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1
Ho, Gwendolyn, Ted Wun, Qian Li, Ann M. Brunson, Aaron S. Rosenberg, Brian Jonas, and Theresa Keegan. "Decreased Early Mortality Associated with Treatment of Acute Myeloid Leukemia (AML) at NCI-Designated Cancer Centers in California." Blood 128, no. 22 (December 2, 2016): 391. http://dx.doi.org/10.1182/blood.v128.22.391.391.
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Abstract Background Patients with solid tumors treated at a National Cancer Institute designated cancer center (NCI-CC) have been found to have improved survival when compared to those treated elsewhere. Few population-based studies have evaluated the association between location of care, complications associated with intensive therapy and early mortality (defined here as death ² 60 days from diagnosis) in patients with AML. Methods Using linked data from the California Cancer Registry and Patient Discharge Dataset from 1999 to 2012, we identified patients ³15 years of age diagnosed with AML who received inpatient treatment. Hospitals where patients received their care were classified as either NCI-CC or non-NCI designated facilities (non-NCI-CC). Logistic regression was used to estimate associations between patient characteristics (age, sex, race/ethnicity, year of diagnosis, marital status, neighborhood socioeconomic status, health insurance, and medical comorbidities) and location of care (NCI-CC vs non-NCI-CC facilities), and then to build a propensity score. Inverse probability weighted logistic regression models were used to determine associations between location of care and complications with early mortality. Interactions of complications and location of care with early mortality were also considered. Results are presented as adjusted odds ratios (OR) and 95% confidence intervals (CI). Results Of the 5613 patients with AML identified, 1406 (25%) were treated at an NCI-CC. Compared to patients treated elsewhere, AML patients treated at an NCI-CC were more likely to be <65 years of age, Hispanic (versus non-Hispanic white), live in higher socioeconomic status neighborhoods, have fewer comorbidities and have Medicare or public (versus private) health insurance. Patients treated at NCI-CCs had higher rates of renal failure (21% vs 18%, P=0.03) and lower rates of respiratory failure (11% vs 14%, P=0.002) and sepsis (33% vs 36%, P=0.04) than those treated at non-NCI-CCs. Rates of bleeding, thrombosis, liver failure and cardiac arrest did not differ by location of care. After propensity-score weighting, baseline characteristics were balanced between patients treated at NCI-CCs versus non-NCI-CCs (all standardized mean differences <2.3%). In multivariable, inverse probability weighted models, treatment at an NCI-CC (versus non-NCI-CC) was associated with lower early mortality (OR 0.50, CI 0.42-0.59) (Table). Complications associated with higher early mortality, regardless of treatment location, included: bleeding (OR 1.91, CI 1.54-2.37), liver (OR 3.41, CI 1.91-6.09), renal (OR 2.39, CI 1.97-2.90) and respiratory (OR 6.08, CI 4.88-7.57) failure and cardiac arrest (OR 15.28, CI 8.11-27.78) (Table). The impact of complications on early mortality did not differ by location of care with the exception of respiratory failure (P for interaction=0.001); AML patients with respiratory failure had a higher odds of early mortality when treated at non-NCI-CCs (OR 8.59, CI 6.66-11.07) versus NCI-CCs (OR 4.43, CI 2.68-7.33). Other factors significantly associated with early mortality included younger age, treatment after 2002, non-Hispanic White race/ethnicity (versus African Americans, Hispanics and Asians), single marital status (versus married), residence in low socioeconomic status neighborhoods (versus high) and presence of any comorbidities (versus none). Conclusions In patients with AML, initial treatment at a NCI-CC is associated with 50% reduction in early mortality than treatment at a non-NCI-CC, adjusted for baseline socio-demographic variables, comorbidities and complications within 60 days. Lower early mortality may result from differences in supportive care practices, hospital or provider experience and access to clinical trials at NCI-CCs. Future studies should evaluate the specific differences in care at NCI-CCs to inform strategies to improve early mortality outcomes for all AML patients. Table. Table. Disclosures No relevant conflicts of interest to declare.
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Atrash, Shebli, Qing Zhang, Xenofon Papanikolaou, Christoph Heuck, Aziz Bakhous, Jameel Muzaffar, Al-Ola Abdallah, and Bart Barlogie. "Characteristics and Prognosis Of IgM Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 1881. http://dx.doi.org/10.1182/blood.v122.21.1881.1881.
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Abstract Introduction Multiple Myeloma (MM) is considered a malignancy of post germinal center long-lived plasma cells. Nevertheless T-cell independent antigen stimulation before the exposure of the B-cell to the germinal center can happen and results to IgM secreting short lived plasma cells and lymphoplasmacytes representing thus a potential alternative normal counterpart for IgM plasma cell dyscrasias. IgM myeloma is an infrequent subtytpe of MM with an estimated prevalence of 0.5%. Due to its rarity little is known about its characteristics and prognosis in comparison with Waldestrom’s macroglobulinemia (WM) and the other MM subtypes. Purpose To identify the characteristics and the prognosis of IgM MM, and compare it predominantly with WM and subsequently with the rest of the MM subtypes. Methods We interogatted our Multiple Myeloma Data Base for cases of IgM MM and their respective Overall Survival (OS), Progression Free Survival (PFS), bone disease as defined by x-Rays, PET-CT and MRI, Gene Expression Profile (GEP), and common disease characteristics (anemia,calcium, creatinine) and compare it to the prognosis of WM and non-IgM MM. Diagnosis was based on the morphological and immunophenotypical findings of pathologically examined biopsy specimens along with the presence or not of typical clinical characteristics of MM (lytic bone lesions, hypercalcemia, renal failure) or typical clinical characteristics of WM (organomegaly, lymphadenopathy). Results There were 22 confirmed IgM MM cases. 14 of them presented at MIRT at initial diagnosis while 8 had previously been treated elsewhere. Osteolytic bone lesions and/or pathological fractures by x-ray and CT examination were evident in 16 cases. For the remaining 6 cases active bone focal lesions by either MRI or PET were identified in three. There was no organomegaly evident in cases with an available PET/CT at baseline, while only one had evidence of hilar and mediastinal lymphadenopathy along with calcified lung nodules. Elevated creatinine levels (>2.0 mg/dl) were evident in 4 cases at initial diagnosis. Their disease characteristics are depicted in the table 1. Median OS for IgM MM was 4.9 years while PFS could not be accurately estimated due to lack of data on patients treated elsewhere. Median OS for a historical control of 158 WM cases in MIRT was 9.2 years (Clin Lymphoma Myeloma Leuk. 11(1):139-42). Median OS of the WM group remained largely unaffected, even when the subgroup of the WM cases requiring treatment was analyzed (9.0 years).To further clarify if the IgM MM differs in terms of OS from the other isotypes of MM, we compared the IgM group to a group of 61 non-IgM MM cases which were matched by important prognostic clinical factors (age, creatinine> 2mg/dl, LDH>190u/L, b-2M >5.5mg/dl and Albumin<3.5gr/dl). No statistical difference was found for OS (p=0.846). Out of 22 cases, 14 of them had available GEP data on initial diagnosis. In 6 of these cases the cyclin D1 gene expression was high enough to be consistent with a t(11;14) translocation at FISH analysis, one case was consistent with a t(14;16) translocation, one with a t(4;14) translocation and two more were classified as belonging to the hyperdiploid subgroup. A comparative genomic analysis was performed on the IgM MM, the non-IgM MM and WM cases with available GEP data at initial diagnosis (14, 61 and 42 cases respectively). 1155 probesets that had expression level significantly different between WM and non IgM MM (FDR<3E-06) were identified. Then, the expression values of these 1155 probesets in all GEP samples, including WM, non IgM MM, and IgM MM, were used to build a clustering tree. We found that IgM MM mainly clustered with non IgM MM, supporting the findings of the clinical data. Conclusion IgM MM is a discrete clinical entity that should be distinguished from WM. Bone disease is evident in the majority of the cases, especially when specialized radiological techniques are incorporated at the initial work up. It holds a distinct prognosis from WM, while when balanced for prognostic factors that hold importance in MM it does not differ from the other MM isotypes. Finally analysis of the genetic data further supports the resemblance between IgM MM and the non IgM MM, and the difference with WM. Disclosures: Zhang: University of Arkansas for Medical Sciences: Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations, Co-inventor of the DNA probes for FISH of IGHC/IGHV (14q32), MMSET/FGFR3 (4p16), CCND3 (6p21), CCND1 (11q13), MAF (16q23), and MAFB (20q12) loci, sub. to the US Patent & Trademark Office as Prov. App# 61/726,327: Methods of Detecting 14q32 Translocations Patents & Royalties.
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Gallamini, Andrea, Alessandro Rambaldi, Alberto Biggi, Silvia Tavera, Caterina Patti, Caterina Stelitano, Alessandro M. Gianni, et al. "BEACOPP Chemotherapy Is Able to Induce Durable Complete Remission in Poor-Prognosis Hodgkin’s Lymphoma Patients with a Positive Interim PET after 2 ABVD Cycles." Blood 112, no. 11 (November 16, 2008): 2594. http://dx.doi.org/10.1182/blood.v112.11.2594.2594.
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Abstract Background: Early interim-PET (PET-2) is the most powerful factor able to predict treatment outcome in advanced-stage Hodgkin Lymphoma (HL) patients treated with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). The 2-y PFS of PET-2 positive patients is only 12%, but the optimal treatment for this patient subset is still unknown. For this reason in January 2006 a treatment policy was designed by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) to early intensify chemotherapy with BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) for HL patients with a PET-2 positive after 2 ABVD cycles. Patients and methods: 136 HL patients with advanced-stage or intermediate-stage with adverse prognostic factors (more than 3 nodal sites, ESR > 50 mm, sub diaphragmatic presentation, bulky lesion), consecutively admitted to nine GITIL Italian centers were treated with two ABVD courses and re-evaluated with interim-PET. Twenty-one of these 136 patients proved to be PET-2 positive, and 19/21 are the object of this analysis. The mean age was 31.7 years (16–64), 10 patients were in stage II, 9 in stage III–IV. Bulky disease was present in 11, and B-symptoms in 16. Fourteen patients showed an IPS score 0–2, 5 patients a score 3–7. The median interval between the end of second ABVD course and PET-2 was 11 days (5–14). BEACOPP (4 escalated and 4 standard cycles) was followed by consolidation radiotherapy in 3 patients for bulky mediastinal tumor. PET scan were centrally reviewed by two well-experienced nuclear medicine experts, using the blood pool mediastinal structures (BPMS) as reference for the residual uptake, as elsewhere published (Gallamini, JCO 2007). Results. Upon central review, 2 interim-PET scan were classified as minimally positive in 2 patients, with a single MRU (Minimal Residual Uptake) lesion showing a SUV (Standardized Uptake Value) lower than BPMS, and therefore only 19 cases were suitable for the BEACOPP salvage treatment. After a mean follow-up of 14.3 months (7.0–30.2), 15 patients remain in continuous CR and 4 had a treatment failure because of disease relapse (1) or progression (3). For the responding patients the mean duration of CR was 13.0 months (6.5–30.2). The IPS score for progressing patients was 2, 3, and 4; for the relapsing-one, 0. At time of this analysis, l8 patients are still alive and 1 died during BEACOPP treatment for disease progression. The 1-year second treatment failure-free survival (1-y 2TFFS) was 94.7 % (95% C.I. 84.7–100). The 1 y OS survival was 93.3 (95%C.I. 80.7–100). In univariate analysis the only clinical factor related to treatment failure was the presence of extra-nodal disease. (Log-rank=6.8 p=0.009). Conclusions. BEACOPP-escalated regimen was able to induce durable CR in most (15/19) HL patients with a positive interim-PET. These results, although requiring a longer follow-up and a higher number of patients, seem to suggest that the very-poor prognosis of PET-2 positive, ABVD-treated HL patients can be substantially improved by early chemotherapy intensification; escalated-BEACOPP is likely to represent a good treatment choice for this very poor prognosis patient subset.
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Rotulo, Gioacchino Andrea, Blandine Beaupain, and Jean Donadieu. "ELANE Neutropenia Beyond the Classification into Cyclic Neutropenia and Severe Congenital Neutropenia: The Inconstant Time Clock." Blood 138, Supplement 1 (November 5, 2021): 986. http://dx.doi.org/10.1182/blood-2021-149759.
