Tetrahydrofolate Attenuates Cognitive Impairment after Hemorrhagic Stroke by Promoting Hippocampal Neurogenesis via PTEN Signaling.

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated AKT and mTOR. Furthermore, conditional deletion of PTEN in NSCs of the hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.

Analysis of clinical characteristics and histopathological transcription in 40 patients afflicted by epilepsy stemming from focal cortical dysplasia.

OBJECTIVE: This study aims to comprehensively analyze the clinical characteristics and identify the differentially expressed genes associated with drug-resistant epilepsy (DRE) in patients with focal cortical dysplasia (FCD). METHODS: A retrospective investigation was conducted from July 2019 to June 2022, involving 40 pediatric cases of DRE linked to FCD. Subsequent follow-ups were done to assess post-surgical outcomes. Transcriptomic sequencing and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to examine differential gene expression between the FCD and control groups. RESULTS: Among the 40 patients included in the study, focal to bilateral tonic-clonic seizures (13/40, 32.50%) and epileptic spasms (9/40, 22.50%) were the predominant seizure types. Magnetic resonance imaging (MRI) showed frequent involvement of the frontal (22/40, 55%) and temporal lobes (12/40, 30%). In cases with negative MRI results (13/13, 100%), positron emission tomography/computed tomography (PET-CT) scans revealed hypometabolic lesions. Fused MRI/PET-CT images demonstrated lesion reduction in 40.74% (11/27) of cases compared with PET-CT alone, while 59.26% (16/27) yielded results consistent with PET-CT findings. FCD type II was identified in 26 cases, and FCD type I in 13 cases. At the last follow-up, 38 patients were prescribed an average of 1.27 ± 1.05 anti-seizure medications (ASMs), with two patients discontinuing treatment. After a postoperative follow-up period of 23.50 months, 75% (30/40) of patients achieved Engel class I outcome. Transcriptomic sequencing and qRT-PCR analysis identified several genes primarily associated with cilia, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1. SIGNIFICANCE: This study highlights focal to bilateral tonic-clonic seizures as the most common seizure type in patients with DRE due to FCD. Surgical intervention primarily targeted lesions in the frontal and temporal lobes. Patients with FCD-related DRE showed a promising prognosis for seizure control post-surgery. The identified genes, including CFAP47, CFAP126, JHY, RSPH4A, and SPAG1, could serve as potential biomarkers for FCD. PLAIN LANGUAGE SUMMARY: This study aimed to comprehensively evaluate the clinical data of individuals affected by focal cortical dysplasia and analyze transcriptomic data from brain tissues. We found that focal to bilateral tonic-clonic seizures were the most prevalent seizure type in patients with drug-resistant epilepsy. In cases treated surgically, the frontal and temporal lobes were the primary sites of the lesions. Moreover, patients with focal cortical dysplasia-induced drug-resistant epilepsy exhibited a favorable prognosis for seizure control after surgery. CFAP47, CFAP126, JHY, RSPH4A, and SPAG1 have emerged as potential pathogenic genes for the development of focal cortical dysplasia.

Efficacy and safety of sirolimus early conversion protocol in liver transplant patients with hepatocellular carcinoma: A single-arm, multicenter, prospective study.

Mammalian target of rapamycin (mTOR) inhibitor as an attractive drug target with promising antitumor effects has been widely investigated. High quality clinical trial has been conducted in liver transplant (LT) recipients in Western countries. However, the pertinent studies in Eastern world are paucity. Therefore, we designed a clinical trial to test whether sirolimus can improve recurrence-free survival (RFS) in hepatocellular carcinoma (HCC) patients beyond the Milan criteria after LT. This is an open-labeled, single-arm, prospective, multicenter, and real-world study aiming to evaluate the clinical outcomes of early switch to sirolimus-based regimens in HCC patients after LT. Patients with a histologically proven HCC and beyond the Milan criteria will be enrolled. The initial immunosuppressant regimens are center-specific for the first 4-6 weeks. The following regimens integrated sirolimus into the regimens as a combination therapy with reduced calcineurin inhibitors based on the condition of patients and centers. The study is planned for 4 years in total with a 2-year enrollment period and a 2-year follow-up. We predict that sirolimus conversion regimen will provide survival benefits for patients particular in the key indicator RFS as well as better quality of life. If the trial is conducted successfully, we will have a continued monitoring over a longer follow-up time to estimate indicator of overall survival. We hope that the outcome will provide better evidence for clinical decision-making and revising treatment guidelines based on Chinese population data. Trial register: Trial registered at http://www.chictr.org.cn: ChiCTR2100042869.

