Excavating regulated cell death signatures to predict prognosis, tumor microenvironment and therapeutic response in HR+/HER2- breast cancer.

Regulated cell death (RCD) has been documented to have great potentials for discovering novel biomarkers and therapeutic targets in malignancies. But its role and clinical value in HR+/HER2- breast cancer, the most common subtype of breast cancer, are obscure. In this study, we comprehensively explored 12 types of RCD patterns and found extensive mutations and dysregulations of RCD genes in HR+/HER2- breast cancer. A prognostic RCD scoring system (CDScore) based on six critical genes (LEF1, SLC7A11, SFRP1, IGFBP6, CXCL2, STXBP1) was constructed, in which a high CDScore predicts poor prognosis. The expressions and prognostic value of LEF1 and SFRP1were also validated in our tissue microarrays. The nomogram established basing on CDScore, age and TNM stage performed satisfactory in predicting overall survival, with an area under the ROC curve of 0.89, 0.82 and 0.8 in predicting 1-year, 3-year and 5-year overall survival rates, respectively. Furthermore, CDScore was identified to be correlated with tumor microenvironments and immune checkpoints by excavation of bulk and single-cell sequencing data. Patients in CDScore high group might be resistant to standard chemotherapy and target therapy. Our results underlined the potential effects and importance of RCD in HR+/HER2- breast cancer and provided novel biomarkers and therapeutic targets for HR+/HER2- breast cancer patients.

Efficacy and Safety of General Anesthesia Induction with Ciprofol in Hip Fracture Surgery of Elderly Patients: A Randomized Controlled Trial.

Background: Ciprofol is a new intravenous sedative / anesthetic drug. In recent years, many clinical studies have also confirmed the sedative effect of ciprofol. However, more clinical research is still needed on its clinical application characteristics in special populations. Objective: The aim of this study was to compare the clinical effects of ciprofol and propofol in general anesthesia induction of elderly patients. Methods: 60 elderly (aged ≥ 75 years) patients underwent hip fracture surgery were randomly into two groups of a 1:1 ratio. Group C (ciprofol group): 0.3mg/kg ciprofol was infused. Group P (propofol group): 1.5mg/kg propofol was infused. The observation period was from the infusion of test drug to 5 min after endotracheal intubation. The primary outcomes included the incidence of severe hypotension and hypotension during the observation period. The secondary outcomes were as follows: the success rate of general anesthesia induction, the number of additional sedation, the time of loss of consciousness (LOC), Δ MAP, Δ HR, adverse events and the frequency of vasoactive drugs used. Results: Finally, 60 subjects completed the study. Compared with Group P, the incidence of severe hypotension in Group C was lower (26.7% vs 53.3%, P = 0.035), the incidence of hypotension was also lower (36.7% vs 63.3%, P = 0.037), Δ MAP in Group C was significantly lower (31.4 ± 11.4 vs 39.6 ± 15.7, P = 0.025), the frequency of ephedrine used and the incidence of injection pain in Group C were also significantly lower. Conclusion: Ciprofol showed similar efficacy to propofol when used for general anesthesia induction in elderly patients underwent hip fracture surgery and could maintain more stable blood pressure.

Changes in short-chain fatty acids affect brain development in mice with early life antibiotic-induced dysbacteriosis.

Background: Early enteral nutrition and the gut microbiota profoundly influence neonatal brain development, with short-chain fatty acids (SCFAs) from the microbiota playing a pivotal role. Understanding the relationship between dysbiosis, SCFAs, and brain development is crucial. In this study, we investigated the impact of antibiotics on the concentration of SCFAs in neonatal feces. Additionally, we developed a model of gut dysbiosis in neonatal mice to examine the potential relationship between this imbalance, SCFAs production, and brain function development. Methods: We measured the SCFAs content in the feces of two groups of neonates, categorized based on whether antibiotics were used, and conducted the Neonatal Behavioral Neurological Assessment (NBNA) test on all neonates. Then we evaluated fecal SCFAs levels in neonates and neonatal mice post-antibiotic treatment using liquid chromatography-mass spectrometry (LC-MS) analysis. Morris water maze (MWM) tests assessed behavioral performance, and western blot analysis examined brain tissue-related proteins-neuron-specific enolase (NSE), ionized calcium binding adaptor molecule-1 (IBA1), and myelin basic proteins (MBP). Results: The use of antibiotics did not affect the NBNA scores of the two groups of neonates, but it did reduce the SCFAs content in their feces. Antibiotic administration induced gut dysbiosis in mice, resulting in decreased IBA1 and MBP expression. Interventions to restore gut microbiota ameliorated these effects. Mice with dysbiosis displayed cognitive deficits in the MWM test. SCFAs levels decreased during dysbiosis, and increased upon microbiota recovery. Conclusions: Neonatal dysbiosis affects the microbiota-gut-brain axis, impairing cognitive function and nervous system development. Reduced SCFAs may contribute significantly to these alterations.

