Artificial intelligence-based prognostic model accurately predicts the survival of patients with diffuse large B-cell lymphomas: analysis of a large cohort in China.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. METHODS: We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our "molecular-contained prognostic model" (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. RESULTS: Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). CONCLUSIONS: Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development.

Regioselective N-Trideuteromethylation of Tautomeric Polyaza Heterocycles.

Methods for regioselective N-trideuteromethylation of tautomeric polyaza heterocycles are highly sought-after. Disclosed herein is an N-trideuterated methylation reaction of imidazoles and pyrazoles with high regioselectivity and deuterium purity using easily available CF3SO3CD3 as the -CD3 source. This method enables the easy synthesis of important deuterium-labeled azoles, including dimetridazole-d3, ipronidazole-d3, hydroxy dimetridazole-d3, and ronidazole-d3.

Selective Separation of Americium(III), Curium(III), and Lanthanide(III) by Aqueous and Organic Competitive Extraction.

Adding hydrophilic ligands into aqueous solutions for the selective binding of actinides(III) is acknowledged as an advanced strategy in Ln(III)/An(III) separation. In view of the recycling and radioactive waste disposal of the minor actinide, there remains an urgent need to design and develop the appropriate ligand for selective separation of An(III) from Ln(III). Herein, four novel hydrophilic ligands with hard-soft hybrid donors, derived from the pyridine and phenanthroline skeletons, were designed and synthesized as masking agents for selective complexation of An(III) in the aqueous phase. The known N,N,N',N'-tetraoctyl diglycolamide (TODGA) was used as lipophilic extractant in the organic phase for extraction of Ln(III), and a new strategy for the competitive extraction of An(III) and Ln(III) was developed based on TODGA and the above hydrophilic ligands. The optimal hydrophilic ligand of N,N'-bis(2-hydroxyethyl)-2,9-dicarboxamide-1,10-phenanthroline (2OH-DAPhen) displayed exceptional selectivity toward Am(III) over Ln(III), with the concentrations of HNO3 ranging from 0.05 to 3.0 M. The maximum separation factors were up to 1365 for Eu/Am, 417.66 for Eu/Cm, and 42.38 for La/Am. The coordination mode and bonding property of 2OH-DAPhen with Ln(III) were investigated by 1H NMR titration, UV-vis spectrophotometric titration, luminescence titration, FT-IR, ESI-HRMS analysis, and DFT calculations. The results revealed that the predominant species formed in the aqueous phase was a 1:1 ligand/metal complex. DFT calculations also confirmed that the affinity of 2OH-DAPhen for Am(III) was better than that for Eu(III). The present work using a competitive extraction strategy developed a feasible alternative method for the selective separation of trivalent actinides from lanthanides.

Identification and assessment of new PIM2 inhibitors for treating hematologic cancers: A combined approach of energy-based virtual screening and machine learning evaluation.

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential. Ten compounds were selected and subjected to an adequate evaluation of their biological activity. Compound 2 emerged as the most potent inhibitor with an IC50 of approximately 135.7 nM. It also displayed significant activity against various hematological cancers, including acute myeloid leukemia, mantle cell lymphoma, and anaplastic large cell lymphoma (ALCL). Molecular dynamics simulations elucidated the binding mode of compound 2 with PIM2, offering insights for drug development. These results highlight the reliability and efficacy of our virtual screening workflow, promising new drugs for hematologic cancers, notably ALCL.

Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients.

