Clinical features and outcome in childhood T-cell leukemia-lymphoma according to stage of thymocyte differentiation: a Pediatric Oncology Group Study

The immunophenotypes of lymphoblasts from children with newly diagnosed T-cell acute lymphoid leukemia (T-ALL, n = 101) or T-cell non-Hodgkin lymphoma (T-NHL, n = 31) were analyzed to correlate stage of thymocyte differentiation with clinical features and outcome. The 67 boys and 34 girls with T-ALL were 1 month to 18 years old (median, 8 years) with leukocyte counts ranging from 2 to 810 x 10(9)/L (median, 55 x 10(9)/L). Eighteen of these patients were black, and 70 had a mediastinal mass. Twenty-six boys and five girls with a median age of 9 years (range, 1 to 20 years) had T-NHL. Seven of these patients were black, and 24 had a mediastinal mass. The distributions of thymocyte developmental stages (early [CD7+], intermediate [CD1+ and/or CD4+ and/or CD8+], and mature [CD3+]) in cases of T-ALL and T-NHL were significantly different: 34%, 43%, and 23% v 6%, 62%, and 32% (P = .02). A comparison of the patients' clinical features according to the maturational stage of thymocytes failed to disclose significant differences in the majority of characteristics studied. However, patients with mature-stage T-NHL, with or without the addition of subjects with mature-stage T-ALL, were less likely to have a mediastinal mass (P = .02 for both comparisons). Those with intermediate-stage T-cell malignancy (T-ALL and T-NHL combined) were the subgroup most likely to have a mediastinal mass (P = .01). Response to remission induction therapy was significantly worse in the T-ALL subgroup with an early-stage phenotype: a failure rate of 21% v 0% and 6% for the two more differentiated phenotypic subgroups (P = .007). Event-free survival was not affected by thymocyte maturational stage in cases of either T-ALL or T-NHL. Despite evidence of clinical heterogeneity among the maturational stages of T-cell malignancies in children, these developmental subdivisions do not appear to be critical determinants of outcome once remission is achieved. We conclude that such phenotypes need not be included in the stratification plans for clinical trials using common induction treatment.     

Retrovirally marked CD34-enriched peripheral blood and bone marrow cells contribute to long-term engraftment after autologous transplantation

We report here on a preliminary human autologous transplantation study of retroviral gene transfer to bone marrow (BM) and peripheral blood (PB)-derived CD34-enriched cells. Eleven patients with multiple myeloma or breast cancer had cyclophosphamide and filgrastim-mobilized PB cells CD34-enriched and transduced with a retroviral marking vector containing the neomycin resistance gene, and CD34-enriched BM cells transduced with a second marking vector also containing a neomycin resistance gene. After high-dose conditioning therapy, both transduced cell populations were reinfused and patients were followed over time for the presence of the marker gene and any adverse effects related to the gene-transfer procedure. All 10 evaluable patients had the marker gene detected at the time of engraftment, and 3 of 9 patients had persistence of the marker gene for greater than 18 months posttransplantation. The marker gene was detected in multiple lineages, including granulocytes, T cells, and B cells. The source of the marking was both the transduced PB graft and the BM graft, with a suggestion of better long-term marking originating from the PB graft. The steady- state levels of marking were low, with only 1:1000 to 1:10,000 cells positive. There was no toxicity noted, and patients did not develop detectable replication-competent helper virus at any time posttransplantation. These results suggest that mobilized PB cells may be preferable to BM for gene therapy applications and that progeny of mobilized peripheral blood cells can contribute long-term to engraftment of multiple lineages.     

Crystal structure of Mycobacterium tuberculosis ClpP1P2 suggests a model for peptidase activation by AAA+ partner binding and substrate delivery

