tbuckley/cabot-search huggingface dataset:
From the authors
Authors: E. Kostadima, A. Kaditis, E. Alexopoulos, E. Zakynthinos, D. Sfyras
Journal: European Respiratory Journal (2006)

the patients should be very carefully assessed.The PEG feeding patients with dysphagia may be suffering from aspiration pneumonia [11].Considered together, we believe that the prevention of aspiration by using oral care, angiotensin-converting enzyme inhibitors and swallowing rehabilitation may be an alternative approach in reducing the risk of ventilator-associated pneumonia in patients.
Treatment of recurrent Langerhans cell histiocytosis of the vulva with lenalidomide.
Authors: Ibrahim Fuad Ibrahim, Harris V. K. Naina
Journal: Journal of Clinical Oncology (2013)

e16555 Background: Langerhans cell histiocytosis (LCH) of the female genital tract is an extremely rare disease. We report a 14 year follow up of a patient with LCH successfully treated with lenalidomide in the relapsed setting. Methods: N/A. Results: A 43 year old Ethiopian woman initially presented to another institution with a nodular lesion on her left vulva with biopsy consistent with LCH. Metastatic workup at the time did not reveal evidence of distant disease. The patient was initially treated with radiotherapy to the vulva and 2 years later she was diagnosed with recurrent disease in the vulva and underwent a wide local excision. Six months afterwards she developed a lesion on her right labium majus consistent with disease recurrence. She was treated with radiotherapy again and underwent a wide radical vulvar excision. She recurred only 3 months later and was started on salvage therapy with thalidomide, 3 years after the initial diagnosis. Within 2 months of starting thalidomide therapy, the patient experienced resolution of vulvar lesions and symptoms. She remained symptom free for 8 years while on thalidomide but then presented to our institution with a new central vulvar lesion after being off therapy for 4 months. Vulvar biopsy confirmed the presence of LCH. She was subsequently restarted on thalidomide and achieved symptom control for an additional 18 months before developing worsening pain and neuropathy associated with therapy. Imaging revealed no evidence of metastatic disease. We then started lenalidomide therapy at dose of 10 mg daily for 21 days in a 28 day cycle and subsequently increased the dose to 25 mg daily continuously. She achieved marked improvement in vulvar symptoms within a month of initiation of lenalidomide. She has tolerated therapy well with no neuropathy or cytopenias. Conclusions: Primary vulvar LCH is a rare disease with no standard therapies. Thalidomide has been described in the literature as an effective treatment option. We describe the use of lenalidomide as an alternative and well tolerated therapy in the relapsed setting. Further investigation is required to determine whether lenalidomide is a viable first line therapy for this rare disease.
Atrial Fibrillation Detection and R-Wave Synchronization by Metrix Implantable Atrial Defibrillator
Authors: Hung-Fat Tse, Chu-Pak Lau, Jasbir S. Sra, Herry J. G. M. Crijns, Nils Edvardsson, Salem Kacet, D. George Wyse
Journal: Circulation (1999)

Background —The long-term efficacy of atrial fibrillation (AF) detection and R-wave synchronization are critical safety requirements for the development of an implantable atrial defibrillator (IAD) for treatment of AF. Methods and Results —The long-term efficacy of the Metrix IAD for AF detection and R-wave synchronization was tested in 51 patients. The mean duration of follow-up was 259±138 days (72 to 613 days). AF detection tests were performed 2240 times during observed operation with 100% specificity and 92.3% sensitivity for differentiation between sinus rhythm and AF; 2219 episodes and their electrograms stored in the device during AF detection were analyzed. The positive predictive value of the AF detection algorithm was 97.4% (lower 95% confidence limit [CL], 94.5%) in the out-of-hospital setting. A total of 242 435 R waves were analyzed for R-wave synchronization. Of these, 49% were marked for synchronized shock delivery, 82% of sinus rhythm and 36% of AF R waves, respectively. All shock markers were properly synchronized and within the R wave (overall synchronization accuracy, 100%; lower 95% CL, 99.999%). Overall, 3719 shocks have been delivered via the IAD with no instance of unsynchronized shock delivery or any episode of proarrhythmia. The observed proarrhythmic risk was 0%, with an estimated maximum proarrhythmic risk of 0.084% per shock (95% upper CL). Conclusions —The Metrix IAD can appropriately detect AF with a high specificity and sensitivity and reliably synchronize within a suitable R wave for shock delivery to minimize the risk of ventricular proarrhythmia.
Abstract 255: Sex Differences in Survival, Ventricular Remodeling, and Cardiomyocyte Contractility After Isoproterenol
Authors: Angela K Peter, Christa L Trexler, Kimberly R Lugo, Amy R Perry, Leslie A Leinwand
Journal: Circulation Research (2017)

