bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional Outcomes After Isolated and Combined Posterior Cruciate Ligament Reconstruction in a Military Population
Authors: Tucker Christopher J. , Cotter Eric J. , Waterman Brian R. , Kilcoyne Kelly G. , Cameron Kenneth L. , Owens Brett D. 
Published: October 2019

Background: The rates of return to full activity, persistent disability, complications, and surgical revisions after operative management of posterior cruciate ligament (PCL) tears in a physically active population have not been reported. Purpose: To evaluate the clinical outcomes of active military patients with symptomatic PCL tears who underwent surgical reconstruction and compare outcomes between isolated PCL and multiligament injuries. Study Design: Cohort study; Level of evidence, 3. Methods: Individuals undergoing surgical reconstruction of the PCL (Current Procedural Terminology code 29889) were isolated from the Military Health System Management Analysis and Reporting Tool between fiscal years 2005 and 2010. Demographic variables and rates of postoperative complications, activity limitations, rates of revision surgery, physical disability ratings, and ultimate medical discharge were recorded from the electronic medical record and US Army Physical Disability Agency database. Results: A total of 182 patients underwent 193 surgeries, including 118 isolated PCL reconstructions and 75 multiligament knee reconstructions, with an average follow-up of 19.5 months. There were 174 primary procedures and 19 revision reconstructions. The mean ± SD patient age was 28.4 ± 7.2 years, with males comprising 96.2% of patients. The overall surgical complication rate was 12.4%, with a significantly higher rate in multiligament knee reconstructions compared with isolated PCL reconstructions (18.7% vs 8.5%; P = .045). Overall, 35.1% of patients were discharged from military service due to disability. Rates of discharge were significantly higher in those undergoing surgery at lower volume institutions (those that performed <2 PCL reconstructions per year during the study period) than those at higher volume institutions (41.1% vs 26%; P = .040). The overall revision rate was 10.9%, with no significant difference between the isolated PCL and multiligament knee reconstructions. Of the 103 patients with primary isolated PCL reconstructions, 35% underwent medical discharge for persistent knee complaints, and 12.6% required revision PCL reconstruction. The overall failure rate for primary isolated PCL reconstructions, which includes both revision surgery and knee-related medical discharge from military service, was 42.7%. Conclusion: In a physically active, military population, nearly one-third of patients were unable to return to previous level of military function, and 12.6% required revision at short-term follow-up due to persistent instability. Perioperative complication rates were significantly higher among patients with multiligament knee reconstructions.
Unsupervised Analysis of Human Leukemia Cells Identifies the Valosin-Containing Protein as a Putative Marker for Glucocorticoid Resistance.
Authors: Lauten Melchior , Neuhoff Nils v. , Welte Karl , Schlegelberger Brigitte , Schrappe Martin 
Published: October 2019

Abstract
The prednisone response (PR) is a clinical phenomenon in childhood acute lymphoblastic leukemia (ALL) indicating in vivo glucocorticoid (GC) resistance. For patients treated within the ALL-Berlin-Frankfurt-Muenster treatment protocols, the PR is the strongest predictor for therapy outcome. PR is defined by the number of peripheral leukemic blasts on day eight of initial prednisone treatment. The threshold value for the distinction between good and poor prednisone response is 1000 blasts/μl. In trial ALL-BFM 90, prednisone good responders (PGR) had an estimated probability of 6-years event free survival (6y-pEFS) of 82% in contrast to prednisone poor responders (PPR), who showed a 6y-pEFS of only 34% (Schrappe et al., Blood 95(11):3310–3322, 2000). Despite various attempts to elucidate the cause of glucocorticoid resistance, its biological background still remains unclear. Therefore, we performed a case-control study for PR using two-dimensional electrophoresis (2-DE) as screening method to broadly investigate proteome differences in leukemic blasts from in vivo glucocorticoid sensitive and resistant childhood B-cell precursor ALL patients. Producing virtual average gels and difference maps for the proteomes of each responder group by software analysis we identified differentially expressed proteins in glucocorticoid sensitive as well as in glucocorticoid resistant patients. Among the differentially expressed proteins, the valosin-containing protein (VCP) appeared to be overexpressed in PPR. VCP was identified after excision of the respective spot from the 2-DE gel, tryptic digestion and analysis by surface enhanced laser desorption and ionisation (SELDI) mass spectrometry. In previous studies VCP had already been associated with prognosis in different solid tumour entities. This was the reason, why we chose the VCP for validation and quantification by Western Blot analysis. For the Western Blot analysis, a second independent case-control-group of B-cell precursor ALL patients was investigated (cases: 10 PPR, controls: 20 PGR), which confirmed the 2-DE results: median VCP expression (P25-P75) in all ALL samples was 0.19 (0.12 – 0.40) compared to 0.15 (0.11 – 0.28) in PGR and 0.34 (0.14 – 0.99) in PPR patients (P>0.05). This is the first study detecting the association of VCP and GC resistance in two different sets of closely matched patient samples representing one of the leading disease entities treated with GCs.
