A negative feedback loop between TET2 and leptin in adipocyte regulates body weight.

Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

The efficacy and safety of short-course radiotherapy followed by sequential chemotherapy and Cadonilimab for locally advanced rectal cancer: a protocol of a phase II study.

BACKGROUND: For patients with locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT), namely, intensifying preoperative treatment through the integration of radiotherapy and systemic chemotherapy before surgery, was commonly recommended as the standard treatment. However, the risk of distant metastasis at 3 years remained higher than 20%, and the complete response (CR) rate was less than 30%. Several clinical trials had suggested a higher complete response rate when combining single-agent immunotherapy with short-course radiotherapy (SCRT). The CheckMate 142 study had shown encouraging outcomes of dual immunotherapy and seemingly comparable toxicity for CRC compared with single-agent immunotherapy in historical results. Therefore, dual immunotherapy might be more feasible in conjunction with the TNT paradigm of SCRT. We performed a phase II study to investigate whether the addition of a dual immune checkpoint inhibitor bispecific antibody, Cadonilimab, to SCRT combined with chemotherapy might further increase the clinical benefit and prognosis for LARC patients. METHODS: This single-arm, multicenter, prospective, phase II study included patients with pathologically confirmed cT3-T4N0 or cT2-4N + rectal adenocarcinoma with an ECOG performance score of 0 or 1. Bispecific antibody immunotherapy was added to SCRT combined with chemotherapy. Patients enrolled would be treated with SCRT (25 Gy in five fractions over 1 week) for the pelvic cavity, followed by 4 cycles of CAPOX or 6 cycles of mFOLFOX and Cadonilimab. The primary endpoint was the CR rate, which was the ratio of the pathological CR rate plus the clinical CR rate. The secondary endpoints included local-regional control, distant metastasis, disease-free survival, overall survival, toxicity profile, quality of life and functional outcome of the rectum. To detect an increase in the complete remission rate from 21.8% to 40% with 80% power, 50 patients were needed. DISCUSSION: This study would provide evidence on the efficacy and safety of SCRT plus bispecific antibody immunotherapy combined with chemotherapy as neoadjuvant therapy for patients with LARC, which might be used as a candidate potential therapy in the future. TRIAL REGISTRATION: This phase II trial was prospectively registered at ClinicalTrials.gov, under the identifier NCT05794750.

Comparison of efficacy and safety of equivalent doses of remimazolam versus propofol for gastroscopy anesthesia in elderly patients.

Remimazolam, a novel intravenous anesthetic, has been proven to be safe and efficacious in the gastroscopy setting among the elderly. However, reports comparing the effectiveness and safety of using equivalent doses of remimazolam with propofol have not been seen. The aim of this study was to compare the sedation efficacy and safety of the 95% effective doses (ED95) of remimazolam versus propofol combined with sufentanil in the gastroscopy setting among the elderly. In the first step of this two-step study, a modified up-and-down method was used to calculate the ED95 of remimazolam and propofol when combined with 0.1 µg/kg sufentanil in inhibiting body movement of elderly patients undergoing gastroscopy. In the second step, ED95 of both agents calculated in the first step were administered, endpoints of efficacy, safety, and incidence of adverse events were compared. A total of 46 individuals completed the first step. The ED95 of remimazolam was 0.163 mg/kg (95% CI 0.160-0.170 mg/kg), and that of propofol was 1.042 mg/kg (95% CI 1.007-1.112 mg/kg). In the second step, 240 patients completed the trial. The anesthetic effective rates of the remimazolam group and the propofol group were 78% and 83%, respectively, with no statistical difference (P = 0.312). Patients in the remimazolam group had more stable circulatory functions (P < 0.0001) and a lower incidence of pain on injection (3.3% vs. 19.5%, P < 0.0001). The incidence of hypotension was low in the remimazolam versus propofol group (15.6% vs. 39.0%, P < 0.0001). Overall adverse event was low in the remimazolam versus propofol group (21.3% vs. 62.7%, P < 0.0001).In this study, we found that when anesthesia was administered to elderly gastroscopy patients based on 95% effective doses of remimazolam and propofol, remimazolam was as effective as propofol, but was safer with a lower incidence of adverse events.Study registration: Chinese Clinical Trial Registry, ChiCTR2000034234. Registered 29/06/2020, https://www.chictr.org.cn .

