System analysis based on the T cell exhaustion­related genes identifies CD38 as a novel therapy target for ovarian cancer.

Ovarian cancer (OV) is highly heterogeneous tumor with a very poor prognosis. Studies increasingly show that T cell exhaustion is prognostically relevant in OV. The aim of this study was to dissect the heterogeneity of T cell subclusters in OV through single cell transcriptomic analysis. The single RNA-sequencing (scRNA-seq) data of five OV patients were analyzed, and six major cell clusters were identified after threshold screening. Further clustering of T cell-associated clusters revealed four subtypes. Pathways related to oxidative phosphorylation, G2M checkpoint, JAK-STAT and MAPK signaling were significantly activated, while the p53 pathway was inhibited in the CD8+ exhausted T cells. The standard marker genes of CD8+ T cell exhaustion were screened to develop a T-cell related gene score (TRS) based on random forest plots in TCGA cohort. The patients with low TRS have better prognosis compared to the patients with high TRS in both TCGA and GEO. In addition, most genes included in the TRS showed significant differences in expression levels between the high- and low-risk groups. Immune cell infiltration was analyzed using the MCPcounter and xCell algorithms, which revealed significant differences between the two risk groups, indicating that the different prognoses may stem from the respective immune landscapes. In addition, CD38 knockdown in OV cell lines increased apoptosis and inhibited invasion in vitro. Finally, we performed a drug sensitivity analysis and identified six potential drug candidates for OV. To summarize, we identified the heterogeneity and clinical significance of T cell exhaustion in OV and built a superior prognostic model based on T cell exhaustion genes, which can contribute to the development of more precise and effective therapies.

A novel cervix carcinoma biomarker: Pathological-epigenomics, integrated analysis of MethylMix algorithm and pathology for predicting response to cancer immunotherapy.

Herein, A non-invasive pathomics approach was developed to reveal the methylation status in patients with cervical squamous cell carcinoma and predict clinical outcomes and treatment response. Using the MethylMix algorithm, 14 methylation-driven genes were selected for further analysis. We confirmed that methylation-driven genes were differentially expressed in immune, stromal, and tumor cells. In addition, we constructed a methylation-driven model and explored the alterations in immunocyte infiltration between the different models. The methylation-driven subtypes identified in our investigation could effectively predict the clinical outcomes of cervical cancer. To further evaluate the level of methylation-driven patterns, we constructed a risk model with four genes. Significant correlations were observed between the score and immune response markers, including PD1 and CTLA4. Multiple immune infiltration algorithms evaluated the level of immunocyte infiltration between the high- and low-risk groups, while the components of anti-tumor immunocytes in the low-risk group were significantly increased. Subsequently, a total of 205 acquired whole-slide imaging (WSI) images were processed to capture image signatures, and the pathological algorithm was employed to construct an image prediction model based on the risk score classification. The model achieved an area under the curve (AUC) of 0.737 and 0.582 for the training and test datasets, respectively. Moreover, we conducted vitro assays for validation of hub risk gene. The proposed prediction model is a non-invasive method that combines pathomics features and genomic profiles and shows satisfactory performance in predicting patient survival and treatment response. More interdisciplinary fields combining medicine and electronics should be explored in the future.

Elevated troponin I levels on admission predict long-term mortality in patients with acute cerebral infarction following thrombolysis.

BACKGROUND/OBJECTIVE: Cardiac diseases are frequently accompanied by elevated levels of biomarkers, among which, troponin is commonly investigated. The levels of plasma cardiac troponin I (cTnI), which has been shown to predict short-term mortality, are elevated in patients with acute cerebral infarction (ACI). However, few studies have assessed the association between cTnI concentration and long-term mortality in patients with ACI following thrombolysis. METHODS: Patients with ACI admitted between January 1, 2014, and December 31, 2016, were registered. Data on demographics and outcomes with elevated cTnI levels were also collected. RESULTS: A total of 145 patients with ACI were recruited; 97 (66%), 30 (20%), and 18 (12%) patients had cTnI concentrations < 0.030 (group 1), 0.030-0.10 (group 2), and > 0.10 µg/L (group 3), respectively. cTnI elevation was associated with older age, atrial fibrillation, congestive heart failure, renal insufficiency, coronary artery disease, stroke severity (National Institutes of Health Stroke Scale score), and prior smoking history at admission. After adjusting for comorbidities and severity at 3 months after ACI, cTnI elevation on admission was significantly associated with ascending 5-year mortality (hazard ratio, 1.80; 95% confidence interval, 1.22-2.65). CONCLUSIONS: Even after adjusting for several possible confounders, cTnI elevation in patients with ACI treated with rt-PA was associated with a 1.80-fold increased risk of 5-year mortality.

