A randomised, double-blind, placebo-controlled, first-in-human phase I study to characterise the safety, pharmacokinetics and immunogenicity of 9MW1411 in healthy Chinese subjects.

INTRODUCTION: 9MW1411 is a humanised monoclonal antibody against Staphylococcus aureus alpha-toxin. The safety, pharmacokinetics (PK) and immunogenicity of 9MW1411 should be characterised in humans before further clinical development. METHODS: A single-centre, randomised, double-blind, placebo-controlled phase I clinical study was conducted in humans for the first time. A total of 42 healthy Chinese subjects were randomised to receive a single ascending dose of 9MW1411 (200, 600, 1500, 3000 or 5000 mg) or placebo. Safety, PK parameters and anti-drug antibody (ADA) were analysed. Monte Carlo simulations (MCS) were performed to predict the probability of target attainment (PTA) after single dose IV administration of 1500, 3000 and 5000 mg of 9MW1411. RESULTS: Thirty-four subjects received 9MW1411, completed the study and were included in data analysis. Five cases of drug-related AEs occurred in four subjects. All the adverse events (AEs) were mild or moderate. The Cmax, AUC0-t and AUC0-∞ of 9MW1411 increased with dose after IV administration of 200 to 5000 mg 9MW1411. The mean Cmax increased from 85.40 ± 5.43 to 2082.11 ± 343.10 µg/mL and AUC0-∞ from 29,511.68 ± 5550.91 to 729,985.49 ± 124,932.18 h·µg/mL. The elimination half-life (T1/2) was 19-23 days. 9MW1411 ADA was positive in three subjects. MCS indicated that a single dose of 3000 or 5000 mg 9MW1411 could achieve PTA > 90% for S. aureus. CONCLUSIONS: 9MW1411 has shown a good safety profile in healthy Chinese subjects after a single dose up to 5000 mg. A single dose of 3000 mg 9MW1411 is appropriate for use in subsequent studies.

Transcriptome Profiling Based at Different Time Points after Hatching Deepened Our Understanding on Larval Growth and Development of Amphioctopus fangsiao.

As the quality of life improves, there is an increasing demand for nutrition-rich marine organisms like fish, shellfish, and cephalopods. To address this, artificial cultivation of these organisms is being explored along with ongoing research on their growth and development. A case in point is Amphioctopus fangsiao, a highly valued cephalopod known for its tasty meat, nutrient richness, and rapid growth rate. Despite its significance, there is a dearth of studies on the A. fangsiao growth mechanism, particularly of its larvae. In this study, we collected A. fangsiao larvae at 0, 4, 12, and 24 h post-hatching and conducted transcriptome profiling. Our analysis identified 4467, 5099, and 4181 differentially expressed genes (DEGs) at respective intervals, compared to the 0 h sample. We further analyzed the expression trends of these DEGs, noting a predominant trend of continuous upregulation. Functional exploration of this trend entailed GO and KEGG functional enrichment along with protein-protein interaction network analyses. We identified GLDC, DUSP14, DPF2, GNAI1, and ZNF271 as core genes, based on their high upregulation rate, implicated in larval growth and development. Similarly, CLTC, MEF2A, PPP1CB, PPP1R12A, and TJP1, marked by high protein interaction numbers, were identified as hub genes and the gene expression levels identified via RNA-seq analysis were validated through qRT-PCR. By analyzing the functions of key and core genes, we found that the ability of A. fangsiao larvae to metabolize carbohydrates, lipids, and other energy substances during early growth may significantly improve with the growth of the larvae. At the same time, muscle related cells in A. fangsiao larvae may develop rapidly, promoting the growth and development of larvae. Our findings provide preliminary insights into the growth and developmental mechanism of A. fangsiao, setting the stage for more comprehensive understanding and broader research into cephalopod growth and development mechanisms.

Type I Mirizzi syndrome treated by electrohydraulic lithotripsy under the direct view of SpyGlass: A case report.

