bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osteoclast Function Is Essential in the Hematopoietic Stem Cell Niche
Authors: Lymperi Stefania , Horwood Nikki , Dazzi Francesco 
Published: April 2020

Abstract
Hematopoietic stem cell (HSC) function and number are tightly regulated in a specific microenvironment - the HSC niche - constituted of several cell types. Amongst them, osteoblasts have a prominent role since their increment is associated with an expansion of HSC. However, we demonstrated that an overall increase in osteoblasts does not necessarily promote hematopoiesis (Lymperi et al, Blood 2008 111:1173-81). We hypothesised that osteoclast mediated bone resorption, a component of the bone remodelling process which regulates osteoblast formation, takes active part in the HSC niche. To address this question we inhibited osteoclast function with the bone catabolic agents bisphosphonates. In vivo administration of bisphosphonates to C57BL/6 mice altered the architecture of the trabecular bone as defined by micro-CT and histomorphometric analysis. Treated mice exhibited increased bone volume and trabecular number and reduced trabecular separation and trabecular pattern factor compared to the untreated controls. This was accompanied to a decrease in the proportion and absolute number of HSC in the bone marrow (BM) as assessed by both the immunophenotypic enumeration of Lin-Sca1+c-kit+Flk2-HSC and the long-term culture- initiating cell (LTC-IC) assay. The number of the colony forming unit-cells (CFU-C) in the BM of bisphosphonate treated mice was increased, while more Lin-Sca1+c-kit+ enriched cells were found in the S/M phase of the cell cycle. These results indicate that, in osteoclast-impaired mice a proportion of HSC enters the cell cycle changing the balance in favour of hematopoietic progenitors. The ability of BM cells from bisphosphonate treated mice to engraft and reconstitute the hematopoietic system was tested in a competitive transplantation assay, whereby BM cells from treated and untreated mice were transplanted into syngeneic irradiated recipients. The long-term engraftment of treated BM cells was inferior to the one of controls, indicating a decrease in HSC numbers. Furthermore, recipient mice treated with bisphosphonates prior to conditioning and BM transplantation experienced a delayed hematopoietic recovery as compared to untreated recipients. Since it has been shown that parathyroid hormone (PTH) administration increases the number of HSC by stimulating osteoblast numbers, mice receiving micro-pump delivered PTH were also injected with bisphosphonates. We observed that the administration of bisphosphonates abolished the ability of PTH to increase the primitive HSC pool size as measured by FACS analysis of the Lin-Sca1+c-kit+Flk2- BM cells and their capacity to engraft and reconstitute irradiated recipients. Our findings demonstrate that the osteoclast function is fundamental for the HSC niche, possibly by promoting the recruitment of osteoblasts with HSC supporting capacity.
Structural Positioning of the SH2 Domain Is Critical for Bcr-Abl Kinase Activity, Signal Transduction and Oncogenic Transformation
Authors: Hantschel Oliver D. , Grebien Florian , Kaupe Ines , Superti-Furga Giulio 
Published: April 2020

Abstract
We have recently shown that the SH2 domain stimulates c-Abl catalytic activity and substrate phosphorylation. This effect is exerted directly through the establishment of a tight SH2-kinase domain interface in the active conformation of c-Abl (Filippakopoulos et al. (2008) Cell, in press, scheduled to be published on September 5, 2008). Mutations in the SH2 domain that presumably disrupt this SH2-kinase domain interface, such as the Ile164Glu mutation, result in severe impairment of Abl catalytic activity. Thus, correct positioning of the SH2 and kinase domain modules appears to be critical for efficient activation of cytoplasmic tyrosine kinases. Here, we present data showing that the same structural coupling of the SH2 and kinase domain is also a critical factor for full activation of the oncogenic fusion kinase Bcr-Abl. A single point mutation in the SH2 domain (Ile164Glu) led to a dramatic reduction in Bcr-Abl in vitro tyrosine kinase activity and Bcr-Abl autophosphorylation, both on the activation loop (pTyr-412) and the SH2-kinase domain linker (pTyr-245). This resulted in a strong decrease in global cellular tyrosine phosphorylation, as well as decreased phosphorylation of critical downstream mediators of Bcr-Abl signaling. Both wildtype Bcr-Abl, as well as the Bcr-Abl Ile164Glu mutant were able to confer factor independent growth to Ba/F3- and UT-7 cell lines, although to a different extent. Detailed data on the properties of the Ile164Glu mutation in vitro, in imatinib inhibition assays, transformation assays and mouse bone marrow transplant models will be presented. We propose that the structural positioning of the SH2 domain is a crucial factor for constitutive activity, signal transduction and transforming capacity of Bcr-Abl. Besides oligomerization via the N-terminal coiled-coiled domain and loss of the auto-inhibitory N-terminal myristoyl group, the proper positioning of the SH2 domain appears to be another critical factor that is required for constitutive activation of Bcr- Abl, which is the prerequisite for its ability to induce chronic myeloid leukemia (CML). Inhibitors of the SH2-kinase domain interface of Bcr-Abl may comprise alternative or additional points of pharmacological intervention for the treatment of imatinib-sensitive or -resistant CML or Ph+ acute lymphocytic leukemia.
Switch Pocket Inhibitors of the ABL Tyrosine Kinase: Distinct Kinome Inhibition Profiles and in Vivo Efficacy in Mouse Models of CML and B-Lymphoblastic Leukemia Induced by BCR-ABL T315I
Authors: Van Etten Richard A. , Chan Wayne W. , Zaleskas Virginia M. , Walz Christoph , Evangelista Peter , Lazarides Katherine , Betancur Monica , Wise Scott , Petillo Peter A. , Flynn Daniel L. 
Published: April 2020