Clinical applications of neurolinguistics in neurosurgery.

The protection of language function is one of the major challenges of brain surgery. Over the past century, neurosurgeons have attempted to seek the optimal strategy for the preoperative and intraoperative identification of language-related brain regions. Neurosurgeons have investigated the neural mechanism of language, developed neurolinguistics theory, and provided unique evidence to further understand the neural basis of language functions by using intraoperative cortical and subcortical electrical stimulation. With the emergence of modern neuroscience techniques and dramatic advances in language models over the last 25 years, novel language mapping methods have been applied in the neurosurgical practice to help neurosurgeons protect the brain and reduce morbidity. The rapid advancements in brain-computer interface have provided the perfect platform for the combination of neurosurgery and neurolinguistics. In this review, the history of neurolinguistics models, advancements in modern technology, role of neurosurgery in language mapping, and modern language mapping methods (including noninvasive neuroimaging techniques and invasive cortical electroencephalogram) are presented.

Kinesin Family Member C1 Increases Temozolomide Resistance of Glioblastoma Through Promoting DNA Damage Repair.

Glioblastoma (GBM) is one of the most frequent primary malignant brain tumors with a poor prognosis. Unfortunately, due to the intrinsic or acquired chemoresistance of GBM cells, it easily becomes refractory disease and tumors are easy to recur. Therefore, it is critical to elucidate the molecular mechanisms underlying the chemoresistance of GBM cells to discover more efficient therapeutic treatments. Kinesin family member C1 (KIFC1) is a normal nonessential kinesin motor that affects the progression of multiple types of cancers. However, whether KIFC1 have a function in GBM is still unexplored. Here we found that KIFC1 was upregulated in human temozolomide (TMZ)-resistant GBM tissues. KIFC1 silencing is sufficient to inhibit GBM cell proliferation and amplify TMZ-induced repression of cell proliferation. Mechanistically, KIFC1 silencing contributed to DNA damage, cell cycle arrest, and apoptosis through regulating Rad51, Akt, and DNA-PKcs phosphorylation. We also noticed that KIFC1 silencing also inhibited tumor formation and increased TMZ sensitivity through regulating Ki67, Rad51, γ-H2AX, and phosphorylation of AKT in vivo. Our findings therefore confirm the involvement of KIFC1 in GBM progression and provide a novel understanding of KIFC1-Akt axis in the sensitivity of GBM to chemotherapy.

Hangzhou criteria as downstaging criteria in hepatocellular carcinoma before liver transplantation: A multicenter study from China.

BACKGROUND: The downstaging of hepatocellular carcinoma (HCC) has been confirmed to benefit liver transplantation (LT) patients whose tumors are beyond the transplantation criteria. Milan criteria (MC), a tumor size and number-based assessment, is currently used as the endpoint in these patients. However, many studies believe that tumor biological behavior should be added to the evaluation criteria for downstaging efficacy. Hence, this study aimed to explore the feasibility of Hangzhou criteria (HC), which introduced tumor grading and alpha-fetoprotein in addition to tumor size and number, as an endpoint of downstaging. METHODS: We performed a multicenter and retrospective study of 206 patients accepted locoregional therapy (LRT) as downstaging/bridge treatment prior to LT in three centers of China. RESULTS: Recipients were divided into four groups: failed downstaging to the HC (group A, n = 46), successful downstaging to the HC (group B, n = 30), remained within the HC all the time (group C, n = 113), and tumor progressed (group D, n = 17). The 3-year HCC recurrence probabilities of groups B and C were not significantly different (10.3% vs. 11.6%, P = 0.87). The HCC recurrent rate was significantly higher in group A (52.3%) compared with that in group B/C (P < 0.05). Seven patients (7/76, 9.2%) whose tumor exceeded the the HC were successfully downstaged to the MC, and 39.5% (30/76) to the the HC. In group B, 23 patients remained beyond the MC and their survivals were as well as those of patients within the MC. CONCLUSIONS: Compared to the MC, HC downstaging criteria can give more HCC patients access to LT and furthermore, the outcome of these patients is the same as those matching MC downstaging criteria. Hangzhou downstaging criteria therefore is applicable in clinical practice.