A prospective phase II clinical trial of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma.

To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.

Labor market segmentation and the gender wage gap: Evidence from China.

Although the Chinese government has implemented a variety of measures, the gender wage gap in 21st century China has not decreased. A significant body of literature has studied this phenomenon using sector segmentation theory, but these studies have overlooked the importance of the collective economy beyond the public and private sectors. Moreover, they have lacked assessment of the gender wage gap across different wage groups, hindering an accurate estimation of the gender wage gap in China, and the formulation of appropriate recommendations. Utilizing micro-level data from 2004, 2008, and 2013, this paper examines trends in the gender wage gap within the public sector, private sector, and collective economy. Employing a selection bias correction based on the multinomial logit model, this study finds that the gender wage gap is smallest and most stable within the public sector. Furthermore, the private sector surpasses the collective economy in this period, becoming the sector with the largest gender wage gap. Meanwhile, a recentered influence function regression reveals a substantial gender wage gap among the low-wage population in all three sectors, as well as among the high-wage population in the private sector. Additionally, employing Brown wage decomposition, this study concludes that inter-sector, rather than intra-sector, differences account for the largest share of the gender wage gap, with gender discrimination in certain sectors identified as the primary cause. Finally, this paper provides policy recommendations aimed at addressing the gender wage gap among low-wage groups and within the private sector.

A novel ACE2-Based electrochemical biosensor for sensitive detection of SARS-CoV-2.

SARS-CoV-2 emerged in late 2019 and quickly spread globally, resulting in significant morbidity, mortality, and socio-economic disruptions. As of now, collaborative global efforts in vaccination and the advent of novel diagnostic tools have considerably curbed the spread and impact of the virus in many regions. Despite this progress, the demand remains for low-cost, accurate, rapid and scalable diagnostic tools to reduce the influence of SARS-CoV-2. Herein, the angiotensin-converting enzyme 2 (ACE2), a receptor for SARS-CoV-2, was immobilized on two types of electrodes, a screen-printed gold electrode (SPGE) and a screen-printed carbon electrode (SPCE), to develop electrochemical biosensors for detecting SARS-CoV-2 with high sensitivity and selectivity. This was achieved by using 1H, 1H, 2H, 2H-perfluorodecanethiol (PFDT) and aryl diazonium salt serving as linkers for SPGEs and SPCEs, respectively. Once SARS-CoV-2 was anchored onto the ACE2, the interaction of the virus with the redox probe was analyzed using electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). Aryl diazonium salt was observed as a superior linker compared to PFDT due to its consistent performance in the modification of the SPCEs and effective ACE2 enzyme immobilization. A distinct pair of redox peaks in the cyclic voltammogram of the biosensor modified with aryl diazonium salt highlighted the redox reaction between the functional groups of SARS-CoV-2 and the redox probe. The sensor presented a linear relationship between the redox response and the logarithm of SARS-CoV-2 concentration, with a detection limit of 1.02 × 106 TCID50/mL (50% tissue culture infectious dose). Furthermore, the biosensor showed remarkable selectivity towards SARS-CoV-2 over H1N1virus.

Biodegradable ferroelectric molecular crystal with large piezoelectric response.

