Enantioconvergent Cu-catalysed N-alkylation of aliphatic amines.

Chiral amines are commonly used in the pharmaceutical and agrochemical industries1. The strong demand for unnatural chiral amines has driven the development of catalytic asymmetric methods1,2. Although the N-alkylation of aliphatic amines with alkyl halides has been widely adopted for over 100 years, catalyst poisoning and unfettered reactivity have been preventing the development of a catalyst-controlled enantioselective version3-5. Here we report the use of chiral tridentate anionic ligands to enable the copper-catalysed chemoselective and enantioconvergent N-alkylation of aliphatic amines with α-carbonyl alkyl chlorides. This method can directly convert feedstock chemicals, including ammonia and pharmaceutically relevant amines, into unnatural chiral α-amino amides under mild and robust conditions. Excellent enantioselectivity and functional-group tolerance were observed. The power of the method is demonstrated in a number of complex settings, including late-stage functionalization and in the expedited synthesis of diverse amine drug molecules. The current method indicates that multidentate anionic ligands are a general solution for overcoming transition-metal-catalyst poisoning.

Copper-Catalyzed Enantioconvergent Radical N-Alkylation of Diverse (Hetero)aromatic Amines.

The 3d transition metal-catalyzed enantioconvergent radical cross-coupling provides a powerful tool for chiral molecule synthesis. In the classic mechanism, the bond formation relies on the interaction between nucleophile-sequestered metal complexes and radicals, limiting the nucleophile scope to sterically uncongested ones. The coupling of sterically congested nucleophiles poses a significant challenge due to difficulties in transmetalation, restricting the reaction generality. Here, we describe a probable outer-sphere nucleophilic attack mechanism that circumvents the challenging transmetalation associated with sterically congested nucleophiles. This strategy enables a general copper-catalyzed enantioconvergent radical N-alkylation of aromatic amines with secondary/tertiary alkyl halides and exhibits catalyst-controlled stereoselectivity. It accommodates diverse aromatic amines, especially bulky secondary and primary ones to deliver value-added chiral amines (>110 examples). It is expected to inspire the coupling of more nucleophiles, particularly challenging sterically congested ones, and accelerate reaction generality.

Overcoming Radical Stability Order via DABCO-Triggered Desulfurization: Visible-Light-Promoted 1,2,4-Trifunctionalization of Butenyl Benzothiazole Sulfone with Thiosulfonate.

A radical 1,2,4-trifunctional reaction of thiosulfonate to unactivated olefin is achieved by a migration strategy under mild conditions. In this reaction, the more unstable primary free radicals are in situ generated after the migration of heteroaryl groups in the presence of DABCO. This trifunctionalization of unactivated olefins involves two C-S bond formations and one C-C bond formation.

Chemotherapy-related symptoms in children with leukemia: application of latent profile analysis and network analysis.

PURPOSE: Children with leukemia may experience a range of chemotherapy-related symptoms. Identifying subgroups and their distinct characteristics of symptoms may improve symptom management. We aimed to identify subgroups and their distinct characteristics of chemotherapy-related symptoms in children with leukemia. METHODS: A cross-sectional survey was conducted among 500 children with leukemia, who completed questionnaires that assessed their demographic and clinical characteristics, as well as the Memorial Symptom Assessment Scale. Latent profile analysis was conducted to identify subgroups of symptoms. Additionally, multiple regression analysis and network analysis were utilized to reveal the characteristics of each subgroup. RESULTS: Four subgroups were identified: "Profile 1: low symptom burden subgroup" (26.2%), "Profile 2: moderate symptom burden subgroup in transitional period" (14.8%), "Profile 3: moderate psychological symptom burden subgroup" (35.6%), and "Profile 4: high symptom burden subgroup" (23.4%). Multiple logistic regression analysis indicated that lower primary caregiver's education level, lower family monthly income, self-paid medical expenses, induction remission period, and consolidation enhancement period were associated with more severe symptoms of subgroups. Network analysis further revealed that nausea was the core symptom in Profiles 1 and 2, while the core symptom in Profile 3 was "I don't look like myself." Additionally, worrying was the core symptom in Profile 4. CONCLUSION: There exists heterogeneity in chemotherapy-related symptoms. Four subgroups and their corresponding characteristics of children with varying symptom severity were identified. Identifying these subgroups will facilitate personalized care, maximize intervention effectiveness, and alleviate symptom burden.

