Sequential neoadjuvant chemotherapy using pegylated liposomal doxorubicin and cyclophosphamide followed by taxanes with complete trastuzumab and pertuzumab treatment for HER2-positive breast cancer: A phase II single-arm study.

Objective: Despite cardiotoxicity overlap, the trastuzumab/pertuzumab and anthracycline combination remains crucial due to significant benefits. Pegylated liposomal doxorubicin (PLD), a less cardiotoxic anthracycline, was evaluated for efficacy and cardiac safety when combined with cyclophosphamide and followed by taxanes with trastuzumab/pertuzumab in human epidermal growth factor receptor-2 (HER2)-positive early breast cancer (BC). Methods: In this multicenter, phase II study, patients with confirmed HER2-positive early BC received four cycles of PLD (30-35 mg/m2) and cyclophosphamide (600 mg/m2), followed by four cycles of taxanes (docetaxel, 90-100 mg/m2 or nab-paclitaxel, 260 mg/m2), concomitant with eight cycles of trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) every 3 weeks. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints included breast pCR (bpCR), objective response rate (ORR), disease control rate, rate of breast-conserving surgery (BCS), and safety (with a focus on cardiotoxicity). Results: Between May 27, 2020 and May 11, 2022, 78 patients were treated with surgery, 42 (53.8%) of whom had BCS. After neoadjuvant therapy, 47 [60.3%, 95% confidence interval (95% CI), 48.5%-71.2%] patients achieved tpCR, and 49 (62.8%) achieved bpCR. ORRs were 76.9% (95% CI, 66.0%-85.7%) and 93.6% (95% CI, 85.7%-97.9%) after 4-cycle and 8-cycle neoadjuvant therapy, respectively. Nine (11.5%) patients experienced asymptomatic left ventricular ejection fraction (LVEF) reductions of ≥10% from baseline, all with a minimum value of >55%. No treatment-related abnormal cardiac function changes were observed in mean N-terminal pro-BNP (NT-proBNP), troponin I, or high-sensitivity troponin. Conclusions: This dual HER2-blockade with sequential polychemotherapy showed promising activity with rapid tumor regression in HER2-positive BC. Importantly, this regimen showed an acceptable safety profile, especially a low risk of cardiac events, suggesting it as an attractive treatment approach with a favorable risk-benefit balance.

Effects of LEF-11 acetylation modification on the regulation of baculovirus infection.

Late expression factor 11 (LEF-11) is an essential protein in the regulation of Bombyx mori nucleopolyhedrovirus (BmNPV) DNA replication and late gene expression. Our recent quantitative analysis of protein acetylome revealed for the first time that LEF-11 can be acetylated at one lysine residue (K83) during viral infection, but the underlying mechanism is unclear. The acetylation level for K83 was down-regulated after 36 h post-infection by approximately 30%. To clarify the regulatory function of this modification, overlap PCR was used for site-specific mutagenesis for acetylated (K83Q) or deacetylated (K83R) mimic mutants of LEF-11. The results of viral titration and quantitative polymerase chain reaction showed that after K83 acetylation, budding virion production and the viral genome replication level were significantly upregulated. Meanwhile, the results of yeast two-hybrid (Y2H) system confirmed that K83 deacetylation modification inhibited the interaction between LEF-11 and immediate early gene 1 (IE-1). In conclusion, the acetylation of LEF-11 at K83 might enhance the interaction with IE-1 in the host cell nucleus to promote viral DNA replication, and might be one of the antiviral strategies of the silkworm host. The host inhibits virus proliferation by deacetylating LEF-11. Keywords: BmNPV; LEF-11; acetylation; virus replication; protein interaction.

Efficacy and Safety of Light Therapy as a Home Treatment for Motor and Non-Motor Symptoms of Parkinson Disease: A Meta-Analysis.