Transient implantable piezoelectric materials are desirable for biosensing, drug delivery, tissue regeneration, and antimicrobial and tumor therapy. For use in the human body, they must show flexibility, biocompatibility, and biodegradability. These requirements are challenging for conventional inorganic piezoelectric oxides and piezoelectric polymers. We discovered high piezoelectricity in a molecular crystal HOCH2(CF2)3CH2OH [2,2,3,3,4,4-hexafluoropentane-1,5-diol (HFPD)] with a large piezoelectric coefficient d33 of ~138 picocoulombs per newton and piezoelectric voltage constant g33 of ~2450 × 10-3 volt-meters per newton under no poling conditions, which also exhibits good biocompatibility toward biological cells and desirable biodegradation and biosafety in physiological environments. HFPD can be composite with polyvinyl alcohol to form flexible piezoelectric films with a d33 of 34.3 picocoulombs per newton. Our material demonstrates the ability for molecular crystals to have attractive piezoelectric properties and should be of interest for applications in transient implantable electromechanical devices.

Treatment outcome, toxicity, and quality of life of patients with bronchus-associated lymphoid tissue lymphoma.

The disease failure patterns and optimal treatment of bronchus-associated lymphoid tissue (BALT) lymphoma are unknown. This retrospective study involved 71 patients with primary BALT lymphoma who had received radiotherapy (RT), surgery, immunochemotherapy (IC), or observation. The median follow-up time was 66 months. The 5-year overall survival and lymphoma-specific survival were 91.2% and 96.1%, respectively, and were not significantly different among treatments. The 5-year cumulative incidence of overall failure for RT, surgery, IC, and observation was 0%, 9.7% (p = .160), 30.8% (p = .017), and 31.3% (p = .039). There was no grade ≥3 toxicity in RT group according to the CTCAE 5.0 reporting system. Quality of life (QoL) was at similarly good levels among the treatment groups. BALT lymphoma had a favorable prognosis but persistent risk of relapse after IC or observation. Given the very low disease failure risk and good QoL, RT remains an effective initial treatment for BALT lymphoma.Key PointsBALT lymphoma has a favorable prognosis but a persistent progression and relapse risk.Radiotherapy is associated with lower failure of disease progression and relapse, low toxicity and good quality of life.

Combined effects of biochar and biodegradable mulch film on chromium bioavailability and the agronomic characteristics of tobacco.

Biochar (BC) and biodegradable mulch film (BMF) are both commonly used means of production in agriculture. In recent years, most studies have focused on the effects of BC or BMF on soil heavy metal pollution, while they have neglected the combined effects. In this study, a pot experiment was conducted to examine the impacts of BMF, BC, and combined BMF and BC (CMB) on the mobility of chromium (Cr) and the agronomic characteristics of flue-cured tobacco. Compared with the control, BMF, BC, and CMB significantly reduced the concentrations of diethylenetriamine pentaacetic acid (DTPA) extractable Cr in soils by 29.07-29.75%, 45.35-48.54%, and 34.21-37.92%, respectively. In comparison to the application of BMF and BC alone, co-application reduced the availability of Cr in soil via increasing the adsorption of soil Cr and soil enzyme activity, which resulted in the decrease of Cr content and bioconcentration factor and in plants. Moreover, the combined application increased the plant height, stem diameter, leaf area, total root area, root tip number, and root activity of tobacco, which leaded to increase in leaf and root biomass by 11.40-67.01% and 23.91-50.74%, respectively. Therefore, the application of CMB can reduce the heavy metal residues in tobacco leaves and improve tobacco yield and quality.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac: Estimated delivered dose and early toxicity results.

Background: Magnetic resonance (MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation (UHF-WPRT) is a novel approach to radiotherapy for patients with high-risk (HR) and very high-risk (VHR) prostate cancer (PCa). However, the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time. We aimed to estimate the delivered dose, study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac. Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa, who consecutively received UHF-WPRT, were enrolled prospectively. The contours of the target and organ-at-risks on the position verification-MR (PV-MR), beam-on 3D-MR(Bn-MR), and post-MR (after radiotherapy delivery) were derived from the pre-MR data by deformable image registration. The physician then manually adjusted them, and dose recalculation was performed accordingly. GraphPad Prism 9 (GraphPad Prism Software Inc.) was utilized for conducting statistical analyses. Results: In total, we collected 188 MR scans (50 pre-MR, 50 PV-MR, 44 Bn-MR, and 44 post-MR scans). With median 59 min, the mean prostate clinical target volume (CTV)-V100% was 98.59% ± 2.74%, and the mean pelvic CTVp-V100% relative percentages of all scans was 99.60% ± 1.18%. The median V29 Gy change in the rectal wall was -2% (-18% to 20%). With a median follow-up of 9 months, no patient had acute Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or more severe genitourinary (GU) or gastrointestinal (GI) toxicities (0%). Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape (ATS) workflow was technically feasible for patients with HR and VHR PCa, presenting only mild GU and GI toxicities. The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis. Clinical trial registration: Chinese Clinical Trial Registry ChiCTR2000033382.