CNOT3 is the central component of the CCR4-NOT protein complex, which is a global regulator of RNA polymerase II transcription. Loss of function mutations in CNOT3 lead to intellectual developmental disorder with speech delay, autism, and dysmorphic facies (IDDSADF), which is very rare. Herein, we reported two novel heterozygous frameshift mutations (c.1058_1059insT and c.724delT) and one novel splice site variant (c.387 + 2 T > C) in CNOT3 (NM_014516.3) gene in three Chinese patients with dysmorphic features, developmental delay, and behavior anomalies. The functional study showed that the CNOT3 mRNA levels were significantly decreased in the peripheral blood of two patients with c.1058_1059insT and c.387 + 2 T > C variants, respectively, and minigene assay demonstrated that the splice variant (c.387 + 2 T > C) resulted in exon skipping. We also found that CNOT3 deficiency was linked to alterations of expression levels of other CCR4-NOT complex subunits in mRNA level in the peripheral blood. By analyzing the clinical manifestations of all these patients with CNOT3 variants, including our three cases and 22 patients previously reported, we did not observe a correlation between genotypes and phenotypes. In summary, this is the first time to report cases with IDDSADF in the Chinese population, and three novel CNOT3 variants in these patients expand its mutational spectrum.

Deciphering and advancing CAR T-cell therapy with single-cell sequencing technologies.

Chimeric antigen receptor (CAR) T-cell therapy has made remarkable progress in cancer immunotherapy, but several challenges with unclear mechanisms hinder its wide clinical application. Single-cell sequencing technologies, with the powerful unbiased analysis of cellular heterogeneity and molecular patterns at unprecedented resolution, have greatly advanced our understanding of immunology and oncology. In this review, we summarize the recent applications of single-cell sequencing technologies in CAR T-cell therapy, including the biological characteristics, the latest mechanisms of clinical response and adverse events, promising strategies that contribute to the development of CAR T-cell therapy and CAR target selection. Generally, we propose a multi-omics research mode to guide potential future research on CAR T-cell therapy.

Biological activity of a new recombinant human coagulation factor VIII and its efficacy in a small animal model.

Deficiency in human coagulation factor VIII (FVIII) causes hemophilia A (HA). Patients with HA may suffer from spontaneous bleeding, which can be life-threatening. Recombinant FVIII (rFVIII) is an established treatment and prevention agent for bleeding in patients with HA. Human plasma-derived FVIII (pdFVIII), commonly used in clinical practice, is relatively difficult to prepare. In this study, we developed a novel B-domain-deleted rFVIII, produced and formulated without the use of animal or human serum-derived components. rFVIII promoted the generation of activated factor X and downstream thrombin, and, similar to that of other available FVIII preparations, its activity was inhibited by FVIII inhibitors. In addition, rFVIII has ideal binding affinity to human von Willebrand factor. Activated FVIII (FVIIIa) could be degraded by activated protein C and lose its procoagulant activity. In vitro, commercially available recombinant FVIII (Xyntha) and pdFVIII were used as controls, and there were no statistical differences between rFVIII and commercial FVIII preparations, which demonstrates the satisfactory efficacy and potency of rFVIII. In vivo, HA mice showed that infusion of rFVIII rapidly corrected activated partial thromboplastin time, similar to Xyntha. Moreover, different batches of rFVIII were comparable. Overall, our results demonstrate the potential of rFVIII as an effective strategy for the treatment of FVIII deficiency.

Peripheral immune cell profiling of double-hit lymphoma by mass cytometry.

BACKGROUND: Double-hit or Triple-hit lymphoma (DHL/THL) is a subset of high-grade B cell lymphoma harboring rearrangements of MYC and BCL2 and/or BCL6, and usually associate with aggressive profile, while current therapies tend to provide poor clinical outcomes and eventually relapsed. Further explorations of DHL at cellular and molecular levels are in demand to offer guidance for clinical activity. METHODS: We collected the peripheral blood of DHL patients and diffused large B cell lymphoma (DLBCL) patients from single institute and converted them into PBMC samples. Mass cytometry was then performed to characterize these samples by 42 antibody markers with samples of healthy people as control. We divided the immune cell subtypes based on the expression profile of surface antigens, and the proportion of each cell subtype was also analyzed. By comparing the data of the DLBCL group and the healthy group, we figured out the distinguished immune cell subtypes of DHL patients according to their abundance and marker expression level. We further analyzed the heterogeneity of DHL samples by pairwise comparison based on clinical characteristics. RESULTS: We found double-positive T cells (DPT) cells were in a significantly high percentage in DHL patients, whereas the ratio of double-negative T cells (DNT) was largely reduced in patients. Besides, CD38 was uniquely expressed at a high level on some naïve B cells of DHL patients, which could be a marker for the diagnosis of DHL (distinguishing from DLBCL), or even be a drug target for the treatment of DHL. In addition, we illustrated the heterogeneity of DHL patients in terms of immune cell landscape, and highlighted TP53 as a major factor that contributes to the heterogeneity of the T cells profile. CONCLUSION: Our study demonstrated the distinct peripheral immune cell profile of DHL patients by contrast to DLBCL patients and healthy people, as well as the heterogeneity within the DHL group, which could provide valuable guidance for the diagnosis and treatment of DHL.

