and April 2021. Good outcome was defined as modified Rankin Scale score of 0-3 at 3 months. The clinical and imaging characteristics were compared between primary ICH and ICH caused by structural vascular lesions. Multivariable logistic regression analysis was performed to test the associations of etiology with clinical outcome. RESULTS: All patients enrolled in this study were Asian. Compared with patients with primary ICH, those with structural vascular lesions were younger (48 vs. 62 years, P < 0.001), had a lower incidence of hypertension (26.4% vs. 81.7%, P < 0.001) and diabetes (7.4% vs. 16.2%, P = 0.003), and had mostly lobar hemorrhages (49.1% vs. 22.8%). ICH from structural vascular lesions had smaller baseline hematoma volume (8.4 ml vs. 13.8 ml, P = 0.010), had lower mortality rate at 30 days and 3 months (5.8% vs. 12.0%, P = 0.020; 6.7% vs. 14.8%, P = 0.007), and are associated with better functional outcome at 3 months (88% vs.70.3%, P < 0.001). CONCLUSIONS: Compared with primary ICH, ICH due to vascular lesions has smaller hematoma volume and less severe neurological deficit at presentation and better functional outcomes.

Safety and immunogenicity of the COVID-19 mRNA vaccine CS-2034: A randomized, double-blind, dose-exploration, placebo-controlled multicenter Phase I clinical trial in healthy Chinese adults.

BACKGROUND: The novel coronavirus pneumonia (COVID-19) is an infectious disease caused by the infection of a novel coronavirus known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has resulted in millions of deaths. We aimed to evaluate the safety and immunogenicity of the COVID-19 mRNA vaccine (CS-2034, CanSino, Shanghai, China) in adults without COVID-19 infection from China. METHOD: This is a multicenter Phase I clinical trial with a randomized, double-blinded, dose-exploration, placebo-controlled design. The trial recruited 40 seronegative participants aged 18-59 years who had neither received any COVID-19 vaccine nor been infected before. They were divided into a low-dose group (administered with either the CS-2034 vaccine containing 30 µg of mRNA or a placebo of 0.3 ml type 5 adenovirus vector) and a high-dose group (administered with either the CS-2034 vaccine containing 50 µg of mRNA or a placebo of 0.5 ml type 5 adenovirus vector). Participants were randomly assigned in a 3:1 ratio to receive either the mRNA vaccine or a placebo on days 0 and 21 according to a two-dose immunization schedule. The first six participants in each dosage group were assigned as sentinel subjects. Participants were sequentially enrolled in a dose-escalation manner from low to high dose and from sentinel to non-sentinel subjects. Blood samples were collected from all participants on the day before the first dose (Day 0), the day before the second dose (day 21), 14 days after the second dose (day 35), and 28 days after the second dose (day 49) to evaluate the immunogenicity of the CS-2034 vaccine. Participants were monitored for safety throughout the 28-day follow-up period, including solicited adverse events, unsolicited adverse events, adverse events of special interest (AESI), and medically attended adverse events (MAE). This report focuses solely on the safety and immunogenicity analysis of adult participants aged 18-59 years, while the long-term phase of the study is still ongoing. This study is registered at ClinicalTrials.gov, NCT05373485. FINDINGS: During the period from May 17, 2022, to August 8, 2022, a total of 155 participants aged 18-59 years were screened for this study. Among them, 115 participants failed the screening process, and 40 participants were randomly enrolled (15 in the low-dose group, 15 in the high-dose group, and 10 in the placebo group). Throughout the 28-day follow-up period, the overall incidence of adverse reactions (related to vaccine administration) in the low-dose group, high-dose group, and placebo group was 93.33% (14/15), 100.00% (15/15), and 80.00% (8/10), respectively. There was a statistically significant difference in the incidence of local adverse reactions (soreness, pruritus, swelling at the injection site) among the low-dose group, high-dose group, and placebo group (P = 0.002). All adverse reactions were mainly of severity grade 1 (mild) or 2 (moderate), and no adverse events of severity grade 4 or higher occurred. Based on the analysis of Spike protein Receptor Binding Domain (S-RBD) IgG antibodies against the BA.1 strain, the seroconversion rates of antibodies at day 21 after the first dose were 86.67%, 93.33%, and 0.00% in the low-dose group, high-dose group, and placebo group, respectively. The geometric mean titer (GMT) of antibodies was 61.2(95%CI 35.3-106.2), 55.4(95%CI 36.3-84.4), and 15.0(95%CI 15.0-15.0), and the geometric mean fold increase (GMI) was 4.08(95%CI 2.35-7.08), 3.69(95%CI 2.42-5.63), and 1.00(95%CI 1.00-1.00) for each group. At day 28 after the full vaccination, the seroconversion rates of antibodies were 100.00%, 93.33%, and 0.00%, and the GMT of antibodies was 810.0(95%CI 511.4-1283.0), 832.2(95%CI 368.1-1881.6), and 15.0(95%CI 15.0-15.0), and the GMI was 54.00(95%CI 34.09-85.53), 55.48(95%CI 24.54-125.44), and 1.00(95%CI 1.00-1.00) for each group, respectively. Based on the analysis of CD3+/CD4+ cell cytokine response, the percentages of IL-2+, IL-4+, IFN-γ+, and TNF-α+ cells increased after 14 days and 28 days of full vaccination in both the low-dose group and high-dose group. The increase was most pronounced in the high-dose group. INTERPRETATION: At day 28 after the full vaccination, both the low-dose and the high-dose CS-2034 vaccine were able to induce the production of high titers of S-RBD IgG antibodies against the BA.1 strain. Adverse reactions in the low-dose and high-dose groups were mainly of severity grade 1 or 2, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine.

