Development and Validation of a Supplementary Grading Scale for Outcomes of Brainstem Cavernous Malformations.

BACKGROUND: Surgical risk assessment is intriguing for clinical decision-making of brainstem cavernous malformation (BSCM) treatment. While the BSCM grading scale, encompassing size, developmental venous anomaly, crossing axial midpoint, age, and timing of intervention, is increasingly utilized, the clinical relevance of neurological fluctuation and recurrent hemorrhage has not been incorporated. This study aimed to propose a supplementary grading scale with enhanced predictive efficacy. METHODS: Using a retrospective nationwide registry of consecutive patients with BSCMs undergoing surgery in China from March 2011 to May 2023, a new supplementary BSCM grading scale was developed from a derivative cohort of 260 patients and validated in an independent concurrent cohort of 67 patients. The primary outcome was unfavorable neurological function (modified Rankin Scale score >2) at the latest follow-up. The performance of the supplementary grading system was evaluated for discrimination, calibration, and clinical utility and further compared with its original counterpart. RESULTS: Over a follow-up of at least 6 months after surgery, the unfavorable outcomes were 31% in the overall cohort (101/327 patients). A preoperative motor deficit (odds ratio, 3.13; P=0.001), recurrent hemorrhage (odds ratio, 3.05; P<0.001), timing of intervention (odds ratio, 7.08; P<0.001), and crossing the axial midpoint (odds ratio, 2.57; P=0.006) were associated with the unfavorable outcomes and composed the initial Huashan grading variables. A supplementary BSCM grading system was subsequently developed by incorporating the Huashan grading variables into the original BSCM grading scale. The predictive capability of the supplementary scale was consistently superior to the original counterpart in either the derivative cohort (area under the receiver operating characteristic curve, 0.74 [95% CI, 0.68-0.80] for the supplementary versus 0.68 [95% CI, 0.61-0.74] for the original) or the validation cohort (0.75 [95% CI, 0.62-0.87] versus 0.64 [95% CI, 0.48-0.81]). CONCLUSIONS: This study highlights the neurological relevance of BSCM hemorrhage in surgical risk assessment. Via compositing preoperative motor function and recurrent hemorrhages, a supplementary grading scale may improve a dynamic risk assessment for clinical decisions in the management of BSCMs.

Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

Emulation and evaluation of tumor cell combined chemotherapy in isotropic/anisotropic collagen fiber microenvironments.

The rapid emergence of anisotropic collagen fibers in the tissue microenvironment is a critical transition point in late-stage breast cancer. Specifically, the fiber orientation facilitates the likelihood of high-speed tumor cell invasion and metastasis, which pose lethal threats to patients. Thus, based on this transition point, one key issue is how to determine and evaluate efficient combination chemotherapy treatments in late-stage cancer. In this study, we designed a collagen microarray chip containing 241 high-throughput microchambers with embedded metastatic breast cancer cell MDA-MB-231-RFP. By utilizing collagen's unique structure and hydromechanical properties, the chip constructed three-dimensional isotropic and anisotropic collagen fiber structures to emulate the tumor cell microenvironment at early and late stages. We injected different chemotherapeutic drugs into its four channels and obtained composite biochemical concentration profiles. Our results demonstrate that anisotropic collagen fibers promote cell proliferation and migration more than isotropic collagen fibers, suggesting that the geometric arrangement of fibers plays an important role in regulating cell behavior. Moreover, the presence of anisotropic collagen fibers may be a potential factor leading to the poor efficacy of combined chemotherapy in late-stage breast cancer. We investigated the efficacy of various chemotherapy drugs using cell proliferation inhibitors paclitaxel and gemcitabine and tumor cell migration inhibitors 7rh and PP2. To ensure the validity of our findings, we followed a systematic approach that involved testing the inhibitory effects of these drugs. According to our results, the drug combinations' effectiveness could be ordered as follows: paclitaxel + gemcitabine > gemcitabine + 7rh > PP2 + paclitaxel > 7rh + PP2. This study shows that the biomimetic chip system not only facilitates the creation of a realistic in vitro model for examining the cell migration mechanism in late-stage breast cancer but also has the potential to function as an effective tool for future chemotherapy assessment and personalized medicine.

