Cadonilimab plus platinum-based chemotherapy with or without bevacizumab as first-line treatment for persistent, recurrent, or metastatic cervical cancer (COMPASSION-16): a randomised, double-blind, placebo-controlled phase 3 trial in China.

BACKGROUND: Cadonilimab is a bispecific antibody targeting PD-1 and CTLA-4, which has shown substantial clinical benefits in advanced cervical cancer. In the COMPASSION-16 trial, we aimed to evaluate the addition of cadonilimab to first-line standard chemotherapy in persistent, recurrent, or metastatic cervical cancer. METHODS: In this randomised, double-blind, multicentre, placebo-controlled phase 3 trial, women aged 18-75 years across 59 clinical sites in China with previously untreated persistent, recurrent, or metastatic cervical cancer were randomly assigned (1:1) to receive cadonilimab (10 mg/kg) or placebo plus platinum-based chemotherapy with or without bevacizumab every 3 weeks for six cycles, followed by maintenance therapy every 3 weeks for up to 2 years. Randomisation was performed centrally through an interactive web-response system. Stratification factors were the use of bevacizumab (yes or no) and previous concurrent chemoradiotherapy (yes or no). The dual primary outcomes were progression-free survival as assessed by blinded independent central review and overall survival in the full analysis set. This study is registered with ClinicalTrials.gov, NCT04982237; the study has completed enrolment and is ongoing for treatment and follow-up. FINDINGS: 445 eligible women were enrolled between Sept 11, 2021, and June 23, 2022. Median progression-free survival was 12·7 months (95% CI 11·6-16·1) in the cadonilimab group and 8·1 months (7·7-9·6) in the placebo group (hazard ratio 0·62 [95% CI 0·49-0·80], p<0·0001); median overall survival was not reached (27·0 months to not estimable) versus 22·8 months (17·6-29·0), respectively (hazard ratio 0·64 [0·48-0·86], p=0·0011). The most common grade 3 or higher adverse events were decreased neutrophil count, decreased white blood cell count, and anaemia. INTERPRETATION: The addition of cadonilimab to first-line standard chemotherapy significantly improved progression-free survival and overall survival with a manageable safety profile in participants with persistent, recurrent, or metastatic cervical cancer. The data support the use of cadonilimab plus chemotherapy as an efficacious first-line therapy in persistent, recurrent, or metastatic cervical cancer. FUNDING: Akeso Biopharma.

Heterogeneity in diet-related non-communicable disease risks in a Chinese population.

PURPOSE: Sub-optimal food choices contribute to the risk of multiple non-communicable diseases (NCDs) which can be mitigated by improving diet quality. Food consumption patterns may partly account for variation of NCD risks in population subgroups in China. This study aimed to evaluate the risk of diet-related NCDs of observed Chinese diets, and to assess the potential reduction in NCD risks by adhering to certain diet recommendations. METHODS: Dose-response meta-analyses were used to derive relative risks between three diet-related NCDs and consumption of 15 food groups. 24-h dietary recall data of 12,809 adults from the 2011 China Health and Nutrition Survey were used to estimate the diet-related summed risks (SRs) of NCDs. Twelve Chinese provinces were aggregated into five regions, and stratified by age, gender, overweight status, education, income, and urbanicity. The Chinese Dietary Guideline-2016 (CDG-2016) and the EAT-Lancet diet were used as recommended diets. RESULTS: Associations between SRs and gender, age, educational level, income level, and urbanicity were observed. No association was found between SRs and overweight status. Both diet recommendations have lower SRs compared to observed diets among all regions. The food groups that contributed most to the variation of the SRs of diet-related NCDs in China were high consumption of red meat and refined grains, and low consumption of whole grains, fruits, and legumes. CONCLUSION: To address the heterogeneity in diet-related NCD risks, focusing on region-specific dietary practical is imperative for Chinese population, in order to propose tailored guidance to adhere to diet recommendations.

Sequential release of interacting proteins and Ub-modifying enzymes by disulfide heterotypic ubiquitin reagents.

Heterotypic ubiquitin (Ub) chains have emerged as fundamental components in a wide range of cellular processes. The integrative identification of Ub-interacting proteins (readers) and Ub-modifying enzymes (writers and erasers) that selectively recognize and regulate heterotypic ubiquitination may provide crucial insights into these processes. In this study, we employed the bifunctional molecule-assisted (CAET) strategy to develop a type of disulfide bond-activated heterotypic Ub reagents, which allowed to enrich heterotypic Ub-interacting proteins and modifying enzymes simultaneously. The sequential release of readers which are non-covalently bound and writers or erasers which are covalently conjugated by using urea and reductant, respectively, combined with label-free quantitative (LFQ) MS indicated that these heterotypic Ub reagents would facilitate future investigations into functional roles played by heterotypic Ub chains.