CD24-Fc suppression of immune related adverse events in a therapeutic cancer vaccine model of murine neuroblastoma.

Introduction: The combination of Myc-suppressed whole tumor cells with checkpoint inhibitors targeting CTLA-4 and PD-L1 generates a potent therapeutic cancer vaccine in a mouse neuroblastoma model. As immunotherapies translate from pre-clinical to clinical trials, the potential immune-related adverse events (irAEs) associated with induction of potent immunity must be addressed. The CD24-Siglec 10/G interaction is an innate checkpoint that abrogates inflammatory responses to molecules released by damaged cells, but its role in cancer immunology is not well defined. We investigate irAEs of an effective whole cell neuroblastoma vaccine and subsequently the effect of CD24-Fc, a CD24 and Fc fusion protein, on both the vaccine efficacy and induced irAEs in a mouse neuroblastoma model. Methods: To test whether the whole tumor cell vaccination leads to autoimmune responses in other organ systems we harvested lung, heart, kidney and colon from naïve mice (n=3), unvaccinated tumor only mice (n=3), and vaccinated mice with CD24 Fc (n=12) or human IgG-Fc control (n=12) after tumor inoculation and vaccination therapy at day 30. The Immune cell infiltrates and immunogenic pathway signatures in different organ systems were investigated using NanoString Autoimmune Profiling arrays. Nanostring RNA transcript results were validated with immunohistochemistry staining. Results: The whole tumor cell vaccine combined with immune checkpoint therapy triggers occult organ specific immune cell infiltrates, primarily in cardiac tissue and to a lesser extent in the renal and lung tissue, but not in the colon. CD24-Fc administration with vaccination partially impedes anti-tumor immunity but delaying CD24-Fc administration after initial vaccination reverses this effect. CD24-Fc treatment also ameliorates the autoimmune response induced by effective tumor vaccination in the heart. Discussion: This study illustrates that the combination of Myc suppressed whole tumor cell vaccination with checkpoint inhibitors is an effective therapy, but occult immune infiltrates are induced in several organ systems in a mouse neuroblastoma model. The systemic administration of CD24-Fc suppresses autoimmune tissue responses, but appropriate timing of administration is critical for maintaining efficacy of the therapeutic vaccine.

Randomized controlled trial for anesthesia during gastroscopy: interactions between remimazolam and propofol in combination with sufentanil.

