Two Novel Genetic Variants Involved in the Oxygen Sensing Pathway in JAK2-unmutated Erythrocytosis.

JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.

Evolution of chromosome-arm aberrations in breast cancer through genetic network rewiring.

The basal breast cancer subtype is enriched for triple-negative breast cancer (TNBC) and displays consistent large chromosomal deletions. Here, we characterize evolution and maintenance of chromosome 4p (chr4p) loss in basal breast cancer. Analysis of The Cancer Genome Atlas data shows recurrent deletion of chr4p in basal breast cancer. Phylogenetic analysis of a panel of 23 primary tumor/patient-derived xenograft basal breast cancers reveals early evolution of chr4p deletion. Mechanistically we show that chr4p loss is associated with enhanced proliferation. Gene function studies identify an unknown gene, C4orf19, within chr4p, which suppresses proliferation when overexpressed-a member of the PDCD10-GCKIII kinase module we name PGCKA1. Genome-wide pooled overexpression screens using a barcoded library of human open reading frames identify chromosomal regions, including chr4p, that suppress proliferation when overexpressed in a context-dependent manner, implicating network interactions. Together, these results shed light on the early emergence of complex aneuploid karyotypes involving chr4p and adaptive landscapes shaping breast cancer genomes.

Alkaline humic acid fertilizer alters the distribution, availability, and translocation of cadmium and zinc in the acidic soil-Sauropus androgynus system.

Humic acids (HA) are a popular soil additive to reduce metal availability, but they have the drawbacks of reduced effectiveness over time and a significant reduction in soil pH. An alkaline humic acid fertilizer (AHAF) combining alkaline additives with HA was developed to overcome such drawbacks. A field experiment was conducted to investigate the effects of different AHAF application rates on the physicochemical properties, bioavailability, accumulation, and translocation of Cd and Zn heavy metals in Sauropus androgynus grown in acidic soil. Based on our results, the 100AF (100% AHAF) treatment significantly increased soil pH, cation exchange capacity (CEC), and organic matter content (OM) after one year of application. Compared with the control treatment (CK), the application of different rates of AHAF resulted in a 37.1-40.3% decrease in soil exchangeable Cd fractions (Exc-Cd) and an increase in the humic acid-bound Cd fractions (HA-Cd) Fe- and Mn-oxide-bound Cd fractions (OX-Cd), and organic matter-bound Cd fractions (OM-Cd) by 9.5-64.6%, 24.8-45.1%, and 158.8-191.2%, respectively (P < 0.05). The different AHAF treatments decreased the Res-Zn, Exc-Zn, and OM-Zn fractions by 69.6-73.0%, 7.4-23.9%, and 18.1-23.2%, respectively (P < 0.05), and increased the HA-Zn fraction by 8.4-28.1%. In the control treatment, the bioconcentration factors (BCFs) for Cd and Zn in different S. androgynus plant organs were in the following order: (Cd) Leaves > Stems > Branches > Roots > Edible branches; (Zn) Roots > Stems > Leaves > Branches > Edible branches. The transfer factors (TFs) of Cd and Zn in S. androgynus were classified as follows: TF2 > TF1 > TF3 > TF4. Thus, S. androgynus stems, and roots had a strong ability to transport Cd and Zn to the leaves. Compared with CK, the 100AF treatment significantly increased the BCFs for Zn in all plant parts (except BCFedible branches). In contrast, it significantly decreased all BCFs and TFs for Cd and the TF4 for Zn, effectively reducing Cd and Zn accumulation in the edible branches of S. androgynus. Soil pH, CEC, OM, and HA-M fraction were highly and significantly negatively correlated with Cd and Zn content in edible branches (P < 0.001). Stepwise multiple linear regression analysis revealed that the soil HA-M fraction was the key contributing factor for Zn accumulation and translocation in S. androgynus. Moreover, based on our findings, the absorption, uptake, and translocation of Cd and Zn were mainly determined by metal speciation and the pH in the soil. Moreover, the competitive antagonistic mechanisms between Zn and Cd absorption also affected their accumulation in S. androgynus. Thus, AHAF can be used as a soil amendment to sustainably improve acidic soils and effectively reduce Cd and Zn accumulation in edible branches of S. androgynus.

