Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.     

The factor V B-domain provides two functions to facilitate thrombin cleavage and release of the light chain

Blood coagulation factors V and VIII are homologous proteins that have the domain organization A1-A2-B-A3-C1-C2. Upon thrombin activation, the B-domains of both molecules are released. Previous studies on factor VIII showed that the B-domain was not required for thrombin cleavage or activity. In contrast, deletion of the factor V B-domain (residues 709 to 1545) yielded a molecule with sevenfold reduced procoagulant activity that was not cleaved by thrombin. However, this factor V B- domain deletion molecule was activated by factor Xa, although the fold- activation was 85% that of wild-type factor V. Thrombin cleavage of factor V occurs initially after residue 709 and subsequently after residues 1018 and 1545. The requirement for thrombin cleavage within the B-domain at residue 1018 was evaluated by mutagenesis of Arg1018 to Ile. In the resultant R1018I mutant, the rate of thrombin activation and appearance of maximal cofactor activity was delayed and was consistent with delayed cleavage of the light chain at residue 1545. In contrast, the rate of factor Xa activation in the R1018I mutant was not altered. This finding suggests that thrombin cleavage at 1018 facilitates subsequent thrombin cleavage at 1545. Further mutagenesis was used to study the requirement for sequences within the factor V B- domain for thrombin cleavage at residue 1545. Whereas the factor V deletion molecule removing residues 709 to 1545 was not cleaved by thrombin, a smaller B-domain deletion molecule (residues 709 to 1476) containing an acidic amino acid-rich region (residues 1490 to 1520) was effectively cleaved by thrombin. These results show that residues 1476 to 1545, which contain an acidic amino acid-rich region, were required for thrombin cleavage of the light chain. Introduction of an acidic amino acid-rich region from factor VIII (residues 337 to 372) into the factor V 709 to 1545 deletion also restored thrombin cleavage of the light chain. In contrast, similar replacement with the acidic region from the factor VIII light chain (residues 1649 to 1689) was significantly less effective in promoting thrombin cleavage of the light chain. This finding suggests that the different acidic regions in factors V and VIII are not functionally equivalent in their interaction with thrombin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

新疆疏附县2005-2012年炭疽流行病学分析

目的 分析疏附县炭疽流行病学特征,为制订炭疽防控策略提供依据和参考.方法 对疏附县2005-2012年网络报告的炭疽发病资料进行描述性流行病学分析.结果 2005-2012年疏附县共报告炭疽137例,占同期全国病例总数的5.09％,年平均发病率为5.34/10万.病例全部为皮肤型炭疽,多为散发;夏秋两季高发,7月为高峰月份;男女性别比为1.36∶1,男性发病率高于女性.超过54％的病例为20岁以下儿童和青年,10-14岁高发.病例职业多为农牧民和学生,民族以维吾尔族为主（99.27％）.结论 疏附县炭疽发病率极高且呈低龄化特点,应采取针对性措施进一步加强其预防控制.     

Assessing blinding in trials of psychiatric disorders: A meta-analysis based on blinding index

The assessment of blinding in RCTs is rarely performed. Currently most studies that do report data on evaluation of blinding merely report percentages of correct guessing, not taking into account correct guessing by chance. Blinding assessment using the blinding index (BI) has never been performed in a systematic review on studies of major psychiatric disorders. This study is a systematic review of psychiatric randomized control trials using the BI as a chance-corrected measurement of blinding, a tool to analyze and understand the patterns of blinding across studies of major psychiatric disorders with available data. Of 2467 psychiatric RCTs from 2000 to 2010, 66 reported on blinding and 40 studies were found to have enough information on evaluation of blinding to be analyzed using the BI. The experimental treatment groups had an average BI value of 0.14 and the control groups had an average BI value of 0.00. The most common BI scenario was random–random, indicating ideal blinding. A positive correlation between effect size and more correct guesses was also found. Overall, based on BI values and the most common blinding scenario, the published articles on major psychiatric disorders from 2000 to 2010, which reported on blinding assessment for patients, were effectively blinded.     