BACKGROUND: Mirizzi syndrome is an uncommon clinical complication for which the available treatment options mainly include open surgery, laparoscopic surgery, endoscopic retrograde cholangiopancreatography (ERCP), electrohydraulic lithotripsy, and laser lithotripsy. Here, a patient diagnosed with type I Mirizzi syndrome was treated with electrohydraulic lithotripsy under SpyGlass direct visualization, which may provide a reference to explore new treatments for Mirizzi syndrome. CASE SUMMARY: This paper describes a middle-aged female patient with suspected choledocholithiasis who complained for over 1 mo of intermittent abdominal pain, dark yellow urine, jaundice, and was proposed to undergo ERCP lithotomy. Mirizzi syndrome was found during the operation and confirmed by SpyGlass. Electrohydraulic lithotripsy was performed under the direct vision of SpyGlass. After the lithotripsy, the stones were extracted using the stone extraction basket and balloon. After the operation, the patient developed transient hyperamylasemia. Through a series of symptomatic treatments (such as fasting, fluids and anti-inflammation medications), the symptoms of the patient improved. Finally, laparoscopic cholecystectomy or open cholecystectomy was performed after a half-year post-operatively. CONCLUSION: Direct visualization-guided laser or electrohydraulic lithotripsy with SpyGlass is feasible and minimally invasive for type I Mirizzi syndrome without apparent unsafe outcomes.

Safety, tolerability, pharmacokinetic characteristics, and immunogenicity of MW33: a Phase 1 clinical study of the SARS-CoV-2 RBD-targeting monoclonal antibody.

MW33 is a fully humanized IgG1κ monoclonal neutralizing antibody, and may be used for the prevention and treatment of coronavirus disease 2019 (COVID-19). We conducted a randomized, double-blind, placebo-controlled, single-dose, dose-escalation Phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of MW33. Healthy adults aged 18-45 years were sequentially enrolled into the 4, 10, 20, 40, and 60 mg/kg dose groups and infused with MW33 over 60 ± 15 min and followed for 85 days. All 42 enrolled participants completed the MW33 infusion, and 40 participants completed the 85-day follow-up period. 34 participants received a single infusion of 4 (n = 2), 10 (n = 8), 20 (n = 8), 40 (n = 8), and 60 mg/kg (n = 8) of MW33. 27 subjects in the test groups experienced 78 adverse events (AEs) post-dose, with an incidence of 79.4% (27/34). The most common AEs included abnormal laboratory test results, vascular and lymphatic disorders, and infectious diseases. The severity of AEs was mainly Grade 1 (92 AEs), and three Grade 2 and one Grade 4. The main PK parameters, maximum concentration (Cmax), and area under the concentration-time curve (AUC0-t, and AUC0-∞) in 34 subjects showed a linear kinetic relationship in the range of 10-60 mg/kg. The plasma half-life was approximately 25 days. The positive rates of serum ADAs and antibody titres were low with no evidence of an impact on safety or PK. In conclusion, MW33 was well-tolerated, demonstrated linear PK, with a lower positive rate of serum ADAs and antibody titres in healthy subjects.Trial registration: ClinicalTrials.gov identifier: NCT04427501.Trial registration: ClinicalTrials.gov identifier: NCT04533048.Trial registration: ClinicalTrials.gov identifier: NCT04627584.

A rare case of duodenal diaphragm in an adult during ERCP treatment for choledocholithiasis.

BACKGROUND: Duodenal Diaphragm in adults is very uncommon, caused by congenital and acquired changes. It is reported that acquired duodenal diaphragm is related to the long-term use of nonsteroidal anti-inflammatory drugs. We report an adult presentation of duodenal diaphragm in a 77-year-old woman, suffered from acute cholangitis and choledocholithiasis. She was performed endoscopic retrograde cholangiopancreatography (ERCP) procedure to remove the stone in common bile duct (CBD). After the stenosis ring dilated by endoscopic balloon dilatation, ERCP procedure was applied, and the CBD stone was removed successfully. CONCLUSION: Duodenal diaphragm is difficult to diagnose in clinic. Although the patient in this case had relatively mild symptoms of incomplete upper hemi-abdominal obstruction, these symptoms could be obscured by the emergency acute upper abdominal pain with fever as clinical manifestations of acute cholangitis.

Facile addition of E-H bonds to a dicarbondiphosphide.

