bluuebunny/crossref_metadata_2025_split huggingface dataset:
Persistence of High Viral Load Abrogates Long-Term HIV-Specific Memory CD4 T-Cells Producing Interleukin-2.
Authors: Boulassel Mohamed-Rachid , Younes Souheil-Antoine , Yacine-Diab Bader , Sekaly Rafick-Pierre , Routy Jean Pierre 
Published: April 2020

Abstract
Virus-specific CD4 T-cells are believed to play a critical role in determining the persistence of memory and effector CD8 T-cell responses during viral infections. However, the reasons for which human immunodeficiency virus (HIV)-specific CD4 cells fail to generate effective CD8 cell responses remain incompletely understood. In this study, we analyzed the HIV-specific CD4 cells in 10 aviremic (viral load &lt; 50 copies/ml) and 8 viremic (mean viral load 45,295 copies/ml) patients treated during primary HIV infection and followed for up to 6 years. At the time of apheresis, median CD4 T cell counts for aviremic and viremic patients were 671 cells/μl and 485 cells/μl respectively. Using Gag and Nef overlapping HIV peptides, the highly sensitive CFSE-based proliferation assay and intracellular staining techniques, we observed that proliferative Gag and Nef peptide-specific CD4 cell responses were 30-fold higher in aviremic patients compared to viremic. Several subsets of HIV-specific memory CD4 cells endowed with different proliferative and functional capacities were identified. We observed two subsets of HIV-specific memory CD4 cells in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively IL-2 and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and IFN-γ. In contrast, in viremic patients, Tem were found to unexpectedly produce IFN-γ exclusively. Longitudinal data showed that only cells, which were capable of producing IL-2, persisted as long-term memory cells. In viremic patients, HIV-specific CD4 cells that produce INF-γ were found only during periods of elevated viral loads. To test if the presence of IL-2 could restore the proliferation of these cells, we stimulated CD4 cells from viremic patients with a pool of peptides, which gave strong IFN-γ responses in these patients in the presence of exogenous IL-2. The addition of IL-2 during the in vitro peptide stimulation dramatically increased the fraction of proliferating cells. This experiment strongly suggests that the impaired proliferation of CD4 cells from viremic patients is not caused by a virus-mediated destruction of proliferating cells but a lack of producing IL-2. Altogether, these results indicate that long-term memory HIV-specific CD4 cell produce mainly IL-2, while those producing IFN-γ are short-lived. These findings favor a model in which Tcm are continuously produced in limited numbers but under continuous viral stimulation are rapidly induced to differentiate into IFN-γ only-producing cells that lack the capacity for self-renewal.These findings also indicate that treatment strategies aimed to increase the long-term memory CD4 cells are needed for future HIV vaccine development.
Zoledronic Acid (ZA)- Associated Nephrotoxicity: An Analysis of Adverse Drug Reaction (ADR) Reports by the Research on Adverse Drug Events and Reports (RADAR) Project.
Authors: McKoy June M. , Obadina Eniola , Yarnold Paul R. , Kut Victoria , Raisch Dennis W. , Bennett Charles L. 
Published: April 2020

Abstract
Background-The FDA originally approved zoledronic acid (ZA) in August 2001 for the treatment of hypercalcemia of malignancy and subsequently for prevention of skeletal related events among patients with multiple myeloma (MM), breast, and prostate cancer. Since its approval, the FDA has received several reports of nephrotoxicity. Many of these individuals have myeloma, a malignancy associated with renal damage. Herein, RADAR investigators reviewed the clinical characteristics of ZA-induced nephrotoxicity among cancer patients with multiple myeloma versus other malignancies. We investigated the clinical characteristics and reporting quality of all adverse event (AE) reports describing ZA-associated neprotoxicity.
Methods- We analyzed reports of ZA-associated nephrotoxicity from the FDA’s Adverse Event Reporting System, which included a total of 141 AE reports, with exclusion of cases/trials reported in duplicate.
Results- Overall, 141 cases of ZA-associated renal failure (RF) were identified: 92 case reports were from the United States and 44 were from non-United States countries. Reporting completeness was generally poor, with respect to serum creatinine levels and frequency of ZA administration, especially in reports from Canada and Great Britain respectively. Two thirds of the patients with scheduling information had received ZA every 4 weeks. Infusion rate was reported for 21%, and was usually 15 minutes or longer. NSAIDS and Cox-II inhibitor exposures were reported in 25%, and 20% of the patients who had prior diagnoses of renal insufficiency. Patients with MM (n=82) had similar mean age as patients with other cancers (n= 54) (72.05 versus 72.9 years). For patients for whom data was available (n=62), pamidronate was used by 97.8% in the MM group versus 86.9% in the non-myeloma group. The onset of RF occurred after a mean of 67.9 days in the MM group (range, 3–366) versus 73.7 days in the non-myeloma group (range, 0–546 days) post initiation of ZA; after a mean number of ZA doses (2.5 vs. 1.8 doses). Only one dose of ZA was received by 24.4% and 25.4% of MM versus non-myeloma patients respectively, which occurred after an average of 14.7 days and 30 days. RF manifestations included serum Cr &gt; 2 for 59.7% of the MM and 83.1% of the other cancer patients. Outcomes of RF in MM and non-myeloma patients, respectively, included hospitalization (61% and 71%) and dialysis, (38% and 22%).
Conclusions- Close monitoring of serum creatinine prior to ZA, is important for both MM and other cancer patients; completeness of current case reporting efforts of ZA-associated renal insufficiency is poor in both US and non-US countries; and information about the potential occurrence of renal toxicity should be prominently described in the packet insert for ZA.
RNA Expression Levels of (Co)Chaperone Molecules of the Glucocorticoid Receptor Are Not Related to In Vitro Prednisolone Resistance in Childhood ALL.
Authors: Tissing Wim , Meijerink Jules P.P. , den Boer Monique L. , Brinkhof Bas , Pieters Rob 
Published: April 2020

