Identifying individuals poised to gain from immune checkpoint inhibitor (ICI) therapies is a pivotal element in the realm of tailored healthcare. The expression level of Programmed Death Ligand 1 (PD-L1) has been linked to the response to ICI therapy, but its assessment typically requires substantial tumor tissue, which can be challenging to obtain. In contrast, blood samples are more feasible for clinical application. A number of promising peripheral biomarkers have been proposed to overcome this hurdle. This research aims to evaluate the prognostic utility of the albumin-to-lactate dehydrogenase ratio (LAR), the Pan-immune-inflammation Value (PIV), and the Prognostic Nutritional Index (PNI) in predicting the response to ICI therapy in individuals with advanced non-small cell lung cancer (NSCLC). Furthermore, the study seeks to construct a predictive nomogram that includes these markers to facilitate the selection of patients with a higher likelihood of benefiting from ICI therapy. A research initiative scrutinized the treatment records of 157 advanced NSCLC patients who received ICI therapy across two Jiangxi medical centers. The cohort from Jiangxi Provincial People\'s Hospital (comprising 108 patients) was utilized for the training dataset, while the contingent from Jiangxi Cancer Hospital (49 patients) served for validation purposes. Stratification was based on established LAR, PIV, and PNI benchmarks to explore associations with DCR and ORR metrics. Factorial influences on ICI treatment success were discerned through univariate and multivariate Cox regression analysis. Subsequently, a Nomogram was devised to forecast outcomes, its precision gauged by ROC and calibration curves, DCA analysis, and cross-institutional validation. In the training group, the optimal threshold values for LAR, PIV, and PNI were identified as 5.205, 297.49, and 44.6, respectively. Based on these thresholds, LAR, PIV, and PNI were categorized into high (≥ Cut-off) and low (< Cut-off) groups. Patients with low LAR (L-LAR), low PIV (L-PIV), and high PNI (H-PNI) exhibited a higher disease control rate (DCR) (P < 0.05) and longer median progression-free survival (PFS) (P < 0.05). Cox multivariate analysis indicated that PS, malignant pleural effusion, liver metastasis, high PIV (H-PIV), and low PNI (L-PNI) were risk factors adversely affecting the efficacy of immunotherapy (P < 0.05). The Nomogram model predicted a concordance index (C-index) of 0.78 (95% CI: 0.73-0.84). The areas under the ROC curve (AUC) for the training group at 6, 9, and 12 months were 0.900, 0.869, and 0.866, respectively, while the AUCs for the external validation group at the same time points were 0.800, 0.886, and 0.801, respectively. Throughout immunotherapy, PIV and PNI could act as prospective indicators for forecasting treatment success in NSCLC patients, while the devised Nomogram model exhibits strong predictive performance for patient prognoses.

BACKGROUND: Serum lactate dehydrogenase to albumin ratio (LAR) is associated with poor outcomes in malignancy and pneumonia. However, there are few studies suggesting that LAR is associated with the occurrence of acute kidney injury (AKI) in patients with sepsis, which was investigated in this study.
METHODS: We conducted a retrospective cohort study based on the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary outcome was the occurrence of AKI within 2 days and 7 days. Multivariable logistic regression models were used to calculate odds ratios to validate the association between LAR and AKI, in-hospital mortality, RRT use, and recovery of renal function, respectively.
RESULTS: A total of 4010 participants were included in this study. The median age of the participants was 63.5 years and the median LAR was 10.5. After adjusting for confounding variables, patients in the highest LAR quartile had a higher risk of AKI than those in the lowest LAR quartile within 2 days and 7 days, with odds ratios of 1.37 (95% confidence interval [CI]: 1.23-1.52) and 1.95 (95% CI: 1.72-2.22), respectively. The adjusted odds of AKI within 2 and 7 days were 1.16 (95% CI: 1.12-1.20) and 1.29 (95% CI: 1.24-1.35) for each 1 unit increase in LAR(log2), respectively.
CONCLUSIONS: This study demonstrated that elevated LAR was associated with poor prognosis in patients with sepsis. The risk of AKI and in-hospital mortality increased, the need for RRT increased, and the chance of recovery of renal function decreased with the increase of LAR.