Changes of Mycobacterium tuberculosis specific antigen-stimulated CD27-CD38+IFN-γ+CD4+ T cells before and after anti-tuberculosis treatment.

BACKGROUND: The aim of the study was to investigate whether the expression of CD27-CD38+ in interferon (IFN)-γ+CD4+ T cells stimulated by the specific antigen early secreted antigenic target-6 (ESAT-6)/culture filter protein-10 (CFP-10) could be a potential new therapeutic evaluation indicator for anti-tuberculosis (TB) treatment. METHODS: Newly diagnosed active pulmonary TB patients, latent TB infection (LTBI) and healthy controls were enrolled from January 2021 to December 2021. PTB patients were treated by standard anti-TB regimen 2HREZ/4HR (2 months of isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (Z) followed by 4 months of isoniazid (H) and rifampin (R)). The difference of CD27-CD38+ expression in IFN-γ+CD4+ T cells before treatment, 2 months after treatment, and 6 months after treatment were compared. RESULTS: Total 45 PTB patients, 38 LTBI cases and 43 healthy controls were enrolled. The expression of CD27-CD38+ decreased significantly after anti-TB treatment and was comparable with that in LTBI and healthy controls when the 6-month anti-TB treatment course was completed. The decline rate of CD27-CD38+ between 6 months after treatment and baseline was positively correlated with erythrocyte sedimentation rate (r = 0.766, P < 0.0001), C-reactive protein (r = 0.560, P = 0.003) and chest computerized tomography severity score (r = 0.632, P = 0.0005). The area under receiver operator characteristic curve of CD27-CD38+ in distinguish pulmonary TB patients before and after treatment was 0.779. CONCLUSION: The expression of CD27-CD38+ in ESAT-6/CFP-10 stimulated IFN-γ+CD4+T cells can well reflect the changes of the disease before and after anti-TB treatment, which is expected to be a potential new therapeutic evaluation index. Clinical Registry number chiCTR1800019966.

Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.

Background: Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods: We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results: Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion: We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Electrolyte Chemistry toward Ultrawide-Temperature (-25 to 75 °C) Sodium-Ion Batteries Achieved by Phosphorus/Silicon-Synergistic Interphase Manipulation.

All-weather operation is considered an ultimate pursuit of the practical development of sodium-ion batteries (SIBs), however, blocked by a lack of suitable electrolytes at present. Herein, by introducing synergistic manipulation mechanisms driven by phosphorus/silicon involvement, the compact electrode/electrolyte interphases are endowed with improved interfacial Na-ion transport kinetics and desirable structural/thermal stability. Therefore, the modified carbonate-based electrolyte successfully enables all-weather adaptability for long-term operation over a wide temperature range. As a verification, the half-cells using the designed electrolyte operate stably over a temperature range of -25 to 75 °C, accompanied by a capacity retention rate exceeding 70% even after 1700 cycles at 60 °C. More importantly, the full cells assembled with Na3V2(PO4)2O2F cathode and hard carbon anode also have excellent cycling stability, exceeding 500 and 1000 cycles at -25 to 50 °C and superb temperature adaptability during all-weather dynamic testing with continuous temperature change. In short, this work proposes an advanced interfacial regulation strategy targeted at the all-climate SIB operation, which is of good practicability and reference significance.