BACKGROUND Non-visual effects of the retina have been increasingly confirmed in developing Parkinson disease (PD). Light therapy (LT) has been proven to be an effective non-pharmacotherapy for improving the prognosis of PD, but the pathway of action is unclear, and there is a lack of a unified and standardized LT regimen. We aimed to evaluate the efficacy and safety of various LT measures in improving motor and non-motor symptoms in patients with idiopathic PD via a meta-analysis. MATERIAL AND METHODS CENTRAL, EMBASE, CINAHL, PEDro, and PubMed were searched for randomized controlled trials (RCTs) investigating the efficacy of LT for PD. Cochrane's Risk of bias tool and the GRADE approach were used to assess evidence quality. A meta-analysis and subgroup analyses evaluated the differences in efficacy produced by the different LT protocols. Trial sequential analysis (TSA) verified the analyses outcome and quantified the statistical relevance of the data.[color=#0e101a] [/color] RESULTS Patients receiving LT had significantly better scores for motor function (MD=-4.68, 95% Cl -8.25 to -1.12, P=0.01) compared with the control group exposed to dim-red light. In addition, in terms of non-motor symptoms, depression (SMD=-0.27, 95% Cl -0.52 to -0.02, P=0.04) and sleep disturbance-related scores (MD=3.45, 95% Cl 0.12 to 6.78, P=0.04) similarly showed significant optimization after receiving LT. CONCLUSIONS The results of this meta-analysis show strong evidence that LT has significant efficacy on motor and non-motor function in PD patients.

Treatment of status epilepticus in pediatrics: curriculum learning combined with in-situ simulations.

BACKGROUND: Appropriate and timely treatment of status epilepticus (SE) reduces morbidity and mortality. Therefore, skill-based identification and management are critical for emergency physicians. PURPOSE: To assess whether the ability of training physicians, residents, nurses, and others to respond to SE as a team could be improved by using curriculum learning [Strategies and Tools to Enhance Performance and Patient Safety of Team (TeamSTEPPS) course training] combined with in-situ simulations of emergency department (ED) staff. APPROACH: A pre-training-post-training design was used on SE skills and teamwork skills. Emergency training, residents, and N1 and N2 nurses completed the SE skill and teamwork assessments (pre-training) through in-situ simulation. Next, the participating physicians and nurses attended the SE course [Strategies and Tools to Enhance Performance and Patient Safety of Team (TeamSTEPPS) course training], followed by conscious skill practice, including in-situ simulation drills every 20 days (eight times total) and deliberate practice in the simulator. The participants completed the SE skill and teamwork assessments (post-training) again in an in-situ simulation. Pre-training-post-training simulated SE skills and teamwork performance were assessed. The simulation training evaluation showed that the training process was reasonable, and the training medical staff had different degrees of benefit in increasing subject interest, improving operational skills, theoretical knowledge, and work self-confidence. FINDINGS: Sixty doctors and nurses participated in the intervention. When comparing the SE skills of 10 regular training physicians pre-training and post-training, their performance improved from 40% (interquartile range (IQR): 0-1) before training to 100% (IQR: 80.00-100) after training (p < 0.001). The teamwork ability of the 10 teams improved from 2.43 ± 0.09 before training to 3.16 ± 0.08 after training (p < 0.001). CONCLUSION: SE curriculum learning combined with in-situ simulation training provides the learners with SE identification and management knowledge in children and teamwork skills.

A novel missense pathogenic variant in NEFH causing rare Charcot-Marie-Tooth neuropathy type 2CC.

The purpose of this research is to explore the underlying genes of Charcot-Marie-Tooth (CMT). Technologies such as electrophysiological testing and gene sequencing have been applied. We identified a novel variant NEFH c.2215C>T(p.P739S)(HGNC:7737) in a heterozygous state, which was considered to be pathogenic for CMT2CC(OMIM:616924).The proband and his brothers presented with muscle atrophy of hand and calf and moderately decreased conduction velocities. By whole exome sequencing analysis, we found the novel missense pathogenic variant in the proband, his brother and mother. This report broadened current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with NEFH. In addition, the proband carried other five variants {HSPD1c.695C>A (p.S232X), FLNCc.1073A>G (p.N358S), GUSBc.323C>A (p.P108Q), ACY1 c.1063-1G>A and APTX c.484-2A>T}, which have not been reported until now. The NEFH c.2215C>T (p.P739S) give us a new understanding of CMT, which might provide new therapeutic targets in the future.

