A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion

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Increased expression of CD152 (CTLA-4) by normal T lymphocytes in untreated patients with B-cell chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) have defects in both cellular and humoral immunity. Since CD152 (CTLA-4) plays a critical role in downregulating T-cell responses, we studied the expression of surface and cytoplasmic CD152 (sCD152 and cCD152, respectively) in freshly isolated T cells from treatment-na?ve patients with CLL. CD4+ and CD8+ T cells from these patients demonstrated significantly increased sCD152 and cCD152 compared to normal donors. Furthermore, these patients had an increased proportion of the regulatory CD4(+)/CD25(+)/CD152+ subset that correlated with advanced Rai stage, unfavorable cytogenetics and low serum IgG and IgA levels. The expression of sCD152 by T cells also correlated with ZAP-70 expression by CLL B cells. The proportion of CD4(+)/CD25+ cells was also correlated with unmutated immunoglobulin heavy chain variable gene status. Blockade of CD152 with monoclonal antibody (mAb) in proliferation assays was associated with potent T-cell proliferation in response to autologous and allogeneic CD40-activated CLL B cells. In summary, T cells from patients with CLL may be primed for anergy by expressing increased amounts of CD152; anti-CD152 mAb may represent a therapeutic opportunity to enhance an immune response against autologous leukemia cells.     

k阿片受体激动剂抑制大鼠吗啡戒断症状的发生

用多次注射吗啡的方法造成大鼠对吗啡的依赖，给大鼠脊髓蛛网下腔（ｉ．ｔ．）注射ｋ（ｋａｐｐａ）阿片受体激动剂Ｕ－５０，４８８Ｈ（２．５、５、１０μｌ）或ｋ受体拮抗剂ｎｏｒ—ＢＮＩ（１．２５、２．５、５μｌ／１０μｌ）后，用纳洛酮（ＮＸ）催瘾，观察并记录四种戒断症状：湿科（ｗｅｔｓｈａｋｅｓ）、咬牙（ｔｅｅｔｈｃｈａｔｔｅｒｉｎｇ）、逃跑企图（ｅｓｃａｐｅａｔｔｅｍｐｔｓ）、体重丢失（ｗｅｉｇｈｔｌｏｓｅ）。结果表明Ｕ—５０，４８８Ｈ可以明显减轻湿抖、咬牙和逃跑企图，并呈量效关系；ｎｏｒ—ＢＮＩ则使温抖、咬牙和体重丢失三种症状明显加重，也呈量效关系。上述结果表明，激活脊髓。受体对吗啡戒断症状有明显的抑制作用，阻断Ｋ受体则加重戒断症状。     

肾移植术后服药前和服药后2小时新山地明血药浓度监测的临床意义比较

目的:新山地明给药后,个体间吸收变异相当明显,血药浓度监测管理对减少急性排斥反应发生及降低肝肾毒性十分重要。比较传统的服药前血药浓度(谷值)、服药后2h血药浓度(峰值)监测的临床意义。方法:选择2005-01/2006-04在中山大学附属第一医院行首次同种异体尸肾移植的受者60例,均知情同意。按随机数字表法分成服药前血药浓度组和服药后2h血药浓度组,各30例。两组患者肾移植后前3个月均接受新山地明5～7mg/(kg·d)、霉酚酸酯1.0～1.5g/d和皮质激素三联治疗。采用荧光偏振法测定患者新山地明服药前和服药后2h血药浓度,比较服药前血药浓度与服药后2h血药浓度监测方法预测肾移植急性排斥反应和不良反应(肝毒性、肾毒性)的有效性。结果:60例患者全部进入结果分析。①60例患者在术后3个月内急性排斥反应发生率为13.3%(8/60);不良反应发生率为28.3%(17/60),肝毒性发生率为20.0%(12/60),肾毒性发生率为8.3%(5/60)。②急性排斥反应发生时与非急性排斥反应时服药前血药浓度差异无显著性意义(P=0.08);急性排斥反应发生时服药后2h血药浓度显著低于非急性排斥反应时服药后2h血药浓度(P<0.01)。③发生肝肾毒性1周内的服药前血药浓度与未发生时服药前血药浓度差异无显著性意义(P=0.15);发生肝肾毒性1周内的服药后2h血药浓度显著高于肝肾毒性未发生时(P<0.01)。结论:在肾移植术后早期,与服药前血药浓度相比,服药后2h血药浓度能更敏感的反映急性排斥反应和不良反应的发生。     

