Elevated ALOX12 in renal tissue predicts progression in diabetic kidney disease.

Diabetic kidney disease (DKD) is one of the major causes of end-stage renal disease and one of the significant complications of diabetes. This study aims to identify the main differentially expressed genes in DKD from transcriptome sequencing results and analyze their diagnostic value. The present study sequenced db/m mouse and db/db mouse to determine the ALOX12 genetic changes related to DKD. After preliminary validation, ALOX12 levels were significantly elevated in the blood of DKD patients, but not during disease progression. Moreover, urine ALOX12 was increased only in macroalbuminuria patients. Therefore, to visualize the diagnostic efficacy of ALOX12 on the onset and progression of renal injury in DKD, we collected kidney tissue from patients for immunohistochemical staining. ALOX12 was increased in the kidneys of patients with DKD and was more elevated in macroalbuminuria patients. Clinical chemical and pathological data analysis indicated a correlation between ALOX12 protein expression and renal tubule injury. Further immunofluorescence double staining showed that ALOX12 was expressed in both proximal tubules and distal tubules. Finally, the diagnostic value of the identified gene in the progression of DKD was assessed using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) value for ALOX12 in the diagnosis of DKD entering the macroalbuminuria stage was 0.736, suggesting that ALOX12 has good diagnostic efficacy. During the development of DKD, the expression levels of ALOX12 in renal tubules were significantly increased and can be used as one of the predictors of the progression to macroalbuminuria in patients with DKD.

Novel target and treatment agents for natural killer/T-cell lymphoma.

The rapidly increasing use of high-throughput screening had produced a plethora of expanding knowledge on the molecular basis of natural killer/T-cell lymphoma (NKTCL), which in turn has revolutionized the treatment. Specifically, the use of asparaginase-containing regimens has led to substantial improvement in survival outcomes in NKTCL patients. Novel treatment strategies that are currently under development include cell-surface-targeted antibodies, immune checkpoint inhibitors, Epstein-Barr virus targeted cytotoxic T lymphocyte, immunomodulatory agents, chimeric antigen receptor T cells, signaling pathway inhibitors and epigenetic targeted agents. In almost all cases, initial clinical studies of newly developed treatment are conducted in patients relapsed, and refractory NKTCL due to very limited treatment options. This review summarizes the results of these novel treatments for NKTCL and discusses their potential for likely use in NKTCL in a wider setting in the future.

Clinical significance of Interleukin 17 receptor E in diabetic nephropathy.

OBJECTIVE: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Since there are limited therapeutic options available for the prevention of DN progression, it is imperative to explore novel differentially expressed genes and therapeutic targets for DN. METHODS: In this study, mice kidney tissue were subjected to transcriptome sequencing and the results were analysed using bioinformatics methods. Interleukin 17 receptor E (IL-17RE) was screened from the sequencing data and its expression was validated in the animal tissues and a cross-sectional clinical study. Fifty-five DN patients were enrolled and further subdivided into two groups based on the urinary albumin-to-creatinine ratio (UACR). Two control groups were used for comparison (minimal change disease group, 12 patients; normal control group, 6 patients). Correlation analysis was conducted to study the relationship between IL-17RE expression and the clinicopathological indices. Logistic regression and receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic value. RESULTS: IL-17RE expression was significantly higher in db/db mice and the kidney tissues of DN patients than the control group. IL-17RE protein levels in the kidney tissues were strongly correlated with neutrophil gelatinase-associated lipocalin (NGAL) levels, UACR, and certain clinicopathological indices. IL-17RE levels, total cholesterol (TC) levels, and glomerular lesions were independent risk factors for macroalbuminuria. ROC curves showed a good detection value for IL-17RE in macroalbuminuria (area under the curve = 0.861). CONCLUSION: The results of this study provide novel insights into DN pathogenesis. Kidney IL-17RE expression levels were associated with DN disease severity and albuminuria.

Diagnostic performance and prognostic value of circulating tumor DNA methylation marker in extranodal natural killer/T cell lymphoma.

Circulating tumor DNA (ctDNA) carries tumor-specific genetic and epigenetic variations. To identify extranodal natural killer/T cell lymphoma (ENKTL)-specific methylation markers and establish a diagnostic and prognosis prediction model for ENKTL, we describe the ENKTL-specific ctDNA methylation patterns by analyzing the methylation profiles of ENKTL plasma samples. We construct a diagnostic prediction model based on ctDNA methylation markers with both high specificity and sensitivity and close relevance to tumor staging and therapeutic response. Subsequently, we built a prognostic prediction model showing excellent performance, and its predictive accuracy is significantly better than the Ann Arbor staging and prognostic index of natural killer lymphoma (PINK) risk system. Notably, we further establish a PINK-C risk grading system to select individualized treatment for patients with different prognostic risks. In conclusion, these results suggest that ctDNA methylation markers are of great value in diagnosis, monitoring, and prognosis, which might have implications for clinical decision-making of patients with ENKTL.