Sodium Tanshinone IIA Sulfonate Protects Primary Cardiomyocytes Against Radiation-Induced Myocardial Injury via the p38 Pathway.

Sodium tanshinone IIA sulfonate (STS), which is extracted from a Chinese medicinal herb, possesses many pharmacologic functions, such as coronary dilation, anti-inflammatory properties, and antiapoptotic and antioxidant effects. It remains unknown whether STS can protect cardiomyocytes injured after radiation therapy. An in vitro Sprague-Dawley (SD) rat neonatal cardiomyocyte system was established. Primary cardiomyocytes (PCMs) from neonatal SD rats were isolated under sterile conditions. PCM cells were divided into a control group (0 Gy/hour) and 5 experimental radiation therapy groups (0.25 Gy/hour, 0.5 Gy/hour, 1 Gy/hour, 2 Gy/hour, and 4 Gy/hour). Cell viability, the content of malondialdehyde (MDA), the lactate dehydrogenase (LDH) leakage rate, and superoxide dismutase (SOD) and glutathione (GSH) activities were recorded separately in each group after 7 days of culture. Western blot was used to detect the levels of p38, caspase-3 protein, and X protein (BAX) associated with B-cell lymphoma 2 (Bcl-2) in PCMs. X-rays inhibited cell growth, decreased cell viability, and induced an oxidative stress response in PCMs. STS and SB203580 (the inhibitor of P38 mitogen-activated protein kinase pathway) alleviated X-ray-induced damage to PCMs. An enzyme-linked immunosorbent assay showed that X-rays increased the cTnT level. STS and SB203580 ameliorated the X-ray-induced increase in cTnT leakage. X-rays enhanced the expression of p38/p-p38 and caspase-3 while reducing the expression of Bcl-2/BAX in PCMs, as demonstrated by western blotting. STS and SB203580 mitigated the changes in protein expression triggered by X-ray radiation. In conclusions, STS was shown to exert significant cardioprotective, anti-inflammatory, and antioxidant effects in PCMs by inhibiting the p38 mitogen-activated protein kinase pathway.

Ion-Specific Interactions Engender Dynamic and Tailorable Properties in Biomimetic Cationic Polyelectrolytes.

Biomaterials such as spider silk and mussel byssi are fabricated by the dynamic manipulation of intra- and intermolecular biopolymer interactions. Organisms modulate solution parameters, such as pH and ion co-solute concentration, to effect these processes. These biofabrication schemes provide a conceptual framework to develop new dynamic and responsive abiotic soft material systems. Towards these ends, the chemical diversity of readily available ionic compounds offers a broad palette to manipulate the physicochemical properties of polyelectrolytes via ion-specific interactions. In this study, we show for the first time that the ion-specific interactions of biomimetic polyelectrolytes engenders a variety of phase separation behaviors, creating dynamic thermal- and ion-responsive soft matter that exhibits a spectrum of physical properties, spanning viscous fluids to viscoelastic and viscoplastic solids. These ion-dependent characteristics are further rendered general by the merger of lysine and phenylalanine into a single, amphiphilic vinyl monomer. The unprecedented breadth, precision, and dynamicity in the reported ion-dependent phase behaviors thus introduce a broad array of opportunities for the future development of responsive soft matter; properties that are poised to drive developments in critical areas such as chemical sensing, soft robotics, and additive manufacturing.

Postprandial Plasma Lipidomics Reveal Specific Alteration of Hepatic-derived Diacylglycerols in Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Hepatic energy metabolism is a dynamic process modulated by multiple stimuli. In nonalcoholic fatty liver disease (NAFLD), human studies typically focus on the static fasting state. We hypothesized that unique postprandial alterations in hepatic lipid metabolism are present in NAFLD. METHODS: In a prospective clinical study, 37 patients with NAFLD and 10 healthy control subjects ingested a standardized liquid meal with pre- and postprandial blood sampling. Postprandial plasma lipid kinetics were characterized at the molecular lipid species level by untargeted lipidomics, cluster analysis, and lipid particle isolation, then confirmed in a mouse model. RESULTS: There was a specific increase of multiple plasma diacylglycerol (DAG) species at 4 hours postprandially in patients with NAFLD but not in controls. This was replicated in a nonalcoholic steatohepatitis mouse model, where postprandial DAGs increased in plasma and concomitantly decreased in the liver. The increase in plasma DAGs appears early in the disease course, is dissociated from NAFLD severity and obesity, and correlates with postprandial insulin levels. Immunocapture isolation of very low density lipoprotein in human samples and stable isotope tracer studies in mice revealed that elevated postprandial plasma DAGs reflect hepatic secretion of endogenous, rather than meal-derived lipids. CONCLUSIONS: We identified a selective insulin-related increase in hepatic secretion of endogenously derived DAGs after a mixed meal as a unique feature of NAFLD. DAGs are known to be lipotoxic and associated with atherosclerosis. Although it is still unknown whether the increased exposure to hepatic DAGs contributes to extrahepatic manifestations and cardiovascular risk in NAFLD, our study highlights the importance of extending NAFLD research beyond the fasting state.

