Outcomes of COVID-19 in multiple myeloma patients treated with daratumumab.

Despite concerns about an increased risk of adverse outcomes following coronavirus disease (COVID-19) in multiple myeloma patients treated with anti-CD38 Abs, the impact of COVID-19 on this group of patients is unclear. We tried to evaluate the clinical outcomes of these patients. We collected data from 1036 patients with multiple myeloma and enrolled 509 cases with COVID-19. We divided enrolled patients into daratumumab or nondaratumumab cohorts based on whether they had received daratumumab-based treatment within 6 months of COVID-19 infection. We applied a propensity score matching method to reduce the bias of baseline characteristics, and then compared the incidence of adverse outcomes between these two cohorts. A total of 117 patients were enrolled in the daratumumab cohort, and 392 patients in the nondaratumumab cohort. After propensity score matching, 204 patients were matched. The proportions of patients who developed COVID-19 pneumonia (59.8% vs. 34.3%, p < 0.001), were hospitalized (33.3% vs. 11.8%, p < 0.001) and developed severe disease (23.5% vs. 6.9%, p = 0.001) were higher in the matched daratumumab cohort. By multivariate analysis, daratumumab exposure was an independent risk factor for severe disease. An ECOG performance status >2 and history of chronic kidney disease were independent risk factors for COVID-19-related mortality among patients who received daratumumab-based therapy. This study suggested that multiple myeloma patients exposed to daratumumab were at a higher risk of adverse outcomes from COVID-19.

Single-cell profiling transcriptomic reveals cellular heterogeneity and cellular crosstalk in choroidal neovascularization model.

Choroidal neovascularization (CNV) is a hallmark of neovascular age-related macular degeneration (nAMD) and a major contributor to vision loss in nAMD cases. However, the identification of specific cell types associated with nAMD remains challenging. Herein, we performed single-cell sequencing to comprehensively explore the cellular diversity and understand the foundational components of the retinal pigment epithelium (RPE)/choroid complex. We unveiled 10 distinct cell types within the RPE/choroid complex. Notably, we observed significant heterogeneity within endothelial cells (ECs), fibroblasts, and macrophages, underscoring the intricate nature of the cellular composition in the RPE/choroid complex. Within the EC category, four distinct clusters were identified and EC cluster 0 was tightly associated with choroidal neovascularization. We identified five clusters of fibroblasts actively involved in the pathogenesis of nAMD, influencing fibrotic responses, angiogenic effects, and photoreceptor function. Additionally, three clusters of macrophages were identified, suggesting their potential roles in regulating the progression of nAMD through immunomodulation and inflammation regulation. Through CellChat analysis, we constructed a complex cell-cell communication network, revealing the role of EC clusters in interacting with fibroblasts and macrophages in the context of nAMD. These interactions were found to govern angiogenic effects, fibrotic responses, and inflammatory processes. In summary, this study reveals noteworthy cellular heterogeneity in the RPE/choroid complex and provides valuable insights into the pathogenesis of CNV. These findings will open up potential avenues for deep understanding and targeted therapeutic interventions in nAMD.

Copper Loading-Controlled Selective Synthesis of 2,5-Bis(trifluoromethyl) and Monotrifluoromethyl-Substituted Oxazoles.

A general domino annulation reaction of sulfonylmethyl isocyanide with trifluoroacetic anhydride in the presence of copper chloride as an additive is developed. The reaction affords 2,5-bis(trifluoromethyl)oxazoles in modest to good yields under mild conditions. A wide variety of sulfonylmethyl isocyanide and perfluorocarboxylic anhydride substrates are amenable to this transformation. Under a higher copper salt loading conditions, the reaction led to the formation of monotrifluoromethyl-substituted oxazole product.

Outcomes of proton therapy to infradiaphragmatic sites in pediatric patients with Hodgkin lymphoma.