Caseinolytic peptidase P (ClpP), a double-ring peptidase with 14 subunits, collaborates with ATPases associated with diverse activities (AAA+) partners to execute ATP-dependent protein degradation. Although many ClpP enzymes self-assemble into catalytically active homo-tetradecamers able to cleave small peptides, the Mycobacterium tuberculosis enzyme consists of discrete ClpP1 and ClpP2 heptamers that require a AAA+ partner and protein–substrate delivery or a peptide agonist to stabilize assembly of the active tetradecamer. Here, we show that cyclic acyldepsipeptides (ADEPs) and agonist peptides synergistically activate ClpP1P2 by mimicking AAA+ partners and substrates, respectively, and determine the structure of the activated complex. Our studies establish the basis of heteromeric ClpP1P2 assembly and function, reveal tight coupling between the conformations of each ring, show that ADEPs bind only to one ring but appear to open the axial pores of both rings, provide a foundation for rational drug development, and suggest strategies for studying the roles of individual ClpP1 and ClpP2 rings in Clp-family proteolysis.The self-compartmentalized caseinolytic peptidase P (ClpP) functions in collaboration with the ATPases associated with diverse activities (AAA+) ClpX, ClpA, or ClpC enzymes to carry out ATP-dependent proteolysis in bacteria and eukaryotic organelles (1). The physiological importance of these proteolytic complexes is reflected in their requirement for the viability and/or virulence of some bacteria and the observation that loss-of-function mutations in mammals are linked to developmental defects and disease (2–8). Most well-characterized ClpP enzymes come from organisms that have a single clpP gene and consist of identical heptameric rings, which stack face-to-face to enclose a degradation chamber in which 14 active sites mediate peptide-bond hydrolysis (1, 9, 10). Importantly, the proteolytic chamber is accessible only via narrow axial pores that allow entry of small peptides, greatly slow entry of larger peptides or unfolded proteins, and block access of native proteins (11, 12). Degradation of proteins is mediated by the ClpXP, ClpAP, or ClpCP proteolytic complexes. In these enzymes, the AAA+ partner forms a ring hexamer that binds peptide degrons in target proteins, unfolds native structure if necessary, and translocates the unfolded polypeptide through a central channel and into the lumen of ClpP for degradation (13).When AAA+ partner proteins bind to ClpP, one consequence is opening of the narrow axial pores (12, 14, 15). Binding is mediated in part by tripeptide motifs [typically Ile-Gly-Phe or Leu-Gly-Phe (LGF)] in flexible loops in the AAA+ hexamer, which dock into hydrophobic pockets at subunit interfaces on each ClpP heptamer (16–19). In a remarkable example of protein mimicry by a natural product, cyclic acyldepsipeptide (ADEP) antibiotics bind in the same hydrophobic pockets on ClpP and also open the axial pores, potentially leading to unregulated protein degradation and cell death (14, 15, 20, 21).In contrast to organisms with one ClpP, two or more ClpP isoforms are characteristic of two large bacterial phyla (Actinobacteria and Cyanobacteria) and also occur in individual species from other phyla (22, 23). For example, Mycobacterium tuberculosis, a pathogenic actinobacterium, encodes cotranscribed clpP1 and clpP2 genes (24, 25). The importance of Clp-family proteolysis in M. tuberculosis is highlighted by the facts that the clpP1, clpP2, clpX, and clpC1 genes are all essential and that mechanism-based ClpP inhibitors suppress growth (24, 26–28). Recent studies indicate that M. tuberculosis ClpP1 and ClpP2 form discrete heptameric rings that assemble into an active ClpP1P2 tetradecamer only in the presence of a ClpX or ClpC1 AAA+ partner and one additional factor, either protein substrates being actively translocated into the degradation chamber or N-blocked peptide agonists (23, 29). Because M. tuberculosis resistance to conventional antibacterial drugs is a major health hazard, there is substantial interest in developing drugs that target ClpP1P2. At the outset of this work, however, there was no structure of M. tuberculosis ClpP1P2 or any heteromeric ClpP enzyme to guide design efforts.Here, we show that a catalytically active ClpP1P2 tetradecamer can be stabilized by the combination of a novel ADEP and an agonist peptide, which allowed crystallization and determination of the 3D structure. Together, our structural and biochemical results reveal the basis for ClpP1P2 assembly and activation, establish that the conformations of the ClpP1 and ClpP2 rings are tightly coupled, show that ADEPs bind exclusively to one ring, and suggest strategies for the design of active ClpP1 or ClpP2 tetradecamers for studies of AAA+ partner specificity and biological function.     