BACKGROUND: Remimazolam is a new short-duration anesthetic currently used for gastroscopy and can be mixed with propofol and potent opioids. AIM: The study aimed to investigate the synergistic interaction between remimazolam and propofol after sufentanil administration and to determine the appropriate dose ratios between remimazolam and propofol. METHOD: This study used a randomized controlled design. Patients scheduled for gastrointestinal endoscopy were included and randomized into five groups. The randomized block design was applied at a randomization ratio of 1:1. Patients in each group received sufentanil (0.1 µg/kg) and the calculated doses of remimazolam and propofol. Using the up and down method, the median effective dose (ED50) and the 95% confidence interval (CI) were determined based on whether the eyelash reflex disappeared in each treatment group. Isobolographic analysis was used to analyze the presence of drug interactions. The interaction coefficient and the dose ratio between remimazolam and propofol were calculated by algebraic analysis. Statistical analysis was performed using interval estimates and 95% CI for statistical attributes. RESULTS: Cross-sectional analysis of the isobologram showed a clinically significant synergistic effect between remimazolam and propofol. When 0.016, 0.032, and 0.047 mg/kg of remimazolam were combined with 0.477, 0.221, and 0.131 mg/kg of propofol, the interaction coefficients were 1.04, 1.21, and 1.06, respectively. The dose ratio of remimazolam to propofol was approximately 1:7. CONCLUSION: Remimazolam and propofol have synergistic clinical effects. A strong synergistic effect was observed when the remimazolam and propofol dose ratio was 1:7 (mg/kg). CLINICAL TRIAL: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR2100052425).

The ectonucleotidases CD39 and CD73 on T cells: The new pillar of hematological malignancy.

Hematological malignancy develops and applies various mechanisms to induce immune escape, in part through an immunosuppressive microenvironment. Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment (TME). Adenosine signaling through the A2A receptor expressed on immune cells, such as T cells, potently dampens immune responses. Extracellular adenosine generated by ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5'-nucleotidase (CD73) molecules is a newly recognized 'immune checkpoint mediator' and leads to the identification of immunosuppressive adenosine as an essential regulator in hematological malignancies. In this Review, we provide an overview of the detailed distribution and function of CD39 and CD73 ectoenzymes in the TME and the effects of CD39 and CD73 inhibition on preclinical hematological malignancy data, which provides insights into the potential clinical applications for immunotherapy.

TIGIT axis: novel immune checkpoints in anti-leukemia immunity.

Hematologic malignancy evades immune-mediated recognition through upregulating various checkpoint inhibitory receptors (IRs) on several types of lymphocytes. Immunotherapies targeting IRs have provided ample evidence supporting regulating innate and adaptive immunity and obtaining clinical benefits. Newly described IRs have received considerable attention and are under investigation in cancer immunotherapy. Specifically, T cell immunoglobulin and ITIM domain is a novel inhibitory checkpoint receptor, and its immune checkpoint axis includes additional receptors such as CD96 and CD226, which are very promising targets. However, how the dynamics and functions of these receptor networks remain unknown, this review addresses the recent findings of the relevance of this complex receptor-ligand system and discusses their potential approaches in translating these preclinical findings into novel clinical agents in anti-leukemia immunotherapy.

Utilizing exosomes as sparking clinical biomarkers and therapeutic response in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a malignant clonal tumor originating from immature myeloid hematopoietic cells in the bone marrow with rapid progression and poor prognosis. Therefore, an in-depth exploration of the pathogenesis of AML can provide new ideas for the treatment of AML. In recent years, it has been found that exosomes play an important role in the pathogenesis of AML. Exosomes are membrane-bound extracellular vesicles (EVs) that transfer signaling molecules and have attracted a large amount of attention, which are key mediators of intercellular communication. Extracellular vesicles not only affect AML cells and normal hematopoietic cells but also have an impact on the bone marrow microenvironment and immune escape, thereby promoting the progression of AML and leading to refractory relapse. It is worth noting that exosomes and the various molecules they contain are expected to become the new markers for disease monitoring and prognosis of AML, and may also function as drug carriers and vaccines to enhance the treatment of leukemia. In this review, we mainly summarize to reveal the role of exosomes in AML pathogenesis, which helps us elucidate the application of exosomes in AML diagnosis and treatment.

[Validation the clinical value of good outcome following attempted resuscitation scores in Chinese populations in predicting the prognosis of in-hospital cardiac arrest].