Lenalidomide or bortezomib as maintenance treatment remedy the inferior impact of high-risk cytogenetic abnormalities in non-transplant patients with newly diagnosed multiple myeloma: a real-world multi-centered study in China.

Maintenance treatment is a pivotal part in the whole process management of multiple myeloma (MM), which further deepens response and improves survival. However, evidence of maintenance in non-transplant MM patients is inadequate in real-world practice. Here, we retrospectively analyzed the efficacy and survival of 375 non-transplant MM patients from 11 centers between 2010 and 2021 in north China. After a median of seven cycles of front-line regimens, there were 141, 79, and 155 patients receiving lenalidomide maintenance (L-MT), bortezomib maintenance (B-MT), or thalidomide maintenance (T-MT), respectively. Patients on L-MT and B-MT had significantly greater proportions of high-risk cytogenetic abnormalities (HRCAs) detected by fluorescence in situ hybridization (FISH), which was defined as 1q21 gain, 17p deletion, adverse immunoglobulin heavy chain (IgH) translocations. Although the progression-free survival (PFS) and overall survival (OS) were comparable among the three groups, L-MT and B-MT remedied the negative impact of HRCAs on survival (PFS of patients with HRCAs vs. patients without HRCAs: L-MT, 26.9 vs. 39.2 months, p=0.19; B-MT, 20.0 vs. 29.7 months, p=0.36; OS not reached in all groups). Patients with HRCAs in the T-MT group presented inferior clinical outcomes compared to standard-risk patients (PFS, 12.1 vs. 22.8 months, p=0.02, HR=1.8, 95% CI 1.0-3.4; OS, 54.9 months vs. NR, p<0.001, HR=3.2, 95% CI 1.5-7.0). Achieving complete response (CR) after induction therapy led to superior PFS compared to other degrees of response, regardless of maintenance medication. Furthermore, maintenance duration over 24 months correlated with favorable survival. Due to the large gap of transplant eligibility in China, optimizing maintenance therapy is important for non-transplant MM patients. In this real-world multi-centered study, our findings suggest that clinicians prefer to prescribe lenalidomide or bortezomib as maintenance therapy in high-risk settings, which are superior to thalidomide in non-transplant MM patients. Achievement of CR and maintenance duration over 2 years are positive factors that influence survival.

Development of Diagnostic Recommendations for Vitreoretinal Lymphoma.

PURPOSE: To develop diagnostic recommendations for diffuse large B-cell vitreoretinal lymphoma (VRL) in Chinese patients. METHODS: Retrospective observational case series. Seventy-three eyes of 40 VRL patients and 8 control patients were analyzed. Eighteen patients from Beijing Tongren Hospital and 46 patients from literature were involved as validations. RESULTS: Diagnostic methods included (1) typical clinical manifestations; (2) vitreous cytology; (3) immunohistochemical examination of vitreous or choroid/retina; (4) aqueous humor or vitreous cytokine; (5) vitreous cell gene rearrangement; (6) vitreous flow cytometry. If patients meet (1)+(2)+(3), or if they meet (1), and two of (4), (5), (6) are positive, they can be diagnosed as VRL. The sensitivity and specificity values for accurate diagnosis were 0.975 and 1.00. One hundred percent eyes from Beijing Tongren Hospital and 92.7% eyes from literature can be diagnosed. CONCLUSION: We developed diagnostic recommendations for diffuse large B-cell VRL through vitreous cytology combined with multiple auxiliary examinations.

Cell-Free DNA in Cerebrospinal Fluid Complements the Monitoring Value of Interleukin-10 in Newly Diagnosed Primary Central Nervous System Lymphoma.