Immunoglobulin (Ig) Variable Gene Usage Identifies a Subset of Unmutated Chronic Lymphocytic Leukemia (CLL) Patients Expressing 51p1-Like alleles and a Particularly Unfavorable Prognostic Outcome.
Authors: Ghia Emanuela M. , Guarini Anna , Mauro Francesca R. , Gentile Massimo , Starza Irene Della , Capello Daniela , Gaidano Gianluca , Foa Robert 
Published: October 2019

Abstract
Great interest has recently focused on a biased use of the immunoglobulin (Ig) heavy chain variable region genes (VH genes) and on a preferential light chain (VL gene) usage in patients with chronic lymphocytic leukemia (CLL). VH / VL bias maybe correlated with a possible response to a common antigen epitope. To further investigate the Ig VH gene usage in CLL, DNA was extracted from peripheral blood mononuclear cells of 137 consecutive unrelated and untreated CLL cases. PCR amplification was performed using VH family specific and consensus JH primers, followed by automated sequencing. The sequences were aligned to Ig sequences from the GenBank and V-BASE databases. The VH family gene usage was as follows: VH1 19.7%, VH2 4.4%, VH3 49.6%, VH4 21.9%, VH5 2.2% and VH6 2.2%. Mutated VH genes (>2% mutations) were found in 58.4% of the cases analyzed and unmutated VH genes (<2% mutations) were detected in 41.6% of samples. Within the VH1 gene family, 88.9% of cases were unmutated and the most frequently expressed alleles were related to 51p1 (a major VH1-69 allele), that accounted for 10.2% of all VH rearranged genes and for 51.9% of rearranged VH1 genes. Among all patients expressing unmutated 51p1-like alleles, a preferential use of certain D segments was observed: D2-2 accounted for 28% of cases, followed by D3-3 and D3-16 that accounted for 21.4% and 14.3%, respectively; D1-20, D3-10, D3-22, D5-18 and D6-6 were less frequently expressed (1 case each). The most frequently used JH gene segment was JH6 (64.3%), whereas JH4 and JH3 accounted for 21.4% and 14.3%, respectively. All patients expressing 51p1-like alleles showed an identical CDR2 region. The CDR3 region was characterized by similarities in a subset of cases: the amino acid motifs DIVVVPAA(I/M) and GGXYDY(I/V)WGSYRPNDAFDI were the most common and accounted each for 14.3% of CLL samples that expressed 51p1-like alleles: 79% of all patients expressing 51p1-like alleles had a long CDR3 region of 19.4 ± 2.9 codons. In contrast to what has been observed in other diseases, e.g. mixed cryoglobulinemia and non-Hodgkin lymphoma, all VH1-69 expressing CLL cases analyzed were not associated with HCV infection. The overall median survival for this subset of patients was 40 months, considerably shorter than the reported median survival of unmutated CLL cases; furthermore, to date 36% of patients have succumbed of their disease. The results of this study confirm, on the one hand, that restricted CDR3 features and a biased VH gene repertoire are suggestive of a role of antigen selection operational in this disease and have allowed, on the other hand, to identify a subset of patients with a particularly unfavorable survival compared to the overall population of unmutated CLL cases.
DNA Microarray Analysis of Stage Progression Mechanism in Adult T-Cell Leukemia.