Identifying symptom clusters and temporal interconnections in patients with lung tumors after CT-guided microwave ablation: A network analysis.

PURPOSE: To explore symptom clusters and interrelationships using a network analysis approach among symptoms in patients with lung tumors who underwent computed tomography (CT)-guided microwave ablation (MWA). METHODS: A longitudinal study was conducted, and 196 lung tumor patients undergoing MWA were recruited and were measured at 24 h, 48 h, and 72 h after MWA. The Chinese version of the MD Anderson Symptom Inventory and the Revised Lung Cancer Module were used to evaluate symptoms. Network analyses were performed to explore the symptom clusters and interrelationships among symptoms. RESULTS: Four stable symptom communities were identified within the networks. Distress, weight loss, and chest tightness were the central symptoms. Distress, and weight loss were also the most key bridge symptoms, followed by cough. Three symptom networks were temporally stable in terms of symptom centrality, global connectivity, and network structure. CONCLUSION: Our findings identified the central symptoms, bridge symptoms, and the stability of symptom networks of patients with lung tumors after MWA. These network results will have important implications for future targeted symptom management intervention development. Future research should focus on developing precise interventions for targeting central symptoms and bridge symptoms to promote patients' health.

E3-Independent Constitutive Monoubiquitination Complements Histone Methyltransferase Activity of SETDB1.

Ubiquitination typically occurs through the sequential action of three enzymes catalyzing ubiquitin activation (E1), conjugation (E2), and ligation (E3) and regulates diverse eukaryotic cellular processes. Although monoubiquitination commonly confers nondegradative activities, mechanisms underlying its temporal and spatial regulation and functional plasticity still remain largely unknown. Here we demonstrate that SETDB1, a major histone H3K9 methyltransferase is monoubiquitinated at the evolutionarily conserved lysine-867 in its SET-Insertion domain. This ubiquitination is directly catalyzed by UBE2E family of E2 enzymes in an E3-independent manner while the conjugated-ubiquitin (Ub) is protected from active deubiquitination. The resulting constitutive lysine-867 monoubiquitination is essential for SETDB1's enzymatic activity and endogenous retrovirus silencing in murine embryonic stem cells. Furthermore, the canonical hydrophobic patch on the conjugated-Ub is critical for Ub protection and function. Together, our findings highlight an E3-independent mechanism for monoubiquitination and reveal mechanistic details of SETDB1's enzymatic activity and the functional significance of its SET-Insertion.

Facile adipocyte uptake and liver/adipose tissue delivery of conjugated linoleic acid-loaded tocol nanocarriers for a synergistic anti-adipogenesis effect.

Obesity is a major risk to human health. Adipogenesis is blocked by α-tocopherol and conjugated linoleic acid (CLA). However, their effect at preventing obesity is uncertain. The effectiveness of the bioactive agents is associated with their delivery method. Herein, we designed CLA-loaded tocol nanostructured lipid carriers (NLCs) for enhancing the anti-adipogenic activity of α-tocopherol and CLA. Adipogenesis inhibition by the nanocarriers was examined using an in vitro adipocyte model and an in vivo rat model fed a high fat diet (HFD). The targeting of the tocol NLCs into adipocytes and adipose tissues were also investigated. A synergistic anti-adipogenesis effect was observed for the combination of free α-tocopherol and CLA. Nanoparticles with different amounts of solid lipid were developed with an average size of 121‒151 nm. The NLCs with the smallest size (121 nm) showed greater adipocyte internalization and differentiation prevention than the larger size. The small-sized NLCs promoted CLA delivery into adipocytes by 5.5-fold as compared to free control. The nanocarriers reduced fat accumulation in adipocytes by counteracting the expression of the adipogenic transcription factors peroxisome proliferator activated receptor (PPAR)γ and CCAAT/enhancer-binding protein (C/EBP)α, and lipogenic enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS). Localized administration of CLA-loaded tocol NLCs significantly reduced body weight, total cholesterol, and liver damage indicators in obese rats. The biodistribution study demonstrated that the nanoparticles mainly accumulated in liver and adipose tissues. The NLCs decreased adipocyte hypertrophy and cytokine overexpression in the groin and epididymis to a greater degree than the combination of free α-tocopherol and CLA. In conclusion, the lipid-based nanocarriers were verified to inhibit adipogenesis in an efficient and safe way.