Non-Nutritive Sweeteners in Human Amniotic Fluid and Cord Blood: Evidence of Transplacental Fetal Exposure.

OBJECTIVE: This study aimed to investigate human fetal exposure to non-nutritive sweeteners (NNS) by analyzing amniotic fluid and umbilical cord blood. STUDY DESIGN: Concentrations of four NNS (acesulfame-potassium [ace-K], saccharin, steviol glucuronide, and sucralose) were measured in amniotic fluid (n = 13) and cord blood samples (n = 15) using liquid chromatography-mass spectrometry. Amniotic fluid samples were obtained for research purposes at the time of term elective cesarean birth or clinically indicated third trimester amnioreduction at Mercy Hospital for Women (Melbourne, Australia). All except four women were in the fasting state. Cord blood samples were obtained from an independent cohort of newborns whose mothers were enrolled in a separate clinical trial at the National Institutes of Health. RESULTS: Ten of 13 amniotic fluid samples contained at least one NNS (ace-K, saccharin, steviol glucuronide, and/or sucralose). Maximum amniotic fluid NNS concentrations of ace-K, saccharin, steviol glucuronide, and sucralose were 78.9, 55.9, 93.5, and 30.6 ng/mL, respectively. Ace-K and saccharin were present in 100% and 80% of the cord blood samples, with maximal concentrations of 6.5 and 2.7 ng/mL, respectively. Sucralose was not detected and steviol glucuronide was not measurable in any of the cord blood samples. CONCLUSION: Our results provide evidence of human transplacental transmission of NNS. Based on results predominantly obtained from rodent models, we speculate that NNS exposure may adversely influence the offsprings' metabolic health. Well-designed, prospective clinical trials are necessary to understand the impact of NNS intake during pregnancy on human development and long-term health. KEY POINTS: · NNS consumption during pregnancy has increased in recent years.. · Maternal NNS intake during pregnancy is associated with preterm birth and higher infant weight gain in epidemiologic studies.. · In rodents, in utero NNS exposure induces metabolic abnormalities in mothers and their offspring, alters offspring gut microbiota composition, and promotes sweet taste preference in adulthood.. · It is presently unknown whether and to what degree maternal NNS ingestion in humans leads to direct in utero exposure.. · This study provides the first evidence of in utero NNS exposure in humans and highlights the urgent need to investigate clinical consequences of early life NNS exposure on metabolism, weight, taste preference, and general health..

Highly Efficient Separation of C8 Aromatic Isomers by Rationally Designed Nonaromatic Metal-Organic Frameworks.

The separation of C8 aromatics (xylenes and ethylbenzene) remains one of the most challenging industrial separations due to their similar structures and properties. Suitable adsorbents that can distinguish the small differences among isomers are urgently demanded. Herein, we demonstrate a strategy to realize the precise discrimination of C8 aromatics by constructing a nonaromatic confined pore environment with mixed polycycloalkane-type ligands. The nonaromatic low-polar pore environment avoids strong convergent interactions between the framework and the common phenyl rings while creating possibilities to amplify the difference between host-guest/guest-guest interactions regarding the different methyl (ethyl) group positions of isomers. The resultant metal-organic framework, ZUL-C3, with either tetragonal or monoclinic lattice, exhibits outstanding separation performance for C8 aromatics, not only realizing the simultaneous separation of four isomers from each other but also setting a benchmark for the dynamic separation performance of OX/PX and OX/MX.

Highly stretchable ionically crosslinked acrylate elastomers inspired by polyelectrolyte complexes.

