T cells play an essential role in controlling the development of B-cell lymphoproliferative disorders (BLPDs), but the dysfunction of T cells in BLPDs largely remains elusive.Using multiplexed flow cytometry, we quantified all major subsets of CD4+ helper T cells (Th) and CD8+ cytotoxic T cells (Tc) in 94 BLPD patients and 66 healthy controls. Statistics was utilised to rank T-cell signatures that distinguished BLPDs from healthy controls and differentially presented between indolent and aggressive categories.By comparing with healthy controls, we found that the indolent but not aggressive type of BLPDs demonstrated a high degree of T-cell activation, showing the increase in type I helper T (Th1) cells and follicular B-helper T (Tfh) cells, both of which strongly associated with the enhanced differentiation of exhaustion-like effector cytotoxic CD8+ T cells expressing PD-1 (Tc exhaustion-like) in indolent BLPDs. Random forest modelling selected a module of T-cell immune signatures best performing binary classification of all BLPD patients. This signature module was composed of low naïve Th cells and high Th1, Tfh and Tc exhaustion-like cells which efficiently identified > 85% indolent cases and was, therefore, assigned as the Indolent Dominant Module of T-cell immune signature. In indolent BLPD patients, a strong bias towards such signatures was found to associate with clinical characteristics of worse prognosis.Our study identified a prominent signature of T-cell dysregulation specifically for indolent BLPDs, suggesting Th1, Tfh and Tc exhaustion-like cells represent potential prognostic biomarkers and targets for immunotherapies.
Mantle cell lymphoma (MCL) is a phenotypically and genetically heterogeneous malignancy in which the genetic alterations determining clinical indications are not fully understood. Here, we performed a comprehensive whole-exome sequencing analysis of 152 primary samples derived from 134 MCL patients, including longitudinal samples from 16 patients and matched RNA-Seq data from 48 samples. We classified MCL into 4 robust clusters (C1-C4). C1 featured mutated immunoglobulin heavy variable (IGHV), CCND1 mutation, amp(11q13), and active B cell receptor (BCR) signaling. C2 was enriched with del(11q)/ATM mutations and upregulation of NF-κB and DNA repair pathways. C3 was characterized by mutations in SP140, NOTCH1, and NSD2, with downregulation of BCR signaling and MYC targets. C4 harbored del(17p)/TP53 mutations, del(13q), and del(9p), and active MYC pathway and hyperproliferation signatures. Patients in these 4 clusters had distinct outcomes (5-year overall survival [OS] rates for C1-C4 were 100%, 56.7%, 48.7%, and 14.2%, respectively). We also inferred the temporal order of genetic events and studied clonal evolution of 16 patients before treatment and at progression/relapse. Eleven of these samples showed drastic clonal evolution that was associated with inferior survival, while the other samples showed modest or no evolution. Our study thus identifies genetic subsets that clinically define this malignancy and delineates clonal evolution patterns and their impact on clinical outcomes.
To investigate the efficacy of different regimens in previously untreated follicular lymphoma (FL) patients with bone marrow involvement.Clinical data of 38 previously untreated FL patients with bone marrow involvement visited Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences during the period from January 2002 to December 2013 were analyzed retrospectively, in order to compare the efficacy and survival status of different regimens.The median age of onset was 43 years (19-74 years). The number of patients in low, intermediate and high risk group according to the follicular lymphoma international prognostic index (FLIPI) was 11 (28.9%), 11 (28.9%), and 16 (42.1%) respectively.And 36 of the 38 patients received combined chemotherapies. The overall response rate (ORR), complete remission (CR) rate, and partial remission (PR) rate were 100%, 66.7%, and 33.3%, respectively.A total of 31 patients (86.1%) used rituximab, in whom the 3-year overall survival (OS) was significantly higher than that in those who had not used rituximab (94.4% vs 80.0%, P=0.012), but the difference between 3-year progression-free survival (PFS) rate had no statistical significance (P=0.305). In the rituximab group, 16 patients had received RCHOP (rituximab, cyclophosphamide, epirubicin, vincristine, prednisone), 9 patients had received RFC (rituximab, fludarabine, cyclophosphamide), 6 young patients with high invasion and high tumor burden had received R-HyperCVAD (rituximab , cyclophosphamide, epirubicin, vincristine, dexamethasone). In the RFC/R-HyperCVAD group, the 3-year PFS was significantly higher than that in the RCHOP group (92.3% vs 48.9%, P=0.036), but the 3-year OS rate had no statistically significant difference (P=0.190). Compared with the RCHOP group, the 3-year PFS was significantly higher in the RFC group (100% vs 48.9%, P=0.029), but the 3-year OS rate had no statistically significant difference (100% vs 85.7%, P=0.285). Of the 36 patients who had received combined chemotherapy, 13 had received rituximab for maintenance treatment, whose 3-year PFS (92.3% vs 58.7%, P=0.025) and OS (100% vs 80.0%, P=0.040) were significantly higher than those not receiving maintenance treatment.FL patients with bone marrow involvement may tend to have an onset at young age and intermediate to high FLIPI scores. These patients may benefit from rituximab combined with intensive chemotherapy. Rituximab as maintenance treatment may further improve the survival of these patients.