Introduction: Significant sexual dimorphisms have been demonstrated to be important modifiers of cardiovascular disease (CVD). However, women have traditionally been omitted from clinical trials and female animals have been excluded from most preclinical research studies, ultimately leading to therapeutics that are not as effective, or with different side effects, in women relative to men. In light of the effects that sex has on CVD, the National Institutes of Health has called for the inclusion of both male and female animals in preclinical CVD research. Methods and Results: Through recent RNAseq experiments, we found both the α- and β-adrenergic receptors were significantly increased in isolated female adult rat ventricular myocytes (ARVMs) when compared to male ARVMs. In order to test whether this difference in gene expression translated to functional differences, the β-adrenergic receptor agonist, isoproterenol (ISO), was utilized to induce pathological cardiac hypertrophy in male and female rats. Survival of both sexes following a 7 day ISO treatment was significantly lower compared to vehicle. In addition, male ISO treated rats had significantly lower survival compared to female ISO treated rats (44% survival versus 77% survival, respectively). Both sexes developed significant cardiac hypertrophy compared to vehicle controls, but male ISO treated rats developed greater cardiac hypertrophy compared to ISO treated females. ARVM contractility experiments revealed no significant increases in peak shortening in response to ISO treatment in either sex. However, in both sexes, ARVMs isolated from ISO treated animals took less time to reach peak shortening and displayed increased departure velocity. Conversely, only male ISO treated ARVMs took less time to relax, exhibiting an increase in return velocity. Conclusions: Chronic in vivo β-adrenergic receptor stimulation revealed dramatic sex differences both in the intact heart and at the cellular level including increased mortality, increased cardiac hypertrophy, and altered myocyte contractility in males compared to females. These findings suggest that 7 day ISO treatment in rats may serve as a reliable, reproducible animal model for testing current and future CVD therapeutics in both sexes.
PF250 HNRNP K OVEREXPRESSION INDUCE NUCLEOLAR STRESS, A HALLMARK OF ACUTE MYELOID LEUKEMIA
Authors: P. Aguilar-Garrido, C. Crespo-García, L. Carrasco-Rubio, M.J. Aitken, P. Malaney, X. Zhang, K.H. Young, S.M. Post, J. Martinez-Lopez, M. Gallardo
Journal: HemaSphere (2019)

