Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Design and Evolution of an Artificial Friedel-Crafts Alkylation Enzyme Featuring an Organoboronic Acid Residue.

Creating artificial enzymes by the genetic incorporation of noncanonical amino acids with catalytic side chains would expand the enzyme chemistries that have not been discovered in nature. Here, we report the design of an artificial enzyme that uses p-boronophenylalanine as the catalytic residue. The artificial enzyme catalyzes Michael-type Friedel-Crafts alkylation through covalent activation. The designer enzyme was further engineered to afford high yields with excellent enantioselectivities. We next developed a practical method for preparative-scale reactions by whole-cell catalysis. This enzymatic C-C bond formation reaction was combined with palladium-catalyzed dearomative arylation to achieve the efficient synthesis of spiroindolenine compounds.

ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Combination of different local anesthetic adjunct for supraclavicular brachial plexus block after arthroscopic shoulder surgery: a prospective randomized controlled trial.

BACKGROUND: Acute pain is a major concern after arthroscopic shoulder surgery, supraclavicular brachial plexus blockade has shown favorable postoperative analgesic effects. However, its duration of analgesia does not meet clinical needs. We aimed to explore whether the combination of different local anesthetic adjunct can prolong the analgesic duration of supraclavicular brachial plexus block for arthroscopic shoulder surgery. METHODS: In this prospective randomized controlled trial, we allocated 80 patients into four groups: Group DMD (dexamethasone 10 mg + ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group DM (ropivacaine 100 mg + dexmedetomidine 50 µg + magnesium sulfate 250 mg), Group M (ropivacaine 100 mg + magnesium sulfate 250 mg) and Group D (ropivacaine 100 mg + dexmedetomidine 50 µg). The primary outcome was the time to first request for analgesia. Secondary outcome measures included cumulative opioid consumption at 6, 12, 18, 24, and 48 h postoperatively, VAS scores at 6, 12, 18, 24, and 48 h postoperatively and so on. RESULTS: The time to first request for analgesia in Group DMD was significantly longer than Group DM (P = 0.011) and Group M (P = 0.003). The cumulative opioid consumption at 18 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.002) and Group M (P = 0.007). The cumulative opioid consumption at 24 h postoperatively in Group DMD was significantly lower than in Group DM (P = 0.016). The VAS score at 6 h postoperatively in Group DMD was significantly lower than in Group DM and Group M. The VAS score at 12 h postoperatively in Group DMD was significantly lower than in Group M. For American Shoulder and Elbow Surgeons Score, Group DMD had a better score than Group DM and Group D. CONCLUSIONS: The analgesic efficacy of supraclavicular brachial plexus blockade combined with dexamethasone, magnesium sulfate, and dexmedetomidine is significantly superior to the combination of magnesium sulfate and dexmedetomidine, and significantly superior to the use of magnesium sulfate alone. TRIAL REGISTRATION: This trial was registered in Chinese Clinical Trial Registry. (ChiCTR2200061181, Date of registration: June 15, 2022, http://www.chictr.org.cn ).

Adipose Triglyceride Lipase Deficiency Aggravates Angiotensin II-Induced Atrial Fibrillation by Reducing Peroxisome Proliferator-Activated Receptor α Activation in Mice.

Atrial fibrillation (AF) is a main risk factor for cerebrovascular diseases but lacks precision therapy. Adipose triglyceride lipase (ATGL) is a key enzyme involved in the intracellular degradation of triacylglycerol and plays an important role in lipid and energy metabolism. However, the role of ATGL in the regulation of AF remains unclear. In this study, AF was induced by infusion of angiotensin II (Ang II, 2000 ng/kg/min) for 3 weeks in male ATGL knockout (KO) mice and age-matched C57BL/6 wild-type mice. The atrial volume was measured by echocardiography. Atrial fibrosis, inflammatory cells, and superoxide production were detected by histologic examinations. The results showed that ATGL expression was significantly downregulated in the atrial tissue of the Ang II-infused mice. Moreover, Ang II-induced increase in the inducibility and duration of AF, atrial dilation, fibrosis, inflammation, and oxidative stress in wild-type mice were markedly accelerated in ATGL KO mice; however, these effects were dramatically reversed in the ATGL KO mice administered with peroxisome proliferator-activated receptor (PPAR)-α agonist clofibric acid. Mechanistically, Ang II downregulated ATGL expression and inhibited PPAR-α activity, activated multiple signaling pathways (inhibiting kappa B kinase α/ß-nuclear factor-κB, nicotinamide adenine dinucleotide phosphate oxidase, and transforming growth factor-ß1/SMAD2/3) and reducing Kv1.5, Cx40, and Cx43 expression, thereby contributing to atrial structural and electrical remodeling and subsequent AF. In summary, our results indicate that ATGL KO enhances AF inducibility, possibly through inhibiting PPAR-α activation and suggest that activating ATGL might be a new therapeutic option for treating hypertensive AF.