BACKGROUND: Proton therapy (PT) has potential advantages in pediatric Hodgkin lymphoma (pHL). However, there are limited data on PT, specifically to infradiaphragmatic targets. We report on PT planning details, doses achieved to organs at risk (OARs), and clinical and toxicity outcomes for patients with pHL who received PT to infradiaphragmatic regions. METHODS: This is a retrospective study including patients treated between 2011 and 2022. Demographic and clinical factors were collected, and toxicity was reported using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Dosimetric and clinical factors associated with key outcomes were assessed via Cox regression. Photon plans were generated for all patients, and the paired t-tests or Wilcoxon signed rank sum tests were used for dosimetric comparisons. RESULTS: Twenty-one patients comprising 22 PT courses were included. Median follow-up was 5.0 years, and mean age was 14.2 years. Median dose was 21 Gray equivalent (GyE) over 14 fractions. Top acute grade 1 (G1) toxicities included fatigue (59%) and anorexia (36%). Rates of acute G2 and G3+ toxicity were 18% and 0%, respectively. After PT, no local or marginal failures occurred. Five percent experienced disease progression, who were all successfully salvaged, and all patients were alive and disease-free at last follow-up. No secondary malignancies developed. Compared to photon radiotherapy, PT achieved significantly lower doses to the bowels, stomach, spleen, pancreatic tail, liver, kidneys, and pelvic bones. CONCLUSIONS: PT is well-tolerated and leads to excellent oncologic and toxicity outcomes with long-term follow-up. PT confers dosimetric advantages when compared to photons.

Effects of long-term exposure to air pollutant mixture on blood pressure in typical areas of North China.

BACKGROUND: Studies about the combined effects of gaseous air pollutants and particulate matters are still rare. OBJECTIVES: This study was performed based on baseline survey of the Diverse Life-Course Cohort in the Beijing-Tianjin-Hebei (BTH) Region of North China to evaluate the association of long-term air pollutants with blood pressure and the combined effect of the air pollutants mixture among 32821 natural han population aged 20 years or above. METHODS: Three-year average exposure to air pollutants (PM10, PM2.5, PM1, O3, SO2, NO2, and CO) and PM2.5 components [black carbon (BC), ammonium (NH4+), nitrate (NO3-), sulfate (SO42-), and organic matter (OM)] of residential areas were calculated based on well-validated models. Generalized linear mixed models (GLMMs) were used to estimate the associations of air pollutants exposure with the systolic blood pressure (SBP), diastolic blood pressure (DBP), Mean arterial pressure (MAP), pulse pressure (PP) and prevalent hypertension. Quantile g-Computation and Bayesian Kernel Machine Regression (BKMR) were employed to assess the combined effect of the air pollutant mixture. RESULTS: We found that long-term exposures of O3, PM2.5, and PM2.5 components were stably and strongly associated with elevated SBP, DBP, and MAP and prevalent hypertension. O3 increased SBP, DBP, and MAP at a similar extent, but with greater effects; while, PM2.5 and PM2.5 components had a greater impact on SBP than DBP, which increased PP simultaneously. In multi-pollutant models, the combined effects of the air pollutant mixture on blood pressure and prevalent hypertension was predominantly influenced by O3, PM2.5, and O3, OM in different models, respectively. For example, O3, PM2.5 contributed 57.25 %, 39.22 % of the positive combined effect of the air pollutant mixture on SBP; and O3, OM positively contributed 70.00 %, 30.00 % on prevalent hypertension, respectively. There were interactions between O3, CO, SO2 and PM2.5 components on hbp, SBP and PP. CONCLUSIONS: The results showed positive associations of air pollutant mixtures with blood pressure, where O3 and PM2.5 (especially OM) might be primary contributors. There were interactions between gaseous air pollutants and PM2.5 components on blood pressure and prevalent hypertension.

Trust and virtual communication during the COVID-19 pandemic for adults with asthma from low-income neighborhoods: What have we learned?

