Distinct orientation of the alloreactive monoclonal CD8 T cell activation program by three different peptide/MHC complexes

We have characterized three different programs of activation for alloreactive CD8 T cells expressing the BM3.3 TCR, their elicitation depending on the characteristics of the stimulating peptide/MHC complex. The high-affinity interaction between the TCR and the K(b)-associated endogenous peptide pBM1 (INFDFNTI) induced a complete differentiation program into effector cells correlated with sustained ERK activation. The K(bm8) variant elicited a partial activation program with delayed T cell proliferation, poor CTL activity and undetectable ERK phosphorylation; this resulted from a low-avidity interaction of TCR BM3.3 with a newly identified endogenous peptide, pBM8 (SQYYYNSL). Interestingly, mismatched pBM1/K(bm8) complexes induced a split response in BM3.3 T cells, with total reconstitution of T cell proliferation but defective generation of CTL activity that was correlated with strong but shortened ERK phosphorylation. Crystal structures highlight the molecular basis for the higher stability of pBM8/K(bm8) compared to pBM1/K(bm8) complexes that exist in two conformers. This study illustrates the importance of the stability of both peptide/MHC and peptide/MHC-TCR interactions for induction of sustained signaling required to induce optimal CTL effector functions. Subtle allelic structural variations, amplified by peptide selection, may thus orient distinct outcomes of alloreactive TCR-based therapies.     

Loss of the Y chromosome in Philadelphia-positive cells predicts a poor response of chronic myeloid leukemia patients to imatinib mesylate therapy

In chronic myeloid leukemia (CML), cytogenetic abnormalities found in addition to the t(9;22) translocation may impact the response to therapy. Loss of the Y chromosome is generally overlooked in this context, owing to its relatively frequent occurrence in healthy elderly patients. In this multicenter retrospective study, the outcome after imatinib treatment of 30 CML patients with karyotype showing Y chromosome loss (Y−) was compared to 30 Y+ control males diagnosed and treated at the same time in the same institutions. Y− patients had significantly delayed cytogenetic and molecular responses, lower event-free survival and shorter overall survival than Y+ patients. The negative impact of this abnormality was particularly marked when it occurred in a sub-clone (clonal evolution) rather than in all mitoses. These data indicate that loss of the Y chromosome should be taken into account in the prognostic evaluation of chronic myelogenous leukemia patients.     

Diagnostic accuracy, reproducibility and robustness of fibrosis blood tests in chronic hepatitis C: a meta-analysis with individual data

ObjectivesTo evaluate the diagnostic accuracy of liver fibrosis tests and its influencing factors in a meta-analysis with individual data.Design and methodsFour independent centers provided four blood tests and Metavir staging from 825 patients with chronic hepatitis C.ResultsFibroMeter AUROC (0.840) for significant fibrosis was superior to those of Fibrotest (0.803, p = 0.049), APRI (0.789, p = 0.001) and Hepascore (0.781, p < 0.001). The misclassification rate was lower for FibroMeter (23%) than for Fibrotest and Hepascore (both 28%, p < 0.001). The variation in the diagnostic cut-offs of tests among centers, reflecting the overall reproducibility, was: FibroMeter: 4.2%, APRI: 24.0%, Fibrotest: 24.2%, Hepascore: 35.0%. Accordingly, the proportion of patients diagnosed with significant fibrosis changed: FibroMeter: 0.8%, Hepascore: 2.4% (p = 0.02 vs FibroMeter), Fibrotest: 5.8% (p < 10^? 3), APRI: 18.2% (p < 10^? 3).ConclusionsThis study on clinical applicability shows significant differences in diagnostic accuracy, inter-center reproducibility, and robustness of biomarkers to changes in population characteristics between blood tests.     

Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study

Extranodal NK/T-cell lymphoma, nasal type, is a rare and highly aggressive disease with a grim prognosis. No therapeutic strategy is currently identified in relapsing patients. We report the results of a French prospective phase II trial of an L-asparaginase-containing regimen in 19 patients with relapsed or refractory disease treated in 13 centers. Eleven patients were in relapse and 8 patients were refractory to their first line of treatment. L-Asparaginase-based treatment yielded objective responses in 14 of the 18 evaluable patients after 3 cycles. Eleven patients entered complete remission (61%), and only 4 of them relapsed. The median overall survival time was 1 year, with a median response duration of 12 months. The main adverse events were hepatitis, cytopenia, and allergy. The absence of antiasparaginase antibodies and the disappearance of Epstein-Barr virus serum DNA were significantly associated with a better outcome. These data confirm the excellent activity of L-asparaginase-containing regimens in extranodal NK/T-cell lymphoma. L-Asparaginase-based treatment should thus be considered for salvage therapy, especially in patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma warrants evaluation in prospective trials. This trial is registered at www.clinicaltrials.gov as #NCT00283985.     

Hematologic,immunologic reconstitution,and outcome of 342 autologous peripheral blood stem cell transplantations after cryopreservation in a −80°C mechanical freezer and preserved less than 6 months