OBJECTIVE: To verify the clinical value of the good outcome following attempted resuscitation (GO-FAR) score in predicting the neurological status of patients with in-hospital cardiac arrest (IHCA) in the Chinese population. METHODS: The clinical data of patients with IHCA who were admitted to the Zigong Fourth People's Hospital from January 1 to December 31, 2020 were retrospectively analyzed. Used Glasgow-Pittsburgh cerebral performance category (CPC) score 1 point as the end point, the subjects were divided into 4 groups according to the score: ≤ 0 group, 1-8 group, 9-20 group and ≥ 21 group. Taken the group which GO-FAR score ≤ 0 as the reference group, the odds ratio (OR) of the other three groups compared with this group was calculated. The receiver operator characteristic curve (ROC curve) was performed to evaluate the predictive value of the GO-FAR score in favorable neurological outcome. A calibration curve was drawn for the Hosmer-Lemeshow test to analyze the degree of calibration of the GO-FAR score for predicting good neurological outcome. RESULTS: A total of 230 IHCA patients were enrolled in the study, including 130 males, aged 74 (65, 81) years old, and 23 case (10.0%) had good neurological prognosis. There were statistically significant differences in GO-FAR-related variables, including age, a normal neurological function on admitted, acute stroke, metastatic cancer, septicemia, medical noncardiac admission, hepatic insufficiency, hypotension, renal insufficiency or dialysis, respiratory insufficiency, pneumonia, etc (all P < 0.05). Taken the GO-FAR score ≤ 0 group as the reference group, the OR values of good neurological prognosis in the GO-FAR score 1-8 group were 0.54 [95% confidence interval (95%CI) was 0.17-1.53, P = 0.250], 9-20 group were 0.17 (95%CI was 0.02-0.67, P = 0.009) and ≥ 21 group were 0.25 (95%CI was 0.05-0.85, P = 0.025). The area under the ROC curve (AUC) of the GO-FAR score for predicting favorable neurological outcome in IHCA patients was 0.653 (95%CI was 0.529-0.777, P = 0.015) and there was no significant difference in Hosmer-Lemeshow test (P = 0.311). All these suggested that there was no significant difference between the predicted value and the actual value. CONCLUSIONS: GO-FAR score can be applied to predict neurological prognosis of IHCA patients in Chinese population. It can help clinicians to predict the prognosis of cardio-pulmonary resuscitation (CPR) and propose critical recommendations in treatment for these patients or their families.

Tumor Apolipoprotein E is a key checkpoint blocking anti-tumor immunity in mouse melanoma.

Immunotherapy is a key modality in the treatment of cancer, but many tumors remain immune resistant. The classic mouse model of B16-F10 melanoma is immune resistant even in the face of checkpoint inhibition. Apolipoprotein E (apoE), a known immune suppressant is strikingly elevated in many human tumors, but its role in cancer immunology is not defined. We investigated the role of apoE in the immune micro-environment using a mouse melanoma model. We demonstrate that ApoE is -highly expressed in wild-type B16-F10 melanoma and serum levels progressively increase as tumors grow. The conditioned media from wild type ApoE secreting melanoma cells suppress T-cell activation in vitro while this suppressive effect is absent in conditioned media from ApoE knock out tumor cells. Mechanistically, apoE induces IL-10 secreting dendritic cells and stimulates T-cell apoptosis and arrest partially via the lrp8 receptor. Ablating ApoE in mice inoculated with tumor cells enabled tumor cell rejection and was associated with induction of immune pathway activation and immune cell infiltration. Tumor secreted apoE appears to be a potent immune cell checkpoint and targeting apoE is associated with enhanced tumor immunity in the mouse melanoma model.

[Analysis of clinical characteristics and surgical efficiency of severe laryngomalacia in children].