Berberine inhibits gluconeogenesis in spontaneous diabetic rats by regulating the AKT/MAPK/NO/cGMP/PKG signaling pathway.

This work was aimed to investigate the action mechanism of berberine (BBR) on gluconeogenesis. The effects of BBR were examined in rat primary hepatocytes and confirmed in vivo in spontaneous diabetic rats. Protein levels were assessed by Western blot. Immunofluorescence staining was utilized for visualizing protein expression, while qRT-PCR helped for the determination of gene expression at the mRNA level. Besides, cGMP concentration was measured using ELISA, whereas NO level was assessed by spectrophotometry. BBR inhibited gluconeogenesis by downregulating G6Pase and PEPCK via inhibition of CREB phosphorylation. Moreover, BBR enhanced NO and cGMP concentrations, leading to the activation of the NO/cGMP/PKG signaling via activating AKT1/MAPK axis. The in vivo experiments were consistent with the findings obtained in vitro. Hence, BBR represents a drug candidate for diabetic patients and its mechanism of action may be driven via the AKT/MAPK/NO/cGMP/PKG pathway.

Efficacy and safety of empagliflozin in combination with insulin in Chinese patients with type 2 diabetes and insufficient glycaemic control: A phase III, randomized, double-blind, placebo-controlled, parallel study.

AIM: To evaluate the efficacy and safety of empagliflozin in combination with insulin ± oral antidiabetic drugs (OADs) over 24 weeks, in Chinese patients with type 2 diabetes (T2D) who had insufficient glycaemic control. MATERIALS AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel group, multicentre phase III study. Adult patients with T2D and insufficient glycaemic control who received insulin ± up to two OADs were randomized (1:1:1) to receive empagliflozin 10 or 25 mg, or placebo for 24 weeks. The primary endpoint was change from baseline in HbA1c at week 24. RESULTS: Of 219 randomized patients, 73 patients were in each treatment group; baseline characteristics were comparable among the groups. There was a significantly larger decrease from baseline in HbA1c (adjusted mean treatment difference -0.99 and -0.98 for in the empagliflozin 10 and 25 mg groups, respectively; P < .0001) with both doses of empagliflozin than with placebo. There were also significantly larger decreases from baseline in fasting plasma glucose, 2-hour postprandial glucose and body weight with both empagliflozin doses than with placebo. Among patients in the empagliflozin 10 mg, 25 mg and placebo groups, 17.8%, 9.6% and 11.0% reported confirmed hypoglycaemic events, respectively (nominal P = .2422 and .7661 in the empagliflozin 10 and 25 mg groups, respectively), and no Clinical Events Committee-confirmed diabetic ketoacidosis events were reported. CONCLUSIONS: In Chinese patients with T2D, empagliflozin combined with insulin ± OADs improved glycaemic control and was well tolerated, without an increased risk of hypoglycaemia.

The average 30-minute post-prandial C-peptide predicted diabetic retinopathy progress: a retro-prospective study.

