miRNA-21-5p is an important contributor to the promotion of injured peripheral nerve regeneration using hypoxia-pretreated bone marrow-derived neural crest cells.

JOURNAL/nrgr/04.03/01300535-202501000-00035/figure1/v/2024-05-14T021156Z/r/image-tiff Our previous study found that rat bone marrow-derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Efficient narrowband yellow organic light-emitting diodes based on iridium(III) complexes with the rigid indolo[3,2,1-jk]carbazole unit.

Phosphorescent material with narrowband emission is crucial for advancing wide-color-gamut organic light-emitting diodes (OLEDs). In this work, two iridium(III) complexes, (PhthzICz)2Ir(tmd) and (thzICz)2Ir(tmd), using rigid 2-(benzothiazole-2-yl)indolo[3,2,1-jk]carbazole (PhthzICz) and 2-(thiazole-2-yl)indolo[3,2,1-jk]carbazole (thzICz) as cyclometalated ligands and 2,2,6,6-tetramethyl-3,5-heptanedione (tmd) as ancillary ligands, were synthesized. When these complexes were doped into the host material 3,3'-di(9H-carbazol-9-yl)-1,1'-biphenyl, the doped films exhibited yellow photoluminescence (PL) peaking at 537 and 531 nm, full width at half maximum (FWHM) bands of 35 and 60 nm, and PL quantum yields of 89.9% and 85.9%, respectively. OLEDs based on these two emitters display moderate performance characteristics with maximum external quantum efficiencies of 25.2% and 22.7%. Notably, the device based on (PhthzICz)2Ir(tmd) exhibits a narrow FWHM of 31 nm. Overall, the study highlights the practicality of incorporating rigid groups into the cyclometalated ligands of Ir(III) complexes as a viable strategy for achieving efficient Ir(III) complexes for OLEDs with narrow emission and high efficiency.

Inflammatory bowel disease and osteoporosis: Common genetic effects, pleiotropy, and causality.

INTRODUCTION: Previous studies have shown that inflammatory bowel disease (IBD) is associated with osteoporosis (OP) and bone mineral density (BMD), but the underlying genetic mechanisms are unclear. Our study wanted to explore the genetic and causal relationship between IBD and OP. MATERIALS AND METHODS: Based on large-scale genome-wide association summary statistics and individual-level datasets (i.e., the UK Biobank), this study performed linkage disequilibrium score regression (LDSC), pleiotropic analysis under the composite null hypothesis (PLACO), and Mendelian randomization (MR) analyses to explore the genetic association, the pleiotropic genes and the causal relationship between IBD and BMD. RESULTS: LDSC revealed significant genetic correlations between IBD and BMD (e.g., forearm BMD (rg = -0.3479, P = 0.019) and femoral neck BMD (rg = -0.1335, P = 0.0307). PLACO identified 14 overlapping pleiotropic loci, 1 shared risk gene (CDYL), and multiple shared pathways, revealing possible mechanisms for IBD and OP. MR analysis demonstrated a causal association between IBD and BMD. CONCLUSIONS: Our study indicates that IBD may increase the risk of OP and reveals a complex genetic mechanism linking IBD and the risk of osteoporosis, which has important implications for diagnosing and treating IBD and OP.

AcornHRD: an HRD algorithm highly associated with anthracycline-based neoadjuvant chemotherapy in breast cancer in China.

