Development and Validation of Pretreatment Serum Total Bilirubin as a Biomarker to Predict the Clinical Outcomes in Primary Central Nervous System Lymphoma: A Multicenter Cohort Study.

Primary central nervous system lymphoma (PCNSL) is a predominantly aggressive neoplasm isolated to the central nervous system or vitreoretinal space. Bilirubin is an important biomarker reflecting hepatic function and oxidative stress status that is associated with the occurrence and development of various tumors. However, its prognostic role in PCNSL has yet to be evaluated. Therefore, we conducted a prospective-retrospective study to analyze the predictive value of serum total bilirubin (STB) in PCNSL patients. The association between the pretreatment STB and clinical outcomes in PCNSL was developed in the discovery cohort (retrospective [n = 44] and prospective [n = 45]) and validated in an independent retrospective cohort (n = 69). A generalized additive model, Kaplan-Meier curve, and Cox analysis were applied. In the discovery cohort, the STB showed a linear relationship with overall survival (OS, p = 0.011) and progression-free survival (PFS, p = 0.0476). The median STB level of 12.0 µmol/L was determined as the cutoff value to predict the clinical outcomes with area under the receiver operating characteristic curve (AUROC) values of 0.9205 and 0.8464 for OS and PFS, respectively. The median STB level resulted in similar accuracy for predicting the clinical outcomes in the validation cohort with AUROC values of 0.8857 and 0.8589 for OS and PFS, respectively. In both the discovery and validation cohorts, the Kaplan-Meier survival curve and Cox regression analysis showed that the upper median STB groups showed significantly worse OS than the lower median STB groups. In conclusion, the pretreatment STB could be considered a novel biomarker to predict the clinical outcomes in patients with PCNSL receiving high-dose methotrexate-based combination immunochemotherapy.

Proposed new prognostic model using the systemic immune-inflammation index for primary central nervous system lymphoma: A prospective-retrospective multicohort analysis.

Purpose: The systemic immune-inflammation index (SII) has been considered a novel prognostic biomarker in several types of lymphoma. Our aims were to determine the best statistical relationship between pretreatment SII and survival and to combination of SII and the Memorial Sloan Kettering Cancer Center model (MSKCC) to derive the best prognostic mode in primary central nervous system lymphoma (PCNSL). Methods: Pretreatment SII and clinical data in 174 newly diagnosed PCNSL patients were included from two retrospective discovery cohorts (n = 128) and one prospective validation cohort (n = 46). A generalized additive model, Kaplan-Meier curve, and Cox analysis were performed. The high risk versus low risk of SII-MSKCC for the PCNSL cutoff point (0-1 vs. 2-4) was determined by the minimum P-value approach. Results: The SII showed a U-shaped relationship with the risk of overall survival (OS; P = 0.006). The patients with low SII or high SII had poorer OS and progression-free survival (PFS) than those with median SII. For PFS and OS, SII-MSKCC was a better predictor than MSKCC alone. The area under the receiver operating characteristic curve of the SII-MSKCC score was 0.84 for OS and 0.78 for PFS in the discovery cohorts. The predictive value of the SII-MSKCC score (OS, 0.88; PFS, 0.95) was verified through the validation cohort. Multivariable Cox analysis and Kaplan-Meier curve showed excellent performance for SII-MSKCC, with significant separation of two groups and better performance than MSKCC alone. Conclusions: We propose a new prognostic model using SII, age, and Karnofsky score that outperforms MSKCC alone and enables individualized estimates of patient outcome.

Prognostic significance of pretreatment red blood cell distribution width in primary diffuse large B-cell lymphoma of the central nervous system for 3P medical approaches in multiple cohorts.