Optimizing the prognostic capacity of baseline 18F-FDG PET/CT metabolic parameters in extranodal natural killer/T-cell lymphoma by using relative and absolute thresholds.

Objectives: To investigate the prognostic capacity of baseline 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in extranodal natural killer/T-cell lymphoma (ENKTCL), and the influence of relative thresholds (RT) and absolute thresholds (AT) selection on prognostic capacity. Materials and methods: Metabolic tumor volume (MTV)-based parameters were defined using RTs (41 % or 25 % of maximum standardized uptake value [SUVmax]), ATs (SUV 2.5, 3.0, 4.0, or mean liver uptake) in 133 patients. Metabolic parameters were classified into avidity-related parameters (SUVmax, mean SUV [SUVmean], standard deviation of SUV [SUVsd]), volume-related parameters (RT-MTV), and avidity- and volume-related parameters (total lesion glycolysis [TLG] and AT-MTV). The prognostic capacity of the metabolic parameters and the effects of different threshold types (RT vs. AT) were evaluated. Results: All metabolic parameters were moderately associated with prognosis. However, the area under the receiver operating characteristic curve of MTV and TLG was slightly higher than that of avidity-related parameters for predicting 5-year progression-free survival (PFS) (0.614-0.705 vs. 0.563-0.609) and overall survival (OS) (0.670-0.748 vs. 0.562-0.593). Correlations of MTV and avidity-related parameters differed between RTs (r < 0.06, P = 0.324-0.985) and ATs (r 0.56-0.84, P ≤ 0.001). AT-MTV was the optimal predictor for PFS and OS, while RT-TLG was the optimal predictor for PFS, and the combination of RT-MTV with SUVmax was the optimal predictor for OS. Conclusion: The incorporation of volume and avidity significantly improved the prognostic capacity of PET in ENKTCL. Composite parameters that encompassed both avidity and volume were recommended.

Model-guided metabolic rewiring to bypass pyruvate oxidation for pyruvate derivative synthesis by minimizing carbon loss.

Engineering microbial hosts to synthesize pyruvate derivatives depends on blocking pyruvate oxidation, thereby causing severe growth defects in aerobic glucose-based bioprocesses. To decouple pyruvate metabolism from cell growth to improve pyruvate availability, a genome-scale metabolic model combined with constraint-based flux balance analysis, geometric flux balance analysis, and flux variable analysis was used to identify genetic targets for strain design. Using translation elements from a ~3,000 cistronic library to modulate fxpK expression in a bicistronic cassette, a bifido shunt pathway was introduced to generate three molecules of non-pyruvate-derived acetyl-CoA from one molecule of glucose, bypassing pyruvate oxidation and carbon dioxide generation. The dynamic control of flux distribution by T7 RNAP-mediated synthetic small RNA decoupled pyruvate catabolism from cell growth. Adaptive laboratory evolution and multi-omics analysis revealed that a mutated isocitrate dehydrogenase functioned as a metabolic switch to activate the glyoxylate shunt as the only C4 anaplerotic pathway to generate malate from two molecules of acetyl-CoA input and bypass two decarboxylation reactions in the tricarboxylic acid cycle. A chassis strain for pyruvate derivative synthesis was constructed to reduce carbon loss by using the glyoxylate shunt as the only C4 anaplerotic pathway and the bifido shunt as a non-pyruvate-derived acetyl-CoA synthetic pathway and produced 22.46, 27.62, and 6.28 g/L of l-leucine, l-alanine, and l-valine by a controlled small RNA switch, respectively. Our study establishes a novel metabolic pattern of glucose-grown bacteria to minimize carbon loss under aerobic conditions and provides valuable insights into cell design for manufacturing pyruvate-derived products.IMPORTANCEBio-manufacturing from biomass-derived carbon sources using microbes as a cell factory provides an eco-friendly alternative to petrochemical-based processes. Pyruvate serves as a crucial building block for the biosynthesis of industrial chemicals; however, it is different to improve pyruvate availability in vivo due to the coupling of pyruvate-derived acetyl-CoA with microbial growth and energy metabolism via the oxidative tricarboxylic acid cycle. A genome-scale metabolic model combined with three algorithm analyses was used for strain design. Carbon metabolism was reprogrammed using two genetic control tools to fine-tune gene expression. Adaptive laboratory evolution and multi-omics analysis screened the growth-related regulatory targets beyond rational design. A novel metabolic pattern of glucose-grown bacteria is established to maintain growth fitness and minimize carbon loss under aerobic conditions for the synthesis of pyruvate-derived products. This study provides valuable insights into the design of a microbial cell factory for synthetic biology to produce industrial bio-products of interest.