Abstract
In vitro resistance to Glucocorticoids (GC) is an important adverse risk factor in the treatment of ALL. To induce apoptosis in ALL cells, GC have to bind to the GC receptor (hGR), which is tightly regulated by various (co)chaperone molecules. HSP70, ST13 and HSP40 facilitate hGR binding to HSP90 and HOP in an energy dependent fashion. This complex is stabilised by immunophillins FKBP 51, FKBP59, CYP40 and P23 and is necessary for the hGR to be able to bind GC. The ATPase BAG1 can function as negative regulator of HSP70, and may downregulate hGR activity. After the GC-hGR complex is formed, it is transported to the nucleus to regulate GC responsive genes. In this study, we tested the hypothesis that RNA expression levels of these (co) chaperone molecules are important determinants for in vitro prednisolone sensitivity in childhood ALL.
Methods: 20 children with leukemic cells in vitro sensitive to prednisolone (LC50&lt;0.1μg/ml) were matched (according to age, immunophenotype and white blood cell count at diagnosis) each with an in vitro resistant patient (LC50 &gt; 150 μg/ml). RNA expression levels of the different (co)chaperone molecules were measured by a quantitative real-time RT-PCR (Taqman) assay and standardised to endogenous GAPDH and RNAseP mRNA levels. In vitro resistance to prednisolone was measured by the MTT assay.
Results. The highest median expression levels, indicated as percentage of GAPDH levels were found for HSP90 (29%) and p23 (10%), whereas FKBP51 and ST13 were expressed at 2% and 1.6% respectively. HSP70 (0.1%), HSP40 (0.44%), HOP (0.2%), FKBP59 (0.4%), PPID (0.3%) and BAG-1 (0.4%) were expressed at relatively low levels. Using matched pair analysis, no significant differences were found for the expression levels of the various (co)chaperone molecules between in vitro sensitive and resistant patients. The ratio of different (co)chaperone molecules with opposing effect (HIP versus BAG-1, FKBP-51 versus FKBP-52, HSP-90 versus P23, and HSP-90 versus the functional GR-alpha receptor, positive and negative effect respectively) was not related to GC resistance as well.
Conclusion: Glucocorticoid resistance in childhood ALL can not be attributed to basal expression levels of the diverse (co)chaperone molecules involved in GC binding and transport of the GC-GR complex to the nucleus of the GR.
Immunophenotyping to Detect Minimal Residual Disease in Adult Acute Lymphoblastic Leukemia - Feasibility and Prognostic Significance.
Authors: Holowiecki Jerzy , Giebel Sebastian , Jagoda Krystyna , Krawczyk-Kulis Malgorzata , Stella-Holowiecka Beata , Kyrcz-Krzemien Slawomira , Paluszewska Monika , Kopera Malgorzata , Medrek Wlodzimierz , Bober Grazyna , Najda Jacek 
Published: April 2020