Charge transfer at P atoms in an N-heterocyclic carbene stabilized 6π-electron aromatic dicarbondiphosphide 1 has been observed upon interaction with a variety of small molecule substrates that feature a polar E-H bond (E = C, N, and O). As a result, these P atoms exhibit fleeting nucleophilicity and electrophilicity behaving as potential independent active sites, which effect the spontaneous addition of E-H bonds leading to a series of unsymmetrical 1,3-diphosphetane frameworks bearing P-C (2), P-N (6 and 7), and P-O bonds (8b, 8c, and 9). In addition, 1,3-diphosphetanium salts have been achieved when X-type substituents are weakly coordinating (i.e. [(CN)2CH]- (3), I- (4), and [(PhOH)2PhO]- (10)). The mechanisms of such transformations are investigated using density functional theory calculations.

Nanoreactor Based on Macroporous Single Crystals of Metal-Organic Framework.

A sacrificial template strategy is developed for the synthesis of yolk-shell Au@ZIF-8 nanoreactor. The Au@ZIF-8 nanoreactor possesses single-crystalline metal-organic framework (MOF) shell with intrinsic monodisperse micropores and introduced macropores. In each of the macropores, one Au NP is encapsulated to form a nanoreactor unit. The quantity of the reactor units in the MOF shell can be readily regulated. Such structure features of the Au@ZIF-8 nanoreactor facilitate the size selectivity of reactants, the accessibility of Au nanoparticles to reactants, and the mass transfer of reactants and products. As a result, the Au@ZIF-8 nanoreactor delivers excellent size selectivity, enhanced conversion, and good cycling stability when used to catalyze the aerobic oxidation of alcohols with different molecular size.

Nanoparticle Cookies Derived from Metal-Organic Frameworks: Controlled Synthesis and Application in Anode Materials for Lithium-Ion Batteries.

The capacity of anode materials plays a critical role in the performance of lithium-ion batteries. Using the nanocrystals of oxygen-free metal-organic framework ZIF-67 as precursor, a one-step calcination approach toward the controlled synthesis of CoO nanoparticle cookies with excellent anodic performances is developed in this work. The CoO nanoparticle cookies feature highly porous structure composed of small CoO nanoparticles (≈12 nm in diameter) and nitrogen-rich graphitic carbon matrix (≈18 at% in nitrogen content). Benefiting from such unique structure, the CoO nanoparticle cookies are capable of delivering superior specific capacity and cycling stability (1383 mA h g(-1) after 200 runs at 100 mA g(-1) ) over those of CoO and graphite.

Combined probiotic bacteria promotes intestinal epithelial barrier function in interleukin-10-gene-deficient mice.

AIM: To investigate the protective effects of combinations of probiotic (Bifico) on interleukin (IL)-10-gene-deficient (IL-10 KO) mice and Caco-2 cell monolayers. METHODS: IL-10 KO mice were used to assess the benefits of Bifico in vivo. IL-10 KO and control mice received approximately 1.5 × 10(8) cfu/d of Bifico for 4 wk. Colons were then removed and analyzed for epithelial barrier function by Ussing Chamber, while an ELISA was used to evaluate proinflammatory cytokines. The colon epithelial cell line, Caco-2, was used to test the benefit of Bifico in vitro. Enteroinvasive Escherichia coli (EIEC) and the probiotic mixture Bifico, or single probiotic strains, were applied to cultured Caco-2 monolayers. Barrier function was determined by measuring transepithelial electrical resistance and tight junction protein expression. RESULTS: Treatment of IL-10 KO mice with Bifico partially restored body weight, colon length, and epithelial barrier integrity to wild-type levels. In addition, IL-10 KO mice receiving Bifico treatment had reduced mucosal secretion of tumor necrosis factor-α and interferon-γ, and attenuated colonic disease. Moreover, treatment of Caco-2 monolayers with Bifico or single-strain probiotics in vitro inhibited EIEC invasion and reduced the secretion of proinflammatory cytokines. CONCLUSION: Bifico reduced colon inflammation in IL-10 KO mice, and promoted and improved epithelial-barrier function, enhanced resistance to EIEC invasion, and decreased proinflammatory cytokine secretion.

TSLC1 gene silencing in cutaneous melanoma.

