Rhodium-Catalyzed Asymmetric N2-C5 Allylation of Indazoles with Dienyl Allylic Alcohols.

The development of site-selective and regio- and enantioselective reactions of substrates with multiple active sites is an important topic and remains a substantial challenge in synthetic chemistry. Here, we describe a rhodium-catalyzed asymmetric N2-C5 allylation of indazoles with dienyl allylic alcohols under mild conditions. In the presence of a Rh/(P/olefin) catalyst and formic acid, chiral N2-C5 allylic indazoles were formed in good yields with excellent enantioselectivities (up to 97% ee). The mechanism proceeds through an elusive intermediate Int B, which represents a challenging task on asymmetric allylic substitution (AAS) of dienyl substrates.

Fifty-five cases of hepatic alveolar echinococcosis combined with lymph node metastasis: A retrospective study.

BACKGROUND: Lymph node metastasis is a specific type of metastasis in hepatic alveolar echinococcosis (AE). Currently, there is a scarcity of describing the clinical characteristics and lymph node metastasis rules of patients with hepatic AE combined with lymph node metastasis and its mechanism and management are still controversial. Radical hepatectomy combined with regional lymph node dissection is a better treatment. AIM: To analyse the clinical features of hepatic AE combined with lymph node metastasis to explore its treatment and efficacy. METHODS: A total of 623 patients with hepatic AE admitted to the First Affiliated Hospital of Xinjiang Medical University from 1 January 2012 to 1 January 2022 were retrospectively analysed. Fifty-five patients with combined lymph node metastasis were analysed for their clinical data, diagnosis and treatment methods, follow-up efficacy, and characteristics of lymph node metastasis. Finally, we comparatively analysed the lymph node metastasis rates at different sites. Categorical variables are expressed as frequencies and percentages, and the analysis of difference was performed using the χ 2 test. The Bonferroni method was used for pairwise comparisons when statistical differences existed between multiple categorical variables. RESULTS: A lymph node metastasis rate of 8.8% (55/623) was reported in patients with hepatic AE, with a female predilection (69.1%) and a statistically significant sex difference (χ 2 = 8.018, P = 0.005). Of the 55 patients with lymph node metastasis, 72.7% had a parasite lesion, neighbouring organ invasion, and metastasis stage of P3N1M0 and above, of which 67.3%, 78.2%, and 34.5% of hepatic AE lesions invaded the bile ducts, blood vessels, and distant metastases, respectively. Detection rates of lymph node metastasis of 16.4%, 21.7%, and 34.2% were reported for a preoperative abdominal ultrasound, magnetic resonance imaging, and computed tomography examinations. All patients were intraoperatively suspected with enlarged lymph nodes and underwent radical hepatectomy combined with regional lymph node dissection. After surgery, a routine pathological examination was conducted on the resected lymph nodes. A total of 106 positive lymph nodes were detected in six groups at various sites, including 51 single-group metastasis cases and four multi-group metastasis cases. When the metastasis rates at different sites were statistically analysed, we observed that the metastasis rate in the para-hepatoduodenal ligament lymph nodes was significantly higher than that of the other sites (χ 2 = 128.089, P = 0.000 < 0.05). No statistical difference was observed in the metastasis rate between the five other groups. Clavien-Dindo grade IIIa complication occurred in 14 cases, which improved after administering symptomatic treatment. Additionally, lymph node dissection-related complications were not observed. Recurrence after 2 years was observed in one patient. CONCLUSION: Lymph node metastasis is a rare form of metastasis in hepatic AE, which is more frequent in women. Para-hepatoduodenal ligament lymph nodes are commonly observed. Radical hepatectomy combined with regional lymph node dissection is a safe, effective, and feasible treatment for liver AE combined with lymph node metastasis.

Apoptosis and NETotic cell death affect diabetic nephropathy independently: An study integrative study encompassing bioinformatics, machine learning, and experimental validation.