Critical roles and clinical perspectives of RNA methylation in cancer.

RNA modification, especially RNA methylation, is a critical posttranscriptional process influencing cellular functions and disease progression, accounting for over 60% of all RNA modifications. It plays a significant role in RNA metabolism, affecting RNA processing, stability, and translation, thereby modulating gene expression and cell functions essential for proliferation, survival, and metastasis. Increasing studies have revealed the disruption in RNA metabolism mediated by RNA methylation has been implicated in various aspects of cancer progression, particularly in metabolic reprogramming and immunity. This disruption of RNA methylation has profound implications for tumor growth, metastasis, and therapy response. Herein, we elucidate the fundamental characteristics of RNA methylation and their impact on RNA metabolism and gene expression. We highlight the intricate relationship between RNA methylation, cancer metabolic reprogramming, and immunity, using the well-characterized phenomenon of cancer metabolic reprogramming as a framework to discuss RNA methylation's specific roles and mechanisms in cancer progression. Furthermore, we explore the potential of targeting RNA methylation regulators as a novel approach for cancer therapy. By underscoring the complex mechanisms by which RNA methylation contributes to cancer progression, this review provides a foundation for developing new prognostic markers and therapeutic strategies aimed at modulating RNA methylation in cancer treatment.

Inhibition of PARP1 improves cardiac function after myocardial infarction via up-regulated NLRC5.

The incidence and mortality rate of myocardial infarction are increasing per year in China. The polarization of macrophages towards the classically activated macrophages (M1) phenotype is of utmost importance in the progression of inflammatory stress subsequent to myocardial infarction. Poly (ADP-ribose) polymerase 1(PARP1) is the ubiquitous and best characterized member of the PARP family, which has been reported to support macrophage polarization towards the pro-inflammatory phenotype. Yet, the role of PARP1 in myocardial ischemic injury remains to be elucidated. Here, we demonstrated that a myocardial infarction mouse model induced cardiac damage characterized by cardiac dysfunction and increased PARP1 expression in cardiac macrophages. Inhibition of PARP1 by the PJ34 inhibitors could effectively alleviate M1 macrophage polarization, reduce infarction size, decrease inflammation and rescue the cardiac function post-MI in mice. Mechanistically, the suppression of PARP1 increase NLRC5 gene expression, and thus inhibits the NF-κB pathway, thereby decreasing the production of inflammatory cytokines such as IL-1ß and TNF-α. Inhibition of NLRC5 promote infection by effectively abolishing the influence of this mechanism discussed above. Interestingly, inhibition of NLRC5 promotes cardiac macrophage polarization toward an M1 phenotype but without having major effects on M2 macrophages. Our results demonstrate that inhibition of PARP1 increased NLRC5 gene expression, thereby suppressing M1 polarization, improving cardiac function, decreasing infarct area and attenuating inflammatory injury. The aforementioned findings provide new insights into the proinflammatory mechanisms that drive macrophage polarization following myocardial infarction, thereby introducing novel potential targets for future therapeutic interventions in individuals affected by myocardial infarction.

Association of hemorrhage-to-treatment time with outcomes in patients with brainstem cavernous malformations: a nationwide cohort study.