Background/aims: Predicting the clinical outcomes of primary diffuse large B-cell lymphoma of the central nervous system (PCNS-DLBCL) to methotrexate-based combination immunochemotherapy treatment in advance and therefore administering the tailored treatment to the individual is consistent with the principle of predictive, preventive, and personalized medicine (PPPM/3PM). The red blood cell distribution width (RDW) has been reported to be associated with the clinical outcomes of multiple cancer. However, its prognostic role in PCNS-DLBCL is yet to be evaluated. Therefore, we aimed to effectively stratify PCNS-DLBCL patients with different prognosis in advance and early identify the patients who were appropriate to methotrexate-based combination immunochemotherapy based on the pretreatment level of RDW and a clinical prognostic model. Methods: A prospective-retrospective, multi-cohort study was conducted from 2010 to 2020. We evaluated RDW in 179 patients (retrospective discovery cohorts of Huashan Center and Renji Center and prospective validation cohort of Cancer Center) with PCNS-DLBCL treated with methotrexate-based combination immunochemotherapy. A generalized additive model with locally estimated scatterplot smoothing was used to identify the relationship between pretreatment RDW levels and clinical outcomes. The high vs low risk of RDW combined with MSKCC score was determined by a minimal P-value approach. The clinical outcomes in different groups were then investigated. Results: The pretreatment RDW showed a U-shaped relationship with the risk of overall survival (OS, P = 0.047). The low RDW (< 12.6) and high RDW (> 13.4) groups showed significantly worse OS (P < 0.05) and progression-free survival (PFS; P < 0.05) than the median group (13.4 > RDW > 12.6) in the discovery and validation cohort, respectively. RDW could predict the clinical outcomes successfully. In the discovery cohort, RDW achieved the area under the receiver operating characteristic curve (AUC) of 0.9206 in predicting the clinical outcomes, and the predictive value (AUC = 0.7177) of RDW was verified in the validation cohort. In addition, RDW combined with MSKCC predictive model can distinguish clinical outcomes with the AUC of 0.8348 for OS and 0.8125 for PFS. Compared with the RDW and MSKCC prognosis variables, the RDW combined with MSKCC scores better identified a subgroup of patients with favorable long-term survival in the validation cohort (P < 0.001). RDW combined MSKCC score remained to be independently associated with clinical outcomes by multivariable analysis. Conclusions: Based on the pretreatment RDW and MSKCC scores, a novel predictive tool was established to stratify PCNS-DLBCL patients with different prognosis effectively. The predictive model developed accordingly is promising to judge the response of PCNS-DLBCL to methotrexate-based combination immunochemotherapy treatment. Thus, hematologists and oncologists could tailor and adjust therapeutic modalities by monitoring RDW in a prospective rather than the reactive manner, which could save medical expenditures and is a key concept in 3PM. In brief, RDW combined with MSKCC model could serve as an important tool for predicting the response to different treatment and the clinical outcomes for PCNS-DLBCL, which could conform with the principles of predictive, preventive, and personalized medicine. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-022-00290-5.

Association between clinical factors and orofacial dyskinesias in anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND AND PURPOSE: We aimed to determine whether demographic information, clinical characteristics, laboratory tests, and imaging features are associated with orofacial dyskinesias (OFLD) in patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHODS: In this retrospective study, patients who were diagnosed with anti-NMDAR encephalitis were enrolled. All patients' factors, including demographic information, clinical characteristics, laboratory tests, and imaging features, were obtained at the time of hospitalization. The neurological function was assessed using the modified Rankin scale (mRS). Univariate and multivariate logistic regressions were used to examine the associations between clinical factors and OFLD. RESULTS: In total, 119 patients (median age: 28.0 [19.0-41.0] years; 67 females) were recruited. Of 119 patients, 44 (37.0%) had OFLD. OFLD was associated with increased mRS at admission, serum sodium, lumbar puncture pressure, female biologic sex, fever, psychiatric symptoms, seizures, impaired consciousness, autonomic dysfunction, and central hypoventilation in univariate logistic regression, respectively. Multivariate regression analysis revealed that female biologic sex (odds ratios [OR], 4.73; 95% confidence interval [CI], 1.27-17.64; p = .021), increased mRS at admission (OR, 2.09; 95% CI, 1.18-3.71; p = .011), psychiatric symptoms (OR, 7.27; 95% CI, 1.20-43.91; p = .031), and seizures (OR, 5.11; 95% CI, 1.22-21.43; p = .026) were associated with OFLD, after adjusting for confounding factors. CONCLUSIONS: Our analysis suggests that the following clinical factors are associated with OFLD: female biologic sex, increased mRS at admission, psychiatric symptoms, and seizures.

Identification of hub genes and pathways in bladder cancer using bioinformatics analysis.

Bladder cancer (BC) is the most common malignant tumor of urinary tract system. The aim of this study was to investigate the genetic signatures of bladder cancer (BC) and identify its potential molecular mechanisms. The gene expression profiles of GSE3167 (50 samples, including 41BC and 9 non-cancerous urothelial cells) was downloaded from the GEO database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) were performed to identify enriched pathways, and a protein-protein interaction (PPI) network was used to identify hub genes and for module analysis. Moreover, we conducted expression and survival analyses to screen and validate hub genes. In total, 1528 DEGs were identified in bladder cancer (BC), including 1212 up-regulated genes and 316 down-regulated genes. Up-regulated differentially expressed genes (DEGs) were significantly enriched in negative regulation of macromolecule metabolic process, macromolecule catabolic process, proteolysis and regulation of cell death, while the down-regulated differentially expressed genes (DEGs) were mainly involved in cell surface receptor linked signal transduction, ion transport, cell-cell signaling and defense response. The top 10 hub genes with the highest degrees were selected from the PPI network. These genes included HSP90AA1, MYH11, MYL9, CNN1, ACTC1, RAN, ENO1, HNRNPC, ACTG2 and YWHAZ. From sub-networks, we found these genes were involved in the proteasome, pathways in cancer and cell cycle. Hence, the identified DEGs and hub genes may be beneficial to elucidate the mechanisms underlying BC.