BRD4-specific PROTAC inhibits basal-like breast cancer partially through downregulating KLF5 expression.

Interest in the use of proteolysis-targeting chimeras (PROTACs) in cancer therapy has increased in recent years. Targeting bromodomain and extra terminal domain (BET) proteins, especially bromodomain-containing protein 4 (BRD4), has shown inhibitory effects on basal-like breast cancer (BLBC). However, the bioavailability of BRD4 PROTACs is restricted by their non-selective biodegradability and low tumor-targeting ability. We demonstrated that 6b (BRD4 PROTAC) suppresses BLBC cell growth by targeting BRD4, but not BRD2 and BRD3, for cereblon (CRBN)-mediated ubiquitination and proteasomal degradation. Compound 6b also inhibited expression of Krüppel-like factor 5 (KLF5) transcription factor, a key oncoprotein in BLBC, controlled by BRD4-mediated super-enhancers. Moreover, 6b inhibited HCC1806 tumor growth in a xenograft mouse model. The combination of 6b and KLF5 inhibitors showed additive effects on BLBC. These results suggest that BRD4-specific PROTAC can effectively inhibit BLBC by downregulating KLF5, and that 6b has potential as a novel therapeutic drug for BLBC.

[Retracted] MicroRNA­9 inhibits gastric cancer cell proliferation and migration by targeting neuropilin­1.

[This retracts the article DOI: 10.3892/etm.2019.7841.].

LMP1 enhances aerobic glycolysis in natural killer/T cell lymphoma.

Natural killer/T cell lymphoma (NKTCL) exhibits highly aggressive clinical behavior, and the outcomes for relapsed/refractory patients are still poor. Recently, the mechanism underlying the effect of Epstein-Barr virus (EBV) infection, which has not been fully defined in NKTCL, has attracted great attention. We explored how LMP1 promoted aerobic glycolysis via metabolic sequencing combined with mRNA sequencing and immunoprecipitation coupled to mass spectrometry. Experimental assays were used to determine the effects of LMP1 and its downstream pathway on the function and glucose metabolism of NKTCL cells. The correlations between LMP1 expression in patients and their clinical features, treatment response, and prognosis were analyzed. Results show that LMP1 enhances NKTCL cell proliferation in vitro and in vivo, inhibits apoptosis, and decreases gemcitabine sensitivity. In addition, LMP1 also enhances aerobic glycolysis in NKTCL cells, as indicated by increases in glucose uptake, lactate production, and extracellular acidification rate. Clinically, LMP1 expression is correlated with risk stratification, treatment response, and prognosis, and higher LMP1 expression indicates greater SUVmax for NKTCL patients. Mechanistically, LMP1 competitively binds to TRAF3 to promote cell proliferation and aerobic glycolysis by regulating the noncanonical NF-κB pathway. The application of an NF-κB pathway inhibitor or reactivation of the NF-κB pathway affects aerobic glycolysis and the biological function of NKTCL cells. In summary, this study is the first to describe and define in detail how LMP1 affects glucose metabolism in NKTCL and might provide a novel perspective for further treatment.

Rhabdomyosarcoma of the biliary tract in a child: a case report.

Pediatric rhabdomyosarcoma of the biliary tract (BRMS) is extremely rare. Here, we present a case of a 2-year-old child who was initially misdiagnosed with choledocholithiasis upon admission. The diagnosis was later confirmed as BRMS through endoscopic retrograde cholangiopancreatography (ERCP). The patient was cured through surgery followed by chemotherapy. Due to the lack of specific early symptoms and the challenges in imaging differentiation, particularly in pediatric patients, clinical awareness of this condition needs to be heightened. Our findings indicate that ERCP is currently the optimal diagnostic tool for this disease, and a combination of surgery and chemotherapy can yield better therapeutic outcomes.