OBJECTIVE: Although programmed cell death (PCD) and diabetic nephropathy (DN) are intrinsically conneted, the interplay among various PCD forms remains elusive. In this study, We aimed at identifying independently DN-associated PCD pathways and biomarkers relevant to the related pathogenesis. METHODS: We acquired DN-related datasets from the GEO database and identified PCDs independently correlated with DN (DN-PCDs) through single-sample Gene Set Enrichment Analysis (ssGSEA) as well as, univariate and multivariate logistic regression analyses. Subsequently, applying differential expression analysis, weighted gene co-expression network analysis (WGCNA), and Mfuzz cluster analysis, we filtered the DN-PCDs pertinent to DN onset and progression. The convergence of various machine learning techniques ultimately spotlighted hub genes, substantiated through dataset meta-analyses and experimental validations, thereby confirming hub genes and related pathways expression consistencies. RESULTS: We harmonized four DN-related datasets (GSE1009, GSE142025, GSE30528, and GSE30529) post-batch-effect removal for subsequent analyses. Our differential expression analysis yielded 709 differentially expressed genes (DEGs), comprising 446 upregulated and 263 downregulated DEGs. Based on our ssGSEA as well as univariate and multivariate logistic regressions, apoptosis and NETotic cell death were appraised as independent risk factors for DN (Odds Ratio > 1, p < 0.05). Next, we further refined 588 apoptosis- and NETotic cell death-associated genes through WGCNA and Mfuzz analysis, resulting in the identification of 17 DN-PCDs. Integrating protein-protein interaction (PPI) network analyses, network topology, and machine learning, we pinpointed hub genes (e.g., IL33, RPL11, and CX3CR1) as significant DN risk factors with expression corroborating in subsequent meta-analyses and experimental validations. Our GSEA enrichment analysis discerned differential enrichments between DN and control samples within pathways such as IL2/STAT5, IL6/JAK/STAT3, TNF-α via NF-κB, apoptosis, and oxidative phosphorylation, with related proteins such as IL2, IL6, and TNFα, which we subsequently submitted to experimental verification. CONCLUSION: Innovatively stemming from from PCD interactions, in this study, we discerned PCDs with an independent impact on DN: apoptosis and NETotic cell death. We further screened DN evolution- and progression-related biomarkers, i.e. IL33, RPL11, and CX3CR1, all of which we empirically validated. This study not only poroposes a PCD-centric perspective for DN studies but also provides evidence for PCD-mediated immune cell infiltration exploration in DN regulation. Our results could motivate further exploration of DN pathogenesis, such as how the inflammatory microenvironment mediates NETotic cell death in DN regulation, representing a promising direction for future research.

Sideroflexin-1 promotes progression and sensitivity to lapatinib in triple-negative breast cancer by inhibiting TOLLIP-mediated autophagic degradation of CIP2A.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and it lacks specific therapeutic targets and effective treatment protocols. By analyzing a proteomic TNBC dataset, we found significant upregulation of sideroflexin 1 (SFXN1) in tumor tissues. However, the precise function of SFXN1 in TNBC remains unclear. Immunoblotting was performed to determine SFXN1 expression levels. Label-free quantitative proteomics and liquid chromatography-tandem mass spectrometry were used to identify the downstream targets of SFXN1. Mechanistic studies of SFXN1 and cellular inhibitor of PP2A (CIP2A) were performed using immunoblotting, immunofluorescence staining, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Functional experiments were used to investigate the role of SFXN1 in TNBC cells. SFXN1 was significantly overexpressed in TNBC tumor tissues and was associated with unfavorable outcomes in patients with TNBC. Functional experiments demonstrated that SFXN1 promoted TNBC growth and metastasis in vitro and in vivo. Mechanistic studies revealed that SFXN1 promoted TNBC progression by inhibiting the autophagy receptor TOLLIP (toll interacting protein)-mediated autophagic degradation of CIP2A. The pro-tumorigenic effect of SFXN1 overexpression was partially prevented by lapatinib-mediated inhibition of the CIP2A/PP2A/p-AKT pathway. These findings may provide a new targeted therapy for patients with TNBC.

Long-term exposure to PM2.5 chemical constituents and diabesity: evidence from a multi-center cohort study in China.