Mesenchymal stromal cells-derived small extracellular vesicles modulate DC function to suppress Th2 responses via IL-10 in patients with allergic rhinitis.

Mesenchymal stromal cells (MSCs) are well known for their immunoregulatory roles on allergic inflammation particularly by acting on T cells, B cells, and dendritic cells (DCs). MSC-derived small extracellular vesicles (MSC-sEV) are increasingly considered as one of the main factors for the effects of MSCs on immune responses. However, the effects of MSC-sEV on DCs in allergic diseases remain unclear. MSC-sEV were prepared from the induced pluripotent stem cells (iPSC)-MSCs by anion-exchange chromatography, and were characterized with the size, morphology, and specific markers. Human monocyte-derived DCs were generated and cultured in the presence of MSC-sEV to differentiate the so-called sEV-immature DCs (sEV-iDCs) and sEV-mature DCs (sEV-mDCs), respectively. The phenotypes and the phagocytic ability of sEV-iDCs were analyzed by flow cytometry. sEV-mDCs were co-cultured with isolated CD4+ T cells or peripheral blood mononuclear cells (PBMCs) from patients with allergic rhinitis. The levels of Th1 and Th2 cytokines produced by T cells were examined by ELISA and intracellular flow staining. And the following mechanisms were further investigated. We demonstrated that MSC-sEV inhibited the differentiation of human monocytes to iDCs with downregulation of the expression of CD40, CD80, CD86, and HLA-DR, but had no effects on mDCs with these markers. However, MSC-sEV treatment enhanced the phagocytic ability of mDCs. More importantly, using anti-IL-10 monoclonal antibody or IL-10Rα blocking antibody, we identified that sEV-mDCs suppressed the Th2 immune response by reducing the production of IL-4, IL-9, and IL-13 via IL-10. Furthermore, sEV-mDCs increased the level of Treg cells. Our study identified that mDCs treated with MSC-sEV inhibited the Th2 responses, providing novel evidence of the potential cell-free therapy acting on DCs in allergic airway diseases.

Optofluidic zoom system with increased field of view and less chromatic aberration.

Imaging systems are widely used in many fields. However, there is an inherent compromise between field of view (FOV) and resolution. In this paper, we propose an optofluidic zoom system with increased FOV and less chromatic aberration, which can realize switching between large FOV and high resolution. The proposed system consists of a liquid prism, a zoom objective, an image sensor and image processing module, which can realize optical zoom and deflection. The proposed system achieves non-mechanical optical zoom from f = 40.5 mm to f = 84.0 mm. Besides, the angular resolution of zoom objective is up to 26"18 at f = 84.0 mm. The deflection range is ±10°, and the whole FOV of proposed system can reach up to 30.3°. The proposed system is compact and easy to machine. In addition, we reduce chromatic aberration produced by the liquid prism significantly. The proposed system can be used in monitor system, target tracking system, telescope system and so on.

The positive effects of postbiotic (SWF concentration®) supplemented diet on skin mucus, liver, gut health, the structure and function of gut microbiota of common carp (Cyprinus carpio) fed with high-fat diet.