Background: hnRNP K is a poly(C)-binding protein that tenaciously binds C-rich tracks of DNA and RNA, involved not only in the processing of hnRNAs into mature mRNAs but also in regulating gene expression. Large complexes are mobilized through nuclear pores to ribosomes, and hence, hnRNP K participates in the nuclear-cytoplasmic shuttling and transmission of information from the nucleus to the cytoplasm. Moreover, one of the most prominent cancer drivers, regulated by hnRNP K, is c-Myc. Nuclear to ribosome mobilization and c-Myc are both factors involved in nucleolar stress induction, a well-known mechanism of tumorigenesis. Aims: Our working hypothesis will test the impact in proliferation and tumour development of hnRNP K overexpression due to nucleolar stress. Methods: Clinical bone marrow samples from acute myeloid leukaemia (AML) patients were used to study the levels of expression of HNRNPK gene. Additionally, we analyzed the number of copies by FISH. Moreover, reverse phase protein array (RPPA) analysis of AML patients was performed and it showed HNRNPK and C-MYC overexpression correlation. Further validation of human patients was performing with two hnRNP K overexpression mice models, hnRNPK Tg /EIIa-Cre and hnRNPK Tg /UBC-Cre. Tissues and MEFs molecular analysis (RT-PCR and WB) of hnRNP K, c-Myc and nucleolar stress markers (B23: NPM1, C23: Nucleolin) were performed. In addition, we analyzed by confocal microscopy the co-localization of nucleolar sensors and hnRNP K protein. Finally, nucleolar stress induction by POL1 inhibitors (e.g. Actinomycin D, BMH-21, etc.) was tested in transgenic mice derived MEFs. Results: The clinical results in AML patients reveal overexpression of HNRNPK, that could be justified by the amplification in the number of copies of the gene found by FISH analysis. Moreover, HNRNPK overexpression correlates with c-MYC overexpression in AML patients. hnRNP K overexpression mice models tissues and MEFs showed hnRNP K direct correlation with c-Myc and nucleolar stress sensors elevation (B23 and C23). Furthermore, we observed a hnRNP K miss-localization, similar that the one showed with nucleolar stress induction by POL1 inhibitors.Summary/Conclusion: HNRNPK is amplified and overexpressed in AML patients. Moreover, c-MYC is positively correlated with HNRNPK, suggesting a direct regulation of HNRNPK over C-MYC in AML. We revealed that hnRNP K overexpression induces nucleolar stress, a common hallmark of AML as we observed in the molecular profile of a plethora of patients in molecules involved with nucleolar stress (e.g. NPM1, HNRNPK, TET2, DNMT3A, or RUNX1 mutations). To conclude, we revealed such a novel leukemogenic mechanism in AML through nucleolar stress activation induced by hnRNP K, with or without the collaboration of c-Myc. This work was financially supported by CRIS contra el Cancer Association (NGO) and AES ISCIII (PI18/00295)
PB2379 INVASIVE FUNGAL INFECTIONS IN PATIENTS UNDERGOING ALLOGENEIC STEM CELL TRANSPLANTATION CONDITIONED WITH REDUCED BUCY2
Authors: F. M. Armillas, M. Rivera Franco, E. León Rodríguez
Journal: HemaSphere (2019)

Background: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (allo‐SCT). We previously reported (Ann Hematol 2017) that reduced BUCY2 (rBUCY2) preserves an immunosuppressive and myeloablative effect, achieving an adequate bone marrow engraftment with acceptable toxicity, low graft‐versus‐host disease (GVHD), and low transplant‐related mortality (TRM) Aims: To determine the frequency of IFI in patients undergoing allo‐HSCT using rBUCY2 as the conditioning regimen Methods: We conducted a retrospective study of consecutive patients undergoing allo‐SCT using rBUCY2 between November 1998 and December 2014. The median follow‐up was 90 months. Data was analyzed in March 2018.All the SCT procedure and follow‐up was performed at the National Institute of Medical Sciences and Nutrition “Salvador Zubiran”, a public tertiary/referral center in Mexico City.Patients were conditioned with rBUCY2 (busulfan 12 mg/kg, ORAL and cyclophosphamide 80 mg/kg, IV), using G‐CSF‐primed bone marrow as the stem cell source. Antifungal prophylaxis consisted of low‐dose amphotericin B (0.2 mg/kg/day) administered until neutrophil engraftment.The primary endpoint was 1‐year cumulative incidence of proven or probable IFI and the secondary endpoint was the IFI‐associated mortality. Risk factors of IFI were also assessed. Results: From all the cohort, 57% were male and the median age was 39 years (range, 17‐67). Hematological malignancies were the underlying diseases in most patients (n = 55, 94.8%). Within 100 days post‐SCT, IFI was presented in 4 patients (6.8%) and only 1 patient presented late IFI. The multivariate analysis showed that cytomegalovirus (CMV) viremia was the main risk factor associated with the development of IFI (p = 0.031). IFI‐associated mortality was 5% and showed an association with matched unrelated donors (p = 0.022), parenteral nutrition (p = 0.027), and early IFI (p = 0.004). The TRM was 17% Summary/Conclusion: Our results highlight the low incidence of IFI using our modified conditioning regimen compared to international literature. As other studies have reported, we demonstrated that CMV was associated with the development of IFI. We emphasize the safety of rBUCY2 demonstrated by the low incidence of IFI and the low TRM.
Structural simplification: an efficient strategy in lead optimization
Authors: Shengzheng Wang, Guoqiang Dong, Chunquan Sheng
Journal: Acta Pharmaceutica Sinica B (2019)

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.
Early Adoption of New Supplemental Benefits by Medicare Advantage Plans
Authors: David J. Meyers, Shayla N. M. Durfey, Emily A. Gadbois, Kali S. Thomas
Journal: JAMA (2019)