Leukocyte common antigen-related protein tyrosine phosphatase (LAR) is a member of the protein tyrosine phosphatase family that serves as a key regulator of cellular survival. It is also involved in neurodevelopment and brain disorders. This study was designed to investigate the role of LAR in a cell-based model of Parkinson\'s disease (PD) in which U251 and SH-SY5Y cells were used as models of astrocytes and dopaminergic neurons, respectively. Cell viability, cell death, cell morphology, protein phosphorylation and expression, ATP levels, reactive oxygen species (ROS) generation, and mitochondrial membrane potential were analyzed in the wild-type (WT) and heterozygous LAR-knockout astrocytoma U251 cells to assess the cell state, signal transduction, and mitochondrial function. LAR downregulation showed a protective effect in rotenone-exposed U251 cells by increasing cell viability, reducing cell mortality, and restoring appropriate cellular morphology. LAR downregulation enhanced IGF-1R phosphorylation and downstream signal transduction as evidenced by increases in the Akt and GSK-3β phosphorylation, as well as the upregulation of NRF2 and HO-1. The downregulation of LAR also augmented DJ-1 levels in these cells. The enhanced Akt and GSK-3β phosphorylation contributed to a reduced Bax/Bcl2 ratio and suppressed apoptosis after rotenone exposure. Heterozygous LAR-knockout U251 cells exhibited higher mitochondrial function evidenced by increased mitochondrial membrane potential, ATP contents, and reduced ROS production compared to the WT cells following rotenone exposure. Further studies showed that the astrocytic protection mediated by the heterozygous knockout of LAR was associated with the activation of Akt. A specific Akt inhibitor, MK2206, reduced the cell viability, Akt and GSK3β phosphorylation, and HO-1 and NRF2 expression in U251 cells exposed to rotenone. Astrocytes provide structural and metabolic support to maintain neuronal health. Astrocytic glial cell-derived neurotrophic factor (GDNF) production is vital for dopaminergic neuron survival. Heterozygous LAR-knockout U251 cells produced higher amounts of GDNF than the WT cells. The SH-SY5Y cells cocultured with heterozygous LAR-knockout U251 cells exhibited greater viability than that of cells cocultured with WT U251 cells in response to rotenone. Together, these findings demonstrate that the heterozygous knockout of LAR in astrocytes can play a key role in protecting both astrocytic cells and cocultured neurons in a rotenone-induced cell-based model of PD. This neuroprotective effect is attributable to the augmentation of IGF1R-Akt-GDNF signaling and the maintenance of astrocytic mitochondrial function.

Leukocyte common antigen-related phosphatase (LAR) is widely expressed in the central nervous system and is known to regulate a variety of processes including cell growth, differentiation, and inflammation. However, little is currently known about LAR signaling mediated neuroinflammation after intracerebral hemorrhage (ICH). The objective of this study was to investigate the role of LAR in ICH using autologous blood injection-induced ICH mouse model. Expression of endogenous proteins, brain edema and neurological function after ICH were evaluated. Extracellular LAR peptide (ELP), an inhibitor of LAR, was administered to ICH mice and outcomes were evaluated. LAR activating-CRISPR or IRS inhibitor NT-157 was administered to elucidate the mechanism. The results showed that expressions of LAR, its endogenous agonist chondroitin sulfate proteoglycans (CSPGs) including neurocan and brevican, and downstream factor RhoA increased after ICH. Administration of ELP reduced brain edema, improved neurological function, and decreased microglia activation after ICH. ELP decreased RhoA and phosphorylated serine-IRS1, increased phosphorylated tyrosine-IRS1 and p-Akt, and attenuated neuroinflammation after ICH, which was reversed by LAR activating-CRISPR or NT-157. In conclusion, this study demonstrated that LAR contributed to neuroinflammation after ICH via RhoA/IRS-1 pathway, and ELP may be a potential therapeutic strategy to attenuate LAR mediated neuroinflammation after ICH.

Tetrastigma hemsleyanum Diels et Gilg is a rare and wild medicinal resource. Metabolites, especially secondary metabolites, have an important influence on T. hemsleyanum adaptability and its medicinal quality. The metabolite proanthocyanidin (PA) is a polyphenol compound widely distributed in land plants, which can be used as antioxidants and anticancer agents. Here, we discovered that three types of PA accumulated in large amounts in purple leaves (PL), but not in green leaves (RG), based on widely non-targeted metabolomics. In addition, we further found that catechins and their derivatives, which are the structural units of PA, are also enriched in PL. Afterwards, we screened and obtained five key genes, DNR1/2, ANS, ANR and LAR closely related to PA biosynthesis through transcriptome analysis and found they were all highly expressed in PL compared to RG. Therefore, observed the regulatory relationship between the main compounds and genes network, and the PA metabolism regulatory pathway was complicated, which may be different to other species.

Triple-negative breast cancer is a heterogeneous disease with different molecular and histological subtypes. The Androgen receptor is expressed in a portion of triple-negative breast cancer cases and the activation of the androgen receptor pathway is thought to be a molecular subtyping signature as well as a therapeutic target for triple-negative breast cancer. Thus, identification of the androgen receptor pathway status is important for both molecular characterization andclinical management. In this study, we investigate the expression of the androgen receptor pathway in metaplastic breast cancer and luminal androgen receptor subtypes of triple-negative breast cancer and found that the androgen receptor pathway was downregulated in metaplastic breast cancer compared to luminal androgen receptor subtype. Using random forest, we found that the two subtypes of breast cancer can be molecularly classified with the gene expression of the androgen receptor pathway.

