A protocol for a multidisciplinary early intervention during chemotherapy to improve dietary management behavior in breast cancer patients: a two-arm, single-center randomized controlled trial.

BACKGROUND: Adverse reactions are prone to occur in the early stage of chemotherapy and can negatively affect the dietary intake and nutritional status of breast cancer (BC) patients. Consequently, they need to participate in health self-management and lifestyle promotion programs. Early multidisciplinary interventions aim to enhance dietary management behavior and quality of life in chemotherapy-treated BC patients. METHODS: This single-blinded, single-center, randomized controlled trial will include 88 females who have not yet started the early or middle stage of the chemotherapy cycle. A random number table will be used randomly assign females to the intervention group or usual group at a 1:1 ratio. The intervention elements are based on the theoretical guidance of the Integrated Theory of Health Behavior Change (ITHBC). A multidisciplinary team (MDT) comprising oncologists, dietitians, nurses, traditional Chinese medicine (TCM) practitioners, and psychologists will provide the intervention. Intervention sessions will be conducted once a week for 8 weeks, beginning in the early or middle stage of the chemotherapy cycle and continuing through admission and a home-based interval chemotherapy period. The intervention includes face-to-face discussions, online meetings, WeChat messaging, and telephone calls. The themes target adverse reactions, dietary information and habits, self-care self-efficacy, treatment self-regulation, dietary supplement and TCM use, social support, weight management, and outcome expectations. The primary outcome is dietary management behavior measured by the Dietary Management Behavior Questionnaire (DMBQ). Secondary outcomes are self-care self-efficacy assessed by the Strategies Used by People to Promote Health (SUPPH); quality of life measured by the Functional Assessment of Cancer Therapy-Breast (FACT-B); and body mass index (BMI) measured by an electronic meter. All participants will be assessed at baseline and immediately, 1 month, 3 months, 6 months, and 12 months after the intervention. DISCUSSION: Early dietary intervention is needed, as diet is one of the most common health self-management behaviors influenced by chemotherapy. Early multidisciplinary interventions may provide a foundation for dietary self-management and improve nutritional status in the survival period. TRIAL REGISTRATION: This intervention protocol was registered with the Chinese Clinical Trials Registry (ChiCTR2300076503, October 10, 2023).

FPR1: A critical gatekeeper of the heart and brain.

G protein-coupled receptors (GPCRs) are currently the most widely focused drug targets in the clinic, exerting their biological functions by binding to chemicals and activating a series of intracellular signaling pathways. Formyl-peptide receptor 1 (FPR1) has a typical seven-transmembrane structure of GPCRs and can be stimulated by a large number of endogenous or exogenous ligands with different chemical properties, the first of which was identified as formyl-methionine-leucyl-phenylalanine (fMLF). Through receptor-ligand interactions, FPR1 is involved in inflammatory response, immune cell recruitment, and cellular signaling regulation in key cell types, including neutrophils, neural stem cells (NSCs), and microglia. This review outlines the critical roles of FPR1 in a variety of heart and brain diseases, including myocardial infarction (MI), ischemia/reperfusion (I/R) injury, neurodegenerative diseases, and neurological tumors, with particular emphasis on the milestones of FPR1 agonists and antagonists. Therefore, an in-depth study of FPR1 contributes to the research of innovative biomarkers, therapeutic targets for heart and brain diseases, and clinical applications.

Genotype-phenotype correlations of AR-CMT2S in a cohort of axonal Charcot-Marie-Tooth patients from Central South China.

BACKGROUND AND AIMS: This study aimed to report nine Charcot-Marie-Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR-CMT2S patients reported worldwide. METHODS: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR-CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. RESULTS: In our CMT2 cohort, we detected 17 AR-CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early-onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR-CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty-nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile-onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. INTERPRETATION: AR-CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR-CMT2S. Furthermore, 17 AR-CMT2S families could provide more resources for natural history study, drug research and development.

Genetic and clinical profile of 15 Chinese families with GDAP1-related Charcot-Marie-Tooth disease and identification of H256R as a frequent mutation.