Effects of motor imagery training on lower limb motor function of patients with chronic stroke: A pilot single-blind randomized controlled trial.

AIMS: This pilot study aimed to evaluate the effects of motor imagery training on lower limb motor function of stroke patients. BACKGROUND: Motor imagery training has played an important role in rehabilitation outcomes of stroke patients. METHODS: In this pilot randomized controlled trial 32 stroke patients were randomly divided into experimental and control groups from January to June 2017. Patients in both groups received conventional neuro-rehabilitation five times a week in 3-h segments for 6 weeks. Patients in the experimental group underwent an additional 20 min of motor imagery training. Measures were evaluated by motor function of the lower extremity, activities of daily living and balance ability. RESULTS: The outcomes significantly improved by motor imagery training were the Fugl-Meyer Assessment of the lower extremity, the Functional Independence Measure dealing with transfers and locomotion, and the Berg Balance Scale. CONCLUSION: Motor imagery training could be used as a complement to physical rehabilitation of stroke patients. Our findings may be helpful to develop nursing strategies aimed at improving functional ability of stroke patients and thus enhancing their quality of life.

Choice of intravenous thrombolysis therapy in patients with mild stroke complaining of acute dizziness.

BACKGROUND: Quick identification of patients with mild ischemic stroke complaining of dizziness from other patients with benign peripheral vestibular disorders who also experience dizziness in the emergency department (ED) may be difficult. Decision-making on intravenous thrombolysis therapy (IVT) in patients whose chief symptoms include acute dizziness or vertigo remains a severe challenge for ED physicians. This study evaluated the diagnosis, treatment processes and the short-term outcomes in patients with mild vestibular stroke in the ED. METHODS: A total of 89 consecutive patients with mild ischemic stroke primarily presenting with vestibular symptoms, who arrived at ED within 4.5 after onset, and were admitted at the stroke center of Zhejiang Provincial People's Hospital between January 2015 and March 2021 were retrospectively enrolled. Patients treated with IVT (n = 47) were compared to patients without IVT (n = 42) in terms of demographics, onset-to-door time (ODT), baseline clinical characteristics, risk factors of stroke, imaging findings, and short-term outcomes. The correlation between these parameters and IVT decision-making was analyzed. RESULTS: Patients in IVT group more frequently presented with shorter ODT, focal neurological deficits (dysarthria, facial palsy, hemiglossoplegia, hemiparesis, hemisensory loss), disabling deficits, higher baseline National Institute of Health Stroke Scale (NIHSS) scores, and underwent multi-mode imaging before a decision. A higher proportion of isolated vestibular symptoms, acute transient vestibular syndrome, and vestibulo-vagal symptoms were found in the no-IVT group. There were no differences in demographics between the two groups. ODT was negatively correlated with the decision-making on IVT, and baseline NIHSS scores were positively correlated with the decision-making on IVT. CONCLUSION: ODT and baseline NIHSS scores were correlated with the IVT decision in mild stroke patients primarily presenting with vestibular symptoms. Severe vestibular symptoms and disabling deficits were weakly associated with IVT decision, while the vestibulo-oculomotor signs and multi-mode imaging did not result as the influencing factors promoting the IVT decision-making for mild vestibular stroke.

Case report: Spiller syndrome initially mimicking vestibular neuritis.

