Cell-cycle-specific genes differentially expressed in human leukemias.

Three cDNA clones isolated from Syrian hamster cells (p4F1, p2F1, and p2A9) contain sequences that are preferentially expressed in the G1 phase of the cell cycle. The expression of these sequences was investigated in human peripheral blood cells from normal individuals and from patients with leukemia. The expression of p4F1 and p2F1 is clearly dependent on the cell cycle in peripheral blood mononuclear cells stimulated to proliferate with phytohemagglutinin; the p2A9 sequences cannot be clearly detected in human lymphocytes but are expressed in a cell-cycle-dependent manner in human diploid fibroblasts (WI-38). These genes also show different levels of expression in lymphoid and myeloid leukemias. The highest level of expression for p2A9 is found in patients with chronic myelogenous leukemia, and the lowest in patients with chronic lymphocytic leukemia. For p2F1 and p4F1, the highest levels of expression are found in chronic and acute myelogenous leukemia. At least two other cell-cycle genes are not expressed at detectable levels in human leukemias. These findings suggest that the activation of cell-division-cycle genes might contribute, like cellular oncogenes, to the phenotype of human malignancies and that, perhaps, new oncogenes could be found by identifying and isolating genes whose expression is dependent on the cell cycle.     

Hepatic trauma (90 consecutive cases treated in 9 years

90 consecutive hepatic traumatisms at the Hospital de Navarra are presented over a period of 9 years, excluding those which did not overcome the initial reanimation phase and those diagnosed as necropsy. The etiology is presented (76 closed and 14 open), the degree of lesion, associated intra and extra-abdominal lesions plus the results (12.2% mortality) and causes of death related to the degree of lesion and associated lesion. Finally, our casuistics and results are compared with those appearing in the existing bibliography on the subject.     

In vivo release and turnover of secreted platelet antiheparin proteins in rhesus monkey (Macaca mulatta)

Human and rhesus monkey platelets secrete at least two antiheparin proteins: platelet factor 4 (PF4) and low affinity platelet factor 4 (LA-PF4). Neither of these proteins showed species-related antigenic differences. As determined by radioimmunoassay, the levels of PF4 and LA-PF4 antigen per 10(9) monkey platelets amounted to 10.7 and 20.3 microgram, respectively. One milliliter of monkey plasma prepared from blood collected into an anticoagulant composed of EDTA, prostaglandin E1, and theophylline solution contained 22.4 ng LA-PF4 and 8.0 ng PF4. Concentrations of these two platelet-specific proteins in monkeys closely resembled levels found in human platelets and plasma. Infusion of prostacyclin (PGI2) (100 or 300 ng/kg/min) into monkeys for 15 min resulted in a significant decrease of plasma levels of LA-PF4 antigen and of PF4 by 40%--60% (p < 0.0001). This decrease was related to the inhibitory effect of PGI2 on the secretion of platelets stimulated by a catheter or by venipuncture. Longer infusion of PGI2 did not produce further significant change. The supernate obtained after aggregation of human platelets stimulated by thrombin was injected into monkeys receiving PGI2 infusion. The disappearance of LA-PF4 antigen in monkey plasma followed a biphasic exponential curve with half-lives for the fast and slow components of 8.4 and 63 min. PF4 disappeared faster but followed the same pattern (half-lives for the fast and slow component of 2.1 and 70 min). Analysis of the experimental data suggests that the low levels of secreted platelet proteins in monkey plasma are related to their minimal in vivo release and to their rapid clearance.     

Characterization of autoantigenic epitopes on platelet glycoprotein IIb/IIIa using random peptide libraries

Most patients with chronic immune thrombocytopenic purpura (ITP) have autoantibodies directed against the glycoprotein (GP) IIb/IIIa complex. We have used a filamentous phage library that displays random linear hexapeptides to identify peptide sequences recognized by these autoantibodies. Plasma antibody eluates from two patients were used to select for phage displaying autoantibody-reactive peptides. From patient ITP-1 (known to have two distinct autoantibodies), we identified anti-GPIIb/IIIa antibody-specific phage encoding the peptide sequences Arg-Glu-Lys-Ala-Lys-Trp (REKAKW) and Pro-Val-Val-Trp-Lys-Asn (PVVWKN). Patient ITP-2 bound phage encoding the hexapeptide sequence Arg-Glu-Leu-Leu-Lys-Met. Each phage showed saturable dose-dependent binding to immobilized autoantibody, and binding could be blocked with purified GPIIb/IIIa. Patient ITP-1 autoantibody recognition of phage encoding REKAKW could be blocked with a synthetic peptide derived from the GPIIIa cytoplasmic tail; however, the PVVWKN was not. Using sequential overlapping peptides from the GPIIIa cytoplasmic region, an epitope for ITP-1 was localized to the sequence Arg-Ala-Arg-Ala-Lys-Trp (GPIIIa 734-739). Inhibition studies using synthetic peptides showed that phage REKAKW and PVVWKN were recognized by distinct autoantibodies from patient ITP-1. To determine whether individual patients with ITP possessed autoantibodies that recognize similar antigenic determinants on GPIIb/IIIa, the three phage were tested for binding to five other ITP patient autoantibodies. The phage encoding the peptide PVVWKN was found to bind ITP-1 and one other patient autoantibody. This result suggests that ITP patients recognize a limited number of shared epitopes.     