Development of nanoparticles incorporated with quercetin and ACE2-membrane as a novel therapy for COVID-19.

INTRODUCTION: Angiotensin-converting enzyme 2 (ACE2) and AXL tyrosine kinase receptor are known to be involved in the SARS-CoV-2 entry of the host cell. Therefore, targeting ACE2 and AXL should be an effective strategy to inhibit virus entry into cells. However, developing agents that can simultaneously target ACE2 and AXL remains a formidable task. The natural compound quercetin has been shown to inhibit AXL expression. MATERIALS AND METHODS: In this study, we employed PLGA nanoparticles to prepare nanoparticles encapsulated with quercetin, coated with ACE2-containing cell membranes, or encapsulated with quercetin and then coated with ACE-2-containing cell membranes. These nanoparticles were tested for their abilities to neutralize or inhibit viral infection. RESULTS: Our data showed that nanoparticles encapsulated with quercetin and then coated with ACE2-containing cell membrane inhibited the expression of AXL without causing cytotoxic activity. Nanoparticles incorporated with both quercetin and ACE2-containing cell membrane were found to be able to neutralize pseudo virus infection and were more effective than free quercetin and nanoparticles encapsulated with quercetin at inhibition of pseudo virus and SARS-CoV-2 infection. CONCLUSIONS: We have shown that the biomimetic nanoparticles incorporated with both ACE-2 membrane and quercetin showed the most antiviral activity and may be further explored for clinical application.

Two-year dermal carcinogenicity bioassay of triclosan in B6C3F1 mice.

Triclosan is a widely used antimicrobial agent in personal care products, household items, medical devices, and clinical settings. Due to its extensive use, there is potential for humans in all age groups to receive lifetime exposures to triclosan, yet data on the chronic dermal toxicity/carcinogenicity of triclosan are still lacking. We evaluated the toxicity/carcinogenicity of triclosan administered dermally to B6C3F1 mice for 104 weeks. Groups of 48 male and 48 female B6C3F1 mice received dermal applications of 0, 1.25, 2.7, 5.8, or 12.5 mg triclosan/kg body weight (bw)/day in 95% ethanol, 7 days/week for 104 weeks. Vehicle control animals received 95% ethanol only; untreated, naïve control mice did not receive any treatment. There were no significant differences in survival among the groups. The highest dose of triclosan significantly decreased the body weight of mice in both sexes, but the decrease was ≤ 9%. Minimal-to-mild epidermal hyperplasia, suppurative inflammation (males only), and ulceration (males only) were observed at the application site in the treated groups, with the highest incidence occurring in the 12.5 mg triclosan/kg bw/day group. No tumors were identified at the application site. Female mice had a positive trend in the incidence of pancreatic islet adenoma. In male mice, there were positive trends in the incidences of hepatocellular carcinoma and hepatocellular adenoma or carcinoma (combined), with the increase of carcinoma being significant in the 5.8 and 12.5 mg/kg/day groups and the increase in hepatocellular adenoma or carcinoma (combined) being significant in the 2.7, 5.8, and 12.5 mg/kg/day groups.

The anti-inflammatory activity of flavonoids and alkaloids from Sophora flavescens alleviates psoriasiform lesions: Prenylation and methoxylation beneficially enhance bioactivity and skin targeting.