MicroRNA-130b promotes cell migration and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma.

Glioma is the most common and aggressive type of primary brain tumor. MicroRNA (miR)-130b functions as a tumor-associated miR. The dysregulation of miR-130b is involved in numerous biological characteristics and properties of certain types of cancer. The present study revealed the function and possible molecular mechanism of miR-130b in glioma cells, reporting that the level of miR-130b was markedly higher, increasing progressively as the histologic grade of the glioma increased, compared with the level in normal tissues. Additionally, the present study demonstrated that patients with high miR-130b expression exhibited a poor 3-year survival rate and miR-130b was an independent factor for predicting the prognosis of patients with glioma. The downregulation of miR-130b reduced invasion and migration in U373 and U87 cells. Furthermore, the downregulation of miR-130b increased peroxisome proliferator-activated receptor-γ (PPARγ) expression and inhibited epithelial-mesenchymal transition (EMT) in glioma cells. The present study identified PPARγ as a direct target of miR-130b in glioma in vitro. Furthermore, PPARγ knockdown was revealed to reduce the effect on EMT caused by the downregulation of miR-130b in U87 cells. The present study demonstrated that miR-130b promotes glioma proliferation, migration and invasion by suppressing PPARγ and subsequently inducing EMT.

Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern.

BACKGROUND: Four tumor markers for hepatocellular carcinoma (HCC), alpha-fetoprotein (AFP), glypican-3 (GPC3), vascular endothelial growth factor (VEGF) and des-gamma-carboxy prothrombin (DCP), are closely associated with tumor invasion and patient's survival. This study estimated the predictability of preoperative tumor marker levels along with pathological parameters on HCC recurrence after hepatectomy. METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion (MaVI+) and those without MaVI (MaVI-). The predictive value of tumor markers and clinical parameters were evaluated by univariate and multivariate analysis. RESULTS: In all patients, tumor size (>8 cm) and MaVI were closely related to HCC recurrence after hepatectomy. For MaVI+ patients, VEGF (>900 pg/mL) was a significant predictor for recurrence (RR=2.421; 95% CI: 1.272-4.606; P=0.007). The 1- and 2-year tumor-free survival rates for MaVI+ patients with VEGF ≤900 pg/mL versus for those with VEGF >900 pg/mL were 51.5% and 17.6% versus 19.0% and 4.8% (P<0.001). For MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were two independent risk factors for tumor recurrence (RR=2.307, 95% CI: 1.132-4.703, P=0.021; RR=3.150, 95% CI: 1.392-7.127, P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP ≤445 mAu/mL and those with DCP >445 mAu/mL were 90.4% and 70.7% versus 73.2% and 50.5% respectively (P=0.048). The 1- and 2-year tumor-free survival rates for the patients with tumor size ≤8 cm and >8 cm were 83.2% and 62.1% versus 50.0% and 30.0%, respectively (P=0.003). CONCLUSIONS: The MaVI+ patients with VEGF ≤900 pg/mL had a relatively high tumor-free survival than those with VEGF >900 pg/mL. In the MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were predictive factors for postoperative recurrence.

Cigarette smoking among Chinese PLWHA: An exploration of changes in smoking after being tested HIV positive.

Prevention and cessation of Tobacco use among persons living with HIV/AIDS (PLWHA) represents a significant challenge for HIV/AIDS patient care in China and across the globe. Awareness of HIV-positive status may alter the likelihood for PLWHA smokers to change their smoking habit. In this study, we tested the risk enhancement and risk reduction hypotheses by assessing changes in cigarette smoking behavior among PLWHA after they received the positive results of their HIV tests. Cross-sectional survey data collected from a random sample of 2973 PLWHA in care in Guangxi, China were analyzed. Changes in cigarette smoking after receiving the HIV-positive test results, as well as the current levels of cigarette smoking were measured. Among the total participants, 1529 (51.7%) were self-identified as cigarette smokers, of whom 436 (28.9%) reduced smoking and 286 (19.0%) quit after receiving their HIV-positive test results. Among the quitters, 210 (73.9%) remained abstinent for a median duration of two years. There were also 124 (8.2%) who increased cigarette smoking. Older age, female gender, more education, and receiving antiretroviral therapy were associated with quitting. In conclusion, our study findings support the risk reduction and risk enhancement hypotheses. A large proportion of smoking PLWHA reduced or quit smoking, while a small proportion increased smoking. Findings of this study suggest that the timing when a person receives his or her HIV-positive test result may be an ideal opportunity for care providers to deliver tobacco cessation interventions. Longitudinal studies are indicated to verify the findings of this study and to support smoking cessation intervention among PLWHA in the future.

