Case Report: HAVCR2 mutation-associated Hemophagocytic lymphohistiocytosis.

Germline HAVCR2 mutation has been reported to be associated with subcutaneous panniculitis-like T-cell lymphoma (SPTCL) leading to Hemophagocytic lymphohistiocytosis (HLH). Several studies have indicated that HAVCR2 mutation can cause HLH even in the absence of lymphoma, though the exact mechanism remains unclear. In this article, we reported five cases of HAVCR2 mutation-associated HLH. Our analysis revealed an elevated level of IL-1RA in the serum of these patients. Furthermore, we investigated the potential mechanisms underlying HLH associated with HAVCR2 mutation based on changes in cytokine levels. Our findings suggest that HAVCR2 mutation may represent a distinct genetic defect underlying HLH, differing from traditional primary HLH.

Misdiagnosis of adult primary hemophagocytic lymphohistiocytosis as NK/T-cell lymphoma: A case report.

We reported a case of a 19-year-old male patient with central nervous system symptoms as the main clinical manifestations, and multiple intracranial and abdominal occupying lesions visualized by imaging examinations, who was initially misdiagnosed as NK/T-cell lymphoma but poorly responsive to the treatment. Finally, he was diagnosed as familial hemophagocytic lymphohistiocytosis type-2 by genome sequencing, perforin test and pedigree study. The patient survived well after allogeneic hematopoietic stem cell transplantation. Central nervous system symptoms could be the main clinical manifestations in patients with primary hemophagocytic lymphohistiocytosis , whose early-stage manifestations of blood system were usually atypical, easily leading to misdiagnosis. In clinical practice, primary hemophagocytic lymphohistiocytosis should be considered in patients with central nervous system symptoms and unknown causes. The combination of rapid immunological function test and genome sequencing contributes to the diagnosis of primary hemophagocytic lymphohistiocytosis.

BMSC-derived extracellular matrix better optimizes the microenvironment to support nerve regeneration.

A favorable microenvironment plays an important role in nerve regeneration. Extracellular matrix (ECM) derived from cultured cells or natural tissues can facilitate nerve regeneration in the presence of various microenvironmental cues, including biochemical, spatial, and biomechanical factors. This study, through proteomics and three-dimensional image analysis, determines that the components and spatial organization of the ECM secreted by bone marrow mesenchymal cells (BMSCs) are more similar to acellular nerves than those of the ECMs derived from Schwann cells (SCs), skin-derived precursor Schwann cells (SKP-SCs), or fibroblasts (FBs). ECM-modified nerve grafts (ECM-NGs) are engineered by co-cultivating BMSCs, SCs, FBs, SKP-SCs with well-designed nerve grafts used to bridge nerve defects. BMSC-ECM-NGs exhibit the most promising nerve repair properties based on the histology, neurophysiology, and behavioral analyses. The regeneration microenvironment formed by the ECM-NGs is also characterized by proteomics, and the advantages of BMSC-ECM-NGs are evidenced by the enhanced expression of factors related to neural regeneration and reduced immune response. Together, these findings indicate that BMSC-derived ECMs create a more superior microenvironment for nerve regeneration than that by the other ECMs and may, therefore, represent a potential alternative for the clinical repair of peripheral nerve defects.

Combination of Decitabine and a Modified Regimen of Cisplatin, Cytarabine and Dexamethasone: A Potential Salvage Regimen for Relapsed or Refractory Diffuse Large B-Cell Lymphoma After Second-Line Treatment Failure.

OBJECTIVE: The prognosis for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R-DLBCL) after second-line treatment failure is extremely poor. This study prospectively observed the efficacy and safety of decitabine with a modified cisplatin, cytarabine, and dexamethasone (DHAP) regimen in R/R-DLBCL patients who failed second-line treatment. METHODS: Twenty-one R/R-DLBCL patients were enrolled and treated with decitabine and a modified DHAP regimen. The primary endpoints were overall response rate (ORR) and safety. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: ORR reached 50% (complete response rate, 35%), five patients (25%) had stable disease (SD) with disease control rate (DCR) of 75%. Subgroup analysis revealed patients over fifty years old had a higher complete response rate compared to younger patients (P = 0.005), and relapsed patients had a better complete response rate than refractory patients (P = 0.031). Median PFS was 7 months (95% confidence interval, 5.1-8.9 months). Median OS was not achieved. One-year OS was 59.0% (95% CI, 35.5%-82.5%), and two-year OS was 51.6% (95% confidence interval, 26.9%-76.3%). The main adverse events (AEs) were grade 3/4 hematologic toxicities such as neutropenia (90%), anemia (50%), and thrombocytopenia (70%). Other main non-hematologic AEs were grade 1/2 nausea/vomiting (40%) and infection (50%). No renal toxicity or treatment-related death occurred. CONCLUSION: Decitabine with a modified DHAP regimen can improve the treatment response and prognosis of R/R-DLBCL patients with good tolerance to AEs, suggesting this regimen has potential as a possible new treatment option for R/R-DLBCL patients after second-line treatment failure. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier: NCT03579082.