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Abstract Introduction: ELANE neutropenia represents the cause of 25-30% of the cases of congenital neutropenia. Classically, its appears in the literature as in OMIM, under two distinct entities: Severe congenital neutropenia (SCN) and cyclic neutropenia (CyN). The delineation between the 2 entities is the "cyclicity" i.e. the periodic variation of the absolute neutrophils count (ANC), also called a 21-day time clock 1. However, it is extremely difficult to obtain enough sequential complete blood counts (CBC) at the onset of the disease, during an enough length period, while the patient is not experiencing a severe infection or receiving GCSF therapy. The purpose of our study is to analyze the ANC periodicity at the onset of the disease, prior to the initiation of GCSF in a cohort of patients with ELANE neutropenia. Methods : Available data from the patients, with ELANE class 4 and 5 variants, enrolled in the French Severe Chronic Neutropenia Registry, were analysed. The final diagnostic of CyN and SCN was performed considering all the follow up period (median 16.7 years) and based on the presence of recurrent periodic variation of ANC in the absence of GCSF therapy. CyN was defined as multiple documented ANCs >500 cells/mm 3 , with intermittent ANC variation (n=49), while SCN is defined as ANC persistently <500 cells/mm 3 (n=94). In case of irregularity (i.e. not a regular periodic pattern during all the follow up), the classification takes in consideration the majority of the follow up. A comprehensive analysis of the infectious profile is available elsewhere 2. We were focused here on the diagnostic period (roughly the 2 first months since the diagnosis). We have analysed the initial blood count of the patients and cast the patients by categories if at least 4 ANCs can be evaluated. ANC oscillations defined 4 groups: Group 1: oscillation of ANC values above and below 500 ANC/mm 3 for at least 2 cycles lead to consider the patient as Cyclic; Group 2: clear oscillation of ANC values above and below 200 ANC/mm 3 (but ever<500 ANC/mm 3) for at least 2 cycles; Group 3: no oscillation of ANC values whose level are ever below 500 ANC/mm 3; Group 4: Early GCSF treatment. Results : Among the 143 patients enrolled in this study (Table 1), 137 have at least 4 CBC evaluable during the diagnosis period, including 30 who have been treated almost front line after diagnosis of neutropenia by GCSF hampering evaluation of periodicity. Such patients were all initially considered as SCN. Among the 67 finally classified as SCN, 28 (27.38%) showed an oscillation pattern (group 1), 14 (15.48%) showed minor oscillations (group 2), while 25 (30.95%) had a persistent and severe neutropenia (group 3). Among the 40 CyN, 1 have showed minor oscillations (group 2) below 500/mm 3, while 3 had a persistent and severe neutropenia (group 3). Globally, 32 /107 patients were miss- classified at diagnosis compare to the final diagnosis. Additional data shows that many health indicators could not be deducted from the initial classification like the infections rate, the use of GCSF, the death rate, the sequels rate. Conclusions: Periodic variation of ANC despite being the criteria to define the sub type of ELANE neutropenia is difficult to evaluate at the initial presentation of the disease. In addition, cyclicity is not a permanent feature in ELANE neutropenia, some patients being cyclic only for a certain time in their life span. It results a high rate of miss classification if we compare the initial diagnostic period and all the medical history of the patients. Noteworthy, the rate of several severe complications is not so clearly different between diagnosis sub categories. We propose to consider ELANE neutropenia as a unique disease characterized by a clinical spectrum ranging from more severe forms (corresponding to SCN) to milder forms, the latter often characterized at onset by ANC fluctuations. In addition, some intermediate severity forms could be characterized by minor oscillations. References 1 Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat.Genet. 1999;23:433-436. 2 Rotulo GA, Plat G, Beaupain B et al. Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE-related neutropenia: a French Severe Chronic Neutropenia Registry study. Br J Haematol. 2021 doi: 10.1111/bjh.17695 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Masarova, Lucia, Prithviraj Bose, Naveen Pemmaraju, Zeev E. Estrov, Lingsha Zhou, Sherry A. Pierce, Jorge E. Cortes, Hagop M. Kantarjian, and Srdan Verstovsek. "Evaluation of Cytogenetic Stratifications in Myelofibrosis." Blood 132, Supplement 1 (November 29, 2018): 1763. http://dx.doi.org/10.1182/blood-2018-99-120225.
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Abstract Introduction: The revised cytogenetic risk stratification of patients with primary myelofibrosis (PMF) divided patients into 3 prognostic categories, with additional new category of very high risk patients (VHR). This score should enhance traditional classification incorporated in the Dynamic International Prognostic Scoring System-Plus (DIPPS-Plus). Objective: To evaluate the prognostic utility of cytogenetic stratifications (DIPSS-Plus and the revised cytogenetic model) in patients with PMF referred to our institution between 1984 and 2016. Methods: We retrospectively reviewed the charts of 883 patients with PMF with available cytogenetic analysis at the time of referral to our institution (> 10 metaphases). Cytogenetic was reported according to the International System for Human Cytogenetic Nomenclature. Patients were classified into cytogenetic risks based on DIPSS-Plus (Gangat, JCO, 2011), and the revised cytogenetic model (Tefferi, Leukemia, 2017). Overall survival (OS) was estimated using the Kaplan-Meier method, and groups were compared by the log rank test. Impact of cytogenetic abnormalities on OS was also evaluated by comparing them against patients with diploid karyotype using stepwise Cox regression. Results: Median age was 66 years (range, 27-88), and 64% of patients were male. The distribution of DIPSS scores was as follows: 8% low, 48% intermediate 1, 44% intermediate 2 and 14% high. OS in each DIPSS category was 53, 46, 26, 15 months (p<0.001). The JAK2, MPL and CALR mutation was present in 55% (n=486), 6% (n=50), and 7% (n=64). Overall, 563 (64%) patients had diploid karyotype. The most frequent abnormal karyotypes were single 20q- (n=68, 8%), single 13q- (n=40, 4.5%), and ≥3 abnormalities (Abn; complex karyotype, CK, n=52, 6%). Among patients with CK, 27 (52%) pts had VHR Abn. After a median follow-up of 22.4 months (range, 0.5-251); 708 (80%) of patients died. Eighty five patients (10%) developed acute leukemia, 39% of these patients had CK. According to DIPSS-plus, patients were stratified into favorable (FAV, n=758, 86%) and unfavorable (UNF, n=126, 14%) category with distinct median OS of 35 months (range, 31-39), and 17 months (range, 11.6-22), p < 0.001 (HR 1.37, [95% CI 1.11-1.7]). Three year OS was 49% and 32%, respectively (Figure 1a). The revised cytogenetic stratification classified patients into favorable (n=687, 78%), unfavorable (n=151, 17%), and VHR (n=47, 5%) with respective OS of 35, 32 and 10 months (overall p<0.001, FAV vs UNF p= 0.8; Figure 1b); similar between patients in favorable and unfavorable groups. Three year OS for each group was 49%, 46% and 12%, respectively. OS of patients with individual cytogenetics (as used in the revised classification) is depicted in Table. Patients with single deletion 13q have significantly inferior OS than the remaining patients in FAV group. Patients with sole abnormality of chromosome 1 and trisomy 9 had the longest OS within the FAV group, but without reaching a statistical significance. Similarly, patients with sole trisomy 8, sole deletion 7q/5q, and other sole Abn not included elsewhere, had inferior OS when compared to the remaining patients in UNF group (Table 1). After re-grouping patients with different OS from FAV and UNF groups, we have noticed an intermediate group of patients containing the above mentioned Abn with distinctly different OS from FAV and UNF group of 24 months (range, 14.5-33; Figure 1c). Conclusions: Results from our cohort of 883 PMF patients did not confirm better discriminatory power of revised cytogenetic stratification model when compared to the DIPSS-Plus, as it failed to differentiate different OS between favorable and unfavorable groups. In our cohort, patients with single deletion 13q, single trisomy 8, and abnormalities of 5q/7q have superior OS to very high risk patients, but inferior to all remaining patients. Because the revised cytogenetic stratification has been already incorporated into newer complex molecular prognostic models of patients with PMF (MIPSSversion2.0, GIPSS), its further validation is warranted. Table Abbr.: Chr, chromosome, del, deletion, DUP, duplication, transl, translocation, excl, excluding; ¥OTHER solo: INV(9) in [3], Abn chr. 11, 12, 16, 17, 18 (mostly deletion of p/q arms, or addition) [7]; VHR = very high risk (-7; inv(3)/3q21; i(17q); 12p-/12p11.2; 11q-/11q23; autosomal trisomies excl. +8/+9). Disclosures Bose: Incyte Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding. Pemmaraju:plexxikon: Research Funding; cellectis: Research Funding; Affymetrix: Research Funding; daiichi sankyo: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; SagerStrong Foundation: Research Funding. Cortes:novartis: Research Funding. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Italfarmaco: Membership on an entity's Board of Directors or advisory committees.
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Nakano, Nobuaki, Hiroo Katsuya, Takahiro Itoyama, Mototsugu Shimokawa, Atae Utsunomiya, Shuichi Hanada, Tetsuya Eto, et al. "Impact of Chromosomal Abnormalities in Acute and Lymphoma Types Adult T-Cell Leukemia-Lymphoma." Blood 128, no. 22 (December 2, 2016): 4123. http://dx.doi.org/10.1182/blood.v128.22.4123.4123.
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Abstract Background: Adult T-cell leukemia-lymphoma (ATL), which is a hematological malignancy related to human T-lymphotropic virus type I (HTLV-1), is known as a malignant lymphoid disease with poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a treatment modality to contribute prolonging the survival in some population of patients (Katsuya H et al. 2015 Blood). A small study indicated that ATL cells frequently have chromosomal abnormalities including various numerical aberrations and complex structural abnormalities (Kamada N et al. Cancer Res. 1992). However, there has been no large study to examine the relationship between chromosomal abnormalities and survival. Here we report the impact of chromosomal abnormalities on survival in ATL patients with conventional chemotherapy. Patients and Methods: In this study, we extracted a population of patients from the database of ATL-PI project, which is a nation-wide survey of ATL patients newly diagnosed between January 2000 and May 2009, and the overall results were reported elsewhere (Katsuya H et al. JCO 2012, Blood 2015). Fifteen hundred and twelve patients were registered in this project, and we excluded the patients who received allo-HSCT, and who were diagnosed with smoldering and chronic type ATL. Moreover, patients whose chromosomal analysis with G-banding stain showed normal, multiploid or no mitosis, or no information on chromosomal analysis and on the factors to determine the ATL-PI were also excluded. As a consequence, 210 patients with acute (n=157) and lymphoma (n=53) types were selected for this analysis. Abnormal karyotypes were analyzed from the aspect of numerical and structural break points. To identify the specific abnormalities and to avoid the secondary changes, the stem-line karyotype, which meant the simplest abnormal clone, was used as the representative karyotype for this study. A statistical analysis was performed with 'EZR' (Kanda T. BMT 2013). We examined an overall survival (OS) in relation to chromosomal abnormalities using cox proportional hazard regression model, and p-value of less than 0.05 was considered as statistically significant. Results: Among the 210 patients, 119 and 91 patients were male and female, respectively. The median age of patients was 66 years (40-89). With respect to other factors of ATL-PI, the median level of soluble interleukin-2 receptor (sIL-2R), serum albumin, were 30800 U/mL (620-1,219,000), 3.6 g/dL (1.6-5.3), respectively. Almost all patients were diagnosed with stage II-IV of clinical stage (n=200), and almost half of patients certified 2-4 of ECOG-PS (n=113). Sixty-nine, 106, and 35 patients were classified as high, intermediate and low risk by ATL-PI, respectively. Specimens used for chromosomal analysis were taken from lymph nodes (n=77), bone marrow (n=72), peripheral blood (n=50), pleural fluids (n=4), ascites (n=4) and 1 each of stomach, sinusoidal tumor, and tonsillar lesions. The median number of numerical abnormalities and marker chromosomes were 2 (0-20) and 1 (0-20), and the median number of structural break points was 6 (0-21). The numerical abnormalities were loss of sex chromosomes (31%) followed in decreasing order by -14 (24%), -13 (19%), -9 (12%) and -17 (12%) while the structural break points were located at 1p (30%), 3q (30%), 14q (30%), 6q (26%) and 1q (22%). The median OS was 286 days (1-2565). ECOG-PS, serum albumin level, sIL-2R, and structural break points at 9q or 19p, and the number of structural break points over 4 or 5 points were shown to be the significant factors affecting the survival by univariate analysis. Then, the multivariate analysis indicated that 2-4 of ECOG-PS (HR: 2.021, 95%CI: 1.436-2.791, p<0.001), serum albumin level < 3.5 g/dl (HR: 1.631, 95%CI: 1.282-2.074, P<0.001), and chromosomally structural break points at 9q (HR: 1.584, 95%CI: 1.096-2.289, p<0.001) and 19p (HR: 1.765, 95%CI: 1.038-2.999, p<0.001) were factors that negatively contributed to OS. Discussions and Conclusion: This is the first large study showing the impact of chromosomal abnormality in acute and lymphoma types ATL on OS. It demonstrated that structural break points at 9q and 19p were the independent risk factors for OS in addition to those of ATL-PI. Disclosures Katsuya: The Uehara Memorial Foundation: Research Funding. Utsunomiya:Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Suzumiya:Takeda: Honoraria; Astellas: Research Funding; Kyowa Hakko kirin: Research Funding; Chugai: Honoraria, Research Funding; Toyama Chemical: Research Funding; Eisai: Honoraria, Research Funding.
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Tomlins, Jo, Nick Telford, Mike Dennis, Tim Somervaille, Adrian Bloor, Jim Cavet, Mike Green, Sven Armin Sommerfeld, John Murray, and Samar Kulkarni. "Population Based Study of Cytogenetic Abnormalities in Addition to Philadelphia (Ph) Chromosome in Patients with Chronic Myeloid Leukaemia (CML) and Impact on Survival." Blood 124, no. 21 (December 6, 2014): 4567. http://dx.doi.org/10.1182/blood.v124.21.4567.4567.