Background: Long-term exposure to PM2.5 is known to increase the risks for diabetes and obesity, but its effects on their coexistence, termed diabesity, remain uncertain. This study aimed to investigate the associations of long-term exposure to PM2.5 and its chemical constituents with the risks for diabesity, diabetes, and obesity. Methods: This cross-sectional study used the baseline data of a multi-center cohort, consisting of three provincially representative cohorts comprising a total of 134,403 participants from the eastern (Fujian Province), central (Hubei Province), and western (Yunnan Province) regions of China. Obesity and diabetes, and diabesity were identified by a body mass index (BMI) ≥28 kg/m2 and fasting plasma glucose (FPG) ≥126 mg/dL. The average concentrations of PM2.5 and five chemical constituents (NO3 -, SO4 2-, NH4 +, organic matter, and black carbon) over participants' residence during the past three years were estimated using machine learning models. Logistic regression models with double robust estimators, Bayesian kernel machine regression, and weighted quantile sum regression were employed to estimate independent and joint effects of PM2.5 chemical constituents on the risks for diabesity, diabetes, and obesity, as well as the differences from the effects on obesity. Stratified analyses were performed to examine effect modification of sociodemographic and lifestyle factors. Findings: There were 129,244 participants with a mean age of 54.1 ± 13.8 years included in the study. Each interquartile range increase in PM2.5 concentration (8.53 µg/m3) was associated with an increased risk for diabesity (OR = 1.23 [1.17, 1.30]), diabetes only (OR = 1.16 [1.13, 1.19]), and obesity only (OR = 1.03 [1.00, 1.05]). Long-term exposure to each PM2.5 chemical constituent was associated with an increased risk for diabesity, where organic matter exposure, with maximum weight (48%), was associated with a higher risk for diabesity (OR = 1.21 [1.16, 1.27]). Among those with obesity, black carbon contributed most (68%) to the joint effect of PM2.5 chemical constituents on diabesity (OR = 1.16 [1.11, 1.22]). Physical activity reduced adverse effects of PM2.5 on diabesity. Also, additive rather than multiplicative effects of obesity on the PM2.5-diabetes association were observed. Interpretation: Long-term exposure to PM2.5 and its chemical constituents was associated with an increased risk for diabesity, stronger than associations for diabetes and obesity alone. The main constituents associated with diabesity and obesity were black carbon and organic matter. Funding: National Natural Science Foundation of China (42271433, 723B2017), National Key R&D Program of China (2023YFC3604702), Fundamental Research Funds for the Central Universities (2042023kfyq04, 2042024kf1024), the Science and Technology Major Project of Tibetan Autonomous Region of China (XZ202201ZD0001G), Science and technology project of Tibet Autonomous Region（XZ202303ZY0007G), Key R&D Project of Sichuan Province (2023YFS0251), Renmin Hospital of Wuhan University (JCRCYG-2022-003), Jiangxi Provincial 03 Special Foundation and 5G Program (20224ABC03A05), Wuhan University Specific Fund for Major School-level Internationalization Initiatives (WHU-GJZDZX-PT07).

Decarboxylative Cyclization of Ethynyl Benzoxazinanones with Imidazolidines to Access 2,3-Indole-Fused 1,4-Diazocines.

2,3-Indole-fused 1,4-diazocines represent a new family of indole alkaloid compounds and are difficult to access by the reported protocols. Herein, we report a copper-catalyzed decarboxylative cyclization of cyclic propargylic carbamates with imidazolidines via sequential C-N/C-N/C-C bond formation to deliver a series of 2,3-indole-fused 1,4-diazocines, with a broad substrate scope and mild conditions.

Changes in blood lipid levels and influencing factors among treatment-naïve adult male HIV/AIDS patients following BIC/FTC/TAF vs . 3TC+EFV+TDF.