Authors: Choi Young Lim , Tsukasaki Kunihiro , Onimaru Yasuyuki , Yamada Yasuaki , Kamihira Shimeru , Tomonaga Masao , Mano Hiroyuki 
Published: October 2019

Abstract
Adult T-cell leukemia (ATL) is an intractable malignancy of peripheral CD4-positive T cells, in which human T-cell leukemia virus type I plays a pathological role. Clinical course of ATL can be subdivided into several phases; indolent “smoldering” and “chronic” stages, and aggressive “acute” stage. Individuals at the former usually undergo a stage progression toward the latter within several years, and ATL cells at the acute stage are highly refractory to current chemotherapeutic reagents. Molecular mechanisms underlying this stage progression are poorly understood yet. DNA microarray enables us to quantitate the mRNA amount for tens of thousands of genes simultaneously, and may provide novel insights into the pathogenesis as well as the stage progression mechanism of ATL. However, since the proportion of ATL cells within mononuclear cells (MNCs) of peripheral blood (PB) varies among different stages, it would be desirable to purify and directly compare ATL cells for an accurate profiling of gene expression. Given the fact that most PB MNCs are occupied by ATL cells in both chronic and acute stages, we purified CD4-positive T cells from PB of ATL individuals at chronic (n = 19) or acute (n = 22) stage. As a normal control, surface marker-matched T cells were purified from PB of healthy volunteers, and stimulated in vitro or not with PHA (n = 3 for each). A total of 47 specimens were thus subject to DNA microarray analysis with Affymetrix HGU133 A&B array sets, measuring the transcriptional level of ~33,000 human genes. Unsupervised hierarchical clustering based on the whole genes indicated that normal CD4-positive T cells, irrespective of PHA stimulation, had a molecular signature distinct from that of CD4-positive ATL cells, while the acute and chronic stages of ATL were not clearly separated from each other. Combination of a t-test (Welch’s ANOVA, P<0.001) and an effect size selection (>150 U) identified 46 genes, expression of which contrasted the two clinical stages of ATL. Correspondence analysis of such stage-associated genes also demonstrated visually that both phases of ATL have a distinct molecular signature. Additionally, a very high accuracy was obtained by an artificial neural network in a trial of gene expression-based stage diagnosis. Further, we tried to screen, from our data set, novel “acute stage-specific gene markers”, resulting in the identification of a gene for a cytokine receptor. Intriguingly, the serum concentration of its ligand protein was elevated in ATL patients, especially at the acute stage. This autocrine loop for cell growth would be an interesting candidate for the transforming events which triggers the stage-progression in ATL, and also be a candidate for the targets of novel ATL therapies.
Gene Expression Profiling of Leukemic Cell Lines and Primary Leukemias Reveals Conserved Molecular Signatures among Subtypes with Specific Genetic Aberrations: Identification of Fusion Gene-Specific Transcriptional Profiles and Expression Pattern of Tyrosine Kinase-Encoding Genes.
Authors: Andersson Anna , Edén Patrik , Lindgren David , Nilsson Jens , Lassen Carin , Heldrup Jesper , Fontes Magnus , Borg Åke , Mitelman Felix , Johansson Bertil , Höglund Mattias , Fioretos Thoas 
Published: October 2019

Abstract
Hematologic malignancies are characterized by fusion genes of biological/clinical importance. Immortalized cell lines with such aberrations are today widely used to model different aspects of leukemogenesis. Using cDNA microarrays, we determined the gene expression profiles of 40 cell lines as well as of primary leukemias harboring 11q23/MLL-rearrangements, t(1;19)[TCF3/PBX1], t(12;21)[ETV6/RUNX1], t(8;21)[RUNX1/CBFA2T1], t(8;14)[IGH@/MYC], t(8;14)[TRA@/MYC], t(9;22)[BCR/ABL1], t(10;11)[PICALM/MLLT10], t(15;17)[PML/RARA], or inv(16)[CBFB/MYH11]. Unsupervised classification revealed that hematopoietic cell lines of diverse origin, but with the same primary genetic changes, segregated together, suggesting that pathogenetically important regulatory networks remain conserved despite numerous passages. Moreover, primary leukemias co-segregated with cell lines carrying identical genetic rearrangements, further supporting that critical regulatory pathways remain intact in hematopoietic cell lines. Transcriptional signatures correlating with clinical subtypes/primary genetic changes were identified and annotated based on their biological/molecular properties and chromosomal localization. Furthermore, the expression profile of tyrosine kinase-encoding genes was investigated, identifying several differentially expressed members, segregating with primary genetic changes, which may be targeted with tyrosine kinase inhibitors. The identified conserved signatures are likely to reflect regulatory networks of importance for the transforming abilities of the primary genetic changes and offer important pathogenetic insights as well as a number of targets for future rational drug design.