Dynamic bonds are a powerful approach to tailor the mechanical properties of elastomers and introduce shape-memory, self-healing, and recyclability. Among the library of dynamic crosslinks, electrostatic interactions among oppositely charged ions have been shown to enable tough and resilient elastomers and hydrogels. In this work, we investigate the mechanical properties of ionically crosslinked ethyl acrylate-based elastomers assembled from oppositely charged copolymers. Using both infrared and Raman spectroscopy, we confirm that ionic interactions are established among polymer chains. We find that the glass transition temperature of the complex is in between the two individual copolymers, while the complex demonstrates higher stiffness and more recovery, indicating that ionic bonds can strengthen and enhance recovery of these elastomers. We compare cycles to increasing strain levels at different strain rates, and hypothesize that at fast strain rates ionic bonds dynamically break and reform while entanglements do not have time to slip, and at slow strain rates ionic interactions are disrupted and these entanglements slip significantly. Further, we show that a higher ionic to neutral monomer ratio can increase the stiffness, but its effect on recovery is minimal. Finally, taking advantage of the versatility of acrylates, ethyl acrylate is replaced with the more hydrophilic 2-hydroxyethyl acrylate, and the latter is shown to exhibit better recovery and self-healing at a cost of stiffness and strength. The design principles uncovered for these easy-to-manufacture polyelectrolyte complex-inspired bulk materials can be broadly applied to tailor elastomer stiffness, strength, inelastic recovery, and self-healing for various applications.

Tanshinone IIA Accomplished Protection against Radiation-Induced Cardiomyocyte Injury by Regulating the p38/p53 Pathway.

Background: Radiotherapy is one of the major strategies for treating tumors, and it inevitably causes damage to relevant tissues and organs during treatment. Radiation-induced heart disease (RIHD) refers to radiation-induced cardiovascular adverse effects caused by thoracic radiotherapy. Currently, there is no uniform standard in the treatment of RIHD. Methods: In our group study, by administering a dose of 4 Gy radiation, we established a radiation injured cardiomyocyte model and explored the regulatory relationship between tanshinone IIA and p38 MAPK in cardiomyocyte injury. We assessed cell damage and proliferation using clonogenic assay and lactate dehydrogenase (LDH) release assay. The measures of antioxidant activity and oxidative stress were conducted using superoxide dismutase (SOD) and reactive oxygen species (ROS). The apoptosis rate and the relative expression of apoptotic proteins were conducted using flow cytometry and western blot. To assess p38 and p53 expressions and phosphorylation levels, western blot was performed. Results: Experimental results suggested that tanshinone IIA restored cell proliferation in radiation-induced cardiomyocyte injury (∗∗P < 0.01), and the level of LDH release decreased (∗P < 0.05). Meanwhile, tanshinone IIA could decrease the ROS generation induced by radiation (∗∗P < 0.01) and upregulate the SOD level (∗∗P < 0.01). Again, tanshinone IIA reduced radiation-induced cardiomyocyte apoptosis (∗∗P < 0.01). Finally, tanshinone IIA downregulated radiation-induced p38/p53 overexpression (∗∗∗P < 0.001). Conclusions: The treatment effects of tanshinone IIA against radiation-induced myocardial injury may be through the regulation of the p38/p53 pathway.

Photocaging of Activity-Based Ubiquitin Probes via a C-Terminal Backbone Modification Strategy.

Photocaged, activity-based ubiquitin (Ub) probes (Ub-ABPs) have been developed for the time-resolved probing of deubiquitinating enzyme (DUB) activities, but many Ub-ABPs are still challenging to photocage because their warheads (e.g. propargylamide (PA) or dehydroalanine (Dha)) are difficult to temporally block and activate. Here, we describe a new C-terminal backbone modification strategy for the construction of photocaged Ub-ABPs in which a light-sensitive group is placed at the backbone amide bond of the Ub Gly75. This strategy enabled the facile generation of cell-permeable photocaged Ub-PA and Dha probes that could be activated to capture DUBs after photo-irradiation, and were used to profile DUBs in cells under specially designed conditions (e.g. in cells experiencing oxidative stress) or DUBs with isopeptide linkage selectivity. This backbone modification strategy is anticipated to provide a general solution for the development of photocaged Ub ABPs bearing any warheads for DUB profiling.

Measuring the ratio of femoral vein diameter to femoral artery diameter by ultrasound to estimate volume status.

