On the Information Matrix of Exponential Mixture Models with Long-term Survivors

The aim of this paper is to study the properties of the asymptotic variances of the maximum likelihood estimators of the parameters of the exponential mixture model with long-term survivors for randomly censored data. In addition, we study the asymptotic relative efficiency of these estimators versus those which would be obtained with complete follow-up. It is shown that fixed censoring at time T produces higher precision as well as higher asymptotic relative efficiency than those obtainable under uniform and uniform-exponential censoring distributions over (0, T). The results are useful in planning the size and duration of survival experiments with long-term survivors under random censoring schemes.     

Potentiating effect of heparin in the activation of procollagenase by a low-Mr angiogenesis factor

A low-Mr freely dialysable endothelial cell-stimulating angiogenesis factor (ESAF) from conditioned medium of a mouse lymphoma cell line has previously been shown to activate latent skin fibroblast procollagenase. Activation comparable with the maximum that can be achieved with trypsin is obtained with chemically undetectable amounts of the factor. We now show that when even smaller amounts of ESAF are used heparin is able to potentiate its action in this system. The relationship between this activity and the mechanism of angiogenesis, which is itself potentiated by heparin, is discussed.     

Rapamycin can restore the negative regulatory function of transforming growth factor beta 1 in high grade lymphomas

TGF-β1 (transforming growth factor beta 1) is a negative regulator of lymphocytes, inhibiting proliferation and switching on the apoptotic program in normal lymphoid cells. Lymphoma cells often lose their sensitivity to proapoptotic/anti-proliferative regulators such as TGF-β1. Rapamycin can influence both mTOR (mammalian target of rapamycin) and TGF-β signaling, and through these pathways it is able to enhance TGF-β induced anti-proliferative and apoptotic responses. In the present work we investigated the effect of rapamycin and TGF-β1 combination on cell growth and on TGF-β and mTOR signalling events in lymphoma cells.Rapamycin, an inhibitor of mTORC1 (mTOR complex 1) did not elicit apoptosis in lymphoma cells; however, the combination of rapamycin with exogenous TGF-β1 induced apoptosis and restored TGF-β1 dependent apoptotic machinery in several lymphoma cell lines with reduced TGF-β sensitivity in vitro. In parallel, the phosphorylation of p70 ribosomal S6 kinase (p70S6K) and ribosomal S6 protein, targets of mTORC1, was completely eliminated. Knockdown of Smad signalling by Smad4 siRNA had no influence on apoptosis induced by the rapamycin + TGF-β1, suggesting that this effect is independent of Smad signalling. However, apoptosis induction was dependent on early protein phosphatase 2A (PP2A) activity, and in part on caspases. Rapamycin + TGF-β1 induced apoptosis was not completely eliminated by a caspase inhibitor.These results suggest that high mTOR activity contributes to TGF-β resistance and lowering mTORC1 kinase activity may provide a tool in high grade B-cell lymphoma therapy by restoring the sensitivity to normally available regulators such as TGF-β1.     

Evaluation of disparities in maintaining healthy lifestyle behaviors among female cancer survivors by race/ethnicity and US nativity

BackgroundThere are well-known racial/ethnic disparities in maintaining healthy lifestyle behaviors throughout cancer survivorship among US-born women. Less is known about these associations among women born outside the US, as these women may experience disparities in survivorship care due to the lack of access to culturally appropriate health services. We evaluated disparities in the associations between race/ethnicity and US nativity and the likelihood of meeting recommendations for maintaining a healthy lifestyle during cancer survivorship.Methods2044 female cancer survivors contributed data from the National Health and Nutrition Examination Survey (NHANES) (1999–2018). Adjusted odds ratios (aORs) and 95 % confidence intervals (CIs) were calculated with multivariable logistic regression models to measure the association between independent variables (race/ethnicity, US nativity, length of time in the US) and outcomes (obesity, meeting weekly physical activity (PA) recommendations, smoking history, alcoholic drinks/day) overall and by comorbidity.ResultsMost survivors were breast cancer survivors (27.6 %), non-Hispanic white (64.2 %), and US native (84.5 %). Compared to US native survivors, foreign-born survivors were less likely (aOR, 0.30, 95 % CI, 0.10–0.87) to not meet PA recommendations, while foreign-born survivors living in the US ≥ 15 years were 2.30 times more likely (95 % CI, 1.12–4.73) to not meet PA recommendations. Having at least one comorbidity modified (p-interaction< 0.05) the relationships between US nativity and length of time in the US.ConclusionOur findings provide new evidence for disparities in maintaining healthy lifestyle behaviors among female cancer survivors and can help inform lifestyle interventions for female cancer survivors from different racial/ethnic backgrounds.     

Expression of the MDR1 and MRP Genes in Patients with Lymphoma with Primary Bone Marrow Involvement

Expression of MDR1 and MRP genes in patients with low‐grade and high‐grade non‐Hodgkin's lymphomas with primary bone marrow involvement before and after chemotherapy was investigated. The data demonstrate that overexpression of MDR1 and MRP genes in hematological malignancies elevates in patients after chemotherapy and correlates with poor clinic prognosis and more frequent recurrences of the malignancies.     