Objective:To analyze the clinical characteristics and factors affecting surgical efficiency in children with severe laryngomalacia. Methods:Retrospectively collect medical records of children with severe laryngomalacia who underwent supraglottoplasty in Children's Hospital of Chongqing Medical University between January 1, 2015 and May 1, 2019. And analyze the clinical characteristics, the improvement of main symptoms at different time points, and the influence factors on the surgical efficiency. Results:According to the anatomical classification of severe laryngomalacia, type Ⅳ accounted for the highest proportion（66.1%）, and type Ⅰ was the lowest（3.6%）. All children had stridor and dyspnea, 82.1% cases presented feeding difficulties, and 67.9% cases presented failure to thrive. The proportion of children with medical comorbidities was 62.5%, of which congenital heart disease had the highest incidence（39.3%） The surgical efficiency of severe laryngomalacia without comorbidities was 100.0%, with one type of comorbidity was 96.0%, with multiple comorbidities was 30.0%（P<0.01）. Stridor, dyspnea, feeding difficulties were significantly improved at one month after surgery in most cases. In the group of surgical age less than 3 months, the surgical efficiency were 61.5%, 61.5% and 69.2% at 1, 3, 6 months after surgery, respectively; the surgical efficiency of children without comorbidities were 100.0%（P>0.05） at 1, 3 ,6 months after surgery. In the group of surgical age older than 3 months, the surgical efficiency of children were 100.0% at 1, 3, 6 months after surgery regardless with or without comorbidities. The surgical failure rate and reoperation rate in children without comorbidities was 0, but in the children with comorbidities were 22.9%（P<0.05） and 20.0%（P<0.05）, respectively. The surgical failure rate and reoperation rate in children with multiple comorbidities was significantly higher than children with only one comorbidity（70.0% vs. 4.0%; 60.0% vs. 4.0%, P<0.01）. The overall operation success rate was 85.7% in severe laryngomalacia children in our hospital. Conclusion:Most children with severe laryngomalacia are associated with multiple medical comorbidities, and with more complex anatomical types. Supraglottoplasty can effectively improve the symptoms in most children with severe laryngomalacia. The existence of multiple comorbidities is the main cause of surgical failure.

Molecular typing and epidemiology profiles of human adenovirus infection among hospitalized patients with severe acute respiratory infection in Huzhou, China.

BACKGROUND: Severe acute respiratory infections (SARI) threaten human health and cause a large number of hospitalizations every year. However, as one of the most common pathogen that cause acute respiratory tract infection, the molecular epidemiological information relating to human adenoviruses (HAdVs) among patients with SARI is limited. Here, we evaluate the epidemiological and molecular characteristics of HAdV infections among hospitalized patients with SARI from January 2017 to December 2019 in Huzhou, China. METHODS: From January 2017 to December 2019, a total of 657 nasopharyngeal swabs collected from inpatients with SARI were screened for HAdV and other common respiratory viruses by multiplex real-time PCR. All samples that tested positive for HAdV were further typed by sequencing partial sequences of hexon gene. Genotypes of HAdV were confirmed by phylogenetic analysis. Epidemiological data were analyzed using Microsoft Excel 2010 and service solutions (SPSS) 21.0 software. RESULTS: 251 (38.20%) samples were positive for at least one respiratory virus. HAdV was the second common viral pathogen detected, with a detection rate of 7.08%. Infection with HAdV was found in all age groups tested (0<2, 2<5, 5<15, 15<50, 50<65, ≥65). Children under 15 years old accounted for 84.62% (44/52) of the infections. Higher activity of HAdV infection could be seen in spring-early autumn season. Seven different types of HAdV belonging to 4 species (HAdV-A, B, C, E) were identified in hospitalized SARI cases, with HAdV-B3 as the most prevalent HAdV types, followed by HAdV-B7 and HAdV-E4. HAdV-B3 was the most frequently detected genotype in 2017 and 2019, accounting for 75.00% (9/12) and 63.64% (7/11) of typed HAdV infections in 2017 and 2019, respectively. No predominant strain was responsible for HAdV infections in 2018, although HAdV-B7 (28.57%, 2/7) and HAdV-C1 (28.57%, 2/7) were the major causative genotypes. CONCLUSIONS: This study revealed the prevalence and the molecular epidemiological characteristics of HAdV infections among hospitalized patients with SARI in Huzhou from January 2017 to December 2019. The HAdV prevalence is related to age and season. As the most prevalent HAdV types, HAdV-B3 was co-circulating with other types and presented an alternate prevalence pattern.

Mapping the changes of CH4 emissions in global supply chains.