PURPOSE: Our study aimed to develop and validate a homologous recombination deficiency (HRD) scoring algorithm in the Chinese breast cancer population. METHODS AND MATERIALS: Ninety-six in-house breast cancer (BC) samples and 6 HRD-positive standard cells were analyzed by whole-genome sequencing (WGS). Besides, 122 BCs from the TCGA database were down-sampled to ~ 1X WGS. We constructed an algorithm named AcornHRD for HRD score calculated based on WGS at low coverage as input data to estimate large-scale copy number alteration (LCNA) events on the genome. A clinical cohort of 50 BCs (15 cases carrying BRCA mutation) was used to assess the association between HRD status and anthracyclines-based neoadjuvant treatment outcomes. RESULTS: A 100-kb window was defined as the optimal size using 41 in-house cases and the TCGA dataset. HRD score high threshold was determined as HRD score ≥ 10 using 55 in-house BCs with BRCA mutation to achieve a 95% BRCA-positive agreement rate. Furthermore, the HRD status agreement rate of AcornHRD is 100%, while the ShallowHRD is 60% in standard cells. BRCA mutation was significantly associated with a high HRD score evaluated by AcornHRD and ShallowHRD (p = 0.008 and p = 0.003, respectively) in the TCGA dataset. However, AcornHRD showed a higher positive agreement rate than did the ShallowHRD algorithm (70% vs 60%). In addition, the BRCA-positive agreement rate of AcornHRD was superior to that of ShallowHRD (87% vs 13%) in the clinical cohort. Importantly, the high HRD score assessed by AcornHRD was significantly correlated with a residual cancer burden score of 0 or 1 (RCB0/1). Besides, the HRD-positive group was more likely to respond to anthracycline-based chemotherapy than the HRD-negative group (pCR [OR = 9.5, 95% CI 1.11-81.5, p = 0.040] and RCB0/1 [OR = 10.29, 95% CI 2.02-52.36, p = 0.005]). CONCLUSION: Using the AcornHRD algorithm evaluation, our analysis demonstrated the high performance of the LCNA genomic signature for HRD detection in breast cancers.

Krause corpuscles are genital vibrotactile sensors for sexual behaviours.

Krause corpuscles, which were discovered in the 1850s, are specialized sensory structures found within the genitalia and other mucocutaneous tissues1-4. The physiological properties and functions of Krause corpuscles have remained unclear since their discovery. Here we report the anatomical and physiological properties of Krause corpuscles of the mouse clitoris and penis and their roles in sexual behaviour. We observed a high density of Krause corpuscles in the clitoris compared with the penis. Using mouse genetic tools, we identified two distinct somatosensory neuron subtypes that innervate Krause corpuscles of both the clitoris and penis and project to a unique sensory terminal region of the spinal cord. In vivo electrophysiology and calcium imaging experiments showed that both Krause corpuscle afferent types are A-fibre rapid-adapting low-threshold mechanoreceptors, optimally tuned to dynamic, light-touch and mechanical vibrations (40-80 Hz) applied to the clitoris or penis. Functionally, selective optogenetic activation of Krause corpuscle afferent terminals evoked penile erection in male mice and vaginal contraction in female mice, while genetic ablation of Krause corpuscles impaired intromission and ejaculation of males and reduced sexual receptivity of females. Thus, Krause corpuscles of the clitoris and penis are highly sensitive mechanical vibration detectors that mediate sexually dimorphic mating behaviours.

Sialic Acids Blockade-Based Chemo-Immunotherapy Featuring Cancer Cell Chemosensitivity and Antitumor Immune Response Synergies.

Immune checkpoint blockade (ICB) has significantly improved the prognosis of patients with cancer, although the majority of such patients achieve low response rates; consequently, new therapeutic approaches are urgently needed. The upregulation of sialic acid-containing glycans is a common characteristic of cancer-related glycosylation, which drives disease progression and immune escape via numerous pathways. Herein, the development of self-assembled core-shell nanoscale coordination polymer nanoparticles loaded with a sialyltransferase inhibitor, referred to as NCP-STI which effectively stripped diverse sialoglycans from cancer cells, providing an antibody-independent pattern to disrupt the emerging Siglec-sialic acid glyco-immune checkpoint is reported. Furthermore, NCP-STI inhibits sialylation of the concentrated nucleoside transporter 1 (CNT1), promotes the intracellular accumulation of anticancer agent gemcitabine (Gem), and enhances Gem-induced immunogenic cell death (ICD). As a result, the combination of NCP-STI and Gem (NCP-STI/Gem) evokes a robust antitumor immune response and exhibits superior efficacy in restraining the growth of multiple murine tumors and pulmonary metastasis. Collectively, the findings demonstrate a novel form of small molecule-based chemo-immunotherapy approach which features sialic acids blockade that enables cooperative effects of cancer cell chemosensitivity and antitumor immune responses for cancer treatment.

Effect of Implementing an Informatization Case Management Model on the Management of Chronic Respiratory Diseases in a General Hospital: Retrospective Controlled Study.