Comparison of Gene Expression by Normal and Leukemic Progenitor Cells in Childhood B Cell Precursor ALL - Are There ALL Stem Cells? .
Authors: Anthony J. , George A. , Senadheera S. , Barsky L. , McCarthy C. , Schaub B. , Triche T. , Schofield D. , Franklin J. , Parkman R. , Crooks G. , Marjoram P. , Weinberg K. 
Published: October 2019

Abstract
B-cell precursor ALL (B-ALL) are generally believed to express genes, including those encoding surface antigens like CD19, CD22 and CD38, which correspond to those normally expressed by B-cell progenitors. Our previous efforts to immunophenotypically isolate normal HSC from B-ALL marrow for autologous transplantation demonstrated that patients’ putative normal CD34+ CD38− HSC populations contained leukemic cells, even though the B-ALL was positive for CD38 expression. These results raised the question of whether B-ALL stem cells, like normal HSC and ANLL stem cells, might be CD34+ CD38− . Therefore, gene expression was analyzed in rare CD34+ CD38− and more common CD34+ CD38+ B-ALL cells, and in normal CD34+ CD38− HSC and CD34+ CD38+ CD19+ B cell progenitors (BCP). RNA from stringently FACS isolated cells from marrow samples of >10 different B-ALL patients were amplified and hybridized to Affymetrix U133A microarrays. CD34+ CD38+ B-ALL cells expressed numerous genes expected of either B-ALL or normal BCP, including CD19, CD22, CD79a/b, Tdt, RAGs, Pax5 which were not expressed by normal CD34+ CD38− HSC. The expression pattern of the CD34+ CD38− B-ALL cells was different from that of the CD34+ CD38+ B-ALL cells, and from normal HSC or BCP. Compared to normal CD34+ CD38− HSC, the CD34+ CD38− B-ALL cells also expressed several B cell differentiation markers including CD19, CD22 and CD79, but underexpressed CD59, a modulator of responses to decay accelerating factor. There were also differences between the CD34+ CD38− B-ALL cells and the CD34+ CD38+ B-ALL cells. As predicted, CD34+ CD38− B-ALL cells underexpressed CD38, but unexpectedly lacked Tdt. The CD34+ CD38− B-ALL cells expressed multiple genes involved in cell cycle checkpoint control (cullin, MAD2, BUB3, MCMs, DDA3), survival and cellular/genomic maintenance (IAPs, translin), and immortalization (prohibitin), which were not expressed by the CD38+ B-ALL cells. FACS analyses of newly diagnosed patients with B-ALL demonstrated a rare population of CD34+ CD38− CD19+ leukemia cells, confirming that the CD19 mRNA found by array was translated. B-ALL consists of at least two subpopulations, one of which (CD34+ CD38− CD19+) has features that distinguish it both from normal HSC and the majority of B-ALL cells in the marrow. Besides their unique immunophenotype, the CD34+ CD38− CD19+ B-ALL cells express genes likely to be important for processes needed to maintain a malignant stem cell population. Potential implications of a phenotypically identifiable B-ALL stem cell include improved understanding of the biology of ALL and its therapy, the confounding results of MRD analyses, and the limitations of array analyses of unfrationated leukemic cells.
High Glucose Activates AKT Signaling and Induces Upregulation of Genes Encoding Glycolytic Enzymes Glut-1 and HK-2 in Acute Lymphocytic Leukemia.
Authors: Buglio Daniela , Schober Wendy , Contractor Rooha , McQueen Teresa , Zeng Zhihong , Kantarjian Hagop , Weiser Mary A. , Andreeff Michael , Konopleva Marina 
Published: October 2019

Abstract
Background: Hyperglycemia represents a common side effect of steroid therapy and is not uncommon during treatment of patients with acute lymphocytic leukemia (ALL). Our recent retrospective study in 278 adult patients with ALL demonstrated that hyperglycemia during induction chemotherapy occurred in up to 37% of patients and was associated with a shorter median complete remission duration and a shorter median survival (Cancer 2004 Mar 15;100(6):1179–85). The serine/threonine AKT, a major downstream PI3K target, promotes continued cell growth and metabolism by increasing glucose uptake, stimulating glycolysis and ATP production. Recent data in transgenic models demonstrated that AKT activation resulted in transcriptional upregulation of enzymes essential for glycolysis including hexokinase (HK) and Glut-1 (Nature Med., 2004, 10:594). The purpose of this study was to determine whether high AKT activity in leukemic blasts in the setting of hyperglycemia promotes survival and chemoresistance of leukemic cells by stimulation of glycolysis.
