Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. CONCLUSIONS: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Rab11a in the spinal cord: an essential contributor to complete Freund's adjuvant-induced inflammatory pain in mice.

Inflammatory pain is a commonly observed clinical symptom in a range of acute and chronic diseases. However, the mechanism of inflammatory pain is far from clear yet. Rab11a, a small molecule guanosine triphosphate enzyme, is reported to regulate orofacial inflammatory pain in our previous works. However, the mechanism of Rab11a's involvement in the regulation of inflammatory pain remains obscure. Here, we aim to elucidate the potential mechanisms through which Rab11a contributes to the development of inflammatory pain in the spinal level. It's shown that neurons, rather than glial cells, were the primary cell type expressing Rab11a in the spinal dorsal horn (SDH). After intra-plantar injection of CFA, both the number of Fos/Rab11a-immunopositive neurons and the expression of Rab11a were increased. Administration of Rab11a-shRNA into the SDH resulted in significantly analgesic effect in mice with CFA injection. Application of Rab11a-shRNA also reduced the NMDA receptor-mediated excitatory post-synaptic current (EPSC) and the spike number of neurons in lamina II of the SDH in mice with CFA injection, without affecting the presynaptic glutamate release and the postsynaptic AMPA receptor-mediated EPSC. Our results thus suggest that the enhanced expression of neuronal Rab11a may be important for the process of inflammatory pain in mice with CFA injection, which is likely mediated by Rab11a's potentiation of the competence of post-synaptic NMDAR and spiking of SDH neurons.

Analysis of the Risk Factors of Breast Cancer-Related Lymphedema and Construction and Evaluation of a Prediction Model.

Objective: The occurrence of breast cancer-related lymphedema (BCRL) in postoperative breast cancer survivors is described and the independent risk factors of BCRL are analyzed. A BCRL nomogram prediction model is constructed, and its effectiveness is evaluated to screen out high-risk patients with BCRL. Methods: A univariate analysis was carried out to determine the risk factors possibly related to BCRL, and a logistic regression analysis was utilized to determine the independent risk factors related to BCRL. A BCRL nomogram prediction model was built, and a nomogram was drawn by R software v4.1.0. The area under the curve (AUC) of the receiver operating characteristic (ROC) and the Hosmer-Lemeshow test were used to evaluate the efficacy of the constructed model to assess its clinical application value. Results: The risk factors independently associated with BCRL were body mass index (BMI), handedness on the operation side, no BCRL-related rehabilitation plan, axillary lymph node dissection (ALND), taxane-based chemotherapy, and radiotherapy (all p < 0.05). The BCRL nomogram prediction model was built on this basis, and the results of the efficacy evaluation showed a good fit: AUC = 0.952 (95% confidence interval: 0.930-0.973) for the ROC and χ2 = 6.963, p = 0.540 for the Hosmer-Lemeshow test. Conclusions: The risk factors for BCRL included higher BMI, handedness on the operation side, no BCRL-related rehabilitation plan, ALND, taxane-based chemotherapy, and radiotherapy. In addition, the BCRL nomogram prediction model accurately calculated the risk of possible BCRL among breast cancer survivors and effectively screened for high-risk patients with BCRL. Therefore, this prediction model can provide a basis for rehabilitation physicians and therapists to formulate early and individualized prevention and treatment programs.

Low-frequency repetitive transcranial magnetic stimulation to the right Broca mirror area for improving auditory comprehension in a sensory aphasia after stroke: a case report.

Aphasia is a common consequence of stroke and repetitive transcranial magnetic stimulation (rTMS) may be a promising brain stimulation technique in the treatment of aphasia. However, there are few reports about the therapeutic effect of rTMS for Broca's area in patients with sensory aphasia. This study reported one stroke patient with sensory aphasia who received 6 treatment sessions of low-frequency rTMS before speech and language therapy. The target area was the Broca mirror area in the right hemisphere. After treatment, the auditory comprehension of the patient improved from 46 to 112, the naming improved from 18 to 32, and the AQ improved from 34.2 to 42.6. However, the level of functional language, spontaneous speech and repetition did not show obvious improvement.

Correlation between focal lesion sites and language deficits in the acute phase of post-stroke aphasia.