BACKGROUND: Brainstem cavernous malformations (BSCMs) often present with haemorrhage, but the optimal timing for microsurgical intervention remains unclear. This study aims to explore how intervention timing relates to neurological outcomes in haemorrhagic BSCM patients undergoing microsurgery, offering insights for clinical decisions. METHODS: A total of 293 consecutive patients diagnosed with BSCMs, who underwent microsurgery were identified between March 2011 and January 2023 at two comprehensive centres in China, with a postoperative follow-up duration exceeding 6 months. Utilizing logistic regression models with restricted cubic splines, distinct time groups were identified. Subsequently, matching weight analysis compared these groups in terms of outcomes, new haemorrhage rates, cranial nerve deficits, and perioperative complications. The primary outcome was an unfavourable outcome, which was defined as a mRS score greater than 2 at the latest follow-up. RESULTS: Among the 293 patients, 48.5% were female, median age was (39.9±14.3) years, and median haemorrhage-to-treatment time was 42 days. Patients were categorized into acute (≤21 days), subacute (22-42 days), and delay (>42 days) intervention groups. After matching, 186 patients were analyzed. Adjusted analysis showed lower unfavourable outcome rates for acute [adjusted odds ratio (OR), 0.73; 95% CI, 0.65-0.82; P<0.001] and subacute (adjusted OR, 0.83; 95% CI, 0.72-0.95; P=0.007) groups compared to the delay group. Subacute intervention led to fewer cranial nerve deficits (adjusted OR, 0.76; 95% CI, 0.66-0.88, P<0.001). New haemorrhage incidence didn't significantly differ among groups. CONCLUSIONS: For haemorrhagic BSCMs patients, delayed microsurgical intervention that exceeded 42 days after a prior haemorrhage were associated with an increased risk of unfavourable neurological outcomes.

Characterization of Flavor Profiles of Cigar Tobacco Leaves Grown in China via Headspace-Gas Chromatography-Ion Mobility Spectrometry Coupled with Multivariate Analysis and Sensory Evaluation.

Although cigar tobacco leaves (CTLs) have a high economic value, research regarding the flavor characteristics of CTLs is currently limited. A comprehensive study of the flavor characteristics of CTLs from different regions of China was conducted by identifying their volatile-flavor-containing compounds (VFCs) and flavors. The samples were analyzed via gas chromatography-ion mobility spectrometry (GC-IMS) and sensory evaluation. Results revealed considerable differences in the VFC contents of CTLs from different regions of China, suggesting that the VFLs of CTLs could be influenced by geographical origin. Mainly, phenols, pyrazines, and aldehydes were present in the CTLs from Sichuan. High contents of esters and pyrazines were present in the CTLs from Hubei, while esters were the major components of the CTLs from Hainan. Multivariate analysis results showed the effective differentiation of samples from different geographical origins based on the GC-IMS results. Sensory evaluation revealed that the flavors of CTLs from different geographical origins were different. 1,8-Pinene, 3-methyl-3-butene-1-ol, 2,3-dimethyl-5-ethylpyrazine, 4-methyl-3-penten-2-one, and (E)-2-pentenal might serve as geographical marker compounds, indicating the geographical origin of CTLs based on the results of GC-IMS and sensory evaluation. This study may be beneficial for the trade of CTLs and the development of cigar products.

Adding Granular Activated Carbon and Zerovalent Iron to the High-Solid Anaerobic Digestion System of the Organic Fraction of Municipal Solid Waste: Anaerobic Digestion Performance and Microbial Community Analysis.

Anaerobic digestion (AD) performance and microbial dynamics were investigated in a high-solid anaerobic digestion (HSAD) system of the organic fraction of municipal solid waste (OFMSW). 1, 5, 10, and 15% (w/w, dry weight of the OFMSW) of granular activated carbon (GAC) and zerovalent iron (ZVI) were added to the HSAD system. The results showed that adding ZVI and GAC can improve the methane yield of the OFMSW. Notably, R-(GAC + ZVI) exhibited the highest cumulative methane yield of 343.0 mL/gVS, which was 57.1% higher than that of the R-control. At the genus level, the dominant bacteria included norank_f__norank_o__MBA03, norank_f__norank_o__norank_c__norank_p__Firmicutes, Fastidiosipila, norank_f__Rikenellaceae, and Sphaerochaeta, while Methanoculleus, Methanobacterium, and Methanosarcina were the dominant archaea. The highest relative abundance of norank_f__norank_o__norank_c__norank_p__Firmicutes was 30.8% for the R-(GAC + ZVI), which was 71.4% higher than that of the R-control. The relative abundance of Methanoculleus and Methanobacterium for the R-(GAC + ZVI) and the R-control group accounted for 79.0 and 90.8% of the total archaeal abundance, respectively. Additionally, the relative abundance of Methanosarcina was 10.6% for R-(GAC + ZVI), which was higher than that of the R-control (1.1%). After the addition of GAC and ZVI, the electron transfer capacity of the HSAD system was enhanced, resulting in promoted methane production. Thus, the simultaneous addition of GAC and ZVI to the HSAD system can be an effective strategy to promote the cumulative methane yield of the OFMSW.