Objectives: Primary central nervous system lymphoma (PCNSL) usually has a poor prognosis. Cerebrospinal fluid (CSF) interleukin (IL)-10 has shown diagnostic, prognostic, and monitoring value in our previous studies. Cell-free circulating tumor DNA can be detected in the CSF of refractory/relapse cases and has also shown monitoring value. However, information about its monitoring value in newly diagnosed PCNSL patients and comparisons of CSF IL-10 and CSF cell-free DNA (cfDNA) are scarce. Methods: We performed next-generation sequencing on paraffin-embedded tissue and the serial CSF cfDNA of 10 newly diagnosed PCNSL patients and on the baseline CSF cfDNA of 11 other central nervous system lymphoma patients. We also monitored the CSF IL-10 levels of the 10 newly diagnosed PCNSL patients. Results: In seven newly diagnosed PCNSL patients with sufficient baseline CSF cfDNA, six had ≥1 mutated genes in their CSF cfDNA. The most common were MYD88(4/7), PIM1(3/7), MLL2(3/7), and ETV6(2/7). We also identified multiple somatic mutations, most commonly in PIM1. MYD88L265P can be detected in both tumor tissue and CSF cfDNA. The genomic profiles of CFS cfDNA were similar in PCNSL and PIOL patients. Newly diagnosed PCNSL patients with persistently positive cfDNA and negative IL-10 progressed quickly, while those with negative cfDNA and negative IL-10 were in maintenance therapy for more than 18 months. Two patients without cfDNA had increased CSF IL-10 concentrations before disease relapse. These results indicate that negative CSF cfDNA predicts better results, and persistently positive CSF cfDNA predicts disease progression earlier than conventional magnetic resonance imaging. Conclusion: In conclusion, CSF cfDNA is a potential predictor of relapse and progression, which complements the monitoring value of CSF IL-10 in newly diagnosed PCNSL patients.

Circulating cell-free DNA and IL-10 from cerebrospinal fluids aid primary vitreoretinal lymphoma diagnosis.

Primary vitreoretinal lymphoma (PVRL) is a rare variant of primary central nervous system lymphoma (PCNSL) that presents diagnostic challenges. Here, we focused on circulating cell-free DNA (cfDNA) and interleukin-10 (IL-10) isolated from cerebrospinal fluid. Twenty-three VRL patients (17 PVRL, 2 PCNSL/O, and 4 relapsed VRL, from 10/2018 to 12/2021) and 8 uveitis patients were included in this study. CSF samples from 19 vitreoretinal lymphoma patients had sufficient cfDNA for next-generation sequencing. Of these patients, 73.7% (14/19) had at least one meaningful non-Hodgkin lymphoma-related mutation. The characteristic MYD88 L265P mutation was detected in the CSF of 12 VRL patients, with a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 63.2%, 100%, 100%, and 46.2%, respectively. No meaningful lymphoma related mutations were found in CSF samples from uveitis controls with typical intraocular lesions. Meanwhile, CSF IL-10 levels were elevated in 95.7% of the VRL patients, with a sensitivity, specificity, PPV, and NPV of 95.7%, 100%, 100% and 88.9%, respectively. Key somatic mutations like MYD88 L265P and CD79B detected from CSF cfDNA and elevated CSF IL-10 levels can be promising adjuncts for primary vitreoretinal lymphoma diagnosis.

LncRNA MEG3 up-regulates SIRT6 by ubiquitinating EZH2 and alleviates nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a global health threat. Here, we presented the significant role of a novel signaling axis comprising long non-coding RNA maternally expressed gene 3 (MEG3), enhancer of zeste homolog 2 (EZH2), and sirtuin 6 (SIRT6) in controlling lipid accumulation, inflammation, and the progression of NAFLD. Mice fed with high-fat diet (HFD) were established as in vitro and in vivo NAFLD models, respectively. Lipid accumulation was measured by oil red O staining and assays for triglycerides or cholesterol. Inflammation was examined by ELISA for pro-inflammatory cytokines. Gene expressions were examined by RT-qPCR or Western blot. Interactions between key signaling molecules were examined by combining expressional analysis, RNA immunoprecipitation, cycloheximide stability assay, co-immunoprecipitation, and chromatin immunoprecipitation. MEG3 level was reduced in FFA-challenged hepatocytes or liver from HFD-fed mice, and the reduction paralleled the severity of NAFLD in clinic. Overexpressing MEG3 suppressed FFA-induced lipid accumulation or inflammation in hepatocytes. By promoting the ubiquitination and degradation of EZH2, MEG3 upregulated SIRT6, an EZH2 target. SIRT6 essentially mediated the protective effects of MEG3 in hepatocytes. Consistently, overexpressing MEG3 alleviated HFD-induced NAFLD in vivo. By controlling the expressions of genes involved in lipid metabolism and inflammation, the MEG3/EZH2/SIRT6 axis significantly suppressed lipid accumulation and inflammation in vitro, and NAFLD development in vivo. Therefore, boosting MEG3 level may benefit the treatment of NAFLD.