BACKGROUND: The conclusion between Connecting peptide (C-peptide) and diabetic chronic complication was controversial. The purpose of this study is to explore the possible association between average C-peptide with diabetic retinopathy (DR) progression in Chinese patients with type 2 diabetes. METHODS: This is a retro-prospective study. 622 patients with type 2 diabetes were included. DR was evaluated using non-mydriatic fundus photography and DR progression was defined as any deterioration of either eye. Fasting and postprandial c-peptide levels were assayed at baseline and follow-up period. Differences between continuous variables were compared using the Mann-Whitney U test; and categorical variables were analyzed by the chi-square test. Correlation between parameters and 30-minute postprandial C-peptide were determined by Spearman correlation test. The relationship between C-peptide and DR progression was evaluated by multivariable binary logistic regression. Two-tailed P-values < 0.05 were regarded as statistically significant. RESULTS: DR was present in 162 (26.0%) patients at baseline, and 26.4% of patients were found progression of DR at follow-up. Patients with progression of DR had lower average levels of 30-minute postprandial C-peptide (2.01 ng/ml vs. 2.6 ng/ml, p = 0.015) and 120-minute postprandial C-peptide (3.17 ng/ml vs. 3.92 ng/ml, p < 0.029), as well as average increment of 30-minute (0.41 ng/ml vs. 0.64 ng/ml, p = 0.015) and 120-minute postprandial C-peptide (1.48 ng/ml vs. 1.93 ng/ml, p < 0.017), than those without DR aggravation. Multivariate logistic regression analysis determined that 30-minute postprandial C-peptide and its increment were related to reduced odds ratios for DR progression (odds ratios [OR] = 0.83 and 0.74, respectively). CONCLUSION: Our results suggest that the Average 30-minute post-prandial C-peptide and increment were negatively correlated with DR progression, which further demonstrates the importance to preserve ß-cell residual function in the prevention for DR progression. TRIAL REGISTRATION: Not applicable.

T1-weighted images-based radiomics for structural lesions evaluation in patients with suspected axial spondyloarthritis.

PURPOSE: The aim of this study was to investigate the feasibility of radiomics based on T1-weighted images (T1WI) for assessing sacroiliac joint (SIJ) structural lesions in patients with suspected axial spondyloarthritis (axSpA). MATERIALS AND METHODS: A total of 266 patients with clinical suspicion of axSpA between December 2016 and January 2022 were enrolled. Structural lesions were assessed on low-dose CT (ldCT) and MRI, respectively. Radiomic features, extracted from SIJ T1WI, were included to generate the radiomics model. The performance of the radiomics model was evaluated using receiver operating characteristic (ROC) curve. Furthermore, point-biserial correlation analysis was used to interpret the associations between the radiomic feature and structural lesions. RESULTS: Using ldCT as the reference standard, the radiomics model showed favorable performance for detecting positive global structural lesions in the training cohort (AUC, 0.82 [95% CI: 0.76, 0.88]) and validation cohort (AUC, 0.82 [95% CI: 0.72, 0.91]. Experienced MRI raters yielded predictive AUCs of 0.73 (95% CI: 0.67, 0.79), and 0.74 (95% CI: 0.66, 0.83) in the training and validation cohort, respectively. The seven radiomic features included in the radiomics model showed significant correlation with different kinds of structural lesions (P all < 0.05). Among them, Wavelet.LHL_firstorder_90Percentile showed the strongest association with fat lesion (r = 0.48, P < 0.05). CONCLUSION: The radiomics analysis with T1WI could effectively detect SIJ structural lesions and achieved expert-level performance. Each radiomic feature was correlated with different structural lesions significantly, which might inform radiomic-based applications for axSpA intelligent diagnosis.

Lewis Acid-Relayed Singlet Oxygen Reaction with Enamines: Selective Dimerization of Enamines to Pyrrolin-4-ones.