Postbiotics are an emerging research interest in recent years, which shows that metabolites, lysate extracts, cell wall components and even culture supernatants of probiotics can also exhibit significant prebiotic effects. In this study postbiotic stress worry free concentration® (SWFC) were prepared from the composition of culture supernatant of Cetobacterium somerae and Lactococcus lactis. The positive effects of SWFC supplemented diets on the growth performance, skin mucus, liver and gut health, and intestinal microbiota profile of Cyprinus carpio fed with high fat diets were investigated. 180 C. carpio with an average body weight of (3.01 ± 0.01) g were selected and randomly divided into three groups. They were fed with one of the three experimental diets supplemented with SWFC of 0 (control), 0.2 and 0.3 g/kg for 98 days, afterwards indexes were detected. The results revealed that, addition of SWFC had no significant effect on growth performance of C. carpio, while it can improve the health of the fish remarkably. In addition, SWFC improved mucosal C3, T-AOC, SOD activities, and decreased lipid peroxidation product MDA level, which were notably better than those in the control group (P < 0.05). In terms of the liver health systems, C. carpio fed on the diet supplemented with 0.2 g/kg of SWFC, showed significant improvement of the liver injured by HFD and reduce the contents of serum ALT and AST, and liver TAG (P < 0.05; P < 0.01). The expression of inflammation-related and lipid synthesis genes revealed that SWFC0.2 group could noteworthy enhance antioxidant capacity, reduced the expression of pro-inflammatory factors (TNF-α, IL-1ß) and lipid synthesis genes (ACC, FAS, PPAR-ß, PPAR-γ), and up-regulated the expression of anti-inflammatory factors (TGF-ß). Additionally, intestinal morphology arose inflammatory cell infiltration, while intestinal integrity was better in SWFC groups compared with the control. Furthermore, the contents of serum LPS and LBP were remarkably lower in the SWFC0.2 group compared with the control (P < 0.01). The mRNA expression of genes related to gut health indicated that SWFC supplementation noteworthy up-regulated the expression of antioxidant (Nrf2, CAT, GPX), immune (Hepcidin, IL-10) and tight junction protein-related (ZO-1, Occludin). Simultaneously, the results of GF-zebrafish showed that the relative expression of anti-inflammatory genes (IL-1ß, TGF-ß) and antioxidant related genes (Nrf2, HO-1) were significantly up-regulated in SWFC groups. Data on intestinal microbiota profile verified that, at the phylum level, the abundance of Fusobacteria was remarkably elevated in the SWFC groups (P < 0.05), whereas the abundance of Firmicutes was declined noteworthy in SWFC0.2 and SWFC0.3 compared to the control group (P < 0.05; P < 0.01) respectively. At the genus level, the abundance of Cetobacterium in the SWFC groups were notably higher than those in the control group (P < 0.05), while the Vibrio content in the SWFC groups was significantly decreased (P < 0.05). PCoA result indicated that the intestinal microflora of SWFC0.2 group was abundant and diverse. Our results elucidate that dietary supplementation of SWFC protects C. carpio from HFD induced inflammatory response and oxidative stress, ameliorate skin mucus, liver and gut health, and improve the gut microbiota balance. Therefore, SWFC could be considered as an improving-fish-health additive, when supplemented to aquatic animal feed. With regards to how SWFC regulates the immunity and inflammatory responses and which signal transductions are involved remains unclear and more scientific evidences are needed to address these issues.

ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway.

Persistent myocardial hypertrophy frequently leads to heart failure (HF). Intramyocardial triacylglycerol (TAG) accumulation is closely related with cardiac remodeling and abnormal contractile function. Adipose triglyceride lipase (ATGL), a key enzyme in TAG metabolism, regulates cardiac function. However, its associated molecular pathways have not been fully defined. Here, cardiac hypertrophy and HF were induced in wild-type (WT) or ATGL knockout (KO) mice through transverse aortic constriction (TAC) for up to 4 weeks. TAC in WT mice significantly reduced cardiac function and autophagy while enhancing left ventricular hypertrophy, interstitial fibrosis, inflammatory response, superoxide generation, and cardiomyocyte apoptosis, accompanied with upregulation of the proteasome activity, reduction of PTEN level and activation of AKT-mTOR signaling, and these effects were further aggravated in ATGL KO mice. Interestingly, ATGL KO-mediated cardiac dysfunction and remodeling were markedly reversed by proteasome inhibitor (epoxomicin) or autophagic activator (rapamycin), but accelerated by PTEN inhibitor (VO-OHpic) or autophagy inhibitor 3-MA. Mechanistically, ATGL KO upregulated proteasome expression and activity, which in turn mediates PTEN degradation leading to activation of AKT-mTOR signaling and inhibition of autophagy, thereby enhancing hypertrophic remodeling and HF. In conclusion, ATGL KO contributes to TAC-induced cardiac dysfunction and adverse remodeling probably associated with the proteasome-PTEN-mTOR-autophagy pathway. Therefore, modulation of this pathway may have a therapeutic effect potential for hypertrophic heart disease. TAC-induced downregulation of ATGL results in increased proteasome (ß1i/ß2i/ß5i) activity, which in turn promotes degradation of PTEN and activation of AKT-mTOR signaling and then inhibits autophagy and ATP production, thereby leading to cardiac hypertrophic remodeling and dysfunction. Conversely, blocking proteasome activity or activating autophagy attenuates these effects.

