bluuebunny/crossref_metadata_2025_split huggingface dataset:
Daptomycin (DAP) Use in Patients with Hematologic (HEM) Cancer History; Post-Marketing Experience in a Registry.
Authors: Akpek Gorgun , Forrest Graeme , Lamp Kenneth C. , Donovan Brian J. , Friedrich Lawrence V. 
Published: April 2020

Abstract
Background: DAP is a novel lipopeptide antibiotic, approved for complicated skin and skin structure infections, with potent in vitro activity against many resistant Gram-positive organisms. Registration studies often limit or exclude patients with severe illness. Antibiotic resistant Gram-positive pathogens are frequently encountered in compromised patient populations; however, minimal information is available pre-approval in these patients.
Methods: Cubicin® Outcomes Registry and Experience (CORE) is a Phase IV retrospective observational chart review (45 institutions) to quantitate characteristics and clinical outcomes of patients (pts) receiving DAP. A standard case report form including demographic, disease state, clinical, and microbiologic data was completed by each investigator. Cure, failure, and improvement were assessed using standard definitions. Nonevaluable pts had insufficient data available to determine clinical outcome. Of the 1160 pts in CORE, 56 were reported with a history of HEM cancer. Eighteen (32%) were nonevaluable; 6 of those expired. This report describes the 38 pts with an assigned outcome.
Results: Fifty-five percent of pts were female, 63% were 31 to 65 years of age, and 76% of infections developed in a hospital setting. Common comorbidities included cardiovascular disease (24%), immunosuppression (18%), and transplant (11%). The most common infections were; bacteremia catheter-related (53%), skin and skin structure (34%), and bacteremia noncatheter-related (18%). Seventy-one percent (27/38) of pts were culture positive before DAP with the most common pathogens being Enterococcus sp. (52%, of which 71% were VRE), coagulase-negative staphylococci (41%), and S. aureus (19%, of which 80% were MRSA). A high percentage of pts (92%) received antibiotics (abx) prior to DAP. The most frequent initial dosing regimens were 4mg/kg QD (50%), and 6mg/kg QD (29%). The mean duration of DAP therapy was 13.6 days (range 2–44). Dose (P=0.3) and duration (P=0.58) did not vary by primary pathogen. Twenty-nine (76%) pts received concomitant abx therapy, most commonly with fluoroquinolones (31%), metronidazole (28%) or cephalosporins (24%). The mean time to clinical response was 2.4 days (n=28) and unaffected by primary pathogen (P=0.43) or the influence of concomitant abx therapy (P=0.55). All pts were reported as cured (66%) or improved (34%).
Conclusion: The data from the CORE registry demonstrates that DAP shows early clinical response and clinical cure for HEM patients where catheter associated infections and VRE are prevalent. These data provide preliminary data on the use of DAP in this compromised patient population. This information should lead to further prospective studies in cancer patients with DAP.
Cost-Effectiveness of Itraconazole for the Prophylaxis of Invasive Fungal Infections for Neutropenic Patients; a Study for 3 European Countries.
Authors: Postma Maarten J. , de Vries Robin , Christopherson Harriet , Howells Sarah , Tolley Keith , Daenen Simon , Glasmacher Axel , Prentice Archibald , Christie Angela 
Published: April 2020

Abstract
Background: Invasive fungal infections present a leading cause of mortality and morbidity in neutropenic patients treated for hematologic malignancies. As the diagnosis and management of invasive fungal infections is difficult, effective antifungal prophylaxis is desirable. Itraconazole is a broad spectrum antifungal agent with activity against Candida species as well as Aspergillus species, whereas fluconazole primarily targets Candida. There is no published data comparing cost-effectiveness of both antifungal agents.
Objective: To asses the cost-effectiveness of itraconazole compared with (i) prophylactic fluconazole and with (ii) no prophylaxis in the prevention of invasive fungal infections in Germany, the Netherlands and the UK.
Methods: A probabilistic decision model was designed to evaluate the incremental cost-effectiveness of itraconazole versus fluconazole and versus no prophylaxis (see Figure). Baseline risks for invasive fungal infections and risk reductions for itraconazole (&gt;200mg/day) and fluconazole (400mg/day PO or 200mg/day IV) were taken from studies recently published in two meta-analyses. Costs were evaluated from the health care perspective. Drug acquisition costs for the two prophylactic regimens were calculated using 2003 prices. We estimated the increase in the length of stay as a result of an invasive infection using local or national databases and costed this using reference prices.
Results: The meta-analysis revealed that itraconazole is effective in averting invasive fungal disease, in particular aspergillosis. The mean increase in the length of stay for invasive fungal infections was estimated at 9.3 days (rather similar for all 3 countries). As an illustration for our findings: in the Netherlands, itraconazole prophylaxis was expected to be cost-saving compared to fluconazole and provided limited extra costs compared to no prophylaxis at all. Cost-effectiveness was €470 per invasive infection averted for the itraconazole compared to no prophylaxis (95%-CI ranging from cost-saving to €5926 per infection averted). Other country-specific results will be presented at the conference.
Discussion & Conclusions: Our study shows that itraconazole prophylaxis is effective and is clinically likely to result in cost-savings or provide an acceptable cost-effectiveness. Itraconazole should be the first choice in the prophylaxis of invasive fungal infections in neutropenic patients with hematologic malignancies, from the clinical and economic point of view.
Figure Figure
Constitutive Activation of STAT5 and Bcl-XL Overexpression Can Induce Endogenous Erythroid Colony Formation in Human Primary Cells.
Authors: Garçon Loïc , James Chloe , Lacout Catherine , Camara-Clayette Valérie , Ugo Valérie , Raphael Martine , Vainchenker William 
Published: April 2020