Abstract
Although well documented for pediatric patients, the prognostic value of minimal residual disease (MRD) detected with the use of immunophenotyping has not been established for adults with acute lymphoblastic leukemia (ALL) so far. With the use of standard “quadrans” analysis based on evaluation of the number of blasts bearing atypicial antigen combinations, the method may be applied to the majority of T-derived and only approximately half of B-lineage ALL. In this study we tested the feasibility and prognostic significance of a new “empty spaces” method taking into account the individual antigen expression pattern for each blast cell tested. The “forbidden” gates were established with the use of triple staining by comparison with the pattern obtained for healthy volunteer bone marrow donors. At least two antigen combinations were tested for each patient. MRD was evaluated after induction and after consolidation therapy. Only patients who achieved complete remission after a single course of induction were analysed with regard to the impact of MRD on long-term outcome.
Thirty adult ALL patients (B-lineage n=24, T-lineage n=6) were included in the study. For all cases it was possible to determine unique antigen expression pattern and to monitor MRD with the use of immunophenotyping at the level of 1/1000 cells. MRD was detected in 8/30 patients after induction and in 7/28 patients after consolidation tharapy (two patients relapsed during consolidation). For 11/30 patients the MRD resulted positive at least once.
At 20 months the relapse rate equaled 53% for patients with MRD detected after induction or consolidation and 28% for those with MRD always negative (p=0.08). The difference was more pronounced for patients with B-lineage ALL (67% vs. 26%, p=0.02). A single MRD evaluation after induction therapy had no significant prognostic value for the risk of relapse whereas there was a trend for higher relapse rate in B-lineage ALL patients with positive MRD after completion of consolidation therapy compared to those MRD-negative at that time-point (75% vs. 32%, p=0.06).
Results of the study prove the feasibility of immunophenotypic MRD evaluation in ALL. “Empty spaces” in addition to the standard “quadrans” analysis allows monitoring of the vast majority of patients regardless the immune subtype. Even with a small number of cases we were able to demonstrate its prognostic value for long-term outcome of adults with ALL.
Pharmacokinetics of Vincristine in Infants with Acute Lymphoblastic Leukemia.
Authors: Bomgaars Lisa , Hunter Chelsea , Huang Rong , Schmidt Mark , Dreyer ZoAnn , Blaney Susan , Berg Stacey , Murry D.J. 
Published: April 2020

Abstract
An understanding of vincristine (VCR) pharmacokinetics (PK) is important to achieve drug dosing that optimizes efficacy and minimizes toxicity. Limited information is available on the PK behavior of VCR in infants.
Objectives: To determine the PK of VCR in infants, and to compare the PK parameters of infants to those in older children.
Methods: A subset of 28 patients enrolled on the Pediatric Oncology Group 9407 infant leukemia study participated in this VCR PK study. PK samples were collected following the administration of VCR (0.05 mg/kg) i.v. push on week 1, day 1 of treatment. Twenty-eight patients, median age 7.1 months (range, 0.1–11.9 months) had blood samples collected for analysis of VCR concentrations at 5 minutes, and 0.5, 1, 4, and 24 h after drug administration. Samples were analyzed using a validated LC-MS method. A two-compartment model was fit to each patients data using Bayesian estimation (Adapt II software).
Conclusions: PK parameters in infants &lt; and &gt; 6 months of age were similar. CL in this population ranged from 7.8–31 ml/min/kg and was correlated with body weight, however only 25% of the variability in VCR CL could be accounted for by this variable. CL and t1/2 values are similar to those previously reported in older children. Evaluation of pharmacokinetic/pharmacodynamic correlation is ongoing.
Results:
VCR (mean ± SD) AUC (mcg•hr/L ) 41.7 ± 19 CL (ml/min/kg) 19.2 ± 6 Vc (L/kg) 1.3 ± 1 t 1/2 elimination (h) 17.1 ± 8.3 Kcp (hr-1) 5.2 ± 1.7 Kpc (hr-1) 0.3 ± 0.14
Pegfilgrastim Provides Safe and Rapid Neutrophil Support in Patients with Acute Myeloid Leukemia (AML) Undergoing Myelosuppressive Chemotherapy.
Authors: Ranze Oliver , Arland Malte , Hoeffkes Heinz-Gert 
Published: April 2020