An intramolecular vibrationally excited intermolecular potential energy surface and predicted 2OH overtone spectroscopy of H2O-Kr.

A new five-dimensional potential energy surface (PES) for H2O-Kr which explicitly includes the intramolecular 2OH overtone state of the H2O monomer is presented. The intermolecular potential energies were evaluated using explicitly correlated coupled cluster theory [CCSD(T)-F12] with a large basis set. Four vibrationally averaged analytical intermolecular PESs for H2O-Kr with H2O molecules in its |00+〉, |02+〉, |02-〉, and |11+〉 states are obtained by fitting to the multi-dimensional Morse/Long-Range potential function form. Each vibrationally averaged PES fitted to 578 points has root-mean-square (RMS) deviations smaller than 0.14 cm-1 and requires only 58 parameters. The combined radial discrete variable representation/angular finite basis representation method and the Lanczos algorithm were employed to calculate the rovibrational energy levels for |00+〉, |02+〉, |02-〉, and |11+〉 states of the H2O-Kr complexes. The calculated |02-〉Πf/e(101) ← |00+〉Σe(000) and |02+〉Πf/e(110) ← |00+〉Σe(101) infrared transitions are in excellent agreement with the experimental values with RMS discrepancies being only 0.007 and 0.016 cm-1, respectively. These analytical PESs can be used to provide reliable theoretical guidance for future infrared overtone spectroscopy of H2O-Kr.

Opioid infusions at different times of the day produce varying degrees of opioid-induced hyperalgesia.

BACKGROUND: Opioids are metabolised by enzymes the activities of which vary with the circadian rhythm. We examined whether opioid infusions administered at different times of the day produce varying degrees of opioid-induced hyperalgesia (OIH) in animal experiments and clinical studies. METHODS: Male Sprague-Dawley rats received remifentanil infusions (1 µg kg-1·min-1 for 1 h) at Zeitgeber times (ZT) 0, 4, 8, 12, 16, or 20 h. Rhythmicity of mechanical hypersensitivity was assayed after the infusion. Mechanical hypersensitivity, drug concentration, and metabolic enzyme activity of Wistar rats that received sufentanil (10 µg kg-1; four consecutive i.p. injections at 15-min intervals) or remifentanil infusion at ZT0 or ZT8 were assayed. Sixty patients who underwent abdominal laparoscopic surgery under general anaesthesia received remifentanil infusion (0.15 µg kg-1 min-1) and sufentanil injection (0.2 µg kg-1) at induction and skin incision, respectively. Postoperative pressure pain sensitivity, pain Numeric Rating Scale (NRS), drug concentrations, and nonspecific esterase activity were assessed. RESULTS: Sprague-Dawley rats that received remifentanil infusion exhibited a robust rhythmic paw withdrawal threshold (JTK_CYCLE: P=0.001, Q=0.001, Phase=26). Wistar rats infused with remifentanil or sufentanil at ZT8 exhibited greater OIH (P<0.001) than those infused at ZT0, with higher blood concentrations (P<0.001) and lower metabolic enzyme activities (P=0.026 and P=0.028, respectively). Patients in the afternoon group exhibited higher pressure pain sensitivity at forearm (P=0.002), higher NRS (P<0.05), higher drug concentrations (sufentanil: P=0.037, remifentanil: P=0.005), and lower nonspecific esterase activity (P=0.024) than the morning group. CONCLUSIONS: Opioid infusions administered at different times of day produced varying degrees of OIH, possibly related to circadian rhythms of metabolic enzyme activities. CLINICAL TRIAL REGISTRATION: NCT05234697.

Comparative diagnostic accuracy of the IOTA SRR and LR2 scoring systems for discriminating between malignant and Benign Adnexal masses by junior physicians in Chinese patients: a retrospective observational study.