BACKGROUND: Low-income and marginalized adults disproportionately bear the burden of poor asthma outcomes. One consequence of the structural racism that preserves these inequities is decreased trust in government and health care institutions. OBJECTIVE: We examined whether such distrust extended to health care providers during the pandemic. METHODS: We enrolled adults living in low-income neighborhoods who had required a hospitalization, an emergency department visit, or a prednisone course for asthma in the prior year. Trust was a dichotomized measure derived from a 5-item questionnaire with a 5-point Likert scale response. The items were translated to the binary variable "strong" versus "weak" trust. Communication was measured using a 13-item questionnaire with a 5-point Likert scale. Logistic regression was used to examine the association between communication and trust, controlling for potential confounders. RESULTS: We enrolled 102 patients, aged 18 to 78 years; 87% were female, 90% were Black, 60% had some post-high school education, and 57% were receiving Medicaid. Of the 102 patients, 58 were enrolled before the March 12, 2020, pandemic start date, and 70 (69%) named doctors as their most trusted source of health information. Strong trust was associated with a negative response to the statement "It is hard to reach a person in my doctor's office by phone." There was no evidence of an association between the overall communication scores and trust. Satisfaction with virtual messaging was weaker among those with less trust. CONCLUSIONS: These patients trust their physicians, value their advice, and need to have accessible means of communication.

Targeting choroidal vasculopathy via up-regulation of tRNA-derived fragment tRF-22 expression for controlling progression of myopia.

BACKGROUND: Myopia has emerged as a major public health concern globally, which is tightly associated with scleral extracellular matrix (ECM) remodeling and choroidal vasculopathy. Choroidal vasculopathy has gradually been recognized as a critical trigger of myopic pathology. However, the precise mechanism controlling choroidal vasculopathy remains unclear. Transfer RNA-derived fragments (tRFs) are known as a novel class of small non-coding RNAs that plays important roles in several biological and pathological processes. In this study, we investigated the role of tRF-22-8BWS72092 (tRF-22) in choroidal vasculopathy and myopia progression. METHODS: The tRF-22 expression pattern under myopia-related stresses was detected by qRT-PCR. MTT assays, EdU incorporation assays, Transwell migration assays, and Matrigel assays were conducted to detect the role of tRF-22 in choroidal endothelial cell function in vitro. Isolectin B4 staining and choroidal sprouting assay ex vivo were conducted to detect the role of tRF-22 in choroidal vascular dysfunction in vivo. Immunofluorescent staining, western blot assays and ocular biometric parameters measurement were performed to examine whether altering tRF-22 expression in choroid affects scleral hypoxia and ECM remodeling and myopia progression in vivo. Bioinformatics analysis and luciferase activity assays were conducted to identify the downstream targets of tRF-22. RNA-sequencing combined with m6A-qPCR assays were used to identify the m6A modified targets of METTL3. Gain-of-function and Loss-of-function analysis were performed to reveal the mechanism of tRF-22/METTL3-mediated choroidal vascular dysfunction. RESULTS: The results revealed that tRF-22 expression was significantly down-regulated in myopic choroid. tRF-22 overexpression alleviated choroidal vasculopathy and retarded the progression of myopia in vivo. tRF-22 regulated choroidal endothelial cell viability, proliferation, migration, and tube formation ability in vitro. Mechanistically, tRF-22 interacted with METTL3 and blocked m6A methylation of Axin1 and Arid1b mRNA transcripts, which led to increased expression of Axin1 and Arid1b. CONCLUSIONS: Our study reveals that the intervention of choroidal vasculopathy via tRF-22-METTL3- Axin1/Arid1b axis is a promising strategy for the treatment of patients with myopic pathology.

Impact of sex on treatment-related adverse effects and prognosis in nasopharyngeal carcinoma.