NF-κB mediates early blood-brain barrier disruption in a rat model of traumatic shock.

BACKGROUND: Blood-brain barrier (BBB) disruption is associated with a large number of central nervous system and systemic disorders. The aim of the present study was to investigate the dynamic change of BBB changes during traumatic shock and resuscitation as well as the mechanisms involved. METHODS: The experiments were performed on male Sprague-Dawley rats anesthetized with pentobarbital sodium. To produce traumatic shock, the rats were subjected to bilateral femoral traumatic fracture and blood withdrawal from the femoral artery to decrease mean arterial pressure (MAP) to 35 mm Hg. Hypovolemic status (at a MAP of 35 to 40 mm Hg) was sustained for 1 hour followed by fluid resuscitation with shed blood and 20 mL/kg of lactated Ringer's solution. RESULTS: The rats were sacrificed at 1 hour, 2 hours, or 6 hours after fluid resuscitation. Blood-brain barrier permeability studies showed that traumatic shock significantly increased brain water contents and sodium fluorescein leakage, which was aggravated by fluid resuscitation. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analyses revealed that Na-K-Cl cotransporter-1 and vascular endothelial growth factor (VEGF) expression were upregulated in cortical brain tissue of traumatic shock rats, and this change was accompanied by downregulation of occludin and claudin-5. Traumatic shock also significantly increased the protein levels of NF-κB-p65 subunit. Of note, administration of NF-κB inhibitor PDTC effectively attenuated augmentation of the above changes. CONCLUSION: Our results suggest that traumatic shock is associated with early BBB disruption, and inhibition of NF-κB may be an effective therapeutic strategy in protecting the BBB under traumatic shock conditions.

Defective autophagy in osteoblasts induces endoplasmic reticulum stress and causes remarkable bone loss.

Macroautophagy/autophagy is a highly regulated process involved in the turnover of cytosolic components, however its pivotal role in maintenance of bone homeostasis remains elusive. In the present study, we investigated the direct role of ATG7 (autophagy related 7) during developmental and remodeling stages in vivo using osteoblast-specific Atg7 conditional knockout (cKO) mice. Atg7 cKO mice exhibited a reduced bone mass at both developmental and adult age. The trabecular bone volume of Atg7 cKO mice was significantly lower than that of controls at 5 months of age. This phenotype was attributed to decreased osteoblast formation and matrix mineralization, accompanied with an increased osteoclast number and the extent of the bone surface covered by osteoclasts as well as an elevated secretion of TNFSF11/RANKL (tumor necrosis factor [ligand] superfamily, member 11), and a decrease in TNFRSF11B/OPG (tumor necrosis factor receptor superfamily, member 11b [osteoprotegerin]). Remarkably, Atg7 deficiency in osteoblasts triggered endoplasmic reticulum (ER) stress, whereas attenuation of ER stress by administration of phenylbutyric acid in vivo abrogated Atg7 ablation-mediated effects on osteoblast differentiation, mineralization capacity and bone formation. Consistently, Atg7 deficiency impeded osteoblast mineralization and promoted apoptosis partially in DDIT3/CHOP (DNA-damage-inducible transcript 3)- and MAPK8/JNK1 (mitogen-activated protein kinase 8)-SMAD1/5/8-dependent manner in vitro, while reconstitution of Atg7 could improve ER stress and restore skeletal balance. In conclusion, our findings provide direct evidences that autophagy plays crucial roles in regulation of bone homeostasis and suggest an innovative therapeutic strategy against skeletal diseases.

[Correlation between Plasma microRNA Expression and Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To investigate the microRNA (miRNA) expression in plasma of patients with aGVHD and without aGVHD after allo-hematopoietic stem cell transplantation (allo-HSCT). METHODS: The miRNAs (miR-423, mirR199a-3p, miR93*, miR377) expression levels in peripheral blood plasma of 25 patients before and after allo-HSCT were detected by real-time PCR. RESULTS: miR-423, miR199a-3p and miR-93* in aGVHD group were significantly upregulated (P<0.05); miR-377 expression was not significantly different between aGVHD and non-aGVHD (P>0.05). CONCLUSION: The expression of miR-423, miR-199a-3p, miR-93* are upregulated in aGVHD group, which can be used as biomarkes to monitor and to diagnose aGVHD.