Background: The use of chronic disease information systems in hospitals and communities plays a significant role in disease prevention, control, and monitoring. However, there are several limitations to these systems, including that the platforms are generally isolated, the patient health information and medical resources are not effectively integrated, and the "Internet Plus Healthcare" technology model is not implemented throughout the patient consultation process. Objective: The aim of this study was to evaluate the efficiency of the application of a hospital case management information system in a general hospital in the context of chronic respiratory diseases as a model case. Methods: A chronic disease management information system was developed for use in general hospitals based on internet technology, a chronic disease case management model, and an overall quality management model. Using this system, the case managers provided sophisticated inpatient, outpatient, and home medical services for patients with chronic respiratory diseases. Chronic respiratory disease case management quality indicators (number of managed cases, number of patients accepting routine follow-up services, follow-up visit rate, pulmonary function test rate, admission rate for acute exacerbations, chronic respiratory diseases knowledge awareness rate, and patient satisfaction) were evaluated before (2019-2020) and after (2021-2022) implementation of the chronic disease management information system. Results: Before implementation of the chronic disease management information system, 1808 cases were managed in the general hospital, and an average of 603 (SD 137) people were provided with routine follow-up services. After use of the information system, 5868 cases were managed and 2056 (SD 211) patients were routinely followed-up, representing a significant increase of 3.2 and 3.4 times the respective values before use (U=342.779; P<.001). With respect to the quality of case management, compared to the indicators measured before use, the achievement rate of follow-up examination increased by 50.2%, the achievement rate of the pulmonary function test increased by 26.2%, the awareness rate of chronic respiratory disease knowledge increased by 20.1%, the retention rate increased by 16.3%, and the patient satisfaction rate increased by 9.6% (all P<.001), while the admission rate of acute exacerbation decreased by 42.4% (P<.001) after use of the chronic disease management information system. Conclusions: Use of a chronic disease management information system improves the quality of chronic respiratory disease case management and reduces the admission rate of patients owing to acute exacerbations of their diseases.

Pairwise machine learning-based automatic diagnostic platform utilizing CT images and clinical information for predicting radiotherapy locoregional recurrence in elderly esophageal cancer patients.

OBJECTIVE: To investigate the feasibility and accuracy of predicting locoregional recurrence (LR) in elderly patients with esophageal squamous cell cancer (ESCC) who underwent radical radiotherapy using a pairwise machine learning algorithm. METHODS: The 130 datasets enrolled were randomly divided into a training set and a testing set in a 7:3 ratio. Clinical factors were included and radiomics features were extracted from pretreatment CT scans using pyradiomics-based software, and a pairwise naive Bayes (NB) model was developed. The performance of the model was evaluated using receiver operating characteristic (ROC) curves and decision curve analysis (DCA). To facilitate practical application, we attempted to construct an automated esophageal cancer diagnosis system based on trained models. RESULTS: To the follow-up date, 64 patients (49.23%) had experienced LR. Ten radiomics features and two clinical factors were selected for modeling. The model demonstrated good prediction performance, with area under the ROC curve of 0.903 (0.829-0.958) for the training cohort and 0.944 (0.849-1.000) for the testing cohort. The corresponding accuracies were 0.852 and 0.914, respectively. Calibration curves showed good agreement, and DCA curve confirmed the clinical validity of the model. The model accurately predicted LR in elderly patients, with a positive predictive value of 85.71% for the testing cohort. CONCLUSIONS: The pairwise NB model, based on pre-treatment enhanced chest CT-based radiomics and clinical factors, can accurately predict LR in elderly patients with ESCC. The esophageal cancer automated diagnostic system embedded with the pairwise NB model holds significant potential for application in clinical practice.

Calmodulin-like 5 promotes PEDV replication by regulating late-endosome synthesis and innate immune response.

The infection caused by porcine epidemic diarrhea virus (PEDV) is associated with high mortality in piglets worldwide. Host factors involved in the efficient replication of PEDV, however, remain largely unknown. Our recent proteomic study in the virus-host interaction network revealed a significant increase in the accumulation of CALML5 (EF-hand protein calmodulin-like 5) following PEDV infection. A further study unveiled a biphasic increase of CALML5 in 2 and 12 â€‹h after viral infection. Similar trends were observed in the intestines of piglets in the early and late stages of the PEDV challenge. Moreover, CALML5 depletion reduced PEDV mRNA and protein levels, leading to a one-order-of-magnitude decrease in virus titer. At the early stage of PEDV infection, CALML5 affected the endosomal trafficking pathway by regulating the expression of endosomal sorting complex related cellular proteins. CALML5 depletion also suppressed IFN-ß and IL-6 production in the PEDV-infected cells, thereby indicating its involvement in negatively regulating the innate immune response. Our study reveals the biological function of CALML5 in the virology field and offers new insights into the PEDV-host cell interaction.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.

