Lumbar spinal stenosis (LSS) can cause a range of cauda equina symptoms, including lower back and leg pain, numbness, and intermittent claudication. This disease affects approximately 103 million people worldwide, particularly the elderly, and can seriously compromise their health and well-being. Ligamentum flavum hypertrophy (LFH) is one of the main contributing factors to this disease. Surgical treatment is currently recommended for LSS caused by LFH. For patients who do not meet the criteria for surgery, symptom relief can be achieved by using oral nonsteroidal anti-inflammatory drugs (NSAIDs) and epidural steroid injections. Exercise therapy and needle knife can also help to reduce the effects of mechanical stress. However, the effectiveness of these methods varies, and targeting the delay in LF hypertrophy is challenging. Therefore, further research and development of new drugs is necessary to address this issue. Several new drugs, including cyclopamine and N-acetyl-l-cysteine, are currently undergoing testing and may serve as new treatments for LSS caused by LFH.
Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long–Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus (DG), the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote abnormal, bistable representations under certain conditions. SIGNIFICANCE STATEMENT Prior work suggested that age-related CA3 hyperactivity enhances pattern completion, resulting in rigid representations. Implicit in prior studies is the notion that hyperactivity is present throughout a functionally homogeneous CA3 network. However, more recent work has demonstrated functional heterogeneity along the CA3 transverse axis, in that proximal CA3 is involved in pattern separation and distal CA3 is involved in pattern completion. Here, we show that age-related hyperactivity is present only in proximal CA3, with potential hypoactivity in distal CA3. This result provides new insight in the role of CA3 in age-related memory impairments, suggesting that the rigid representations in aging result primarily from dysfunction of computational circuits involving the dentate gyrus (DG) and proximal CA3.
Abstract Intergenerational trauma increases lifetime susceptibility to depression and other psychiatric disorders. Whether intergenerational trauma transmission is a consequence of in-utero neurodevelopmental disruptions versus early-life mother–infant interaction is unknown. Here, we demonstrate that trauma exposure during pregnancy induces in mouse offspring social deficits and depressive-like behavior. Normal pups raised by traumatized mothers exhibited similar behavioral deficits to those induced in pups raised by their biological traumatized mothers. Good caregiving by normal mothers did not reverse prenatal trauma-induced behaviors, indicating a two-hit stress mechanism comprising both in-utero abnormalities and early-life poor parenting. The behavioral deficits were associated with profound changes in the brain metabotranscriptome. Striking increases in the mitochondrial hypoxia marker and epigenetic modifier 2-hydroxyglutaric acid in the brains of neonates and adults exposed prenatally to trauma indicated mitochondrial dysfunction and epigenetic mechanisms. Bioinformatic analyses revealed stress- and hypoxia-response metabolic pathways in the neonates, which produced long-lasting alterations in mitochondrial energy metabolism and epigenetic processes (DNA and chromatin modifications). Most strikingly, early pharmacological interventions with acetyl-L-carnitine (ALCAR) supplementation produced long-lasting protection against intergenerational trauma-induced depression.