BACKGROUND: Controlled‐rate freezing and storage in nitrogen is the standard technique for cryopreservation of peripheral hematopoietic progenitor cells (PHPCs) but presents high cost and dimethyl sulfoxide (DMSO) toxicity. Cryopreservation at ?80°C, by uncontrolled rate freezing with only 3.5% DMSO, preserves the functional capacities of PHPCs, produces successful engraftment, and reduces toxicity during infusion. STUDY DESIGN AND METHODS: Long‐term hematopoietic and immunologic reconstitution for 342 autografts (311 adults, 31 children) after PHPCs were cryopreserved at ?80°C was studied at 3, 6, and 12 months. The median (range) storage time of PHPCs cryopreserved was 1.7 (0.1‐5.99) months. RESULTS: Hemoglobin (Hb), white blood cells, and platelets (PLTs) reach normal values to trilineage at 12 months for 39% patients. Multivariate analysis shows a significant impact on CD34+ infused and on conditioning regimen for PLTs. Hb was influenced by growth factor administration at 3 months. Long‐term recovery is also highly dependent on blood counts (Hb, PLT, and neutrophil) at start of high‐dose chemotherapy. Only 43% of patients had reached normal lymphocyte values at 12 months after transplant, and a profound CD4+ T‐lymphocyte deficit remained, as others reported. CONCLUSION: Transplantation with PHPCs cryopreserved at ?80°C for no more than 6 months is satisfactory for long‐term hematopoietic and immunologic reconstitution, even if a profound CD4+ T lymphocyte deficit persists at 1 year. This easier and cheaper cryopreservation method also leads to successful engraftment.     

Study on acupuncture improving insomnia comorbid with depression and anxiety based on rs-fMRI: A protocol for systematic review and meta-analysis

Background:Long term insomnia and low sleep quality often lead to depression, anxiety and other negative emotions, and often interact with each other. Many studies have confirmed the effectiveness of acupuncture in the treatment of insomnia comorbid with emotional disorders, but its specific mechanism needs to be further explored. Resting-state functional magnetic resonance (rsfMRI) is an important means to study the changes of brain activity. However, the results are inconsistent and lack of systematic evaluation and analysis.Methods:Nine databases will be searched, including PubMed, EMBASE, EBSCOhost-medline, Web of Science, Cochrane Library, China National Knowledge Infrastructure, VIP Database and Wan-Fang Database, Chinese Biomedical Literature Database from inception to January 2021. And screening clinical registration platform related research, in order to obtain more relevant studies. The outcomes include the change of rs-fMRI, sleep quality, depression, and anxiety. Quality assessment of the included studies will be performed according to the Cochrane Risk of Bias tool. Evidence quality will be assessed by using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method. RevMan software (Version 5.3) and stata13.1will be used for statistical analyses. Subgroup analysis will be performed if necessary. If the data is insufficient, qualitative synthesis will be conducted instead of quantitative synthesis.Results:This study will analyze the effect of acupuncture on the brain activity changes, improvement of sleep quality and clinical symptoms of anxiety and depression with insomnia comorbid with emotional disorders.Conclusion:This study used meta-analysis method to explore the characteristics of acupuncture on brain activity changes in insomnia comorbid with emotional disorders, so as to provide effective evidence for clarifying its pathogenesis.     

A public T cell clonotype within a heterogeneous autoreactive repertoire is dominant in driving EAE

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis. Immunization of B10.PL mice with the Ac1–9 peptide, the immunodominant determinant of myelin basic protein (MBP), produced a single episode of EAE followed by recovery and resistance to reinduction of disease. Using the CDR3 length spectratyping technique, we characterized the clonal composition of the Ac1–9–specific T cell repertoire from induction through onset and resolution of disease. Two clonally restricted subsets within a heterogeneous self-reactive repertoire were found in mouse lymph nodes, spleen, and spinal cord soon after immunization, before any sign of EAE. These clonotypes, designated BV8S2/BJ2S7 and BV16/BJ2S5, were present in all mice examined and thus considered public. BV8S2/BJ2S7 was found in far greater excess; was exclusively Th1 polarized; disappeared from the spinal cord, spleen, and lymph nodes concomitantly with recovery; and transferred disease to naive recipients. In contrast, BV16/BJ2S5 and numerous private clonotypes were either Th1 or Th2 and persisted following recovery. These results are consistent with the hypothesis that the public clonotype BV8S2/BJ2S7 is a driver of disease and necessary for its propagation.     

Silymarin protects against acute ethanol-induced hepatotoxicity in mice

BACKGROUND: Accumulated evidence has demonstrated that both oxidative stress and abnormal cytokine production, especially tumor necrosis factor-alpha (TNF), play important etiological roles in the pathogenesis of alcoholic liver disease (ALD). Agents that have both antioxidant and anti-inflammation properties, particularly anti-TNF production, represent promising therapeutic interventions for ALD. We investigated the effects and the possible mechanism(s) of silymarin on liver injury induced by acute ethanol (EtOH) administration. METHODS: Nine-week-old mice were divided into 4 groups, control, silymarin treatment, EtOH treatment, and silymarin/EtOH treatment, with 6 mice in each group. Because control and silymarin values were virtually identical, only control treatment is shown for ease of viewing. Ethanol-treated mice received EtOH [5 g/kg body weight (BW)] by gavage every 12 hours for a total of 3 doses. Control mice received an isocalorical maltose solution. In the silymarin/EtOH group, silymarin was dissolved in the EtOH and gavaged simultaneously with EtOH at a dose of 200 mg/kg BW. At 4 hours after the last dosing, the mice were anesthetized and subsequent serum alanine aminotransferase (ALT) level, hepatic lipid peroxidation, enzymatic activity of hepatic cytochrome P450 2E1, hepatic TNF-alpha, and glutathione (GSH) levels were measured. Histopathological change was assessed by hematoxylin and eosin staining. RESULTS: Acute EtOH administration caused prominent hepatic microvesicular steatosis with mild necrosis and an elevation of serum ALT activity, induced a significant decrease in hepatic GSH in conjunction with enhanced lipid peroxidation, and increased hepatic TNF production. Supplementation with a standardized silymarin attenuated these adverse changes induced by acute EtOH administration. CONCLUSIONS: Silymarin protects against the liver injury caused by acute EtOH administration. In view of its nontoxic nature, it may be developed as an effective therapeutic agent for alcohol-induced liver disease by its antioxidative stress and anti-inflammatory features.