tbuckley/cabot-search huggingface dataset:
Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation
Authors: Francisco M. Marty, Per Ljungman, Roy F. Chemaly, Johan Maertens, Sanjeet S. Dadwal, Rafael F. Duarte, Shariq Haider, Andrew J. Ullmann, Yuta Katayama, Janice Brown, Kathleen M. Mullane, Michael Boeckh, Emily A. Blumberg, Hermann Einsele, David R. Snydman, Yoshinobu Kanda, Mark J. DiNubile, Valerie L. Teal, Hong Wan, Yoshihiko Murata, Nicholas A. Kartsonis, Randi Y. Leavitt, Cyrus Badshah
Journal: New England Journal of Medicine (2017)

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic-cell transplantation. Letermovir is an antiviral drug that inhibits the CMV-terminase complex.In this phase 3, double-blind trial, we randomly assigned CMV-seropositive transplant recipients, 18 years of age or older, in a 2:1 ratio to receive letermovir or placebo, administered orally or intravenously, through week 14 after transplantation; randomization was stratified according to trial site and CMV disease risk. Letermovir was administered at a dose of 480 mg per day (or 240 mg per day in patients taking cyclosporine). Patients in whom clinically significant CMV infection (CMV disease or CMV viremia leading to preemptive treatment) developed discontinued the trial regimen and received anti-CMV treatment. The primary end point was the proportion of patients, among patients without detectable CMV DNA at randomization, who had clinically significant CMV infection through week 24 after transplantation. Patients who discontinued the trial or had missing end-point data at week 24 were imputed as having a primary end-point event. Patients were followed through week 48 after transplantation.From June 2014 to March 2016, a total of 565 patients underwent randomization and received letermovir or placebo beginning a median of 9 days after transplantation. Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (122 of 325 patients [37.5%] vs. 103 of 170 [60.6%], P<0.001). The frequency and severity of adverse events were similar in the two groups overall. Vomiting was reported in 18.5% of the patients who received letermovir and in 13.5% of those who received placebo; edema in 14.5% and 9.4%, respectively; and atrial fibrillation or flutter in 4.6% and 1.0%, respectively. The rates of myelotoxic and nephrotoxic events were similar in the letermovir group and the placebo group. All-cause mortality at week 48 after transplantation was 20.9% among letermovir recipients and 25.5% among placebo recipients.Letermovir prophylaxis resulted in a significantly lower risk of clinically significant CMV infection than placebo. Adverse events with letermovir were mainly of low grade. (Funded by Merck; ClinicalTrials.gov number, NCT02137772 ; EudraCT number, 2013-003831-31 .).
Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels
Authors: Yael Kenig-Kozlovsky, Rizaldy P. Scott, Tuncer Onay, Isabel Anna Carota, Benjamin R. Thomson, Hyea Jin Gil, Veronica Ramirez, Shinji Yamaguchi, Christine E. Tanna, Stefan Heinen, Christine Wu, Radu V. Stan, Janet D. Klein, Jeff M. Sands, Guillermo Oliver, Susan E. Quaggin
Journal: Journal of the American Society of Nephrology (2017)

Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle–associated protein). Taken together, our data redefine the AVRs as Tie2 signaling–dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.
Isolated Multinodular Soft-Tissue Rosai-Dorfman Disease on FDG PET/CT
Authors: Darko Pucar, William B. Laskin, Lawrence Saperstein
Journal: Clinical Nuclear Medicine (2017)

Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy) is a rare systemic histiocytic disorder of unknown etiology characterized by the accumulation of enlarged non-Langerhans histiocytes within lymph nodes and extranodal sites. The histiocytes display characteristic emperipolesis (nondestructive engulfment of inflammatory cells) and are CD68 and S100 positive and CD1a negative. Although extranodal disease frequently occurs with nodal involvement, isolated extranodal disease is uncommon. We report a case of isolated localized subcutaneous multinodular disease on FDG PET/CT. We also include a companion classic Rosai-Dorfman case with extensive nodal involvement and a characteristic benign clinical course with spontaneous improvement.
Overall Survival of Patients with Relapsed Multiple Myeloma Treated with Carfilzomib and Dexamethasone Versus Bortezomib and Dexamethasone According to Prior Line of Therapy and Previous Exposure to Bortezomib: Secondary Analysis of the Phase 3 Endeavor Study
Authors: Katja C. Weisel, David Siegel, Jesus F. San Miguel, Roman Hájek, P. Joy Ho, Gianluca Gaidano, Robert Z. Orlowski, Lifen Zhou, Amy S. Kimball, Philippe Moreau
Journal: Blood (2017)
Abstract 16656: Cardiosphere-derived Cell Exosomes Reduce Proinflammatory Gene Expression and Enhance Efferocytosis of Macrophages to Reduce Infarct Size Following Ischemia-reperfusion Injury
Authors: Geoffrey de Couto, Ervin Jaghatspanyan, Elijah Kravets, Eduardo Marbán
Journal: Circulation (2016)

Introduction: Cardiosphere-Derived Cells (CDCs) are cardioprotective against ischemia/reperfusion (I/R) injury if delivered within 20-30 min of reperfusion (Kanazawa et al, Circ HF 2015; de Couto e...
Abstract 20799: Novel G Alpha 12 N-Terminal Alpha-SNAP Binding Domain Peptide Inhibits vWF Secretion, Prevents Microvascular Thrombosis and Increases Survival in Septic Mice
Authors: Luiza Rusu, Misuk Bae, Maricela Castellon, Aleksandra Stojanovic-Terpo, John W Christman, Xiaoping Du, Hayat Onyuksel, Richard D Minshall
Journal: Circulation (2016)

Introduction:  Severe sepsis can be associated with a 2-3-fold increase in circulating active von Willebrand Factor (vWF)and thus is representative of the early vascular consequence of systemic inflammation and also a critical determinant of sepsis-induced microvascular thrombosis. Recently, we demonstrated that endogenous Gα12 promotes vWF secretion from Weibel Palade bodies by associating directly with α-SNAP via a portion of its unique N-terminal end, from which we synthesized a peptide, the αSNAP Binding Domain (SBD) antagonistic peptide.   Hypothesis and Research Design:  In this study, we assess the hypothesis that SBD peptide can be titrated into activated endothelial cells in vivo to reduce vWF secretion evoked by inflammatory cytokines and disturbed flow in mice made septic by cecal ligation and puncture (CLP).   Results:  Cellular uptake (8% of instilled) of a derivative of SBD peptide labelled with fluorescent 1-pyrenyuldiazomethane (PDAM) by cultured human endothelial cells, as well as blood and lung homogenate levels of PDAM-SBD peptide and blood clearance in rats were estimated by fluorometry. We found that a novel micellar ( m ) formulation of a cell-permeable form ( Myr istoylated) of SBD peptide ( mMyr-SBD ) as compared to Myr-scrambled peptide or vehicle only group (n=6 mice/group) reduced the level of plasma vWF 24 hrs after CLP surgery when given as a one-time i.v. bolus (80 μg/30 g mouse) at the time of surgery (p -/-  mice, shown previously to have significantly reduced plasma vWF levels, survived. In contrast, Gα12 -/-  mice that were subjected to CLP and injected i.v. with purified vWF (2 μg/g BW) exhibited mortality rates similar to WT mice.   Conclusions:  We conclude that inhibition of Gα12/αSNAP dependent vWF secretion may be an effective strategy for blocking microvascular thrombosis, disseminated intravascular coagulation, and death due to sepsis.
Dual turn-on fluorescence signal-based controlled release system for real-time monitoring of drug release dynamics in living cells and tumor tissues
Authors: Xiuqi Kong, Baoli Dong, Xuezhen Song, Chao Wang, Nan Zhang, Weiying Lin
Journal: Theranostics (2017)