The efficiency of rituximab (Mabthera) is related to CD20 expression density on cell membrane. It is not yet to be solved how to heighten expression level of CD20 on multiple myeloma (MM) cell membrane and to increase the efficacy of Mabthera to MM. This study was designed to observe whether thalidomide could promote the effect of Mabthera on suppressing myeloma cells in vitro and its possible mechanism.Colony growth of 18 untreated and 20 relapsed or refractory MM patients' myeloma cells were observed in the methylcellulose semisolid medium adding thalidomide (10, 50, 75, 100, 150, 200, 300 micrograms/ml) or Mabthera (0.5, 1, 2, 4, 8, 12, 16 micrograms/ml) or thalidomide above 7 doses in combination with Mabthera of 16 micrograms/ml or Mabthera above 7 doses in combination with thalidomide of 75 micrograms/ml. Change of CD20 expression on the myeloma cells were measured by flow cytometer after and before myeloma cells were treated with thalidomide.The inhibition of the colony formation of untreated MM patients' myeloma cells occurred in 1. use only of thalidomide at more than or equal to 75 micrograms/ml or use only of Mabthera at 16 micrograms/ml, 2. use of thalidomide at 75 micrograms/ml with or without Mabthera at 16 micrograms/ml, 3. use of thalidomide at more than or equal to 75 micrograms/ml with or without Mabthera at 16 micrograms/ml; The inhibition of the colony formation of relapsed or refractory MM patients' myeloma cells occurred in 1. use of thalidomide at 75 micrograms/ml with Mabthera at 16 micrograms/ml, 2. use of thalidomide at more than or equal to 100 micrograms/ml with or without Mabthera at 16 micrograms/ml; Thalidomide at more than 75 micrograms/ml enhanced the expression of CD20 antigen in untreated and relapsed or refractory MM patients' myeloma cells.Thalidomide could enhance the inhibition of Mabthera on colony formation of MM patients' myeloma cells, which is related to that thalidomide enhances CD20 antigen expression of myeloma cells.
Zinc, an essential trace mineral, plays a pivotal role in cell proliferation, maintenance of redox homeostasis, apoptosis, and aging. Serum zinc concentrations are reduced in patients with polycystic ovary syndrome (PCOS). However, the underlying mechanism of the effects of zinc deficiency on the female reproductive system, especially oocyte quality, has not been fully elucidated. Thus, we established an in vitro experimental model by adding N,N,N',N'-Tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) into the culture medium, and to determine the potential regulatory function of zinc during porcine oocytes maturation. In the present study, we found that zinc deficiency caused aberrant meiotic progress, accompanied by the disrupted cytoskeleton structure in porcine oocytes. Zinc deficiency impaired mitochondrial function and dynamics, leading to the increase of reactive oxygen species (ROS) and acetylation level of the antioxidative enzyme superoxide dismutase 2 (SOD2), eventually induced the occurrence of oxidative stress and early apoptosis. Moreover, zinc deficiency perturbed cytosolic Ca2+ homeostasis, lipid droplets formation, demonstrating the aberrant mitochondrial function in porcine oocytes. Importantly, we found that zinc deficiency in porcine oocytes induced the occurrence of mitophagy by activating the PTEN-induced kinase 1/Parkin signaling pathway. Collectively, our findings demonstrated that zinc was a critical trace mineral for maintaining oocyte quality by regulating mitochondrial function and autophagy in porcine oocytes.
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