BACKGROUND: Currently, the accepted effective method for assessing blood volume status, such as measuring central venous pressure (CVP) and mean pulmonary artery pressure (mPAP), is invasive. The purpose of this study was to explore the feasibility and validity of the ratio of the femoral vein diameter (FVD) to the femoral artery diameter (FAD) for predicting CVP and mPAP and to calculate the cut-off value for the FVD/FAD ratio to help judge a patient's fluid volume status. METHODS: In this study, 130 patients were divided into two groups: in group A, the FVD, FAD, and CVP were measured, and in group B, the FVD, FAD, and mPAP were measured. We measured the FVD and FAD by ultrasound. We monitored CVP by a central venous catheter and mPAP by a Swan-Ganz floating catheter. Pearson correlation coefficients were calculated. The best cut-off value for the FVD/FAD ratio for predicting CVP and mPAP was obtained according to the receiver operating characteristic (ROC) curve. RESULTS: The FVD/FAD ratio was strongly correlated with CVP (R = 0.87, P < 0.0000) and mPAP (R = 0.73, P < 0.0000). According to the ROC curve, an FVD/FAD ratio ≥ 1.495 had the best test characteristics to predict a CVP ≥ 12 cmH2O, and an FVD/FAD ratio ≤ 1.467 had the best test characteristics to predict a CVP ≤ 10 cmH2O. An FVD/FAD ratio ≥ 2.03 had the best test characteristics to predict an mPAP ≥ 25 mmHg. According to the simple linear regression curve of the FVD/FAD ratio and CVP, when the predicted CVP ≤ 5 cmH2O, the FVD/FAD ratio was ≤ 0.854. CONCLUSION: In this study, the measurement of the FVD/FAD ratio obtained via ultrasound was strongly correlated with CVP and mPAP, providing a non-invasive method for quickly and reliably assessing blood volume status and providing good clinical support.

Nuclear factor-kappaB regulates the transcription of NADPH oxidase 1 in human alveolar epithelial cells.

OBJECTIVE: Acute lung injury (ALI) is characterized by inflammation and oxidative stress. Nuclear factor-kappaB (NF-κB) mediates the expression of various inflammation-related genes, including the NADPH oxidase family. This study aimed to identify the potential regulatory role of NF-κB on NADPH oxidases in tumor necrosis factor-α (TNF-α)-induced oxidative stress in human alveolar epithelial cells. METHODS: A549 cells were treated with TNF-α for 24 h to establish ALI cell models. RT-PCR, western blot, assessment of oxidative stress, Alibaba 2.1 online analysis, electrophoretic mobility shift assays and luciferase reporter analysis were employed to identify the potential regulatory role of NF-κB on NADPH oxidases in TNF-α-induced oxidative stress in human alveolar epithelial cells. RESULTS: The expression of NF-κB/p65 was notably upregulated in TNF-α-stimulated A549 cells. NF-κB knockdown by siRNA significantly inhibited the TNF-α-induced oxidative stress. Moreover, NF-κB/p65 siRNA could inhibit the activation of NOX1, NOX2 and NOX4 mRNA and protein expression in TNF-α-stimulated A549 cells. The next study demonstrated that NF-κB activated the transcription of NOX1 by binding to the -261 to -252 bp (NOX1/κB2, TAAAAATCCC) region of NOX1 promoter in TNF-α-stimulated A549 cells. CONCLUSION: Our data demonstrated that NF-κB can aggravate TNF-α-induced ALI by regulating the oxidative stress response and the expression of NOX1, NOX2 and NOX4. Moreover, NF-κB could promote the NOX1 transcriptional activity via binding its promoter in TNF-α-stimulated A549 cells.

Metformin improves blood glucose by increasing incretins independent of changes in gluconeogenesis in youth with type 2 diabetes.

