LRP4-related signalling pathways and their regulatory role in neurological diseases.

The mechanism of action of low-density lipoprotein receptor related protein 4 (LRP4) is mediated largely via the Agrin-LRP4-MuSK signalling pathway in the nervous system. LRP4 contributes to the development of synapses in the peripheral nervous system (PNS). It interacts with signalling molecules such as the amyloid beta-protein precursor (APP) and the wingless type protein (Wnt). Its mechanisms of action are complex and mediated via interaction between the pre-synaptic motor neuron and post-synaptic muscle cell in the PNS, which enhances the development of the neuromuscular junction (NMJ). LRP4 may function differently in the central nervous system (CNS) than in the PNS, where it regulates ATP and glutamate release via astrocytes. It mayaffect the growth and development of the CNS by controlling the energy metabolism. LRP4 interacts with Agrin to maintain dendrite growth and density in the CNS. The goal of this article is to review the current studies involving relevant LRP4 signaling pathways in the nervous system. The review also discusses the clinical and etiological roles of LRP4 in neurological illnesses, such as myasthenia gravis, Alzheimer's disease and epilepsy. In this review, we provide a theoretical foundation for the pathogenesis and therapeutic application of LRP4 in neurologic diseases.

The neutrophil-to-lymphocyte ratio and lactate dehydrogenase combined in predicting liver metastasis and prognosis of colorectal cancer.

Background: The neutrophil-to-lymphocyte ratio (NLR) and lactate dehydrogenase (LDH) level are inflammatory markers related to tumor growth and metabolism. This study investigated the value of preoperative NLR, LDH and the combination of NLR and LDH (NLR-LDH) for predicting colorectal cancer liver metastasis (CRLM) and tumor prognosis in the early stages of colorectal cancer (CRC). Materials and methods: Three hundred patients undergoing CRC resection were included. Logistic regression analysis was used to estimate the correlation between CRLM time and inflammatory markers, and Kaplan-Meier survival and Cox regression analyses were used to estimate overall survival (OS). Forest plots were prepared based on the multivariate Cox analysis model and evaluated by receiver operating characteristic (ROC) curve analysis. Results: The NLR cut-off value was 2.071 according to the ROC curve. The multivariate analysis showed that the elevated LDH level and a high NLR-LDH level were independent predictors of synchronous CRLM and OS (p < 0.05). The combination of a high NLR and elevated LDH and NLR-LDH levels suggested a poor prognosis and a significantly shorter median survival time than a low NLR and low levels of LDH and NLR-LDH. The ROC curve analysis results illustrated that the predictive value of the NLR-LDH score for synchronous CRLM [area under the curve (AUC) = 0.623, p < 0.001] and OS (AUC = 0.614, p = 0.001) was superior to that of the NLR or LDH score used alone. Conclusion: LDH and NLR-LDH are reliable, easy-to-use, independent biomarkers for predicting synchronous or metachronous CRLM and OS in CRC patients. The NLR is an important monitoring index for CRLM. Preoperative NLR, LDH and NLR-LDH may help to guide the use of therapeutic strategies and cancer surveillance.

The prognostic value of preoperative serum lactate dehydrogenase levels in patients underwent curative-intent hepatectomy for colorectal liver metastases: A two-center cohort study.

BACKGROUND: The prognostic value of lactate dehydrogenase (LDH) in colorectal cancer patients has remained inconsistent between nonmetastatic and metastatic settings. So far, very few studies have included LDH in the prognostic analysis of curative-intent surgery for colorectal liver metastases (CRLM). PATIENTS AND METHODS: Five hundred and eighty consecutive metastatic colorectal cancer patients who underwent curative-intent CRLM resection from Sun Yat-sen University Cancer Center (434 patients) and Sun Yat-sen University Sixth Affiliated Hospital (146 patients) in 2000-2019 were retrospectively collected. Overall survival (OS) was the primary end point. Cox regression model was performed to identify the prognostic values of preoperative serum LDH levels and other clinicopathology variables. A modification of the established Fong CRS scoring system comprising LDH was developed within this Chinese population. RESULTS: At the median follow-up time of 60.5 months, median OS was 59.5 months in the pooled cohort. In the multivariate analysis, preoperative LDH >upper limit of normal (250 U/L) was the strongest independent prognostic factor for OS (HR 1.73, 95% confidence interval [CI], 1.22-2.44; p < 0.001). Patients with elevated LDH levels showed impaired OS than patients with normal LDH levels (27.6 months vs. 68.8 months). Five-year survival rates were 53.7% and 22.5% in the LDH-normal group and LDH-high group, respectively. Similar results were also confirmed in each cohort. In the subgroup analysis, LDH could distinguish the survival regardless of most established prognostic factors (number and size of CRLM, surgical margin, extrahepatic metastases, CEA, and CA19-9 levels, etc.). Integrating LDH into the Fong score contributed to an improvement in the predictive value. CONCLUSION: Our study implicates serum LDH as a reliable and independent laboratory biomarker to predict the clinical outcome of curative-intent surgery for CRLM. Composite of LDH and Fong score is a potential stratification tool for CRLM resection. Prospective, international studies are needed to validate these results across diverse populations.

High percentage atypical hepatocellular carcinoma in chronic hepatitis B patients treated with nucleos(t)ide analogs.

Nucleos(t)ide analogs are used for preventing liver cirrhosis in chronic hepatitis B patients, but the risk factors of hepatocellular carcinoma (HCC) in these patients remain unclear. We designed this retrospective cohort study, the aim is to determine the risk factors for HCC development and its image presentation under nucleos(t)ide analogs treatment.In this study, patients were treated with lamivudine (LAM), entecavir 0.5 mg (ETV), or telbivudine (LdT), and followed-up for at least 2 years to detect HCC and its presentation. Assessment of the risk factors for HCC included age, sex, HBeAg, viral load, liver cirrhosis, current and previous medications, and liver function tests.Totally, 396 patients were recruited, and 18 patients developed HCC. The mean time from the treatment to HCC development was 28.5 ±â€Š16.7 months. The clinical characteristics in HCC and no-HCC groups showed significant differences among age (52.8 ±â€Š6.1 vs 47.1 ±â€Š12.6 years, P <.01), baseline alanine transaminase (ALT) levels (161.4 ±â€Š177.3 vs 361.7 ±â€Š496.3, P <.01), and baseline liver cirrhosis (72.2% vs 29.9%, P <.01). In patients aged ≥45 years, the hazard ratio of HCC was 10.2 and liver cirrhosis was 4.1. Majority of HCCs developed in the right liver (14/18), were single numbered (13/18), had tumor size about 1.9 ±â€Š0.7 cm, were classified as T1 (14/18, TNM staging), and the atypical image occupied 88% of the HCC cases.The patients aged ≧45 years on long-term nucleos(t)ide analog therapy, and with baseline liver cirrhosis were at a high risk of HCC. Regular alpha-fetoprotein (AFP) assessment and image study of these patients are the gold standards for early HCC detection in patients with high percentage atypical HCC appearances.