tbuckley/cabot-search huggingface dataset:
Role of Alternative Donor Allogeneic Transplants in the Therapy of Acute Myeloid Leukemia
Authors: Hany Elmariah, Keith W. Pratz
Journal: Journal of the National Comprehensive Cancer Network (2017)

Adult acute myeloid leukemia (AML) is often associated with a poor prognosis, with allogeneic transplantation representing the greatest chance of cure for eligible patients. Historically, the preferred donor source is a human leukocyte antigen–matched blood relative, although only approximately 30% of patients have access to such a donor. Alternative donor sources, including matched unrelated donors, umbilical cord blood, and haploidentical related donors, are available for almost every patient and are increasingly being used for patients without a matched related donor. Survival outcomes with these alternative donor sources now approximate those of matched related donor transplants. Given the safety and success of alternative donor transplants, comparative trials are needed to reassess the optimal donor source for patients with AML. This review summarizes the available data on these alternative donor transplants. Further investigation is needed to contemporize donor selection algorithms, but, in the current era, donor availability should no longer preclude a patient's eligibility for an allogeneic blood or marrow transplant.
Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations
Authors: Charline Miot, Kohsuke Imai, Chihaya Imai, Anthony J. Mancini, Zeynep Yesim Kucuk, Tokomki Kawai, Ryuta Nishikomori, Etsuro Ito, Isabelle Pellier, Sophie Dupuis Girod, Jeremie Rosain, Shinya Sasaki, Shanmuganathan Chandrakasan, Jana Pachlopnik Schmid, Tsubasa Okano, Estelle Colin, Alberto Olaya-Vargas, Marco Yamazaki-Nakashimada, Waseem Qasim, Sara Espinosa Padilla, Andrea Jones, Alfons Krol, Nyree Cole, Stephen Jolles, Jack Bleesing, Thomas Vraetz, Andrew R. Gennery, Mario Abinun, Tayfun Güngör, Beatriz Costa-Carvalho, Antonio Condino-Neto, Paul Veys, Steven M. Holland, Gulbu Uzel, Despina Moshous, Benedicte Neven, Stéphane Blanche, Stephan Ehl, Rainer Döffinger, Smita Y. Patel, Anne Puel, Jacinta Bustamante, Erwin W. Gelfand, Jean-Laurent Casanova, Jordan S. Orange, Capucine Picard
Journal: Blood (2017)
A potential non-invasive glioblastoma treatment: Nose-to-brain delivery of farnesylthiosalicylic acid incorporated hybrid nanoparticles
Authors: Emine Sekerdag, Sevda Lüle, Sibel Bozdağ Pehlivan, Naile Öztürk, Aslı Kara, Abbas Kaffashi, Imran Vural, Ilkay Işıkay, Burҫin Yavuz, Kader Karlı Oguz, Figen Söylemezoğlu, Yasemin Gürsoy-Özdemir, Melike Mut
Journal: Journal of Controlled Release (2017)
A Phase I Study of Donor Regulatory T Cells As Treatment for Steroid Dependent/Refractory Chronic Graft Versus Host Disease
Authors: Laura Johnston, Randall Armstrong, Jeanette Baker, Bita Sahaf, Joanne Otani, Keri Tate, Cynthia Tudisco, Kevin Sheehan, Everett Meyer, David Miklos, Robert S. Negrin
Journal: Blood (2016)
Normalization of Tumor Vasculature and Microenvironment by Antiangiogenic Therapies: From the Bench to Bedside and Back
Authors: Rakesh Jain
Journal: Clinical Cancer Research (2007)