Controlled release systems with capabilities for direct and real-time monitoring of the release and dynamics of drugs in living systems are of great value for cancer chemotherapy. Herein, we describe a novel dual turn-on fluorescence signal-based controlled release system (CDox), in which the chemotherapy drug doxorubicin (Dox) and the fluorescent dye (CH) are conjugated by a hydrazone moiety, a pH-responsive cleavable linker. CDox itself shows nearly no fluorescence as the fluorescence of CH and Dox is essentially quenched by the C=N isomerization and N-N free rotation. However, when activated under acidic conditions, CDox could be hydrolyzed to afford Dox and CH, resulting in dual turn-on signals with emission peaks at 595 nm and 488 nm, respectively. Notably, CDox exhibits a desirable controlled release feature as the hydrolysis rate is limited by the steric hindrance effect from both the Dox and CH moieties. Cytotoxicity assays indicate that CDox shows much lower cytotoxicity relative to Dox, and displays higher cell inhibition rate to cancer than normal cells. With the aid of the dual turn-on fluorescence at different wavelengths, the drug release dynamics of CDox in living HepG2 and 4T-1 cells was monitored in double channels in a real-time fashion. Importantly, two-photon fluorescence imaging of CDox in living tumor tissues was also successfully performed by high-definition 3D imaging. We expect that the unique controlled release system illustrated herein could provide a powerful means to investigate modes of action of drugs, which is critical for development of much more robust and effective chemotherapy drugs.
30 s Response Time of K<sup>+</sup> Ion‐Selective Hydrogels Functionalized with 18‐Crown‐6 Ether Based on QCM Sensor
Authors: Zhenxiao Zhang, Qian Dou, Hongkai Gao, Bing Bai, Yongmei Zhang, Debo Hu, Ali K. Yetisen, Haider Butt, Xiaoxia Yang, Congju Li, Qing Dai
Journal: Advanced Healthcare Materials (2017)

Abstract Potassium detection is critical in monitoring imbalances in electrolytes and physiological status. The development of rapid and robust potassium sensors is desirable in clinical chemistry and point‐of‐care applications. In this study, composite supramolecular hydrogels are investigated: polyethylene glycol methacrylate and acrylamide copolymer (P(PEGMA‐ co ‐AM)) are functionalized with 18‐crown‐6 ether by employing surface initiated polymerization. Real‐time potassium ion monitoring is realized by combining these compounds with quartz crystal microbalance. The device demonstrates a rapid response time of ≈30 s and a concentration detection range from 0.5 to 7.0 × 10 −3 m . These hydrogels also exhibit high reusability and K + ion selectivity relative to other cations in biofluids such as Na + , NH 4 + , Mg 2+ , and Ca 2+ . These results provide a new approach for sensing alkali metal ions using P(PEGMA‐ co ‐AM) hydrogels.
Abstract B37: Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer
Authors: Tomas Bruha, Jiri Votruba, Vladimír Cech, Josef Skvarek
Journal: Cancer Research (2017)

Abstract Background: Recently due to advances in biological therapy and immunotherapy there is an increased need for precise morphological and mutational verification of lung cancer. We have been testing the possibilities of NIR (near infrared) n spectroscopy in the process lung cancer detection. Methods: For the analyses, we used a custom-made endoscopic lensed microprobe consisting of one excitation and one collection optical fibers that were coupled to a NIR spectrometer. In 55 patients with lung cancer diagnosis undergoing bronchoscopy we carried on 110 measurements of NIR penetrated spectra from both normal and malignant lung tissues. Detected spectral curves of absolute transmittance for normal tissue and pathological tissue were further analyzed utilizing two chosen parameters which are corresponding to important characteristics of the curves. First parameter was statical moment of area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected average intensity of detected signal as well as rate of shifting higher intensities to shorter wavelengths of spectral band (that means how much is investigated tissue permeable on shortest possible wavelengths). As the second parameter serve horizontal coordinates of the centrum of gravity of the area under spectral curve referenced to vertical axis of maximal wavelength whose value reflected just the rate of shifting signal to shorter wavelengths of spectral band regardless absolute intensity (this parameter compared shifting to shorter wavelengths for spectral curves as if were normalized to its maximal intensity value). Finally ratio of pathological to normal value for both parameters was calculated. Results: Resulting values of these ratios for both above mentioned parameters were higher than 1 for all types of pathologies. Moreover ratio for second parameter is significantly higher for adenocarcinoma than for any type of pathologies. Conclusion: NIR spectroscopy showed a potential for a reliable discrimination between normal and pathological lung tissue. We observed spectral differences between adenocarcinoma and all other types of lung pathologies. Acknowledgement: PROGRAM MPO-TRIO PROJECT: FV 10657, OPROX, a.s. Research and development of technologies and methods for optical penetrating spectroscopy of atypical lung tissue nodules. Note: This abstract was not presented at the conference. Citation Format: Tomas Bruha, Jiri Votruba, Vladimír Cech, Josef Skvarek. Value of penetrated NIR spectroscopy in the diagnostic process of lung cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B37.
Eg5 expression is closely correlated with response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy
Authors: Takamoto Saijo, Genichiro Ishii, Atsushi Ochiai, Kiyotaka Yoh, Koichi Gotoh, Kaoru Kubota, Kanji Nagai, Yutaka Nishiwaki, Nagahiro Saijo
Journal: Cancer Research (2006)