Methods and Results: A 24-hour culture of REH cells in serum-free medium supplemented with 14mM glucose resulted in induction of AKT phosphorylation (by Western blot analysis) and increase in mRNA levels of Glut-1 and HK-2 (by quantitative TaqMan PCR). PI3K inhibitor LY294002 (15 μM) prevented AKT phosphorylation and decreased mRNA expression of Glut-1 and HK-2 in high-glucose conditions and enhanced doxorubicin- and dexamethasone-induced killing. We next investigated expression of AKT 1, Glut1, and HK2 mRNA in bone marrow samples from 14 adult patients with ALL (9 pre-B-, 2 B-, 3 pre-T-ALL). The results demonstrated elevated (> 2-fold compared with normal bone marrow or peripheral blood) levels of AKT in 7/14 patients, 6 of those showed increased levels of Glut1 and 5 of HK2. In addition, in samples from 2 patients with low baseline AKT expression high HK-2 mRNA levels were observed.
Conclusions: High expression of AKT, glucose transporter Glut-1 and the glycolytic enzyme HK-2 is prevalent in primary ALL blast cells. Our results suggest that high glucose further stimulates AKT signaling in ALL blast cells resulting in upregulation of glucose transporter Glut-1 and of the glycolytic enzyme HK-2. This effect was abrogated by inhibition of PI3K/AKT signaling, resulting in chemosensitization. These data provide rationale for use of PI3K/AKT inhibitors in the therapy of ALL. The hypothesis that tight blood glucose control improves outcome in ALL patients is currently being tested in a Phase III clinical trial at M.D. Anderson Cancer Center.
CXCR4+ CD45− Tissue-Committed Stem Cells (TCSC) for Myocardium Reside in the Bone Marrow, Are Mobilized into the Peripheral Blood during Myocardial Infarction, and “Home” to Infarcted Myocardium in CXCR4-SDF-1 and HGF/SF-c-Met Dependent Manner.
Authors: Kucia Magda , Dawn Buddhadeb , Guo Yiru , Hunt Greg , Wysoczynski Marcin , Majka Marcin , Zuba Ewa , Rezzoug Francine , Ildstad Suzanne T. , Bolli Roberto , Ratajczak Mariusz Z. 
Published: October 2019

Abstract
Several recent studies in animals as well as humans support the notion that bone marrow (BM)-derived cells participate in myocardial regeneration. However, this subject remains highly controversial and the identity of the specific cell type responsible for regeneration remains unknown. Recent work from our laboratory revealed that BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSC) and which are distinct from hematopoietic stem cells (HSC) (Leukemia2004:18;29–40). In the current study we investigated whether BM also contains a mobile pool of TCSC destined to differentiate into cardiomyocytes. Our data demonstrate that TCSC for cardiomyocytes (i) are present in significant amounts in BM harvested from young (1–2 month-old) while being barely detectable in older (1-year-old) mice; ii) reside in populations of murine BM-derived non-hematopoietic Sca-1+ CD45− cells and in population of human CXCR4+ CD34+ AC133+ CD45− BMMNC, iii) are mobilized from BM into peripheral blood (PB) during pharmacological mobilization or myocardial infarction; iv) the identified by us chemoattractants for these cells: stromal derived factor -1 (SDF-1), and hepatocyte growth factor/scatter factor (HGF/SF) are upregulated in infarcted myocardium, and v) blocking experiments with T140 (CXCR4 antagonist) and K252a (c-MET antagonist) confirmed that TCSC for cardiomyocytes are chemoattracted to the damaged myocardium in SDF-1-CXCR4 and SF/HGF-c-Met dependent manner. Thus, we conclude that the bone marrow is a potential source of TCSC for heart repair and since purified CD45+ HSC neither express cardiac markers nor differentiate in vitro into cardiomyocytes, we provide for the first time evidence that cardiac TCSC residing in bone marrow but not “plastic” HSC may account for cardiac differentiation of BM-derived cells. These observations provide rationale for further studies aimed at optimizing therapeutic cardiac regeneration by BM-derived non-hematopoietic cardiac TCSC. Finally, our observation that the number of marrow derived mobile/circulating cardiac TCSC is the highest in BM of young animals and decreases with age provides a novel insight into aging and may explain why the heart regeneration process becomes less effective in older individuals.