BACKGROUND: In nasopharyngeal cancer (NPC), women have a lower incidence and mortality rate than men. Whether sex influences the prognosis of NPC patients remains debatable. We retrospectively examined the influence of sex on treatment-related side effects and prognosis in NPC. METHODS: Clinical data of 1,462 patients with NPC treated at the Southern Hospital of Southern Medical University from January 2004 to December 2015 were retrospectively examined. Statistical analysis was performed to assess differences in overall survival (OS), distant metastasis-free survival (DMFS), local recurrence-free survival(LRFS), and progression-free survival(PFS), as well as treatment-related adverse effects, including myelosuppression, gastrointestinal responses, and radiation pharyngitis and dermatitis, between men and women. RESULTS: Women had better 5-year OS (81.5% vs. 87.1%, P = 0.032) and DMFS (76.2% vs. 83.9%, P = 0.004) than men. Analysis by age showed that the prognoses of premenopausal and menopausal women were better than those of men, whereas prognoses of postmenopausal women and men were not significantly different. Additionally, women had a better prognosis when stratified by treatment regimen. Furthermore, chemotherapy-related adverse effects were more severe in women than in men; however, the incidences of radiation laryngitis and dermatitis were not significantly different between the sexes. Logistic regression analysis revealed that the female sex was an independent risk factor for severe myelosuppression and gastrointestinal reactions. CONCLUSIONS: Chemotherapy-related side effects are more severe but the overall prognosis is better in women with NPC than in men with NPC. Patients may benefit from a personalized treatment approach for NPC. TRIAL REGISTRATION: This study was approved by the Medical Ethics Committee of Nanfang Hospital of the Southern Medical University (NFEC-201,710-K3).

"One stone and two birds" strategy to treat neovascular age-related macular degeneration by a novel retinoid drug, EYE-101.

Choroidal neovascularization (CNV) is a typical pathological feature of neovascular age-related macular degeneration and has become a major cause of vision loss in the elderly. Current therapies require repeated intraocular injections of anti-VEGF drugs by inhibiting endothelial angiogenic effects, which is painful and may cause adverse effects on normal vascular and neuronal functions. Herein, we designed a novel retinoid drug, EYE-101, determined its therapeutic effects on CNV, and clarified the anti-angiogenic mechanism. The results show that administration of EYE-101 did not cause obvious cytotoxicity and ocular tissue toxicity at the concentrations less than 5 µM. Topical administration of EYE-101 could reduce choroidal sprouting, suppress laser-induced CNV formation, and decrease pericyte coverages on ocular vessels. Administration of EYE-101 also suppressed endothelial cell proliferation, migration, and tube formation and reduced pericyte proliferation, migration, recruitment towards endothelial cells. EYE-101 exerted its anti-angiogenic effects by targeting endothelial cells and pericytes via antagonizing Wnt/ß-catenin signaling and PDGF signaling. Thus, EYE-101 administration may offer an"one stone and two birds" strategy for the prevention and treatment of ocular neovascular disorders.

miR-1273h-5p protects the human corneal epithelium against UVR-induced oxidative stress and apoptosis: Role of miR-1273h-5p in climatic droplet keratopathy.

Climatic droplet keratopathy (CDK) is characterized by an increased number of oil-like deposits on the most anterior corneal layers, which affect vision and can cause blindness. Environmental ultraviolet radiation (UVR) exposure is a major risk factor, but the underlying mechanism of CDK pathogenesis is unclear. Increasing evidence has demonstrated that miRNAs participate in the cross-talk with oxidative stress. We aimed to explore whether certain miRNAs are involved in the pathogenesis of CDK. We performed miRNA sequencing of tears from patients with CDK and healthy individuals from Tacheng region of Xinjiang and conducted bioinformatic analysis of key miRNAs. We also evaluated viability, migration, and apoptosis of human corneal epithelial cells (HCECs) subjected to UVR treatment. miR-1273h-5p expression was abnormally downregulated in the tears of patients with CDK. miR-1273h-5p promoted cell proliferation and migration and inhibited UVR-induced mitochondrial apoptosis. miR-1273h-5p protected HCECs against UVR-induced oxidative damage by reducing the accumulation of reactive oxygen species and inhibiting mitochondrial apoptosis via the activation of the Nrf2 pathway. Thus, our results suggest that miR-1273h-5p protects the corneal epithelium against UVR-induced oxidative stress damage.