Spiller syndrome is a rare subtype of medial medullary infarction (MMI). Herein, we report on a patient with progressing stroke who presented with the initial features of acute peripheral vestibulopathy and MMI (Spiller syndrome), as confirmed by magnetic resonance imaging (MRI). A 42-year-old man experienced acute persistent vertigo with nausea, vomiting, and severe gait instability for 6 h before presenting to the emergency department. He exhibited spontaneous right-beating horizontal-torsional nystagmus that intensified on rightward gaze. The patient fell to the left side during the Romberg test. Cranial computed tomography (CT) performed immediately upon admission did not provide evidence for ischemia or hemorrhage of the brainstem and cerebellum; however, the symptoms underwent exacerbation 4 h after admission, manifesting as left-sided limb weakness and dysarthria, without dysphagia. Furthermore, bedside examination revealed difficulty in extending the tongue to the right, positive left Babinski's sign, and abnormal vibration and position sense in the paralyzed limb. Head impulse test recording revealed a normal gain in the vestibulo-ocular reflex, and numerous consistent covert corrective saccades were captured upon turning the head to the left side. Cranial MRI depicted an acute infarct confined to the right side of the medial medulla, which met the diagnostic criteria for Spiller syndrome. Our study underscores the importance of considering the possibility of a nucleus prepositus hypoglossi lesion even if the signs and symptoms support the diagnosis of peripheral lesions in patients with acute vestibular syndrome exhibiting vascular risk factors.

Cancer occurrence following azathioprine treatment in myasthenia gravis patients: A systematic review and meta-analysis.

Treatments of myasthenia gravis (MG) usually include immunosuppressants such as glucocorticoids, tacrolimus, and azathioprine (AZA). In clinical practice, azathioprine therapy is thought to have a potential risk for developing secondary malignancies in myasthenia gravis patients. However, published data on the long-term safety of azathioprine in myasthenia gravis patients are limited and not consistent among studies. To explore cancer occurrence following azathioprine therapy in myasthenia gravis patients in the long term, we searched Medline, EMBASE, and the Cochrane Library for terms related to azathioprine, myasthenia gravis and cancer occurrence. Two investigators independently extracted trial data. A pooled estimate was calculated from fixed-effects meta-analysis. Our analysis included 1650 azathioprine-treated patients and 2481 non-azathioprine-treated patients. All five studies showed some concerns regarding the risk of bias. In a meta-analysis of 5 studies, we observed no significantly elevated risk of cancer occurrence among individuals with prior myasthenia gravis diagnosis who received long-term azathioprine treatment (OR 1.09; 95% CI 0.86-1.38, p = 0.46). Prospective studies are needed to observe the safety of azathioprine.

Epilepsy imitator: tongue biting caused by sleep-related facio-mandibular myoclonus.

PURPOSE: Sleep-related facio-mandibular myoclonus(SRFMM) is a rare and under-recognized stereotyped parasomnia. SRFMM can present with isolated tongue biting, which can be misdiagnosed as epilepsy and sleep bruxism. We aimed to investigate the clinical characteristics and demographics of patients with SRFMM. METHODS: We reported a case of SRFMM and presented a literature review on SRFMM. We searched the Medline, Pubmed, and Web of Science database using the following search algorithm: "facio-mandibular myoclonus" or "masticatory myoclonus" or "tongue biting" limited to publications in English. RESULTS: In total, nine studies were included. In addition to our case, a total of 17 patients were analyzed. SRFMM was found to be more prevalent in males, with a mean age of 48.2 years old. Most of the patients experienced tongue biting during non-rapid eye movement sleep. A majority of the patients were misdiagnosed with epilepsy or sleep bruxism. The simultaneous video EEG and surface EMG was beneficial in confirming the diagnosis of SRFMM. In some patients, clonazepam was reported to ameliorate the tongue biting event. CONCLUSION: This study represents a comprehensive summary of SRFMM, which has unique clinical features. Extra-caution may be needed in these cases as it may puzzle neurologists in terms of management.

A novel human-derived tissue-engineered patch for vascular reconstruction.

Vascular patches are commonly applied in tissue repair and reconstruction in congenital cardiac surgery. However, the currently available patch materials are inappropriate to be used in the pediatric population due to their lack of supporting tissue growth potential. In our study an active patch material was developed by seeding pediatric patient's bone marrow stem cells on a decellularized aortic extracellular matrix (ECM) scaffold. The patch was then implanted to repair abdominal aorta defects of nude rats. Two months after implantation, tissue remodeling, vascular cell regeneration, and cellular integration were investigated using histology and fluorescent staining. Histology demonstrated infiltration of host cells and formation of organized cell layers as well as intact collagen and elastic fibers inside the patch material. Immunofluorescence indicated regeneration of endothelial and smooth muscle cells. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified multiple vascularization-promoting components and growth factors in decellularized aortic ECM scaffold. These results demonstrated growth potential and suitability of human derived tissue-engineered patch for vascular reconstruction, and thus, it might be considered in the future as treatment option in pediatric patients.