Trans-radial artery microcatheter angiography-assisted juvenile ruptured brainstem arteriovenous malformation resection.

BACKGROUND: Due to their crucial functional location, surgical treatment of brainstem arteriovenous malformations (AVMs) has always been challenging. For unruptured AVMs, we can determine whether radiological therapy, interventional treatment, or surgical resection is feasible based on the AVM structure. However, for ruptured AVMs, microsurgical resection and interventional embolization are effective methods to prevent further rupture. In the microsurgical resection of AVMs, we usually use a hybrid operation to confirm the AVM structure and determine if the AVM is completely resected during the surgery. METHOD: We report a case of juvenile ruptured brainstem AVM resection. The right lateral position and left suboccipital retrosigmoid approach were used. We established an interventional approach via left radial artery and set a microcatheter in the feeding artery. Methylene blue injection via a microcatheter showed the AVM structure, and we totally resected the brainstem AVM under electrophysiological monitoring and navigation. Intraoperative angiography was performed to ensure complete resection without residual nidus. CONCLUSION: This case demonstrates that the trans-radial approach is convenient and safe for special positions in hybrid operations. Methylene blue injection via a microcatheter in the feeding artery provides clearer visualization of the AVM structure under the microscope.

Promotion effect of FOXCUT as a microRNA sponge for miR-24-3p on progression in triple-negative breast cancer through the p38 MAPK signaling pathway.

BACKGROUND: Triple-negative breast cancer (TNBC) is a type of highly invasive breast cancer with a poor prognosis. According to new research, long noncoding RNAs (lncRNAs) play a significant role in the progression of cancer. Although the role of lncRNAs in breast cancer has been well reported, few studies have focused on TNBC. This study aimed to explore the biological function and clinical significance of forkhead box C1 promoter upstream transcript (FOXCUT) in triple-negative breast cancer. METHODS: Based on a bioinformatic analysis of the cancer genome atlas (TCGA) database, we detected that the lncRNA FOXCUT was overexpressed in TNBC tissues, which was further validated in an external cohort of tissues from the General Surgery Department of the First Affiliated Hospital of Nanjing Medical University. The functions of FOXCUT in proliferation, migration, and invasion were detected in vitro or in vivo. Luciferase assays and RNA immunoprecipitation (RIP) were performed to reveal that FOXCUT acted as a competitive endogenous RNA (ceRNA) for the microRNA miR-24-3p and consequently inhibited the degradation of p38. RESULTS: lncRNA FOXCUT was markedly highly expressed in breast cancer, which was associated with poor prognosis in some cases. Knockdown of FOXCUT significantly inhibited cancer growth and metastasis in vitro or in vivo. Mechanistically, FOXCUT competitively bounded to miR-24-3p to prevent the degradation of p38, which might act as an oncogene in breast cancer. CONCLUSION: Collectively, this research revealed a novel FOXCUT/miR-24-3p/p38 axis that affected breast cancer progression and suggested that the lncRNA FOXCUT could be a diagnostic marker and therapeutic target for breast cancer.

Bone marrow mesenchymal stem cell­derived exosomes: A novel therapeutic agent for tendon­bone healing (Review).