PL06-01  Solid tumors require blood vessels for growth, and many new cancer therapies are targeted against the tumor vasculature. The widely held view is that these antiangiogenic therapies destroy the tumor vasculature, thereby depriving the tumor of oxygen and nutrients. Indeed that is the ultimate goal of antiangiogenic therapies. However, emerging preclinical and clinical evidence support an alternative hypothesis — that judicious application of agents that block angiogenesis directly (e.g., Avastin, Recentin) and indirectly (e.g., Herceptin) can also transiently  the abnormal structure and function of tumor vasculature. In addition to being more efficient for oxygen and drug delivery, the normalized vessels are fortified with pericytes, which can hinder intravasation of cancer cells — a necessary step in hematogenous metastasis. Drugs that induce  normalization can also normalize the tumor microenvironment — reduce hypoxia and interstitial fluid pressure — and thus increase the efficacy of many conventional therapies if both are carefully scheduled. Reduced interstitial fluid pressure can decrease tumor-associated edema as well as the probability of lymphatic dissemination. Independent of these effects, alleviation of hypoxia can decrease the selection pressure for a more malignant phenotype. Finally, the increase in proliferation of cancer cells during the vascular normalization  can potentially sensitize tumors to cytotoxic agents. Our recent Phase II clinical trials in patients with rectal carcinomas and glioblastomas (GBM) support our pre-clinical findings on  normalization. Moreover, in GBM patients, the normalization window — identified using advanced MRI techniques — can last one to four months, and the resulting changes in tumor vasculature correlate with circulating molecular and cellular biomarkers in these patients. The encouraging results on patients survival from the GBM Phase II trial has led to an international multi-center randomized Phase III clinical trial in GBM patients.
Robotic surgical systems in maxillofacial surgery: a review
Authors: Hang-Hang Liu, Long-Jiang Li, Bin Shi, Chun-Wei Xu, En Luo
Journal: International Journal of Oral Science (2017)

Throughout the twenty-first century, robotic surgery has been used in multiple oral surgical procedures for the treatment of head and neck tumors and non-malignant diseases. With the assistance of robotic surgical systems, maxillofacial surgery is performed with less blood loss, fewer complications, shorter hospitalization and better cosmetic results than standard open surgery. However, the application of robotic surgery techniques to the treatment of head and neck diseases remains in an experimental stage, and the long-lasting effects on surgical morbidity, oncologic control and quality of life are yet to be established. More well-designed studies are needed before this approach can be recommended as a standard treatment paradigm. Nonetheless, robotic surgical systems will inevitably be extended to maxillofacial surgery. This article reviews the current clinical applications of robotic surgery in the head and neck region and highlights the benefits and limitations of current robotic surgical systems. Robotic surgery has shown promise for head and neck diseases, although more research is needed before it supplants traditional approaches. In a review article, En Luo and colleagues from Sichuan University's West China Hospital of Stomatology in Chengdu discuss the history of robot surgical systems and the recent growth in popularity of such techniques for treating oropharyngeal cancer, cleft palates, craniofacial asymmetries and other conditions that require maxillofacial surgery. The authors describe how robot-assisted surgery in the head and neck region can result in less blood loss, fewer complications, shorter hospitalizations and better cosmetic results than conventional or endoscopic surgery. However, robotic surgery is expensive, takes longer to perform and lacks the human touch of a trained surgeon. More prospective trials are needed to determine if robotic surgery is truly superior.
Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial
Authors: H Goldschmidt, H M Lokhorst, E K Mai, B van der Holt, I W Blau, S Zweegman, K C Weisel, E Vellenga, M Pfreundschuh, M J Kersten, C Scheid, S Croockewit, R Raymakers, D Hose, A Potamianou, A Jauch, J Hillengass, M Stevens-Kroef, M S Raab, A Broijl, H W Lindemann, G M J Bos, P Brossart, M van Marwijk Kooy, P Ypma, U Duehrsen, R M Schaafsma, U Bertsch, T Hielscher, Le Jarari, H J Salwender, P Sonneveld
Journal: Leukemia (2017)
Disseminated Whitish Papules and Scars on a Patient With Bowel Perforation
Authors: Felipe Partarrieu-Mejías, Patricio Llancapi, Jorge Monardes
Journal: JAMA Dermatology (2017)

A woman in her 30s with a 1-year history of unintentional weight loss, mild diffuse abdominal pain, and occasional episodes of vomiting after bowel perforation 3 years prior had a 24-hour history of intense abdominal pain, fever, and loose stools. What is your diagnosis?
Abstract 226: Human Cardiomyocytes Are Protected From Stress-induced Stiffening By Binding Of Small Heat Shock Proteins To Titin Spring Elements
Authors: Sebastian Kotter, Andreas Unger, Nazha Hamdani, Wolfgang A Linke
Journal: Circulation Research (2013)