4537    Purpose:  Eg5, a member of the kinesin superfamily, is one of the microtubule motor proteins and functions in bipolar spindle assembly. The purpose of this study was to investigate the relationship between the level of Eg5 expression and response to chemotherapy and outcome in advanced non-small cell lung cancer (NSCLC).  Experimental Design:  Expression of Eg5 was investigated immunohistochemically in 122 formalin-fixed tumor samples from untreated stage IIIB or IV NSCLC patients. We also investigated the expression of cyclin B1 as a molecule involved in the G2/M transition. All patients received antimitotic agents combined with platinum chemotherapy. Response to chemotherapy, progression-free survival (PFS), and overall survival were compared in relation to expression of Eg5 and cyclin B1 and in relation to clinicopathological factors.  Results:  The response rate to chemotherapy of patients with Eg5-positive tumors was 37%, as opposed to 10% of patients with Eg5-negative tumors, and expression of Eg5 was significantly associated with response to chemotherapy (P=0.002), but not with PFS or overall survival. The response rate of cyclin B1-positive tumors (53%) was significantly higher than that of cyclin B1-negative tumors (23%) (P=0.009), and Eg5 expression was significantly correlated with cyclin B1 expression (P=0.005). Multivariate analysis confirmed Eg5 status as an independent variable related to response to chemotherapy (P=0.008). Conclusion:  Expression of the mitotic kinesin Eg5 is a predictive factor for responders to antimitotic agents combined with platinum chemotherapy among patients with advanced NSCLC. This finding indicates that Eg5 may serve as a molecular target for apoptosis of tumor cells in patients with advanced NSCLC.
Recent Progress in Micro/Nanoreactors toward the Creation of Artificial Organelles
Authors: Maria Godoy‐Gallardo, Maria J. York‐Duran, Leticia Hosta‐Rigau
Journal: Advanced Healthcare Materials (2017)

Abstract Artificial organelles created from a bottom up approach are a new type of engineered materials, which are not designed to be living but, instead, to mimic some specific functions inside cells. By doing so, artificial organelles are expected to become a powerful tool in biomedicine. They can act as nanoreactors to convert a prodrug into a drug inside the cells or as carriers encapsulating therapeutic enzymes to replace malfunctioning organelles in pathological conditions. For the design of artificial organelles, several requirements need to be fulfilled: a compartmentalized structure that can encapsulate the synthetic machinery to perform an enzymatic function, as well as a means to allow for communication between the interior of the artificial organelle and the external environment, so that substrates and products can diffuse in and out the carrier allowing for continuous enzymatic reactions. The most recent and exciting advances in architectures that fulfill the aforementioned requirements are featured in this review. Artificial organelles are classified depending on their constituting materials, being lipid and polymer‐based systems the most prominent ones. Finally, special emphasis will be put on the intracellular response of these newly emerging systems.
Assessing the value of weekly blood analysis in patients with localized breast cancer receiving adjuvant treatment with weekly paclitaxel.
Authors: Raul Diez-Fernandez, Santos Enrech-Frances, Jimena Ramon Garcia, Pedro Rodriguez Quesada, Teresa Molina Garcia
Journal: Journal of Clinical Oncology (2014)