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Abstract Ph chromosome is the hallmark of CML. However there are few reports of additional chromosomal abnormalities at the time of diagnosis and the impact this has on overall survival (OS). [NT1] The Cytogenetic laboratory at this hospital provides a regional service as a single facility. The data from this laboratory was combined with survival information to evaluate the impact of additional chromosomal changes on outcomes in patients with CML. Methods: This is a retrospective population based study, it was not possible to obtain consent from individual patients and details about haematological parameters or treatments delivered were not available. The aim was to evaluate if cytogenetic changes should be considered in addition to established risk scoring systems. Patients were classified as complex-Philadelphia (Ph) if they had t(9;22)(q31;q34) with additional chromosomal abnormalities. Impact of individual additional abnormalities was analysed and then the effect was stratified according to presence of chromosomal gains, deletions or translocations. Few cases who had normal cytogenetics on their first sample as they were initially treated elsewhere. Results: 1129 patients were diagnosed with CML between 1985 and 2013, with 4760 samples analysed. The median age of the patient was 52.4 years (4.3-103, 602 male; 511 female; 16 unknown). Median follow up was 6.4 years [0-26.8 years, 725/1129 (64.2%) had follow-up more than 10 years]. End point for analysis was probability of survival at 10yr. 194/1129 (17.2%) had complex-Ph at diagnosis, 759/1129 (67.2%) had standard Ph, 77/1129 (6.8%) had negative cytogenetics and in 34/1129 (3%) cytogenetic analysis failed at diagnosis. Patients with standard Ph translocation had significantly better chance of achieving cytogenetic CR than those with complex-Ph (23.4% vs. 13.4%, p<0.001). OS was significantly better in patients below the age of 45 (65% vs 25% p <0.0001). OS was also better in patients diagnosed after 2000 (67 % vs 40 %, p<0.0001). In univariate analysis OS was significantly lower with trisomy 8 (10% vs 50%, p<0.0001), del(5q) [NT2] (20% vs 50%, p=0.001), other deletions (12% vs 48%, p=0.0005), del 17( 48% vs. 0%, p<0.0001), add 21 (50% vs. 0%, p<0.0001), any translocations (50% vs. 22%, p<0.0001), der 22 or iso 17 (48% vs. 10%, p<0.0001), any deletions (50% vs. 20%, p<0.0001) and variant Ph translocations (50% vs 22%, p=0.004). In multivariate analysis, excluding year of diagnosis, age group (HR 1.93, 95% CI:1.6-2.4 P=<0.0001), complex t(9;22;v) (HR 1.8, 95% CI:1.0-3.1, P=0.035), del(17q) (HR 3.8, 95% CI:1.1-12.6, P=0.033), translocations (HR:1.6, 95% CI: 1.1-2.25, p=0.013), trisomy 8 (HR: 1.76, 95% CI: 1.19-2.65, p=0.005), add 21 (HR: 3.21, 95% CI: 1.65-6.25, p=0.001) and der 22 or iso17 (HR: 1.57, 95% CI: 1.1-2.25, p=0.013) were independently associated with inferior OS. Number of risk factors in individual patients was used to design a scoring system. Patients with 0 risk factor (70% OS at 10 yr.), 1 risk factor (40% OS at 10 years), 2 risk factors (22% OS at 10 years) or more than 3 risk factors (12% OS at 10 years) had incrementally reduced OS. This was true of patients diagnosed before and after 2000. This analysis suggests that incorporating nature of karyotype at diagnosis can refine established scoring systems. However this data needs to be analysed with larger patient population to include all established risk factors and the effect of therapeutic measures. Disclosures Cavet: Novartis: Research Funding; BMS: Research Funding.
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Woyach, Jennifer A., Daphne Guinn, Amy S. Ruppert, James S. Blachly, Arletta Lozanski, Nyla A. Heerema, Weiqiang Zhao, et al. "the Development and Expansion of Resistant Subclones Precedes Relapse during Ibrutinib Therapy in Patients with CLL." Blood 128, no. 22 (December 2, 2016): 55. http://dx.doi.org/10.1182/blood.v128.22.55.55.
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Abstract The Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib is very effective in chronic lymphocytic leukemia (CLL). Resistance in CLL is at least in part mediated by acquired mutations in BTK or down-stream PLCG2. Here we describe the largest institutional cohort of CLL patients treated with ibrutinib, focusing on risk factors for relapse, prevalence of known resistance mutations, and development of a monitoring strategy to identify patients at risk for relapse. All 308 patients from The Ohio State University Comprehensive Cancer Center participating in 4 clinical trials of ibrutinib were included. Deep sequencing for BTK and PLCG2 was performed using Ion Torrent Personal Genome Machine and covered coding regions of both genes. Preclinical experiments used XLA cell lines (Coriell Institute) infected with lentiviral constructs containing empty vector, wild type BTK, or C481S BTK. With a median follow-up of 40.5 months (range 4-71 months), 136 patients remain on study, 14 have received transplant or therapy elsewhere, and 158 have discontinued. 83 patients experienced disease progression, classified as Richter's or PLL transformation (n=28) and progressive CLL (n=55). Using multivariable models, baseline risk factors for ibrutinib discontinuation due to transformation include complex karyotype (p<0.01) and MYC abnormalities on FISH (p=0.051). Age<65, del(17p) by FISH, and complex karyotype all associated with discontinuation due to CLL progression (p<0.05). Relapse generally has a poor prognosis, with a median survival from ibrutinib discontinuation for patients with transformation and progressive CLL of 3.9 (95% CI 2.0 to 10.1) and 22.7 (95% CI 13.5 to not reached) months, respectively. 46 patients with progressive CLL had samples at relapse available for deep sequencing. Of these, 39 had mutations in BTK and/or PLCG2 (84.8%; 95% CI 71.1-93.7). Distribution of mutation included patients with BTK C481 mutation only (n=30), mutation in PLCG2 only (n=3) and both BTK/PLCG2 genes (n=6). Given the poor prognosis at relapse and presence of acquired mutations in the majority of progressive CLL patients, we were interested to evaluate whether the emergence of small clones of mutated cells could be used as a biomarker to predict relapse. For 15 patients with BTK or PLCG2 mutations, serial samples were available prior to relapse, and a clone of resistant cells could first be detected a median of 9.3 months prior to clinical relapse (95% CI: 7.6-11.7). Based on the finding that patients who relapsed on ibrutinib often had rapid progression and poor outcomes, we initiated a clinical-grade monitoring strategy in our institutional CLIA-certified molecular lab starting in November 2014. Mutational analysis of the entire coding regions of BTK and PLCG2 was performed on a cohort of 112 patients every 3 months. To date, 8 patients have clinically relapsed and all 8 had BTK C481S mutations with expansion of the clone prior to relapse. BTK C481S mutations of over 1% allelic frequency were detected in an additional 8 patients. All patients have had expansion of the resistant clones and all but one, who discontinued therapy without clinical relapse, have had increasing circulating CLL cells in the peripheral blood. Four of these 7 patients have also had increasing lymph node size on CT scan. In 11 patients who relapsed with BTK C481S, samples were available following discontinuation. In 5 patients treated subsequently with venetoclax, allelic fractions of C481S decreased dramatically or were eliminated, but in 6 patients treated with other agents, the mutant clone persisted. To investigate whether this was due to differences in biology between wild type and C481S BTK, we created XLA cell lines without BTK protein expression stably expressing BTK, or C481S BTK. C481S BTK showed enhanced BCR signaling as evidenced by pERK and cMYC expression, and enhanced migration compared to wild type BTK (p=0.04). This demonstrates for the first time that this acquired resistance mutation fundamentally alters the tumor cell biology. These data confirm our initial findings that relapse on ibrutinib is primarily mediated through mutations in BTK and PLCG2 and suggest that the presence of these mutations may have utility as an early biomarker to predict clinical relapse. Early identification of relapsing patients could improve outcomes by facilitating initiation of adjunct therapies such as venetoclax to eliminate the small resistant clone. Disclosures Woyach: Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Andritsos:Hairy Cell Leukemia Foundation: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Lozanski:Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding; Genentech: Research Funding.
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Saskin, Aliza, Yulia Lin, Richard A. Wells, Martha Lenis, Alex Mamedov, Jeannie Callum, and Rena Buckstein. "Prophylactic Rh and Kell Antigen Matching Significantly Decreases Rates of Alloimmunization in Transfusion Dependent MDS Patients." Blood 124, no. 21 (December 6, 2014): 4297. http://dx.doi.org/10.1182/blood.v124.21.4297.4297.
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Abstract Background: 40-80 % of patients with myelodysplastic syndrome (MDS) become transfusion dependent during their disease course and are at risk for the development of alloimmunization. Red blood cell (RBC) alloantibodies can make finding compatible blood for transfusion more difficult, expensive and time consuming. Allommunization rates of approximately 30-47% have been reported in patients with sickle cell disease and the transfusion of RBCs prophylactically matched for Rh antigens E and C, and K antigens reduced the rate of alloimmunization from 3% to 0.5% per unit (Vichinsky et al, 2001). In 2007, our hospital instituted a policy of transfusing prophylactic Rh and K matched blood to MDS patients. The objectives of this study were to compare the rates of alloimmunization in MDS patients who received prophylactic Rh and K matched blood compared to those that did not and identify potential risk factors for alloimmunization. Methods: 193 Transfusion dependent MDS patients were identified out of 387 patients registered and prospectively followed in a local MDS registry. Transfusion dependence was defined as the receipt of at least 1 unit of PRBC every 8 weeks for a minimum of 16 weeks. Records of transfusions received up to May 1, 2014 were collected from blood bank databases of the hospitals at which patients were transfused. Patients were classified according to whether phenotyping had been performed, the location of transfusions (transfused only at our institution, transfused only at an outside institution or transfused at both sites) and whether prophylactic Rh (E, C antigens) and K matched blood was transfused. Data were descriptively analyzed and we conducted univariate and multivariate logistic regression using p< 0.05 as statistically significant to identify risk factors for alloimmunization. Results: 176 MDS patients with complete transfusion records are included, 73 transfused at Sunnybrook, 92 transfused in community hospitals and 11 at both. The median age was 72 yrs (range 22-89), 60% were male, and 8%, 43% and 27% had very low, low and intermediate risk R-IPSS scores respectively. Median follow up was 2.9 years (IQR 1.6-5) 3.49 SD). Blood groups O, A, B, AB and O were 45%, 38%, 15% and 2% respectively, while 85% were RhD+. The median time from diagnosis until first transfusion was 4 months (IQR: 0.2-14), with 51 patients having received at least 1 transfusion prior to diagnosis at a median time of 0.9 months. 4.5% had a pre-existing allo-antibody at time of MDS diagnosis. With a median follow up from diagnosis of 3 years (IQR:1.6-5)), the median number of RBC units transfused was 38 (IQR: 15-98)) and 36 (20%) patients developed new alloantibodies (median 2 (IQR (1-2.5) alloantibodies). The median number of RBC units until first allo antibody was 13.5 units (range 0-121) and 1.25 years from diagnosis (95% CI:0.4-2.1). The majority of the alloantibodies were in the Rh (n=28) and K (n=14) groups (80%) and co-existed 27% of the time. More patients transfused at our hospital received prophylactic Rh K matched blood sometimes or always (60% versus 26%) and rates of allo-immunization were decreased by 65% (absolute rate of alloimmunization 10% versus 29%). By multivariate analysis analysis, number of rbc transfused (p<.0001), receiving prophylactic phenotype matched blood (p=.0008) and location of transfusions (Sunnybrook versus elsewhere (p=.03)) were independent risk factors for alloimmunization. Conclusions: 20-30% of RBC transfusion dependent MDS patients will become allo-immunized to clinically significant blood group antigens, the majority being Rh and K antigens. The practice of phenotyping at baseline and prophylactically transfusing Rh and Kell matched blood decreases rates of alloimmunization up to 65% and should be strongly considered for routine transfusion practice in centres that treat MDS. Table 1. All Patients (n=176) Sunnybrook (n=73) Community(n=92) Ever phenotyped 45% 64% 28% Phenotyped before 1st transfusion 20% 38% 8% Developed allo-antibodies 20% 10% 29% Received prophylactic Rh K matched blood (developed alloantibodies) Never Sometimes Always 58% (16%) 24% (42%) 18% (6%) 40% (3%) 23% (23%) 37% (7%) 74% (22%) 22% (60%) 4% (0%) Figure 1. Allo Antibody free survival according to number of red cell units transfused in patients that developed an allo-antibody Figure 1. Allo Antibody free survival according to number of red cell units transfused in patients that developed an allo-antibody Disclosures Wells: Celgene: Honoraria, Other, Research Funding; Novartis: Honoraria, Research Funding; Alexion: Honoraria, Research Funding. Buckstein:Celgene: Research Funding.
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Girnius, Saulius K., Habte A. Yimer, Stephen J. Noga, Sudhir Manda, Roger M. Lyons, Kimberly Bogard, Presley Whidden, et al. "In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study." Blood 136, Supplement 1 (November 5, 2020): 2–4. http://dx.doi.org/10.1182/blood-2020-140482.