Thoracic SMARCA4-deficient undifferentiated tumor: A clinicopathological and prognostic analysis of 35 cases and immunotherapy efficacy.

BACKGROUND: Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a recently recognized distinct clinicopathological entity according to the fifth edition of the 2021 World Health Organization Classification (WHO) for thoracic tumors. Thoracic SMARCA4-UTs are diagnostically challenging to diagnose, especially on small biopsies. METHODS: We identified 35 thoracic SMARCA4-UTs from the Department of Pathology of West China Hospital, Sichuan University, between January 2017 and December 2022. In the present study, we summarized the clinicopathological features, prognostic significance and immunotherapy efficacy of thoracic SMARCA4-UTs. RESULTS: All 35 patients were male, and 88.6 % were smokers. The left upper lobe (25.7 %) and mediastinum (20.0 %) were the most affected sites. 17.1 % of the patients received surgical treatment. 30.4 % of the patients were stage III, and 69.6 % were stage IV. Solid architecture (100 %), rhabdoid morphology (51.4 %) and necrosis (42.9 %) were the common histological features. Immunohistochemical staining revealed CD34 and synaptophysin positivity in most patients (76.9 % and 65.2 %, respectively). Patients had unfavorable outcomes. Patients who received immunotherapy had better OS and PFS than those who did not (p = 0.007 and p = 0.02, respectively). Five patients were evaluated for immunotherapy efficacy, and four of those patients were negative expression of PD-L1. Cases 1-4 presented TIL counts ranging from 20 to 1000/HPF. Case 5 presented TIL counts of 5-10/HPF. Mutations in SMARCA4 were confirmed in cases 4 and 5, and the TMB was 5.98 and 5.03 mutations/Mb, respectively. Case 1 achieved a CR, cases 2-4 achieved a PR, and case 5 had a PD. Five patients who received immunotherapy were all alive, with OS ranging from 10.7 to 33.6 months. CONCLUSIONS: Thoracic SMARCA4-UTs exhibited an aggressive clinical course, presented solid architecture with or without necrosis and/or rhabdoid morphology, and frequently expressed CD34 and synaptophysin. Some thoracic SMARCA4-UTs appear to be associated with responsiveness to immunotherapy, suggesting the need for validation in larger series.

Combining PLGA microspheres loaded with Liver X receptor agonist GW3965 with a chitosan nerve conduit can promote the healing and regeneration of the wounded sciatic nerve.

Globally, peripheral nerve injury (PNI) is a common clinical issue. Successfully repairing severe PNIs has posed a major challenge for clinicians. GW3965 is a highly selective LXR agonist, and previous studies have demonstrated its positive protective effects in both central and peripheral nerve diseases. In this work, we examined the potential reparative effects of GW3965-loaded polylactic acid co-glycolic acid microspheres in conjunction with a chitosan nerve conduit for peripheral nerve damage. The experiment revealed that GW3965 promoted Schwann cell proliferation and neurotrophic factor release in vitro. In vivo experiments conducted on rats showed that GW3965 facilitated the restoration of motor function, promoted axon and myelin regeneration in the sciatic nerve, and enhanced the microenvironment of nerve regeneration. These results offer a novel therapeutic approach for the healing of nerve damage. Overall, this work provides valuable insights and presents a promising therapeutic strategy for addressing PNI.