Singlet oxygen (1O2)-mediated oxidation represents an attractive strategy for incorporation of oxygen atoms from air under mild and environmentally benign conditions. However, the 1O2 reaction with enamine suffers from fragmentation, leading to very unsuccessful transformation. Here, Lewis acid is introduced to intercept [2 + 2] or "ene" reaction intermediates of the 1O2 reaction and enables oxidative dimerization of enamines to produce pyrrolin-4-ones in good to excellent yields. Mechanistic studies reveal the formation of the imino ketone intermediate from the interaction of 1O2 and enamine, which is able to interact with Lewis acid, relaying the 1O2 reaction in enamine chemistry. For the first time, selective cross-dimerization of two different enamines is achieved. Due to the advantages of mild conditions, high chemoselectivity, and up to 99% yield, a promising strategy has been developed for synthesizing aza-heterocycles under ambient conditions, which can be further applied for the synthesis of imidazolone, quinoxaline, and highly functionalized imine.

High efficacy of PD-1 inhibitor after initial failure of PD-L1 inhibitor in Relapsed/Refractory classical Hodgkin Lymphoma.

PURPOSE: We sought to understand the clinical course and molecular phenotype of patients who showed disease progression after programmed cell death ligand 1 (PD-L1) inhibitor treatment but subsequently responded to PD-1 inhibitor treatment. We also explored the response to PD-1-axis targeted therapy of classical Hodgkin lymphoma (cHL) according to genetically driven PD-L1 and programmed cell death ligand 2 (PD-L2) expression. METHODS: Five patients in a phase II clinical trial of CS1001 (PD-L1 inhibitor) for relapsed or refractory (R/R) cHL were retrospectively reviewed. Formalin-fixed, paraffin-embedded whole tissues from the five patients were evaluated for 9p24.1 genetic alterations based on FISH and the expression of PD-L1, PD-L2, PD-1, major histocompatibility complex (MHC) class I-II, and the tumor microenvironment factorsCD163 and FOXP3 in the microenvironmental niche, as revealed by multiplex immunofluorescence. RESULTS: All five patients showed primary refractory disease during first-line treatment. Four patients received PD-1 inhibitor after dropping out of the clinical trial, and all demonstrated at least a partial response. The progression-free survival ranged from 7 to 28 months (median = 18 months), and 9p24.1 amplification was observed in all five patients at the PD-L1/PD-L2 locus. PD-L1 and PD-L2 were colocalized on Hodgkin Reed-Sternberg (HRS) cells in four of the five (80%) patients. There was differential expression of PD-L1 and PD-L2 in cells in the tumor microenvironment in cHL, especially in HRS cells, background cells and tumor-associated macrophages. CONCLUSIONS: PD-L1 monotherapy may not be sufficient to block the PD-1 pathway; PD-L2 was expressed in HRS and background cells in cHL. The immunologic function of the PD-L2 pathway in anti-tumor activity may be underestimated in R/R cHL. Further study is needed to elucidate the anti-tumor mechanism of PD-1 inhibitor and PD-L1 inhibitor treatment.

The Relationship Between Baseline Cortisol Levels and Surgery Method of Primary Bilateral Macronodular Adrenal Hyperplasia.

Aim was to explore the associations between baseline cortisol levels and surgery method of primary bilateral macronodular adrenal hyperplasia (PBMAH). We retrospectively reviewed the clinical features and management of 30 patients (18 females and 12 males) who were diagnosed with PBMAH in our center between 2005 and 2019. Based on surgery method, we divided the patients into two groups: unilateral adrenalectomy (UA) group; and bilateral adrenalectomy (BA) group. Serum cortisol rhythm and 24-hour urinary free cortisol (UFC/24 h) levels were assayed using chemiluminescence method. Associations between baseline cortisol levels and BA were assessed using logistic regression. The predictive value of baseline cortisol levels for BA was calculated using receiver operating characteristic (ROC) curves. Twenty patients (66.7%) underwent UAs and ten patients (33.3%) underwent BAs. After adjusting for age, sex, BMI, SBP, and adrenal volume, the concentrations of baseline serum cortisol (8 AM, 4 PM, and 0 AM) and UFC/24 h were associated with bilateral adrenalectomy (all p<0.05). The area under the ROC curve based on 8 AM serum cortisol level model was larger than that in models based on 4 PM, 0 AM serum cortisol levels and UFC/24 h, but the differences were non-significant (all p>0.05). According to maximum Youden index criteria, the optimal cutoffs of 8 AM serum cortisol level and UFC were 26.89 µg/dl and 406.65 µg/24 h, respectively, for BA. The baseline cortisol levels are positively associated with BA. Increased levels of baseline cortisol levels may predict higher possibility of BA, which should be confirmed by prospective studies.