Studies on the Biomimetic Synthesis of Marine Ladder Polyethers via Endo-Selective Epoxide-to-Epoxonium Ring-Opening Cascades.

Marine ladder polyethers have attracted the attention of chemists and biologists because of their potent biological activities. Synthetic chemists have attempted to construct their polyether frameworks by epoxide ring-opening cascades, as Nakanishi hypothesis describes. However, Baldwin's rules of ring closure state that exo-selective intramolecular cyclization of epoxy alcohols is preferred over endo-selective cyclization. Herein, we investigated epoxide ring-opening cascades of polyepoxy alcohols in [EMIM]BF4/PFTB (1-ethyl-3-methylimidazolium tetrafluoroborate /perfluoro-tert-butyl alcohol) and found that all-endo products were formed via epoxide-to-epoxonium ring-opening cyclizations (not restricted by Baldwin's rules, which only apply to intramolecular hydroxyl-to-epoxide cyclizations). We determined that the key factor enabling polyepoxy alcohols to undergo a high proportion of all-endo-selective cyclization was inhibition of exo-selective hydroxyl-to-epoxide cyclization starting from the terminal hydroxyl group of a polyepoxy alcohol. By introducing a slow-release protecting group to the terminal hydroxyl group, we could markedly increase the cyclization yields of polyether fragments with hydrogen atoms at the ring junctions. For the first time, we constructed consecutively fused six-membered-ring and fused seven-, eight-, and nine-membered-ring polyether fragments by epoxide-to-epoxonium ring-opening cyclizations through the addition of a suitable Lewis acid. We also suggest that the biosynthesis of marine ladder polyethers may proceed via epoxide-to-epoxonium ring-opening cyclization of polyepoxide.

Role of autophagy-related genes in liver cancer prognosis.

Autophagy, a highly conserved process of protein and organelle degradation, has emerged as a critical regulator in various diseases, including cancer progression. In the context of liver cancer, the predictive value of autophagy-related genes remains ambiguous. Leveraging chip datasets from the TCGA and GTEx databases, we identified 23 differentially expressed autophagy-related genes in liver cancer. Notably, five key autophagy genes, PRKAA2, BIRC5, MAPT, IGF1, and SPNS1, were highlighted as potential prognostic markers, with MAPT showing significant overexpression in clinical samples. In vitro cellular assays further demonstrated that MAPT promotes liver cancer cell proliferation, migration, and invasion by inhibiting autophagy and suppressing apoptosis. Subsequent in vivo studies further corroborated the pro-tumorigenic role of MAPT by suppressing autophagy. Collectively, our model based on the five key genes provides a promising tool for predicting liver cancer prognosis, with MAPT emerging as a pivotal factor in tumor progression through autophagy modulation.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome.

Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP-SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.

The influence of community park characteristics on satisfaction in Guangzhou: Moderating and mediating effects analysis.

Community parks in old urban areas have problems such as outdated facilities and low quality, which inhibit the development of healthy aging. However, limited research has examined the correlation between such park characteristics and park satisfaction among elderly individuals. Additionally, the mechanisms underlying this association remain unclear. In this investigation, a moderated mediation framework grounded in self-determination theory was formulated to probe the interplay between these variables, with a specific focus on the mediating influence of social self-efficacy among the elderly and the moderating effect of use intention. A questionnaire survey (N = 319) was conducted in Shamian Park, Guangzhou, employing structural equation modeling for data analysis. Findings indicate that, even after controlling for demographic factors, park characteristics not only exert a direct influence on satisfaction but also exhibit an indirect impact through the mediation of social self-efficacy, with both pathways being moderated by use intention. This study has implications for how to improve the design of community parks in old urban areas in developing countries to better meet the basic needs of the elderly and promote healthy aging.