Carcinoma‐associated fibroblasts,its implication in head and neck squamous cell carcinoma: a mini review

The communication between tumor stromal and parenchymal cells provides an insight to tumor progression. One of the main elements of the stroma, a major contributor to the extracellular environment of tumors, is carcinoma‐associated fibroblasts. They can originate from either normal fibroblasts in the immediate vicinity of the tumor or from circulating bone marrow–derived mesenchymal stem cells. These myofibroblasts can arise locally from an endothelial–mesenchymal transformation at the invasive edge of the cancer and are physically associated with carcinoma cells, that is, in the development of high‐grade malignancies and poor prognosis. These carcinoma‐associated fibroblasts feed the epithelial tumor cells in a host–parasite relationship establishing its role in head and neck squamous cell carcinoma progression.     

The dopamine D-2 antagonist, Ro 22-1319, inhibits the persistent behavioral syndrome induced by iminodipropionitrile (IDPN) in mice

Chronic administration of beta,beta'-iminodipropionitrile causes a persistent syndrome of excitement, choreoathetoid movements, and circling (the "ECC-syndrome") which persists indefinitely after termination of the IDPN injections. Ro 22-1319 is a specific D-2 dopamine receptor antagonist which was recently synthesized to fit a hypothetical model of the D-2 receptor. Ro 22-1319 inhibited several aspects of the ECC-syndrome, although some of its components, such as backward pedaling and forepaw treading reminiscent of the serotonin syndrome, were exacerbated. These results suggest that several neurotransmitter systems may be involved in the ECC-syndrome.     

Embryonic substantia nigra grafts innervate embryonic striatal co-grafts in preference to mature host striatum

Embryonic substantia nigra grafts partially reinnervate the dopamine-denervated corpus striatum when implanted adjacent to that structure. This reinnervation is generally limited to a small portion of the denervated striatum and does not completely compensate for the behavioral effects of a 6-hydroxydopamine lesion of the substantia nigra. This limited reinnervation may be due to the fact that adult denervated striatum is not an ideal target for dopaminergic neurites. To test this hypothesis, embryonic striatum and embryonic substantia nigra were implanted together into the lateral ventricle of adult rats, adjacent to the denervated striatum. Five months after transplantation, fluorescence histochemistry showed that the embryonic striatal grafts were exclusively reinnervated with little or no reinnervation of the adult host striatum. When substantia nigra was implanted without embryonic striatal co-grafts, reinnervation of the host striatum was observed. We conclude that embryonic striatum is a better target tissue than adult denervated striatum for developing dopaminergic neurites and hypothesize that this difference may be due to the presence or the absence of specific trophic factors.     

化疗联合HLA不全相合G-PBSC输注治疗恶性血液病的临床分析

目的初步探讨化疗联合HLA不全相合G-PBSC输注(微移植)治疗恶性血液病的临床应用。方法回顾性分析2015-05～2016-12接受微移植治疗的13例恶性血液病患者的临床及随访资料。根据病情,对13例患者行不同的预处理方案化疗后,计划给予微移植3～4次。观察微移植后患者的缓解情况,生存时间,血象恢复时间,急、慢性移植物抗宿主病(GVHD)及其他不良反应发生情况。结果随访至2017-04,中危组8例,其中存活6例,死亡2例;高危组5例,其中存活2例,死亡3例。中位生存期为9个月(4～24个月)。微移植治疗后,中性粒细胞和血小板平均恢复时间分别为8 d(5～14 d)和11 d(6～20 d)。所有患者在微移植过程中均未出现急、慢性GVHD及其他不良反应。结论微移植在供者选择上不受限制,移植后血小板及中性粒细胞恢复较快,且无急、慢性GVHD及其他不良反应发生;微移植在中高危恶性血液病的临床应用尚处于探索阶段,仍需多中心、大样本的临床研究来进一步验证。