Abstract
In contrast with secondary erythrocytosis, progenitor cells from polycythemia vera (PV) patients can undergo in vitro erythroid differentiation despite absence of erythropoietin (EPO) and presence of such endogenous erythroid colonies (EEC) is routinely used as a diagnostic assay. Recent focus on the JAK2 mutation V617F in PV patients argue for a direct implication of JAK2 dependent signaling pathways in EEC formation. Because STAT5 is the principal target of JAK2 in erythroid cells, we investigated whether EEC formation was only dependent on STAT5 activation or required other signaling pathways that would be activated by JAK2. For this purpose, we transduced a retroviral vector coding for a constitutively active form of STAT5 (MIGR-STAT5CA) in UT7 cells, a leukemic cell line with erythroid properties. We observed in cells transduced with the MIGR-STAT5CA vector a spontaneous induction of erythroid differentiation in comparison with cells infected with the empty vector MIGR, as assessed by GPA staining. We next investigated effects of STAT5CA on erythroid differentiation of human primary progenitors. Purified CD34+ cells obtained from peripheral blood (PB) of patients treated with G-CSF were transduced with the STA5CA vector, the CD36+/GPA− erythroid progenitor cells were sorted and cultured in presence of SCF alone. When expressing STAT5CA, they both proliferate and undergo erythroid terminal differentiation despite the absence of EPO. We concluded that a phosphorylated form of STAT5 was sufficient to support in vitro erythroid differentiation of human primary cells. Because STAT5 has been shown to play a crucial role in erythropoiesis via induction of the antiapoptotic protein Bcl-xL, we next investigated whether effects of STAT5CA on erythroid maturation was dependent on Bcl-xL induction. Tansduction of human CD36+/GPA− cells with a retrovirus containing the coding sequence of human Bcl-xL progenitors allowed survival, proliferation and GPA acquisition despite the absence of EPO. We next investigated whether STAT5CA or Bcl-xL overexpression in normal primary cells could reproduce the malignant phenotype observed in PV patients, i.e. induction of EEC formation. CD36+/GPA− transduced with either the STAT5 CA or the Bcl-XL vectors were plated in methylcellulose in the absence of EPO. Bcl-xL as well as STAT5CA vectors could both induce endogenous erythroid colony formation. Regardless to these results, we hypothesized that the EEC formation observed in myeloproliferative disorders could be at least partially due to the JAK2 dependent activation of the STAT5/Bcl-XL pathway. Thus, both constitutive activation of STAT5 and Bcl-xL overexpression could substitute to EPO to induce terminal differentiation of human primary erythroid progenitors.
The Role of K-ras Signaling in Erythropoiesis In Vivo.
Authors: Zhang Jing , Liu Yangang , Beard Caroline , Jaenisch Rudolf , Jacks Tyler , Lodish Harvey F. 
Published: April 2020