This study aims to identify methane (CH4) emission flows along global supply chains from both production- and consumption-based perspectives and their temporal changes from 2000 to 2014. We employed the structural path analysis (SPA) method to examine the embodied CH4 emission trade through inter-sectoral and inter-regional supply chains. Production activities in the sector of Agriculture (such as crop and animal production) and consumption activities in Construction (such as infrastructure) were the most significant contributors to global CH4 emission increases during 2000-2014. Agriculture and Mining (such as coal mining) accounted for large shares of global embodied CH4 trade at the final consumption tier (i.e., the trade of final goods or services), while Food (such as beverages and tobacco) and Heavy manufacturing (such as steel or automobile manufacturing) were significant contributors to embodied CH4 emissions in the trade of intermediate goods or services directly used to produce final goods or services. This finding highlights the different potential of the sectors for CH4 abatement along global supply chains. The United States imported the most embodied CH4 emissions from foreign areas in 2000 in contrast to China, which dominated imports in 2014. Over 80% of China's embodied CH4 emissions in 2014 were related to intermediate production along global supply chains due to industrial upgrading. India surpassed China as the largest direct emitter for producing final goods or services. Given the critical role of non-CO2 greenhouse gases in global climate change, the spatiotemporal changes of CH4 emissions in global supply chains can help explore the justified allocation of reduction responsibility between countries and sectors connected by the chains.

The Role of NLRP3 Inflammasome in IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease worldwide today. The NLRP3 inflammasome is a polyprotein complex and an important participant in inflammation. Accumulating studies have shown that the NLRP3 inflammasome participates in a variety of kidney diseases, including IgAN. This review focuses on the role of the NLRP3 inflammasome in IgAN and summarizes multiple involved pathways, which may provide novel treatments for IgAN treatment.

Increased PD-1+Foxp3+ γδ T cells associate with poor overall survival for patients with acute myeloid leukemia.

Problems: γδ T cells are essential for anti-leukemia function in immunotherapy, however, γδ T cells have different functional subsets, including regulatory cell subsets expressing the Foxp3. Whether they are correlated with immune-checkpoint mediated T cell immune dysfunction remains unknown in patients with acute myeloid leukemia (AML). Methods: In this study, we used RNA-seq data from 167 patients in TCGA dataset to analyze the correlation between PD-1 and FOXP3 genes and these two genes' association with the prognosis of AML patients. The expression proportion of Foxp3+/PD-1+ cells in γδ T cells and two subgroups Vδ1 and Vδ2 T cells were performed by flow cytometry. The expression level of FOXP3 and PD-1 genes in γδ T cells were sorted from peripheral blood by MACS magnetic cell sorting technique were analyzed by quantitative real-time PCR. Results: We found that PD-1 gene was positively correlated with FOXP3 gene and highly co-expressed PD-1 and FOXP3 genes were associated with poor overall survival (OS) from TCGA database. Then, we detected a skewed distribution of γδ T cells with increased Vδ1 and decreased Vδ2 T cell subsets in AML. Moreover, significantly higher percentages of PD-1+ γδ, Foxp3+ γδ, and PD-1+Foxp3+ γδ T cells were detected in de novo AML patients compared with healthy individuals. More importantly, AML patients containing higher PD-1+Foxp3+ γδ T cells had lower OS, which might be a potential therapeutic target for leukemia immunotherapy. Conclusion: A significant increase in the PD-1+Foxp3+ γδ T cell subset in AML was associated with poor clinical outcome, which provides predictive value for the study of AML patients.

Meta-analysis for the evaluation of perioperative enhanced recovery after gynaecological surgery.

OBJECTIVES: To systematically evaluate the effectiveness and safety of enhanced recovery after surgery (ERAS) in gynaecological surgery and provide a scientific basis for its clinical promotion and application in the Chinese population. MATERIAL AND METHODS: Systematic retrieval from CNKI, Wanfang, VIP database and other Chinese literature databases. Studies on ERAS application with a randomised controlled trial in gynaecological surgery were included in the present report. Outcome indicators: hospitalisation time, postoperative ambulation time, postoperative feeding time, postoperative exhaust time, postoperative defecation time, operation time, postoperative blood loss, postoperative morbidity, patient satisfaction, hospitalisation expenses, etc. The meta-analysis was performed using the Revman 5.3 software. RESULTS: A total of 24 studies were included in the analysis. The results showed that, compared with the traditional group, the ERAS group had a lower hospitalisation time (SMD = -1.67, 95% CI = -2.03 ~ -1.30, p < 0.0001), postoperative ambulation time (SMD = -4.16, 95% CI = -5.12 ~ -3.20, p < 0.0001), postoperative feeding time (SMD = -7.36, 95% CI = -9.67 ~ -5.05, p < 0.0001), postoperative exhaust time (SMD = -2.59, 95% CI = -3.15 ~ -2.03, p < 0.0001), postoperative defecation time (SMD = -2.23, 95% CI = -2.88 ~ -1.57, p < 0.0001), postoperative morbidity (OR = 0.22, 95% CI = 0.15 ~ 0.31, p < 0.0001) and hospitalisation expenses (SMD = -0.53, 95% CI = -0.78 ~ -0.28, p < 0.0001). The patient satisfaction was significantly improved (odds ratio = 8.11, 95% CI = 4.96 ~ 13.24, p < 0.0001), and there were no significant differences in intraoperative blood loss and operation time between the two groups. CONCLUSIONS: The application of the ERAS protocol in gynaecological surgery significantly improves the effectiveness and safety of the procedure. Thus, it can be promoted and applied in clinical practice in China.