Efficacy and safety of anlotinib in metastatic adenoid cystic carcinoma: a retrospective study.

Background: Metastatic adenoid cystic carcinoma (ACC) is a malignant tumor lacking effective therapies. We evaluated a multitargeted tyrosine kinase inhibitor anlotinib in patients with metastatic ACC. Methods: From September 2018 to October 2020, nineteen patients with histologically confirmed metastatic ACC of any primary site were treated with anlotinib 12 mg orally per day at the two-week on/one-week off schedule at a single institution. Disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were analyzed. Adverse events (AEs) were recorded. Results: The DCR of anlotinib in metastatic ACC was 63.2% (12/19), including 1 partial response and 11 stable disease. After a median follow-up of 11.0 months, median PFS was 10.1 (95% CI: 6.8-14.8) months. Median OS was not reached. The most common AEs included hypertension (n=6, 32%), oral pain (n=6, 32%), hypothyroidism (n=6, 32%), hand-foot skin syndrome (n=5, 26%), proteinuria (n=5, 26%), fatigue (n=4, 21%), and anorexia (n=4, 21%). Grade 3 AEs occurred in two cases (oral pain and hand-foot skin syndrome) and could be managed. Conclusions: Anlotinib demonstrated antitumor activity and manageable toxicity in metastatic ACC patients. Thus, metastatic ACC patients could benefit from anlotinib as a palliative targeting therapy.

A novel clinical immune-related prognostic model predicts the overall survival of mantle cell lymphoma.

The mantle cell lymphoma (MCL) International Prognostic Index (MIPI) and combined MIPI (MIPI-c) are commonly used for risk classification of MCL patients. However, these indexes lack immune-related parameters. The purpose of this study was to develop a novel prognostic model that integrated clinical and immune parameters. A total of 189 patients with newly diagnosed MCL from January 2010 to June 2020 were enrolled in our study. A nomogram and immune-related prognostic index (IRPI) were established to predict the overall survival (OS) of patients according to univariate and multivariate analyses. Discrimination and calibration were used to compare the prognostic performance of the IRPI, MIPI, and MIPI-c. External validation was performed based on validation dataset (n = 150) from two other centers. The results for the training dataset indicated that B symptoms, platelet count, B2M level, CD4+ T-cell count<26.7% and CD8+ T-cell count>44.2% were predictors for OS. All the prognostic factors were integrated into the nomogram. For the overlap of confidence intervals of each variable, we assigned one point for each factor. The IRPI categorized patients into three risk categories: a score of zero indicated low risk, a score of one or two indicated intermediate risk, and a score of ≥3 indicated high risk. The IRPI showed better discrimination and calibration power than the MIPI and MIPI-c in the training dataset and validation dataset. The novel IRPI is a refined risk stratification index and reflects the strong complementary prognostic effects between clinical and immune parameters in MCL.

Comparison of Chemotherapy Combined With Chidamide Versus Chemotherapy in the Frontline Treatment for Peripheral T-Cell Lymphoma.

Background: Peripheral T-cell lymphoma (PTCL) is featured with a poor survival outcome. China has approved chidamide, an oral novel histone deacetylase inhibitor, for patients diagnosed with relapsed or refractory PTCL. Objective: We compared the benefit of traditional chemotherapy alone and a combination of chidamide and traditional chemotherapy against newly diagnosed PTCL. Prognostic factors related to progression and survival in patients diagnosed with untreated PTCL were also investigated. Methods: 104 patients with newly diagnosed PTCL were enrolled and divided into chemotherapy (ChT) group and chemotherapy combined with chidamide (ChT+C) group. Survival curves were plotted by the Kaplan-Meier method. Univariate and multivariate analysis were conducted with Log-rank test and Cox's proportional hazard regression. Subgroup analysis and interaction tests were conducted to evaluate factors associated with prognostic differences between ChT and ChT+C groups. Results: Compared with patients in ChT group, those in ChT+C group had superior progression-free survival (PFS) (p=0.047). However, there was no significantly statistical difference observed between the two groups in overall survival (OS) (p=0.212). High IPI scores have a negative relationship with survival. Multivariate analysis revealed that the type of frontline treatment regimen is an independent factor associated with PFS of PTCL patients (p=0.045). In the subgroup of patients with high international prognostic index scores (3-5), the HR value for PFS comparing ChT with ChT+C was 4.675. A test of interaction between IPI and treatment showed statistical significance (p = 0.037), implying that the benefits of ChT+C are higher for patients with high IPI scores. Conclusions: In summary, the combination of ChT and chidamide may provide a promising prospect for patients with newly diagnosed PTCL.

Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4-6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0 months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2 g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2 g/m2) may not be necessary for the moderate-risk patients.

Combination of PD-1 inhibitor with GVD (gemcitabine, vinorelbine, liposomal doxorubicin) versus GVD regimen as second-line therapy for relapsed/refractory classical Hodgkin lymphoma.

Patients with classical Hodgkin lymphoma (cHL) who do not achieve complete remission (CR) after second-line chemotherapy have poor clinical outcomes. Besides, conventional salvage chemotherapy regimens have an unsatisfactory CR rate. The present retrospective study reports the efficacy and toxicity of the GVD (gemcitabine, vinorelbine, liposomal doxorubicin) regimen with or without programmed cell death 1 (PD-1) inhibitor for patients with cHL who failed first-line treatment. A total of 103 patients with cHL (GVD+PD-1 group, n = 27; GVD group, n = 76) with response assessment based on positron emission tomography were included. The GVD+PD-1 group tended to have a higher CR rate than GVD group (85·2% vs. 65·8%, P = 0·057) and had a better event-free survival (EFS) (P = 0·034). Subgroup analysis showed that patients with low-risk second-line International Prognostic Score might benefit from the addition of PD-1 inhibitor (GVD+PD-1 vs. GVD, 100·0% vs. 64·7%, P = 0·028) and had better EFS than GVD alone (P = 0·016). Further analysis demonstrated that PD-1 consolidation therapy might provide an EFS benefit (P = 0·007). The toxicity of the GVD+PD-1 regimen was comparable to the GVD regimen, except for higher rates of hypothyroidism and autoimmune pneumonitis, which were manageable. In conclusion, combining a PD-1 inhibitor with a GVD regimen could be a potentially effective second-line therapy for patients with cHL.

Comparison of chidamide-contained treatment modalities versus chemotherapy in the second-line treatment for relapsed or refractory peripheral T-cell lymphoma.

Peripheral T-cell lymphoma (PTCL) is characterized by an aggressive clinical behavior. Chidamide has been approved for the treatment of relapsed/refractory (R/R) PTCL in China. We compared the efficacy of chidamide-contained regimens with chemotherapy (ChT) in R/R PTCL. Based on the second-line treatments, patients were divided into three groups, including ChT, ChT combined with chidamide (chidamide + ChT) and chidamide combined with or without other targeted agents (targeted therapy) group. Chidamide + ChT group had a better progression-free survival (PFS) compared with targeted therapy group (p = 0.013), and showed a trend towards superior PFS compared with ChT group (p = 0.079). Among patients with high second-line International Prognostic Index (IPI) (3-5), chidamide+ChT group had a longer PFS than ChT group(p = 0.018), and PFS in targeted therapy group was not inferior to that in chidamide+ChT group (p = 0.200). Among patients younger than 60 years, chidamide+ChT group demonstrated a PFS benefit over targeted therapy group (p = 0.010). Among CD30-negative patients, PFS was superior in the chidamide+ChT group compared with ChT group (p < 0.001). Conversely, results observed above were absent in patients with low second-line IPI or patients older than 60 years or CD30-positive patients. Overall, the combination of chidamide and ChT may be an effective treatment strategy for R/R PTCL.

A prognostic immune risk score for diffuse large B-cell lymphoma.

We constructed a prognostic score for persons with diffuse large B-cell lymphoma (DLBCL) based on infiltrating immune cells. Data of 956 consecutive subjects were retrieved from the Gene Expression Omnibus database and assigned to training (GSE10846, n = 305) or validation (GSE87371 n = 206 and GSE117556 n = 445 combined) cohorts. Proportions of non-lymphoma cells in the sample were inferred using the ESTIMATE algorithm. An immune risk score was constructed comprised of eight types of non-lymphoma immune cells calculated using the CIBERSORT algorithm. Five-year survival of subjects with an immune risk score ≤ 0·45 in the training cohort was better than that of subjects with a score > 0·45 (hazard ratio [HR] = 3·99; 95% confidence interval [CI] = 2·74, 5·82; P < 0·001). HR in the validation cohort was HR = 2·17 (1·47, 3·21; P < 0·001). Enrichment analyses indicated correlations with genes controlling immune-related biological processes and pathways. A nomogram comprised of the immune risk score and most covariates including age, lactate dehydrogenase concentration (LDH), lymphoma-type (germinal centre B cell [GCB] versus non-GCB), Eastern Cooperative Oncology Group performance status (ECOG-PS) and rituximab therapy had a C-statistic of 0·76 compared with C-statistics of 0·69 and 0·69 for the International Prognostic Index (IPI) and Revised International Prognostic Index (R-IPI). These data indicate the immune risk score is an accurate, independent survival predictor in persons with DLBCL.