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Background Long-term PI-based treatment is associated with improved outcomes in MM. Nonetheless, prolonged therapy with parenteral PIs (e.g. bortezomib) can be challenging in the real world, with median duration of therapy (DOT) of 4-7 months. Barriers to this long-term approach may include the burden of repeated intravenous/subcutaneous administration, difficulty travelling to/accessing treatment centers (e.g. due to environmental factors, travel restrictions, social/family situations), patient preference for treatment outside of a hospital or clinic setting, comorbidities, and toxicity. The US MM-6 study (NCT03173092) is investigating in-class transition (iCT) from parenteral bortezomib-based induction to all-oral ixazomib-based therapy (ixazomib-lenalidomide-dexamethasone; IRd) in the diverse US community population with the aim of increasing PI-based treatment duration while maintaining quality of life and improving outcomes. We report updated efficacy and safety for the first 101 patients. Methods Transplant-ineligible/delayed-transplant (>24 months) NDMM patients with stable disease or better after 3 cycles of bortezomib-based induction are being enrolled at US community sites (including Veterans Affairs hospitals) to receive IRd (ixazomib 4 mg, days 1, 8, 15; lenalidomide 25 mg, days 1-21; dexamethasone 40 mg, days 1, 8, 15, 22) for up to 39 x 28-day cycles or until progression/toxicity. The primary endpoint is progression-free survival (PFS); key secondary endpoints include rates of partial (PR), very good PR (VGPR), and complete response (CR), and DOT. Results As of June 1 2020, 101 patients had been treated at 21 sites. Median age was 73 years (range 48-90), with 46% aged ≥75 years; 16% and 10% were of African American and Hispanic ethnicity, respectively. Table 1 summarizes the key characteristics of these real-world patients. A total of 95% of patients had ≥1 comorbidity at the start of IRd therapy including renal and urinary disorders (38%), cardiac disorders (29%), peripheral neuropathy (PN; 14%), and diabetes mellitus (13%) (Table 2). With 53 (52%) patients remaining on therapy and enrollment ongoing, mean duration of PI therapy from the start of bortezomib-based induction was 12.4 months, and mean duration of IRd therapy after iCT was 9.2 months (Table 3). Patients have received up to 29.4 months (31 cycles) of IRd to date. The overall response rate (ORR) after bortezomib-based induction was 62% (7% CR, 32% ≥VGPR). After iCT to IRd, the ORR increased to 71%, with the CR and ≥VGPR rates increasing to 29% and 53%, respectively (Figure); of 33 patients with stable disease following bortezomib-based induction, 14 (42%) achieved CR (n=10) or VGPR (n=4) after iCT. With a median follow-up of 12 months and enrollment ongoing, 13 patients had progressed and two had died during PFS analysis. The 12-month PFS rate was 84% (95% CI, 73-91) from the start of bortezomib-based induction and 80% (95% CI, 69-88) from the start of IRd. During IRd treatment to date, 91% of patients have had treatment-emergent adverse events (TEAEs) (54% grade ≥3). Grade 3 TEAEs (≥5% of patients) were diarrhea (8%), pneumonia (7%), and syncope (5%). TEAEs led to study drug modification in 52% of patients and discontinuation in 7% of patients; 37% had serious TEAEs. Diarrhea, nausea, and vomiting occurred in 43%, 23%, and 14% of patients (8%, 2%, 2% grade 3), and led to dose modification in 11%, 5%, and 2%. PN (not elsewhere classified; high-level term) occurred in 32% of patients (2% grade 3) and led to dose modification in 9%. There were three on-study deaths (i.e. occurring <30 days after last dose). Conclusions US MM-6 patients reflect the heterogeneous real-world US MM population; the population for this study includes patients from the community who may not be eligible for traditional clinical trials. These updated data in mostly elderly, comorbid, NDMM patients treated in the community setting demonstrate the feasibility and tolerability of iCT to IRd after 3 cycles of bortezomib-based induction; approximately half of patients remain on treatment, and enrollment is ongoing. iCT to IRd resulted in improved responses, with increased rates of ≥VGPR, and prolonged DOT and may thereby improve outcomes for real-world patients. iCT to an all oral regimen could also prevent treatment interruptions for patients who are unable to or prefer not to travel in the context of travel restrictions or other factors. Disclosures Girnius: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yimer:TG Therapeutics: Consultancy; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Sanofi: Speakers Bureau; Texas Oncology: Current Employment; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months. Noga:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Lyons:Texas Oncology/US Oncology: Current Employment; Novartis: Honoraria. Bogard:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Whidden:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Aiello:Takeda: Honoraria; Travera: Honoraria; Celgene: Honoraria; Karyopharm: Honoraria. Richter:Celgene: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Speakers Bureau; Janssen: Speakers Bureau; Sanofi: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; AstraZeneca: Consultancy; Secura Bio: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Antengene: Consultancy. Rifkin:McKesson: Current equity holder in publicly-traded company, Ended employment in the past 24 months, Other: Stock ownership; Takeda, Amgen, Celgene, BMS, Mylan, Coherus BioSciences, Fresenius: Consultancy; AbbVie: Other: Investigator in AbbVie sponsored clinical trials; Takeda, Amgen, BMS (Celgene): Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Real-world evaluation of long-term proteasome inhibition with ixazomib in combination with lenalidomide and dexamethasone for the treatment of newly diagnosed multiple myeloma in non-transplant patients with stable disease after 3 cycles of a bortezomib-based induction.
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Siva, Nayanah. "US stem cell climate improves, raising concerns elsewhere." Nature Medicine 15, no. 3 (March 2009): 224. http://dx.doi.org/10.1038/nm0309-224a.
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McClelland, Sarah E. "Single-cell approaches to understand genome organisation throughout the cell cycle." Essays in Biochemistry 63, no. 2 (May 15, 2019): 209–16. http://dx.doi.org/10.1042/ebc20180043.
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Abstract Mammalian genomes are ordered at several scales, ranging from nucleosomes (beads on a string), to topologically associated domains (TADs), laminar associated domains (LADs), and chromosome territories. These are described briefly below and we refer the reader to some recent comprehensive reviews on genome architecture summarising the current state of knowledge of the organisational principles of the nucleus [1,2]. Biological observations from populations of millions of individual cells can reveal consensus behaviour. New methods to study and interpret biological data at the single-cell level have recently been instrumental in revealing new understanding of cell-to-cell variation and novel biology. Here we will summarise the recent advances in single-cell technology that have provided insights into the behaviour of the mammalian genome during a cell cycle. We will focus on the interphase domain structure of chromosomes, including TADs and LADs, and how chromosome architecture changes during the cell cycle. The role of genome architecture relating to gene expression has been reviewed elsewhere [3].
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Doi, Hiroshi, and Misako Kawakami. "Purification of aminopeptidase from Australian classified barley flour." International Journal of Biochemistry & Cell Biology 29, no. 2 (February 1997): 345–52. http://dx.doi.org/10.1016/s1357-2725(96)00094-5.
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Williams, R. J. P. "The history of proton-driven ATP formation." Bioscience Reports 13, no. 4 (August 1, 1993): 191–212. http://dx.doi.org/10.1007/bf01123502.
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This article sets down the beginnings of some thoughts in bio-energetics. It illustrates how difficult it is in science as elsewhere to know how a new idea is generated. The literature needs very careful examination and separation from personalities.
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Miyazaki, Kana, Motoko Yamaguchi, Hiroshi Imai, Tohru Kobayashi, Satoshi Tamaru, Kazuhiro Nishii, Masao Yuda, Hiroshi Shiku, and Naoyuki Katayama. "Gene expression profiling of peripheral T-cell lymphoma including γδ T-cell lymphoma." Blood 113, no. 5 (January 29, 2009): 1071–74. http://dx.doi.org/10.1182/blood-2008-07-166363.
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Abstract The gene expression profile of peripheral γδ T-cell lymphoma (γδTCL) has not been investigated. Using oligonucleotide microarrays, we analyzed total RNA from 7 patients with γδTCL (4 hepatosplenic, 1 cutaneous, 1 intestinal, and 1 thyroidal) and 27 patients with αβTCL (11 peripheral TCL-unspecified, 15 angioimmunoblastic TCL, and 1 hepatosplenic). Unsupervised microarray analyses classified all hepatosplenic γδTCLs into a single cluster, whereas other γδTCLs were scattered within the αβTCL distribution. We identified a T-cell receptor signature gene set, which accurately classified γδTCL and αβTCL. A classifier based on gene expression under supervised analysis correctly identified γδTCL. One case of hepatosplenic αβTCL was placed in the γδTCL grouping. γδTCL signature genes included genes encoding killer cell immunoglobulin-like receptors and killer cell lectin-like receptors. Our results indicate that hepatosplenic γδTCL is a distinct form of peripheral TCL and suggest that nonhepatosplenic γδTCLs are heterogeneous in gene expression.
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Benga, Gheorghe, Victor Ioan Pop, Octavian Popescu, Ileana Benga, and William Ferdinand. "Amino acid composition of band 3 protein from red blood cells of normal and epileptic children." Bioscience Reports 11, no. 1 (February 1, 1991): 53–57. http://dx.doi.org/10.1007/bf01118605.
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Amino acid analyses of the band 3 protein purified from erythrocyte membranes of control and epileptic children showed that no major structural abnormalities of this protein could be linked with the red blood cell membrane alterations previously described in child epilepsy and, consequently, the molecular basis of these alterations should be looked for elsewhere.
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Yawalkar, Nikhil, Katalin Ferenczi, David A. Jones, Keiichi Yamanaka, Ki-Young Suh, Sarah Sadat, and Thomas S. Kupper. "Profound loss of T-cell receptor repertoire complexity in cutaneous T-cell lymphoma." Blood 102, no. 12 (December 1, 2003): 4059–66. http://dx.doi.org/10.1182/blood-2003-04-1044.
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Abstract Cutaneous T-cell lymphoma (CTCL) is a malignancy of skin-homing T cells. A major feature of CTCL is profound immunosuppression, such that patients with advanced mycosis fungoides or Sézary syndrome have been compared with patients with advanced HIV disease and are susceptible to opportunistic infection. The etiology of this immunosuppression is unclear. We analyzed peripheral blood T cells of patients with CTCL with stage I to IV disease, using a sensitive beta-variable complementarity-determining region 3 spectratyping approach. Our data revealed a profound disruption of the complexity of the T-cell repertoire, which was universally observed in patients with advanced disease (stages III and IV), and present in up to 50% of patients with early-stage disease (stages I and II). In most patients, multiple monoclonal and oligoclonal complementarity-determining region 3 (CDR3) spectratype patterns in many different beta-variable families were seen. Equally striking was a reduction of normal T cells (as judged by absolute CD4 counts) across multiple beta-variable families. In general, CTCL spectratypes were reminiscent of advanced HIV spectratypes published elsewhere. Taken together, these data are most consistent with a global assault on the T-cell repertoire in patients with CTCL, a process that can be observed even in early-stage disease. (Blood. 2003;102:4059-4066)
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Campbell, I. D. "Modular proteins at the cell surface." Biochemical Society Transactions 31, no. 6 (December 1, 2003): 1107–14. http://dx.doi.org/10.1042/bst0311107.
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Many proteins, including cell-surface receptors, extracellular matrix (ECM) proteins and intracellular signalling systems, are constructed from a relatively small number of domains or modules. Modularity provides biological systems with a convenient way of presenting binding sites on a stable protein scaffold, in the correct position for function; it also allows regulation by module rearrangement. Knowledge about modular proteins is increasing rapidly because of good databases and more systematic approaches to protein expression and structure determination. There have been a number of important recent structures of modular proteins at the cell surface, including the low-density-lipoprotein receptor, epidermal growth factor receptor and an integrin. These and other studies show how the main task of structural biology has moved from determination of module structures to the task of assessing how modular proteins are regulated and how they bind their various ligands. These aspects are illustrated here by recent studies of modular proteins carried out in our laboratory and elsewhere. Examples will include studies of ECM proteins, such as fibronectin, and proteins associated with focal adhesion complexes that involve fibronectin, integrins and various intracellular modular proteins, such as focal adhesion kinase, Src family kinases, talin and paxillin.
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Dahlbäck, Björn. "Factor V Leiden and the genetics of myocardial infarction: we need to look elsewhere." Blood 100, no. 3 (August 1, 2002): 742. http://dx.doi.org/10.1182/blood-2002-06-1713.
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Hagiwara, Shotaro, Yoshinari Suzuki, Akihiro Nakayama, Akihiro Matsunaga, Yutaka Iida, and Mari Shimura. "Multiple Elements Classified Hematological Malignancies from Healthy Population." Blood 124, no. 21 (December 6, 2014): 5959. http://dx.doi.org/10.1182/blood.v124.21.5959.5959.
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Abstract Introduction It is a little known about how multiple elements interacts and functions in cells, although a specific element had already reported to take a role, enzymatic, transcriptional activities, etc. Although, several metals such as cadmium, nickel, lead, and chrome were known as carcinogen, it is also not known about relations of multiple elements in disease mechanisms. To investigate the impact of multiple elements on the features of hematological malignancies, we analyzed the multiple elements in the serum of patients with hematological malignancies and healthy persons. Methods We obtained 47 of peripheral blood samples from 40 patients with hematological malignancies, and 102 of healthy persons: 50 persons who visited to medical check-up and 52 volunteers. Hematological malignancies were 16 acute myeloid leukemia, 5 acute lymphoblastic leukemia, 9 non-Hodgkin's lymphoma, 9 Multiple myeloma, and 1 Chronic myeloid leukemia. Samples were centrifuged, and 1.0-1.5ml of plasma was separated. We measured 23 elements were measured using inductively coupled plasma mass spectrometry. To assess the difference of the element patterns between hematological malignancies and healthy persons, multivariate discrimination analysis was performed. Overall survival of hematological malignancies was assessed by Log-rank test. Multivariate analysis with the elements highly discriminated hematological malignancies from healthy persons' samples. Elements data increased the accuracy to discriminate hematological malignancies from healthy persons close to 100 % in addition to clinical data such as complete blood count, albumin, total bilirubin, blood urine nitrogen, creatinine. To our knowledge, this is the first report on the successful classifying disease from healthy persons by measurements of multiple elements with more than 90% accuracy using peripheral blood serum (Table 1). Five year overall survival of patients with hematological malignancy was likely dependent on this discriminant score. Data suggested the potential interaction between multiple elements and hematological malignancies, and the possibility future applications on diagnosis and prognosis. Table 1. Accuracy of cross-validated classification patients with hematological malignancies and healthy persons by discriminant analysis Accuracy Clinical data Multi-elements Multi-elements + Clinical data % 93.7 91.3 98.9 Disclosures No relevant conflicts of interest to declare.
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Dalton, WT Jr, MJ Ahearn, KB McCredie, EJ Freireich, SA Stass, and JM Trujillo. "HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3." Blood 71, no. 1 (January 1, 1988): 242–47. http://dx.doi.org/10.1182/blood.v71.1.242.242.
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Abstract The leukemia from which the human cell line HL-60 was derived was classified in 1976 as acute progranulocytic leukemia (APL), although it was recognized to show a number of atypical features. In the ensuing 10 years, the concept of APL and its integral association with t(15;17) has evolved, and the concept of APL as a morphologically recognizable entity has become embodied in the term French-American-British classification M3 (FAB-M3). It is now recognized that not every case of leukemia with a high proportion of progranulocytes can be classified as FAB-M3. We reviewed the light and ultrastructural morphology of the original diagnostic material from this case, and we report that the leukemia from which HL-60 was derived does not conform to the currently recognized entity of FAB-M3 and is more appropriately classified as an acute myeloblastic leukemia with maturation, FAB-M2.
