delta-Aminolevulinate dehydratase in human erythroleukemia cells: an immunologically distinct enzyme

Physicochemical and immunologic properties of delta-aminolevulinate (ALA) dehydratase in human K562 erythroleukemia cells were examined. ALA dehydratase activity was found to increase in K562 cells after treatment with butyric acid or selenium oxide. Enzyme activity in untreated K562 cells was comparable to that in normal adult erythrocytes but was increased three- to six-fold in K562 cells treated with 1.2 mmol/L butyric acid or 0.03 mmol/L selenium oxide. The Michaelis-Menten constant (Km), the inhibitor constant (Ki), and elution profile by diethylaminoethyl (DEAE) cellulose chromatography were similar for ALA dehydratase from K562 cells and normal human adult and human fetal erythrocytes. However, ALA dehydratase from K562 cells did not react with a monospecific rabbit antibody against ALA dehydratase purified from normal adult erythrocytes, although the antibody reacted with the enzyme from normal adult and fetal red cells. These findings indicate that ALA dehydratase in K562 cells is immunologically distinct from the normal enzyme.     

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n?=?302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53–10.7)?months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.     

Modulation of Apo-1/Fas (CD95)-induced programmed cell death in myeloma cells by interferon-α2

The Apo-1/Fas (CD95) antigen is known to be involved in the process of T cell-mediated target cell killing and has recently been shown to be expressed on myeloma cell lines and native malignant plasma cells. Several cytokines have been reported to interfere with spontaneous and even Apo-1/Fas-induced apoptosis, but no attempt has been made yet to investigate these interactions and the possible underlying mechanisms in myeloma cells. Since in myeloma patients Interferon (IFN)-α₂ displays a profound therapeutic effect in vivo, which is usually attributed to its growth inhibitory and/or immunomodulatory capacity, we set out to study the potential interference of IFN-α₂ with Apo-1/Fas-induced apoptosis. Contrary to expectations, IFN-α₂ reduced the degree of apoptosis caused by the treatment of five Apo-1/Fas-sensitive myeloma cell lines with a Fas monoclonal antibody (mAb). Simultaneous application of IFN-α₂ and Fas mAb was superior to the prolonged (i.e. > 8 h) preincubation with the cytokine as far as inhibition of Apo-1/Fas-induced apoptosis was concerned. This effect of IFN-α₂ was neither explained by a down-regulation of the Apo-1/Fas receptor nor caused by modulation of the expression levels of c-myc, bcl-2-, bcl-x_L, bax- or p53 genes. IFN-α₂ did not alter the Apo-1/Fas-induced activity of Mitogen-activated protein kinase (MAPK) 1 and did not inhibit the Apo-1/Fas-mediated proteolytic cleavage of ADP-ribosyltransferase, a substrate of Interleukin-β1 converting enzyme (ICE) and homologues. However, activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) mimicked the effects of IFN-α₂. Furthermore, the bis-indolylmaleimide GF 109203X, a specific inhibitor of PKC, inhibited the effect of PMA as well as that of IFN-α₂ on Apo-1/Fas-induced apoptosis. These results point to a PKC-dependent mechanism of transient interaction between the intracellular signaling along the IFN-α₂ and the Apo-1/Fas pathway (downstream of MAPK signaling as well as of ICE homologues), which becomes exhausted by prolonged stimulation with the cytokine. According to our data IFN-α₂, applied continuously and in high doses resembling the therapeutic situation in vivo, inhibits myeloma growth. However, based on the observed inhibitory effect of IFN-α₂ on Apo-1/Fas-induced apoptosis, a partial inhibition of the natural immune surveillance on myeloma cells by endog-genous IFN-α₂ present in the bone marrow microenvironment of this malignancy should be investigated.     

经肛门内镜显微手术切除直肠肿瘤

目的评价经肛门内镜显微手术(TEM)切除直肠绒毛状腺瘤和早期直肠癌的应用效果。方法分析我院总结1995年11月至2001年12月27例TEM手术的临床资料。结果本组患者肿瘤直径中位值2.5cm,肿瘤下缘与齿状线距离(8.9±3.4)cm,肿瘤侵犯直肠周径范围(35.7±17.5)%。平均手术时间(109±46)min。平均住院日4.5d。无围手术期死亡。手术并发症有尿潴留、暂时性大便失禁和慢性阻塞性肺病(COPD)复发。术中2例切穿至腹腔,即刻内镜下修补成功。切缘100%瘤细胞阴性。病理示直肠绒毛状腺瘤14例、直肠腺癌13例,后者包括pTis2例,pT16例和pT25例。直肠癌腔内超声肿瘤T分期符合率为84.6%。5例pT2中2例中转前切除术,1例接受术后放疗,2例无附加任何治疗。平均随访18个月,所有病例无局部复发。死亡2例,但无复发迹象。结论TEM易行且安全,是直肠绒毛状腺瘤和部分T1直肠癌的治愈性手术,也可作为T2直肠癌的姑息性治疗手段。     

经肛门内镜显微手术治疗直肠绒毛状腺瘤和早期直肠癌31例

目的探讨经肛门内镜显微手术（transanal endoscopicmic rosurgery，TEM）治疗直肠绒毛状腺瘤和早期直肠癌的疗效。方法1995年11月～2003年12月，我院行TEM治疗直肠肿瘤31例。全麻下根据肿瘤位置选择合适的体位，经肛门插入特殊的手术直肠镜，保持CO2充气状态，在立体视镜和腔镜系统下，采用针形电刀或5mm超声刀将直肠肿瘤完整切除（黏膜下或全层切除），手术创口在腔内连续缝合。结果31例直肠肿瘤均获完整切除，切缘均阴性。手术时间45～220min，平均95min；术中出血量0～180ml，平均40ml。手术并发症：暂时性排气失控2例，急性尿潴留1例，慢性阻塞性气道疾病急性发作1例，因服用阿斯匹林而出现继发性出血1例。术后病理分期：pT0期16例，pTis期2例，pT1期7例，pT2和pT3期各3例。31例随访2～92个月，平均23个月，肿瘤无原位复发。结论TEM是治疗直肠绒毛状腺瘤和早期直肠癌的一种安全、有效的微创手术方法。     

Pregnancy Loss and Distress Among U.S. Women

Although pregnancy loss—especially miscarriage—is a relatively common experience among reproductive‐aged women, much of our understanding about the experience has come from small clinic‐based or other nonrepresentative samples. We compared fertility‐specific distress among a national sample of 1,284 women who have ever experienced a stillbirth or miscarriage. We found that commitment/attachment to pregnancy that ended in loss as well as current childbearing contexts and attitudes were associated with distress following pregnancy loss. Practitioners working with women or couples who have experienced pregnancy loss should be aware of the importance of characteristics associated with higher distress, such as whether the pregnancy had been planned, recency of the loss, no subsequent live births, having a medical explanation for the loss, a history of infertility, current childbearing desires, importance of motherhood, and locus of control over fertility.