Changes in sensory function and force production in adults with type II diabetes

Introduction: The purpose of this study was to evaluate the relationship among sensory function, disease severity, and upper extremity force production in adults with type II diabetes (T2D) as compared with healthy age‐ and gender‐matched controls. Methods: Ten adults with T2D and 10 healthy age‐ and gender‐matched control subjects underwent a battery of sensory and motor function evaluations. Data on disease severity and duration were also collected. Results: The T2D group exhibited sensory deficits and altered force production as compared with healthy controls. Sensory function correlated with disease severity, as did signal predictability of kinetic output during submaximal force production tasks. Maximal force production tasks were associated with altered output in T2D, but these data did not correlate with disease severity or sensory dysfunction. Conclusions: Some, not all, motor performance deficits in T2D are associated with sensory dysfunction. Mechanisms responsible for these changes in adult‐onset T2D are described. Muscle Nerve 50: 984–990, 2014     

Real world outcomes with Bortezomib Thalidomide dexamethasone and Cyclophosphamide Bortezomib dexamethasone induction treatment for transplant eligible multiple myeloma patients in a Latin American country. A Retrospective Cohort Study from Grupo Argentino de Mieloma Múltiple

Data about treatment outcomes and toxicity in Latin America are scarce. There are differences with central countries based on access to healthcare system and socioeconomic status. Argentinean Society of Hematology recommends bortezomib-based triplets for induction treatment of transplant eligible newly diagnosed multiple myeloma patients. Most common options are CyBorD (cyclophosphamide, bortezomib and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone). Main goal of our retrospective, multicentric study was to compare very good partial response rate (VGPR) or better after induction treatment in a real-world setting in Argentina. Secondary objectives included comparison of complete response (CR) post-induction and after bone marrow transplantation, grade 3-4 adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Three hundred twenty-two patients were included (median age at diagnosis: 57 years; 52% male; 28% had ISS3; 14% with high-risk cytogenetics; median follow up: 34 months). CyBorD was indicated in 74% and 26% received VTD. In VTD arm, 72.62% of patients achieved at least VGPR vs 53.36% receiving CyBorD (odds ratio, OR: 1.96 [95% confidence interval, CI: 1.08-3.57; P = .026] after adjusting by age, ISS [International Staging System], lactate dehydrogenase levels (LDH) and cytogenetic risk. Difference in VGPR was 19.26% (95% CI: 15-24). CR rate were 35.92% (VTD) vs 22.55% (CyBorD) (adjusted OR: 2.13 [95% CI: 1.12-4.05]). Difference in CR was 13.37% (95% CI: 9.6-17.53). Adverse events (AEs) were more common with VTD (69.05% vs 55.46% for CyBorD; P = .030), especially grade 3-4 neuropathy (P = .005) and thrombosis (P = .001). Thromboprophylaxis was inadequate in 20.24% of patients. Hematological AEs were more common with CyBorD, especially thrombocytopenia (P = .017). PFS and OS at 24 months were not different between treatments. In this real-world setting, VTD was associated with better CR and VGPR than CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina, based on safety profile. Frontline autologous stem cell transplantation improves quality of responses, especially in countries with limited access to new drugs.     

儿童癌症幸存者成年后的慢性疾病

由于治疗方法的进步,近80%的儿童和青少年癌症患者能够长期生存。在美国,约有270000例儿童癌症的幸存者,即每640名20至39岁成年人中就有一名幸存者。大量的幸存者有利于儿童癌症治疗后长期健康结果的研究。现在可以明确的是,化疗和放疗所致的儿童各器官系统损害在临床上可能潜伏多年。为了全面了解治疗儿童癌症而继发的健康问题,重要的是衡量三项长期结果:健康状况、死亡率和患病率。这三项中,关于前两项已有相当好的研究报道。在一项对20227例癌症5年生存者的回顾性分析中,Mertens等发现以下原因导致的超额死亡率具有统计学意义:继发癌症(…