PI3K/AKT/mTOR signaling pathway: an important driver and therapeutic target in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. It has higher aggressiveness and metastasis than other subtypes, with limited effective therapeutic strategies, leading to a poor prognosis. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway is prevalently over-activated in human cancers and contributes to breast cancer (BC) growth, survival, proliferation, and angiogenesis, which could be an interesting therapeutic target. This review summarizes the PI3K/AKT/mTOR signaling pathway activation mechanism in TNBC and discusses the relationship between its activation and various TNBC subtypes. We also report the latest clinical studies on kinase inhibitors related to this pathway for treating TNBC. Our review discusses the issues that need to be addressed in the clinical application of these inhibitors.

Lineage-specific gene duplication and expansion of DUF1216 gene family in Brassicaceae.

Proteins containing domain of unknown function (DUF) are prevalent in eukaryotic genome. The DUF1216 proteins possess a conserved DUF1216 domain resembling to the mediator protein of Arabidopsis RNA polymerase II transcriptional subunit-like protein. The DUF1216 family are specifically existed in Brassicaceae, however, no comprehensive evolutionary analysis of DUF1216 genes have been performed. We performed a first comprehensive genome-wide analysis of DUF1216 proteins in Brassicaceae. Totally 284 DUF1216 genes were identified in 27 Brassicaceae species and classified into four subfamilies on the basis of phylogenetic analysis. The analysis of gene structure and conserved motifs revealed that DUF1216 genes within the same subfamily exhibited similar intron/exon patterns and motif composition. The majority members of DUF1216 genes contain a signal peptide in the N-terminal, and the ninth position of the signal peptide in most DUF1216 is cysteine. Synteny analysis revealed that segmental duplication is a major mechanism for expanding of DUF1216 genes in Brassica oleracea, Brassica juncea, Brassica napus, Lepidium meyneii, and Brassica carinata, while in Arabidopsis thaliana and Capsella rubella, tandem duplication plays a major role in the expansion of the DUF1216 gene family. The analysis of Ka/Ks (non-synonymous substitution rate/synonymous substitution rate) ratios for DUF1216 paralogous indicated that most of gene pairs underwent purifying selection. DUF1216 genes displayed a specifically high expression in reproductive tissues in most Brassicaceae species, while its expression in Brassica juncea was specifically high in root. Our studies offered new insights into the phylogenetic relationships, gene structures and expressional patterns of DUF1216 members in Brassicaceae, which provides a foundation for future functional analysis.

Redox-neutral α-functionalization of pyrrolidines: facile access to α-aryl-substituted pyrrolidines.

α-Aryl-substituted pyrrolidine moiety is found in many natural alkaloids. Starting from pyrrolidine, we were able to synthesize α-aryl-substituted pyrrolidines in one step using quinone monoacetal as the oxidizing agent and DABCO as the base. We also discovered the reaction condition needed to efficiently remove the N-aryl moiety from the α-arylated product. When the above reaction was carried out without the addition of an aryl nucleophile, the reaction of pyrrolidine and quinone monoacetal in 2,2,2-trifluoroethanol afforded octahydro-dipyrroloquinoline in high yield, which has the same skeleton as that of natural product incargranine B.

Case report: Emerging BRCA mutation confers benefit from olaparib after chemotherapy intolerance in advanced triple-negative breast cancer.

Key Clinical Message: In a patient with metastatic breast cancer, an acquired BRCA mutation in the BRCA gene was detected, resulting in benefits from olaparib treatment. This underscores the importance of ongoing genetic phenotype testing after paclitaxel chemotherapy. Abstract: Triple-negative breast cancer (TNBC) is associated with a poor prognosis and elevated mortality risk. BRCA mutations are commonly regarded as prevalent mutations in TNBC patients, strongly associated with congenital familial heredity. Dynamic changes in mutation sites, however, are rarely reported. In this case report, we report a 59-year-old TNBC patient who developed pulmonary metastases post-chemoradiotherapy. No BRCA mutations were detected through NGS. After 7.6 months of nab-paclitaxel treatment, the patient experienced progression of lung metastases, and BRCA mutations were detected through NGS testing. Subsequent administration of olaparib resulted in a reduction in lung metastasis, demonstrating significant therapeutic efficacy. This case underscores the infrequent occurrence of treatment-induced BRCA mutations and emphasizes the significance of dynamic NGS genetic testing for real-time assessment of a patient's mutational status.

Characterizing the Efficacy and Safety of Chemotherapy Plus Everolimus in HER2-Negative Metastatic Breast Cancer Harboring Altered PI3K/AKT/mTOR.