AIMS/HYPOTHESIS: Metformin is the only approved oral agent for youth with type 2 diabetes but its mechanism of action remains controversial. Recent data in adults suggest a primary role for the enteroinsular pathway, but there are no data in youth, in whom metformin efficacy is only ~50%. Our objectives were to compare incretin concentrations and rates of glucose production and gluconeogenesis in youth with type 2 diabetes before and after short-term metformin therapy compared with peers with normal glucose tolerance (NGT). METHODS: This is a case-control observational study in youth with type 2 diabetes who were not on metformin (n = 18) compared with youth with NGT (n = 10) who were evaluated with a 2 day protocol. A 75 g OGTT was administered to measure intact glucagon-like 1 peptide (iGLP-1), gastric inhibitory polypeptide (GIP) and peptide YY (PYY). Insulinogenic index (IGI) and whole-body insulin sensitivity were calculated using glucose and insulin levels from the OGTT. Basal rates of gluconeogenesis (2H2O), glucose production ([6,6-2H2]glucose) and whole-body lipolysis ([2H5]glycerol) were measured after an overnight fast on study day 2. Youth with type 2 diabetes (n = 9) were subsequently evaluated with an identical 2 day protocol after 3 months on the metformin study. RESULTS: Compared with individuals with NGT, those with type 2 diabetes had higher fasting (7.8 ± 2.5 vs 5.1 ± 0.3 mmol/l, mean ± SD p = 0.002) and 2 h glucose concentrations (13.8 ± 4.5 vs 5.9 ± 0.9 mmol/l, p = 0.001), higher rates of absolute gluconeogenesis (10.0 ± 1.7 vs 7.2 ± 1.1 µmol [kg fat-free mass (FFM)]-1 min-1, p < 0.001) and whole-body lipolysis (5.2 ± 0.9 vs 4.0 ± 1.4 µmol kgFFM-1 min-1, p < 0.01), but lower fasting iGLP-1 concentrations (0.5 ± 0.5 vs 1.3 ± 0.7 pmol/l, p < 0.01). Metformin decreased 2 h glucose (pre metformin 11.4 ± 2.8 vs post metformin 9.9 ± 1.9 mmol/l, p = 0.04) and was associated with ~20-50% increase in IGI (median [25th-75th percentile] pre 1.39 [0.89-1.47] vs post 1.43 [0.88-2.70], p = 0.04), fasting iGLP-1 (pre 0.3 ± 0.2 vs post 1.0 ± 0.7 pmol/l, p = 0.02), 2 h iGLP (pre 0.4 ± 0.2 vs post 1.2 ± 0.9 pmol/l, p = 0.06), fasting PYY (pre 6.3 ± 2.2 vs post 10.5 ± 4.3 pmol/l, p < 0.01) and 2 h PYY (pre 6.6 ± 2.9 vs post 9.0 ± 4.0 pmol/l, p < 0.01). There was no change in BMI, insulin sensitivity or GIP concentrations pre vs post metformin. There were no differences pre vs post metformin in rates of glucose production (15.0 ± 3.9 vs 14.9 ± 2.2 µmol kgFFM-1 min-1, p = 0.84), absolute gluconeogenesis (9.9 ± 1.8 vs 9.7 ± 1.7 µmol kgFFM-1 min-1, p = 0.76) or whole-body lipolysis (5.0 ± 0.7 vs 5.3 ± 1.3 µmol kgFFM-1 min-1, p = 0.20). Post metformin iGLP-1 and PYY concentrations in youth with type 2 diabetes were comparable to levels in youth with NGT. CONCLUSIONS/INTERPRETATION: Overall, the improved postprandial blood glucose levels and increase in incretins observed in the absence of changes in insulin sensitivity and gluconeogenesis, support an enteroinsular mechanistic pathway in youth with type 2 diabetes treated with short-term metformin.

Induction chemotherapy followed by neoadjuvant chemoradiotherapy and surgery for patients with locally advanced rectal cancer: a systematic review and meta-analysis.

BACKGROUND: Controversy persists about whether additional induction chemotherapy (ICT) before neoadjuvant chemoradiation (NCRT) yields improved oncological outcomes. We performed a systematic review and meta-analysis to compare ICT+ NCRT+ surgery(S) with NCRT+ S in patients with locally advanced rectal cancer (LARC). METHODS: We searched the PubMed, EMBASE, Cochrane Library, and China Biology Medicine (CBM) databases. The data were analyzed with Stata version 12.0 software. RESULTS: We identified 9 relevant trials that enrolled 1538 patients. We detected no significant difference in the 5-year overall survival (OS) (OR 1.50, 95% CI 0.48-4.64), disease-free survival (DFS) (OR 1.03, 95% CI 0.73-1.46), local recurrence (LR) (OR 0.80, 95% CI 0.45-1.43), and distant metastasis (DM) rates (OR 1.03, 95% CI 0.55-1.93) between patients who did and did not receive ICT. The addition of ICT before NCRT had a similar pathological complete response rate compared to NCRT (OR 1.26, 95% CI 0.90-1.77). Our findings suggest that between the ICT + NCRT+S and NCRT+S groups, ICT improved the incidence of grade 3 to 4 toxicity effects (OR 4.81, 95% CI 2.38-9.37), but between the ICT + NCRT+S and NCRT+S+ adjuvant chemotherapy (ACT) groups, ICT might reduce toxicity (OR 0.19, 95% CI 0.08-0.50). ICT had no significant impact on surgical complications (OR 0.97, 95% CI 0.63-1.51). CONCLUSIONS: The addition of ICT before NCRT seemingly shows no survival benefit on patients with LARC, and might increase the toxicity.