Abstract
Background: Administration of recombinant G-CSF has found extensive use in the support of chemotherapy-induced neutropenia in patients undergoing myelosuppressive chemotherapy. We retrospectively analyzed patients with acute myeloid leukemia (AML) who received either pegfilgrastim or lenograstim in this setting.
Patients and Methods: Unselected patients with AML according to FAB, age &gt;18 years, performance status ECOG &lt; 3, excluding pregnancy received at least one cycle of chemotherapy. On day 1 after chemotherapy has ended G-CSF treatment was initiated with pegfilgrastim 6 mg once per cycle or lenograstim 5 micg/kg b.w. until leucocyte counts (LC) raised &gt; 1,000/micL. Primary objective was the difference in the time to elevating LC &gt; 1,000/micL in each G-CSF treatment groups if LC nadired &lt; 1,000/micL and the difference in the substitution of packed red blood (PRB) and platelets (PLT).
Results: Twenty-eight patients, 12 males and 16 females, aged median 61.4 years (range: 27–75 years) received 46 cycles. Six patients died due to the underlying disease. In four patients (two patients in the pegfilgrastim and two patients in the lenograstim group) G-CSF treatment failed to elevate LC &gt; 1,000/micL. There was a difference in the time-to-recovery of leucocyte counts between pegfilgrastim 11.3 ± 3.8 days (range: 6 to 28 days) and lenograstim 13.3 ± 3.3 days (range: 6 to 22 days). The frequency of transfusions of PRB was 3.3 ± 2.6 in pegfilgrastim treated patients compared with 5.0 ± 2.9 in patients treated with lenograstim and the frequency of transfusions of PLT was 4.8 ± 2.5 vs. 6.0 ± 4.5. These differences received no statistical significance.
Conclusion: In this retrospective analysis unselected patients received myelodepressive chemotherapy because of acute myeloid leukemia. Both G-CSF showed adequate recovery of leucocyte counts with a faster increase in those patients to whom pegfilgrastim was administered. No statistical difference in the frequency of donation of human blood products was recognized. This retrospective study was limited because of the small number of patients included, thus these promising results need to be confirmed in a larger, prospective trial.
Combination Therapy of Humanized Chimeric-Anti-Human VLA4 Monoclonal Antibodies and Anti-Cancer Drugs for AML.
Authors: Matsunaga Takuya , Kato Kazunori , Tanaka Maki , Masuta Yukari , Kuribayashi Kageaki , Takemoto Naofumi , Tanaka Ikuta , Fujimi Akihito , Akiyama Takehide , Hamada Hirofumi , Niitsu Yoshiro 
Published: April 2020

Abstract
Bone marrow (BM) minimal residual disease causes relapse after chemotherapy in AML. We have previously reported that VLA4-positive leukemic cells acquired resistance to drug-induced apoptosis through the PI-3K/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA4 and fibronectin on BM stromal cells. This resistance was negated by mouse-anti-human VLA4Ab (mouse VLA4Ab). In human leukemia SCID mouse model, we demonstrated a 100% survival rate with combination of mouse VLA4 Ab and AraC, while with AraC alone, only slight prolongation of survival was attained. In clinical study, overall survival at 5 years was 90% for 10 VLA4− patients and 25% for 15 VLA4+ patients (Matsunaga T et al, Nature Med 2003, 9, 1158–1165). In the present study, to perform the translational research, we first examined the myelosuppressive effect of the combination of rat-anti-mouse VLA4 Ab and AraC in C57/BL6 mice, and found that CBC data were almost the same as those of the mice treated with AraC alone. We next produced humanized chimeric-anti-human VLA4 Ab (chimeric-VLA4Ab), and examined its efficacy in combination with anti-cancer drugs in vitro and in vivo (human leukemia SCID mouse model). Chimeric-VLA4Abs were produced as follows: (i) total RNA of mouse VLA4 Abs were extracted from two hybridomas (SG/17 and SG/73), (ii) cDNA were synthesized by reverse transcriptase, (iii) variable region gene of mouse VLA4 Abs were amplified by 5′RACE method, (iv) TA cloning of amplified gene was performed, (v) sequence of mouse VLA4Abs gene was determined, (v) cloned variable region gene of mouse VLA4 Abs and constant region gene of human IgG1 were inserted into expression vector, and the expression vector was transfected into 293T cells, (vi) supernatant of the 293T cells was collected and purified to obtain chimeric-VLA4 Abs. The effects of chimeric-VLA4 Abs thus obtained in in vitro and in vivo (human leukemia SCID mouse model) were comparable to those of mouse VLA4 Abs. To perform the clinical study, we are presently producing the GMP-graded chimeric-VLA4 Abs.
Predictive Value of Bcl-2 and Bcl-6 Protein Expression in Diffuse Large B-Cell Lymphoma Patients from a Single Institution.
Authors: Paszkiewicz-Kozik Ewa , Mioduszewska Olga , Federowicz Irena , Kraszewska Ewa , Kulczycka Elzbieta , Domanska-Czyz Katarzyna , Ostrowska Beata , Romejko-Jarosinska Joanna , Osowiecki Michal , Walewski Jan A. 
Published: April 2020