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Dalton, WT Jr, MJ Ahearn, KB McCredie, EJ Freireich, SA Stass, and JM Trujillo. "HL-60 cell line was derived from a patient with FAB-M2 and not FAB-M3." Blood 71, no. 1 (January 1, 1988): 242–47. http://dx.doi.org/10.1182/blood.v71.1.242.bloodjournal711242.
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The leukemia from which the human cell line HL-60 was derived was classified in 1976 as acute progranulocytic leukemia (APL), although it was recognized to show a number of atypical features. In the ensuing 10 years, the concept of APL and its integral association with t(15;17) has evolved, and the concept of APL as a morphologically recognizable entity has become embodied in the term French-American-British classification M3 (FAB-M3). It is now recognized that not every case of leukemia with a high proportion of progranulocytes can be classified as FAB-M3. We reviewed the light and ultrastructural morphology of the original diagnostic material from this case, and we report that the leukemia from which HL-60 was derived does not conform to the currently recognized entity of FAB-M3 and is more appropriately classified as an acute myeloblastic leukemia with maturation, FAB-M2.
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Harayama, S., and M. Rekik. "Bacterial aromatic ring-cleavage enzymes are classified into two different gene families." Journal of Biological Chemistry 264, no. 26 (September 1989): 15328–33. http://dx.doi.org/10.1016/s0021-9258(19)84830-5.
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Noguchi, Taro Q. P., Yuki Gomibuchi, Kenji Murakami, Hironori Ueno, Keiko Hirose, Takeyuki Wakabayashi, and Taro Q. P. Uyeda. "Dominant Negative Mutant Actins Identified in FlightlessDrosophilaCan Be Classified into Three Classes." Journal of Biological Chemistry 285, no. 7 (November 21, 2009): 4337–47. http://dx.doi.org/10.1074/jbc.m109.059881.
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Dimopoulos, Meletios A., Lia A. Moulopoulos, Alice Maniatis, and Raymond Alexanian. "Solitary plasmacytoma of bone and asymptomatic multiple myeloma." Blood 96, no. 6 (September 15, 2000): 2037–44. http://dx.doi.org/10.1182/blood.v96.6.2037.
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Abstract Most patients with multiple myeloma (MM) present with symptoms, have evidence of generalized disease, and require chemotherapy promptly to reduce the malignant clone. Some patients present with a local symptom from a single plasmacytoma but no myeloma elsewhere. Such patients usually become free of symptoms after local radiotherapy. In patients with MM without symptoms, the diagnosis is made on the basis of screening laboratory tests. In patients with either solitary plasmacytoma of bone or asymptomatic MM, systemic treatment should be deferred until there is evidence of disease progression.
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Dimopoulos, Meletios A., Lia A. Moulopoulos, Alice Maniatis, and Raymond Alexanian. "Solitary plasmacytoma of bone and asymptomatic multiple myeloma." Blood 96, no. 6 (September 15, 2000): 2037–44. http://dx.doi.org/10.1182/blood.v96.6.2037.h8002037_2037_2044.
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Most patients with multiple myeloma (MM) present with symptoms, have evidence of generalized disease, and require chemotherapy promptly to reduce the malignant clone. Some patients present with a local symptom from a single plasmacytoma but no myeloma elsewhere. Such patients usually become free of symptoms after local radiotherapy. In patients with MM without symptoms, the diagnosis is made on the basis of screening laboratory tests. In patients with either solitary plasmacytoma of bone or asymptomatic MM, systemic treatment should be deferred until there is evidence of disease progression.
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Yamasaki, Masayuki, Satoko Moriwaki, Osamu Miyake, Wataru Hashimoto, Kousaku Murata, and Bunzo Mikami. "Structure and Function of a HypotheticalPseudomonas aeruginosaProtein PA1167 Classified into Family PL-7." Journal of Biological Chemistry 279, no. 30 (May 10, 2004): 31863–72. http://dx.doi.org/10.1074/jbc.m402466200.
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Worrillow, Lisa, Sharon Barrans, Simon Crouch, Matthew Care, Alex Smith, Russell Patmore, Reuben Tooze, Eve Roman, and Andrew Jack. "RQ-PCR Provides a Superior Alternative to Immunohistochemistry In Defining Prognostic Groups In DLBCL, and Predicts Treatment Failure with CHOP-R." Blood 116, no. 21 (November 19, 2010): 2484. http://dx.doi.org/10.1182/blood.v116.21.2484.2484.
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Abstract Abstract 2484 Diffuse large B cell lymphoma (DLBCL) is a heterogenous disease, which has been subclassified into germinal centre (GCB) and activated B-cell (ABC) type using gene expression profiling. This has been shown to separate DLBCL into distinct prognostic sub-groups in patients treated with either CHOP or CHOP-R therapy. A number of published immunohistochemistry algorithms have attempted to replicate this subclassification using a limited number of markers, however, despite being widely adopted, the reproducibility of the algorithms has proven difficult, possibly due to the subjective nature of interpreting immunohistochemistry results. The aim of this study was therefore to evaluate the most widely accepted immunohistochemistry algorithms, and validate the results using RQ-PCR on RNA extracted from paraffin sections in a large series of well characterised formalin fixed paraffin embedded (FFPE) biopsies of R-CHOP treated DLBCLs. RNA was extracted using the Ambion Recoverall extraction kit. Applied Biosytems Taqman probes were used to evaluate gene expression of CD10, BCL6, GCET1, FOXP1 and IRF4. RQ-PCR was run on an Applied Biosystems 7500Fast cycler, and results were calculated using the deltadeltaCt method, using PGK1 as the reference housekeeper gene and either RAJI cell line or commercial RNA as the standard. Using the Hans criteria, 130/277 (47%) presentation DLBCL biopsies were classified as GCB and 147/277 (53%) were ABC. Further classification of a subset of cases using the Choi algorithm showed concordant results in 48/61 (78.7%) cases, with 1 (1.6%) case classified as GCB using Hans and ABC using Choi, and 12 (19.7%) cases classified as ABC using Hans and GCB using Choi. RQ-PCR data showed excellent correlation with immunohistochemistry for all genes incorporated into the algorithms (CD10, p<0.0001; BCL6, p=0.0003; GCET1, p=0.009; FOXP1, p<0.0001; and IRF4, p=0.008). RQ-PCR defined positivity was characterized by inspecting the distribution histograms of the range of values for each gene, and applying density smooths. Mixture distributions were identified and the minimum values of these plots were used to define the cut-points. Patients were then re-classified using RQ-PCR data to define GCB/ABC status. For the Hans classification, 50/79 (63%) patients were GCB and 29/79 (37%) were ABC. Of these 51/77 (66%) cases resulted in the same sub-classification using RQ-PCR compared to immunohistochemistry, with 26/77 (34%) cases classified differently. For the Choi algorithm, 49/79 (62%) patients were GCB and 30/79 (38%) were ABC, with 23/37 (62%) cases were classified the same using RQ-PCR and immunohistochemistry, and 14/37 (38%) classified differently. In univariate Kaplan-Meier survival analysis, there was no difference in outcome when comparing either Hans (n=170, p=0.7) or Choi (n=60, p=0.3) algorithms using immunohistochemistry, however using RQ-PCR data to define GCB and ABC subgroups, both algorithms showed a poorer survival in the ABC subgroup. For the Hans algorithm, 6 month overall survival (OS) was 76% in the GCB group compared to 55% in patients classified as ABC (p=0.06), and similarly for the Choi algorithm, 6 month OS was 77% in the GCB group and 53% for patients classified as ABC (p=0.03). This data supports the use of gene expression algorithms to classify DLBCL patients into clinically relevant prognostic groups, with patients classified as ABC exhibiting an inferior outcome compared to the GCB group. RQ-PCR provides a quantitative method to determine expression and eliminates the subjective element associated with interpreting immunohistochemistry. Using RQ-PCR to define prognostic subgroups in DLBCL provides a realistic alternative to gene expression profiling, which is currently not applicable to the majority of diagnostic laboratories. Patients classified as ABC type using this approach show early treatment failure with CHOP-R, and alternative therapies should be considered in this group. Disclosures: No relevant conflicts of interest to declare.
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Trautmann, Heiko, Anastasia Hadzidimitriou, Nikos Darzentas, Wolfram Klapper, Reiner Siebert, Hilmar Berger, Monika Szczepanowski, et al. "Evidence for Antigen-Driven Development of Molecularly Classified Burkitt Lymphomas." Blood 114, no. 22 (November 20, 2009): 317. http://dx.doi.org/10.1182/blood.v114.22.317.317.
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Abstract Abstract 317 Evidence for Antigen-driven Development of Molecularly Classified Burkitt Lymphomas The presence of somatic mutations and intraclonal diversity (ID) in the variable region of rearranged immunoglobulin (Ig) genes is commonly used as a marker of the cellular passage of B cells through the germinal center (GC) reaction in secondary lymphoid tissues following an in vivo antigen encounter. Such features have also been documented in different subgroups of aggressive B-cell lymphomas, suggesting that antigen selection pressure has taken place during lymphoma development. We undertook a detailed analysis of the Ig repertoire and somatic hypermutation (SHM) status of 54 molecularly classified Burkitt lymphomas (BL) (Hummel et al. 2006). The IGHV gene repertoire was remarkably biased, with only three genes accounting for 40.8% of all cases (IGHV4-34, 18.5%; IGHV4-39, 11.1%; IGHV3-30, 11.1%). Of note, this bias was even more evident when cases were grouped according to age < or > 14 years, with the IGVH4-34 and IGVH4-39 rearrangements occurring almost exclusively in pediatric BL (7/11 and 5/6 cases respectively). Only 2/54 cases (3.7%) carried unmutated IGHV genes (100% germline identity, GI); 12/54 cases (22.2%) carried IGHV genes of borderline/minimally mutated status (98–99.9% GI); finally, the remaining 40/54 cases (74.1%) carried mutated IGHV genes (<98% GI). The median GI of the cohort was 95.2% (range: 86.4–100%) with a significantly different mutation load according to age below or above 14 years (GI 95.8 vs. 92.9 respectively, p=0.0168). Shared replacement mutations (“stereotyped” amino acid (AA) changes) at certain codon positions were identified in 12/54 (22.2%) BL cases. Stereotyped AA changes were found only amongst rearrangements utilizing the IGHV4-34 and IGHV4-39 genes, strongly indicating evidence for an antigen driven SHM process in BL. The majority of stereotyped AA changes identified here were distinct from those previously reported in other entities, in particular CLL, and thus can be considered as BL-biased. Also, of note, the IGVH4-34 specific motif responsible for binding the N-acetyl-lactosamine antigenic determinant was found intact in 11 IGVH4-34 BL sequences, implying that these clones retained the ability to bind to and be activated by superantigens. Furthermore, the distribution of mutations was different in IGHV4-34 vs. non-IGHV4-34 cases, as evidenced by low R-to-S ratios in the heavy complementarity-determining regions (especially HCDR1), indicating a different selection pattern of VH-genes according to varying antigens. To assess the presence of ID through ongoing SHM, we evaluated 411 subcloned sequences from 11 IGVH4-34 and 6 IGVH4-39 cases. Only one case carried identical sets of subcloned sequences; seven cases carried mutations in single subcloned sequences that were considered as unconfirmed; finally, 9 cases carried at least one confirmed mutation among two or more subcloned sequences and, thus, were considered as exhibiting confirmed ID. However, analysis of the distribution of the so called unconfirmed changes provided further evidence for the very precise targeting of mutations introduced as part of the ID process. Thus, certain changes identified in single subcloned sequences from one case were shared by most or all subcloned sequences of another case utilizing the same IGHV gene (“confirmed by another case”). In conclusion, our data demonstrate that BL is characterized by a highly distinctive IG gene repertoire with a precisely targeted SHM process. In addition, they provide strong evidence for a functionally driven SHM, supporting a role for antigen-driven selection of the clonogenic progenitors. Disclosures: No relevant conflicts of interest to declare.
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CLARKSON, Joanna, Iain D. CAMPBELL, and Michael D. YUDKIN. "Phosphorylation induces subtle structural changes in SpoIIAA, a key regulator of sporulation." Biochemical Journal 372, no. 1 (May 15, 2003): 113–19. http://dx.doi.org/10.1042/bj20021748.
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The phosphorylation state of SpoIIAA is a key factor in the regulation of sporulation in Bacillus subtilis. Previous crystallographic studies had led to the conclusion that phosphorylation alters the binding affinity of SpoIIAA for its partner proteins solely through the additional charge and bulk of the phosphoryl group: small structural changes observed elsewhere in the protein were considered to be random fluctuations rather than the result of phosphorylation. The results presented in the present paper show that NMR studies detect the same subtle structural changes in solution as those seen in the crystal, strongly implying that they are the direct result of phosphorylation. These subtle structural changes are similar to those that occur in a non-phosphorylated mutant that is defective in binding to one of its partner proteins. We propose that the structural changes which occur in SpoIIAA on phosphorylation act in concert with the phosphoryl group to alter its binding properties.
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De Salvo Cardullo, Luigi, Mirian C. Duerto, Dalila DV De Salvo, Rodolfo J. Salas-A, Jesus E. Weir-M, Ana M. Nuñez, Alonso A. Nuñez, et al. "Differential Diagnosis of Myelodisplastic Syndrome, with Flow Cytometry." Blood 114, no. 22 (November 20, 2009): 4860. http://dx.doi.org/10.1182/blood.v114.22.4860.4860.