Abstract Background: Despite the substantial burden of caring schizophrenic patients, primary caregivers can also experience posttraumatic growth (PTG) which may buffer their negative experience. Influencing factors of PTG and their functional pathways among primary caregivers of schizophrenic patients remain unclear. This study is designed to test the simple and serial mediating roles of coping styles and resilience in the relationship between perceived social support and PTG among those primary caregivers.Methods: A cross-sectional study was conducted from October 2018 to January 2019, and 365 primary caregivers (self-reported) of schizophrenic patients were analyzed. Measures used to assess their perceived social support, coping styles, resilience, and PTG were the Perceived Social Support Scale, the Simplified Coping Style Questionnaire, the Connor-Davidson Resilience Scale, and the Posttraumatic Growth Inventory, respectively. Structural equation modeling was used to run the analysis.Results: The average scores of PTG (range: 0-5), perceived social support (range: 1-7), positive coping style (range: 0-3), negative coping style (range: 0-3), resilience (range: 0-4) reported by primary caregivers was (2.91 ± 0.99), (4.80 ± 1.26), (1.79 ± 0.65), (1.49 ± 0.56), and (2.46 ± 0.66), respectively. The fitness indices of measurement and structural models were satisfactory. Three indirect pathways totally explained 55.56% variance of the PTG. The indirect effect of positive coping style between perceived social support and PTG was 0.20 [95% confidence interval (CI) 0.05 to 0.37], and this simple mediation pathway explained 27.78% variance of PTG. The indirect effect of resilience between perceived social support and PTG was 0.11 [95% CI 0.01 to 0.20], and this simple mediation pathway explained 15.28% variance of PTG. The indirect effect of positive coping style and then resilience between perceived social support and PTG was 0.09 [95% CI 0.01 to 0.17], and this serial mediation pathway explained 12.50% variance of PTG. Conclusions: Both simple and serial mediation roles of positive coping style and resilience are established in the relationship between perceived social support and PTG among primary caregivers of schizophrenic patients. Positive coping style and resilience are two important targets for future interventional studies, and interventions on them may bring the synergistic effect on improving PTG.
Abstract Gastric cancer (GC), ranking fifth in global incidence and fourth in mortality. The current treatments for GC include surgery, chemotherapy, and radiotherapy. Although management and treatment strategies for GC have been improved over the last decade, the overall five-year survival rate remains less than 30%. Therefore, there is an urgent need to find novel therapeutic or preventive strategies that can increase GC patient survival rates. In the current study, we found that tegaserod maleate, a FDA-approved drug, could inhibit the proliferation of gastric cancer cells. Tegaserod maleate binds to MEK1 /2 and inhibits MEK1 /2 kinase activity. Moreover, the construction of CRISPER/Cas9 cell line further verified that tegaserod maleate depended on MEK1 /2 to inhibit the progress of gastric cancer. Notably, we found that tegaserod maleate suppressed tumor growth in patient-derived gastric xenograft (PDX) mouse model. We also compared tegaserod maleate with trametinib, a clinical MEK1/2 inhibitor, and comfirmed that tegaserod maleate have the same effect in inhibiting tumor volume and tumor weight. Our findings suggest that tegaserod maleate can inhibit GC proliferation by targeting MEK1/2.
Objective
To investigate the expression of Fascin in early-stage NSCLC, evaluate the relevance between Fascin expression level and prognosis.
Methods
The immunohistochemistry method was used to assess the expression of Fascin in 111 lung cancer FFPE tissues with stage Ⅰ and Ⅱ NSCLC. The relationship between Fascin expression and the clinicopathological characteristics was analyzed. The prognostic significance of Fascin expression was evaluated with Kaplan-Meier survival analysis.
Results
In the early-stage of NSCLC, the positive rate of Fascin expression was 64.8%, no expression in the paracarcinoma tissue. The positive rate of squamous cell carcinoma was 78.7% and was significantly higher than that in adenocarcinoma 48.0%(P<0.01). Whether in squamous cell carcinoma or adenocarcinoma group, the expression of Fascin was correlated significantly with lymph node metastasis tumor stages and DFS(P<0.05). And the positive expression of Fascin was an independent risk factor of poor prognosis for patient with NSCLC.
Conclusion
Fascin is expected to be a biomarker for the prognosis of patients with early-stage NSCLC.