A novel non­selective atypical PKC agonist could protect neuronal cell line from Aß­oligomer induced toxicity by suppressing Aß generation.

Atypical protein kinase C (aPKCs) serve key functions in embryonic development by regulating apical­basal polarity. Previous studies have shed light on their roles during adulthood, especially in the development of Alzheimer's disease (AD). Although the crystal structure of PKCι has been resolved, an agonist of aPKCs remains to be discovered. In the present study, by using the Discovery Studio program and LibDock methodology, a small molecule library (K66­X4436 KINA Set) of compounds were screened for potential binding to PKCι. Subsequently, the computational docking results were validated using affinity selection­mass spectrometry, before in vitro kinase activity was used to determine the function of the hit compounds. A cell­based model assay that can mimic the pathology of AD was then established and used to assess the function of these hit compounds. As a result, the aPKC agonist Z640 was identified, which could bind to PKCι in silico, in vitro and in this cell­based model. Z640 was further confirmed as a non­selective aPKC agonist that can activate the kinase activity of both PKCι and PKCζ. In the cell­based assay, Z640 was found to protect neuronal cell lines from amyloid­ß (Aß) oligomer­induced cell death by reducing reactive oxygen species production and restore mitochondrial function. In addition, Z640 could reduce Aß40 generation in a dose­dependent manner and shift amyloid precursor protein processing towards the non­amyloid pathway. To conclude, the present study is the first, to the best of the authors' knowledge to identify an aPKC agonist by combining computer­assisted drug discovery and cell­based assays. The present study also revealed that aPKC agonists have therapeutic potential for the treatment of AD.

MiR-122-5p promotes peritoneal fibrosis in a rat model of peritoneal dialysis by targeting Smad5 to activate Wnt/ß-catenin pathway.

Peritoneal fibrosis (PF) is the main reason leading to declining efficiency and ultrafiltration failure of peritoneum, which restricts the application of peritoneal dialysis (PD). We aimed to investigate the effects and mechanisms of miR-122-5p on the PF. Sprague-Dawley (SD) rats were infused with glucose-based standard PD fluid to establish PF model. HE staining was performed to evaluate the extent of PF. Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and fluorescence in situ hybridization (FISH) were performed to measure the expression level of miR-122-5p. Western blot was used to test the expression of transforming growth factor (TGF)-ß1, platelet-derived growth factor (PDGF)-A, Fibronectin 1 (FN1), extracellular matrix protein 1 (ECM1), Smad5, α-smooth muscle actin (SMA), collagen type 1(COL-1), Vimentin, E-Cadherin, Wnt1, ß-catenin, p-ß-catenin, c-Myc, c-Jun, and Cyclin D1. Immunohistochemistry (IHC) staining was used to detect type I collagen alpha 1 (Col1α1), α-SMA, and E-Cadherin expression. We found PF was glucose concentration-dependently enhanced in peritoneum of PD rat. The PD rats showed increased miR-122-5p and decreased Smad5 expression. MiR-122-5p silencing improved PF and epithelial-mesenchymal transition (EMT) process in PD rats. MiR-122-5p silencing attenuated the activity of the Wnt/ß-catenin signaling pathway. Importantly, dual-luciferase reporter assay showed Smad5 was a target gene of miR-122-5p. Smad5 overexpression significantly reversed the increases of PF and EMT progression induced by miR-122-5p overexpression. Moreover, miR-122-5p mimic activated Wnt/ß-catenin activity, which was blocked by Smad5 overexpression. Overall, present results demonstrated that miR-122-5p overexpression showed a deterioration effect on PD-related PF by targeting Smad5 to activate Wnt/ß-catenin pathway.