Identification of key gene modules and pathways of human glioma through coexpression network.

Glioma causes great harm to people worldwide. Systemic coexpression analysis of this disease could be beneficial for the identification and development of new prognostic and predictive markers in the clinical management of glioma. In this study, we extracted data sets from the Gene Expression Omnibus data set by using "glioma" as the keyword. Then, a coexpression module was constructed with the help of Weighted Gene Coexpression Network Analysis software. Besides, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on the genes in these modules. As a result, the critical modules and target genes were identified. Eight coexpression modules were constructed using the 4,000 genes with a high expression value of the total 141 glioma samples. The result of the analysis of the interaction among these modules showed that there was a high scale independence degree among them. The GO and KEGG enrichment analyses showed that there was a significant difference in the enriched terms and degree among these eight modules, and module 5 was identified as the most important module. Besides, the pathways it was enriched in, hsa04510: Focal adhesion and hsa04610: Complement and coagulation cascades, were determined as the most important pathways. In summary, module 5 and the pathways it was enriched in, hsa04510: Focal adhesion and has 04610: Complement and coagulation cascades, have the potential to serve as biomarkers for patients with glioma.

The effective clinical outcomes of the Gufoni maneuver used to treat 91 vertigo patients with apogeotropic direction-changing positional nystagmus (apo-DCPN).

This study aimed to observe and analyze the effects and outcomes of patients with apogeotropic direction-changing positional nystagmus (apo-DCPN) who received Gufoni maneuver.A total of 91 patients with positional vertigo admitted to the specialized dizziness clinic in Zhejiang Provincial People's Hospital from February 2014 to August 2017 were included. The immediate treatment responses to the Gufoni maneuver were observed and recorded. The patients in whom the treatment was ineffective were followed up for 4 weeks to observe the outcome of apo-DCPN.In 21 patients, the apo-DCPN was transformed after Gufoni maneuver, and 7 patients developed transformation within 4 weeks of follow-up. Spontaneous remission of apo-DCPN within the follow-up period was observed in 55 patients who were unresponsive to the Gufoni maneuver. The prevalence of migraine was significantly higher in the early remission group (P < .05) and the period between the initial visit and nystagmus remission was significantly shorter in the group of patients with migraine history (P < .05).This study demonstrates that the immediate treatment efficacy of the Gufoni maneuver is poor in positional vertigo patients with apo-DCPN. We believe that the reason for the low efficacy is that the Gufoni maneuver is only effective for some patients with apo-DCPN type HSC-BPPV. In patients with early spontaneous remission and a history of migraine, central positional nystagmus of probable vestibular migraine (VM) or benign recurrent vertigo should be considered for the mechanisms of apo-DCPN generation.

Prominent Hypointense Vessel Sign on Susceptibility-Weighted Imaging Is Associated with Clinical Outcome in Acute Ischaemic Stroke.

BACKGROUND: Prominent hypointense vessel sign (PHVS) is visualized on susceptibility weighted-imaging (SWI) in acute ischaemic stroke (AIS). We aim to test if PHVS is associated with stroke outcome. METHODS: Forty patients with acute middle cerebral artery occlusion were recruited. The presence of PHVS, cortical vessel sign (CVS), brush sign (BS) and susceptibility-diffuse weighted imaging mismatch (S-D mismatch) and Alberta Stroke Program Early CT Score (ASPECTS) on SWI were compared between the good outcome group (90-day modified Rankin scale [mRS] of 0-2) and the poor outcome group (mRS of 3-6). The receiver operating characteristic curves (ROC) were used to evaluate the predictive ability to poor outcome of above imaging characteristics. RESULTS: The presence of PHVS, CVS, BS and S-D mismatch was significantly higher in the poor outcome group (p < 0.001, p = 0.001, p = 0.013, p = 0.014, respectively). SWI-ASPECTS was significantly lower in the poor outcome group (p = 0.002). Regression analysis revealed SWI-ASPECTS; the presence of PHVS and CVS were independently associated with poor outcome (OR 0.347, p = 0.012; OR 55.77, p = 0.004; OR 58.05, p = 0.005). ROC analysis showed that PHVS had the highest predictive value for poor outcome (AUC 0.783). CONCLUSIONS: The presence of PHVS, CVS and SWI-ASPECTS were associated with poor outcome in AIS. The presence of PHVS was the most effective radiographic marker for predicting outcome.