Following CMS’ 2018 expansion of supplemental benefits available to HMO and PPO Medicare Advantage enrollees, this study assesses enrollee adoption by type of benefit (eg, caregiver support, in-home personal care, palliative nursing, and social work) and specific plan characteristics in the first year.
Engineering temperature-sensitive plateletsomes as a tailored chemotherapy platform in combination with HIFU ablation for cancer treatment
Authors: Dongqi Wu, Xing Jin, Xiaobing Wang, Boyu Ma, Chenmei Lou, Haijing Qu, Jian Zheng, Binxuan Zhang, Xiufeng Yan, Yang Wang, Lijia Jing
Journal: Theranostics (2019)

Chemotherapy is widely used in combination with high-intensity focused ultrasound (HIFU) ablation for cancer therapy; however, the spatial and temporal integration of chemotherapy and HIFU ablation remains a challenge. Here, temperature-sensitive plateletsomes (TSPs) composed of platelet (PLT) membrane, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine were developed to adequately integrate chemotherapy with HIFU tumor ablation in vivo. Methods: The thermosensitive permeability of TSPs was evaluated under both water bath heating and HIFU hyperthermia. The targeting performance, pharmacokinetic behavior and therapeutic potential of TSPs in combination with HIFU ablation were evaluated using HeLa cells and a HeLa cell tumor-bearing nude mouse model in comparison with temperature-sensitive liposomes (TSLs). Results: TSPs showed high drug loading efficiency and temperature-sensitive permeability. When applied in vivo, TSPs showed a circulation lifetime comparable to that of TSLs and exhibited PLT-specific cancer cell affinity and a vascular damage response. Upon HIFU hyperthermia, TSPs displayed ultrafast drug release and enhanced tumor uptake, providing high drug availability in the tumor site to cooperate with HIFU ablation. After HIFU ablation, TSPs rapidly targeted the postoperative tumor site by adhesion to the damaged tumor vasculature, leading to targeted and localized postoperative chemotherapy. Conclusion: Due to effective integration at both intraoperative and postoperative stages, TSPs could be a promising chemotherapy nanoplatform in combination with HIFU ablation for cancer therapy.
AB0641 VITAMIN D SERUM LEVELS AND THE RISK OF DIGITAL ULCERS IN SYSTEMIC SCLEROSIS: A LONGITUDINAL STUDY
Authors: Cristian Caimmi, Eugenia Bertoldo, Alice Pozza, Paola Caramaschi, Giovanni Orsolini, Davide Gatti, Maurizio Rossini, Ombretta Viapiana
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Vitamin D is known to influence the immune system in many different diseases although longitudinal studies on systemic sclerosis (SSc) are still missing. Objectives: this study wants to investigate if variations in vitamin D serum levels (25OHD) over time affect digital ulcers (DU) in SSc. Methods: this is a retrospective study on 65 patients. Data on disease characteristics and 25OHD were collected in 2011 and 2016. <h3>Results:</h3> The mean age of our cohort was 58 (12) years with a mean disease duration of 9.5 (5.3) years. Most of our patients had a limited subset (69.2%). At baseline 50.8% and 41.5% after 5 years had 25OHD &lt;30 ng\mL. Supplemented patients (8750 IU\week) at baseline were 39 (60.0%) and 45 (69.2%) at the end of follow up. Nevertheless, 31 (47.7%) had a decrease of 25OHD in 5 years. In univariate analysis, patients with incident digital ulcers (DU) had a decrease in 25OHD as compared to patients with no incident DU (-17.4 (37.0) vs. 13.0 (89.5), p=0.018). No differences in 25OHD variations were found for other disease characteristics. In multivariate analysis correcting for previous DU and mRSS at baseline, patients with a decrease in 25OHD had an increased risk of developing DU (OR (IC95%): 16.6 (1.7 to 164.5), p=0.017). <h3>Conclusion:</h3> In this study we have shown that a decrease in 25OHD increases the risk of developing DUs and that vitamin D supplementation with the doses currently recommended may be insufficient in SSc. Further studies in wider cohorts are needed to confirm these results and to evaluate the effectiveness of a more aggressive or different vitamin D supplementation. <h3>Disclosure of interests:</h3> Cristian Caimmi: None declared, Eugenia Bertoldo: None declared, alice Pozza: None declared, Paola Caramaschi: None declared, Giovanni Orsolini Speakers bureau: Grunenthal, Davide Gatti Speakers bureau: abiogen, amgen, Janssen-Cilag, Mundipharma, Pfeizer, Maurizio Rossini: None declared, Ombretta Viapiana Speakers bureau: Novartis, abbvie, Eli-Lilly, Sanofi Genzyme
The association between antidepressant treatment and brain connectivity in two double-blind, placebo-controlled clinical trials: a treatment mechanism study
Authors: Yun Wang, Joel Bernanke, Bradley S Peterson, Patrick McGrath, Jonathan Stewart, Ying Chen, Seonjoo Lee, Melanie Wall, Vanessa Bastidas, Susie Hong, Bret R Rutherford, David J Hellerstein, Jonathan Posner
Journal: The Lancet Psychiatry (2019)
PB1668 EARLY T‐CELL PRECURSOR (ETP) ACUTE LYMPHOBLASTIC LEUKEMIA (ETP‐ALL) IN ADOLESCENTS AND ADULTS: A HIGH‐RISK SUBTYPE
Authors: S. Chong, S. Hon, K. Law
Journal: HemaSphere (2019)