Abstract
K-ras plays an important role in hematopoiesis. K-ras-deficient mouse embryos die around E12-E13 with severe anemia. In humans, oncogenic mutations in K-ras gene are identified in ~30% of patients with acute myeloid leukemia. We used mouse primary erythroid progenitors as a model system to study the role of K-ras signaling in vivo. Both Epo- and stem cell factor (SCF) - dependent Akt activation are greatly reduced in K-ras-/- fetal liver cells, whereas other cytokine- induced pathways, including Stat5 and p44/p42 MAP kinase, are activated normally. The reduced Akt activation in erythroid progenitors per se leads to delayed erythroid differentiation. Our data identify K-ras as the major regulator for cytokine-dependent Akt activation, which is important for erythroid differentiation in vivo. Overexpression of oncogenic Ras in primary fetal erythroid progenitors led to their continual proliferation and a block in terminal erythroid differentiation. Similarly, we found that primary fetal liver cells expressing oncogenic K-ras from its endogenous locus undergo abnormal proliferation and terminal erythroid differentiation is partially blocked. We are currently investigating the signal transduction pathways activated by this oncogenic K-ras that underlies these cellular phenotypes.
Essential Role and Regulatory Mechanism of the Erythropoietin Gene in the Liver.
Authors: Suzuki Norio , Obara Naoshi , Kim Ki-bom , Pan Xiaoqing , Jishage Ko-ichi , Imagawa Shigehiko , Yamamoto Masayuki 
Published: April 2020

Abstract
Erythropoietin (Epo) is produced from the kidney and liver under anemic and/or hypoxic conditions. This inducible and tissue-specific production of Epo is regulated at the Epo gene transcription level. To elucidate the mechanisms how hypoxia inducible gene expression is regulated, a number of studies have been carried out and the function of the hypoxia-responsible enhancer sequence located in the 3′ flanking region of the Epo gene (3′HRE) were identified using the Epo-producing human hepatoma cell lines, Hep3B and HepG2. In order to clarify in vivo function of 3′HRE, in this study we deleted 500-bp mouse genomic region (referred to as BS region) containing 3′HRE by the gene targeting strategy. The homozygous BS-null mutant neonates suffered from severe anemia (hematocrit 17±2%) compared with wild-type neonate (hematocrit 28±2%). This anemic phenotype was observed from embryonic day 15 (E15). To our surprise, however, erythropoiesis in the adult BS-null mice was within the normal range. We then examined the expression level of Epo gene in the kidney and liver of BS-null mouse line in the embryonic stage, and found that the Epo gene expression was completely silenced in the BS-null embryonic liver after E15 to adulthood. The BS deletion did not affect the Epo gene expression in the liver up to midgestation stage (E10 to E13) and in the kidney throughout life. These results thus demonstrate that the BS region including 3′HRE is the enhancer for Epo gene that is functional after the late embryonic stage and in the hepatocytes. BS-null mice also showed that the hepatic erythropoiesis in the embryonic and neonatal stages requires the paracrine Epo secretion from the hepatocytes, and the Epo production in the kidney is insufficient to compensate the loss of hepatic Epo production.
Ex Vivo Expansion of Human SCID-Repopulating Cells Using Recombinant TAT-HOXB4 Protein.
Authors: Krosl Gorazd , Giard Marie-Pier , Krosl Jana , Beauchemin Stephanie , Humphries Keith , Sauvageau Guy , Roy Denis Claude 
Published: April 2020

Abstract
One of the major obstacles to the successful clinical application of hematopoietic stem cell (HSC) transplantation, particularly in the context of related haplotype-mismatched transplantation, unrelated cord blood transplants for adults, and grafts that are processed ex vivo to remove malignant, or alloreactive T cells, is the number of available long-term repopulating HSCs. The addition of soluble recombinant TAT-HOXB4 protein was recently reported to enable rapid in vitro expansion of murine HSCs that retain their in vivo proliferation and differentiation capacity. However, the ability of this recombinant protein to effectively expand human hematopoietic stem cells remains hypothetical. In addition, limited information is available on underlying mechanisms of HOXB4 HSC expansion. First, to determine the capacity of recombinant TAT-HOXB4 protein to promote human HSC expansion, we treated human CD34+ cells for 4 and 8 days with 40 nM, or 80 nM TAT-HOXB4 protein in X-Vivo 15 medium supplemented with Stem Cell Factor, TPO, IL-6 and Flt3-ligand. Cultures exposed to TAT-HOXB4 treatment for 8 days had no pronounced effect on the total cell yield. During this period, a 2-fold net loss of CFU-GEMM was observed for controls, in comparison to ~8-fold and ~5-fold expansions in response to 40 nM and 80 nM TAT-HOXB4 (p&lt;0.05), respectively. Recombinant TAT-HOXB4 also induced ~10–15-fold expansion of large CFU-GM, compared to only ~2.5-fold increase for controls (p&lt;0.05). HSC numbers were enumerated at the beginning and at the end of the treatment using the principle of limiting dilution in a 4-month NOD/SCID repopulation assay. Culture for 8 days in cytokines devoid of TAT-HOXB4 resulted in ~2-fold loss of SCID Repopulating Cells (SRCs), while cultures supplemented with 40 and 80 nM TAT-HOXB4 protein showed a 2.5-fold (95% CI 1.7 – 3.3 fold) and 5.5-fold (95% CI 3.6 – 7.4 fold) increase, respectively. Then, to determine whether the increase in HSC numbers resulted from HOXB4-enhanced proliferation of HSCs, we examined the cell cycle profile of control and HOXB4-treated cell populations using Hoechst 33342 and pyronin Y dyes. After 4-day treatment with 80 nM TAT-HOXB4, 44%±12% of CD34+CD38+ cells were in Go, compared to only 19%±6% of the controls (p&lt;0.05). In contrast, similar proportions (89–91%) of quiescent CD34+CD38− cells were observed for both conditions. Tracking cell divisions using CFSE also showed that during this period, HOXB4-treated CD34+CD38+ cells underwent ~2 population doublings less than controls (p&lt;0.05). In conclusion, short-term exposure of human CD34+ populations to recombinant TAT-HOXB4 protein has the potential to achieve clinically relevant HSC expansion levels. At the HSC level, these observations suggest that TAT-HOXB4 preferentially affects cell fate (self-renewal?) rather than cell proliferation.
Morphine Induces Kidney Injury in Transgenic Sickle Cell Mice.
Authors: Weber Marc L. , Hebbel Robert P. , Gupta Kalpna 
Published: April 2020