BACKGROUND: Antiretroviral therapy (ART) was often associated with dyslipidemia among human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. This study aimed to assess treatment-naïve adult male patients with HIV/AIDS who initiated ART with either co-formulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF) or lamivudine, efavirenz, and tenofovir disoproxil fumarate (3TC+EFV+TDF), monitoring at weeks 4, 12, 24, and 48. METHODS: A case-control retrospective study was conducted. The newly diagnosed HIV-infected individuals attending the sexual transmission disease (STD)/AIDS clinic of Beijing Youan Hospital, Capital Medical University, from January to December 2021. The patients were divided into BIC/FTC/TAF group or 3TC+EFV+TDF group. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and total cholesterol (TC) at different time points over 48 weeks between two groups were compared. A multivariate Cox regression model was used to identify relevant influencing factors for the population at high risk of increased LDL-C. RESULTS: A total of 870 participants, with 510 in BIC/FTC/TAF group and 360 in 3TC+EFV+TDF group. There were no statistically significant differences in median age, baseline CD4/CD8 ratio, median body mass index (BMI) between the two groups. In both two groups, levels of TG, TC, and LDL-C were higher at 4 weeks, 12 weeks, and 24 weeks of treatment (all P <0.05), and there were no statistically significant differences at 48 weeks compared to those at baseline (all P >0.05). In addition, the differences in average changes of the level of TG, TC, HDL-C, and LDL-C from weeks 4, 12, 24, and 48 to baseline between two groups were not statistically significant (all P >0.05). Multivariate Cox proportional risk model analysis showed that initiating ART with HIV RNA ≥10 5 copies/mL (compared with <10 5 copies/mL) was associated with an increased risk of elevated LDL-C (hazard ratio = 1.26, 95% confidence interval: 1.07-1.48, P  = 0.005). CONCLUSIONS: Transient elevations in blood lipid levels (TC, TG, HDL-C, and LDL-C) were observed in treatment-naïve adult male HIV/AIDS patients with BIC/FTC/TAF at 4 weeks, 12 weeks, and 24 weeks of treatment. However, these levels did not differ significantly from baseline after 48 weeks of treatment, regardless of whether patients were in the BIC/FTC/TAF or 3TC+EFV+TDF group.

Corrigendum: Assessing causal associations between neurodegenerative diseases and neurological tumors with biological aging: a bidirectional Mendelian randomization study.

[This corrects the article DOI: 10.3389/fnins.2023.1321246.].

Adverse tumor events induced by ranitidine: an analysis based on the FAERS database.

BACKGROUND: Ranitidine induced tumor adverse events remains a contradictory clinical question, due to the limited evidence of tumor risk associated with ranitidine in the real world. The purpose of this study was to evaluate the association of ranitidine with all types of tumors through the FAERS database and to provide a reference for clinical use. RESEARCH DESIGN AND METHODS: Cancer cases associated with ranitidine in the FAERS database from the first quarter of 2004 to the fourth quarter of 2023 were extracted to analyze demographic characteristics, and a disproportion analysis was performed. RESULT: A total of 662,998 ranitidine-related cancer cases were screened, and the 50-59 and 60-69 groups accounted for the largest proportion. In PT signal detection, ranitidine was associated with 98 PT, including penal cancer stage II, gastric cancer stage II, et al. In terms of outcome events, adverse events were higher in men (20.65%) than in women (18.47%). CONCLUSIONS: Ranitidine may induce various tumor-related adverse reactions, especially in long-term users and elderly patients. For these patients, tumor screening should be strengthened, and long-term use of ranitidine should be avoided. Since this study cannot prove causality, further evidence is needed for prospective studies with a larger sample size.

Genetically Proxied Autoimmune Diseases and the Risk of Facial Aging.