Structure-activity relationship investigation for imidazopyrazole-3-carboxamide derivatives as novel selective inhibitors of Bruton's tyrosine kinase.

BTK (Bruton's tyrosine kinase) inhibitors are the most promising drugs for the treatment of hematological tumors. A high selectivity of BTK inhibitors ensures reduced side effects from off-targeting. Accordingly, here, based on Zanubrutinib, we designed and synthesized a new range of imidazopyrazole-3-carboxamide derivatives as novel BTK inhibitors that retained the amide group for improved selectivity. These compounds revealed potent inhibitory activity against BTK in vitro. Remarkably, compounds 12a (IC50 5.2 nM) and 18a (IC50 4.9 nM) possessed the highest kinase selectivity. Both of these effectively inhibited the auto-phosphorylation of BTK, blocked the cell cycle in G0/G1 phase, and induced apoptosis in the TMD8 cells. In a TMD8 cells xenograft model, a twice-daily dose of compound 12a at 25 mg/kg and a thrice-daily dose of compound 18a at 15 mg/kg significantly suppressed the tumor growth without obvious toxicity. Collectively, 12a and 18a are the potential selective BTK inhibitors that can be developed further.

MYC oncogene is associated with suppression of tumor immunity and targeting Myc induces tumor cell immunogenicity for therapeutic whole cell vaccination.

BACKGROUND: MYC oncogene is deregulated in 70% of all human cancers and is associated with multiple oncogenic functions including immunosuppression in the tumor microenvironment. The role of MYC in the immune microenvironment of neuroblastoma and melanoma is investigated and the effect of targeting Myc on immunogenicity of cancer cells is evaluated. METHODS: Immune cell infiltrates and immunogenic pathway signatures in the context of MYCN amplification were analyzed in human neuroblastoma tumors and in metastatic melanoma. Dose response and cell susceptibility to MYC inhibitors (I-BET726 and JQ1) were determined in mouse cell lines. The influence of downregulating Myc in tumor cells was characterized by immunogenic pathway signatures and functional assays. Myc-suppressed tumor cells were used as whole cell vaccines in preclinical neuroblastoma and melanoma models. RESULTS: Analysis of immune phenotype in human neuroblastoma and melanoma tumors revealed that MYCN or c-MYC amplified tumors respectively are associated with suppressed immune cell infiltrates and functional pathways. Targeting Myc in cancer cells with I-BET726 and JQ1 results in cell cycle arrest and induces cell immunogenicity. Combining vaccination of Myc-inhibited tumor cells with checkpoint inhibition induced robust antitumor immunity and resulted in therapeutic cancer vaccine therapy in mouse neuroblastoma tumors. Despite vigorous antitumor immunity in the mouse melanoma model, upregulation of immunosuppressive pathways enabled tumor escape. CONCLUSIONS: This study demonstrates that the Myc oncogene is an appropriate target for inducing tumor cell immunogenicity and suggests that Myc-suppressed whole tumor cells combined with checkpoint therapy could be used for formulating a personalized therapeutic tumor vaccine.

Decitabine and Cisplatin are Synergistic to Exert Anti-Tumor Effect on Gastric Cancer via Inducing Sox2 DNA Demethylation.

BACKGROUND: Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC. PURPOSE: The study was performed to explore the synergistic effect of decitabine and cisplatin in GC. MATERIALS AND METHODS: Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2'-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot. RESULTS: Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors. CONCLUSION: Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.