The herb Sophora flavescens displays anti-inflammatory activity and can provide a source of antipsoriatic medications. We aimed to evaluate whether S. flavescens extracts and compounds can relieve psoriasiform inflammation. The ability of flavonoids (maackiain, sophoraflavanone G, leachianone A) and alkaloids (matrine, oxymatrine) isolated from S. flavescens to inhibit production of cytokine/chemokines was examined in keratinocytes and macrophages. Physicochemical properties and skin absorption were determined by in silico molecular modeling and the in vitro permeation test (IVPT) to establish the structure-permeation relationship (SPR). The ethyl acetate extract exhibited higher inhibition of interleukin (IL)-6, IL-8, and CXCL1 production in tumor necrosis factor-α-stimulated keratinocytes compared to the ethanol and water extracts. The flavonoids demonstrated higher cytokine/chemokine inhibition than alkaloids, with the prenylated flavanones (sophoraflavanone G, leachianone A) led to the highest suppression. Flavonoids exerted anti-inflammatory effects via the extracellular signal-regulated kinase, p38, activator protein-1, and nuclear factor-κB signaling pathways. In the IVPT, prenylation of the flavanone skeleton significantly promoted skin absorption from 0.01 to 0.22 nmol/mg (sophoraflavanone G vs. eriodictyol). Further methoxylation of a prenylated flavanone (leachianone A) elevated skin absorption to 2.65 nmol/mg. Topical leachianone A reduced the epidermal thickness in IMQ-treated mice by 47%, and inhibited cutaneous scaling and cytokine/chemokine overexpression at comparable levels to a commercial betamethasone product. Thus, prenylation and methoxylation of S. flavescens flavanones may enable the design of novel antipsoriatic agents.

Copper-Catalyzed Enantioconvergent Radical C(sp3)-N Cross-Coupling of Activated Racemic Alkyl Halides with (Hetero)aromatic Amines under Ambient Conditions.

The enantioconvergent C(sp3)-N cross-coupling of racemic alkyl halides with (hetero)aromatic amines represents an ideal means to afford enantioenriched N-alkyl (hetero)aromatic amines yet has remained unexplored due to the catalyst poisoning specifically for strong-coordinating heteroaromatic amines. Here, we demonstrate a copper-catalyzed enantioconvergent radical C(sp3)-N cross-coupling of activated racemic alkyl halides with (hetero)aromatic amines under ambient conditions. The key to success is the judicious selection of appropriate multidentate anionic ligands through readily fine-tuning both electronic and steric properties for the formation of a stable and rigid chelating Cu complex. Thus, this kind of ligand could not only enhance the reducing capability of a copper catalyst to provide an enantioconvergent radical pathway but also avoid the coordination with other coordinating heteroatoms, thereby overcoming catalyst poisoning and/or chiral ligand displacement. This protocol covers a wide range of coupling partners (89 examples for activated racemic secondary/tertiary alkyl bromides/chlorides and (hetero)aromatic amines) with high functional group compatibility. When allied with follow-up transformations, it provides a highly flexible platform to access synthetically useful enantioenriched amine building blocks.

TcpC inhibits toll-like receptor signaling pathway by serving as an E3 ubiquitin ligase that promotes degradation of myeloid differentiation factor 88.

TcpC is a virulence factor of uropathogenic E. coli (UPEC). It was found that TIR domain of TcpC impedes TLR signaling by direct association with MyD88. It has been a long-standing question whether bacterial pathogens have evolved a mechanism to manipulate MyD88 degradation by ubiquitin-proteasome pathway. Here, we show that TcpC is a MyD88-targeted E3 ubiquitin ligase. Kidney macrophages from mice with pyelonephritis induced by TcpC-secreting UPEC showed significantly decreased MyD88 protein levels. Recombinant TcpC (rTcpC) dose-dependently inhibited protein but not mRNA levels of MyD88 in macrophages. Moreover, rTcpC significantly promoted MyD88 ubiquitination and accumulation in proteasomes in macrophages. Cys12 and Trp106 in TcpC are crucial amino acids in maintaining its E3 activity. Therefore, TcpC blocks TLR signaling pathway by degradation of MyD88 through ubiquitin-proteasome system. Our findings provide not only a novel biochemical mechanism underlying TcpC-medicated immune evasion, but also the first example that bacterial pathogens inhibit MyD88-mediated signaling pathway by virulence factors that function as E3 ubiquitin ligase.

Very high-frequency, gate-tunable CrPS4 nanomechanical resonator with single mode.