INTRODUCTION: Focal lesion sites can predict the language function of patients with aphasia during the subacute or chronic phases. However, the relationship between focal lesion sites and language deficits in the acute phase remains unclear. Therefore, our study aimed to investigate the relationship between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits in patients with acute aphasia to further understand the pathophysiological mechanism of aphasia. MATERIAL AND METHODS: We included a total of 52 patients with acute aphasia who had their first-ever stroke between June 2018 and June 2021 to investigate the association between focal lesion sites and fluency, auditory comprehension, repetition and naming deficits. Language function was assessed by the Western Aphasia Battery scale within one month of onset. The lesion sites were independently assessed by three professional speech and language pathologists according to the main sulcus of the brain within 1-2 days after stroke. RESULTS: Lesions involving the superior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula were significantly associated with low fluency. Lesions involving the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, middle frontal gyrus, inferior frontal gyrus, supramarginal gyrus and angular gyrus significantly resulted in auditory comprehension impairment. Lesions involving the superior temporal gyrus, middle temporal gyrus, middle frontal gyrus, inferior frontal gyrus, precentral gyrus, postcentral gyrus, supramarginal gyrus, angular gyrus and insula significantly resulted in repetition and naming deficits. CONCLUSIONS: Our study suggests that focal lesion sites could lead to different language function impairments in the acute phase of post-stroke aphasia, which adds to our understanding of speech pathology and provides a direction for future research and treatment.

Corrigendum: MicroRNA Let-7i Is a Promising Serum Biomarker for Post-stroke Cognitive Impairment and Alleviated OGD-Induced Cell Damage in vitro by Regulating Bcl-2.

[This corrects the article DOI: 10.3389/fnins.2020.00215.].

Homocysteine is Associated with the Development of Cerebral Small Vessel Disease: Retrospective Analyses from Neuroimaging and Cognitive Outcomes.

OBJECTIVE: As the population ages, a growing burden of cerebral small vessel disease (cSVD) has sparked extensive concerns recently. Homocysteine (Hcy), as a traditional risk factor for atherosclerosis, may also participate in the development of cSVD. By comprehensively assessing Hcy's correlation with different MRI markers of cSVD and cognitive outcomes in a homogeneous population with cSVD, this study aims to explore the value of Hcy in the clinical management of cSVD. METHODS: 231 inpatients with MRI-confirmed cSVD were enrolled in this retrospective study (mean age 66.4±10.0 years, male sex 47.6%). Along with brain MRI and plasma total Hcy (tHcy) examination, Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were also performed to assess their global cognitive function. Burdens of cSVD neuroimaging features encompassing white matter hyperintensity (WMH), lacunes of presumed vascular origin, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS) were evaluated based on brain MRI demonstrations. RESULTS: After adjusting for possible confounders, statistical analyses showed that plasma tHcy levels were not only correlated with burdens of deep/periventricular WMH (P < 0.001, P for trend < 0.001; P < 0.001, P for trend < 0.001), lacunes (P < 0.001, P for trend < 0.001), lobar CMBs (P = 0.002), and EPVS in the basal ganglia (P < 0.001, P for trend = 0.002) but also remained an independent predictor of cognitive impairment (B=-0.159, 95%CI -0.269--0.049, P = 0.005, P for trend < 0.001) in the patients with cSVD. CONCLUSIONS: Plasma tHcy levels are associated with the development of cSVD in a dose-independent manner and may predict the cognitive outcomes in cSVD patients. These findings provide a potential clue to cSVD's physiopathology and future disease management.

MicroRNA Let-7i Is a Promising Serum Biomarker for Post-stroke Cognitive Impairment and Alleviated OGD-Induced Cell Damage in vitro by Regulating Bcl-2.