PPM1G promotes autophagy and progression of pancreatic cancer via upregulating HMGB1.

Pancreatic cancer remains one of the most aggressive and lethal malignancies worldwide, with a dismal 5-year relative survival rates of only 12%. Therefore, it is urgent to discover the key molecular markers to improve the therapeutic outcomes in pancreatic cancer. Herein, we first demonstrated that PPM1G is upregulated in pancreatic cancer and that PPM1G depletion decreases pancreatic cancer cell growth in vitro and in vivo. High PPM1G expression was linked to short overall survival of pancreatic cancer patients, which was further validated in the TCGA database. Moreover, by detecting Beclin 1, LC3-II, and SQSTM1/p62 expressions and observing autolysosome under transmission electron microscope, we discovered that PPM1G is a novel positive regulator of macroautophagy/autophagy. Furthermore, by using immunoprecipitation-mass spectrometry (IP-MS) analysis and following systemic molecular biology experiment, we demonstrated PPM1G promotes the autophagy and proliferation of pancreatic cancer by directly upregulating HMGB1. Additionally, patients with both high PPM1G and high HMGB1 exhibited poorer prognosis in our cohort. This study preliminarily investigated the possibility of PPM1G as a potential therapeutic target and prognostic biomarker in pancreatic cancer patients.

Learning Student Network Under Universal Label Noise.

Data-free knowledge distillation aims to learn a small student network from a large pre-trained teacher network without the aid of original training data. Recent works propose to gather alternative data from the Internet for training student network. In a more realistic scenario, the data on the Internet contains two types of label noise, namely: 1) closed-set label noise, where some examples belong to the known categories but are mislabeled; and 2) open-set label noise, where the true labels of some mislabeled examples are outside the known categories. However, the latter is largely ignored by existing works, leading to limited student network performance. Therefore, this paper proposes a novel data-free knowledge distillation paradigm by utilizing a webly-collected dataset under universal label noise, which means both closed-set and open-set label noise should be tackled. Specifically, we first split the collected noisy dataset into clean set, closed noisy set, and open noisy set based on the prediction uncertainty of various data types. For the closed-set noisy examples, their labels are refined by teacher network. Meanwhile, a noise-robust hybrid contrastive learning is performed on the clean set and refined closed noisy set to encourage student network to learn the categorical and instance knowledge inherited by teacher network. For the open-set noisy examples unexplored by previous work, we regard them as unlabeled and conduct self-supervised learning on them to enrich the supervision signal for student network. Intensive experimental results on image classification tasks demonstrate that our approach can achieve superior performance to state-of-the-art data-free knowledge distillation methods.

The benefit of favorable venous outflow profiles is mediated through the reduced risk of intracranial hemorrhage in acute ischemic stroke patients undergoing endovascular treatment.

BACKGROUND: Favorable venous outflow (VO) has been recognized as an independent predictor of excellent clinical outcomes in acute ischemic stroke caused by anterior circulation large vessel occlusion (AIS-LVO) patients who received endovascular treatment (EVT). However, the reasons why VO affects clinical outcomes have not been fully explained. In this study, we aimed to identify the potential mediators of VO affecting prognosis. METHODS: We conducted a multicenter retrospective cohort study of consecutive patients with AIS-LVO who underwent EVT. Baseline computed tomographic angiography (CTA) was applied to assess VO by the Cortical Vein Opacification Score (COVES). The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS) score of 0-2). Classifying subtypes of intracranial hemorrhage (ICH) to explore the relationship between ICH subtypes and VO. Multivariate logistic regression and causal mediation analyses were used to evaluate the relationship among VO, functional independence, and potential mediators. RESULTS: Among 860 AIS-LVO patients undergoing EVT, a total of 515 patients were included in the present study after strict screening. In multivariate logistic regression analysis, favorable VO profiles (defined as COVES 3-6) were significantly associated with a lower incidence of ICH (24.2% vs 46.9%, adjusted odds ratio (aOR) 0.48, 95% confidence interval (CI) 0.30 to 0.77, P=0.002) and a higher proportion of functional independence (58.9% vs 15.0%, aOR 4.07, 95% CI 2.41 to 6.88, P<0.001). Mediation analysis showed that favorable VO profiles significantly reduced the incidence of parencuymal hematoma (PH) 2 accounting for 8.0% (95% CI 0.9% to 19.0%) of its beneficial effect on functional independence. CONCLUSION: This study demonstrated the potential mediating effects of severe ICH for the beneficial effect of favorable VO on clinical prognosis among patients with AIS-LVO who underwent EVT.