Abstract
Acquired resistance to the ABL tyrosine kinase inhibitor (TKI) imatinib is a significant clinical problem for patients with chronic myeloid leukemia (CML), where a major resistance mechanism is mutations in the ABL kinase domain that render the BCR-ABL enzyme insensitive to the drug. The gatekeeper mutation Thr 315 Ile (T315I) arises at high frequency in patients relapsing after sequential therapy with second-line TKIs such as dasatinib or nilotinib (Shah et al., J Clin Invest2007;117:2562), and confers pan-resistance to all ATP-competitive TKIs. Using structure-based rational drug design, we have developed a novel chemical class of compounds that bind to five distinct structural pockets that the ABL kinase uses to switch between the inactive and active conformations. Diversity in these “switch pockets” between kinases can be exploited to fine-tune the selectivity of an inhibitor against the rest of the kinome. Two development candidate ABL inhibitors have emerged from this effort: DCC-2036 and DCC-2157. Both compounds potently (IC50 = 0.8–4.0 nM) inhibit purified ABL in the switch-off (unphosphorylated) and switch-on (phosphorylated) states via a non-ATP-competitive mechanism, and avoid steric clash with Ile 315. Both drugs also impair proliferation and induce apoptosis of Ba/F3 cells expressing a wide variety of BCR-ABL TKI-resistant mutants, including T315I, many P-loop mutants, and the dasatinib-resistant mutant F317L. DCC-2036 is highly selective for ABL, FLT3, TIE2, and Src family kinases, and when dosed at 100 mg/kg/day by oral gavage, significantly prolonged the survival of mice with CML-like myeloproliferative disease induced by retroviral expression of BCR-ABL WT and T315I in bone marrow. Genetic studies in mice (Hu et al., Nat Genet2004;36:453) suggest that the Src inhibitory activity of DCC-2036 would be beneficial against Ph+ B-cell acute lymphoblastic leukemia (B-ALL), and indeed DCC-2036 was superior to dasatinib (Hu et al., PNAS2006;103:16870) in prolonging survival of mice with B-ALL induced by BCR-ABL T315I. By contrast, DCC-2157 is selective for ABL, KIT, and PDGFRA/B kinases, and pharmacodynamic studies demonstrated prolonged (&gt;18 hour) inhibition of phospho-Stat5 in BCR-ABL+ leukemic cells following a single oral 100 mg/kg dose. Treatment of mice with CML-like disease induced by BCR-ABL T315I with DCC-2157 at 50 mg/kg every other day induced virtually complete suppression of leukemia and extensive prolongation of survival. These results demonstrate that switch pocket drug design technology yields ABL TKIs with distinct pharmacologic profiles that are promising new weapons for the treatment of de novo and drug-resistant Ph+ leukemias.
Gene Expression Profiling of Post-Follicular B-Cell Lymphoma
Authors: Chng Wee-Joo , Huang Gaofeng , Kurtin Paul J. , Dogan Ahmet , Remstein Ellen 
Published: April 2020