High expression of FUT3 is linked to poor prognosis in clear cell renal cell carcinoma.

BACKGROUND AND PURPOSE: Some of the fucosylation catalyzed by fucosyltransferase-III mediates the epithelial-mesenchymal transition and enhances tumor cell-macrophage signaling, which promotes malignant transforming and immune evasion. The aim of the study was to investigate the association between the expression of fucosyltransferase-III and clinical outcomes of patients with clear-cell renal cell carcinoma after surgery. RESULTS: High fucosyltransferase-III expression was associated with a greater risk of recurrence (p = 0.002) and shortened overall survival (p < 0.001). We then established a prognostic nomogram including tumor size, pathologic T, N, M stage, coagulative necrosis, lymphovascular invasion and fucosyltransferase-III expression. Furthermore, the predictive accuracy of the Leibovich prognostic score was improved when fucosyltransferase-III expression was added (p = 0.009 for overall survival and p = 0.002 for recurrence-free survival). MATERIALS AND METHODS: We conducted a retrospective cohort study of 406 patients who underwent partial or radical nephrectomy between January 2008 and December 2009 in a single institute. Fucosyltransferase-III expression levels were evaluated by immunohistochemical staining in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on recurrence-free and overall survival. Harrell's concordance index and Akaike's Information Criteria were calculated to assess predictive accuracy. CONCLUSIONS: Fucosyltransferase-III is a predictive factor for poor overall survival and recurrence free survival in patients with ccRCC. The inhibitor of fucosyltransferase-III might be a potential therapeutic method for the disease.

Tirofiban facilitates the reperfusion process during endovascular thrombectomy in ICAS.

The aim of the present study was to assess the use of tirofiban injections for rescue therapy following artery reocclusion due to intra-luminal thrombosis during endovascular thrombectomy in patients with acute ischemic stroke (AIS). A total of seven cases of patients treated with adjunctive tirofiban injections following failed endovascular thrombectomy due to instant intra-luminal thrombosis were retrospectively assessed. A Solitaire stent was used as the primary thrombectomy device in all patients. Tirofiban was injected intra-arterially via a temporarily deployed Solitaire stent with continuous intravenous infusion for the subsequent 24 h; half of the conventionally recommended dose was employed. Outcome measures included angiographic reperfusion (mTICI), symptomatic intracranial hemorrhage, mortality and functional independence at 90 days (modified Rankin Scale, 0-2). Six patients had occlusions in the middle cerebral artery and one patient had occlusions in the basilar artery. Of the seven patients, five exhibited successful reperfusion (mTICI 2b-3) and achieved functional independence following 90 days. Reperfusion failed in the remaining two patients, who succumbed within 90 days of therapy. No intracranial or extracranial hemorrhage cases were identified. The results of the present study suggest that tirofiban facilitates reperfusion and ameliorates long-term prognosis in patients with AIS undergoing endovascular thrombectomy, and may be safe for those receiving intravenous tissue plasminogen activator therapy.

Good recovery of subarachnoid hemorrhage concomitant with ischemia due to anterior cerebral artery dissection by conservative treatment: A case report.

The present report describes the case of a 57-year-old woman presenting with subarachnoid hemorrhage (SAH) and acute ischemic stroke (AIS) due to anterior cerebral artery (ACA) dissection, which exhibited severe stenosis at the origin with distal dilatation of the A2 segment and occlusion of the A3 segment. In this case, computed tomography (CT) revealed SAH in right superior frontal sulcus and the interhemispheric fissure. Magnetic resonance imaging demonstrated acute infarct in the territory of the right ACA. Brain digital subtraction angiography showed severe stenosis at the origin of the A2 segment with distal dilatation and occlusion at the origin of the A3 segment of the right ACA, suggesting a diagnosis of dissection. Only treatment with atorvastatin, her clinical condition subsequently improved. The stenosis and dilatation of A2 segment were ameliorated as demonstrated by a follow-up CT angiography 5 months after onset. SAH concomitant with ischemia caused by ACA dissection is rare. Conservative treatment may be a safe and effective choice for patients with SAH concomitant with AIS due to ACA dissection.