Transcriptional regulation of a leucine-responsive regulatory protein for directly controlling lincomycin biosynthesis in Streptomyces lincolnensis.

Leucine-responsive regulatory proteins (Lrps) are a family of transcription factors involved in diverse biological processes in bacteria. So far, molecular mechanism of Lrps for regulating antibiotics biosynthesis in actinomycetes remains largely unexplored. This study, for the first time in Streptomyces lincolnensis, identified an Lrp (named as SLCG_Lrp) associated with lincomycin production. SLCG_Lrp was validated to be a positive regulator for lincomycin biosynthesis by directly stimulating transcription of two structural genes (lmbA and lmbV), three resistance genes (lmrA, lmrB and lmrC), and a regulatory gene (lmbU) within the lincomycin biosynthetic gene (lin) cluster. SLCG_Lrp was transcriptionally self-inhibited and triggered the expression of its adjacent gene SLCG_3127 encoding a LysE superfamily protein. Further, the binding site of SLCG_Lrp in the intergenic region of SLCG_3127 and SLCG_Lrp was precisely identified. Inactivation of SLCG_3127 in S. lincolnensis resulted in yield improvement of lincomycin, which was caused by intracellular accumulation of proline and cysteine. Arginine and phenylalanine were identified as specific regulatory ligands, respectively, to reduce and promote DNA-binding affinity of SLCG_Lrp. We further found that SLCG_Lrp was directly repressed by SLCG_2919, the first identified transcription factor outside lin cluster for lincomycin production. Therefore, our findings revealed SLCG_Lrp-mediated transcriptional regulation of lincomycin biosynthesis. This study extends the understanding of molecular mechanisms underlying lincomycin biosynthetic regulation.

Organic Heterojunctions Formed by Interfacing Two Single Crystals from a Mixed Solution.

Organic heterojunctions are widely used in organic electronics and they are composed of semiconductors interfaced together. Good ordering in the molecular packing inside the heterojunctions is highly desired but it is still challenging to interface organic single crystals to form single-crystalline heterojunctions. Here, we describe how organic heterojunctions are formed by interfacing two single crystals from a droplet of a mixed solution containing two semiconductors. Based on crystallization of six organic semiconductors from a droplet on a substrate, two distinct crystallization mechanisms have been recognized in the sense that crystals form at either the top interface between the air and solution or the bottom interface between the substrate and solution. The preference for one interface rather than the other depends on the semiconductor-substrate pair and, for a given semiconductor, it can be switched by changing the substrate, suggesting that the preference is associated with the semiconductor-substrate molecular interaction. Furthermore, simultaneous crystallization of two semiconductors at two different interfaces to reduce their mutual disturbance results in the formation of bilayer single crystals interfaced together for organic heterojunctions. These single-crystalline heterojunctions exhibit ambipolar charge transport in field-effect transistors, with the highest electron mobility of 1.90 cm2 V-1 s-1 and the highest hole mobility of 1.02 cm2 V-1 s-1. Hence, by elucidating the interfacial crystallization events, this work should greatly harvest the solution-grown organic single-crystalline heterojunctions.

In vitro combination of anti-cytomegalovirus compounds acting through different targets: role of the slope parameter and insights into mechanisms of Action.

Conventional therapy for human cytomegalovirus (CMV) relies on inhibition of the viral DNA polymerase. Ganciclovir (GCV) is the first-line therapy, but when GCV-resistant strains emerge, alternative therapies are extremely limited and are associated with significant toxicities. Combination of anti-CMV agents that act on different targets or stages of virus replication has not been well studied, mostly because of the limited number of anti-CMV agents. We report our investigation of combinations of agents that inhibit CMV by targeting the viral DNA polymerase, cellular kinases, or other cell/virus mechanisms yet to be discovered. The selected compounds differed by the slopes of their dose-response curve: compounds with a slope of 1 (GCV) representing one target or noncooperativity and compounds with high slopes indicating positive cooperativity. Analysis of anti-CMV drug combinations using the Bliss model (which accounts for the slope parameter) distinguished between combinations with synergistic, antagonistic, and additive activities. The combination of GCV and foscarnet was slightly synergistic; strong synergism was found when GCV was used with artemisinin-derived monomers or dimers or the MEK inhibitor U0126. The combination of GCV and cardiac glycosides (digoxin, digitoxin, and ouabain) was additive. The monomeric artemisinin artesunate was synergistic when combined with U0126 or the multikinase inhibitor sunitinib. However, the combination of artemisinin-derived dimers (molecular weights, 606 and 838) and U0126 or sunitinib was antagonistic. These results demonstrate that members of a specific drug class show similar patterns of combination with GCV and that the slope parameter plays an important role in the evaluation of drug combinations. Lastly, antagonism between different classes of CMV inhibitors may assist in target identification and improve the understanding of CMV inhibition by novel compounds.