Purpose: Previous studies have suggested a relationship between autoimmune diseases and the risk of facial skin aging. However, evidence from population-based studies on this topic is limited, leaving the causal association between these factors unknown. This study aimed to systematically evaluate the causal effects of 18 autoimmune diseases on the risk of facial skin aging, aim of providing strategies to mitigate early facial aging in patients with autoimmune diseases. Patients and Methods: We conducted univariate Mendelian randomization (UVMR) analyses to examine the causal relationship between 18 autoimmune diseases and facial aging using publicly available summary data from genome-wide association studies (GWASs). We also conducted multivariate Mendelian randomization (MVMR) analyses to adjust for confounding factors, including smoking, alcohol consumption, and body mass index (BMI). Results: The main inverse variance weighted (IVW) method revealed that genetically proxied ankylosing spondylitis (AS) (OR 1.017; 95% CI: 1.003-1.031; P=0.018), sicca syndrome (SS) (OR 1.008; 95% CI: 1.005-1.011; P= 2.66×10-6), systemic lupus erythematosus (SLE) (OR 1.006; 95% 1.001-1.011; P=0.014), multiple sclerosis (MS) (OR 1.004; 95% CI: 1.001-1.007; P=0.021), primary sclerosing cholangitis (PSC) (OR 1.002; 95% CI: 1.000-1.004; P=0.023), and celiac disease (CeD) (OR 1.002; 95% CI: 1.001-1.004; P=0.009) were significantly associated with higher risk of facial aging. After adjusting for potential confounding factors, the association persisted between AS, SLE, and CeD. Conclusion: These findings indicated that autoimmune diseases play a causal role in facial skin aging. Therefore, patients with autoimmune diseases should take appropriate measures to prevent early facial aging.

Applying LASSO logistic regression for the prediction of biliary complications after ex vivo liver resection and autotransplantation in patients with end-stage hepatic alveolar echinococcosis.

BACKGROUND: The purpose of this study was to explore the relevant risk factors associated with biliary complications (BCs) in patients with end-stage hepatic alveolar echinococcosis (HAE) following ex vivo liver resection and autotransplantation (ELRA) and to establish and visualize a nomogram model. METHODS: This study retrospectively analysed patients with end-stage HAE who received ELRA treatment at the First Affiliated Hospital of Xinjiang Medical University between August 1, 2010 and May 10, 2023. The least absolute shrinkage and selection operator (LASSO) regression model was applied to optimize the feature variables for predicting the incidence of BCs following ELRA. Multivariate logistic regression analysis was used to develop a prognostic model by incorporating the selected feature variables from the LASSO regression model. The predictive ability, discrimination, consistency with the actual risk, and clinical utility of the candidate prediction model were evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA). Internal validation was performed by the bootstrapping method. RESULTS: The candidate prediction nomogram included predictors such as age, hepatic bile duct dilation, portal hypertension, and regular resection based on hepatic segments. The model demonstrated good discrimination ability and a satisfactory calibration curve, with an area under the ROC curve (AUC) of 0.818 (95% CI 0.7417-0.8958). According to DCA, this prediction model can predict the risk of BCs occurrence within a probability threshold range of 9% to 85% to achieve clinical net benefit. CONCLUSIONS: A prognostic nomogram with good discriminative ability and high accuracy was developed and validated to predict BCs after ELRA in patients with end-stage HAE.

Clinical Experience With Acute Phase Repair of Facial Nerve Dissections.

The purpose of this study was to evaluate the facial nerve recovery of patients with traumatic facial nerve transections after tension-free end-to-end nerve epineural anastomosis during the acute phase. A total of 11 patients with traumatic facial nerve transections during the acute phase were surgically treated in the authors' department from November 2016 to August 2022. The case data and imaging data were collected from the patients, and the House-Brackman evaluation system of the facial nerve was applied to assess the recovery of facial nerve function, and the higher the grade, the worse the facial nerve function. Of the patients, 90.9% recovered to H-B grade II or below, and there were differences in the degree of recovery of the facial nerve function among the branches, and the ones that recovered to H-B grade II or below after surgery were 100% of the zygomatic branch, of which 80% were H-B grade I, 100% of the buccal branch, of which 44.4% were H-B grade I, 88.9% of the marginal mandibular branch, and 66.7% of the temporal branch. The study showed that the recovery rate of young patients was better than that of middle-aged and old people, and the best recovery of each branch of the facial nerve was the zygomatic branch, followed by the buccal branch, the marginal mandibular branch, and the worse was the temporal branch.

Pyrococcus furiosus argonaute combined with loop-mediated isothermal amplification for rapid, ultrasensitive, and visual detection of fowl adenovirus serotype 4.