Association of immunosuppression treatment with generalization among patients with ocular myasthenia gravis: A propensity score analysis.

BACKGROUND: To analyze disease generalization in patients with ocular myasthenia gravis (OMG) treated with immunosuppression compared with patients without immunosuppression treatment. METHODS: In this retrospective cohort study, we analyzed data from patients with OMG at seven medical centers in China from January 1, 2015 to May 1, 2019 and compared disease generalization in patients (treated with immunosuppression vs. not treated) within 2 years of disease onset using raw and inverse probability of treatment weighting (IPTW) analyses. RESULTS: In the study population of 813 patients with OMG, 425 (52.3%) with immunosuppression had a mean (SD) onset age of 50.0 (15.1) years, and 188 (44.2%) were women. The remaining 388 (47.7%) patients were not immunosuppressed (mean age, 48.4 [15.0] years; 185 [47.7%] women). Disease generalization developed in 122 (31.4%) and 37 (8.7%) patients in the non-immunosuppression and immunosuppression groups, respectively. Relative to non-immunosuppression, immunosuppression was associated with a lower risk of generalization in a multivariable-adjusted Cox model (hazard ratio [HR] 0.27; 95% confidence interval [CI] 0.18-0.40; p < 0.001) and IPTW-weighted Cox model (HR 0.28; 95% CI 0.19-0.42; p < 0.001). In sensitivity analyses, longer duration of immunosuppression was associated with a lower risk of generalization (HR 0.90 for every 1-month increase; 95% CI 0.87-0.92; p < 0.001; IPTW-adjusted). Combination therapy with steroids and non-steroidal immunosuppressants showed superior efficacy in reducing the risk of generalization (HR 0.14; 95% CI 0.07-0.26; p < 0.001). CONCLUSION: Immunosuppression significantly reduced the 2-year risk of generalization in patients with OMG.

Targeted disruption of galectin 3 in mice delays the first wave of spermatogenesis and increases germ cell apoptosis.

Galectin 3 is a multifunctional lectin implicated in cellular proliferation, differentiation, adhesion, and apoptosis. This lectin is broadly expressed in testicular somatic cells and germ cells, and is upregulated during testicular development. Since the role of galectin 3 in testicular function remains elusive, we aimed to characterize the role of galectin 3 in testicular physiology. We found that galectin 3 transgenic mice (Lgals3-/-) exhibited significantly decreased testicular weight in adulthood compared to controls. The transgenic mice also exhibited a delay to the first wave of spermatogenesis, a decrease in the number of germ cells at postnatal day 5 (P5) and P15, and defective Sertoli cell maturation. Mechanistically, we found that Insulin-like-3 (a Leydig cell marker) and enzymes involved in steroid biosynthesis were significantly upregulated in adult Lgals3-/- testes. These observations were accompanied by increased serum testosterone levels. To determine the underlying causes of the testicular atrophy, we monitored cellular apoptosis. Indeed, adult Lgals3-/- testicular cells exhibited an elevated apoptosis rate that is likely driven by downregulated Bcl-2 and upregulated Bax and Bak expression, molecules responsible for live/death cell balance. Moreover, the percentage of testicular macrophages within CD45+ cells was decreased in Lgals3-/- mice. These data suggest that galectin 3 regulates spermatogenesis initiation and Sertoli cell maturation in part, by preventing germ cells from undergoing apoptosis and regulating testosterone biosynthesis. Going forward, understanding the role of galectin 3 in testicular physiology will add important insights into the factors governing the development of germ cells and steroidogenesis and delineate novel biomarkers of testicular function.