Background: Early T‐cell precursor (ETP) acute lymphoblastic leukemia/lymphoma (ALL/LBL) is recognized as high‐risk T‐ALL/LBL subgroup. The optimal therapeutic approached to adult patients with ETP‐ALL/LBL not well characterized. Aims: In this study, we compared the outcomes of adults with ETP‐ALL receiving treatment with frontline regimes to those with other T‐ALL immunophenotypic subtypes. Methods: This is a 10 years retrospective analytical study of adult patient diagnosed with T‐ALL. Patients with newly‐diagnosed T‐ALL/LBL receiving frontline chemotherapy between the years of 2008‐2018 at Ampang Hospital, Malaysia were identified and immunophenotypically categorized into TI(pro‐T), T‐II(pre‐T), T‐III (cortical‐T) and T‐IV(mature‐T) as per European Group for the Immunological Characterization of Leukaemia (EGIL) classification using CD1a and cytoplasmic/surface CD3. Overall survival (OS) was analysed using Kaplan‐Meier survival function and different groups were compared using log‐rank test. Event‐free survival (EFS) was calculated from the time of CR until relapse or death. Results: A total of 77 patients with T‐ALL were identified with adequate immunophenotype data. Of the 77 patients, only 60 could be subtyped into Pro‐T (6.7%), Pre‐T (21.7%), Cortical‐T (6.7%), Mature T (23.3%) and ETP (41.7%) subtypes, largely due to discordant expression of differentiation markers that do not conform to this immunophenotypic classification scheme. The ETP‐ALL group had a median age of 29 years, compared to non‐ETP which was 25 years. Among these subtype T‐ALL, 71.7% (n = 43) were age of 35 and above, and 28.3% (n = 17) were below age of 35. There was male predominance (76.7%). Patients were mainly Malay (58.3%), followed by Chinese (21.7%) and Indian (16.7%), with the remaining 3.3% of other racial origins. There was no significant association between total white count (TWC) at presentation and ALL subtypes (ETP vs non‐ETP) using cut‐off of 100 TWC (χ2 = 1.34, df = 1, p = 0.248). This cohort presented median overall survival (OS) of 13 month (95%CI: 9.4; 18.0) and median event free survival (EFS) of 10 month (95%CI: 6.6; 16.4). The majority of patients underwent induction chemotherapy with curative intent (95%, n = 60)whereas 5%(n = 3) were upfront palliative intent. The induction chemotherapy were mainly GMALL or HyperCVAD (93%, n = 57) where less than 10% were BLOCK and BFM (5.3% and 1.8%, n = 6). Median OS and EFS were further evaluated and we found no significant difference among patients of different subtypes, TWC (cut‐off = 100). However, among these factors, TWC appeared to be a potential predictor for OS due to marginal p‐value to 0.05. Summary/Conclusion: ETP‐ALL/LBL represents a high‐risk disease subtype of adult ALL. Novel treatment strategies are needed to improve treatment outcomes of this T‐ALL/LBL subset.