Since 2015, an outbreak of an infectious disease in broilers caused by fowl adenovirus serotype 4 (FAdV-4) has occurred in China, resulting in substantial economic losses. Rapid, accurate, and specific detection are significant in the prevention and control of FAdV-4. In this study, an FAdV-4 detection method combining loop-mediated isothermal amplification (LAMP) and Pyrococcus furiosus Argonaute (PfAgo) was established. Specific primers, guide DNAs (gDNAs), and molecular beacons were designed to target a conserved region of the FAdV-4 hexon gene. After optimizing the reaction conditions, the minimum detection of this assay could reach 5 copies. It only amplified FAdV-4, and there was no cross-reactivity with other pathogens. The assay took about only 50 min, and the results could be visualized with the naked eye under ultraviolet or blue light, getting rid of specialized instruments. This novel LAMP-PfAgo assay was validated by using 20 clinical samples and the results were identical to gold-standard real-time polymerase chain reaction method. In summary, the LAMP-PfAgo assay established in the paper provides a rapid, reliable, convenient, ultra-sensitive and highly specific tool for the on-site detection and clinical diagnosis of FAdV-4.

Psychometric properties of stigma and discrimination measurement tools for persons living with HIV: a systematic review using the COSMIN methodology.

BACKGROUND: The development of antiretroviral therapy broadly extends the life expectancy of persons living with HIV (PLHIV). However, stigma and discrimination are still great threat to these individuals and the world's public health care system. Accurate and reproducible measures are prerequisites for robust results. Therefore, it is essential to choose an acceptable measure with satisfactory psychometric properties to assess stigma and discrimination. There has been no systematic review of different stigma and discrimination tools in the field of HIV care. Researchers and clinical practitioners do not have a solid reference for selecting stigma and discrimination measurement tools. METHODS: We systematically searched English and Chinese databases, including PubMed, EMBASE, CINAHL, Web of Science, PsycINFO, ProQuest Dissertations and Theses, The Cochrane Library, CNKI,, and Wanfang, to obtain literature about stigma and discrimination measurement tools that have been developed and applied in the field of HIV. The search period was from 1st January, 1996 to 22nd November 2021. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guideline (2018 version) was applied to assess the risk of bias for each involved study and summarize the psychometric properties of each tool. The modified version of the Grading of Recommendations Assessment, Development, and, Evaluation (GRADE) method was used to grade the evidence and develop recommendations. RESULTS: We included 45 studies and 19 PROMs for HIV/AIDS-related stigma and discrimination among PLHIV. All studies had sufficient methodological quality in content validity, structural validity, internal consistency, and the hypothesis testing of structural validity. Limited evidence was found for cross-cultural validity, stability, and criterion validity. No relevant evidence was found concerning measurement error and responsiveness. The Internalized AIDS-related Stigma Scale (IARSS), Internalized HIV Stigma Scale (IHSS), and Wright's HIV stigma scale (WHSS) are recommended for use. CONCLUSIONS: This study recommends three PROMs for different stigma and discrimination scenarios, including IARSS for its good quality and convenience, IHSS for its broader range of items, higher sensitivity, and greater precision, and WHSS for its comprehensive and quick screening. Researchers should also consider the relevance and feasibility of the measurements before putting them into practice. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022308579.

Enhanced Fenton-like process over Z-scheme MoO3 surface decorated with Fe2O3 under visible light.

Photocatalysts consisting of Z-scheme heterojunctions are commonly used in wastewater treatment due to their exceptional reactivity in photocatalysis and highly efficient visible-light utilization. In this work, Fe2O3-decorated MoO3 rods were synthesized through a two-step method and their photodegradation of methylene blue (MB) was evaluated. The Fe2O3/MoO3 rods were characterized by XRD, SEM, micro-Raman, XPS, UV-Vis DRS, and PL to investigate their structural, morphological, and optical properties. The results indicate that the photodegradation efficiency of Fe2O3/MoO3 improved through a reduction in the gap energy and persistence of a 1D hexagonal prism structure. The degradation rate of MB was enhanced from 31.7 to 91.5% after irradiation for 180 min owing to electron-hole separation and Fenton-like process. Formation of the OH radical is a key factor in the photodegradation reaction and with the addition of H2O2 the efficiency can further improve via a Fenton-like mechanism. Furthermore, the Z-scheme mechanism concurrently delineated. The Fe2O3/MoO3 rod composites were also found to retain high photocatalytic efficiency after being reused five times, which may be useful for future applications.