Nomograms for prediction of overall and cancer-specific survival in young breast cancer.

PURPOSE: To assess the prognostic risk factors and establish prognostic nomograms based on lymph node ratio (LNR) to predict the survival of young patients with breast cancer (BC). METHODS: Patients aged < 40 years and diagnosed with BC between 2010 and 2016 from the Surveillance, Epidemiology and End Results database were assessed. Nomograms incorporating LNR were constructed to predict overall survival (OS) and breast cancer-specific survival (BCSS) based on Cox proportional hazards model. The performance of the nomograms was assessed by C-index, calibration curves, receiver operating characteristic (ROC) curves, decision curve analysis (DCA), and risk group stratification and compared with the TNM staging system. RESULTS: Based on the univariate and multivariate Cox regression analysis, significant prognostic factors were identified and integrated to create the nomograms for OS and BCSS. The calibration curves indicated optimal agreement between model predictions and actual observations. The nomograms showed favorable sensitivity with a C-index of 0.8351 (95% CI 0.8234-0.8469) for OS and 0.8474 (95% CI 0.8355-0.8594) for BCSS. The ROC curves of the nomograms showed better predictive ability than those of the TNM staging system for OS (AUC: 0.8503 vs. 0.7819) and BSCC (AUC: 0.8607 vs. 0.8081). Significant differences in Kaplan-Meier curves were observed in patients stratified into different risk groups (p < 0.001). CONCLUSIONS: These nomograms provided more accurate individualized risk prediction of OS and BCSS and may assist clinicians in making decisions for young patients with BC.

Simvastatin Improves Behavioral Disorders and Hippocampal Inflammatory Reaction by NMDA-Mediated Anti-inflammatory Function in MPTP-Treated Mice.

The cognitive function impairment may be related to the inflammation of the hippocampus in Parkinson's disease. Simvastatin can play a positive role in Parkinson's disease. The purpose of this study was to investigate whether simvastatin could improve behavioral disorders, especially depression, anxiety and cognitive function in mouse PD models, and further explore the molecular mechanism. In the present study, C57BL-6 mice underwent intraperitoneal injection of MPTP (30 mg/kg) once a day for 5 consecutive days. At the same time, simvastatin (10 mg/kg) was pretreated for 2 days before the Parkinson's disease model was established, and then continued for 5 days, and the control group underwent intraperitoneal injection of MK801 (dizocilpine, 0.2 mg/kg) and saline solution. Depression status was tested by a tail suspension test and a sucrose splash test, followed by an open-field test and an elevated plus maze test to determine anxiety levels. Spatial behavior and muscle status were measured with a water maze and a rotarod test. The expression of RNA and protein of N-methyl-D-aspartate receptor subtype 2B (NMDAR2B), nerve growth factor IB (Nur77), cyclooxygenase-2 (COX-2), and tumor necrosis factor (TNF) α were assayed by real-time polymerase chain reaction and Western blot. Our results showed that simvastatin can improve the cognitive function, anxiety, and depression of PD mice with MPTP injury. Simvastatin reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice. This role of simvastatin was consistent with MK801 in increasing the expression of Nur77 and inhibiting NMDAR2B and cytokines in MPTP-lesioned PD mice. These findings suggest that reversed the NMDAR2B increase, restored Nur77 downward, and reduced the expression of COX-2 and TNF-α in MPTP-treated mice may be one of the mechanisms that simvastatin improves cognitive functions, depression, and anxiety in MPTP-lesioned mice.

Research Progress of Drug Treatment in Novel Coronavirus Pneumonia.