Conversion between Mini-Mental State Examination and Montreal Cognitive Assessment scores in older adults undergoing selective surgery using Rasch analysis.

AIMS: To develop and validate a conversion table between the MMSE and the MoCA using Rasch analysis in older adults undergoing selective surgery and examine its diagnostic accuracy in detecting cognitive impairment. DESIGN: Cross-sectional study. METHODS: Older patients [N = 129; age 66.0 (4.6) years, education 7.7 (3.5) years] undergoing elective surgery were recruited from December 2017 to June 2018. All participants completed the MMSE and MoCA and 113 of them completed a battery of neuropsychological tests. Common person linking based on Rasch analysis was performed to develop the conversion table. The conversions were validated by calculating the intraclass correlation coefficient (ICC), score differences between actual and converted scores, and root mean squared error of the difference (RMSE). The diagnostic accuracy of the conversions for detecting cognitive impairment was also tested. RESULTS: The MoCA [person measure: 1.3 (1.1) logits] was better targeted to the patients than the MMSE [person measure: 3.2 (1.3) logits]. Conversion from MoCA to MMSE scores (ICC 0.84, 95% CI 0.77-0.88; RMSE 1.36) was more precise than conversion from MMSE to MoCA (ICC 0.82, 95% CI 0.75-0.87; RMSE 2.56). Conversion from MoCA to MMSE demonstrated better diagnostic accuracy in detecting cognitive impairment than the actual MMSE, whereas conversion from MMSE to MoCA exhibited the opposite pattern. CONCLUSION: Conversion from MoCA to MMSE was more precise and had better diagnostic accuracy in detecting pre-operative cognitive impairment in older patients undergoing selective surgery than conversion from MMSE into MoCA. IMPACT: The finding is useful for interpreting, comparing, and integrating cognitive measurements in surgical settings and clinical research. Statistically sound conversion between MoCA and MMSE based on Rasch analysis is now possible for surgical setting and clinical research.

Cinnamon extracts exert intrapancreatic cytoprotection against streptozotocin in vivo.

In the current study, we aimed to investigate the potential hypoglycemic bioactivity of cinnamon extracts (CES) on streptozotocin (STZ)-induced hyperglycemia in mice. In biological methods, glucose metabolic ability of all mice was evaluated by glucose tolerance testing (GTT). Blood levels of pancreas-produced insulin, glucagon, inflammation-associated interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were determined via enzyme-linked immunosorbent assay (ELISA). In gene level, intrapancreatic mRNA expressions of insulin, TNF-α and nuclear-factor kappa B (NF-κB) were assayed by reverse transcription polymerase chain reaction (RT-PCR). Meanwhile, intracellular insulin-immunoactive cells in the pancreas were analyzed by using immunohistochemical staining. In addition, the protein levels of intrapancreatic NF-κB, IκB (p-IκB) and IKK were tested by western blotting. As a result, CES-treated mice showed increased body weight, blood glucose and insulin, reduced IL-6 and TNF-α contents in sera. Further, the TNF-α and NF-κB mRNA expressions in the CES-treated pancreas were down-regulated at a dose-dependent manner, while insulin mRNA was elevated. Moreover, the reduced intrapancreatic NF-κB, IκB (p-IκB) and IKK expression were observed in CES-treated pancreas, respectively. Taken together, our current findings indicate that CES-mediated intrapancreatic cytoprotection is linked to the molecular mechanism that may be through inhibiting inflammatory stress and promoting insulin secretion in the pancreas.

Synthesis, characterization and in vitro anti-tumor activities of matrine derivatives.

Nineteen previously unreported matrine derivatives were synthesized and characterized using elemental analysis, infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, and mass spectrometry. Target compounds 6a-6l and 7a-7c showed stronger inhibitory activities than matrine in the in vitro antitumor tests and inhibited the growth of the Hep7402, B16-F10, A549, and TW03 cell lines. In addition, compound 6i exhibited a potent antitumor activity similar to that of colchicine.