Comprehensive metabolic profiling of diabetic retinopathy.

Diabetic retinopathy (DR) is an important complication of diabetes mellitus and a prevalent blind-causing ophthalmic disease. Despite years of efforts, rapid and accurate diagnosis of DR remains a challenging task. Metabolomics has been used as a diagnostic tool for disease progression and therapy monitoring. In this study, retinal tissues were collected from diabetic mice and age-matched non-diabetic mice. An unbiased metabolic profiling was performed to identify the altered metabolites and metabolic pathways in DR. 311 differential metabolites were identified between diabetic retinas and non-diabetic retinas under the criteria of variable importance in projection (VIP) > 1 and P < 0.05. These differential metabolites were highly enriched in purine metabolism, amino acid metabolism, glycerophospholipid metabolism, and pantaothenate and CoA biosynthesis. We then evaluated the sensitivity and specificity of purine metabolites as the candidate biomarkers for DR through the area under the receiver-operating characteristic curves (AUC-ROCs). Compared with other purine metabolites, adenosine, guanine, and inosine had higher sensitivity, specificity, and accuracy for DR prediction. In conclusion, this study sheds new light on the metabolic mechanism of DR, which can facilitate clinical diagnosis, therapy, and prognosis of DR in the future.

Cognitive Benefit of a Multidomain Intervention for Older Adults at Risk of Cognitive Decline: A Cluster-Randomized Controlled Trial.

OBJECTIVE: We sought to assess cognitive benefits of a community-based multidomain intervention for improving cognition among older adults at risk of cognitive decline (COMBAT). DESIGN: A two-armed cluster-randomized controlled trial. SETTING AND PARTICIPANTS: Community-dwelling older adults aged 60 years or older and were at risk of cognitive decline (n = 209). INTERVENTION: In this 9-month intervention study, 10 community hospitals in Beijing, China, were randomized (1:1) to receive either a multidomain intervention of meditation, cognitive training, exercise, and nutrition counseling or usual care. The intervention was delivered with weekly 1-hour group training sessions and weekly home homework. MEASUREMENTS: Primary outcome was change in cognition as measured by a composite Z score of seven cognitive tests. Secondary outcomes included subjective cognitive abilities, positive and negative affective experiences, physical activity, and dietary habits. Assessments were administered at baseline, end of the intervention, and 1 year after completing the intervention (1-year follow-up). RESULTS: Immediately after the intervention, the intervention group showed significant enhancement in cognitive performance (p = 0.026). The between-group difference in the Z score of change of cognition was 0.20 (95% CI: 0.053, 0.35), with a Hedges' g of 0.40 (95% CI: 0.29, 0.50). However, this cognitive benefit was not significant at 1-year follow-up. CONCLUSION: This multidomain intervention was effective to improve cognition for at-risk individuals. Long-term effects on cognitive function and individual differences in response to the intervention deserve further investigation.

The efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma patients.

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) plus plerixafor has been shown to improve the efficacy of peripheral blood stem cell (PBSC) mobilization, however, due to its high price, the use of plerixafor is limited in China. The purpose of this study was to assess the efficacy of residual plerixafor for second-day stem cell mobilization in multiple myeloma (MM) patients. MATERIALS AND METHODS: In this single-center retrospective study, 69 MM patients received G-CSF + plerixafor to mobilize PBSCs, which were collected from 28 patients only for one day and 41 patients for two days. Some of the patients received residual plerixafor, and PBSCs were collected on the second day. The data on the characteristics, different doses of plerixafor and efficacy of PBSC mobilization were collected and analyzed. RESULTS: After 1 or 2 apheresis procedures, 85.5% of patients collected more than 2 × 106 cells/kg PBSCs. There was no statistically significant difference in the success rate of CD34 + PBSC mobilization with the different doses of plerixafor on the first day, but the higher residual plerixafor dose resulted in better success rates on the second day (P＜0.001). Among the patients who collected PBSCs for two days, the level of the CD34 + cell yield of 24 patients (58.5%) changed better, which was significantly correlated with the dose of residual plerixafor on the second day (P = 0.001). DISCUSSION: These results suggested that the administration of residual plerixafor to mobilize stem cells on the second day is an economical, efficient and clinically feasible method.