Two-dimensional (2D) antiferromagnetic semiconductor chromium thiophosphate (CrPS4) has gradually become a major candidate material for low-dimensional nanoelectromechanical devices due to its remarkable structural, photoelectric characteristics and potentially magnetic properties. Here, we report the experimental study of a new few-layer CrPS4 nanomechanical resonator demonstrating excellent vibration characteristics through the laser interferometry system, including the uniqueness of resonant mode, the ability to work at the very high frequency, and gate tuning. In addition, we demonstrate that the magnetic phase transition of CrPS4 strips can be effectively detected by temperature-regulated resonant frequencies, which proves the coupling between magnetic phase and mechanical vibration. We believe that our findings will promote the further research and applications of the resonator for 2D magnetic materials in the field of optical/mechanical signal sensing and precision measurement.

miR-34a-5p facilitates osteogenic differentiation of bone marrow mesenchymal stem cells and modulates bone metabolism by targeting HDAC1 and promoting ER-α transcription.

OBJECTIVE: Metabolism is essential for bone development. The expressions of catabolic markers in chondrocytes show association with miR-34a-5p. This study discussed the mechanism by which miR-34a-5p regulates osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) as well as bone metabolism. METHODS: Expressions of BMSC surface markers were determined via flow cytometry. Osteogenic differentiation of BMSCs was subsequently induced. miR-34a-5p mimic, oe-HDAC1, or ER-α activator Ferutinin was introduced in BMSCs. Alkaline phosphatase activity and calcification were detected. Expressions of miR-34a-5p, HDAC1, ER-α, and osteogenic markers were determined via RT-qPCR and Western blot. The binding relationship between miR-34a-5p and HDAC1 was verified by a dual-luciferase assay. Mice at the age of 6 months and 18 months were assigned to the young group and age group for in vivo experiments, and aged mice were treated with agomiR miR-34a-5p. Expressions of serum miR-34a-5p, HDAC1, ER-α, and bone metabolism markers in mice were determined. RESULTS: Osteogenic medium-induced BMSCs manifested increased expressions of miR-34a-5p and ER-α and decreased HDAC1 expression. miR-34a-5p overexpression promoted osteogenic differentiation of BMSCs. miR-34a-5p targeted HDAC1. HDAC1 overexpression partially counteracted the promotional action of miR-34a-5p overexpression on osteogenic differentiation of BMSCs. miR-34a-5p overexpression activated ER-α. ER-α activator Ferutinin partially nullified the regulatory function of miR-34a-5p/HDAC1 on osteogenic differentiation of BMSCs. In vivo experiments showed that miR-34a-5p overexpression enhanced the potential of bone metabolism in aged mice. CONCLUSION: miR-34a-5p overexpression promoted osteogenic differentiation of BMSCs and enhanced bone metabolism by promoting ER-α activation via targeting HDAC1.

Novel Metabolites to Improve Glomerular Filtration Rate Estimation.

INTRODUCTION: The glomerular filtration rate (GFR) is crucial for chronic kidney disease (CKD) diagnosis and therapy. Various studies have sought to recognize ideal endogenous markers to improve the estimated GFR for clinical practice. To screen out potential novel metabolites related to GFR (mGFR) measurement in CKD patients from the Chinese population, we identified more biomarkers for improving GFR estimation. METHODS: Fifty-three CKD participants were recruited from the Third Affiliated Hospital of Sun Yat-sen University in 2020. For each participant, mGFR was evaluated by utilizing the plasma clearance of iohexol and collecting serum samples for untargeted metabolomics analyses by ultrahigh-performance liquid chromatography-tandem mass spectroscopy. All participants were divided into four groups according to mGFR. The metabolite peak area data were uploaded to MetaboAnalyst 5.0 for one-way analysis of variance, principal component analysis, and partial least squares-discriminant analysis and confirmed the metabolites whose levels increased or decreased with mGFR and variable importance in projection (VIP) values >1. Metabolites were ranked by correlation with the original values of mGFR, and metabolites with a correlation coefficient >0.8 and VIP >2 were identified. RESULTS: We screened out 198 metabolites that increased or decreased with mGFR decline. After ranking by correlation with mGFR, the top 50 metabolites were confirmed. Further studies confirmed the 10 most highly correlated metabolites. CONCLUSION: We screened out the metabolites that increased or decreased with mGFR decline in CKD patients from the Chinese population, and 10 of them were highly correlated. They are potential novel metabolites to improve GFR estimation.