As of March 10, 2020, more than 100,000 novel coronavirus pneumonia cases have been confirmed globally. With the continuous spread of the new coronavirus pneumonia epidemic in even the world, prevention and treatment of the disease have become urgent tasks. The drugs currently being developed are not adequate to deal with this critical situation. In addition to being controlled through effective isolation, we need a rapid response from the healthcare and biotechnology industries to accelerate drug treatment research. By reviewing the currently available literature published at home and abroad, we summarize the current research progress of drug treatment during the epidemic period. At present, the drugs that can be used for treatment mainly include antiviral drugs, antimalarials, glucocorticoids, plasma therapy, biological agents, and traditional Chinese medicine. The effectiveness and safety of drug therapy need to be confirmed by more clinical studies.

In vivo evolution of drug-resistant Mycobacterium tuberculosis in patients during long-term treatment.

BACKGROUND: In the current scenario, the drug-resistant tuberculosis is a significant challenge in the control of tuberculosis worldwide. In order to investigate the in vivo evolution of drug-resistant M. tuberculosis, the present study envisaged sequencing of the draft genomes of 18 serial isolates from four pre-extensively drug-resistant (pre-XDR) tuberculosis patients for continuous genetic alterations. RESULTS: All of the isolates harbored single nucleotide polymorphisms (SNPs) ranging from 1303 to 1309 with M. tuberculosis H37Rv as the reference. SNPs ranged from 0 to 12 within patients. The evolution rates were higher than the reported SNPs of 0.5 in the four patients. All the isolates exhibited mutations at sites of known drug targets, while some contained mutations in uncertain drug targets including folC, proZ, and pyrG. The compensatory substitutions for rescuing these deleterious mutations during evolution were only found in RpoC I491T in one patient. Many loci with microheterogeneity showed transient mutations in different isolates. Ninety three SNPs exhibited significant association with refractory pre-XDR TB isolates. CONCLUSIONS: Our results showed evolutionary changes in the serial genetic characteristics of the pre-XDR TB patients due to accumulation of the fixed drug-resistant related mutations, and the transient mutations under continuous antibiotics pressure over several years.

Simvastatin Protects Dopaminergic Neurons Against MPP+-Induced Oxidative Stress and Regulates the Endogenous Anti-Oxidant System Through ERK.

BACKGROUND/AIMS: Many clinical studies have demonstrated that statins, especially simvastatin, can decrease the incidence of Parkinson's disease (PD). However, the specific underlying mechanism remains unclear. This study aimed to investigate how simvastatin affects experimental parkinsonian models via the regulation of extracellular signal-regulated kinase 1/2 (ERK1/2)-mediated activation of the anti-oxidant system. METHODS: l-Methyl-4-phenylpyridine ion (MPP+)-treated SH-SY5Y cells and substantia nigra neurons were used to investigate the neuroprotective effect of simvastatin. After incubation with MPP+ and/or simvastatin for 24 h, the MTT assay was used to assess cell viability. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescin diacetate, while cellular superoxide dismutase (SOD) levels were determined based on the blue formazan produced by the reduction of nitroblue tetrazolium. The level of cellular grade micro-reduced glutathione (GSH) was measured with 5,5'-dithiobis-(2-nitrobenzoic acid). Meanwhile, the malondialdehyde content released from SH-SY5Y cells and substantia nigra neuronal cells exposed to different culture media was calculated based on the condensation reaction involving thiobarbituric acid. The mRNA levels of genes encoding nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase 1 (HO-1), and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were determined by a quantitative polymerase chain reaction assay, while the ERK, Nrf2, HO-1, NOX2, and NQO-1 protein levels were analyzed by western blot. Additionally, ERK small interfering RNA (siRNA) was used to investigate the mechanisms underlying MPP+-induced oxidative stress and the regulation of the endogenous anti-oxidant system. RESULTS: Simvastatin (1.5 µM) enhanced the viability of SH-SY5Y cells and primary neurons treated with MPP+, and significantly alleviated the oxidative stress induced by MPP+ in SH-SY5Y cells by regulating the production of SOD, analytical grade micro-reduced GSH, and ROS, which may be associated with the activation of the Nrf2 anti-oxidant system. An analysis involving ERK1/2 siRNA revealed that simvastatin can inhibit NOX2 expression via the activation of ERK1/2 in the MPP+-treated PD cell model. CONCLUSION: Our results provide strong evidence that ERK1/2-mediated modulation of the anti-oxidant system after simvastatin treatment may partially explain the anti-oxidant activity in experimental parkinsonian models. These findings contribute to a better understanding of the critical roles of simvastatin via the ERK1/2-mediated modulation of the anti-oxidant system, which may be relevant for treating PD.