Abstract
Although classified as marginal zone lymphomas under the WHO classification, the molecular relationship between splenic marginal zone lymphoma (SMZL), extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), and nodal marginal zone lymphoma (NMZL) has not been clarified. Furthermore, lymphoplasmacytic lymphoma (LPL) can show clinical morphologic and immunophenotypic overlap with these entities and may present a diagnostic challenge. In this analysis of gene expression data generated using the Affymetrix U133plus 2.0 chip from 32 SMZL, 25 MALTs (GI, salivary gland and lung), 23 NMZL and 25 LPL, we aim to identify the molecular relationship between these pathological entities using unsupervised methods, identify disease specific signatures and markers using supervised methods and also the functional implications of these signatures using a modified gene-set enrichment analysis. Using hierarchical clustering, MALT lymphoma forms a tight cluster regardless of tumor site. In addition, SMZL and NMZL form another large cluster. LPLs are divided into 2 main clusters with occasional samples interspersed amongst the SMZL and NMZL. There is no correlation between the percentage of CD20-positive B-cells, CD3-positive T-cells or CD138- positive plasma cells or tissue origin of the tumor and the way the samples are clustered. However, the separation of the LPLs into 2 major cluster correspond to the presence and absence of underlying Waldenstrom Macroglobulinaemia (WM), suggesting that the genes distinguishing the 2 clusters are potential markers for differentiating WM LPL from non-WM LPL. Next, using supervised analysis we identified a cluster of genes including MMP7, LTF and SFRP2 with high signals specific to MALTs, while other genes including PRDM1 (BLIMP1), XBP1 and TNFRSF17 (BCMA) were specifically over-expressed in LPL. These may therefore represent novel diagnostic marker differentiating these entities. Several of these are further validated at the protein level using immunohistochemistry on a tissue microarray. Consistent with the unsupervised analysis, SMZL and NMZL have little difference and share the over-expression of CD22 and WNT3 among other genes. Clustering of these samples based on the pathways and genesets that are enriched in the individual tumors as compared to their normal tissue counterpart showed a mutually exclusive pattern with significant enrichment of NFKB-related genesets and genes in LPL and MALT, and significant enrichment of B-cell receptor signaling genesets and genes in SMZL and NMZL. Our analysis, for the first time, describes the molecular relationship between these closely related lymphomas. In the process, we identified novel diagnostic markers that may differentiate these conditions and also new insights into molecular pathways that are differentially activated in the different conditions. These may represent potential therapeutic targets
Aneurysmal subarachnoid haemorrhage: effect of CRHR1 genotype on fatigue and depression
Authors: Vetkas Artur , Prans Ele , Kõks Sulev , Rätsep Tõnu , Asser Toomas 
Published: April 2020

Abstract
Background
Emotional health disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) and their causes are largely unexplored. Corticotropin-releasing hormone receptor 1 (CRHR1) is a key factor in stress reactivity and development of mental health disturbances after adverse life-events.

Methods
We explore the effect of CRHR1 genotype on mental health after aSAH in a retrospective cohort study. One hundred twenty-five patients have been assessed using EST-Q mental health questionnaire. Genotyping of CRHR1 single nucleotide polymorphisms (SNP-s) was performed (Rs7209436, Rs110402, Rs242924).

Results
Fatigue was present in almost half of aSAH patients, depression and anxiety in one-third. There was a high prevalence of insomnia and panic complaints. Rs110402 minor allele decreased the risk of depression (OR = 0.25, p = 0.027 for homozygotes). Depression was present in 14% vs 41% in minor and major allele homozygotes, respectively. Rs110402, Rs242924 and Rs7209436 minor alleles and TAT-haplotype, formed by them, were protective against fatigue. After Bonferroni correction only the association of Rs110402 with fatigue remained statistically significant (OR = 0.21, p = 0.006 for minor allele homozygotes). Results remained statistically significant when adjusted for gender, admission state, age and time from aSAH. In multiple regression analysis occurrence of fatigue was dependent on anxiety, modified Rankin score and Rs110402 genotype (R2 = 0.34, p <  0.001).