Abstract
Bcl-2 and Bcl-6 protein expression has been reported to predict progression-free (PFS) and overall (OS) survival of patients with Diffuse Large B-cell Lymphoma (DLBCL) in retrospective and prospective clinical studies. Reports on Bcl-2 expression frequency and predictive value have been conflicting. In the current study, paraffin-embedded tissue specimens from 79 newly diagnosed DLBCL patients subsequently treated with CHOP-like chemotherapy without rituximab were studied retrospectively using immunohistochemistry to evaluate expected influence of Bcl-2 and Bcl-6 on clinical outcome. Bcl-2 and Bcl-6 positivity was defined as staining in any of lymphoma cells and it was demonstrated in 78% of Bcl-2 and 58% of Bcl-6 patients. Frequency of Bcl-2 protein expression in our study was much higher then reported by others. Combinations of possible positive/negative staining results: Bcl2+/Bcl6+, Bcl-2+/Bcl-6-, Bcl-2-/Bcl-6+, Bcl-2-/Bcl-6- were found in 46%, 33%, 13%, and 9% of cases, respectively. Complete remission (CR) after initial chemotherapy was achieved in 54 of 74 evaluable patients (73%) and 6 patients (8%) had progressive disease (PD). CR rate was higher and relapse and death rate was lower in patients with Bcl-6+ tumor irrespective of Bcl-2 status. In patients with Bcl-6 negative lymphoma CR rate was higher when Bcl-2 was positive, but relapse and death rate was not affected by Bcl-2. Median OS and PFS were not reached after 21.3 months of follow-up in this group of patients. In the analysis using multivariate proportional hazards regression model, advanced clinical stage (CS III and IV vs. CS I and II) was the only significant factor predicting OS (p&lt;0.002). Risk of relapse or PD was significantly lower in patients with IPI score of 0 or 1 vs. &gt; 1 (p&lt;0.001), and in patients with both Bcl-2 and Bcl-6 positive lymphoma (p=0.04) as compared to patients with all other protein expression combinations. When analyzed separately, Bcl-6 positivity alone predicted PFS (p=0.025) while Bcl-2 was not significant (p=0.98). These results support predictive value of Bcl-6 protein expression for response to CHOP and PFS in DLBCL patients and are in agreement with the recent findings from the E4494 trial group (Blood102:101a, Abstr. 345, 2003). Unlike the findings of the GELA study (Blood101: 4279, 2003), our data fail to confirm predictive role of Bcl-2 protein.
Figure Figure
The Expression of Protein Kinase C Beta II (PKCβ) by Immunocytochemistry Is Predictive of the Disease Free Survival (DFS) in Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Schaffel Rony , Biasoli Irene , Scheliga Adriana , Morais Jose C. , Romano Sergio , Pulcheri Wolmar , Spector Nelson 
Published: April 2020

Abstract
PKCβ is a regulatory factor involved in the nuclear factor kappa B pathway. PKCβ gene expression was pinpointed through microarray studies by Shipp et al as one of thirteen, among over six thousand studied genes, to be associated with the probability of cure in DLBCL. The authors also reported a good correlation between PKCβ gene expression and protein expression, and added that in their hands PKCβ protein expression was closely associated with the clinical outcome. Therefore, we analyzed the PKCβ protein expression in 71 samples of DLBCL (44 nodal) by immunocytochemistry. A case was considered positive only if the antigen was unequivocally expressed in the large cells. PKCβ expression was found in 10/71 (14%) of the cases. Some cases had PKCβ expression only in the small lymphocytes, and were considered negative, since this antibody intensely stained mantle zone cells. Most samples had positive internal controls, as both plasma cells and residual mantle zone cells were strongly stained by the antibody. The patients’ clinical and biological features were similar in PKCβ positive and negative cases (median age 51 vs. 58 years; male gender 50% vs. 67%; extranodal disease 30% vs. 39%; high IPI 10% vs. 27%; Bcl-2 expression 50% vs. 41%, and CD10 expression 20% vs. 23%). None of these differences were statistically significant. The presence of PKCβ expression was not related to 7-year overall survival (56% vs. 48%, p=0.8). The 5-year event free survival was 54% and 33% in PKCβ negative and positive cases, respectively (p=0,7). A complete remission after an anthracycline based first line chemotherapy was obtained in 75% and 90% of PKCβ negative and positive cases, respectively (p=0,4). However, the 5-year DFS was 80% and 37%, for PKCβ negative and positive cases, respectively (p&lt;0,03). In conclusion, in our cohort of patients the prognostic impact of PKCβ expression was restricted to the DFS.