BACKGROUND: The accuracy of ultrasound in distinguishing benign from malignant adnexal masses is highly correlated with the experience of ultrasound physicians. In China, most of ultrasound differentiation is done by junior physicians. PURPOSE: To compare the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) Simple Rules Risk (SRR) and IOTA Logistic Regression Model 2 (LR2) scoring systems in Chinese patients with adnexal masses. METHODS: Retrospective analysis of ovarian cancer tumor patients who underwent surgery at a hospital in China from January 2016 to December 2021. Screening patients with at least one adnexal mass on inclusion and exclusion criteria. Two trained junior physicians evaluated each mass using the two scoring systems. A receiver operating characteristic curve was used to test the diagnostic performance of each system. RESULTS: A total of 144 adnexal masses were retrospectively collected. Forty masses were histologically diagnosed as malignant. Compared with premenopausal women, postmenopausal women had a much higher rate of malignant masses. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) of the SRR was 97.5% (95% CI: 86.8 -99.9%), 82.7% (95% CI: 74.0 -89.4%), 68.4% (95% CI: 58.7 -76.8%) and 98.9% (95% CI: 92.5 -99.8%). The sensitivity, specificity, PPV, NPV of the LR2 were 90.0% (95% CI: 76.5 -97.2%), 89.4% (95% CI: 81.9 -94.6%), 76.6% (95% CI: 65.0 -85.2%), and 95.9% (95% CI: 90.2 -98.3%). There was good agreement between two scoring systems, with 84.03% total agreement and a kappa value of 0.783 (95% CI: 0.70-0.864). The areas under the curve for predicting malignant tumours using SRR and LR2 were similar for all patients (P > 0.05 ). CONCLUSION: The two scoring systems can effectively distinguish benign from malignant adnexal masses. Both scoring systems have high diagnostic efficacy, and diagnostic efficacy is stable, which can provide an important reference for clinical decision making.

Peripheral blood monocyte status is a predictor for judging occurrence and development on sepsis in older adult population: a case control study.

BACKGROUND: Peripheral blood monocytes are important immune modulatory cells that change during aging. Previous studies on sepsis and monocytes did not distinguish between age groups, especially in the older adult population. The mechanisms of monocyte subsets and function are not well-understood in the aging context with sepsis. METHODS: Monocyte subsets were measured using flow cytometry in 80 sepsis patients and 40 healthy controls. Plasma cytokine levels were measured using cytokine antibody arrays. RESULTS: The percentage of MO3 (CD14 + CD16 + +)/monocytes was higher in sepsis patients than in controls (P = 0.011), whereas the percentage of MO1 (CD14 + + CD16 -)/monocytes was higher in septic shock patients and 28-day death group than in those without shock and 28-day survival group (P = 0.034, 0.038). Logistic regression analysis showed that the percentage of MO3/monocytes (OR = 1.120, P = 0.046) and plasma level of monocyte chemoattractant protein (MCP)-1 (OR = 1.006, P = 0.023) were independently associated with the occurrence of sepsis, whereas the percentage of MO1/monocytes (OR = 1.255, P = 0.048) was independently associated with septic shock. The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) of MO3/monocyte percentage in combination with MCP-1 plasma level (AUC = 0.799) for predicting sepsis was higher than that of each parameter alone (P < 0.001). The AUC of MO1/monocyte percentage with the value 0.706 (P = 0.003) was lower than the AUC of SOFA (sequential organ failure assessment) score with the value 0.966 (P < 0.001) for predicting septic shock, but the value of the two AUCs were similar for predicting 28-day mortality (AUC = 0.705, 0.827; P = 0.020, P < 0.001). The AUC of MO1/monocytes percentage in combination with SOFA score for predicting 28-day mortality was higher than that of each parameter alone (AUC = 0.867, P < 0.001). Using a cut-off of 58.5% (for MO1/monocytes determined by ROC) could discriminate between survivors and non-survivors on Kaplan-Meier curves for 28-day mortality with a positive predictive value of 77.4%. CONCLUSION: The MO3/monocyte percentage and plasma MCP-1 level were independent predictors of sepsis occurrence, whereas the percentage of MO1/monocytes was an independent predictor of prognosis in the Chinese Han older adult population. TRIAL REGISTRATION: Registration number: ChiCTR2200061490, date of registration: 2022-6-26 (retrospectively registered).