Conclusions
CRHR1 minor genotype was associated with a lower risk of fatigue and depression after aSAH. Genetic predisposition to mental health disturbances associated with negative life-events could be a risk factor for fatigue and depression after aSAH and selected patients might benefit from advanced counselling in the recovery phase.
Correction to: Efficacy of the interpersonal and social rhythm therapy (IPSRT) in patients with bipolar disorder: results from a real-world, controlled trial
Authors: Steardo Luca , Luciano Mario , Sampogna Gaia , Zinno Francesca , Saviano Pasquale , Staltari Filippo , Segura Garcia Cristina , De Fazio Pasquale , Fiorillo Andrea 
Published: April 2020

Following publication of the original article [1], the authors reported an error in the legend of Table 2.
Characteristics of ammonia gas emissions from soybean cultivation soils treated with mixed microorganisms
Authors: Park Jong-Hwan , Lee Su-Lim , Hwang Se-Wook , Eom Ju-Hyun , Kim Seong-Heon , Kang Se-Won , Cho Ju-Sik , Seo Dong-Cheol 
Published: April 2020

AbstractThis study was conducted to evaluate (i) the characteristics of ammonia gas emissions from soybean cultivation soils amended with varying levels of urea and soil water, and (ii) the rate of reduction in ammonia emissions that could be obtained by applying mixed microorganisms (MM) to the urea-treated soils. The ammonia gas emissions from all treatments except the control were highest on day 2 of a laboratory-scale experiment and decreased gradually thereafter. The ammonia gas emissions from the soils increased with increasing urea and soil water contents. However, there were less emissions from soils treated with MM than those from the urea only treatment, and emissions also decreased significantly as the concentration of MM increased. In a field-scale experiment, the total cumulative emissions of ammonia from soil treated with a combination of chemical fertilizers and MM was reduced to 85.8% of that from the soil treated with chemical fertilizers only. Although we infer that MM can be used as an agent to reduce ammonia gas emissions from actual soils used for soybean cultivation, our knowledge of the processes involved in reducing ammonia emissions using microbial treatment is still limited. Consequently, further studies are required to investigate the efficient control of ammonia gas emissions from agricultural soils through the application of microorganisms.
Experimental and numerical study on the bearing capacity of encased stone columns
Authors: Hataf N. , Nabipour N. , Sadr A. 
Published: April 2020

AbstractStone columns have attracted considerable attention as a ground improvement techniques recently. Performance of stone columns, however, depends on confining pressure offered by the surrounding soils. In the case of very soft soils, the lateral confining pressure may be insufficient and this may lead to column bulging failure. Encapsulating the individual stone column enhances the lateral resistance against bulging by additional confining pressure. In this study, the influences of the length of encasement and type of aggregate materials on the bearing capacity of a single stone column in both dry sand and clay bed were investigated. The results indicated a clear improvement by encasing the half-length of the column. The numerical study also showed the effect of reinforcement stiffness reduces with increase in the cohesion of the clay. Parametric study showed that the effect of encasement stiffness is insignificant for clay bed with high values of cohesion.
A Positive Cocaine Urine Toxicology Test and the Effect on Intraoperative Hemodynamics Under General Anesthesia
Authors: Moon Tiffany S. , Pak Taylor J. , Kim Agnes , Gonzales Michael X. , Volnov Yuri , Wright Evan , Vu Kevin Q. , Lu Rachael D. , Sharifi Arghavan , Minhajuddin Abu , Chen Joy L. , Fox Pamela E. , Gasanova Irina , Fox Amanda A. , Stewart Jesse , Ogunnaike Babatunde 
Published: April 2020

BACKGROUND:
Cocaine has a short biological half-life, but inactive urine metabolites may be detectable for a week following use. It is unclear if patients who test positive for cocaine but have a normal electrocardiogram and vital signs have a greater percentage of hemodynamic events intraoperatively.

METHODS:
A total of 328 patients with a history of cocaine use who were scheduled for elective noncardiac surgery under general anesthesia were enrolled. Patients were categorized into cocaine-positive versus cocaine-negative groups based on the results of their urine cocaine toxicology test. The primary aim of this study was to evaluate whether asymptomatic cocaine-positive patients had similar percentages of intraoperative hemodynamic events, defined as (1) a mean arterial blood pressure (MAP) of <65 or >105 mm Hg and (2) a heart rate (HR) of <50 or >100 beats per minute (bpm) compared to cocaine-negative patients. The study was powered to assess if the 2 groups had an equivalent mean percent of intraoperative hemodynamic events within specific limits using an equivalence test of means consisting of 2 one-sided tests.