Liraglutide Enhances Autophagy and Promotes Pancreatic ß Cell Proliferation to Ameliorate Type 2 Diabetes in High-Fat-Fed and Streptozotocin-Treated Mice.

BACKGROUND Clinical and experimental studies have revealed that liraglutide has multiple anti-diabetes biological effects. However, little is known about its role in autophagy and pancreatic ß cell proliferation. This study aimed to assessed the effects of liraglutide on pancreatic b cell proliferation and autophagy in a mouse model of type 2 diabetes. MATERIAL AND METHODS The effect of liraglutide on autophagy and proliferation in pancreatic ß cells was investigated using a high-fat-fed and streptozotocin-induced mouse model of type 2 diabetes. RESULTS Liraglutide significantly improved the symptoms of high-fat-fed (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice, as indicated by body weight gain, reduction of blood glucose and plasma insulin, and enhanced sensitivity to insulin. The results of quantitative real-time polymerase chain reaction and Western blot analysis showed that liraglutide upregulated AGT5 expression and promoted the conversion of LC3-I to LC3-II, thus improving the defective autophagy. In addition, we observed that both mRNA and protein expressions of PCNA and Ki-67 were upregulated by liraglutide treatment. Immunocytochemical staining results showed that the number of PCNA- or Ki-67-positive cells in pancreatic islet tissues in the HFD + STZ + liraglutide group were increased compared with the HFD + STZ group. CONCLUSIONS These results strongly suggest that liraglutide is able to enhance autophagy and promote pancreatic ß cell proliferation. This study improves our insights into the mechanism by which liraglutide treatment relieves diabetes, and provides experimental evidence for clinical utilization of liraglutide in type 2 diabetes treatment.

Prospective comparison of Sapylin and Avitene for reducing hydrops after axillary lymphadenectomy in breast cancer patients.

BACKGROUND: This study compared the efficacy of Sapylin and Avitene in reducing postoperative axillary seroma formation and effusion when applied topically after axillary lymphadenectomy. METHODS: A total of 224 patients were randomly divided into a Sapylin treatment group (STG), an Avitene treatment group, and a control group (CG). All patients underwent axillary lymphadenectomy and were treated during surgery with Sapylin, Avitene, or neither according to their group assignment. The duration and amount of postoperative drainage, as well as the occurrence of seromas were recorded. Outcomes were compared by one-way analysis of variance and chi-square tests. RESULTS: Baseline patient data, including age, body mass index, history of neoadjuvant chemotherapy, type of surgery, number of resected lymph nodes, and number of positive metastases did not differ among the three groups. Patients in both the STG and the Avitene treatment group experienced significantly fewer days of drainage than those in the CG; there was no significant difference in drainage tube retention time between the two treated groups. The STG experienced significantly less drainage volume than the CG. Fewer patients in both treatment groups required seroma treatment or experienced complications compared with CG patients. CONCLUSIONS: Both Sapylin and Avitene effectively reduced postoperative subcutaneous fluid accumulation after axillary lymphadenectomy. These treatments may be particularly useful for breast cancer patients at high risk of seroma formation, especially those with hypertension, diabetes mellitus, or a high body mass index who undergo axillary lymphadenectomy.

Significance of Tumor-Infiltrating Lymphocytes and the Expression of Topoisomerase IIα in the Prediction of the Clinical Outcome of Patients with Triple-Negative Breast Cancer after Taxane-Anthracycline-Based Neoadjuvant Chemotherapy.

PURPOSE: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). METHODS: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). RESULTS: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. CONCLUSION: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

The Rho-mDia1 signaling pathway is required for cyclic strain-induced cytoskeletal rearrangement of human periodontal ligament cells.