Chronic mitral regurgitation predicts acute heart failure and worse outcomes after endovascular treatment for large vessel occlusion stroke.

BACKGROUND: Valvular diseases are widely recognized as important etiologies for large vessel occlusion stroke (LVO) but their impact on outcomes among patients with LVO receiving endovascular treatment (EVT) are less well delineated. METHODS: This study was a post hoc exploratory analysis of the RESCUE-BT trial, DEVT trial and BASILAR prospective registry. Outcome measures included the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage, and post-stroke early acute heart failure (EAHF). Chronic significant mitral regurgitation (csMR) was defined as a long-existing mitral regurgitation (MR) with moderate-to-severe MR grade examined by the transthoracic echocardiography. Adjusted odds ratio (aOR) and 95% confidence interval (CI) were obtained by logistic regression models. RESULTS: Among 2011 patients in these three studies, 837 individuals receiving EVT with available information for valvular status were included in this study. In all categories of chronic valvular disorders, only csMR was related to very poor outcomes (mRS 5-6, aOR 2.76 (95% CI 1.59 to 4.78), P<0.001). CsMR (aOR 7.65 (95% CI 4.33 to 13.49), P<0.001) was an independent predictor of post-stroke EAHF. Mediation analysis showed that csMR increased EAHF instead of reocclusion events or venous thrombosis mediated its effects on functional outcome (49.50% (95% CI 24.83% to 90.00%)). Identical results of csMR on clinical outcomes and post-stroke EAHF were detected in novel cohorts constructed by propensity score matching and sensitivity analysis. CONCLUSION: Our study demonstrated that csMR was a mediator of heart-brain interaction associated with poor outcomes of LVO after EVT by increasing the frequency of post-stroke EAHF. Replication of these findings in a larger cohort is warranted.

Prototype Learning Guided Hybrid Network for Breast Tumor Segmentation in DCE-MRI.

Automated breast tumor segmentation on the basis of dynamic contrast-enhancement magnetic resonance imaging (DCE-MRI) has shown great promise in clinical practice, particularly for identifying the presence of breast disease. However, accurate segmentation of breast tumor is a challenging task, often necessitating the development of complex networks. To strike an optimal tradeoff between computational costs and segmentation performance, we propose a hybrid network via the combination of convolution neural network (CNN) and transformer layers. Specifically, the hybrid network consists of a encoder-decoder architecture by stacking convolution and deconvolution layers. Effective 3D transformer layers are then implemented after the encoder subnetworks, to capture global dependencies between the bottleneck features. To improve the efficiency of hybrid network, two parallel encoder sub-networks are designed for the decoder and the transformer layers, respectively. To further enhance the discriminative capability of hybrid network, a prototype learning guided prediction module is proposed, where the category-specified prototypical features are calculated through online clustering. All learned prototypical features are finally combined with the features from decoder for tumor mask prediction. The experimental results on private and public DCE-MRI datasets demonstrate that the proposed hybrid network achieves superior performance than the state-of-the-art (SOTA) methods, while maintaining balance between segmentation accuracy and computation cost. Moreover, we demonstrate that automatically generated tumor masks can be effectively applied to identify HER2-positive subtype from HER2-negative subtype with the similar accuracy to the analysis based on manual tumor segmentation. The source code is available at https://github.com/ZhouL-lab/ PLHN.

Alloferon Mitigates LPS-Induced Endometritis by Attenuating the NLRP3/CASP1/IL-1ß/IL-18 Signaling Cascade.

Endometritis is an inflammatory reaction of the uterine lining that can lead to infertility. Alloferon, a linear non-glycosylated oligopeptide, has been recognized for its potent anti-inflammatory and immunomodulatory effects. In light of these attributes, this study aims to explore the potential therapeutic effects of alloferon in alleviating endometrial inflammation induced by lipopolysaccharide (LPS), while elucidating the underlying protective mechanisms. Two conditions representing pre- and post-menopause states were simulated using an ovariectomized (Ovx) murine model. The findings underscore alloferon's remarkable capacity to alleviate cardinal signs of endometritis, including redness, swelling, and congestion, while concurrently restoring the structural integrity of the endometrial tissue. Moreover, alloferon effectively modulates the expression of key inflammatory mediators, such as nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), cysteine aspartate-specific protease 1 (CASP1), interleukin-1ß (IL-1ß), and interleukin-18 (IL-18). In vitro experiments were conducted to further corroborate and validate these findings. In conclusion, alloferon shows promising potential in mitigating LPS-induced inflammation by attenuating the NLRP3/CASP1/IL-1ß/IL-18 signaling cascade.