Background: The mechanism of post-stroke cognitive impairment (PSCI) has not been explained. We aimed to investigate whether miR-let-7i participates in the PSCI and illuminates its underlying role in oxygen-glucose deprivation (OGD)-induced cell apoptosis. Methods: Blood samples from 36 subjects with PSCI and 38 with post-stroke cognitive normality (Non-PSCI) were collected to evaluate the differential expression of miR-let-7 family members, using qRT-PCT analysis. Spearman correlation was performed to estimate the correlation between the miR-1et-7i level and Montreal Cognitive Assessment (MoCA) score. Treatment of SH-SY5Y cells with OGD was used to induce cell apoptosis in vitro. Effects of miR-let-7i on OGD-induced cell apoptosis was estimated after transfection. The target gene of miR-let-7i was analyzed by dual luciferase reporter gene assay. Results: The expression of miR-let-7i was up-regulated in PSCI patients compared with Non-PSCI (p < 0.001) and negatively correlated with MoCA score (r = -0.643, p < 0.001). When exposed to OGD, SH-SY5Y cells showed significant apoptosis accompanied by miR-let-7i up-regulation. In OGD-treated cells, miR-let-7i up-regulation was accompanied by cell apoptosis, while down-regulation showed the opposite effect. Luciferase reporter assay showed that Bcl-2 was a target gene of miR-let-7i. Western blot showed that miR-let-7i up-regulation promoted Bcl-2 expression, while qRT-PCR showed that miR-let-7i had no effect on Bcl-2 expression. Conclusion: miR-let-7i was overexpressed in PSCI patients and it could be used as a diagnostic biomarker for PSCI. We illuminated the potential mechanism that miR-let-7i alleviated OGD-induced cell damage by targeting Bcl-2 at the post-transcriptional level.

DL-3-n-butylphthalide protects the blood-brain barrier against ischemia/hypoxia injury via upregulation of tight junction proteins.

BACKGROUND: The increased permeability of the blood-brain barrier (BBB) induced by ischemia/hypoxia is generally correlated with alteration of tight junctions (TJs). DL-3-n-butylphthalide (NBP) has been shown to exert neuroprotective effects after ischemic injury. However, few studies have assessed the correlation between NBP and TJs. This study aimed to investigate the potential effect of NBP on the TJ proteins claudin-5, zonula occludens-1 (ZO-1), and occludin during brain ischemia. METHODS: A chronic cerebral hypoperfusion (CCH) Sprague-Dawley rat model was established, and NBP (20, 40, or 80 mg/kg, gavage, once a day) treatment was performed for 14 days. NBP (0.1 or 1.0 µmol/L) pre-treatment was applied to an in vitro hypoxia microvascular endothelial cell model (1% O2, 24 h). BBB permeability was assessed by performing the Evans blue assay. The expressions and localization of claudin-5, ZO-1, occludin, phosphorylated/total protein kinase B (p-Akt/Akt), phosphorylated/total glycogen synthase kinase 3ß (GSK-3ß)/GSK-3ß, and ß-catenin/ß-actin were evaluated by Western blotting or immunofluorescence. Reactive oxygen species (ROS) generation was measured by flow cytometry analysis. TJ ultrastructure was observed by transmission electron microscopy. RESULTS: In CCH rats, treatment with 40 and 80 mg/kg NBP decreased the Evans blue content in brain tissue (9.0 ±â€Š0.9 µg/g vs. 12.3 ±â€Š1.9 µg/g, P = 0.005; 6.7 ±â€Š0.6 µg/g vs. 12.3 ±â€Š1.9 µg/g, P < 0.01), increased the expression of claudin-5 (0.79 ±â€Š0.08 vs. 0.41 ±â€Š0.06, P < 0.01; 0.97 ±â€Š0.07 vs. 0.41 ±â€Š0.06, P < 0.01), and elevated the ZO-1 protein level (P < 0.05) in brain microvascular segments in a dose-dependent manner in comparison with the corresponding values in the model group. There was no significant difference in occludin expression (P > 0.05). In the hypoxia cell model, NBP pre-treatment improved TJ ultrastructure, decreased intracellular ROS level, and increased the expression of claudin-5 (P < 0.01) and ZO-1 (P < 0.01) in comparison with the corresponding values in the hypoxia group. NBP treatment also elevated the relative expression levels of p-Akt/Akt, p-GSK-3ß/GSK-3ß, and ß-catenin/ß-actin in comparison with the corresponding values in the hypoxia group (all P < 0.05). CONCLUSION: NBP improves the barrier function of BBB against ischemic injury by upregulating the expression of TJ proteins, possibly by reducing oxidative stress and activating the Akt/GSK-3ß/ß-catenin signaling pathway.

DL-3-n-butylphthalide alleviates vascular cognitive impairment by regulating endoplasmic reticulum stress and the Shh/Ptch1 signaling-pathway in rats.