Corrigendum: Circulating cell-free DNA and IL-10 from cerebrospinal fluids aid primary vitreoretinal lymphoma diagnosis.

[This corrects the article DOI: 10.3389/fonc.2022.955080.].

A Novel Probiotic Formula, BIOCG, Protects Against Alzheimer's-Related Cognitive Deficits via Regulation of Dendritic Spine Dynamics.

BACKGROUND: The brain-gut-microbiome axis has emerged as an important pathway through which perturbations in the gut and/or microbial microenvironment can impact neurological function. Such alterations have been implicated in a variety of neuropsychiatric disorders, including depression, anxiety, and Alzheimer's Disease (AD) and the use of probiotics as therapy for these diseases remains promising. However, the mechanisms underlying the gut microenvironment's influence on disease pathogenesis and therapy remain unclear. OBJECTIVE: The objective of this study is to investigate the effect of a novel probiotic formula, BIOCG, on cognitive function and pathobiological mechanisms, including amyloid processing and dendritic spine dynamics, in a mouse model of AD. METHODS: BIOCG was administered for 3 months to 3xTg or 3xTg; Thy1-YFP AD mice and functional outcomes were assessed via behavioral testing and electrophysiology. Mechanisms relevant to AD pathogenesis including dendritic spine morphology and turnover, Amyloid Precursor Protein (APP) processing and microglial phenotype were also evaluated. Finally, we sequenced fecal samples following probiotic treatment to assess the impact on gut microbial composition and correlate the changes with the above described measures. RESULTS: Mice treated with BIOCG demonstrated preserved cognitive abilities and stronger Long- Term Potentiation (LTP), spontaneous Excitatory Postsynaptic Currents (sEPSC), and glutamate-induced LTPs, indicative of functional and electrophysiological effects. Moreover, we observed attenuated AD pathogenesis, including reduced Amyloid Beta (Aß) burden, as well as more mature dendritic spines in the BIOCG-treated. Our finding of changes in microglial number and phenotype in the treatment group suggests that this formulation may mediate its effects via attenuation of neuroinflammation. Sequencing data confirmed that the gut microbiome in treated mice was more varied and harbored a greater proportion of "beneficial" bacteria. CONCLUSION: Overall, our results indicate that treatment with BIOCG enhances microbial diversity and, through gut-brain axis interactions, attenuates neuroinflammation to produce histologic and functional improvement in AD pathogenesis.

Lenalidomide and Rituximab Regimen Combined With Intravitreal Methotrexate Followed by Lenalidomide Maintenance for Primary Vitreoretinal Lymphoma: A Prospective Phase II Study.

Primary vitreoretinal lymphoma (PVRL) is a rare variant of primary central nervous system (CNS) lymphoma, for which currently there are no optimal treatment options. This prospective single-center study enrolled immunocompetent patients with newly diagnosed PVRL between August 2018 and January 2020. Patients received local and systemic therapies: intravitreal methotrexate (MTX, 400 µg, 0.1 mL) injections for 1 year (total 16 injections) and six cycles of the rituximab (375 mg/m2 on day 1) and lenalidomide (25 mg on day 1-21; R2) regimen. Lenalidomide was maintained for 2 years in patients who had achieved a response. We enrolled 11 patients with a mean age of 58 (range, 48-70) years, of which 10 achieved complete remission at the first evaluation. The median follow-up period was 18.3 (range, 10.6-27.8) months, and the median progression-free survival was 12.7 months. Moreover, a total of eight patients relapsed. The most common adverse event (AE) was neutropenia, which occurred in seven patients (63.6%), followed by grade 3 ocular toxicities, including cataract formation, in six patients (54%). These findings suggest that the R2 regimen combined with intravitreal MTX, followed by lenalidomide maintenance, is a safe option for PVRL with moderate efficacy. This trial is registered with ClinicalTrials.gov (number NCT03746223).