[Omalizumab Treats Aspirin-Induced Asthma Complicated With Nasosinusitis and Otitis Media:Report of One Case].

Omalizumab,as a biological agent targeting IgE,is a recombinant humanized monoclonal antibody and the first targeted drug approved for treating moderate-to-severe bronchial asthma.By reviewing one case of aspirin-induced asthma complicated with nasosinusitis and otitis media,we discussed the value of omalizumab in the treatment of asthma and its complications,aiming to provide a reference for clinical practice.

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D.

Incorporating enzymatic reactions into natural product synthesis can significantly improve synthetic efficiency and selectivity. In contrast to the increasing applications of biocatalytic functional-group interconversions, the use of enzymatic C-C bond formation reactions in natural product synthesis is underexplored. Herein, we report a concise and efficient approach for the synthesis of [7.7]paracyclophane natural products, a family of polyketides with diverse biological activities. By using enzymatic Friedel-Crafts alkylation, cylindrocyclophanes A and F and merocyclophanes A and D were synthesized in six to eight steps in the longest linear sequence. This study demonstrates the power of combining enzymatic reactions with contemporary synthetic methodologies and provides opportunities for the structure-activity relationship studies of [7.7]paracyclophane natural products.

CENPF as an independent prognostic and metastasis biomarker corresponding to CD4+ memory T cells in cutaneous melanoma.

Owing to recent advances in immunotherapies, the overall survival of patients with skin cutaneous melanoma (SKCM) has increased; however, the 5-year survival rate of metastatic patients remains poor. Skin cutaneous melanoma-upregulated genes were screened via analysis of differentially expressed genes (GSE3189 and GSE46517), and metastasis-related oncogenes were identified via weighted gene coexpression network analysis of the GSE46517 dataset. As confirmed by the Tumor Immune Estimation Resource, we found highly expressed centromere protein F (CENPF) in SKCM and its metastases. Immunostaining of human melanoma tissues demonstrated high CENPF expression. According to the Kaplan-Meier survival curve log-rank test, receiver-operating characteristic curve, and univariate and multivariate analyses, the Cancer Genome Atlas (TCGA) database suggested CENPF be a typical independent predictor of SKCM. The CIBERSORT algorithm classified the types of the immune cells from GSE46517 and showed higher proportion of CD4+ memory-activated T cells in metastatic melanoma. Single-sample gene set enrichment analysis of TCGA data confirmed the correlation between CENPF and activated CD4+ T cells. Centromere protein F was positively correlated with tumor mutational burden and CD4+ memory T cell markers (interleukin [IL]-23A, CD28, and CD62L), negatively associated with memory T cell maintenance factors (IL-7 and IL-15) by correlation analysis. Moreover, immunofluorescence showed high coexpression of CENPF and IL23A, CD4 in melanoma. Upregulated CENPF might lead to premature depletion of CD4+ memory T cells and immunosuppression. Nomogram indicated CENPF clinical predictive value for 1-, 3-, 5-, and 7-year melanoma overall survival. Therefore, CENPF plays a vital role in the progression and metastasis of melanoma and can be an effective therapeutic target.

CACNA1B facilitates breast cancer cell growth and migration by regulating cyclin D1 and EMT: the implication of CACNA1B in breast cancer.

PURPOSE: This study mainly aimed to explore the influences of Calcium Voltage-Gated Channel Subunit Alpha1 B (CACNA1B) on the development of breast cancer and the related mechanism. MATERIALS AND METHODS: The information of patients with breast cancer from TCGA database was used for analyses of CACNA1B expression and its prognostic value. Loss- and gain- of functions of CACNA1B were conducted in MCF7 and Bcap-37 cells, respectively. CCK-8, colony formation and transwell assays were applied for evaluating the cell viability and motility. Western blot was used for protein expression detection. RESULTS: We revealed that highly expressed CACNA1B in breast cancer tissues was related to poor prognosis according to the data gained from TCGA database. The outcomes of functional assays showed that depletion of CACNA1B restrained MCF7 cell growth, invasion and migration and high-expression of CACNA1B fortified the growth, invasion and migration in Bcap-37 cells. Finally, we manifested that silencing CACNA1B obviously raised the protein expression level of E-cadherin and reduced the protein levels of Cyclin D1, N-cadherin and Snail in MCF7 cells, whilst, over-expression of CACNA1B reduced the level of E-cadherin and increased the expression of Cyclin D1, N-cadherin and Snail in Bcap-37 cells. CONCLUSIONS: These results identified CACNA1B as a forwarder of the growth, invasion and migration in breast cancer cells.