Enhanced uptake and transport of (+)-catechin and (-)-epigallocatechin gallate in niosomal formulation by human intestinal Caco-2 cells.

The aim of this study was to evaluate (+)-catechin and (-)-epigallocatechin gallate (EGCG) cellular uptake and transport across human intestinal Caco-2 cell monolayer in both the absence and presence of niosomal carrier in variable conditions. The effect of free drugs and drug-loaded niosomes on the growth of Caco-2 cells was studied. The effects of time, temperature, and concentration on drug cellular uptake in the absence or presence of its niosomal delivery systems were investigated. The intestinal epithelial membrane transport of the drug-loaded niosomes was examined using the monolayer of the human Caco-2 cells. The kinetics of transport, and the effect of temperature, adenosine triphosphate inhibitor, permeability glycoprotein inhibitor, multidrug resistance-associated protein 2 inhibitor, and the absorption enhancer on transport mechanism were investigated. It was found that the uptake of catechin, EGCG, and their niosomes by Caco-2 cells was 1.22 ± 0.16, 0.90 ± 0.14, 3.25 ± 0.37, and 1.92 ± 0.22 µg/mg protein, respectively (n=3). The apparent permeability coefficient values of catechin, EGCG, and their niosomes were 1.68 ± 0.16, 0.88 ± 0.09, 2.39 ± 0.31, and 1.42 ± 0.24 cm/second (n=3) at 37°C, respectively. The transport was temperature- and energy-dependent. The inhibitors of permeability glycoprotein and multidrug resistance-associated protein 2 and the absorption enhancer significantly enhanced the uptake amount. Compared with the free drugs, niosomal formulation significantly enhanced drug absorption. Additionally, drug-loaded niosomes exhibited stronger stability and lower toxicity. These findings showed that the oral absorption of tea flavonoids could be improved by using the novel drug delivery systems.

Development of water-in-oil microemulsions with the potential of prolonged release for oral delivery of L-glutathione.

Oral delivery of L-L-glutathione is quite a challenge due to the enzymatic and physical barriers in the gastrointestinal tract (GIT). Colloidal delivery systems such as microemulsions (ME) can be valuable for oral delivery of L-glutathione, because they may protect L-glutathione from enzymatic degradation and enhance its permeability across the intestinal epithelium. The aim of this study was to identify ME systems capable of accommodating maximum amounts of L-glutathione in internal aqueous phase intended for oral delivery. Pseudoternary phase diagrams for the systems based on a single or a blend of two oily components, one or two nonionic surfactants and an aqueous phase loaded with L-glutathione were constructed, identified and characterized in terms of morphological, rheological and in vitro release studies. Among the tested formulations, the coarse emulsions resulted in the highest release rate, while the ME and liquid crystal systems provided sustained release of L-glutathione in vitro. There was a linear relationship between the cumulative amount of L-glutathione released from the ME and the liquid crystals, and the square root of time indicting a diffusion controlled process. The release of L-glutathione from the ME and the liquid crystal was related to the concentration of L-glutathione remaining in the formulations. In conclusion, two novel delivery colloidal systems of L-glutathione loaded water-in-oil ME and liquid crystal systems were developed and characterized. In addition, a simple isocratic HPLC analytic method was developed and validated, and was used for the qualitative and quantitative analysis of L-glutathione released from the selected formulations.

[Effect of neuronal differentiation induced by nerve growth factor on the tolerance-dosage of ultraviolet radiation of PC12 cells].

OBJECTIVE: To evaluate the effect of neuronal differentiation induced by nerve growth factor (NGF) on the tolerance-dosage of ultraviolet radiation of PC12 Cells. METHODS: Neuron-differentiated PC12 cells and untreated PC12 cells were exposed to different ultraviolet radiation dosage of 10, 30, 60, 80, 100, and 200 mJ/cm2. Cell survival rates were determined by MTT assay. RESULTS: Neuron-differentiated PC12 cells had increased tolerance dose to ultraviolet radiation with noticeable apoptosis at the radiation dose of 100 mJ/cm2 in contrast to 30 mJ/cm2 for normal PC12 cells. CONCLUSION: Neuronal differentiation exerts the effect of increasing the tolerance dose of PC12 cells to ultraviolet radiation.