Introduction: Small heat-shock proteins (sHSPs) generally participate in cellular protein quality-control mechanisms. They are abundant in cardiomyocytes where they bind under diverse stress conditions preferentially to myofilament proteins. The functional role of this association is unclear. Hypothesis: HSP27 and αB-crystallin bind to human cardiac titin spring elements and exert a protective effect on cardiomyocyte passive stiffness under stress conditions. Methods: Binding of sHSPs to recombinant human titin constructs was characterized by GST-pulldown assay and confirmed by immunofluorescence staining of human donor and failing (DCM) cardiomyocytes. Sedimentation-velocity centrifugation, photometric and chromatographic methods were used to test for titin aggregation and protection from it by sHSPs. Passive force was measured in isolated human cardiomyocytes or single myofibrils, in search for a possible protective effect of sHSPs on mechanical function. Results: HSP27 interacted with distinct domains of the human titin-spring region in vitro and in cardiomyocytes, and independent of the presence of actin filaments in the sarcomeres. The binding sites on the elastic titin segment resemble those for αB-crystallin and include proximal Ig-domains, the N2-B and N2-A regions, but not the PEVK-domain. In-vitro assays revealed a monomeric organization of these titin-spring elements; however, unfolded N2-A domain (mainly composed of Ig-domains) aggregated in pH-6.6 buffer but not in normal-pH buffer, whereas αB-crystallin protected from this effect. The intrinsically disordered N2-Bus titin domain did not aggregate. Single skinned human cardiomyocytes showed greatly increased passive stiffness when pre-stretched under acidic stress (pH 6.6), but αB-crystallin or HSP27 corrected the stiffening. In failing patient heart tissue, both HSP27 and αB-crystallin frequently associated with the elastic I-band region, in contrast to a cytosolic and Z-disk location of these sHSPs in donor heart. Conclusions: In cardiomyocytes sHSPs bind to mechanically active titin domains under stress conditions such as intracellular acidosis ( e.g. , ischemia), protecting the titin springs from aggregation and helping reverse diastolic stiffening.
Efficacy of trastuzumab-based therapy after disease progression on lapatinib based therapy in heavily pretreated HER2-positive metastatic breast cancer patients.
Authors: Dogan Uncu, Ibrahim Vedat Bayoglu, Ulku Yalcintas Arslan, Mehmet Kucukoner, Mehmet Artac, Dogan Koca, Arzu Oguz, Umut Demirci, Erkan Arpaci, Mutlu Dogan, Yuksel Kucukzeybek, Ibrahim Turker, Abdurrahman Isikdogan, Tunc Guler, Nurullah Zengin
Journal: Journal of Clinical Oncology (2014)

e11586 Background: We retrospectively analyzed efficacy of trastuzumab-based chemotherapy in patients whose disease progressed after lapatinib. Methods: Between October 2010 and May 2013, 54 patients whose disease progressed after lapatinib received trastuzumab-based treatment. Survival and toxicity results were evaluated retrospectively. Results: Median age of patients were 46 (27-67), 53 were female and 1 was male. 24 patients (44,4%) were ER-positive and 20 (37%) were PR-positive. 14 patients (25,9%) had metastasis at the time diagnosis. 36 of the patients (66,6%) had received adjuvant/neoadjuvant anthracycline and taxane therapy, while 24 (44,4%) had received adjuvant/neoadjuvant anthracycline and 14 (25,9%) adjuvant trastuzumab therapy. 47 patients had received trastuzumab in metastatic setting and all patients received lapatinib plus capecitabine. Median chemotherapy line for metastatic setting was 2 (1-7), 26 patients (48%) had received at least 3 lines of treatments. 39 patients (72,2%) had at least 2 organ metastasis and 27 (50%) had cranial metastasis. 53 patients recevied trastuzumab+chemotherapy following lapatinib while one patient received trastuzumab monotherapy. Combination chemotherapy consisted of navelbin (n=33), taxane (n=16) and gemcitabine or carboplatin (n=4). 6 patients received platinum as triple combination therapy. Median treatment cycle was 5 (1-44). Among 49 patients assessed for response 2 showed CR, 12 PR, 11 SD and 24 disease progression. No unexpected toxicity was observed. At a median follow-up of 9 months (1-39), 45 patients had disease progression, 34 patients died and 4 patients were still on treatment. Median progression-free survival was 5 months (%95 CI 4,1-5,9) and median overall survival was 10 months (%95 CI 6,9-13,0). PFS and OS were not effected by absence/presence of cranial metastasis. Conclusions: Retreatment with trastuzumab-based therapy after lapatinib showed efficacy in patients heavily treated with trastuzumab. Continuing HER2 blockade provides clinical benefit for patients who have received several anti-HER2 treatments.
A single‐cell transcriptomic analysis reveals precise pathways and regulatory mechanisms underlying hepatoblast differentiation
Authors: Li Yang, Wei‐Hua Wang, Wei‐Lin Qiu, Zhen Guo, Erfei Bi, Cheng‐Ran Xu
Journal: Hepatology (2017)