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Abstract Abstract 4860 Our flow cytometry laboratory processed 38 bone marrow (BM) samples (24 males and 14 females) from patients with Myelodisplasic Syndrome diagnosis, from January 2008 to May 2009. Upon examination, most BM smears corresponded with an hypercellular bone marrow and increased intermediate and immature cells. All patients classified according to OMS for Myelodisplasic Syndromes. Twenty-four (n=24) patients (65%) presented RA, five (n=5) patients (13%) RAEB-1, one (n=1) 1% presented RARS, and eight (n=8) patients (21%) classified as RAEB-II. Cytogenetic result analyses for all patients classified according with the Index Prognostic Standard Score (IPSS). Twenty-five (n=25) patients or 66% corresponded with a good cytogenetic risk; seven (n=7) or 20% corresponded with an intermediate risk and six (n=6) or 14% with poor risk. Cell cytometry results corresponded with increased immature cells. In 20 patients, the DR/CD34 average 27,29% (range 0-67); in 24 patients, the DR/CD33 average 31,80% (range 6-100); in 29 patients, the DR/CD117 average 18,89% (range 0-43); in 7 patients, the CD33/CD34 average 22,14% (range 0-50); in 5 patients, the CD38 average 47,60% (range 32-61); in 4 patients, the BCL2 average 21,75% (14-26 and in 3 patients, the DR/CD64 average 44,33% (range 30-60). All patients with high average of DR/CD64 classified as CMML. Patients with RAEB-II diagnosis classified as MDS in transformation. Most patients displayed 10% CD34+ values higher than normal human average. We conclude the cytometry is an important tool in the differential diagnosis of MDS. Disclosures No relevant conflicts of interest to declare.
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Carey, Christopher Daniel, Daniel Gusenleitner, Zhang Xuan, Aliyah R. Sohani, Olga Weinberg, Hongbo Yu, Ben Chen, et al. "Resolving the Biological Heterogeneity of B-Cell Lymphoma, Unclassifiable, with Features Intermediate Between DLBCL and BL (BCL-U) Using Quantitative Profiles of Oncogenic Signaling Networks." Blood 126, no. 23 (December 3, 2015): 3903. http://dx.doi.org/10.1182/blood.v126.23.3903.3903.
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Abstract BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL) have characteristic cellular, phenotypic, and genetic characteristics that reflect their distinctive biology. These distinctions are attributable, in part, to differential activity of defined oncogenic signaling pathways, including TCF3/ID3, NFkB, MYC, and BCL2 (Carey et al, JMD, 2015). B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCL-U) encompasses a group of tumors with ambiguous features and likely heterogeneous biology. We used targeted gene expression profiling and a molecular classifier based on the major signaling networks active in DLBCL and/or BL to address the biological heterogeneity of BCL-U. METHODS: We analyzed RNA isolated from paraffin-embedded tissue sections of 72 aggressive B-cell lymphomas (BCLs) selected according to original pathological diagnoses of BL (12 cases), DLBCL (20 cases), BCL-U (22 cases), and 'large B-cell lymphoma with high grade features' (18 cases). Sixteen genetic double hit lymphomas (DHLs) that combine a MYC -rearrangement with a BCL2 - and / or BCL6 -rearrangement were included in the series. Five hematopathologists reviewed each case to separate those with a consensus diagnosis from those where there was no consensus. We profiled the RNA in 2 laboratories and used a molecular diagnostic classifier to provide a "probability score" for the diagnosis of BL or DLBCL. Cases with a diagnostic score of >0.75 were categorized as "molecular BL" (mBL), between 0.25 and 0.75 as intermediate between BL and DBLCL (intBCL), and ≤0.25 as "molecular DLBCL" (mDLBCL). Finally, we compared the results of expert review with the results of molecular classification. RESULTS: Eight of 8 consensus diagnoses of BL classified molecularly as mBL and 13/13 consensus diagnoses of DLBCL classified as mDLBCL (100%). Seventy of 72 cases (97.2%) were molecularly classified with consensus upon profiling in 2 laboratories. Consensus pathological diagnoses that agreed with the original diagnoses were reached in 6/9 BL (66.7%), 6/12 DLBCL (50%) and 2/22 BCL-U (9.1%). Cases classified as BCL-U by two or more expert pathologists (29) were assigned to all molecular diagnostic categories, including 11 (15.7%) to mBL, 12 (41.4%) to intBCL, and 6 (20.7%) to mDLBCL. Similarly, subsets of DHLs with molecular consensus (14) classified as mBL (21.4%), intBCL(64.3%) and mDLBCL (14.3%). Among cases without a consensus pathological diagnosis, 9 (34.6%) were classified as mBL with high probability, 14 (53.8%) were classified as mDLBCL with high probability, and 3 (11.5%) were classified as intBCL. CONCLUSIONS: We find that the quantitative analysis of oncogenic signaling pathways using targeted expression profiling accurately and reproducibly 1) segregates BL from DLBCL, 2) assigns a subset of BCLs that are not diagnosed with consensus by traditional methods to mBL and mDLBCL and 3) identifies subsets of DHLs with molecular signatures of mBL, intBCL, and mDLBCL. Targeted molecular profiling and molecular classification of aggressive B-cell lymphomas is a useful new ancillary test in the diagnostic evaluation of aggressive B-cell lymphomas that provides a biological framework for designing rational treatment strategies. Figure 1. Figure 1. Disclosures Rodig: Perkin Elmer: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding.
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Fisher, RI, S. Dahlberg, BN Nathwani, PM Banks, TP Miller, and TM Grogan. "A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study." Blood 85, no. 4 (February 15, 1995): 1075–82. http://dx.doi.org/10.1182/blood.v85.4.1075.bloodjournal8541075.
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The objectives of this study were (1) to determine the clinical presentation and natural history associated with two newly recognized pathologic entities termed mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL), including the mucosa-associated lymphoid tissue (MALT) and monocytoid B-cell subcategories, and (2) to determine whether these entities differ clinically from the other relatively indolent non- Hodgkin's lymphomas with which they have been previously classified. We reviewed the conventional pathology and clinical course of 376 patients who had no prior therapy; had stage III/IV disease; were classified as Working Formulation categories A, B, C, D, or E; and received cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) on Southwest Oncology Group (SWOG) studies no. 7204, 7426, or 7713. All slides were reviewed by the three pathologists who reached a consensus diagnosis. Age, sex, performance status, bone marrow and/or gastrointestinal involvement, failure-free survival, and overall survival were compared among all the categories. We found that (1) MCL and MZL each represent approximately 10% of stage III or IV patients previously classified as Working Formulation categories A through E and treated with CHOP on SWOG clinical trials; (2) the failure-free survival and overall survival of patients with MZL is the same as that of patients with Working Formulation categories A through E, but the failure-free survival and overall survival of the monocytoid B-cell patients were higher than that of the MALT lymphoma patients (P = .009 and .007, respectively); and (3) the failure-free survival and overall survival of patients with MCL is significantly worse than that of patients with Working Formulation categories A through E (P = .0002 and .0001, respectively). In conclusion, patients with advanced stage MALT lymphomas may have a more aggressive course than previously recognized. Patients with MCL do not have an indolent lymphoma and are candidates for innovative therapy.
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Megeney, Lynn A., and Michael A. Rudnicki. "Determination versus differentiation and the MyoD family of transcription factors." Biochemistry and Cell Biology 73, no. 9-10 (September 1, 1995): 723–32. http://dx.doi.org/10.1139/o95-080.
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The myogenic regulatory factors (MRFs) form a family of basic helix–loop–helix transcription factors consisting of Myf-5, MyoD, myogenin, and MRF4. The MRFs play key regulatory roles in the development of skeletal muscle during embryogenesis. Sequence homology, expression patterns, and genetargeting experiments have revealed a two-tiered subclassification within the MRF family. Myf-5 and MyoD are more homologous to one another than to the others, are expressed in myoblasts before differentiation, and are required for the determination or survival of muscle progenitor cells. By contrast, myogenin and MRF4 are more homologous to one another than to the others and are expressed upon differentiation, and myogenin is required in vivo as a differentiation factor while the role of MRF4 remains unclear. On this basis, MyoD and Myf-5 are classified as primary MRFs, as they are required for the determination of myoblasts, and myogenin and MRF4 are classified as secondary MRFs, as they likely function during terminal differentiation.Key words: MyoD, Myf-5, myogenin, MRF4, skeletal muscle.
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Zimring, James C. "Established and theoretical factors to consider in assessing the red cell storage lesion." Blood 125, no. 14 (April 2, 2015): 2185–90. http://dx.doi.org/10.1182/blood-2014-11-567750.
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AbstractThe collection and storage of red blood cells (RBCs) is a logistical necessity to provide sufficient blood products. However, RBC storage is an unnatural state, resulting in complicated biological changes, referred to collectively as the “storage lesion.” Specifics of the storage lesion have been studied for decades, including alterations to cellular properties, morphology, molecular biology of carbohydrates, proteins and lipids, and basic metabolism. Recently, mass spectrometry–based “omics” technology has been applied to the RBC storage lesion, resulting in many new observations, the initial effects of which are more information than understanding. Meanwhile, clinical research on RBC transfusion is considering both the efficacy and also the potential untoward effects of transfusing stored RBCs of different ages and storage conditions. The myriad biological changes that have now been observed during the storage lesion have been extensively reviewed elsewhere. This article focuses rather on an analysis of our current understanding of the biological effects of different elements of the storage lesion, in the context of evolving new clinical understanding. A synopsis is presented of both established and theoretical considerations of the RBC storage lesion and ongoing efforts to create a safer and more efficacious product.
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Tang, Xuemei, Peng Gu, and Wenming Lu. "A rare case of adult colocolic intussusception secondary to splenosis." Journal of International Medical Research 50, no. 8 (August 2022): 030006052211153. http://dx.doi.org/10.1177/03000605221115386.
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Intussusception is the invagination of a segment of bowel (intussusceptum) into the lumen of an adjacent segment (intussuscipiens). Adult intussusception is rare and typically asymptomatic, although bowel obstruction can be a predominant symptom, making it difficult to diagnose. Splenosis is an uncommon and benign disease, arising from the self-implantation of splenic tissue elsewhere in the body after splenectomy or splenic trauma. Colocolic intussusception secondary to splenosis is rare. We report a case of colon intussusception with a mass in the intussusception detected by ultrasound. Abdominal ultrasound identified the intussusception location but failed to distinguish its pathological properties. Colonoscopy revealed the exudation of necrotic and fibrous tissue. Surgery was performed because of suspicions of a malignant tumor.
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Nickel, Robert Sheppard, Elizabeth Seashore, Adina L. Alazraki, John T. Horan, Monica Bhatia, and Ann E. Haight. "Improved Splenic Function after Stem Cell Transplant for Sickle Cell Disease." Blood 124, no. 21 (December 6, 2014): 3966. http://dx.doi.org/10.1182/blood.v124.21.3966.3966.
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Abstract Introduction: Splenic dysfunction is a critical complication of SCD that begins in early childhood and can cause fatal sepsis. Hematopoietic stem cell transplant (HSCT) is a proven cure for SCD, however, its long-term effect on the spleen in patients who had SCD is not well characterized. This information could be helpful to further inform medical professionals and families considering HSCT for SCD. Better understanding of the splenic function of patients after transplant for SCD could also provide important information regarding these patients' future risk of infection and other possible problems related to asplenia. Methods: We conducted a retrospective cohort study of pediatric patients who had HSCT for SCD at two transplant centers. Patients were excluded for analysis if they had pre-HSCT splenectomy, died less than one year post-transplant, failed to engraft, or had no post-HSCT spleen function testing. Tc99m liver-spleen (LS) scans and red blood cell (RBC) pit counts, validated tests to evaluate the spleen in SCD, were used to assess splenic function. Splenic uptake on scans was classified as either present or absent. RBC pit count was classified as either normal or abnormal. If a patient had multiple LS scans or RBC pit counts post-HSCT, then the most recent test was used for this analysis. Results: Fifty-five evaluable patients were identified (53 patients with a post-HSCT LS scan, 29 patients with a post-HSCT RBC pit count, and 27 patients with both tests). Almost all (52/55, 95%) patients had hemoglobin SS or Sβ0 disease. Median age at transplant was 8.8 years (range 1.8-22.0 years). Conditioning regimen and stem cell source varied, however, 48/55 (87%) received myeloablative conditioning and an HLA-identical sibling donor HSCT. At a median 2.0 years post-HSCT (range 0.9-8.9 years), 48/53 (91%) had spleen uptake present on LS scan. At a median 3.2 years post-HSCT (range 1.0-11.4 years), 24/29 (83%) had a normal RBC pit count. Analysis of patients who had both pre- and post-HSCT tests showed that patients had significantly improved outcomes post-HSCT: Table Pre-HSCT Post-HSCT p-value Spleen Uptake Present on LS scan 17/36 (47%) 32/36 (89%) 0.0002 Normal RBC pit count 6/20 (30%) 17/20 (85%) 0.0004 All patients (17/17, 100%) with LS scan spleen uptake pre-HSCT had uptake present post-HSCT compared to 15/19 (79%) patients with absent spleen uptake pre-HSCT had uptake present post-HSCT (p=0.11). Four patients had absent spleen uptake at 1 year post-HSCT but had uptake present at 2 years post-HSCT. Conclusion: Our study represents the largest comprehensive evaluation of long-term splenic function in patients after HSCT for SCD. Our results suggest that successful HSCT mitigates damage to the spleen induced by SCD. In patients with splenic function pre-transplant, HSCT appears to preserve this function. In patients lacking splenic function, HSCT appears to engender the return of function in most, but not all patients. Disclosures No relevant conflicts of interest to declare.
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Poudyal, Hemant, and Lindsay Brown. "Should the pharmacological actions of dietary fatty acids in cardiometabolic disorders be classified based on biological or chemical function?" Progress in Lipid Research 59 (July 2015): 172–200. http://dx.doi.org/10.1016/j.plipres.2015.07.002.