Profile and outcomes of patients with mediastinal hematoma after cardiac catheterization: A retrospective analysis.

OBJECTIVE: To provide a comprehensive introduction of mediastinal hematoma. BACKGROUND: Mediastinal hematoma is a rare complication that is usually not considered in the differential diagnosis of chest pain after cardiac catheterization. METHODS: From January 1, 2006, to December 31, 2013, at Fuwai Hospital, 126,265 patients underwent coronary angiography (CAG); 121,215 of them underwent CAG via the radial artery. Ultimately, 10 patients with mediastinal hematoma due to cardiac catheterization were included. Patients' clinical characteristics, diagnosis, treatment, and prognosis were retrospectively analyzed. RESULTS: The incidences of mediastinal hematoma in cardiac catheterization and transradial cardiac catheterization were 0.79‱ and 0.74‱, respectively. A super slide hydrophilic guidewire was used in all 10 patients with mediastinal hematoma. These patients felt chest pain and dyspnea during/after the procedure, and computed tomography (CT) was used to diagnose mediastinal hematoma. Among them, two patients had a neck hematoma. The post-procedural hemoglobin level decreased substantially in all patients. Antiplatelet therapy was discontinued for 8-20 days in three patients without stents implanted, and then only oral aspirin was prescribed. Aspirin was transiently discontinued for 2 days in one patient undergoing percutaneous coronary intervention. The others continued taking dual antiplatelet drugs. Two patients received blood transfusion. There was no case of stent thrombosis, and surgery was not indicated for any patient. No complication was observed after discharge during the 9.0 ± 2.5-year follow-up. CONCLUSION: CT should be performed as early as possible in patients with suspected mediastinal hematoma. The prognosis of mediastinal hematoma is usually good with early diagnosis and suitable therapy.

In situ scarless skin healing of a severe human burn wound induced by a hCTLA4Ig gene-transferred porcine skin graft.

Preventing fibrosis or hypertrophic scar formation following tissue damage is still a big challenge despite the numerous approaches clinicians currently use. Hitherto, no written account was available of a successful case of scarless skin healing after a severe burn injury. Here, we report the first case of the "perfect regenerative healing" of a severe burn wound with no hypertrophic scar formation in which a postage stamp skin autograft was covered with human cytotoxic-T-lymphocyte associated antigen4-immunoglobulin (hCTLA4Ig) gene-transferred pig skin. We also discuss the mechanisms involved in the scarless healing of human burn wounds.

Comprehensive Analysis of Transcriptional Expression of hsa-mir-21 Predicted Target Genes and Immune Characteristics in Kidney Renal Clear Cell Carcinoma.

Background: To uncover advanced prognosis biomarkers in patient with kidney renal clear cell carcinoma (KIRC), our study was the first to make a comprehensive analysis of hsa-mir-21 predicted target genes and explore the immune characteristics in KIRC. Methods: In this study, the comprehensive analysis of hsa-mir-21 predicted target genes and immune characteristics in KIRC were analyzed via TIMER2.0, UALCAN, Metascape, Kaplan-Meier plotter, Human Protein Atlas, CancerSEA, JASPAR, GEPIA, R package: GSVA package (version 1.34.0) & immune infiltration algorithm (ssGSEA) and R package: RMS package (version 6.2-0) & SURVIVAL package (version 3.2-10). Results: Up-transcriptional expressions of RP2, NFIA, SPRY1 were significantly associated with favorable prognosis in KIRC, whereas that of TGFBI was markedly significantly to unfavorable prognosis. Additionally, RP2, NFIA, SPRY1 and TGFBI were significantly relevant to the immune infiltration in KIRC. Finally, ZNF263 was a common predicted transcription factor of RP2, NFIA, SPRY1 and TGFBI, which can as an independent indicator for prognosis in KIRC patients. Conclusions: Hsa-mir-21 predicted target genes (RP2, NFIA, SPRY1 and TGFBI) and the common transcription factor ZNF263 could be the advanced prognosis biomarkers in KIRC patients.