Changes in cerebrospinal fluid interleukin-10 levels display better performance in predicting disease relapse than conventional magnetic resonance imaging in primary central nervous system lymphoma.

BACKGROUD: Establishing diagnostic and prognostic biomarkers of primary central nervous system lymphoma (PCNSL) is a challenge. This study evaluated the value of dynamic interleukin (IL)-10 cerebrospinal fluid (CSF) concentrations for prognosis and relapse prediction in PCNSL. METHODS: Consecutive 40 patients newly diagnosed with PCNSL between April 2015 and April 2019 were recruited, and serial CSF specimens were collected by lumbar punctures (LP) or by Ommaya reservoir at diagnosis, treatment, and follow-up phase. RESULTS: We confirmed that an elevated IL-10 cutoff value of 8.2 pg/mL for the diagnosis value of PCNSL showed a sensitivity of 85%. A persistent detectable CSF IL-10 level at the end of treatment was associated with poor progression-free survival (PFS) (836 vs. 481 days, p = 0.049). Within a median follow-up of 13.6 (2-55) months, 24 patients relapsed. IL-10 relapse was defined as a positive conversion in patients with undetectable IL-10 or an increased concentration compared to the last test in patients with sustained IL-10. IL-10 relapse was detected a median of 67 days (28-402 days) earlier than disease relapse in 10/16 patients. CONCLUSION: This study highlights a new perspective that CSF IL-10 relapse could be a surrogate marker for disease relapse and detected earlier than conventional magnetic resonance imaging (MRI) scan. Further evaluation of IL-10 monitoring in PCNSL follow-up is warranted.

Knee Joint Swelling at Presentation: A Case of Pediatric Crohn Disease With a TNFAIP3 Mutation.

Crohn disease (CD) is a chronic inflammatory disease, and its incidence in children is rising. Despite extensive reports and investigations, the pathogenesis of CD has not been clearly elucidated, particularly in regard to triggering factors. A genetic predisposition is considered important when investigating the mechanism leading to CD, and the discovery of new CD-associated genes has increased our understanding of its immunopathogenesis and improved the efficacy of its treatment of CD. Early detection and treatment (eg, as children) with gene-based precision therapy can effectively prevent complications related to CD. In this case, a Chinese Han boy with CD associated with a mutation of tumor necrosis factor α-induced protein 3 was treated with recombinant human tumor necrosis factor-a receptor II:IgG Fc fusion protein. We suspected the boy had CD because of chronic abdominal pain, aphthous stomatitis, moderate anemia, a high erythrocyte sedimentation rate (36-79 mm/h), multiple intestinal ulcers, knee joint swelling, and a tumor necrosis factor α-induced protein 3 mutation. After total enteral nutrition and hormone therapy for 5 months, his abdominal pain and joint symptoms did not improve, so we started gene-based precision therapy with recombinant human tumor necrosis factor-a receptor II: IgG Fc fusion protein, which may play an important role in restricting TNF-α-induced NF-κB signaling. After 3 weeks, inflammation indicators were within the normal range, and multiple ulcers and joint symptoms were relieved. The present case demonstrates a safe therapeutic schedule that leads to rapid improvements in the clinical and biochemical status of patients with CD.

Successful treatment with lenalidomide plus chidamide combination therapy in 3 heavily treated patients with non-Hodgkin lymphoma: Three cases report.