BACKGROUND AND AIMS: Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause axonal or demyelinating Charcot-Marie-Tooth disease (CMT) with autosomal dominant or recessive inheritance. In this study, we aim to report the genotypic and phenotypic features of GDAP1-related CMT in a Chinese cohort. METHODS: Clinical, neurophysiological, genetic data, and available muscle/brain imaging information of 28 CMT patients with GDAP1 variants were retrospectively collected. RESULTS: We identified 16 GDAP1 pathogenic variants, among which two novel variants c.980dup(p.L328FfsX25) and c.480+4T>G were first reported. Most patients (16/28) presented with AR or AD CMT2K phenotype. Clinical characteristics in our cohort demonstrated that the AR patients presented earlier onset, more severe phenotype compared with the AD patients. Considerable intra-familial phenotypic variability was observed among three AD families. Muscle atrophy and fatty infiltration in the lower extremity were detected by Muscle magnetic resonance imaging (MRI) scans in four patients. MRI showed two AR patients showed more severe muscle involvement of the posterior compartment than those of the anterolateral compartment in the calf. One patient carrying Q38*/H256R variants accompanied with mild periventricular leukoaraiosis. CONCLUSIONS: In this study, we conducted an analysis of clinical features of the GDAP1-related CMT patients, expanded the mutation spectrum in GDAP1 by reporting two novel variants, and presented the prevalent occurrence of the H256R mutation in China. The screening of GDAP1 should be particularly emphasized in Chinese patients with CMT2, given the incomplete penetrance and pathogenic inheritance patterns involving dominant and recessive modes.

Patient-derived models: Promising tools for accelerating the clinical translation of breast cancer research findings.

Breast cancer has become the highest incidence of cancer in women. It was extensively and deeply studied by biologists and medical workers worldwide. However, the meaningful results in lab researches cannot be realized in clinical, and a part of new drugs in clinical experiments do not obtain as good results as the preclinical researches. It is urgently that promote a kind of breast cancer research models that can get study results closer to the physiological condition of the human body. Patient-derived models (PDMs) originating from clinical tumor, contain primary elements of tumor and maintain key clinical features of tumor. So they are promising research models to facilitate laboratory researches translate to clinical application, and predict the treatment outcome of patients. In this review, we summarize the establishment of PDMs of breast cancer, reviewed the application of PDMs in clinical translational researches and personalized precision medicine with breast cancer as an example, to improve the understanding of PDMs among researchers and clinician, facilitate them to use PDMs on a large scale of breast cancer researches and promote the clinical translation of laboratory research and new drug development.

GAS6/Axl is associated with AMPK activation and attenuates H2O2-induced oxidative stress.

Oxidative stress plays a key part in cardiovascular event. Growth arrest-specific gene 6 (GAS6) is a vitamin K-dependent ligand which has been shown to exert important effects in heart. The effects of GAS6 were evaluated against hydrogen peroxide (H2O2) ­induced oxidative stress injury in HL-1 cardiomyocytes. A series of experimental methods were used to analyze the effects of GAS6 on cell viability, apoptosis, oxidative stress, mitochondrial function and AMPK/ACC signaling in H2O2­injured HL-1 cells. In this study, we found that H2O2 reduced cell viability, increased apoptotic rate and intracellular reactive oxygen species (ROS). Meanwhile, H2O2 decreased the protein levels of GAS6, and increased the protein level of p-AMPK/AMPK, p-ACC/ACC. Then, we observed that overexpression of GAS6 significantly reduced cell death, manifested as increased cell viability, improved oxidative stress, apoptosis and upregulated the levels of GAS6, p-Axl/Axl, Nrf2, NQO1, HO-1, Bcl-2/Bax, PGC-1α, NRF1, TFAM, p-AMPK/AMPK, and p-ACC/ACC-related protein expression in HL-1 cells and H2O2­injured cardiomyocytes. To further verify the results, we successfully constructed GAS6 lentiviral vectors, and found GAS6 shRNA partially reversed the above results. These data suggest that AMPK/ACC may be a downstream effector molecule in the antioxidant action of GAS6. In summary, our findings indicate that activation GAS6/Axl-AMPK signaling protects H2O2­induced oxidative stress which is accompanied by the amelioration of oxidative stress, apoptosis, and mitochondrial function.

Expanding the genetic and clinical spectrum of SORD-related peripheral neuropathy by reporting a novel variant c.210T>G and evidence of subclinical muscle involvement.