Abstract
Sickle cell nephropathy is poorly understood and currently lacks any specific therapeutic options. Opioids are used to treat the pain associated with sickle cell disease. Interestingly, heroin (a metabolic precursor of morphine) is associated with glomerulosclerosis. Glomerulomegaly, an early sign of kidney damage, predicts the eventual severity of glomerulosclerosis. Using transgenic sickle mice as a disease model, we evaluated the effects of chronic opioid exposure on kidney pathology in the setting of sickle cell disease.
Transgenic sickle cell mice (carry a single copy of linked transgenes for human alpha and beta-S globins and are homozygous for deletion of murine beta major globin) were treated for three weeks with PBS, morphine (50–150mg/70kg human equivalent), naloxone (equimolar to morphine), or morphine and naloxone (n=6 per group). We evaluated the effects of morphine on kidney pathology by assessing kidney weight, glomerular volume (by the Weibel-Gomez method), and mesangial cell counts per glomerulus. Morphine stimulated kidney growth in transgenic sickle mice. Treatment with morphine significantly increased glomerular volume and mesangial cell counts per glomerulus compared to PBS. These effects were reversed with the addition of naloxone to morphine. (see Table)
Morphine-stimulated cultured mouse mesangial cells underwent proliferation, which was inhibited with the addition of naloxone (202% ±14.3 vs. 108% ±12.9 increase over control, p&lt;0.01). Morphine-stimulated mesangial cells had increased expression of phosphorylated STAT-3 by western blot analysis. Blockade of STAT-3 with PpYLKTK-mts (0.2mM) resulted in inhibition of morphine-stimulated mesangial cell proliferation (202% ±14.3 vs.110±29, p&lt;0.01).
In summary, morphine exposure markedly induced kidney growth in transgenic sickle mice, as evidenced by increased kidney size, glomerular volume, and glomerular cell counts. Furthermore, morphine stimulates a proliferative response in mesangial cells via STAT-3 signaling. These results suggest morphine may accelerate renal injury in sickle cell disease.
Group Kidney Weight (g) Glomerular Volume (mm3) #MC/glomerulus Results (mean ± SD): λ p&lt;0.01 vs. Sickle PBS; π p=0.01 vs. Sickle MS; γ p&lt;0.01 vs. Sickle MS. Sickle PBS 0.190 ± 0.02 133 ± 7 27 ± 0.5 Sickle Naloxone 0.176 ± 0.01 124 ± 13 26 ± 1.2 Sickle Morphine 0.251 ± 0.04 λ 163 ± 14 λ 37 ± 1.9 λ Sickle MS+ Nal 0.193 ± 0.01 π 127 ± 12 π 30 ± 1.5 γ
Myocardial Ischemia without Coronary Artery Obstruction in Patients with Sickle Cell Disease.
Authors: Raman Subha V. , Simonetti Orlando P. , Cataland Spero R. , Hicks William J. , Kraut Eric H. 
Published: April 2020