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Barron, Michelle A., Neil Fishman, G. Mark Baillie, and Helga Brake. "Multicenter Evaluation of Fungal Prophylaxis in Hematopoietic Stem Cell Transplantation." Blood 108, no. 11 (November 16, 2006): 5293. http://dx.doi.org/10.1182/blood.v108.11.5293.5293.
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Abstract BACKGROUND: The University HealthSystem Consortium (UHC) conducted a benchmarking study to assess members’ compliance with published guidelines for prevention of fungal infections in hematopoietic stem cell transplant (HSCT) recipients. METHODS: Adult HSCT patients were evaluated by retrospective chart review of cases discharged between 01/01/04 and 06/30/05. Data collected included demographics, use of prophylaxis (px), and outcomes. Patients were classified as high or low risk for fungal infection according to NCCN and CDC guidelines. RESULTS: Thirteen UHC member hospitals submitted a total of 242 HSCT cases. Patient characteristics and administration of antifungal therapy are shown in Table 1. 57% (137/242) of patients were classified as high risk for fungal infection. Overall, 85% (205/242) of patients received antifungal px. Compliance with national guideline directed antifungal px was 54%. Of patients who did not receive px, 59% (22/37) were high-risk. 32% (7/22) of these patients required empiric antifungal therapy, 29% (2/7) had a confirmed fungal infection and 1 of these patients died. Of patients who received antifungal px, 44% (90/205) were classified as low risk. 6.7% (6/90) went on to require empiric therapy and 2 died. 84.4% of patients had fluconazole as at least one of their prophylactic agents, and 34% of patients received prophylactic antifungals that provided coverage for both Aspergillus and Candida species. 5.4% (13/242) of HSCT recipients died during the target hospitalization. 76.9% (10/13) of these patients were high risk. 61.5% (8/13) had signs/symptoms of a suspected or definitive fungal infection at the time of death (6 were high risk). CONCLUSION: Most HSCT patients did not receive appropriate fungal px based on current guidelines. Failure represented both under and over utilization of px. Further study is required to explain poor adherence to current guidelines. Table 1: Patient Characteristics by Degree of Risk High Risk (n=137) Low Risk (n=105) % (n) % (n) *ABX = broad spectrum antibiotics Chemotherapy prior to admission 53.3% (73) 61.9% (65) Radiation prior to admission 23.4% (32) 17.1% (18) Allogeneic Transplant 75.9% (104) 17.1% (18) Cytomegalovirus disease 11.7% (16) 6.7% (7) GVHD 15.3% (21) 1.0% (1) Mucositis 55.5% (76) 7.6% (8) Systemic corticosteroids 63.5% (87) 44.8% (47) Fever unresponsive to >4 days of ABX 19.0% (26) 12.4% (13) Neutropenia during antifungal therapy 39.4% (54) 27.6% (29) History of Aspergillus infection 3.6% (5) 0.0% (0) Antifungal therapy: Prophylaxis 83.9% (115) 85.7% (90) Failed prophylaxis 21.2% (29) 5.7% (6) Empiric therapy 25.4% (32) 10.5% (11) Definite treatment 6.6% (8) 0.0% (0)
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MONJUSHO, Hatsumi, Nozomu OKINO, Motohiro TANI, Mineko MAEDA, Motonobu YOSHIDA, and Makoto ITO. "A neutral ceramidase homologue from Dictyostelium discoideum exhibits an acidic pH optimum." Biochemical Journal 376, no. 2 (December 1, 2003): 473–79. http://dx.doi.org/10.1042/bj20030652.
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Ceramidases (CDases) are currently classified into three categories (acid, neutral and alkaline) based on their optimal pHs and primary structures. Here, we report the first exception to this rule. We cloned the CDase cDNA, consisting of 2142 nucleotides encoding 714 amino-acid residues, from the slime mould, Dictyostelium discoideum. The putative amino-acid sequence indicates 32–42% identity with various neutral CDases, but does not show any similarity to the acid and alkaline CDases, indicating the enzyme should be classified as a neutral CDase. However, overexpression of the cDNA in D. discoideum resulted in increased CDase activity at an acidic, but not a neutral pH range. Knockout of the gene in slime mould eliminated CDase activity at acidic pH. The recombinant enzyme expressed in the slime mould was purified and then characterized. Consequently, the purified CDase was found to exhibit the maximal activity at approx. pH 3.0. The singular pH dependency of slime mould CDase is not derived from the specific post-translational modification in the slime mould, because the enzyme showed an acidic pH optimum even when expressed in Chinese hamster ovary cells, whereas rat neutral-CDase exhibited a neutral pH optimum when expressed in slime mould.
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Makishima, Hideki, Kenichi Yoshida, Thomas LaFramboise, Bartlomiej P. Przychodzen, Matthew Ruffalo, Inés Gómez-Seguí, Yuichi Shiraishi, et al. "In Analogy to AML, MDS Can be Sub-Classified By Ancestral Mutations." Blood 124, no. 21 (December 6, 2014): 823. http://dx.doi.org/10.1182/blood.v124.21.823.823.
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Abstract Somatic mutations constitute key pathogenetic elements in MDS. Unbiased whole exome sequencing (WES) and deep NGS led to discovery of new somatic mutations and also to the recognition of i) tremendous diversity of mutations and their combinations; ii) individual intra-tumor heterogeneity and clonal hierarchy. Chromosomal lesions further increase the complexity of molecular defects. While in MDS molecular defects are acquired in order, observations made in AML highlight the importance of ancestral events; e.g., t(8;21), inv16 or t(15;17) and other lesions that are used as the basis for nosological sub-classification. Thus, it is the identity of individual ancestral events or their classes rather than the spectrum of secondary events or the distribution of mutations, that will allow for molecular, functionally-relevant and diagnostically useful classification within MDS. This would explain why only a few somatic mutations have been found to be prognostically important, as their position in the clonal hierarchy has not been accounted for. With this in mind, we applied WES (N=206) and targeted deep NGS (N=836) and studied 100 samples serially with analyses focused on ancestral events. Globally, through WES we identified and validated 2386 mutational events in 1458 genes. Of these, 112 genes were mutated at significant frequencies (q<0.05); groups of affected genes involved in splicing, transcription, DNA methylation, histone modification, and others were distinguished. On average, 9 somatic events per MDS case, 10.7 in secondary AML, and 12.5 in MDS/MPN were found. Resequencing in combination with SNP-array karyotyping provided information on variant allelic frequency (VAF) adjusted for corresponding zygosity of mutations; 99% of cases displayed clear intra-tumor heterogeneity due to multiple clones defined by hierarchically acquired somatic mutational patterns. Using cross-sectional analyses, the highest mean VAF could be interpreted as consistent with the ancestral nature of the mutations, as seen for instance in a proportion of TET2 and SF3B1 mutant cases. In contrast, the lowest mean VAF indicated secondary events, as occur in NPM1 and RAS pathway mutations. Similar conclusions were made based on cross-sectional analyses showing a similar distribution of ancestral but not secondary events in MDS and sAML. All gene mutations were categorized into those that are predominantly ancestral and those that are facultatively secondary. The most frequent founder mutations were identified (TET2, DNMT3A, SF3B1, ASXL1, TP53, U2AF1, RUNX1, SRSF2) and used to sub-classify approximately 80% of patients, with the remainder containing more infrequent ancestral mutations. While in a combined fashion (as both founder and secondary events) many of these mutations were not predictive of prognosis, they gained relevance when only cases affected by ancestral mutations were used for prognostication. Thus some of the mutations, when present as secondary events may not be predictive. Founding mutations may determine subsequent clinical and molecular features. While other frequently affected genes, SF3B1 or ASXL1, are not associated with a significant increase in the number of concomitant mutations, cases with TET2 mutations showed significantly more frequent mutations per case than those with wild-type TET2 (14.6 vs. 9.1; p=0.001). Moreover, ancestral TET2 mutations were associated with concomitant mutations due to high C-to-T transitions, possibly because reduced 5-hydroxymethylcytosine might create the specific mutator milieu. Most important is the association not of any type, but of ancestral mutations with certain pathomorphologic features and outcomes. Founding TET2 mutations are associated with MPN/MDS while secondary TET2 mutations are present in MDS. Ancestral DNMT3A mutations determine a rapid progression to AML, whereas subclonal DNMT3A mutations are also found in high-risk MDS. RAS pathway mutations are ancestral in CMML and also secondarily positive in the late stage of MDS (sAML). Specific ancestral events may determine subsequent mutational events, and while both types of mutation may affect the clinical phenotype, the initial events are less diverse and more subtype-specific. In conclusion, WES clarified the distinct landscape and ordering of the somatic mutational spectrum in MDS. Disclosures No relevant conflicts of interest to declare.
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Moller, P., G. Moldenhauer, F. Momburg, B. Lammler, M. Eberlein-Gonska, S. Kiesel, and B. Dorken. "Mediastinal lymphoma of clear cell type is a tumor corresponding to terminal steps of B cell differentiation." Blood 69, no. 4 (April 1, 1987): 1087–95. http://dx.doi.org/10.1182/blood.v69.4.1087.1087.
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Abstract This article reports eight primary mediastinal tumors occurring in young adults (19 to 43 years, mean 29.4 years), predominantly female (six of eight) adults. Most patients responded badly to aggressive therapy. Progression is presently noted in one patient; five patients died 10, 11, 13, 18, and 22 months after diagnosis. No patient developed leukemia. The tumors were highly proliferative, had a diffuse growth pattern, and comprised clear cells of variable size. They could not be classified histologically, but could, however, be immunohistologically characterized as B cell lymphomas. In all cases, the immunophenotype was LC+, cALLa-, CD19+, CD20+, CD21-, Ig (surface/cytoplasm)-, and PC-1+. In addition, the neoplastic cells exhibited variable defects in the expression of HLA-A,B,C and HLA-DR and inconstant expression of other B cell-restricted/associated antigens. This combination of immunophenotypical and clinical features suggests that the mediastinal clear cell lymphoma (MCCL) is a previously undescribed type of B cell lymphoma corresponding to the terminal steps of B cell differentiation.
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Moller, P., G. Moldenhauer, F. Momburg, B. Lammler, M. Eberlein-Gonska, S. Kiesel, and B. Dorken. "Mediastinal lymphoma of clear cell type is a tumor corresponding to terminal steps of B cell differentiation." Blood 69, no. 4 (April 1, 1987): 1087–95. http://dx.doi.org/10.1182/blood.v69.4.1087.bloodjournal6941087.
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This article reports eight primary mediastinal tumors occurring in young adults (19 to 43 years, mean 29.4 years), predominantly female (six of eight) adults. Most patients responded badly to aggressive therapy. Progression is presently noted in one patient; five patients died 10, 11, 13, 18, and 22 months after diagnosis. No patient developed leukemia. The tumors were highly proliferative, had a diffuse growth pattern, and comprised clear cells of variable size. They could not be classified histologically, but could, however, be immunohistologically characterized as B cell lymphomas. In all cases, the immunophenotype was LC+, cALLa-, CD19+, CD20+, CD21-, Ig (surface/cytoplasm)-, and PC-1+. In addition, the neoplastic cells exhibited variable defects in the expression of HLA-A,B,C and HLA-DR and inconstant expression of other B cell-restricted/associated antigens. This combination of immunophenotypical and clinical features suggests that the mediastinal clear cell lymphoma (MCCL) is a previously undescribed type of B cell lymphoma corresponding to the terminal steps of B cell differentiation.
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Macreadie, I., S. Sankovich, P. Failla, M. Lowe, C. Curtain, L. Castelli, and A. Azad. "HIV-1 Nef protein causes death in stressed yeast cells due to determinants near the N-terminus and elsewhere in Nef." IUBMB Life 46, no. 2 (October 1998): 277–86. http://dx.doi.org/10.1080/15216549800203792.
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Scott, Stuart, Richard Dillon, Christian Thiede, Sadia Sadiq, Ashley Cartwright, Clouston Hazel, Debbie Travis, Andrew D. Chantry, and Liam Whitby. "Assessment of Minimal/Measurable Residual Disease Testing in Acute Myeloid Leukaemia By Molecular Methods in an Interlaboratory Study." Blood 138, Supplement 1 (November 5, 2021): 3461. http://dx.doi.org/10.1182/blood-2021-152259.