BACKGROUND: DL-3-n-butylphthalide (NBP) has been approved to be effective in improving cognitive deficits. The aim of the current study was to determine whether NBP protects against cognitive deficits in a rat model of vascular dementia (VD) induced by chronic cerebral hypoperfusion (CCH) by regulating the sonic hedgehog (Shh)/patched1 (Ptch1) pathway and endoplasmic reticulum stress (ERS)-related markers. METHODS: Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid arteries (2VO) to established the model of VD. These rats were randomly divided into five groups: sham, model, NBP30 (30 mg/kg), NBP 60 (60 mg/kg), and NBP 120 (120 mg/kg) groups. The Morris water maze test was used to assess for cognitive function at 4 weeks after operation. RESULTS: NBP significantly alleviated spatial learning and memory impairment, and inhibited the loss of neurons in the CA1 region of the hippocampus. Western blot analysis and real-time quantitative polymerase chain reaction analysis revealed that plasticity-related synaptic markers and the Shh/Ptch1 pathway significantly increased in the NBP treated groups, while ERS-related markers decreased. CONCLUSION: The results of the current study prove that the Shh/Ptch1 pathway plays an essential role in the model of VD. NBP had protective effects on cognitive impairment induced by CCH. This mechanism was associated with ERS and the Shh/Ptch1 pathway. Meanwhile, the Shh/Ptch1 pathway and ERS may interact with each other.

A survey of the enteral nutrition practices in patients with neurological disorders in the tertiary hospitals of China.

BACKGROUND AND OBJECTIVES: With the development of enteral nutrition in patients with neurological disorders in China, related guidelines were published in 2011. The Chinese Society for Parenteral and Enteral Nutrition conducted a survey to evaluate the status quo of enteral nutrition practices in these patients. METHODS AND STUDY DESIGN: This multicenter prospective investigation was conducted from April 2012 to April 2013 and involved 18 tertiary hospitals in China. The survey using standardized questionnaires sought information about the basic protocols for enteral nutrition (devices and staffing) and specific information about patients with neurological conditions who received nutrition by way of enteral feeding. RESULTS: In the 18 hospitals from 13 provinces, 83.3% patients were configured with an enteral nutrition infusion pump, 77.8% had a percutaneous endoscopic gastrostomy (PEG) device, and 88.9% had a clinical nutrition support group. Four hundred four patients participated in this survey (259 men, 145 women; mean age 61.3±14.7 years), 85.7% had suffered a stroke, 83.9% had impaired consciousness, and 98.0% had dysphagia. Of the 10 guidelines for enteral nutrition practices, setting the energy target, choosing the enteral nutrition tube, and monitoring the patient received unsatisfactory ratings were in poor compliance (56.2%, 30.0% and 38.9%, respectively); the remaining seven guidelines were in good compliance (each >75%). CONCLUSION: The survey suggested that configuration of the enteral nutritional devices and staffing was adequate in China's tertiary hospitals. However, some associated practices had not yet reached the desired levels of competency, indicating a need for this to be understood and for improved training.

Diffusion tensor imaging measures of normal appearing white matter in patients who are aging, or have amnestic mild cognitive impairment, or Alzheimer's disease.

To evaluate whether cerebral white matter integrity is related to cognitive function, and whether diffusion tensor imaging (DTI) could differentiate amnestic mild cognitive impairment (aMCI) from Alzheimer's disease (AD), 12 patients with AD, 12 with aMCI, and 12 controls were recruited for this study. Cognitive functions of all subjects were assessed using the Mini-Mental State Examination (MMSE) and AD Assessment Scale - Cognitive Subscale (ADAS-Cog). DTI studies were acquired, and fractional anisotropy (FA) and mean diffusivity (MD) values of normal-appearing white matter (NAWM) in multiple brain regions were obtained. Results showed that MMSE and ADAS-Cog subscores were significantly associated with white matter integrity of the temporal-parietal lobes. A decrease in FA values and an increase in MD values in multiple cortical regions were confirmed in patients with AD compared to controls. MD values in the posterior region of the corpus callosum in aMCI differed from those of early AD. Significant reductions of FA values in the NAWM of the parietal lobe was observed in aMCI compared to controls. Our data indicate that the microstructural white matter integrity in the temporal-parietal lobes is gradually impaired in the progressive process of AD, and that splenium MD values could be used as a biomarker differentiating aMCI from AD.