Key words:
Fascin; Carcinoma, non-small-cell lung; Immunohistochemistry; Prognosis
In order to improve the survival-rates and study the long-term therapeutic effect of stage III lung cancer patients with different treatment modalities.From 1995 to 2004, 1921 patients of stage III lung cancer treated at our hospital were retrospectively analyzed to compare the long-term therapeutic effect of different treatment modalities. There were 606 cases in the combined therapy group (mainly surgical with combined treatment of chemotherapy & radiotherapy), 317 cases in the surgery alone group and 998 cases in the non-surgical group. The 1, 3, 5-year survival rates of these three groups were 66.0% (400/606) vs. 62.7% (199/317) vs. 51.2% (511/998), 32.34% (196/606) vs. 21.45% (68/317) vs. 8.15% (81/998), 19.31% (117/606) vs. 13.2% (42/317) vs. 4.2% (42/998) respectively. In comparison, 1, 3, 5-year survival rates of the combined therapy group was higher than the surgery alone and non-surgical groups; Significant differences in 1-year survival rates were found between the combined therapy group and the surgery alone group or the non-surgical group (P < 0.01) and significant differences in 3, 5-year survival rates among these three groups.The combined therapy of radical resection with chemotherapy and radiotherapy is the best treatment modality for stage III lung cancer.
Laminin gamma2 (Ln-γ2) chain, a distinctive subunit of heterotrimeric laminin-332, is frequently upregulated in carcinomas and is of great importance in cell migration and invasion. Despite this, the status of circulating Ln-γ2 in lung cancer patients is still uncertain.In this retrospective study, serum samples from 538 all-stage (stages I-IV) patients with non-small-cell lung cancer (NSCLC) and 94 age-matched healthy volunteers were investigated by enzyme-linked immunosorbent assay. Data were statistically analyzed in combination with clinicopathological information.Circulating Ln-γ2 was markedly increased in NSCLC, even in stage I cases (P<0.01), reflecting the progression of lung cancer. Survival analysis on 370 eligible patients indicated that serum Ln-γ2-negative patients survived much longer compared with Ln-γ2-positive individuals (P=0.028), and it was especially the case for stage I (P<0.001), stage T1 (P=0.001), and stage N0 patients (P=0.038), all of whom represented early-stage cases. For the advanced patients, however, overall survivals were not significantly different among stages II-IV (P=0.830), stages T2-T4 (P=0.575), stages N1-N3 (P=0.669), and stage M1 (P=0.849). Cox analysis subsequently defined serum Ln-γ2 as an independent prognostic indicator of NSCLC, particularly for early-stage patients. Furthermore, we demonstrated the association of serum Ln-γ2 with smoking behavior, but its association with tumor progression and early prognostic significance were not altered in the nonsmoking cohort.Our study demonstrated that elevation of circulating Ln-γ2 was an early-emerging event in NSCLC and was significantly associated with poor prognosis in NSCLC, especially for early-stage cases.
Abstract Background: Esophageal squamous cell carcinoma (ESCC) is a high recurrence rate of upper-digestive cancer with a low 5-year survival rate. Therefore, there is an urgent need for effective chemopreventive drugs that can extend the survival rate of patients. Through screening of FDA-approved drugs, dasabuvir was found to suppress ESCC proliferation. Methods: Cell number count assay was used to screen for drugs with inhibitory effect on ESCC cells and detect the inhibitory effect of dasabuvir on proliferation of ESCC cells KYSE150 and KYE450. Phosphoproteomics and proteomics were used to investigate the mechanism of dasabuvir inhibiting ESCC. In vitro kinase assay was used to verify the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation by ROCK1 by dasabuvir. The PDX model was used to test the inhibitory effect of dasabuvir on ESCC in vivo . Results: In this study, we found that dasabuvir is a novel inhibitor of Rho-associated protein kinase 1 (ROCK1). Dasabuvir inhibited the growth of the KYSE150 and KYSE450 ESCC cell lines in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was validated in vivo using a patient-derived xenograft tumor model in mice. Dasabuvir inhibited the activation of ERK1/2 by ROCK1 and downregulated cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Conclusions: These results provide the first evidence that dasabuvir serves as a ROCK1 inhibitor, suppresses ESCC growth in vivo and in vitro , and arrests the cell cycle through the ROCK1/ERK signaling pathway.
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