Development of new Malt1 inhibitors and probes

Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (Malt1) is a promising therapeutic target for the treatment of activated B cell-like diffuse large B cell lymphoma (ABC-DLBCL). Several research groups have reported on the development of Malt1 inhibitors and activity-based probes for in vitro and in situ monitoring and modulating Malt1 activity. In this paper, we report on two activity-based Malt1 probes (6 and 7) and a focused library of 19 new Malt1 inhibitors. Our peptide-based probe 6 labels Malt1 in an activity-based manner. In contrast, probe 7, derived from the known covalent inhibitor MI-2, labels both wild type and catalytically inactive Cys to Ala mutant Malt1, suggesting that MI-2 inhibits Malt1 by reacting with a nucleophilic residue other than the active site cysteine. Furthermore, two of our inhibitors (9, apparent IC₅₀ 3.0 μM, and 13, apparent IC₅₀ 2.1 μM) show good inhibitory activity against Malt1 and outperform MI-2 (apparent IC₅₀ 7.8 μM) in our competitive activity-based protein profiling assay.     

Differential seminal plasma proteome signatures of acute lymphoblastic leukemia survivors

With advances in therapeutic methods, there is a high survival rate among leukemia patients, of an extent more than 80%. However, chemotherapeutic drugs used to treat these patients have adverse effects on their overall health profile including fertility. The primary aim of this study was to identify differentially expressed proteins in seminal plasma of acute lymphoblastic leukemia (ALL) survivors compared to age-matched healthy controls, which can provide molecular basis of idiopathic infertility in such survivors. Differential proteome profiling was performed by 2D–differential in-gel electrophoresis, protein spots were identified by mass spectrometry and selective differentially expressed proteins (DEPs) were validated by western blotting and ELISA method. Out of eight DEPs identified, five proteins (isocitrate dehydrogenase 1, semenogelin 1, lactoferrin, prolactin-inducible protein, and human serum albumin) were upregulated and three (pepsinogen, prostate specific antigen and prostatic acid phosphatase) were downregulated. Expression profiles of these proteins are suggestive of reduction in semen quality in ALL survivors and can further be explored to determine their fertility status.     

Identification of amino acid residues critical for the B cell growth-promoting activity of HIV-1 matrix protein p17 variants

Background

HIV-1 matrix protein p17 variants (vp17s) detected in HIV-1-infected patients with non-Hodgkin's lymphoma (HIV-NHL) display, differently from the wild-type protein (refp17), B cell growth-promoting activity. Biophysical analysis revealed that vp17s are destabilized as compared to refp17, motivating us to explore structure-function relationships.

Activatory and Inhibitory Fcγ Receptors Augment Rituximab-mediated Internalization of CD20 Independent of Signaling via the Cytoplasmic Domain

Type I anti-CD20 mAb such as rituximab and ofatumumab engage with the inhibitory FcγR, FcγRIIb on the surface of B cells, resulting in immunoreceptor tyrosine-based inhibitory motif (ITIM) phosphorylation. Internalization of the CD20·mAb·FcγRIIb complex follows, the rate of which correlates with FcγRIIb expression. In contrast, although type II anti-CD20 mAb such as tositumomab and obinutuzumab also interact with and activate FcγRIIb, this interaction fails to augment the rate of CD20·mAb internalization, raising the question of whether ITIM phosphorylation plays any role in this process. We have assessed the molecular requirements for the internalization process and demonstrate that in contrast to internalization of IgG immune complexes, FcγRIIb-augmented internalization of rituximab-ligated CD20 occurs independently of the FcγRIIb ITIM, indicating that signaling downstream of FcγRIIb is not required. In transfected cells, activatory FcγRI, FcγRIIa, and FcγRIIIa augmented internalization of rituximab-ligated CD20 in a similar manner. However, FcγRIIa mediated a slower rate of internalization than cells expressing equivalent levels of the highly homologous FcγRIIb. The difference was maintained in cells expressing FcγRIIa and FcγRIIb lacking cytoplasmic domains and in which the transmembrane domains had been exchanged. This difference may be due to increased degradation of FcγRIIa, which traffics to lysosomes independently of rituximab. We conclude that the cytoplasmic domain of FcγR is not required for promoting internalization of rituximab-ligated CD20. Instead, we propose that FcγR provides a structural role in augmenting endocytosis that differs from that employed during the endocytosis of immune complexes.     

肺淋巴瘤的CT表现

目的：肺部淋巴瘤可为原发,亦可为其他部位淋巴瘤的肺部浸润,临床上很少见。准确的影像学诊断对于采取及时的治疗措施具有重要意义,然而该病影像学表现复杂多变,容易与多种其他肺部病变混淆,以往文献对于肺部淋巴瘤的CT影像特征性表现报道不多,本文旨在探讨肺部淋巴瘤的特征性CT表现,以提高该痛影像诊断的准确率。方法：回顾性分析17例病理证实的肺淋巴瘤患者CT资料,分析特征性影像表现。结果：17例中多发者13例,单发者4例。叶段性或斑片状实变影13例,多发结节影13例,肿块状实变影8例,具有两种以上病灶的12例。特征性的征象有：病灶密度均匀（88．2％,15／17）、病灶边缘模糊（82．3％,14／17）、支气管气相（64．7％,11／17）、支气管血管柬增厚（58．8％,10／17）和CT血管造影征（41．2％,7／17）,对诊断有较大意义。结论：肺部淋巴瘤CT表现以多发、多形态病变居多,具有一定特征性影像表现,密度均匀、边缘模糊的实变、团块或结节影,具有支气管气相、支气管血管束增厚、增强扫描可见CT血管造影征等表现可高度提示本病的可能,结合病史、临床表现以及实验室检查,可提高本病的诊断准确率,对于及时开展有效的治疗措施、改善患者预后具有重要的临床意义。