Exploring core symptoms and interrelationships among symptoms in children with acute leukemia during chemotherapy: A network analysis.

PURPOSE: Children with acute leukemia have suffered from a considerable symptom burden during chemotherapy. However, few studies have focused on exploring the mechanisms among symptoms in children with acute leukemia. Our study aims to explore core symptoms and describe the interrelationships among symptoms in children with acute leukemia during chemotherapy. METHODS: From January 2021 to March 2023, 469 children with acute leukemia were recruited from 20 Chinese cities. The Memorial Symptom Assessment Scale 10-18 (MSAS 10-18) was used to evaluate the prevalence and severity of symptoms during chemotherapy. A network analysis was performed by the R software based on 31 symptoms. Centrality indices and density were used to explore core symptoms and describe interrelationships among symptoms in the network during chemotherapy. RESULTS: Worrying and feeling irritable were the central symptoms across the three centrality indices, including strength, closeness, and betweenness. Lack of energy was the most prevalent symptom; however, it was less central than other symptoms. The density of the "induction and remission" network significantly differed from other cycles' counterparts (p < 0.001). Global strength was greater in the " ≥ 8 years group " network than the " < 8 years group " network (p = 0.023). CONCLUSION: Network analysis provides a novel approach to identifying the core symptoms and understanding the interrelationships among symptoms. Our study indicates the need to assess emotional symptoms in children with acute leukemia during chemotherapy, especially during the induction and remission phases, as well as in older children. Future research is imperative to construct trajectories of dynamic symptom networks and centrality indices in longitudinal data to investigate the causal relationships among symptoms.

Analysis of the association of sugammadex with the length of hospital stay in patients undergoing abdominal surgery: a retrospective study.

BACKGROUND: Sugammadex is a newer medication used for rapid and reliable reversal of neuromuscular blockade. This study evaluated whether sugammadex could reduce the length of postoperative hospital stay in patients undergoing abdominal surgery. METHODS: This single center retrospective cohort study included patients who underwent major abdominal surgery between January 2015 and October 2019. Patients were randomized according to reversal with sugammadex or spontaneous recovery. The primary outcome was length of postoperative hospital stay. The secondary outcomes were length of post-anesthetic care unit (PACU) stay, postoperative ambulation time, time-to-first-defecation, and incidence of pulmonary complications. After 1:1 propensity score matching, univariate and multiple linear regression analyses estimated the differences in outcomes. RESULTS: Of the 1614 patients, 517 received sugammadex and 645 spontaneously recovered. After adjusting for potential confounders, non-linear relationship was detected between administration of sugammadex and the length of postoperative hospital stay (ß = 0.29 95% confidence interval {CI}: [- 1.13, - 0.54], P = 0.4912). However, it was associated with shorter PACU stay (ß = - 20.30 95% CI: [- 24.48, - 17.11], P < 0.0001), shorter time to postoperative ambulation movement (ß = - 0.43 95% CI: [- 0.62, - 0.23], P < 0.0001), and reduced time-to-first-defecation (ß = - 2.25 95% CI: [- 0.45, - 0.05], P = 0.0129), when compared to the spontaneously recovered group. The incidence of pneumonia in the sugammadex group was significantly lower than that in the spontaneously recovered group (18.6% [44/237] vs. 39.2% [93/237] P < 0.05). CONCLUSIONS: Neuromuscular blockade reversal with sugammadex after abdominal surgery demonstrated an excellent recovery profile and was associated with decreased risk of pneumonia, although it did not affect the length of postoperative hospital stay.

Formononetin improves the inflammatory response and bone destruction in knee joint lesions by regulating the NF-kB and MAPK signaling pathways.