Propensity-matched comparison of postoperative stability and visual outcomes of toric intraocular lens with or without a capsular tension ring and updated meta-analysis.

PURPOSE: To assess the contribution of capsular tension ring (CTR) to postoperative stability and visual outcomes of a plate-haptic toric intraocular lens (IOL). METHODS: This prospective cohort study was performed among patients underwent toric IOL (AT TORBI 709 M) implantation with or without CTR at the Eye and ENT hospital between April 2020 and November 2021. Propensity score matching (PSM) was performed to balance baseline factors. Postoperatively, uncorrected distance visual acuity (UCVA) and residual astigmatism, as well as IOLs' rotation, tilt, and decentration, were analyzed. Grouped multiple linear regression analysis was used to model predictive factors of rotation in each group. Additionally, a meta-analysis of data from 4 publications (284 eyes) and current study was performed to evaluate the effect of CTR co-implantation on toric IOL rotation. RESULTS: After PSM, 126 eyes from each group were included for further analysis. Postoperatively, UDVA was 0.31 ± 0.38 logMAR and 0.27 ± 0.36 logMAR in the CTR and NCTR groups, respectively (P = 0.441), and residual astigmatism was 0.75 ± 0.52 D and 0.86 ± 0.65 D, respectively (P = 0.139). The rotation of toric IOL was significantly smaller in the CTR group than in the NCTR group (4.63 ± 6.27 vs. 10.93 ± 16.05 degrees, P < 0.001). The regression models of the two groups and the coefficients of LT were significantly different (P < 0.001 and P = 0.001, respectively). Furthermore, the meta-analysis confirmed that CTR co-implantation reduced toric IOL rotation (MD, - 1.59; 95% CI, - 3.10 to - 0.09; P = 0.038). CONCLUSION: CTR enhances rotational stability of toric IOL by reducing the impact of LT, and CTR co-implantation is recommended in patients with lens thickness (LT) ≥ 4.5 mm, white-to-white (WTW) ≥ 11.6 mm, or high preexisting astigmatism.

Engineering Hierarchical Recognition-Mediated Senolytics for Reliable Regulation of Cellular Senescence and Anti-Atherosclerosis Therapy.

Precise regulation of vascular senescence represents a far-reaching strategy to combat age-related diseases. However, the high heterogeneity of senescence, alongside the lack of targeting and potent senolytics, makes it very challenging. Here we report a molecular design to tackle this challenge through multidimensional, hierarchical recognition of three hallmarks commonly shared among senescence, namely, aptamer-mediated recognition of a membrane marker for active cell targeting, a self-immolative linker responsive to lysosomal enzymes for switchable drug release, and a compound against antiapoptotic signaling for clearance. Such senolytic can target and trigger severe cell apoptosis in broad-spectrum senescent endothelial cells, and importantly, distinguish them from the quiescent state. Its potential for in vivo treatment of vascular diseases is successfully illustrated in a model of atherosclerosis, with effective suppression of the plaque progression yet negligible side effects.

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy.