In sports medicine, injuries related to the insertion of tendons into bones, including rotator cuff injuries, anterior cruciate ligament injuries and Achilles tendon ruptures, are commonly observed. However, traditional therapies have proven to be insufficient in achieving satisfactory outcomes due to the intricate anatomical structure associated with these injuries. Adult bone marrow mesenchymal stem cells possess self­renewal and multi­directional differentiation potential and can generate various mesenchymal tissues to aid in the recovery of bone, cartilage, adipose tissue and bone marrow hematopoietic tissue. In addition, extracellular vesicles derived from bone marrow mesenchymal stem cells known as exosomes, contain lipids, proteins and nucleic acids that govern the tissue microenvironment, facilitate tissue repair and perform various biological functions. Studies have demonstrated that bone marrow mesenchymal stem cell­derived exosomes can function as natural nanocapsules for drug delivery and can enhance tendon­bone healing strength. The present review discusses the latest research results on the role of exosomes released by bone marrow mesenchymal stem cells in tendon­bone healing and provides valuable information for implementing these techniques in regenerative medicine and sports health.

Aneurysmoraphy or bypass? Surgical strategy for large M1 bifurcation aneurysm involving two branches based on vessel wall high-resolution MRI and intraoperative angiography.

BACKGROUND: Middle cerebral artery (MCA) M1 bifurcation aneurysms are common because of hemodynamic. For regular-shaped and small aneurysms, direct clipping is optimal. Aneurysmoraphy or bypass blood flow reconstruction are most commonly used in large aneurysm clipping. Based on preoperative vessel wall high-resolution magnetic resonance imaging (VW-HRMRI) and intraoperative angiography, an appropriate surgery strategy could be decided. METHOD: We report a case of large MCA M1 bifurcation aneurysm aneurysmoraphy according to preoperative VW-HRMRI. Intraoperative digital subtraction angiography (DSA) showed an aneurysm neck remnant, and we adjusted clips according to intraoperative DSA. This patient recovered well with a modified Rankin scale of 0 at discharge. CONCLUSION: This case demonstrates that preoperative VWHRMRI could supply more aneurysm characteristics for direct aneurysmoraphy. Intraoperative DSA effectively reduces the possibility of aneurysm remnant.

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined. METHODS: We identified ubiquitin-specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell-cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19. RESULTS: Multiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B-cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+ ) levels and causing ER stress. We also found that the N6 -methyladenosine (m6 A) "writer" methyltransferase-like 14 (METTL14) increased global m6 A modification. CONCLUSIONS: Our study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.

Signaling pathways in macrophages: molecular mechanisms and therapeutic targets.

Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase-signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage-targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage-targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.

An immunogenic cell death-related classification predicts response to immunotherapy and prognosis in triple-negative breast cancer.

OBJECTIVE: Immunogenic cell death (ICD) of tumor cells is characterized by the induction of adaptive and innate immune responses, which in turn activates the immune surveillance and improves the efficacy of immunotherapy. In this study, we aimed to investigate the effect of ICD on the prognosis and the efficacy of immunotherapy in patients with triple-negative breast cancer (TNBC). METHODS: TNBC samples from The Cancer Genome Atlas-Breast Cancer (TCGA-BRCA) dataset were divided into two subtypes (ICD-high and ICD-low) based on the ICD status by using the consensus clustering method, and their genomic landscape and immune landscape were delineated. Furthermore, we established an ICD-related prognostic model to predict the efficacy of immunotherapy and the survival of TNBC. RESULTS: Our study showed that a poor prognosis of TNBC was associated with ICD-high subtype, while a favorable outcome was associated with ICD-low subtype. The immune landscape profiling results revealed that ICD-high subtype presented an immune-hot phenotype, whereas ICD-low subtype was associated with an immune-cold phenotype. Furthermore, our prognostic model predicted that the high-risk score group had a poor overall survival (OS), which was consistent with the actual data in the Gene Expression Omnibus (GEO) dataset. We also used tumor immune dysfunction and exclusion (TIDE) to determine the predictive significance of our ICD risk signature in immunotherapy efficacy, and found that ICD high-risk group had the highest response rate to immunotherapy in the immunotherapy response group. CONCLUSION: Our results reveal a correlation between ICD status and alterations in the tumor immune microenvironment in patients with TNBC. This finding might help guide clinicians in immunotherapy application for TNBC patients.