Clinical safety study of photobiomodulation in acute spinal cord injury by scattering fiber.

The study aimed to design a reliable and straightforward PBM method by implanting a medical scattering fiber above surgically exposed spinal cord in SCI patients. Moreover, the safety of this method was examined. Twelve patients with acute SCI (ASIA B) requiring posterior decompression were recruited. The medical scattering fiber was implanted above the spinal cord, and was continuously irradiated at 810 nm, 300 mW, 30 min/day, once per day for 7 days. The vital signs (temperature, blood pressure, respiratory rate, heart rate, and oxygen saturation), infection indicators (WBC, NEUT, hs-CRP, and PCT), photo-allergic reaction indicators (Eosinophil and Basophil), coagulation function indicators (PT, APTT, TT) and neurological stability indicators (ASIA sensory and motor scores) were recorded to evaluate the safety of PBM. Three months after surgery, 12 patients completed follow-up. In our study, direct PBM on SCI site did not cause clinically pathologic changes in vital signs of the patients. All patients had higher WBC, NEUT, and hs-CRP at day 3 during irradiation than those before surgery, and returned to normal at day 7. The changes in Eosinophil and Basophil that were closely associated with allergic reactions were within normal limits throughout the course of irradiation. The coagulation function (PT, APTT, and TT) of patients were also in the normal range. The ASIA sensory and motor scores of all patients had no changes throughout the irradiation process. However, in the follow-up, both ASIA sensory and motor scores of all patients had minor improvement than those in pre-irradiation, and 7 patients had adverse events, but they were not considered to be related to PBM. Our study might firstly employ direct PBM in the SCI by using scattered optical fibers. In a limited sample size, our study concluded that direct PBM at the site of SCI would not produce adverse effects within the appropriate irradiation parameters. The method is safe, feasible, and does not add additional trauma to the patient. Our preliminary study might provide a new methodology for the clinical PBM treatment of acute SCI.

[Clinical features and genetic analysis of a case with Perlman syndrome due to variant of DIS3L2 gene].

OBJECTIVE: To analyze the clinical phenotype and genetic characteristics of a child with Perlman syndrome. METHODS: Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Whole exome sequencing (WES) was carried out to detect potential variant in the proband. Candidate variant was verified by Sanger sequencing. The pathogenicity of candidate variants was evaluated according to the guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: The results of WES showed that the proband has harbored compound heterozygous variants of the DIS3L2 gene, namely c.2109delC and c.1829.c.1830insC, which were respectively inherited from her mother and father. The results were confirmed by Sanger sequencing. Based on the ACMG guidelines, the two novel variants were both predicted to be pathogenic (PVS1+PS2+PM2). CONCLUSION: The compound heterozygous variants of the DIS3L2 gene probably underlay the Perlman syndrome in this patient. Above finding has enriched the spectrum of DIS3L2 gene mutations.

Site-Selective N-1 and C-3 Heteroarylation of Indole with Heteroarylnitriles by Organocatalysis under Visible Light.

Site-selective N-1 and C-3 arylation of indole has been sought after because of the prevalent application of arylindoles and the intricate reactivities associated with the multiple sites of the N-unsubstituted indole. Represented herein is the first regioselective heteroarylation of indole via a radical-radical cross-coupling by visible-light irradiation. Steady and time-resolved spectroscopic and computational studies revealed that the hydrogen-bonding interaction of organic base and its conjugated acid, namely with indole and heteroarylnitrile, determined the reaction pathway, which underwent either proton-coupled electron-transfer or energy-transfer for the subsequent radical-radical cross-coupling, leading to the regioselective formation of C-3 and N-1 heteroarylation of indoles, respectively. The parallel methodologies for regioisomeric N-1 and C-3 heteroaryl indoles with good functional group compatibility could be applied to large-scale synthesis and late-stage derivatization of bioactive compounds under extremely mild reaction conditions.