The effect of various interventions on the prevention of radiation dermatitis: a network meta-analysis.

OBJECTIVE: High doses of radiation, while effective at destroying tumor tissues, also result in radiation dermatitis (RD) at irradiated sites, which is one of the most common complications in cancer radiotherapy. Currently, no standardized protocols for the prevention and treatment of RD have been established in clinical practices, and severe RD can compromise treatment efficacy and reduce patients' quality of life. This systematic review and network meta-analysis (NMA) aims to compare the effectiveness of various interventions in preventing RD in patients. METHODS: As of June 2023, four databases, including PubMed, Embase, Web of Science, and the Cochrane Library, were searched, with a total of 19 interventions obtained for comparative analysis of their effectiveness in preventing RD. The Cochrane risk-of-bias tool was employed to screen literature, extract data, and appraise the quality of the studies by two researchers. Bayesian network meta-analysis (NMA) was conducted utilizing StataSE 15 and R 4.2.3. RESULTS: A total of 33 studies involving 4307 patients were included in this analysis. From the 33 studies, 19 interventions, encompassing Barrier Films and Dressings (BFD), Boron_Gel, Best supportive care, Corticosteroids_cream, Doxepin_cream, Eau Thermale Avèn_gel, Epidermal Growth Factor_cream, Hyaluronan_cream, Medicinal_Plants, Mineral_Oil, Olive oil and calcium hydroxide (OOCH), Photobiomodulation therapy, Recove_cream, Silicone_gel, Silver sulfadiazine (SSD), Timolol_Gel, Trolamine, VitD_Gel, and VitE_Gel, were retrieved and compared. The NMA results indicated that Hyaluronan_cream (SUCRA: 94.9%) was highly effective in preventing Grade 0/1 RD. Meanwhile, OOCH (SUCRA: 95.7%) demonstrated the most prominent effect in preventing ≥ Grade 2 RD. CONCLUSION: The study reveals that Hyaluronan_cream and OOCH are two promising treatments for the prevention of RD in patients undergoing radiotherapy. Future research might focus on validating the efficacy of these two therapies with large sample sizes and on identifying an optimal intervention strategy.

Efficacy and mechanism of action of ginsenoside Rg3 on radiation proctitis in rats.

OBJECTIVE: Radiation proctitis (RP) refers to rectal injury caused by radiation treatment of pelvic and retroperitoneal malignancies, which has a major impact on the treatment prognosis and quality of life of patients with cancer. The tetracyclic triterpene saponin monomer ginsenoside Rg3 (GRg3), the primary bioactive ingredient in ginseng extracts, has therapeutic effects against RP in rats. Here, we validated its efficacy and elucidated its mechanism of action. METHODS: A rat RP model was established in 48 Wistar rats. Rats were randomly divided into control (untreated), irradiation, irradiation + dexamethasone, and irradiation + GRg3 (low-, medium-, and high-dose) groups. After 2 weeks' treatment, serum IL-4, IL-10, and TNF-α levels were tested by enzyme-linked immunosorbent assays. In rectal tissue, Ikbkb, Ikka, and Casp8 mRNA expression was detected by a reverse transcription-quantitative polymerase chain reaction. IKK-ß, IκB-α, p-IκB-α, p50, and caspase-8 protein levels were determined by western blot analysis. RESULTS: GRg3 significantly improved the general condition and histopathological damage in rats with RP. Moreover, GRg3 decreased the levels of factors that promote inflammation (TNF-α) and increased the levels of factors that reduce inflammation (IL-4 and IL-10). GRg3 markedly reduced the activation of NF-κB and caspase-8 signaling pathways. CONCLUSIONS: Thus, GRg3 may reduce the inflammatory response by blocking the NF-κB signaling pathway and improving the balance of inflammation-related factors. GRg3 may also inhibit intestinal cell apoptosis by suppressing the TNF-α/caspase-8 signaling cascade, thereby reducing radiological rectal injury. Our results verify that GRg3 is a promising therapeutic agent for RP treatment and shed light on its mechanism.