Tooth movement is the result of periodontal tissue reconstruction. The biomechanical effects produced by orthopedic forces can affect the cytoskeletal rearrangement of human periodontal ligament cells (hPDLCs). However, the mechanisms responsible for the cytoskeletal rearrangement are not completely understood. To analyze the effect, we investigated the role of the Rho-mDia1 signaling pathway in cyclic strain-induced cytoskeletal rearrangement of hPDLCs in detail. We cultured hPDLCs on collagen I-coated six-well Bioflex plates and then exposed them to cyclic strain with physiological loading (10%) at a frequency of 0.1Hz for 6 or 24h using a Flexercell Tension Plus system. Notably, the cells cultured on the Bioflex plates showed increased expression levels of RhoA-GTP, profilin-1 protein, and the combination of RhoA and mDia1, whereas the expression levels of Rho-GDIa were reduced compared with a static control group. Furthermore, the cytoskeletal rearrangement of cells was enhanced. However, profilin-1 protein expression and cytoskeletal reorganization under cyclic strain can decrease due to the overexpression of Rho-GDIa or mDia1-siRNA transfection, whereas Rho-GDIa siRNA transfection has the opposite effect on hPDLCs. Together, our results demonstrate that the Rho-mDia1 signaling pathway is involved in the cytoskeletal rearrangement of hPDLCs induced by cyclic strain. These observations may enable a more in-depth understanding of orthodontic tooth movement and the reconstruction of PDL and alveolar bone.

HER-2 positive breast cancer is associated with an increased risk of positive cavity margins after initial lumpectomy.

BACKGROUND: The effect of breast cancer subtype on margin status after lumpectomy remains unclear. This study aims to determine whether approximated breast cancer subtype is associated with positive margins after lumpectomy, which could be used to determine if there is an increased risk of developing local recurrence (LR) following breast-conserving surgery. METHODS: We studied 1,032 consecutive patients with invasive cancer who received lumpectomies and cavity margin (CM) assessments from January 2003 to November 2012. The following data were collected: patient age, cT stage, pT stage, grade, status of CM, lymph node status, menopausal status, ER, PR, HER-2, and Ki67, as well as the presence of extensive intraductal component (EIC) and lymphovascular invasion (LVI). A χ2 test was used to compare categorical baseline characteristics. Univariate and multivariate logistic regression analyses were performed to evaluate associations between pathologic features of CM status. Kaplan-Meier actuarial cumulative rates of LR (ipsilateral in-breast) were calculated. RESULTS: A total of 7,884 pieces of marginal tissue were collected from 1,032 patients, and 209 patients had positive CMs. Of the patients tested, 52.3% had luminal A subtype, 14.9% were luminal B, 12.8% were luminal-HER-2, 8.1% were HER-2 enriched, and 11.8% were triple negative. Univariate analysis showed that EIC (P < 0.001), LVI (P = 0.026), pN stage (N1 vs. N0: P = 0.018; N3 vs. N0: P < 0.001), and luminal B (P = 0.001) and HER-2 (P < 0.001) subtypes were associated with positive CMs. Multivariable analysis indicated that only EIC (P < 0.001), pN stage (P = 0.003), and HER-2 subtype (P < 0.001) were significantly correlated with positive CMs. On multivariable analysis, HER-2 subtype was an independent prognostic factor in LR (P = 0.031). CONCLUSIONS: The HER-2 subtype was the predictive factor most associated with positive CMs and an independent prognostic factor for LR. This result suggests that the increased risk of LR in HER-2 breast cancer is due to an increased microscopic invasive tumor burden, which is indicated by margin status after lumpectomy.

Knowledge, attitudes and practices towards the diagnosis and management of paediatric sepsis among paediatric physicians and nurses: a cross-sectional study of 21 hospitals in Hubei Province, China.