How bipotential hepatoblasts differentiate into hepatocytes and cholangiocytes remains unclear. Here, using single-cell transcriptomic analysis of hepatoblasts, hepatocytes, and cholangiocytes sorted from embryonic day 10.5 (E10.5) to E17.5 mouse embryos, we found that hepatoblast-to-hepatocyte differentiation occurred gradually and followed a linear default pathway. As more cells became fully differentiated hepatocytes, the number of proliferating cells decreased. Surprisingly, proliferating and quiescent hepatoblasts exhibited homogeneous differentiation states at a given developmental stage. This unique feature enabled us to combine single-cell and bulk-cell analyses to define the precise timing of the hepatoblast-to-hepatocyte transition, which occurs between E13.5 and E15.5. In contrast to hepatocyte development at almost all levels, hepatoblast-to-cholangiocyte differentiation underwent a sharp detour from the default pathway. New cholangiocyte generation occurred continuously between E11.5 and E14.5, but their maturation states at a given developmental stage were heterogeneous. Even more surprising, the number of proliferating cells increased as more progenitor cells differentiated into mature cholangiocytes. Based on an observation from the single-cell analysis, we also discovered that the protein kinase C/mitogen-activated protein kinase signaling pathway promoted cholangiocyte maturation.Our studies have defined distinct pathways for hepatocyte and cholangiocyte development in vivo, which are critically important for understanding basic liver biology and developing effective strategies to induce stem cells to differentiate toward specific hepatic cell fates in vitro. (Hepatology 2017;66:1387-1401).
Successful treatment of Pseudomonas aeruginosa osteomyelitis with antibiotic monotherapy of limited duration
Authors: Nadir Laghmouche, Fabrice Compain, Anne-Sophie Jannot, Pierre Guigui, Jean-Luc Mainardi, Guillaume Lonjon, Benjamin Bouyer, Marie-Paule Fernandez-Gerlinger
Journal: Journal of Infection (2017)
Abstract 127: Structure and Function Relationship of Phospholipid Transfer Protein in Lipid Transfer Activity Revealed by Electron Microscopy
Authors: Meng Zhang
Journal: Circulation Research (2015)

Human phospholipid transfer protein (PLTP) mediates the transfer of lipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would be an important step toward the understanding and regulation of PLTP for treating cardiovascular diseases, hypoalphalipoproteinemia and hyperalphalipoproteinemia. Using electron microscopy, negative-staining, and single-particle image processing, we discovered that PLTP penetrates each class of HDL, LDL and liposome independently, and also bridges a ternary complex with one of its distal end-domains penetrating into HDL and another distal domain interacting with LDL. These new insights into PLTP interaction with lipoproteins and liposomes provide a molecular basis for analyzing PLTP-dependent lipid transfer between lipoprotein particles.
High endocan levels are associated with the need for mechanical ventilation among patients with severe sepsis
Authors: Mandeep Mangat, Bravein Amalakuhan, Sheila Habib, Luis F. Reyes, Cecilia A. Hinojosa, Alejandro H. Rodriguez, Nilam J. Soni, Antonio Anzueto, Stephanie M. Levine, Jay I. Peters, Stefano Aliberti, Oriol Sibila, Jordi Rello, Martin Witzenrath, Grant W. Waterer, Ignacio Martin-Loeches, Jose Blanquer, Francisco Sanz, Pedro J. Marcos, Jordi Solé-Violán, James D. Chalmers, Charles Feldman, Richard G. Wunderink, Charles S. Dela Cruz, Carlos J. Orihuela, Marcos I. Restrepo
Journal: European Respiratory Journal (2017)