Iron deficiency promotes aortic medial degeneration via destructing cytoskeleton of vascular smooth muscle cells.

BACKGROUND: Aortic dissection (AD) and aortic aneurysm (AA) are critical illnesses with an unclear pathogenetic mechanism that seriously threaten human life. Aortic medial degeneration (AMD) is the main pathological feature of AD and AA. Diseases of iron metabolism can cause a variety of physiological dysfunctions. In this study, we aimed to clarify the state of iron metabolism in patients with AD and AA, and to explore the effect of iron metabolism on AMD. METHODS: A total of 200 patients with AD or AA, and 60 patients with hypertension were included in the study. Blood samples were drawn immediately when patients were admitted to the hospital. Aortic specimens from patients with Stanford type A AD were obtained at the time of surgery. The status of iron metabolism in the circulation and the aortic wall was analyzed. In addition, apolipoprotein E knockout mice were fed chow with a different iron content, and angiotensin II (Ang II) was used to induce AMD. Furthermore, transferrin receptor 1 knockout (TFR1-/-) mice were used to study the effects of iron deficiency (ID) on aortic development, to observe the effects of different iron metabolism status on the formation of AMD in mice, and to explore the cytoskeleton of vascular smooth muscle cells (VSMCs) under different iron metabolism. RESULTS: Patients with AMD were iron deficient. ID is associated with the development of AMD in hypertensive patients. Iron-deficient feeding combined with Ang II pumping promoted the formation of AMD and significantly shortened the survival time of mice. ID significantly impaired the cytoskeleton of VSMCs. CONCLUSIONS: Our results highlighted that ID was associated with the formation of AMD in patients with hypertension. In this study, we identified a novel mechanism behind VSMCs dysfunction that was induced by ID, thereby suggesting iron homeostasis as a future precaution in patients with hypertension based on its important role in the maintenance of VSMC function.

DDGP vs. SMILE in Relapsed/Refractory Extranodal Natural Killer/T-cell Lymphoma, Nasal Type: A Retrospective Study of 54 Patients.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a rare peripheral T-cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L-asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty-one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%, P = 0.025). The DDGP group (95% confidence interval (CI) of 5-year progression-free survival (PFS): 24.6-66.2%; 95% CI of 5-year overall survival (OS): 8.5-91.7%) was also significantly associated with longer 5-year PFS and 5-year OS (P = 0.008 for 5-year PFS, P = 0.023 for 5-year OS). More serious leucopenia (P = 0.021), neutropenia (P = 0.041), and allergy (P = 0.040) were observed in the SMILE group. Post-treatment Epstein-Barr virus (EBV)-DNA status (P = 0.001 for PFS, P = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post-treatment EBV-DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.

Inhibition of CACNA1H attenuates doxorubicin-induced acute cardiotoxicity by affecting endoplasmic reticulum stress.