Abstract
Objectives. Sickle cell disease (SCD) is the most common single gene disorder in black Americans, with poorly described cardiovascular sequelae partly due to insensitive techniques to identify microvascular perfusion abnormalities. We employed cardiac magnetic resonance (CMR) and computed tomography (CTA) to assess myocardium, microvascular perfusion and coronary arteries in SCD patients.
Methods. Twelve adult patients with SCD (10 HbSS, 1 HbSC and 1 S-thal) age 20–45 years were enrolled. CMR protocol included: dark blood multiecho imaging, rest and stress myocardial perfusion, multiplane cines, and delayed post-gadolinium imaging (DME) for infarct imaging. Myocardial T2*, reflecting iron content, was calculated and verified using a T2* phantom. Left and right ventricular volumes and ejection fractions were quantified from short axis cines. Coronary CTA was performed in patients and five controls using a 64-slice scanner and 70cc of isotonic, isoosmolar contrast, with vessel review in multiple planes.
Results. Three subjects, all SS genotype, had striking subendocardial ischemia (top image, arrows) with vasodilator stress that was not present at rest (signal intensity-vs-time curves, solid line=abnormal subendocardium, dotted and dashed=normal myocardium, dot-dash=blood pool). Myocardial T2* was normal in all subjects (25 to 33ms) as were DME, LV mass and LVEF. One subject with pulmonary hypertension had marked RV dysfunction (RVEF 26%). No subject had obstructive epicardial coronary disease, though proximal coronary diameters were significantly larger for SCD patients compared to controls (2.7mm/m2 versus 1.9mm/m2, p&lt;0.001).
Conclusions. A subset of SCD patients has quantifiable myocardial ischemia with coronary dilatation and absence of infarcted myocardium. Further studies are ongoing to correlate perfusion abnormalities with episodic chest pain and ischemia-based therapies.
Figure Figure Figure Figure
Lung Function and High Resolution Computed Tomography in Sickle Cell Disease.
Authors: Sylvester Karl P. , Desai Sujal R. , Wells Athol U. , Hansell David M. , Awogbade Moji , Thein Swee Lay , Greenough Anne 
Published: April 2020

Abstract
Adults with sickle cell disease (SCD) may develop sickle chronic lung disease which appears to be a complication of chronic hemolysis and repeated episodes of pulmonary vaso-occlusion. Pulmonary function tests have usually been used to document the severity of lung disease in SCD, but some patients cannot successfully undertake such examinations. Recently, high resolution computed tomography (HRCT) has been shown to be of value in the evaluation of patients with diffuse lung diseases. Assessment of lung disease in SCD by HRCT, however, has not been fully explored. The study sets out to investigate the relationship of any pulmonary function abnormalities in adults with SCD to a non-invasive measure of hemolysis and findings on HRCT. The study population consisted of 33 Hb SS subjects (12 males) with a median age of 36 (range 17–67) years, median height of 167 (range 53–188) cm, and median weight of 69 (range 52–92) kg.
Pulmonary function was assessed by measurements of lung volumes, spirometry, gas transfer and oxygen saturation, and hemolysis by measurement of end-tidal carbon monoxide (ETCO). The degree of a lobar volume loss and ground glass opacification and prominence of central vessels on HRCT were quantitatively assessed.
There was a wide variation in the lung function of the cohort. Nine patients had a restrictive lung function abnormality, five an obstructive abnormality and four a mixed restrictive/obstructive abnormality. Twenty-seven of the patients completed assessment of ETCO levels. ETCO levels correlated positively with bilirubin levels (rs=0.66, p=0.0002) and the absolute reticulocyte count (rs=0.70, p=0.0002), and negatively with hemoglobin (rs=−0.51, p=0.008). ETCO levels negatively correlated with FEV1 (p=0.006), VCpleth (p=0.006), sGaw (p=0.04) and SpO2 (p=0.007). A reticular pattern, lobar volume loss and prominent central vessels were the three most common abnormalities on HRCT. FEV1 (p&lt;0.05), FVC (p&lt;0.005) and TLC (p=0.008) correlated with HRCT findings, particularly lobar volume loss. Lobar volume loss, prominent central vessels and a reticular pattern/ground glass opacification were all present on HRCT in 12 of 18 subjects with a restrictive, obstructive or mixed defect.
Our results suggest that non-invasive assessment of hemolysis and/or HRCT examination might facilitate identification of SCD patients with respiratory function impairment. More of the patients had abnormalities on HRCT than on lung function testing, which suggests that HRCT is a more sensitive detector of respiratory abnormalities than lung function testing. This hypothesis merits testing by serially assessing SCD patients to determine if those with only HRCT abnormalities subsequently develop lung function abnormalities.