ATPase inhibitory factor 1 is a potential prognostic marker for the migration and invasion of glioma.

Adenosine triphosphatase inhibitory factor 1 (IF1) has previously been considered to be a driving oncogene in human cancers. Several studies have revealed that IF1 overexpression is present in a variety of tumor types and promotes tumor growth and metastasis. The present study aimed to investigate the clinical significance of IF1 in glioma and the role of IF1 in cell migration and invasion. The mRNA and protein expression of IF1 in glioma tissues was found to be significantly increased compared with the expression in normal brain tissues (P<0.05). The presence of IF1 expression was significantly associated with an advanced clinical stage in glioma (P<0.05). Furthermore, the presence of IF1 expression was found to be associated with a reduced overall survival rate of glioma patients (P<0.05). Multivariate Cox regression analysis indicated that IF1 was an independent factor for predicting the overall survival rate of patients with glioma (P<0.05). IF1 knockdown also significantly reduced the number of migratory and invasive U251 and U87 cells (P<0.05). In addition, IF1 knockdown inhibited the expression of nuclear factor-κB (NF-κB) and Snai1, and led to increased E-cadherin expression and reduced vimentin expression. In conclusion, the presence of IF1 expression is associated with poor clinicopathological features in glioma. IF1 expression is an independent prognostic marker for predicting the overall survival rate of patients with glioma. Mechanistically, IF1 may promote glioma cell migration and invasion through the NF-κB/Snai1 axis.

Evaluation of TAZ expression and its effect on tumor invasion and metastasis in human glioma.

OBJECTIVES: To evaluate the expression of TAZ and its role in tumor invasion and metastasis in human glioma. METHODS: The expression of TAZ protein was measured in 48 samples of surgically resected human glioma and 13 samples of normal brain tissues using immunohistochemistry. TAZ was knocked down by a retrovirus-mediated TAZ shRNA in a glioma cell line, SNB19. Transwell cell migration and invasion assays were used to determine migration and invasion of SNB19 cells. RESULTS: The positive expression rate of TAZ protein in glioma tissues was significantly higher than that in normal brain tissues (79.2% vs. 15.4%, P<0.001). Furthermore, clinical analysis suggested that the positive expression rate of TAZ protein in poorly differentiated tumor tissues was significantly higher as compared with that in well differentiated tissues (96.0% vs. 60.9%, P<0.01). TAZ was significantly knocked down by TAZ shRNA (P<0.001), and TAZ knockdown significantly reduced cell migration and invasion (P<0.01, respectively) in SNB19 cells. CONCLUSIONS: TAZ protein overexpression is observed in human glioma and its elevated expression is significantly correlated with poor differentiation. TAZ knockdown prominently reduces cell migration and invasion in SNB19 cells, suggesting that TAZ may play a key role in the initiation and progression of human glioma.

Synuclein-γ suppression mediated by RNA interference inhibits the clonogenicity and invasiveness of MCF-7 cells.

The aim of the present study was to investigate the effects of synuclein-γ (SNCG) downregulation by RNA interference (RNAi) on the clonogenicity and invasiveness of MCF-7 breast cancer cells. This study used four pairs of SNCG-specific siRNAs which were designed and cloned into the pGPU6 plasmid for introduction into an MCF-7 cell line. The SNCG knockdown efficacies of the four siRNAs were compared using the reverse transcription polymerase chain reaction (RT-PCR) and immunocytochemistry. The cells' clonogenic and invasive phenotypes were examined with clonogenic and Boyden chamber assays. In comparison with the non-specific siRNA and empty vector controls, all four SNCG siRNAs were observed to significantly inhibit SNCG expression at the mRNA and protein levels (F=481.06, P<0.001; F=147.42, P<0.0001). SNCG suppression mediated by RNAi successfully inhibited the clonogenicity (P=0.002) and invasiveness (P<0.001) of transfected MCF-7 cells. According to the results of the present study, we concluded that SNCG suppression mediated by RNAi significantly suppressed SNCG expression at the mRNA and protein levels, suggesting that SNCG suppression mediated by an RNAi strategy may become a novel approach for treating advanced breast cancer.