Prevalence of major depressive disorder in patients receiving beta-blocker therapy versus other medications

Depression is believed to be a common side effect in patients receiving beta-blocker therapy. However, diagnoses of depression defined by current diagnostic criteria may not be more common in patients receiving beta-blockers than in patients with the same medical disorder receiving other medications. Seventy-seven patients undergoing elective cardiac catheterization for evaluation of chest pain received a semi-structured diagnostic psychiatric interview. Twenty-one percent of the patients receiving beta-blockers and 33 percent of the patients receiving medications other than beta-blockers met the current American Psychiatric Association criteria for major depressive disorder (DSM-III) (p = NS). The mean heart rate and state anxiety scores for patients taking beta-blockers were significantly lower than those measured in patients taking medications other than beta-blockers. No other medical or demographic differences were observed between the two groups. Despite the methodologic limitations of the study, there does not appear to be a difference in the point prevalence of depression between patients receiving beta-blockers and those receiving other medications.     

Ovarian cancer hormonal and environmental risk effect

To understand the influence of hormonal and environmental factors on the risk of ovarian cancer, it is important to remember the established risk factors and postulated mechanisms that lead to the development of ovarian cancer. Several risk factors have been identified as increasing the risk of epithelial ovarian cancer, including low pariety, infertility, early age of menarche, and late age of menopause. This article discusses the different hypotheses and focuses on hormonal and environmental risk factors, as well the chemoprevention of epithelial ovarian cancer.     

Identification and In Vivo Functional Characterization of Novel Compound Heterozygous BMP1 Variants in Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) comprises a heterogeneous group of disorders that are characterized by susceptibility to bone fractures, and range in severity from a subtle increase in fracture frequency to death in the perinatal period. Most patients have defects in type I collagen biosynthesis with autosomal‐dominant inheritance, but many autosomal‐recessive genes have been reported. We applied whole‐exome sequencing to identify mutations in a Korean OI patient who had an umbilical hernia, frequent fractures, a markedly short stature, delayed motor development, scoliosis, and dislocation of the radial head, with a bowed radius and ulna. We identified two novel variants in the BMP1 gene: c.808A>G and c.1297G>T. The former variant caused a missense change p.(Met270Val) and the latter variant caused the skipping of exon 10. The hypofunctional nature of the two variants was demonstrated in a zebrafish assay.     

Assessing learning in the adaptive curriculum

Abstract

Background: Medical education is a dynamic process that will continuously evolve to respond to changes in the foundations of medicine, the clinical practice of medicine and in health systems science.

Purpose: In this paper, we review how assessing learning in such a dynamic environment requires comprehensive flexible and adaptable methodological approaches designed to assess knowledge attainment and transfer, clinical skills/competency development, and ethical/professional behavior. Adaptive assessments should measure the learner’s ability to observe where changes in health care delivery are needed and how to implement them. Balancing formative and summative assessments will promote reflective learning so that each student will reach her/his highest potential. From the programmatic perspective, measuring the design and delivery of instruction in relation to students? efforts to achieve competency will improve learning and foster continuous professional development of faculty and advance the science of learning.

Approach: We describe how two medical schools are approaching adaptive assessment, including using portfolio systems that encompass teaching and learning experiences while offering real-time longitudinal tracking of digital data toward improving learning and provide curricula continuous improvement cycles. Using latest technologies, portfolios produce actionable data displays with precise guidance for learning and program development.     

开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效观察

目的：观察开道散合扶正和胃合剂治疗上消化道癌性狭窄的临床疗效。方法：对40例患者采用口服开道散、扶正和胃合剂联合胃镜下癌灶内注射5-氟脲嘧啶注射液及鸦胆子乳剂方法治疗上消化道癌性狭窄。结果：治疗后无瘤灶消失病例,34例患者肿瘤缩小达50％以上,完全缓解0例,部分缓解34例,稳定4例,进展2例,有效率为85．0％。治疗后患者吞咽困难有了较明显的改善,显效7例,有效31例,无效2例,总有效率95．0％。治疗后所有患者的卡氏评分均有所升高,与治疗前比较,差异有显著性意义（P〈0．05）,提示治疗后患者的生活质量有所改善。结论：开道散合扶正和胃合剂治疗上消化道癌性狭窄疗效满意,能使实体瘤缩小、吞咽困难改善、生活质量提高。