Role of galectin-3 in cardiac dysfunction induced by subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH) is a severe acute cerebrovascular event that not only impairs the central nervous system but also negatively affects various other organs, including the heart. The underlying mechanisms, however, remain unclear. In this study, we discovered that mice with SAH exhibited significant cardiac injuries, such as extended QT and QTc intervals, cardiac fibrosis, and reduced cardiac ejection fractions. This phenomenon was accompanied by increased galectin-3 expression in the cardiac ventricle and can be reversed by galectin-3 inhibitor TD139. Interestingly, we also observed increased co-expression of galectin-3 in macrophage within the heart tissue of SAH mice. Additionally, when macrophage activation was suppressed using the beta-blocker propranolol, cardiac function improved, and galectin-3 expression in the cardiac tissue decreased. Collectively, our findings offer new insights into the role of galectin-3 in SAH-related cardiac dysfunction and suggest a macrophage-galectin-3 axis as a potential therapeutic strategy.

Cognitive Performance in Patients With Sporadic Vestibular Schwannoma.

BACKGROUND: To date, few data are available on the cognitive function of patients with vestibular schwannoma (VS) before treatment. OBJECTIVE: To provide a cognitive profile of patients with VS. METHODS: This cross-sectional observational study recruited 75 patients with an untreated VS and 60 age-, sex-, and education-matched healthy control subjects. A set of neuropsychological tests were administered to each participant. RESULTS: Compared with the matched controls, patients with VS exhibited impaired general cognitive function, memory, psychomotor speed, visuospatial ability, attention and processing speed, and executive function. The subgroup analyses displayed that patients with severe-to-profound unilateral hearing loss were more cognitively impaired than patients with no-to-moderate unilateral hearing loss. In addition, patients with right-sided VS scored worse than those with left-sided VS on tests of memory, attention and processing speed, and executive function. No differences were observed in cognitive performance between patients with or without brainstem compression and those with or without tinnitus. We also found that worse hearing and longer hearing loss duration were associated with poorer cognitive performance in patients with VS. CONCLUSION: The findings of this study provide evidence for cognitive impairment in patients with untreated VS. It can thus be said that including cognitive assessment in the routine clinical management of patients with VS may facilitate more appropriate clinical decision-making and improve patients' quality of life.

3D collagen microchamber arrays for combined chemotherapy effect evaluation on cancer cell numbers and migration.

Breast cancer metastasis involves complex mechanisms, particularly when patients are undergoing chemotherapy. In tissues, tumor cells encounter cell-cell interactions, cell-microenvironment interactions, complex nutrient, and drug gradients. Currently, two-dimensional cell culture systems and animal models are challenging to observe and analyze cell responses to microenvironments with various physical and bio-chemical conditions, and microfluidic technology has been systematically developed to address this dilemma. In this study, we have constructed a combined chemotherapy evaluation chip (CCEC) based on microfluidic technology. The chip possesses 192 diamond-shaped microchambers containing MDA-MB-231-RFP cells, and each microchamber is composed of collagen to mimic breast cancer and its surrounding microenvironment. In addition, by adding medium containing different drugs to the medium channels of CCEC, composite drug (paclitaxel+gemcitabine+7rh and paclitaxel+fluorouracil+PP2) concentration gradients, and single drug (paclitaxel, gemcitabine, 7rh, fluorouracil, PP2) concentration gradients have been established in the five collagen regions, respectively, so that each localized microchamber in the regions has a unique drug microenvironment. In this way, we evaluated the composite and single chemotherapy efficacy on the same chip by statistically analyzing their effects on the numbers and migration of the cell. The quantitative results in CCECs reveal that the inhibition effects on the numbers and migration of MDA-MB-231-RFP cell under the composite drug gradients are more optimal than those of the single drugs. Besides, the cancer cell inhibition effect between the groups composed of two drugs has also been compared, that is the paclitaxel+gemcitabine, paclitaxel+fluorouracil, and paclitaxel+PP2 have better cell numbers and migration inhibition effects than paclitaxel+7rh. The results indicate that the bio-mimetic and high-throughput combined chemotherapy evaluation platform can serve as a more efficient and accurate tool for preclinical drug development and screening.