RESULTS:
The cocaine-positive group had a blood pressure (BP) that was outside the set limits 19.4% (standard deviation [SD] 17.7%) of the time versus 23.1% (SD 17.7%) in the cocaine-negative group (95% confidence interval [CI], 0.5–7.0). The cocaine-positive group had a HR outside the set limits 9.6% (SD 16.2%) of the time versus 8.2% (SD 14.9%) in the cocaine-negative group (95% CI, 4.3–1.5). Adjusted for age, sex, body mass index (BMI), smoking status, and the presence of comorbid hypertension, renal disease, and psychiatric illness, the cocaine-positive and cocaine-negative patients were similar within a 7.5% margin of equivalence for MAP data (β coefficient = 2%, P = .003, CI, 2–6) and within a 5% margin of equivalence for HR data (β coefficient = 0.2%, P < .001, CI, 4–3).

CONCLUSIONS:
Asymptomatic cocaine-positive patients undergoing elective noncardiac surgery under general anesthesia have similar percentages of intraoperative hemodynamic events compared to cocaine-negative patients.
Frequency of pap smear among doctors: A pilot study
Authors: Yusuf Lamia 
Published: April 2020

Background and Objective: Carcinoma of the cervix is one of the three leading causes of deaths among females worldwide. Pap smear is a simple and very cost-effective method to detect carcinoma of the cervix. The objective of our study was to determine the frequency of papsmear among doctors, so the alarming situation of sloppiness in the screening program can be highlighted.
Methods: The interview-based survey was conducted; multiple questions were asked from the participants. It was a pilot study. Sixty doctors who were married (working in a teaching hospital) were recruited from Rashid Latif Medical College, Lahore from June 2018 - November 2018 and associated tertiary care teaching hospitals for the study. Ethical consideration was taken into account and secrecy of participants were maintained.
Results: All data was entered in SPSS 21 and statistical analysis was done in terms of frequencies. Only 25% of doctors have a pap smear once in their life. Majority 75% of the doctors never have papsmear in their lifetime, few reasons were a shortage of time (27%) and shyness (5%). Regarding HPV vaccination 89% of the participants were willing to have HPV vaccination for their daughters.
Conclusion: This study shows the poor implementation of the cancer screening programme in Pakistan. The general public should be informed about the benefits of HPV vaccination.
doi: https://doi.org/10.12669/pjms.36.4.1651
How to cite this:Yusuf L. Frequency of pap smear among doctors: A pilot study. Pak J Med Sci. 2020;36(4):761-764. doi: https://doi.org/10.12669/pjms.36.4.1651
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Relationship Between Physical Fitness and the Physical Demands of 50-Over Cricket in Fast Bowlers
Authors: Webster Thomas M. , Comfort Paul , Jones Paul A. 
Published: April 2020

Abstract
Webster, TM, Comfort, P, and Jones, PA. Relationship between physical fitness and the physical demands of 50-over cricket in fast bowlers. J Strength Cond Res 36(3): e66–e72, 2022—Professional cricket is constantly evolving and resulting in increased physiological demand placed on players. Fast bowlers experience the greatest physical demand during match-play; despite this, research has overlooked the importance of specific physical attributes to optimizing physical match performance. The aim of this study was to investigate the relationships between 50-Over physical match performance and tests of physical qualities in fast bowlers. Fifteen professional male fast bowlers (age = 23.8 ± 4.0 years; height = 183.4 ± 6.7 cm; body mass = 82.9 ± 9.2 kg) participated in the study. Subjects completed the following physical fitness tests; sum of skinfolds, countermovement jump (CMJ), 20-m sprint, and the Yo-Yo intermittent recovery test level 1. Global positioning system data were collected during 6 professional 50-Over fixtures. Moderate correlations were established between CMJ height to total distance covered (r = 0.585; p = 0.022), sprinting distance (ρ = 0.554; p = 0.032), and maximal velocity (r = 0.567; p = 0.027); 20-m sprint time to total distance covered (ρ = −0.519; p = 0.047) and PlayerLoad (ρ = −0.561; p = 0.03); and Yo-Yo distance to total match distance (r = 0.520; p = 0.047) and sprinting distance (ρ = 0.524; p = 0.045). These findings demonstrate the predictive importance of prolonged intermittent running ability, jump, and sprint performance to match running performance of elite fast bowlers in 1-day cricket. Strength and conditioning coaches should use such information to design training to ensure fast bowlers are adequately conditioned to meet the demands of match running performance.