Sepsis affects more than 750 000 Americans each year, with a mortality rate close to 30% [1]. A significant amount of resources has been put into improving our understanding of sepsis and developing new therapies. A push for early sepsis recognition and subsequent timely treatment has led to an interest in inflammatory biomarkers to identify sepsis and its severity [2]. Respiratory dysfunction occurs in up to 81% of cases and a significant proportion requires ventilatory support [1]. Studies have looked at a variety of biomarkers, from inflammatory cytokines such as interleukin (IL)-6 to endothelial proteins like intercellular adhesion molecule-1, to identify patients at greatest risk of developing respiratory compromise [3]. Endocan may have a role as a predictive biomarker for need for mechanical ventilation in patients with severe sepsis <http://ow.ly/raKd30bSqTk>
Circulating complement factor H–related proteins 1 and 5 correlate with disease activity in IgA nephropathy
Authors: Nicholas R. Medjeral-Thomas, Hannah J. Lomax-Browne, Hannah Beckwith, Michelle Willicombe, Adam G. McLean, Paul Brookes, Charles D. Pusey, Mario Falchi, H. Terence Cook, Matthew C. Pickering
Journal: Kidney International (2017)

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
Cytosine Deaminase APOBEC3A Sensitizes Leukemia Cells to Inhibition of the DNA Replication Checkpoint
Authors: Abby M. Green, Konstantin Budagyan, Katharina E. Hayer, Morgann A. Reed, Milan R. Savani, Gerald B. Wertheim, Matthew D. Weitzman
Journal: Cancer Research (2017)

Abstract Mutational signatures in cancer genomes have implicated the APOBEC3 cytosine deaminases in oncogenesis, possibly offering a therapeutic vulnerability. Elevated APOBEC3B expression has been detected in solid tumors, but expression of APOBEC3A (A3A) in cancer has not been described to date. Here, we report that A3A is highly expressed in subsets of pediatric and adult acute myelogenous leukemia (AML). We modeled A3A expression in the THP1 AML cell line by introducing an inducible A3A gene. A3A expression caused ATR-dependent phosphorylation of Chk1 and cell-cycle arrest, consistent with replication checkpoint activation. Further, replication checkpoint blockade via small-molecule inhibition of ATR kinase in cells expressing A3A led to apoptosis and cell death. Although DNA damage checkpoints are broadly activated in response to A3A activity, synthetic lethality was specific to ATR signaling via Chk1 and did not occur with ATM inhibition. Our findings identify elevation of A3A expression in AML cells, enabling apoptotic sensitivity to inhibitors of the DNA replication checkpoint and suggesting it as a candidate biomarker for ATR inhibitor therapy. Cancer Res; 77(17); 4579–88. ©2017 AACR.
Real-world effectiveness of palonosetron within a three-drug regimen to prevent chemotherapy induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC).
Authors: Robert B. Geller, Trent McLaughlin, Kimberly McLeod, Madhuri Bajaj, Shaker R. Dakhil, Eduardo Braun, David T. Chu, Nashat Y. Gabrail, Stanley M. Marks, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

e18231 Background: CINV is among the most debilitating and feared consequences of cancer treatment. It is therefore imperative to determine if patients are achieving similar response rates in practice as demonstrated in trials. This study evaluated the real world effectiveness of palonosetron, an NK-1 inhibitor, and dexamethasone in patients receiving HEC for prevention of CINV according to international antiemetic guidelines (ASCO, MASCC, NCCN). Methods: A phase IV prospective, multi-center observational study was conducted in which 107 patients were enrolled and treated in accordance with standard of care. All medications were commercially available and the decision to treat was made by the primary physician prior to and independent of participation in the study. The primary outcome for analysis was complete response (CR) defined as no emetic episodes and no use of rescue medication for CINV. CR was classified as acute- (0-24 hours), delayed-phase ( > 24-120 hours), and overall (0-120 hours). Nausea, vomiting and retching episodes were captured in daily patient diary entries for 5 days following initiation of chemotherapy administration. Results: Seven research centers contributed 107 study patients with a mean age of 55.02 years with 17.8% males. A majority (69.2%) had a diagnosis of breast cancer followed by lung cancer (9.3%). The overall CR rate for cycle 1 patients was 31.8%, with 56.1% and 38.3% achieving CR in the acute and delayed- phases, respectively. Use of rescue medication was predominantly prochlorperazine alone or with lorazepam, ondansetron, and/or scopolamine. Half of the patients (52.0%) had 2 or more HEC treatment cycles. Conclusions: In prior clinical studies, palonosetron in combination with an NK-1 and dexamethasone demonstrated overall CR ranging from 50-81%, with an average of 84% CR in the acute phase and 70% in the delayed phase. The results of this study indicate that patients may not be attaining the full benefit of CINV treatment with their current regimens. There remains an unmet need for alternative treatment options to improve patient outcomes.