Aquaporin-4-IgG-positive neuromyelitis optica spectrum disorder with recurrent short partial transverse myelitis and favorable prognosis: Two new cases.

Understanding the characteristics of neuromyelitis optica spectrum disorder (NMOSD) with recurrent short partial transverse myelitis (SPTM), which is very rare, contributes to the differential diagnosis of multiple sclerosis (MS). We present two Chinese aquaporin-4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD cases who had at least twice SPTM during 4 and 6 years of follow-up, respectively. Their SPTMs have been mild and responded well to corticosteroids just like in the case of MS. The findings highlight the need of searching for serum AQP4-IgG (cell-based assay strongly recommended) in patients with recurrent SPTM and suggest that those patients may have a mild acute attack phase and favorable long-term prognosis.

Highly expressed lncRNA CRNDE promotes cell proliferation through Wnt/ß-catenin signaling in renal cell carcinoma.

Recently, numerous studies revealed that long non-coding RNAs (lncRNAs) play complex roles in the field of tumor biology, while the functions of lncRNA in renal cell carcinoma (RCC) remain largely unknown. In the current study, we retrieved Oncomine database and found a lncRNA colorectal neoplasia differentially expressed (CRNDE) which is highly expressed in different cohorts of RCC patients; this clue reminds us that CRNDE might exert its functions in RCC tumorigenesis. We then detected the level of CRNDE in fresh RCC tissues and found that CRNDE is significantly up-regulated compared with adjacent tissues. Furthermore, both loss and gain function assays revealed that CRNDE promotes RCC cell proliferation and growth both in vitro and in vivo.In addition, we found that CRNDE regulates the cell cycle transition from G0/G1 stage to S stage and modulates the expression of CCND1 and CCNE1. Moreover, we further illustrated that CRNDE activates Wnt/ß-catenin signaling in RCC cell lines. Taken together, in the current study, we found that lncRNA CRNDE is highly expressed in RCC malignant tissues and the heightened CRNDE robustly promotes RCC cell proliferation through activating Wnt/ß-catenin signaling; our findings enlarge our knowledge in the molecular pathology of RCC tumorigenesis.

High expression of chemokine CCL2 is associated with recurrence after surgery in clear-cell renal cell carcinoma.

PURPOSE: Chemokine (C-C motif) ligand 2 (CCL2) is known to recruit monocytes and macrophages to sites of inflammation. Recent studies suggest CCL2 is overexpressed in multiple cancer types and may play a role in the tumor progression. The aim of this study was to assess the association between CCL2 expression and the risk of recurrence after surgery in patients with clear-cell renal cell carcinoma (ccRCC). METHODS: This study included 268 ccRCC patients who underwent nephrectomy at a single institute between 2001 and 2004. Clinicopathologic variables and recurrence-free survival (RFS) were recorded. CCL2 expression levels were evaluated by immunohistochemical staining in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on recurrence-free survival (RFS). Harrell's concordance index was calculated to assess predictive accuracy. RESULTS: High CCL2 expression was associated with a greater risk of recurrence in ccRCC patients (P<0.001). Multivariate analysis confirmed that CCL2 expression was an independent prognostic factor for RFS (P = 0.045). The predictive accuracy of the Leibovich prognostic score was improved when CCL2 expression was added (0.76 vs. 0.71, P<0.001). Notably, the improvement in prediction was more pronounced in patients with low-risk disease. A nomogram integrating CCL2 expression and pathologic factors was then constructed, which predicted 5- and 10-year RFS well for ccRCC patients. CONCLUSIONS: High chemokine CCL2 expression is an independent predictor of recurrence in ccRCC patients. Evaluation of CCL2 could help guide postsurgical management for ccRCC patients.