OBJECTIVES: To evaluate the knowledge, attitudes and practices towards diagnosing and managing paediatric sepsis among paediatric physicians and nurses. DESIGN: A cross-sectional, questionnaire-based study. SETTING: 21 hospitals in Hubei Province between February 2023 and March 2023. PARTICIPANTS: Paediatric physicians and nurses. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: The questionnaire contained 35 items across four dimensions (demographic information, knowledge, attitude and practice). RESULTS: The study included 295 participants (173 women). The average knowledge, attitude and practice scores were 10.93±2.61 points (possible range, 0-20 points), 32.22±2.65 points (possible range, 7-35 points) and 36.54±5.24 points (possible range, 9-45 points), respectively. Knowledge had a direct influence on both attitude (ß=0.240, 95% CI 0.136 to 0.365, p=0.009) and practice (ß=0.278, 95% CI 0.084 to 0.513, p=0.010), which also indirectly influenced practice through attitude (ß=0.162, 95% CI 0.078 to 0.290, p=0.007). Attitude directly influenced practice (ß=0.677, 95% CI 0.384 to 0.902, p=0.025). A higher attitude score was associated with good practice (OR=1.392; 95% CI 1.231 to 1.576; p<0.001), while not working in a tertiary hospital reduced the odds of good practice (OR=0.443; 95% CI 0.2390.821; p=0.010). CONCLUSIONS: The knowledge regarding paediatric sepsis, especially knowledge about sepsis management, is poor among paediatric physicians and nurses in Hubei Province. The findings of this study may facilitate the development and implementation of training programmes to improve the diagnosis and management of paediatric sepsis.

A novel mechanism of PHB2-mediated mitophagy participating in the development of Parkinson's disease.

JOURNAL/nrgr/04.03/01300535-202408000-00037/figure1/v/2023-12-16T180322Z/r/image-tiff Endoplasmic reticulum stress and mitochondrial dysfunction play important roles in Parkinson's disease, but the regulatory mechanism remains elusive. Prohibitin-2 (PHB2) is a newly discovered autophagy receptor in the mitochondrial inner membrane, and its role in Parkinson's disease remains unclear. Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a factor that regulates cell fate during endoplasmic reticulum stress. Parkin is regulated by PERK and is a target of the unfolded protein response. It is unclear whether PERK regulates PHB2-mediated mitophagy through Parkin. In this study, we established a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. We used adeno-associated virus to knockdown PHB2 expression. Our results showed that loss of dopaminergic neurons and motor deficits were aggravated in the MPTP-induced mouse model of Parkinson's disease. Overexpression of PHB2 inhibited these abnormalities. We also established a 1-methyl-4-phenylpyridine (MPP+)-induced SH-SY5Y cell model of Parkinson's disease. We found that overexpression of Parkin increased co-localization of PHB2 and microtubule-associated protein 1 light chain 3, and promoted mitophagy. In addition, MPP+ regulated Parkin involvement in PHB2-mediated mitophagy through phosphorylation of PERK. These findings suggest that PHB2 participates in the development of Parkinson's disease by interacting with endoplasmic reticulum stress and Parkin.

Nur77 increases mitophagy and decreases aggregation of α-synuclein by modulating the p-c-Abl/p-PHB2 Y121 in α-synuclein PFF SH-SY5Y cells and mice.

Parkinson's disease (PD) is characterized by the progressive death of dopamine (DA) neurons and the pathological accumulation of α-synuclein (α-syn) fibrils. In our previous study, simulated PHB2 phosphorylation was utilized to clarify the regulatory role of c-Abl in PHB2-mediated mitophagy in PD models. In this investigation, we employed an independently patented PHB2Y121 phosphorylated antibody in the PD model to further verify that the c-Abl inhibitor STI571 can impede PHB2Y121 phosphorylation, decrease the formation of α-Syn polymers, and improve autophagic levels. The specific involvement of Nur77 in PD pathology has remained elusive. We also investigate the contribution of Nur77, a nuclear transcription factor, to α-syn and mitophagy in PD. Our findings demonstrate that under α-syn, Nur77 translocates from the cytoplasm to the mitochondria, improving PHB-mediated mitophagy by regulating c-Abl phosphorylation. Moreover, Nur77 overexpression alleviates the expression level of pS129-α-syn and the loss of DA neurons in α-syn PFF mice, potentially associated with the p-c-Abl/p-PHB2 Y121 axis. This study provides initial in vivo and in vitro evidence that Nur77 protects PD DA neurons by modulating the p-c-Abl/p-PHB2 Y121 axis, and STI571 holds promise as a treatment for PD.