Integrated tumor genomic and immune microenvironment analysis identifies predictive biomarkers associated with the efficacy of neoadjuvant therapy for triple-negative breast cancer.

BACKGROUND: Although neoadjuvant chemotherapy (NAC) is currently the best therapy for triple-negative breast cancer (TNBC), resistance still occurs in a considerable proportion, thus it is crucial to understand resistance mechanisms and identify predictive biomarkers for patients selection. METHODS: Biopsy samples were collected from 21 patients with TNBC who underwent NAC. Whole-exome sequencing (WES), targeted sequencing, and multiplex immunohistochemistry (mIHC) were carried out on the clinical samples and used to identify and validate potential biomarkers associated with response to NAC. In addition, data on 190 TNBC patients who had undergone chemotherapy were obtained from The Cancer Genome Atlas (TCGA) and analyzed to further validate our findings. RESULTS: Both the tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were significantly higher in responders than in non-responders. Higher response rates and longer survival rates were observed in patients with higher TMB. Patients with higher ratios of CD8 to M2 macrophages had higher response rates and improved survival rates. Finally, the integrated analysis demonstrated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages could further distinguish patients who benefitted from the treatment in both enrolled patients and public data. CONCLUSIONS: The findings of this study indicated that the combination of TMB and the ratio of CD8 T cells to M2 macrophages may be a potential biomarker for improving the recognition of NAC responders, thereby providing a basis for developing precision NAC regimens.

The advanced lung cancer inflammation index predicts chemotherapy response and infection risk in multiple myeloma patients receiving induction chemotherapy.

Objective: This study aims to determine the clinical significance of the advanced lung cancer inflammation index (ALI) in predicting prognosis, chemotherapy response, and infection risk in newly diagnosed multiple myeloma (MM) patients receiving induction therapy. Methods: A retrospective analysis of the clinical characteristics and laboratory data of 111 newly diagnosed MM patients from the Haematology Department of the Third Xiangya Hospital of Central South University from January 2014 to March 2020 was performed. We first determined the relationship between ALI and overall survival (OS), as well as clinical and laboratory parameters. Second, predictive factors for chemotherapy response were analysed by univariate and multivariate regression analyses. Third, univariate regression analysis of risk factors was performed using infection as the evaluable outcome. Results: Of the 111 evaluable patients, the low ALI group (<32.7) exhibited significantly poorer survival than the high ALI group (51 months versus 77 months). Multivariable analysis showed that advanced age, chemotherapy response and serum calcium level were independent prognostic factors for OS. Better chemotherapy efficacy in the high ALI group (89.3%) than in the low ALI group (42.2%) (p < 0.001) was noted. Multivariate analysis suggested that only ALI [HR: 0.110, 95% CI (0.035-0.350), p = 0.000] is an independent predictive factor in evaluating the efficiency of induction chemotherapy. Forty patients (36.04%) presented with infection after induction chemotherapy. Univariate analysis suggested that low ALI and abnormal renal function increase risk of infection in newly diagnosed MM patients. Conclusion: Our study confirmed that ALI is not only a prognostic biomarker for newly diagnosed patients, but also predicts chemotherapy efficacy in newly diagnosed MM patients receiving induction therapy.