A systematic literature review of 74 Chinese blastic plasmacytoid dendritic cell neoplasm patients.

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological cancer. Due to its low incidence, researchers struggle to gather sufficient prospective data to inform clinical treatment. Objectives: We sought to summarize the clinical characteristics and current treatment methods of BPDCN and provide more specific guidance on treatment options. Design: A systematic literature review using data from 74 Chinese BPDCN patients. Date resources and methods: We retrospectively analyzed the clinical manifestations, treatment response, survival outcomes, and prognostic factors of six BPDCN patients treated at the First Affiliated Hospital of Zhengzhou University and 68 patients described in 28 articles published in the China Knowledge Network database since 2019. Results: In Chinese patients, the disease occurred with a male-to-female ratio of 2.52 and a median age of onset of 50 years in adults and 10 years in pediatric patients. Immunohistochemical analysis revealed distinctive immune phenotypes of BPDCN cells, characterized by high expression levels of CD4, CD56, CD123, and HLA-DR, while showing minimal to no expression of myeloperoxidase (MPO), CD20, and CD79a. There was no significant difference in the initial complete remission (CR) rate, relapse rate, and the overall survival (OS) time of patients receiving acute myeloid leukemia-like, acute lymphocytic leukemia-like, or non-Hodgkin's lymphoma-like chemotherapy regimens. Univariate analysis identified CD3 expression, male gender, and central nervous system infiltration as hazardous factors. In multivariate analysis, age proved to be an independent prognostic indicator, indicating better prognosis and longer OS time in younger patients. Notably, hematopoietic stem cell transplantation (HSCT) emerged as a significant factor in improving the survival outcomes for individuals diagnosed with BPDCN. However, further investigation is needed to explore the role of HSCT and the best timing for its implementation in pediatric BPDCN patients. Conclusion: Administering HSCT during the initial CR state following inductive chemotherapy might extend the OS and improve the prognosis of patients with BPDCN.

Systematic literature review of 74 BPDCN patients Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm that derives from the precursors of plasmacytoid dendritic cell (pDC), accounting for 0.44% of hematological malignancy. Although CD123 targeted therapy has been implemented in the treatment of BPDCN, but a unique complication, capillary leak syndrome presents a therapeutic challenge, and retrospective analysis of conventional chemotherapy regimens is of irreplaceable importance for patients cannot tolerate CD123 targeted therapy. For the first time, we conduced retrospective analysis of large-scale clinical cases based on Chinese patients, and found that age and hematopoietic stem cell transplantation (HSCT) were two independent prognostic factors of BPDCN. In conclusion, younger patients had longer overall survival (OS) time and better prognosis. Combining HSCT in the initial complete remission state significantly prolonged the OS time and improved survival outcomes of BPDCN patients.

Noninvasive imaging-guided ultrasonic neurostimulation with arbitrary 2D patterns and its application for high-quality vision restoration.

Retinal degeneration, a leading cause of irreversible low vision and blindness globally, can be partially addressed by retina prostheses which stimulate remaining neurons in the retina. However, existing electrode-based treatments are invasive, posing substantial risks to patients and healthcare providers. Here, we introduce a completely noninvasive ultrasonic retina prosthesis, featuring a customized ultrasound two-dimensional array which allows for simultaneous imaging and stimulation. With synchronous three-dimensional imaging guidance and auto-alignment technology, ultrasonic retina prosthesis can generate programmed ultrasound waves to dynamically and precisely form arbitrary wave patterns on the retina. Neuron responses in the brain's visual center mirrored these patterns, evidencing successful artificial vision creation, which was further corroborated in behavior experiments. Quantitative analysis of the spatial-temporal resolution and field of view demonstrated advanced performance of ultrasonic retina prosthesis and elucidated the biophysical mechanism of retinal stimulation. As a noninvasive blindness prosthesis, ultrasonic retina prosthesis could lead to a more effective, widely acceptable treatment for blind patients. Its real-time imaging-guided stimulation strategy with a single ultrasound array, could also benefit ultrasound neurostimulation in other diseases.