The Dohner fluorescence in situ hybridization prognostic classification of chronic lymphocytic leukaemia (CLL): the CLL Research Consortium experience

This study revisited the Dohner prognostic hierarchy in a cohort of 1585 well‐documented patients with chronic lymphocytic leukaemia. The duration of both time to first treatment (TTFT) and overall survival (OS) were significantly longer than observed previously, and this is at least partly due to improved therapeutic options. Deletion 13q remains the most favourable prognostic group with median TTFT and OS from fluorescence in situ hybridization (FISH) testing of 72 months and >12 years, respectively. Deletion 11q had the poorest median TTFT (22 months) and 17p deletion the poorest median OS (5 years). The percentages of abnormal nuclei were significantly associated with differential TTFT for the trisomy 12, 13q and 17p deletion cohorts but not for the 11q deletion cohort. From the date of the first FISH study, patients with >85% 13q deletion nuclei had a notably shorter TTFT (24 months). Patients with ≤20% 17p deletion nuclei had longer median TTFT and OS from the date of the first FISH study (44 months and 11 years), and were more likely to be IGHV mutated.     

NOTCH1 mutations in CLL associated with trisomy 12

Two recent studies reported whole-genome sequencing of chronic lymphocytic leukemia (CLL) samples and found repeated mutations in the XPO1 and NOTCH1 genes. XPO1 was found mutated in 2.4% of cases, while NOTCH1 was found mutated in 12.2% or 15.1% of CLL samples. Here we report the results of sequencing of XPO1 and NOTCH1 in 186 CLL cases. Our results confirmed frequency of XPO1 mutations. However, we found only 5 NOTCH1 mutations in 127 IGVH unmutated/ZAP70(+) CLL samples (4%), and one mutation was found in IGVH mutated/ZAP70(-) CLL for a total percentage of 1.5%. Because 4 of 6 mutated samples also showed trisomy 12, we sequenced NOTCH1 in an additional 77 cases with trisomy 12 CLLs, including 47 IGVH unmutated/ZAP70(+) cases. Importantly, we found 41.9% NOTCH1 mutation frequency in aggressive trisomy 12 CLL cases. Our data suggest that activation of NOTCH1 plays a critical role in IGVH unmutated/ZAP70(+) trisomy 12 CLL.     

Use of IGHV3-21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post-germinal center leukemogenic selection

We examined the chronic lymphocytic leukemia (CLL) cells of 2457 patients evaluated by the CLL Research Consortium (CRC) and found that 63 (2.6%) expressed immunoglobulin (Ig) encoded by the Ig heavy-chain-variable-region gene (IGHV), IGHV3-21. We identified the amino acid sequence DANGMDV (motif-1) or DPSFYSSSWTLFDY (motif-2) in the Ig heavy-chain (IgH) third complementarity-determining region (HCDR3) of IgH, respectively, used by 25 or 3 cases. The IgH with HCDR3 motif-1 or motif-2, respectively, was paired with Ig light chains (IgL) encoded by IGLV3-21 or IGKV3-20, suggesting that these Ig had been selected for binding to conventional antigen(s). Cases that had HCDR3 motif-1 had a median time from diagnosis to initial therapy comparable with that of cases without a defined HCDR3 motif, as did cases that used mutated IGHV3-21 (n = 27) versus unmutated IGHV3-21 (n = 30). Of 7 examined cases that used Ig encoded by IGHV3-21/IGLV3-21, we found that 5 had a functionally rearranged IGKV allele that apparently had incurred antigendriven somatic mutations and subsequent rearrangement with KDE. This study reveals that CLL cells expressing IGHV3-21/IGLV3-21 most likely were derived from B cells that had experienced somatic mutation and germinal-center maturation in an apparent antigen-driven immune response before undergoing Ig-receptor editing and after germinal-center leukemogenic selection.      

Relationship between disease course in the temporomandibular joints and mandibular growth rotation in patients with juvenile idiopathic arthritis followed from childhood to adulthood

Objective  

To investigate the relationship between radiographic JIA disease course in the TMJs and mandibular growth rotation, compared with growth in healthy individuals.     

卟啉化合物的研究:取代四苯基卟啉与5-氟脲嘧啶共价相连化合物的合成及其抗癌活性

合成了3个取代四苯基卟啉与5-氟脲嘧啶以共价相连的化合物。通过用它们加光照对小鼠移植瘤生长的抑制作用、对小鼠癌细胞的杀伤效果及对小鼠耳指数的测定,初步结果显示,化合物1,2,3对癌细胞都有光敏毒杀效应,但1远较2和3显著。