BACKGROUND AND AIMS: Biallelic variants in the sorbitol dehydrogenase (SORD) gene have been identified as the genetic cause of autosomal recessive (AR) peripheral neuropathy (PN) manifesting as Charcot-Marie-Tooth disease type 2 (CMT2) or distal hereditary motor neuropathy (dHMN). We aim to observe the genetic and clinical spectrum of a cohort of patients with SORD-related PN (SORD-PN). METHODS: A total of 107 patients with AR or sporadic CMT2/dHMN underwent molecular diagnosis by whole-exome sequencing and subsequent Sanger sequencing validation. Available phenotypic data for SORD-PN were collected and analyzed. RESULTS: Eleven (10.28%) of 107 patients were identified as SORD-PN, including four with CMT2 and seven with dHMN. The SORD variant c.210 T > G;p.His70Gln in F-d3 was firstly reported and subsequent analysis showed that it resulted in loss of SORD enzyme function. Evidence of subclinical muscle involvement was frequently detected in patients with SORD-PN, including mildly to moderately elevated serum creatine kinase (CK) levels in 10 patients, myogenic electrophysiological changes in one patient, and muscle edema in five patients undergoing lower extremity MRI. Fasting serum sorbitol level was 88-fold higher in SORD-PN patients (9.69 ± 1.07 mg/L) than in healthy heterozygous subjects (0.11 ± 0.01 mg/L) and 138-fold higher than in healthy controls (0.07 ± 0.02 mg/L). INTERPRETATION: The novel SORD variant c.210 T > G;p.His70Gln and evidence of subclinical muscle involvement were identified, which expanded the genetic and clinical spectrum of SORD-PN. Subclinical muscle involvement might be a common but easily overlooked clinical feature. The serum CK and fasting serum sorbitol levels were expected to be sensitive biomarkers confirmed by follow-up cohort study.

PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer.

Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxorubicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxorubicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose- and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair competency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methylation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.

Protection of melatonin treatment and combination with traditional antibiotics against septic myocardial injury.

BACKGROUND: Heart failure is a common complication of sepsis with a high mortality rate. It has been reported that melatonin can attenuate septic injury due to various properties. On the basis of previous reports, this study will further explore the effects and mechanisms of melatonin pretreatment, posttreatment, and combination with antibiotics in the treatment of sepsis and septic myocardial injury. METHODS AND RESULTS: Our results showed that melatonin pretreatment showed an obvious protective effect on sepsis and septic myocardial injury, which was related to the attenuation of inflammation and oxidative stress, the improvement of mitochondrial function, the regulation of endoplasmic reticulum stress (ERS), and the activation of the AMPK signaling pathway. In particular, AMPK serves as a key effector for melatonin-initiated myocardial benefits. In addition, melatonin posttreatment also had a certain degree of protection, while its effect was not as remarkable as that of pretreatment. The combination of melatonin and classical antibiotics had a slight but limited effect. RNA-seq detection clarified the cardioprotective mechanism of melatonin. CONCLUSION: Altogether, this study provides a theoretical basis for the application strategy and combination of melatonin in septic myocardial injury.

A Policy Gradient Algorithm to Alleviate the Multi-Agent Value Overestimation Problem in Complex Environments.

Multi-agent reinforcement learning excels at addressing group intelligent decision-making problems involving sequential decision-making. In particular, in complex, high-dimensional state and action spaces, it imposes higher demands on the reliability, stability, and adaptability of decision algorithms. The reinforcement learning algorithm based on the multi-agent deep strategy gradient incorporates a function approximation method using discriminant networks. However, this can lead to estimation errors when agents evaluate action values, thereby reducing model reliability and stability and resulting in challenging convergence. With the increasing complexity of the environment, there is a decline in the quality of experience collected by the experience playback pool, resulting in low efficiency of the sampling stage and difficulties in algorithm convergence. To address these challenges, we propose an innovative approach called the empirical clustering layer-based multi-agent dual dueling policy gradient (ECL-MAD3PG) algorithm. Experimental results demonstrate that our ECL-MAD3PG algorithm outperforms other methods in various complex environments, demonstrating a remarkable 9.1% improvement in mission completion compared to MADDPG within the context of complex UAV cooperative combat scenarios.