1057 Background: Paclitaxel is one of the standard adjuvant treatments in localized breast cancer. Weekly paclitaxel has shown to improve disease-free and overall survival compared to every three weeks paclitaxel (Sparano JA et al, 2008). A retrospective analysis was conducted in our center in order to quantify the incidence of thrombocytopenia, neutropenia and impaired liver blood tests in patients with localized breast cancer receiving adjuvant treatment with weekly paclitaxel (80 mg/m2). Methods: 163 patients over six years were identified from the chemotherapy prescription database. According to blood analysis results, patients were considered deemed well to receive treatment when neutrophils were > 1.5 x109/L, platelets were > 100 x109/L, ALT < 10xULN and bilirubin < 1.25xULN. Results: Patients received 1,862 infusions. 86 % of patients completed the 12 courses of chemotherapy previously planned and the mean number of weekly treatments was 11.42 per patient. Most patients had received previous treatment with anthracyclines (87.7%) and 46 patients (28.2%) received concurrent trastuzumab. Neutropenia (all grades CTC) occurred on 71 administrations (3.81 %) but was grade 3 in only 9 courses (0.48%); no grade 4 neutropenia was observed. Thrombocytopenia of any grade was not seen and only in two courses platelets were below 100 x 109/L. Increased blood bilirubin (any grade CTC) was seen in 25 courses of paclitaxel, but only in 9 of them they were above 1.25xULN (0.48%). No ALT results above 10xULN were observed. In 129 courses of chemotherapy the dose was reduced more than 5% (6.92%) but only in 25 courses this was due to neutropenia (1.34%) and in 3 courses due to increased bilirubin levels (0.16%). Treatment was hold 68 times (3.65%) and only in 16 courses this was because of neutrophil levels (0.86%). Conclusions: The incidence of neutropenia, thrombocytopenia and impaired liver blood tests is very low in patients with localized breast cancer receiving weekly paclitaxel as adjuvant treatment. Liver blood tests might be spared after the first course of chemotherapy and full blood count does not need to be checked on every course.
Abstract P014: Methamphetamine Associated Cardiomyopathy is Associated with Impaired Myocardial Energy Usage via 31Phosphorus Magnetic Resonance Spectroscopy
Authors: Se Kon Won, Nisha Parikh, Steven Buchthal, Todd Seto
Journal: Circulation (2013)

Introduction:  Methamphetamine and related stimulants are now the second most abused illicit drugs worldwide. Methamphetamine associated cardiomyopathy (MAC) has been increasingly reported but still poorly characterized in comparison with other drug-induced cardiomyopathies.   Hypothesis:  Persons with MAC may have left ventricular structural changes as well as altered myocardial energy as compared to persons with ischemic cardiomyopathy or with no known cardiomyopathy.   Methods:  Male persons (mean age=48.2) with MAC (n=10) were selected from a clinic setting. Inclusion criteria included LVEF   Subjects underwent cardiac magnetic resonance imaging (cMRI) at 3 Tesla with Siemens TIM TRIO MRI to assess LV mass and volumes. Subjects then underwent 2 dimensional Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) to obtain phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios in the LV anterior wall to assess cardiac energetics. Results were analyzed with the unequal variance t-test.   Results:  We found a statistically significant difference in PCr: ATP ratios in the current methamphetamine users when compared to normal controls (p=0.03), a result not seen in the ischemic group (p=0.49). A trend towards lower PCR to ATP ratios was seen in all methamphetamine users compared to normal controls (p=0.06). Compared with normal controls, persons with MAC had larger LV diastolic volumes (p=0.004) while persons with ischemic cardiomyopathy were similar (p=0.11) (Table).   Conclusion:  Methamphetamine usage is associated with impaired myocardial energy, beyond that seen in ischemic cardiomyopathy with comparable LV EF. Structurally, MAC is associated with larger LV diastolic volumes than ischemic cardiomyopathy.