Proanthocyanidins (PAs) are mainly composed of epicatechin (EC) or catechin (C) subunits. C-type catechins (C and GC) are generally considered to be catalyzed by leucocyanidin reductase (LAR). In this study, we re-evaluated the function of LAR. LcLAR1 was isolated from Lotus corniculatus, which is rich in C-type catechins. Overexpression of LcLAR1 in tobacco resulted in a significantly increased content of EC and EC-glucoside. Overexpression of LcLAR1 in Arabidopsis thaliana promoted the accumulation of soluble PAs, including EC, PA dimers, and PA trimers. However, in the transgenic ans mutant overexpressing LcLAR1, the contents of C and C-glucoside were increased. In addition, overexpression of LcLAR1 in L. corniculatus resulted in a significant increase of C levels. Taken together, the products of LcLAR1 depended on the substrates, which revealed the substrate diversity of LcLAR1. Our study provides new insights into the flavonoid pathway, especially the role of LAR.

Owing to their inhibitory role in regulating oligodendrocyte differentiation and apoptosis, protein tyrosine phosphatase sigma (PTPσ) and leukocyte common antigen-related phosphatase (LAR) play a crucial potential role in treating spinal cord injury (SCI) disease. In this research, the computer aided drug design (CADD) methods were applied to discover the potential dual-target drug involving virtual screen, molecular docking and molecular dynamic simulation. Initially, the top 20 compounds with higher docking score than the positive controls (ZINC13749892, ZINC14516161) were virtually screened out from NCI and ZINC databases, and then were submitted in ADMET to predict their drug properties. Among these potential compounds, ZINC72417086 showed a higher docking score and satisfied Lipinski\'s rule of five. In addition, the post-analysis demonstrated that when ZINC72417086 bound to PTPσ and LAR, it could stable proteins conformations and destroy the residues interactions between P-loop and other loop regions in active pocket. Meanwhile, residue ARG1595 and ARG1528 could play a crucial role in in the inhibition of PTPσ and LAR, respectively. This research offered a novel approach for rapid discovery of dual-target leads compounds to treat SCI.Communicated by Ramaswamy H. Sarma.

UNASSIGNED: Radical resection is the treatment of choice for hepatocellular carcinoma (HCC). However, even with this treatment, HCC prognosis and the efficacy of current predictive models for such patients remain unsatisfactory. Here, we describe an accurate and easy-to-use prognostic index for patients with HCC who have undergone curative resection.
UNASSIGNED: The study population comprised of 1,041 patients with HCC who underwent curative resection at Zhongshan Hospital. This population was reduced to 768 patients who were treated in 2012 analyzed as the training cohort and 273 patients treated in 2007 who were used as a validation cohort.
UNASSIGNED: The lactic dehydrogenase to albumin ratio (LAR) was identified as a significant prognostic index for both overall survival and recurrence-free survival in two independent cohorts. The optimal cutoff value for LAR was determined to be 5.5. The C-index of LAR was superior to other inflammatory scores and serum parameters. This biomarker was also shown to be a stable predictive index in the validation cohort. The new nomogram combining LAR with the Barcelona Clinic Liver Cancer staging system had an improved ability to discriminate overall survival and recurrence-free survival. Nomogram predictions were consistent with observations based on calibration and decisive curve analysis in both independent cohorts.
UNASSIGNED: LAR is a novel, convenient, reliable, and accurate prognostic predictor in patients with HCC undergoing curative resection. Our results suggest the recommendation of LAR to be used in routine clinical practice.

BACKGROUND: Situs inversus totalis (SIT) refers to an unusual condition involving reversal of abdominal and thoracic viscera, with an incidence rate of 1/5000-20,000 adults. Minimally invasive surgeries for SIT patients are technically challenging, while the surgical experience for SIT patients is quite limited.
METHODS: A 61-year-old man, previously diagnosed as SIT, came to our hospital for 6 months history of hematochezia and altered bowel habit. A diagnosis of rectal cancer was made in view of colonoscopic biopsy which confirmed an irregular circumferential lump of well differentiated adenocarcinoma at 10 cm from the anal verge. The computed tomography contrast-enhanced (thorax + abdomen + pelvis) scan revealed a total transposition of abdominal and thoracic organs and an enhanced eccentric mass of rectal but with no evidence of distant metastasis. Robotic low anterior resection (LAR) plus transanal natural orifice specimen extraction (NOSE) was performed after obtaining informed consent. The procedure was performed successfully and the patient convalesced nicely without any complications. The postoperative pathological diagnosis revealed a 4x4x0.6 cm3 moderately differentiated adenocarcinoma and circumferential clearance.
CONCLUSIONS: Robotic LAR plus transanal NOSE for rectal cancer patients with SIT can be performed safely and may be an effective approach in contrast to open or laparoscopic approach, despite the unconventional anatomy.