BACKGROUND: Doxorubicin (DOX) is an anticancer drug that has been widely used in the clinic. However, recently its application has been limited due to the cardiotoxic effects it has caused. Severe cardiotoxicity of DOX causes cardiac hypertrophy that may lead to heart failure. It has previously been demonstrated that CACNA1H is re-expressed in hypertrophic cardiomyocytes. In this study, we aimed to investigate the role of CACNA1H in DOX-induced acute cardiotoxicity, and to investigate its possible underlying mechanisms of action involved. METHODS: Firstly, DOX-induced cardiac injury and changes in the expression of CACNA1H were evaluated. We explored the role of endoplasmic reticulum (ER) stress and apoptosis in mice that underwent DOX-induced cardiac injury. Next, to explore the role of CACNA1H in this process, we evaluated the changes in DOX-induced cardiac injury and ER stress after treatment with the CACNA1H specific inhibitor ABT-639. Next, we used ER stress inhibitor UR906 to verify the role of ER stress in DOX induced cardiotoxicity in H9C2 cells. RESULTS: DOX-treatment caused acute heart injury, leading to a decrease in cardiac function in mice, an increase in apoptosis of cardiac myocytes, and a significant increase in the expression level of CACNA1H in heart tissue. Next, mice were treated with CACNA1H inhibitor ABT-639 and we demonstrated that it partly protects myocardial function and reduces myocardial cell apoptosis. In addition, our data indicated that CACNA1H may play a role in alleviating DOX-induced cardiotoxicity by reducing the severity of ER stress because the use of ABT-639 significantly changed ER stress-related proteins, including p-PERK, PERK, CHOP, GRP78, ATF6, and ATF4. Furthermore, we found that the use of ER stress inhibitor UR906 in H9C2 cells significantly alleviated the increased expression of ER stress related proteins and apoptosis related proteins caused by DOX, and meanwhile reduced the degree of intracellular oxidative stress and intracellular calcium ion concentration. CONCLUSION: CACNA1H inhibitors significantly alleviated DOX-induced cardiotoxicity and apoptosis induced by ER stress.

Abnormal Ribosome Biogenesis Partly Induced p53-Dependent Aortic Medial Smooth Muscle Cell Apoptosis and Oxidative Stress.

Ribosome biogenesis is a crucial biological process related to cell proliferation, redox balance, and muscle contractility. Aortic smooth muscle cells (ASMCs) show inhibition of proliferation and apoptosis, along with high levels of oxidative stress in aortic dissection (AD). Theoretically, ribosome biogenesis should be enhanced in the ASMCs at its proliferative state but suppressed during apoptosis and oxidative stress. However, the exact status and role of ribosome biogenesis in AD are unknown. We therefore analyzed the expression levels of BOP1, a component of the PeBoW complex which is crucial to ribosome biogenesis, in AD patients and a murine AD model and its influence on the ASMCs. BOP1 was downregulated in the aortic tissues of AD patients compared to healthy donors. In addition, overexpression of BOP1 in human aortic smooth muscle cells (HASMCs) inhibited apoptosis and accumulation of p53 under hypoxic conditions, while knockdown of BOP1 decreased the protein synthesis rate and motility of HASMCs. The RNA polymerase I inhibitor cx-5461 induced apoptosis, ROS production, and proliferative inhibition in the HASMCs, which was partly attenuated by p53 knockout. Furthermore, cx-5461 aggravated the severity of AD in vivo, but a p53-/- background extended the life-span and lowered AD incidence in the mice. Taken together, decreased ribosome biogenesis in ASMCs resulting in p53-dependent proliferative inhibition, oxidative stress, and apoptosis is one of the underlying mechanisms of AD.

Analysis of survival and prognosis of 298 gastric adenocarcinoma patients with no distant metastasis.

This study investigated the survival and prognosis of 298 gastric adenocarcinoma patients with no distant metastasis. For analysis and comparison of the prognosis of patients, a retrospective analysis was performed in 298 patients with perfect clinical data and follow-up data who received the D2 resections for gastric cancer in Shandong Provincial Hospital Affiliated to Shandong University between January, 2005 and January, 2012, and were diagnosed as gastric adenocarcinoma with no distant metastasis in postoperative pathological examination. Among the gastric adenocarcinoma patients without distant metastasis, we found that differences of sex, age, differentiation and position of tumor had no statistical significance (P>0.05), while comparisons of the tumor diameter, regional lymphatic metastasis, vascular invasion and pathological TNM stages (pTNM; T for tumor, N for lymph node and M for metastasis) showed statistical significance (P<0.05). One-way analysis of variance (ANOVA) indicated the correlation between the prognosis of gastric adenocarcinoma patients and tumor diameter, regional lymphatic metastasis, vascular invasion and pTNM stages of patients (P<0.05). Multivariate analysis of Cox regression models was performed for discovering the factors associated with the prognosis of patients, and the results suggested that position of tumor (P=0.016), regional lymphatic metastasis (P=0.042), vascular invasion (P=0.021) and pTNM stage (P=0.009) were the independent risk factors affecting the prognosis of gastric adenocarcinoma patients. During 60-month follow-up, the median survival duration of gastric adenocarcinoma patients with no distant metastasis was 38 months, while the 5-year accumulate survival rate was 49.3%. The results indicated that in gastric adenocarcinoma patients without distant metastasis, tumor diameter, regional lymphatic metastasis, vascular invasion and pTNM stage are major indicators affecting the prognosis of patients.