TMEM189 as a target gene of MiR-499a-5p regulates breast cancer progression through the ferroptosis pathway.

MicroRNA (miR)-499a-5p has been reported to regulate the progression of various tumours. However, the role of miR-499a-5p in breast cancer is unclear. The purpose of this study was to investigate the role and mechanism of miR-499a-5p in breast cancer. The growth effect of miR-499a-5p on breast cancer cells was investigated by the CCK-8 assay, wound healing assay and Transwell invasion assay. The luciferase activity assay was used to verify the downstream targets of miR-499a-5p. The levels of GSH, MDA, and ROS were detected by kits. Quantitative real-time PCR and Western blot were used to determine the expression levels of TMEM189, COX-2, GPX4, and other related genes in cells. miR-499a-5p was down-regulated in MDA-MB-231 cells and was shown to reduced the viability, migration and invasion of MDA-MB-231 cells. Further studies revealed that TMEM189 is a target of miR-499a-5p. miR-499a-5p inhibited breast cancer cell growth by downregulating TMEM189. Furthermore, the down-regulation of TMEM189 promotes ferroptosis in breast cancer cells. The low expression of TMEM189 inhibited the development of breast cancer through the ferroptosis pathway. We have demonstrated for the first time that miR-499a-5p inhibits breast cancer progression by targeting the TMEM189-mediated ferroptosis pathway.

Clinical and molecular genetic characteristics of 24 families of hereditary neuropathy with liability to pressure palsy and literature review. / é—ä¼ æ€§åŽ‹åŠ›æ˜“æ„Ÿæ€§å‘¨å›´ç¥žç»ç— 24ä¸ªå®¶ç³»çš„ä¸´åºŠå’Œåˆ†å­é—ä¼ å­¦ç‰¹å¾åŠæ–‡çŒ®å›žé¡¾.

OBJECTIVES: Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare autosomal dominant peripheral neuropathy, usually caused by heterozygous deletion mutations in the peripheral myelin protein 22 (PMP22) gene. This study aims to investigate the clinical and molecular genetic characteristics of HNPP. METHODS: HNPP patients in the Department of Neurology at Third Xiangya Hospital of Central South University from 2009 to 2023 were included in this study. The general clinical data, nervous electrophysiological and molecular genetic examination results were collected and analyzed. Molecular genetic examination was to screen for deletion of PMP22 gene using multiplex ligation-dependent probe amplification (MLPA) after extracting genomic DNA from peripheral blood; and if no PMP22 deletion mutation was detected, next-generation sequencing was used to screen for PMP22 point mutations. The related literatures of HNPP were reviewed, and the clinical and molecular genetic characteristics of HNPP patients were analyzed. RESULTS: A total of 34 HNPP patients from 24 unrelated Chinese Han families were included in this study, including 25 males and 9 females. The average age at illness onset was 22.0 years. Sixty-two point five percent of the families had a positive family history. Among them, 30 patients had symptoms of peripheral nerve paralysis. Patients often presented with paroxysmal single limb weakness with (or) numbness (25/30), and some patients had paroxysmal unilateral recurrent laryngeal nerve (vagus nerve) paralysis (2/30). Physical examination revealed muscle weakness (23/29), hypoesthesia (9/29), weakened or absent ankle reflexes (20/29), distal limb muscle atrophy (8/29) and high arched feet (5/29). Most patients (26/30) could fully recover to normal after an acute attack. Thirty-one patients in our group underwent nervous electrophysiological examination, and showed multiple demyelinating peripheral neuropathies with both motor and sensory nerves involved. Most patients showed significantly prolonged distal motor latency (DML), mild to moderate nerve conduction velocity slowing, decreased amplitude of compound muscle action potential (CMAP) and sensory nerve action potential (SNAP), and sometimes with conduction block. Nerve motor conduction velocity was (48.5±5.5) m/s, and the CMAP amplitude was (8.4±5.1) mV. Nerve sensory conduction velocity was (37.4±10.5) m/s, and the SNAP amplitude was (14.4±15.2) µV. There were 24 families, 23 of whom had the classical PMP22 deletion, the last one had a heterozygous pathogenic variant in the PMP22 gene sequence (c.434delT). By reviewing clinical data and genetic testing results of reported 1 734 HNPP families, we found that heterozygous deletion mutation of PMP22 was the most common pathogenic mutation of HNPP (93.4%). Other patients were caused by PMP22 small mutations (4.0%), PMP22 heterozygous gross deletions (0.6%), and PMP22 complex rearrangements (0.1%). Thirty-eight sorts of HNPP-related PMP22 small mutations was reported, including missense mutations (10/38), nonsense mutations (4/38), base deletion mutations (13/38), base insertion mutations (3/38), and shear site mutations (8/38). HNPP patients most often presented with episodic painless single nerve palsy. Common peroneal nerve, ulnar nerve, and brachial plexus nerve were the most common involved nerves, accounting for about 75%. Only eighteen patients with cranial nerve involved was reported. CONCLUSIONS: Heterozygous deletion mutation of PMP22 is the most common pathogenic mutation of HNPP. Patients is characterized by episodic and painless peripheral nerve paralysis, mainly involving common peroneal nerve, ulnar nerve, and other peripheral nerves. Nervous electrophysiological examination has high sensitivity and specificity for the diagnosis of HNPP, which is manifested by extensive demyelinating changes. For patients with suspected HNPP, nervous electrophysiological examination and PMP22-MLPA detection are preferred. Sanger sequencing or next generation sequencing can be considered to detect other mutations of PMP22.