Tumor suppressor in lung cancer 1 (TSLC1) is a tumor suppressor gene that encodes a member of the immunoglobulin superfamily, which is involved in the progression of some types of cancer. Several studies have shown that loss of TSLC1 expression is strongly correlated to methylation of the gene promoter, thus leading to poor prognosis in these cancers. However, the role of TSLC1 in cutaneous melanoma (CM) has not been examined. The purpose of this study was to understand the molecular mechanisms and clinical significance of TSLC1 inactivation in CM. The expression and promoter methylation of TSLC1 were analyzed in 120 CMs. TSLC1 expression was examined by immunohistochemistry, whereas its methylation status was determined by methylation-specific PCR. TSLC1 expression was lost in 84 of 120 (70%) CMs; 36 (30%) CMs were scored as positive for TSLC1 protein expression. The TSLC1 promoter was methylated in 58 (48.33%) of 120 CMs. The incidence of the loss of expression and methylation of TSLC1 significantly increased as the tumor stage advanced (P=0.032 and 0.0021, respectively). Furthermore, in CM, disease-related survival was significantly shorter in patients with tumors losing TSLC1 or harboring methylated TSLC1 (P=0.0003 and 0.0329, respectively). The epigenetic silencing of TSLC1 through methylation is an important event in the pathogenesis of CM, and TSLC1 provides an indicator for poor prognosis.

[Effect of Astragalus polysaccharides and berberine on carbohydrate metabolism and cell differentiation in 3T3-L1 adipocytes].

OBJECTIVE: To compare the effects of Astragalus polysaccharides (AP) and berberine (BB) on the adipocyte's carbohydrate metabolism and cell differentiation, for assessing the possible mechanism of them in improving carbohydrate metabolism. METHODS: Adipocytes were treated with AP or BE, the 3H-glucose up-take rate in them was investigated, those of differentiation phase were stained by oil red O to analyze the degree of cell differentiation by spectrophotography quantitatively. The adipocyte differentiation related expression of PPARgamma mRNA and C/EBPalpha mRNA were determined by RT-PCR. RESULTS: The 3H-glucose up-take rate in the AP group and BE group were 109.3% and 182.7% of that in the blank control group respectively. AP obviously promoted the cell differentiation and up-regulated expression of PPARgamma mRNA, while BE suppressed the differentiation and expression of PPARgamma and C/EBPalpha mRNA distinctly, all showing significant difference as compared with that in the blank control (P<0.01). CONCLUSION: AP could promote glucose up-take, cell differentiation and PPARgamma mRNA expression, BB also promote glucose up-take, but suppress the cell differentiation, and inhibit expressions of PPARgamma and C/EBPalpha mRNA in 3T3-L1 adipocytes.

[Effects of salidroside on carbohydrate metabolism and differentiation of 3T3-L1 adipocytes].

OBJECTIVE: To observe the effects of salidroside on carbohydrate metabolism and differentiation of 3T3-L1 adipocytes. METHODS: 3H-glucose uptaking rate in adipocytes treated by salidroside was detected. Adipocytes treated by salidroside in differentiation were stained by oil red O and analyzed by spectrophotography quantitatively. The expression of PPAR-gamma and C/EBP-alpha mRNA relating to differentiation of adipocytes was detected by reverse transcription PCR. RESULTS: 3H-glucose uptaking rate in the salidroside group was 110.4%, higher than that in the blank control group (P < 0.01). Salidroside suppressed the differentiation of 3T3-L1 pre-adipocytes and down-regulated the expression of PPAR-gamma and C/EBP-alpha mRNA (P < 0.01, vs control group). CONCLUSION: Salidroside promotes the 3H-glucose uptaking, suppresses the differentiation and down-regulates the expression of PPAR-gamma and C/EBP-alpha mRNA in 3T3-L1 adipocytes.

[Pathogenesis of insulin resistance and prevention and treatment strategy of integrated traditional Chinese and western medicine].

Insulin resistance is the common pathophysiologic basis of multiple metabolic diseases, but the exact mechanism of insulin resistance is still unclear presently. In the past few years, studies on the pathogenesis of insulin resistance, in which the endocrine function of adipocyte and inflammation reaction participate, as well as the insulin-sensitizing drugs have become the new hotspot. The exploration on pathogenesis and treatment of insulin resistance in traditional Chinese medicine has established a foundation for the prevention and treatment of insulin resistance in integrated traditional Chinese and western medicine.