BACKGROUND: The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) have proven to be disappointing. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, a tumor-promoting signaling cascade frequently mutated in breast cancer (BC), has been implicated in chemoresistance. In this study, our objective is to investigate the efficacy and safety of combining everolimus with chemotherapy in mBC patients exhibiting mutations in the PI3K/AKT/mTOR pathway. METHODS: We conducted a retrospective analysis to characterize the efficacy, safety, and their association with clinical and molecular characteristics of metastatic lesions in 14 patients with HER2- mBC. These patients harbored at least one altered member of the PI3K/AKT/mTOR signaling pathway and were treated with a combination of a chemotherapy agent and the mTOR inhibitor everolimus (CT+EVE). RESULTS: The majority of patients belonged to the triple-negative (TN) subtype (9/14, 64.3%), having already undergone 2 lines of chemotherapy (CT) in the metastatic setting (11, 78.6%). These patients carried altered phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and were administered a vinorelbine-containing regimen (10, 71.4%). The objective response rate (ORR) was 42.9%, with a disease control rate of 92.9%. The median progression-free survival (PFS) and overall survival (OS) were 5.9 (95% confidence interval (CI): 4.9-13.6) months and 14.3 (95% CI: 8.5-not reached (NR)) months, respectively. Patients with fewer prior treatment lines tended to exhibit longer PFS. OS, PFS, and ORR were comparable between hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) patients, but numerical improvements were noted in patients with a single PI3K pathway alteration compared to those with more than one alteration. Genomic alterations that surfaced upon progression on CT+EVE included cyclin dependent kinase 4 (CDK4) and epidermal growth factor receptor (EGFR) amplification, as well as neurofibromin 1 (NF1) mutation, suggesting potential mechanisms of acquired resistance. An analysis of adverse events indicated manageable toxicities. CONCLUSIONS: The findings of this study suggest both activity and safety for the combination of chemotherapy and the mTOR inhibitor everolimus (CT+EVE) in patients with HER2- mBC who have alterations in the PI3K pathway, particularly those who have received fewer prior chemotherapy. However, it is crucial to note that large-scale, randomized control studies are warranted to more comprehensively characterize the efficacy and safety of this combination therapy.

Invigorating human MSCs for transplantation therapy via Nrf2/DKK1 co-stimulation in an acute-on-chronic liver failure mouse model.

Background: Since boosting stem cell resilience in stressful environments is critical for the therapeutic efficacy of stem cell-based transplantations in liver disease, this study aimed to establish the efficacy of a transient plasmid-based preconditioning strategy for boosting the capability of mesenchymal stromal cells (MSCs) for anti-inflammation/antioxidant defenses and paracrine actions in recipient hepatocytes. Methods: Human adipose mesenchymal stem cells (hADMSCs) were subjected to transfer, either with or without the nuclear factor erythroid 2-related factor 2 (Nrf2)/Dickkopf1 (DKK1) genes, followed by exposure to TNF-α/H2O2. Mouse models were subjected to acute chronic liver failure (ACLF) and subsequently injected with either transfected or untransfected MSCs. These hADMSCs and ACLF mouse models were used to investigate the interaction between Nrf2/DKK1 and the hepatocyte receptor cytoskeleton-associated protein 4 (CKAP4). Results: Activation of Nrf2 and DKK1 enhanced the anti-stress capacity of MSCs in vitro. In a murine model of ACLF, transient co-overexpression of Nrf2 and DKK1 via plasmid transfection improved MSC resilience against inflammatory and oxidative assaults, boosted MSC transplantation efficacy, and promoted recipient liver regeneration due to a shift from the activation of the anti-regenerative IFN-γ/STAT1 pathway to the pro-regenerative IL-6/STAT3 pathway in the liver. Importantly, the therapeutic benefits of MSC transplantation were nullified when the receptor CKAP4, which interacts with DKK1, was specifically removed from recipient hepatocytes. However, the removal of the another receptor low-density lipoprotein receptor-related protein 6 (LRP6) had no impact on the effectiveness of MSC transplantation. Moreover, in long-term observations, no tumorigenicity was detected in mice following transplantation of transiently preconditioned MSCs. Conclusions: Co-stimulation with Nrf2/DKK1 safely improved the efficacy of human MSC-based therapies in murine models of ACLF through CKAP4-dependent paracrine mechanisms.