BACKGROUND: For patients with melanoma, gastrointestinal immune-related adverse events are common after receipt of anti-CTLA4 therapy. These present difficult decision points regarding whether to discontinue therapy. Detailing the situations in which colitis might predict for improved survival and how this is affected by discontinuation or resumption of therapy can help guide clinical decision-making. MATERIALS AND METHODS: Patients with stage IV melanoma receiving anti-CTLA4 therapy from 2008 to 2019 were analyzed. Immune-related colitis treated with ≥50 mg prednisone or equivalent daily or secondary immunosuppression was included. Moderate colitis was defined as receipt of oral glucocorticoids only; severe colitis was defined as requiring intravenous glucocorticoids or secondary immunosuppression. The primary outcome was overall survival (OS). RESULTS: In total, 171 patients received monotherapy, and 91 received dual checkpoint therapy. In the monotherapy group, 25 patients developed colitis and a nonsignificant trend toward improved OS was observed in this group. Notably, when colitis was categorized as none, moderate or severe, OS was significantly improved for moderate colitis only. This survival difference was not present after dual checkpoint therapy. There were no differences in known prognostic variables between groups, and on multivariable analysis neither completion of all ipilimumab cycles nor resumption of immunotherapy correlated with OS, while the development of moderate colitis did significantly affect OS. CONCLUSION: This single-institution retrospective series suggests moderate colitis correlates with improved OS for patients with stage IV melanoma treated with single-agent anti-CTLA4, but not dual agent, and that this is true regardless of whether the immune-checkpoint blockade is permanently discontinued.

Ligustrazine Attenuates Liver Fibrosis by Targeting miR-145 Mediated Transforming Growth Factor-ß/Smad Signaling in an Animal Model of Biliary Atresia.

To investigate therapeutic target for ligustrazine during liver fibrosis in an ethanol-induced biliary atresia rat model and transforming growth factor-ß (TGF-ß) induced hepatic stellate cell activation cell model, and the underlying mechanism, a total of 30 rats were randomly assigned into five groups (n = 6 per group): control, sham, ethanol-induced biliary atresia model, model plus pirfenidone, and model plus ligustrazine groups. The liver changes were assessed using H&E and Masson staining and transmission electron microscopy. Expression of miR-145 and mRNA and protein levels of TGF-ß/smads pathway-related proteins were detected. HSC-T6 cells were infected with LV-miR or rLV-miR-145 in the presence or absence of SMAD3 inhibitor SIS3 and treated with 2.5 ng/ml TGF-ß1 and then with ligustrazine. Collected cells were subjected to detect the expression of miR-145 and mRNA and protein expression levels of TGF-ß/smads pathway-related proteins. Ligustrazine rescued liver fibrogenesis and pathology for ethanol-caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Further experiments showed that ligustrazine inhibited intrinsic and phosphorylated Smad2/3 protein expression and modification. Similar results were obtained in cells. In addition, ligustrazine altered miR-145 expression in both animal and cell models. Lentivirus mediated miR-145 overexpression and knockdown recombinant virus showed that miR-145 enhanced the TGF-ß/Smad pathway, which led to hepatic stellate cell activation, and ligustrazine blocked this activation. This work validated that ligustrazine-regulated miR-145 mediated TGF-ß/Smad signaling to inhibit the progression of liver fibrosis in a biliary atresia rat model and provided a new therapeutic strategy for liver fibrosis. SIGNIFICANCE STATEMENT: With an ethanol-induced biliary atresia rat model, ligustrazine was found to rescue liver fibrogenesis and pathology for ethanol caused bile duct injury, revealed by decreased α-smooth muscle actin and collagen I expression and liver tissue and cell morphology integrity. Furthermore, we found ligustrazine upregulated miR-145 expression and inhibited TGF-ß/SMAD signaling pathway both in vivo and in vitro. In addition, overexpression and knockdown of miR-145 confirmed that miR-145 is involved in the ligustrazine inhibition of liver fibrosis through the TGF-ß/SMAD signaling pathway.

Cedecea sulfonylureivorans sp. nov., a novel chlorimuron-ethyldegrading bacterium isolated from an herbicides-degrading consortium.