GDF11 knockdown downregulates SMURF1 to inhibit breast cancer progression by activation of p53 and inactivation of ERα signaling.

Breast cancer (BC) is a prevalent neoplasm that occurs in women all over the world. Growth and differentiation factor 11 (GDF11) plays an essential role in cancer progression. This study focused on investigating the biological role and underlying mechanisms of GDF11 in BC. We detected the expression of GDF11 in 27 patients with BC and BC cell lines. Kaplan-Meier plotter was employed to analyze the relationship between GDF11 expression and overall survival (OS) of BC patients. The proliferative, migratory, invasive, and apoptotic abilities of T47D cells were examined. Correlation analysis of GDF11 with Smad ubiquitination regulatory factor 1 (SMURF1) was conducted. The association between GDF11 and the p53 pathway was analyzed by western blot and PFT-α (a p53 inhibitor)-mediated rescue assays. A brief analysis of the role of estrogen receptor alpha (ERα) signaling in BC progression was performed. The results showed that GDF11 was increased in BC tissues and cell lines, and the high expression of GDF11 was associated with the poor OS of BC patients. GDF11 knockdown inhibited the proliferation, migration, and invasion of T47D cells, but promoted cell apoptosis. Meanwhile, the GDF11 knockdown reduced the SMURF1 expression and invoked the p53 pathway activation. SMURF1 overexpression and PFT-α partially blocked the effects of GDF11 knockdown. In addition, GDF11 knockdown and SMURF1 silencing inhibited the activation of the ERα signaling pathway. In summary, GDF11 was involved in the progression of BC by regulating SMURF1-mediated p53 and ERα pathways, opening up a new way for BC treatment.

Adjuvant tamoxifen switched to exemestane treatment in postmenopausal women with estrogen receptor-positive early breast cancer: A pragmatic, multicenter, and prospective clinical trial in China.

Objective: This post-approval safety study assessed the efficacy and safety of exemestane after 2-3 years of tamoxifen treatment among postmenopausal women with estrogen receptor-positive (ER+) early breast cancer in China. Methods: Enrolled patients had received 2-3 years of tamoxifen and were then switched to exemestane for completion of 5 consecutive years of adjuvant endocrine therapy. The primary endpoint was the time from enrollment to the first occurrence of locoregional/distant recurrence of the primary breast cancer, appearance of a second primary or contralateral breast cancer, or death due to any cause. Other endpoints included the proportion of patients experiencing each event, incidence rate per annum, relationships between human epidermal growth factor receptor 2 status and time to event, and relationship between disease history variables and time to event. Results: Overall, 558 patients were included in the full analysis set: 397 (71.1%) completed the study, 20 experienced an event, and 141 discontinued [47 owing to an adverse event (AE); 37 no longer willing to participate]. Median duration of treatment was 29.5 (range, 0.1-57.7) months. Median time to event was not reached. Event-free survival probability at 36 months was 91.4% (95% CI, 87.7%-95.1%). The event incidence over the total exposure time of exemestane therapy was 3.5 events/100 person-years (20/565). Multivariate analysis showed an association between tumor, lymph node, and metastasis stage at initial diagnosis and time to event [hazard ratio: 1.532 (95% CI, 1.129-2.080); P=0.006]. Most AEs were grade 1 or 2 in severity, with arthralgia (7.7%) being the most common treatment-related AE. Conclusions: This study supports the efficacy and safety of exemestane in postmenopausal Chinese women with ER+ breast cancer previously treated with adjuvant tamoxifen for 2-3 years. No new safety signals were identified in the Chinese population.

Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from central south China.

BACKGROUND AND PURPOSE: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China. METHODS: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. RESULTS: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. CONCLUSIONS: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

A novel WARS mutation (p.Asp314Gly) identified in a Chinese distal hereditary motor neuropathy family.

Distal hereditary motor neuropathy (dHMN) is a clinically and genetically heterogeneous group of inherited neuropathies characterized by distal limb muscle wasting and weakness with no or minimal sensory abnormalities. To investigate the clinical and genetic features of dHMN caused by WARS mutations in mainland China, we performed Sanger sequencing of the coding and untranslated region (UTR) regions of WARS in 160 unresolved dHMN and Charcot-Marie-Tooth (CMT) index patients. We detected a novel heterozygous variant c.941A>G (p.Asp314Gly) of WARS in an index patient from an autosomal dominant dHMN family including five affected members over three generations. The variant completely co-segregates with the dHMN phenotype in the family, and it was classified as likely pathogenic according to the American College of Medical Genetics and Genomics standards and guidelines. The clinical features included juvenile to adult onset (15-23 years), distal wasting and weakness, minimal sensory disturbance and length-dependent motor axonal degeneration with CMT examination score ranging from 6 to 10. Our report further confirms the role of WARS in dHMN and indicates that the variant c.941A>G (p.Asp314Gly) of WARS is related to a mild to moderate affected and later onset phenotype of dHMN.

Triptolide mitigates the inhibition of osteogenesis induced by TNF-α in human periodontal ligament stem cells via the p-IκBα/NF-κB signaling pathway: an in-vitro study.

BACKGROUND: Triptolide is a widely utilized natural anti-inflammatory drug in clinical practice. Aim of this study was to evaluate effects of triptolide on hPDLSCs osteogenesis in an inflammatory setting and to investigate underlying mechanisms. METHODS: Using the tissue block method to obtain hPDLSCs from extracted premolar or third molar. Flow cytometry, osteogenic and adipogenic induction were carried out in order to characterise the features of the cells acquired. hPDLSC proliferative activity was assessed by CCK-8 assay to determine the effect of TNF-α and/or triptolide. The impact of triptolide on the osteogenic differentiation of hPDLSCs was investigated by ALP staining and quantification. Osteogenesis-associated genes and proteins expression level were assessed through PCR and Western blotting assay. Finally, BAY-117,082 was used to study the NF-κB pathway. RESULTS: In the group treated with TNF-α, there was an elevation in inflammation levels while osteogenic ability and the expression of both osteogenesis-associated genes and proteins decreased. In the group co-treated with TNF-α and triptolide, inflammation levels were reduced and osteogenic ability as well as the expression of both osteogenesis-associated genes and proteins were enhanced. At the end of the experiment, both triptolide and BAY-117,082 exerted similar inhibitory effects on the NF-κB pathway. CONCLUSION: The osteogenic inhibition of hPDLSCs by TNF-α can be alleviated through triptolide, with the involvement of the p-IκBα/NF-κB pathway in this mechanism.

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot-Marie-Tooth Disease.