Chronic myeloid leukaemia: Biology and therapy.

Chronic myeloid leukaemia (CML) is caused by BCR::ABL1. Tyrosine kinase-inhibitors (TKIs) are the initial therapy. Several organizations have reported milestones to evaluate response to initial TKI-therapy and suggest when a change of TKI should be considered. Achieving treatment-free remission (TFR) is increasingly recognized as the optimal therapy goal. Which TKI is the best initial therapy for which persons and what depth and duration of molecular remission is needed to achieve TFR are controversial. In this review we discuss these issues and suggest future research directions.

SF3A2 promotes progression and cisplatin resistance in triple-negative breast cancer via alternative splicing of MKRN1.

Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer owing to the lack of effective therapeutic targets. Splicing factor 3a subunit 2 (SF3A2), a poorly defined splicing factor, was notably elevated in TNBC tissues and promoted TNBC progression, as confirmed by cell proliferation, colony formation, transwell migration, and invasion assays. Mechanistic investigations revealed that E3 ubiquitin-protein ligase UBR5 promoted the ubiquitination-dependent degradation of SF3A2, which in turn regulated UBR5, thus forming a feedback loop to balance these two oncoproteins. Moreover, SF3A2 accelerated TNBC progression by, at least in part, specifically regulating the alternative splicing of makorin ring finger protein 1 (MKRN1) and promoting the expression of the dominant and oncogenic isoform, MKRN1-T1. Furthermore, SF3A2 participated in the regulation of both extrinsic and intrinsic apoptosis, leading to cisplatin resistance in TNBC cells. Collectively, these findings reveal a previously unknown role of SF3A2 in TNBC progression and cisplatin resistance, highlighting SF3A2 as a potential therapeutic target for patients with TNBC.

"Severe blepharoptosis correction with the fixation of levator complex and conjoint fascial sheath: 12 Years of Experience in a Single Center."

BACKGROUND: The correction of severe blepharoptosis is one of the most challenging surgeries in plastic surgery. This study introduces a novel self-reinforced fixation technique combining the levator complex with conjoint fascial sheath for the correction of severe blepharoptosis and reviews the postoperative results over the preceding 12 years. METHODS: This retrospective review included all patients who underwent self-reinforced fixation with or without conjoint fascial sheath at the authors' center between 2010 and 2022. The clinical data of the two groups were collected and evaluated. RESULTS: All patients were followed up for 6 months to 8 years postoperatively. The mean postoperative MRD1 and LF increased significantly in both groups. Sufficient correction of ptosis was achieved in 32 (65.31%) and 84 (81.56%) eyelids in Groups I and II, respectively. The mean eyelid lagophthalmos was 1.27± 0.91 mm and 0.85 ± 0.89 mm in Groups I and II, respectively. The most common complication was undercorrection of ptosis, which was observed in 14 eyelids (28.57%) and 15 eyelids (14.56%) in Groups I and II, respectively. CONCLUSIONS: The self-reinforced fixation technique was effective in correcting severe congenital ptosis in Chinese patients. The clinical effect was consistent in the long-term follow-up cases, and the recurrence rate was low. Thus, this technique can enhance the strength of the levator muscle and maintain appropriate elasticity of eye closure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Iridium-Catalyzed Regio- and Enantioselective N-Allylation of Pyrazoles with Dienyl/Monoallylic Alcohols.

Here we report the first example of iridium-catalyzed asymmetric N-allylation of pyrazoles with dienyl allylic alcohols under mild conditions with broad functional group tolerance, exhibiting excellent N1/C3-site selectivities and enantioselectivities (up to >99% ee). In addition to pyrazoles, other nucleophiles including benzotriazole, triazole, and pyrazole precursors (aryl vinyldiazos) are also suitable in this method. Notably, with the use of Sc(OTf)3 as additive and reactions performed at 30 °C for 24 h, the N1-C5 or N1-C1 selective alkylated pyrazoles are also obtained.