RATIONALE: The prognosis of patients with aggressive relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) remains poor. Both immunomodulatory drugs and histone deacetylase inhibitors have demonstrated activity against R/R NHL; yet, the combination of these 2 targeted therapies has rarely been explored. PATIENT CONCERNS: Here, we report 3 cases. Case 1 was a 68-year-old woman who presented to our hospital with dyspnea. Case 2 was a 75-year-old man with massive upper gastrointestinal bleeding. Case 3 was a 62-year-old woman with cough, dyspnea, and lymphadenopathy. DIAGNOSIS: The biopsy results revealed diffuse large B cell lymphoma (DLBCL), DLBCL, and angioimmunoblastic T-cell lymphoma, for Case 1, 2, and 3 respectively. INTERVENTION: All 3 patients experienced relapse after first-line therapy and multiple lines of salvage therapy. Finally, they all received lenalidomide combined with chidamide. OUTCOMES: All 3 patients achieved complete and durable remission. Case 1 relapsed again after 3 months, while the other 2 cases remained in complete remission. LESSONS: To our knowledge, this is the first report of lenalidomide combined with chidamide for the treatment of R/R NHL. Our findings warrant further evaluation of this novel chemo-free therapy in future prospective clinical trials.

Knockdown of Long Noncoding RNAs of Maternally Expressed 3 Alleviates Hyperoxia-Induced Lung Injury via Inhibiting Thioredoxin-Interacting Protein-Mediated Pyroptosis by Binding to miR-18a.

Long-term hyperoxia exposure may cause lung damage with characteristic inflammation. Long noncoding RNA of maternally expressed 3 (MEG3) is up-regulated in lung tissues exposed to hyperoxia; however, the underlying mechanism is unclear. Hyperoxia-induced cells and mouse models were used to study these mechanisms. Molecular assays were used to detect cell viability, cytotoxicity, and expression of miR-18a, MEG3, and inflammatory cytokines. The interaction among MEG3, miR-18a, and thioredoxin-interacting protein (TXNIP) was verified; and pyroptosis-related proteins were analyzed. The in vivo model was established by exposing MEG3 knockdown mice to hyperoxia. Hematoxylin and eosin staining was used to assess pathologic alterations of lung tissues. Hyperoxia suppressed cell viability, induced cell damage, and exacerbated the secretion of IL-1ß and IL-18. Hyperoxia inhibited miR-18a, with increased expression of MEG3, TXNIP, and nonobese diabetic-like receptor family pyrin domain containing 3 (NLRP3). MEG3 aggravated TXNIP expression by binding to miR-18a. Knockdown of MEG3 rescued hyperoxia-induced pyroptosis by up-regulating miR-18a. Furthermore, knockdown of MEG3 inhibited NLRP3 inflammasome activity and caspase-1 signaling by miR-18a. In vivo knockdown of MEG3 and overexpression of miR-18a relieved hyperoxia-induced lung injury via restraining NLRP3 inflammasome-mediated pyroptosis, whereas miR-18a inhibition reversed these effects. In conclusion, knockdown of MEG3 inhibits pyroptosis to alleviate hyperoxia lung injury by suppressing NLRP3 inflammasome and caspase-1 signaling via regulating miR-18a-TXNIP axis.

Type D personality, medication adherence and peritonitis in continuous ambulatory peritoneal dialysis patients.

The present study attempted to investigate the association among Type D, medication adherence and peritonitis in continuous ambulatory peritoneal dialysis (CAPD) patients. Type D personality was assessed by the Chinese 14-item Type D Personality Scale (DS14) in CAPD patients. Patients' medication adherence was assessed by the Medication Adherence Report Scale, retrospectively. Of the 385 CAPD patients who were investigated, 137 (35.6%) patients had a Type D personality. The medication adherence was significantly poorer in the Type Ds compared with that of the non-Type Ds (21.5 ± 2.8 vs. 22.5 ± 2.5 score, p = 0.002). Using multiple linear regression analysis, we found that Type D personality was independently associated with medication adherence (ß = 0.56, p < 0.05). Furthermore, the overall peritonitis-free survival rate of non-Type Ds was significantly higher than that of Type Ds (X2 = 4.41, p = 0.025). Using Cox regression, Type D personality (HR 1.67; 95% confidence interval [CI] 1.07-2.59; p = 0.022) and adherence to bag exchange procedure (HR 1.54; 95% CI 1.11-2.14; p = 0.009) predicted the development of the first peritonitis, even after adjustment for confounders. The current study is the first to identify a strong association among Type D, medication adherence and peritonitis in CAPD patients.