BACKGROUND: To identify genetic causes in 40 whole exome sequencing (WES)-negative Charcot-Marie-Tooth (CMT) families and provide a summary of the clinical and genetic features of the diagnosed patients. METHODS: The clinical information and sequencing data of 40 WES-negative families out of 131 CMT families were collected, and phenotype-driven reanalysis was conducted using the Exomiser software. RESULTS: The molecular diagnosis was regained in 4 families, increasing the overall diagnosis rate by 3.0%. One family with adolescent-onset pure CMT1 was diagnosed [POLR3B: c.2810G>A (p.R937Q)] due to the novel genotype-phenotype association. One infantile-onset, severe CMT1 family with deep sensory disturbance was diagnosed by screening the BAM file and harbored c.1174C>T (p.R392*) and 875_927delinsCTGCCCACTCTGCCCACTCTGCCCACTCTG (p.V292Afs53) of PRX. Two families were diagnosed due to characteristic phenotypes, including an infantile-onset ICMT family with renal dysfunction harboring c.213_233delinsGAGGAGCA (p.S72Rfs34) of INF2 and an adolescent-onset CMT2 family with optic atrophy harboring c.560C>T (p.P187L) and c.616A>G (p.K206E) of SLC25A46. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants of POLR3B and SLC25A46 were classified as likely pathogenic, and the variants of INF2 and PRX were pathogenic. All these variants were first reported worldwide except for p.R392* of PRX. CONCLUSIONS: We identified five novel pathogenic variants in POLR3B, PRX, INF2, and SLC25A46, which broaden their phenotypic and genotypic spectrums. Regular phenotype-driven reanalysis is a powerful strategy for increasing the diagnostic yield of WES-negative CMT patients, and long-term follow-up and screening BAM files for contiguous deletion and missense variants are both essential for reanalysis.

Heat stroke: Pathogenesis, diagnosis, and current treatment.

Recently, the incidence of heat-related illnesses has exhibited a steadily upward trend, which is closely associated with several environmental factors such as climate change and air pollution. The progression of heat-related illnesses is a continuous process and can progress to the terminal period when it transforms into heat stroke, the most severe form. Heat stroke is markedly by a core body temperature above 40°C and central nervous system dysfunction. Current knowledge suggests that the pathogenesis of heat stroke is complex and varied, including inflammatory response, oxidative stress, cell death, and coagulation dysfunction. This review consolidated recent research progress on the pathophysiology and pathogenesis of heat stroke, with a focus on the related molecular mechanisms. In addition, we reviewed common strategies and sorted out the drugs in various preclinical stages for heat stroke, aiming to offer a comprehensive research roadmap for more in-depth researches into the mechanisms of heat stroke and the reduction in the mortality of heat stroke in the future.

Identifying and validating potential therapeutic targets for septic heart failure and the cardioprotective effects of lycorine.

BACKGROUND: Septic heart failure has been recognized as a puzzle since antiquity and poses a major challenge to modern medicine. Our previous work has demonstrated the potential effects of lycorine (LYC) on sepsis and septic myocardial injury. Nonetheless, further exploration is needed to elucidate the underlying cellular and molecular mechanisms. METHODS: In this study, we conducted transcriptome analysis and weighted gene co-expression network analysis (WGCNA) to identify the key genes and reveal the mechanism of LYC against septic heart failure. PURPOSE: This study aims to apply bioinformatic analysis and experimental validations to explore the protective effects and underlying mechanism of LYC on the cecal ligation and puncture (CLP)-induced sepsis model mice. RESULTS: Transcriptome analysis revealed the differentially expressed genes (DEGs) following LYC treatment. WGCNA analysis identified gene modules associated with LYC-mediated protection, with BCL3 emerging as a core gene within these modules. Notably, BCL3 was an overlapping gene of DEGs and WGCNA core genes induced by LYC treatment, and is highly negatively correlated with cardiac function indicator. In vivo and in vitro study further prove that LYC exerted a protective effect against septic myocardial injury through inhibiting BCL3. BCL3 siRNA ameliorated LPS-induced cardiac injury and inflammation, while BCL3 overexpression reversed the protective effect of LYC against LPS injury. CONCLUSION: In summary, our findings demonstrate the significant attenuation of septic myocardial disorder by LYC, with the identification of BCL3 as a pivotal target gene. This study is the first to report the role of BCL3 in sepsis and septic myocardial injury. Furthermore, the strategy for hub genes screening used in our study facilitates a comprehensive exploration of septic targets and reveals the potential targets for LYC effect. These findings may offer a new therapeutic strategy for the management of septic heart failure, highlighting the cardioprotective effect of LYC as adjunctive therapy for sepsis management.