Formononetin (FMN) is a phytoestrogen that belongs to the isoflavone family. It has antioxidant and anti-inflammatory effects, as well as, many other biological activities. Existing evidence has aroused interest in its ability to protect against osteoarthritis (OA) and promote bone remodeling. To date, research on this topic has not been thorough and many issues remain controversial. Therefore, the purpose of our study was to explore the protective effect of FMN against knee injury and clarify the possible molecular mechanisms. We found that FMN inhibited osteoclast formation induced by receptor activator of NF-κB ligand (RANKL). Inhibition of the phosphorylation and nuclear translocation of p65 in the NF-κB signaling pathway plays a role in this effect. Similarly, during the inflammatory response of primary knee cartilage cells activated by IL-1ß, FMN inhibited the NF-κB signaling pathway and the phosphorylation of the ERK and JNK proteins in the MAPK signaling pathway to suppress the inflammatory response. In addition, in vivo experiments showed that both low- and high-dose FMN had a clear protective effect against knee injury in the DMM (destabilization of the medial meniscus) model, and the therapeutic effect of high-dose FMN was stronger. In conclusion, these studies provide evidence of the protective effect of FMN against knee injury.

Indications for Adjuvant Chemotherapy in Stage II Gastric Cancer After D2 Gastrectomy-A Chinese Multicenter Study.

BACKGROUND: The benefit of adjuvant chemotherapy (AC) for patients with stage II gastric cancer remains controversial. This study aimed to explore the indications for adjuvant chemotherapy in patients with stage II gastric cancer by constructing an individual prediction model. PATIENTS AND METHODS: In this Chinese multicenter study, a total of 1012 patients with stage II gastric cancer after D2 radical gastrectomy were retrospectively analyzed. All patients were randomly assigned to a training cohort (n = 674) or a validation cohort (n = 338). A nomogram was constructed according to the training cohort. Concordance index (C-index), the area under the receiver operating characteristic (ROC) curves (AUC), calibration curves, and decision curve analysis (DCA) were applied to evaluate the performance of the nomogram. ROC curves and stratified survival were used to determine the patients' cutoff score for a benefit from adjuvant chemotherapy. An additional 338 patients were used as a validation cohort to validate the feasibility of using this nomogram to guide individualized therapy for patients with stage II gastric cancer. RESULTS: Univariate and multivariate analyses illustrated that age, sex, tumor location, size, carcinoembryonic antigen (CEA), hemoglobin (HB), and T stage were independent prognostic factors for overall survival (OS), and they were used to establish a nomogram. The cutoff value was determined by ROC curve analysis, and patients were divided into a high-risk group (< 239 points) and a low-risk group (≥ 239 points). There was no significant difference in the OS of low-risk patients in either the training cohort or the validation cohort. However, the OS of high-risk patients in the AC group was better than that of patients in the surgery-only group. CONCLUSIONS: This prediction model can be applied to guide treatment of patients with stage II gastric cancer. High-risk patients (< 239 points) are likely to benefit from AC after D2 radical gastrectomy.

Myasthenia gravis coexisting with HINT1-related motor axonal neuropathy without neuromyotonia: a case report.

BACKGROUND: HINT1 mutations cause an autosomal recessive axonal neuropathy with neuromyotonia. This is a first case report of coexistence of myasthenia gravis (MG) and HINT1-related motor axonal neuropathy without neuromyotonia. CASE PRESENTATION: A 32-year-old woman presented with recurrent ptosis for 8 years, diplopia for 2 years and limb weakness for 1 year and a half. Neostigmine test, elevated AChR antibody level and positive repetitive nerve stimulation supported the diagnosis of MG. Electroneurography (ENG) and electromyography (EMG) examinations revealed a motor axonal neuropathy without neuromyotonic or myokymic discharges. Next-generation sequencing and Sanger sequencing were performed to identify the gene responsible for suspected hereditary neuropathy. Genetic testing for a HINT1 mutation was performed and revealed a homozygous mutation at c.278G>T (p. G93V). The patient was treated with pyridostigmine, oral prednisolone and azathioprine. Her ptosis and diplopia have significantly improved at 6-month follow-up. CONCLUSIONS: Concurrence of MG and hereditary motor axonal neuropathy without neuromyotonia is quite rare. Detection of ptosis with or without ophthalmoplegia, distribution of limb weakness, and reflex can help in recognizing the combination of MG and peripheral neuropathy. Early diagnosis is important for initial treatment and prognosis. The novel homozygous variant c.278G>T(p.G93V) contributes to the pathogenic variants spectrum of the HINT1 gene.