Roles of the mammalian target of rapamycin (mTOR) signaling pathway in the repair of hyperoxia-induced acute lung injury.

BACKGROUND: Rapamycin inhibits the mammalian target of rapamycin (mTOR) activity and has been proven effective for the treatment of lung injury. OBJECTIVES: The objective of this study was to investigate the roles of the mTOR pathway and its inhibitor rapamycin in the repair of hyperoxia-induced acute lung injury (ALI). MATERIAL AND METHODS: Firstly, premature rat lung fibroblast L929 cells were cultured under different oxygen concentrations (40%, 60%, and 90%). At day 3, 7 and 14 after exposure, MTT assay and flow cytometry were used to evaluate the effect of oxygen stress on cell viability and apoptosis of L929 cells, respectively. Secondly, microscopy, MTT assay and flow cytometry was used to investigate the effect of 10 nM rapamycin on 90% O2 exposed L929 cells. We also used small interfering RNAs (siRNAs) to abrogate the expression of mTOR in 90% O2 exposed L929 cells, and then evaluated the apoptosis and cell viability using flow cytometry and the MTT assay, respectively. In addition, western blot was used to detect the protein expression of Bcl-2, p53, TGF-ß and connective tissue growth factor (CTGF). A hyperoxia-induced lung injury model was established in Sprague Dawley (SD) rats in order to evaluate the histopathological changes in lung tissues and expression of the mTOR pathway and fibrosis related factors. RESULTS: Exposure to 40%, 60% or 90% oxygen all significantly inhibited the growth of L929 cells. Application of 10 nM rapamycin was found to effectively promote apoptosis of 90% O2 exposed L929 cells. In addition, mTOR siRNA promoted the apoptosis and inhibited the growth of L929 cells. Rapamycin inhibited the activation of the mTOR signaling pathway, down-regulated the expression of downstream proteins p70S6K and 4EBP1, reduced the collagen deposition and the production of fibrosis-inducing factors, including TGF-ß and CTGF in hyperoxia-induced lung injury rats. CONCLUSIONS: Rapamycin may be useful for the treatment of hyperoxia-induced acute lung injury (ALI) by inhibiting the activation of mTOR signaling pathway.

Clinical characteristics and prognostic factors in Chinese patients with classical Hodgkin's lymphoma involving extranodal sites: a retrospective single-center.

Objectives: To analyze the clinical characteristics and prognostic factors in Chinese patients with classical Hodgkin's lymphoma (cHL) involving extranodal sites. Methods: Clinical features and outcomes of 68 patients diagnosed with cHL involving extranodal sites from April 2003 to November 2017 were analyzed retrospectively. The data was compared with that of 76 cHL patients without extranodal involvement in the same period. Results: (1) Extranodal involvement was common in Chinese cHL patients. The most common sites were lung (44.1%) and bone (33.8%), followed by bone marrow, liver, pericardium, pleura and other sites. (2) With a median follow-up period of 4.58 years, the 5-year overall survival (OS) of 68 patients with extranodal involvement was significantly poorer than that of 76 patients with only nodal involvement (81.4% vs. 92.8%, p = 0.018). (3) In univariate analysis, lymphocytopenia (p = 0.027), elevated lactate dehydrogenase (LDH) (p = 0.026) and involved lymph node region (LNR) ≥4 (p = 0.044) predicted inferior freedom from progression (FFP) with significant difference. Elder age (p = 0.010), elevated LDH (p = 0.013), elevated platelet (p = 0.044), involved LNR ≥ 4 (p = 0.047) were also statistically significant in OS. Extranodal sites and number of extranodal sites showed no significant difference in FFP and OS. Factors with p-value smaller than 0.100 were evaluated in multivariate analysis, turning out that lymphocytopenia was the only independent adverse prognostic factor in FFP (p = 0.039; HR = 2.595) and OS (p = 0.028; HR = 4.993). Conclusion: Extranodal involvement was frequent in Chinese cHL patients, with lung to be the most commonly involved site. Lymphocytopenia was the only independent adverse prognostic factor.