A Gram-stain-negative, motile, rod-shaped bacterium, designated strain LAM2020T, was isolated from a sulfonylurea herbicides-degrading bacterial consortium. The optimal temperature and pH for the growth of strain LAM2020T were 30 °C and 7.0, respectively. Strain LAM2020T formed a distinct phylogenetic subclade within the genus Cedecea in the phylogenetic trees built with 16S rRNA gene sequences and shared the highest similarity with Cedecea davisae DSM 4568T (98.4%). The values of digital DNA-DNA hybridization and average nucleotide identity (ANI) based on the genome sequences between LAM2020T and C. davisae DSM 4568T were 22.7% and 80.0%, respectively. It contained 54.0 mol% of G + C in the genomic DNA. The major cellular fatty acids of strain LAM2020T were summed feature 3 (C16:1 ω6c and/or C16:1 ω7c), C16:0 and summed feature 8 (C18:1 ω7c/C18:1 ω6c). The major polar lipids present in strain LAM2020T were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine and aminophospholipid. The respiratory quinone of strain LAM2020T was ubiquinone-8 and ubiquinone-7. Based on the phenotypic characteristics, chemotaxonomic data and genotypic analyses, strain LAM2020T should be classified as a novel species of genus Cedecea, for which the name Cedecea sulfonylureivorans sp. nov. is proposed. The type strain is LAM2020T (= GDMCC 1.2363T = JCM 34640T).

Microbacterium sulfonylureivorans sp. nov., isolated from sulfonylurea herbicides degrading consortium.

A novel Gram-stain positive, aerobic, motile, rod-shaped bacterium, designated strain LAM7116T was isolated from a sulfonylurea herbicides degrading consortium enriched with birch forest soil from Xinjiang. Phylogenetic analysis based on the 16S rRNA gene sequences indicated that strain LAM7116T was closely related to the members of the genus Microbacterium, with the highest similarity to Microbacterium flavescens DSM 20643T (98.48%) and Microbacterium kitamiense Kitami C2T (98.48%). Strain LAM7116T formed a distinct subclade with M. flavescens DSM 20643T within the genus Microbacterium in the 16S rRNA gene phylogenetic trees. The genomic DNA G + C content of LAM7116T was 69.9 mol%. The digital DNA-DNA hybridization (dDDH) value between strain LAM7116T and M. flavescens DSM 20643T was 27.20%. The average nucleotide identity (ANI) value was 83.96% by comparing the draft genome sequences of strain LAM7116T and M. flavescens DSM 20643T. The major fatty acids were anteiso-C15:0, anteiso-C17:0, iso-C17:0, and iso-C16:0. The respiratory menaquinones of strain LAM7116T were MK-13 and MK-14. The main polar lipids were diphosphatidylglycerol, phosphatidylglycerol, an unidentified lipid, and an unidentified glycolipid. The peptidoglycan contained the amino acids glycine, lysine, alanine, and glutamic acid. Based on the phenotypic characteristics and genotypic analyses, we consider that strain LAM7116T represents a novel species, for which the name Microbacterium sulfonylureivorans sp. nov. was proposed. The type strain is LAM7116T (= CGMCC 1.16620T = JCM 32823T). Strain LAM7116T secreted auxin IAA and grew well in Ashby nitrogen-free culture medium. Genomic results showed that strain LAM7116T carried the nitrogenase iron protein (nifU and nifR3) gene, which indicated that strain LAM7116T has the potential to fix nitrogen and promote plant growth. At same time, strain LAM7116T can degrade nicosulfuron (a kind of sulfonylurea herbicides) using glucose as carbon source. Microbacterium sulfonylureivorans sp. nov. LAM7116T is a potential candidate for the biofertilizers of organic agriculture areas, and may possess potential to be used in bioremediation of nicosulfuron-contaminated environments.

Synthesis of 2-trifluoromethyl thiazoles via [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates with CF3CN.

2,2,2-Trifluoroacetaldehyde O-(aryl)oxime was employed for the [3 + 2] cycloaddition of pyridinium 1,4-zwitterionic thiolates for the synthesis of 2-trifluoromethyl 4,5-disubstituted thiazoles. The reaction works well with various substituted pyridinium 1,4-zwitterionic thiolates in moderate to good yields. The synthetic potential of the obtained 2-trifluoromethyl 4,5-disubstituted thiazoles was demonstrated.