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Abstract Background Minimal/measurable residual disease (MRD) testing is increasingly utilised and accepted as standard of care to manage a range of different haematological malignancies. It's use as a surrogate outcome in clinical trials of new therapies is being explored, where it has the potential to accelerate drug assessment and approval. The phenotypic and genetic heterogeneity of acute myeloid leukaemia (AML) has limited the use of MRD in this context; however, the European LeukaemiaNet (ELN) MRD working group have recently published consensus guidelines to standardise both flow cytometric and molecular genetic MRD testing. To assess the accuracy of testing and concordance between laboratories, crucial to patient safety, external quality assessment (EQA)/proficiency testing (PT) is required. Aims To determine the performance of molecular methods for measuring of MRD using the t(8;21)(q22:q22) RUNX1-RUNX1T1, inv(16)(p13q22) CBFB-MYH11, t(15;17)(q24.1;q21.2) PML-RARA and NPM1 Type A markers in an international interlaboratory study. Methods A total of 12 batches of lyophilised EQA material were manufactured. These consisted of three batches of samples for each marker all containing 9x10^6 cells: an MRD 'high' sample; an MRD 'low' sample; and an MRD 'negative' sample. The t(8;21)(q22:q22) RUNX1-RUNX1T1 positive samples were manufactured using the KASUMI-1 cell line, the inv(16)(p13q22) CBFB-MYH11 positive samples using the ME-1 cell line; t(15;17)(q24.1;q21.2 PML-RARA positive samples using the NB4 cell line and the NPM1 Type A (NM_002520.6:c.860_863dup) positive samples using the OCI-AML3 cell line. MRD positive samples were diluted with HL60 cells to achieve the desired MRD level. MRD negative samples were manufactured using the HL60 cell line. The samples were shipped at ambient temperature to the 29 laboratories in 12 countries. Participants were asked to test the blinded samples with their in-house assay and report % normalised ratio of the relevant marker alongside additional methodological and technical data. Results For t(8;21) RUNX1-RUNX1T1, all participants who returned results (n=23) classified the MRD 'high' and MRD 'low' samples as positive and the MRD 'negative' sample as negative. The robust mean log reduction between the MRD 'high' and MRD low sample was 2.7 (range 2.5-2.9). For inv(16) CBFB-MYH11, all participants who returned results (n=22) classified the MRD 'high' sample as positive, 21/22 (95.5%) classified the MRD 'low' sample as positive and 21/22 (95.5%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD 'high' and MRD 'low' sample was 3.16 (range 2.8-4.2). For t(15;17) PML-RARA, all participants who returned results (n=22) classified the MRD 'high' sample as positive, 21/22 (95.5%) classified the MRD 'low' sample as positive and 21/22 (95.5%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD 'high' and MRD 'low' sample was 2.1 (range 1.4-2.4). For NPM1, all participants who returned results (n=23) classified the MRD 'high' as positive, 21/23 (91.3%) classified the MRD 'low' sample as positive and, 17/23 (73.4%) classified the MRD negative sample as negative. The robust mean log reduction between the MRD 'high' and MRD 'low' sample was 3.8 (range 3.2-4.2). Summary/Conclusion The majority of participants in this study were able to detect and accurately quantify MRD when assessing the t(8;21)(q22:q22) RUNX1-RUNX1T1, inv(16)(p13q22) CBFB-MYH11, t(15;17)(q24.1;q21.2) PML-RARA and NPM1 markers, at levels that would be expected within a clinical trial or standard of care setting. A high proportion of participants reported false positive results in the NPM1 marker negative sample. This would have significant consequences clinically, with NPM1 marker false-positivity potentially committing patients to unneeded additional chemotherapy and/or transplant with the attendant risk of morbidity and mortality which highlights the need for ongoing EQA in this area. UK NEQAS LI will work with laboratories advocating they undertake a root cause analysis process to identify the source(s) of error contributing to false positive NPM1 marker results and support their subsequent corrective actions; sharing any educational findings with all participants. Figure 1 Figure 1. Disclosures Scott: Novartis: Research Funding; Biorad: Research Funding. Dillon: Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events; Amgen: Other: Research support (paid to institution); Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Whitby: Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Other: Teaching.
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Roston, Rebecca L., Kun Wang, Leslie A. Kuhn, and Christoph Benning. "Structural Determinants Allowing Transferase Activity in SENSITIVE TO FREEZING 2, Classified as a Family I Glycosyl Hydrolase." Journal of Biological Chemistry 289, no. 38 (August 6, 2014): 26089–106. http://dx.doi.org/10.1074/jbc.m114.576694.
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Rose, James D. "Corticosteroid actions from neuronal membrane to behavior: Neurophysiological mechanisms underlying rapid behavioral effects of corticosterone." Biochemistry and Cell Biology 78, no. 3 (April 2, 2000): 307–15. http://dx.doi.org/10.1139/o00-021.
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Investigation of the rapid suppression of male courtship clasping behavior by corticosterone in roughskin newts (Taricha granulosa) has led to the identification of a specific neuronal membrane receptor for this stress steroid. This paper describes studies of the neurophysiological effects of the rapid, membrane receptor mediated action of corticosterone on neurons that are involved in the control of clasping. In freely behaving newts, medullary neurons, including reticulospinal neurons, process clasp-triggering sensory signals and participate in control of clasping movements. Corticosterone injection causes these brainstem neurons to show selective depression of clasping-related sensorimotor function. These corticosterone effects appear in 3-10 min and are closely associated with the simultaneous depression of clasping. In addition to these functionally specific effects, corticosterone simultaneously causes widespread, primarily depressive effects on neuronal activity and excitability in the medulla and elsewhere in the brain. Thus, the membrane actions of corticosterone lead to diverse neural effects, including changes in membrane excitability as well as specific, network-level actions that are apparent only during behavior. These rapid corticosterone effects strongly interact with actions of the neuropeptides vasotocin and corticotropin-releasing factor, such that the form and magnitude of the steroid's effects depend on the prevailing neuroendocrine state of the brain.Key words: glucocorticoid, membrane receptor, non-genomic, amphibian, reproduction.
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CORRIGAN, Douglas P., Danuta KUSZCZAK, Antonio E. RUSINOL, Douglas P. THEWKE, Christine A. HRYCYNA, Susan MICHAELIS, and Michael S. SINENSKY. "Prelamin A endoproteolytic processing in vitro by recombinant Zmpste24." Biochemical Journal 387, no. 1 (March 22, 2005): 129–38. http://dx.doi.org/10.1042/bj20041359.
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The nuclear lamins form a karyoskeleton providing structural rigidity to the nucleus. One member of the lamin family, lamin A, is first synthesized as a 74 kDa precursor, prelamin A. After the endopeptidase and methylation reactions which occur after farnesylation of the CAAX-box cysteine, there is a second endoproteolysis that occurs 15 amino acids upstream from the C-terminal farnesylated cysteine residue. Studies with knockout mice have implicated the enzyme Zmpste24 (Face-1) as a suitable candidate to perform one or both of these proteolytic reactions. Evidence has been presented elsewhere establishing that Zmpste24 possesses a zinc-dependent CAAX endopeptidase activity. In the present study, we confirm this CAAX endopeptidase activity with recombinant, membrane-reconstituted Zmpste24 and show that it can accept a prelamin A farnesylated tetrapeptide as substrate. To monitor the second upstream endoproteolytic cleavage of prelamin A, we expressed a 33 kDa prelamin A C-terminal tail in insect cells. We demonstrate that this purified substrate possesses a C-terminal farnesylated and carboxyl-methylated cysteine and, therefore, constitutes a valid substrate for assaying the second endoproteolytic step in lamin A maturation. With this substrate, we demonstrate that insect cell membranes bearing recombinant Zmpste24 can also catalyse the second upstream endoproteolytic cleavage.
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De Vos, John, Dirk Hose, Thierry Reme, Hartmut Goldschmidt, Jean-Francois Rossi, Friedrich Cremer, and Bernard Klein. "The Human Plasma Cell Gene Expression Program." Blood 104, no. 11 (November 16, 2004): 3242. http://dx.doi.org/10.1182/blood.v104.11.3242.3242.
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Abstract Seven purified peripheral blood memory B-cells (BM), seven in-vitro-generated polyclonal plasmablastic cells (PPC) and seven purified bone marrow mature plasma cells (BMPC) were studied by oligonucleotide microarrays. All samples were obtained from healthy volunteers. The gene expression profiling of these samples was determined with Affymetrix pan genomic U133A + B arrays (44 928 oligonucleotide probesets). We determined that 2313 genes were differentially expressed between these three B cell categories (P 〈 0.01 by a Kruskal-Wallis test and a ratio between two categories 〉 3). These 2313 genes were classified into six categories, according to the expression profile: early plasma cell genes (EPC), late plasma cell genes (LPC), genes lost early during plasma cell differentiation (LEPC), genes lost late during plasma cell differentiation (LLPC), genes upregulated only in plasmablasts (PBO) and genes lost only in plasmablasts (LPBO). As expected, Ig transcripts where essentially classified as EPC. As a corollary, genes involved in protein synthesis or degradation, transmembrane transporters and metabolism genes were overrepresented in EPC genes. Interestingly, genes involved in intercellular communication and extracellular matrix were enriched in LPC, highlighting the fact that mature plasma cells develop tight interactions with the bone marrow environment. Of note, genes involved in cell cycle are upregulated mainly in plasmablasts, whereas antiapoptotic genes are lost in plasmablasts only. Mains genes known to be involved in plasma cell differentiation display an expression profile in agreement with published data, as illustrated for transcription factors in Figure 1, validating this DNA microarray dataset. However most of these 2313 genes have either never been described yet or have no yet been linked to plasma cell differentiation. The description of those genes among our genome whose expression vary most during plasma cell differentiation will be an essential step in understanding the biology of a cell type essential to immune defenses and involved in deadly diseases. Figure 1: Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response. Figure 1:. Transcription factors involved in plasma cell differentiation. Color indicates the expression profile category. For each gene is given the ratio of the mean expression value in plasma cell samples (PPC and BMPC) to the mean expression value in BM. UPR: Unfolded Protein Response.
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Gomes, Marilia, Sara Duarte, Carolina Afonso, Dulcelena Neves, Bárbara Almeida Marques, Carla Barros Lima, Adriana Roque, et al. "Prognostic Scoring Systems in Diffuse Large B Cell Lymphoma Patients - Is Kyoto Prognostic Index an Added Value?" Blood 138, Supplement 1 (November 5, 2021): 4574. http://dx.doi.org/10.1182/blood-2021-150959.
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Abstract Background: Diffuse large B cell Lymphoma (DLBCL), the most common non-Hodgkin lymphoma, is a clinical and biological heterogeneous entity. R-CHOP is the standard treatment, however 30%-40% of DLBCL patients will have primary refractory or relapsed disease. Several prognostic scoring systems, that include simple clinical parameters, have been developed to assist risk stratification and treatment decisions, namely the International Prognostic Index (IPI), the National Comprehensive Cancer Network IPI (NCCN-IPI) and the GELTAMO-IPI. However, the accurate identification of very high-risk patients is not accomplished by these scores. Recently, the Kyoto Prognostic Index (KPI) was able to identify an extremely poor prognostic group in a Japanese cohort and was proposed as a new robust prognostic model for DLBCL. Our aim was to assess the discriminative performance of IPI, NCCN-IPI and GETALMO-IPI in overall survival (OS) and progression-free survival (PFS) and compare them with the new score KPI, in a cohort of DLBCL patients treated with immunochemotherapy. Methods: Retrospective analysis of HIV-negative DLBCL patients, newly diagnosed between 2010 and 2019 in a single tertiary center, treated with R-CHOP/R-CHOP-like protocol. The Kaplan-Meier method was used to estimate the probabilities of OS and PFS. Stratified models for each of the risk scores (IPI, NCCN-IPI, GELTAMO-IPI and KPI) were compared using Akaike's information criterion (AIC) and the Harrell's concordance index (C-index). The inter-score classification concordance was evaluated by Cohen's kappa test. P-value<0.05 was considered statistically significant. Results: We included 232 patients, 52.6% (n=122) male, with a median age of 64 years (22-87). According to IPI, patients classified as Low (L), Low-Intermediate (LI), High-Intermediate (HI) and High (H) were 73 (31.47%), 59 (25.43%), 63 (27.16%) and 37 (15.95%), respectively. According to NCCCN-IPI, patients classified as L, LI, HI and H were 23 (9.91%), 94 (40.52%), 89 (38.46%) and 26 (11.21%), respectively. GETALMO-IPI was calculated in 170 of 232 patients, classified as L, LI, HI and H in 14 (8.24%), 119 (70.0%), 22 (12.94%) and 15 (8.82%), respectively. According to KPI, patients classified as L, LI, HI and H were 67 (28.88%), 122 (52.59%), 31 (13.36%) and 12 (5.17%), respectively. Between KPI and IPI, a fair concordance was observed (kappa 0.363; with only 10 [27%] IPI-H patients classified as KPI-H, and 10 [83.3%] patients KPI-H as IPI-H). Slight concordance was observed between KPI and NCCN-IPI (kappa 0.115; 9 [34.6%] patients NCNN-IPI-H classified as KPI-H, and 9 [75%] patients KPI-H as NCCN-IPI-H), as well as between KPI and GELTALMO-IPI-H (kappa 0.175; 6 [40%] patients GELTALMO-IPI-H classified as KPI-H, and 6 [60%] patients KPI-H as GELTALMO-IPI-H). With a median follow-up of 55.2 months, 5-year median OS and PFS for the global cohort were not reached (NR) and 128.2 months, respectively. All the scores identify different prognosis groups for OS and PFS, although with modest ability to distinguish between intermediate and high-risk groups (Table 1; Figure 1). GELTAMO-IPI provided the best fit for the data in both OS and PFS (AIC 479.4 and 631.0, respectively) followed by NCCN-IPI (AIC 727.3 and 933.8) and IPI (AIC 738.3 and 937.9), while KPI had the worst performance (AIC 745.6 and 943.7). NCCN-IPI discriminated better between patients with poor and favorable OS (C-index 0.667), compared with the remaining scores (C-index for IPI, GELTAMO-IPI and KPI 0.653, 0.647 and 0.612, respectively). Concerning PFS, IPI had the best discrimination capacity (C-index 0.6313), followed by NCCN-IPI (C-index 0.6232), GELTAMO-IPI (C-index 0.6086) and KPI (C-index 0.5940). Conclusions: In our cohort, GELTAMO-IPI had the best fit to the observed data regarding OS and PFS. NCCN-IPI and IPI discriminated better between patients with poor and favorable OS and PFS, respectively, although the differences in the C-index were small, and all scores exhibited an acceptable difference between short and long survival times. KPI did not seem to improve the capacity for predicting OS and PFS in our population, which could be explained by differences in pathophysiology and genetics of DLBC of Asian and Western patients. Novel risk scores that integrate molecular tumor features might help improve risk stratification, especially in high-risk group. Figure 1 Figure 1. Disclosures Gomes: Takeda: Consultancy; Gilead: Consultancy; Janssen: Consultancy.