Deciphering the role of apoptosis signature on the immune dynamics and therapeutic prognosis in breast cancer: Implication for immunotherapy.

Background: In breast cancer oncogenesis, the precise role of cell apoptosis holds untapped potential for prognostic and therapeutic insights. Thus, it is important to develop a model predicated for breast cancer patients' prognosis and immunotherapy response based on apoptosis-related signature. Methods: Our approach involved leveraging a training dataset from The Cancer Genome Atlas (TCGA) to construct an apoptosis-related gene prognostic model. The model's validity was then tested across several cohorts, including METABRIC, Sun Yat-sen Memorial Hospital Sun Yat-sen University (SYSMH), and IMvigor210, to ensure its applicability and robustness across different patient demographics and treatment scenarios. Furthermore, we utilized Quantitative Polymerase Chain Reaction (qPCR) analysis to explore the expression patterns of these model genes in breast cancer cell lines compared to immortalized mammary epithelial cell lines, aiming to confirm their differential expression and underline their significance in the context of breast cancer. Results: Through the development and validation of our prognostic model based on seven apoptosis-related genes, we have demonstrated its substantial predictive power for the survival outcomes of breast cancer patients. The model effectively stratified patients into high and low-risk categories, with high-risk patients showing significantly poorer overall survival in the training cohort and across all validation cohorts. Importantly, qPCR analysis confirmed that the genes constituting our model indeed exhibit differential expression in breast cancer cell lines when contrasted with immortalized mammary epithelial cell lines. Conclusion: Our study establishes a groundbreaking prognostic model using apoptosis-related genes to enhance the precision of breast cancer prognosis and treatment, particularly in predicting immunotherapy response.

Rutin Attenuates Oxidative Stress Via PHB2-Mediated Mitophagy in MPP+-Induced SH-SY5Y Cells.

Oxidative stress plays a crucial role in the occurrence and development of Parkinson's disease (PD). Rutin, a natural botanical ingredient, has been shown to have antioxidant properties. Therefore, the aim of this study was to investigate the neuroprotective effects of rutin on PD and the underlying mechanisms. MPP+(1-methyl-4-phenylpyridinium ions)-treated SH-SY5Y cells were used as an in vitro model of PD. Human PHB2-shRNA lentiviral particles were transfected into SH-SY5Y cells to interfere with the expression of Prohibitin2 (PHB2). The oxidative damage of cells was analyzed by detecting intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and mitochondrial membrane potential (MMP). Western blotting was used to detect the protein expression of antioxidant factors such as nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NADPH quinone oxidoreductase-1 (NQO-1), and mitophagy factors PHB2, translocase of outer mitochondrial membrane 20 (TOM20), and LC3II/LC3I (microtubule-associated protein II light chain 3 (LC3II) to microtubule-associated protein I light chain 3 (LC3I)). In addition, we also examined the expression of PHB2 and LC3II/LC3I by immunofluorescence staining. MPP+ treatment significantly increased the generation of ROS and MDA and the level of MMP depolarization and decreased the protein expression of Nrf2, HO-1, NQO1, TOM20, PHB2, and LC3II/LC3I. In MPP+-treated SH-SY5Y cells, rutin significantly decreased the generation of ROS and MDA and the level of MMP depolarization and increased the protein expression of Nrf2, HO-1, NQO-1, TOM20, PHB2, and LC3II/LC3I. However, the protective role of rutin was inhibited in PHB2-silenced cells. Rutin attenuates oxidative damage which may be associated with PHB2-mediated mitophagy in MPP+-induced SH-SY5Y cells. Rutin might be used as a potential drug for the prevention and treatment of PD.