tbuckley/cabot-search huggingface dataset:
Phase II study of ERC1671 plus bevacizumab versus bevacizumab plus placebo in recurrent glioblastoma : interim results and correlations with CD4+ T-lymphocyte counts
Authors: Daniela A. Bota, Jinah Chung, Manisha Dandekar, Jose A. Carrillo, Xiao Tang Kong, Beverly D. Fu, Frank Pk Hsu, Axel H. Schönthal, Florence M. Hofman, Thomas C. Chen, Raphael Zidovetzki, Chrystel Pretto, Ankie Strik, Virgil E.J.C. Schijns, Apostolos Stathopoulos
Journal: JAMA Oncology (2018)

AIM: ERC1671 is an allogeneic/autologous therapeutic glioblastoma (GBM) vaccine - composed of whole, inactivated tumor cells mixed with tumor cell lysates derived from the patient and three GBM donors.  METHODS: In this double-blinded, randomized, Phase II study bevacizumab-naive patients with recurrent GBM were randomized to receive either ERC1671 in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine® or sargramostim) and cyclophosphamide plus bevacizumab, or placebo plus bevacizumab. Interim results: Median overall survival (OS) of patients treated with ERC1671 plus bevacizumab was 12 months. In the placebo plus bevacizumab group, median OS was 7.5 months. The maximal CD4+ T-lymphocyte count correlated with OS in the ERC1671 but not in the placebo group.  CONCLUSION: The addition of ERC1671/GM-CSF/cyclophosphamide to bevacizumab resulted in a clinically meaningful survival benefit with minimal additional toxicity.
The contribution of microbiology to neuroscience: More complex than it seems?
Authors: Elisa Borghi, Aglaia Vignoli, Armando D'Agostino
Journal: Behavioral and Brain Sciences (2019)

Abstract The overblown, somewhat dramatic media interpretation of microbiota-gut-brain literature is highly misleading. This phenomenon is not new to neuroscience, wherein rapidly evolving research fields struggle to translate findings into clinical practice. Advances in microbiology might integrate our understanding of complex biological pathways that should be interpreted within neuropsychiatric symptom dimensions rather than specific disorders.
Multilayered control of exon acquisition permits the emergence of novel forms of regulatory control
Authors: Nesli Avgan, Juli I. Wang, Javier Fernandez-Chamorro, Robert J. Weatheritt
Journal: Genome biology (2019)

The long introns of mammals are pools of evolutionary potential due to the multiplicity of sequences that permit the acquisition of novel exons. However, the permissibility of genes to this type of acquisition and its influence on the evolution of cell regulation is poorly understood. Here, we observe that human genes are highly permissive to the inclusion of novel exonic regions permitting the emergence of novel regulatory features. Our analysis reveals the potential for novel exon acquisition to occur in over 30% of evaluated human genes. Regulatory processes including the rate of splicing efficiency and RNA polymerase II (RNAPII) elongation control this process by modulating the "window of opportunity" for spliceosomal recognition. DNA damage alters this window promoting the inclusion of repeat-derived novel exons that reduce the ribosomal engagement of cell cycle genes. Finally, we demonstrate that the inclusion of novel exons is suppressed in hematological cancer samples and can be reversed by drugs modulating the rate of RNAPII elongation. Our work demonstrates that the inclusion of repeat-associated novel intronic regions is a tightly controlled process capable of expanding the regulatory capacity of cells.
Microsponges for dermatological applications: Perspectives and challenges
Authors: Sheefali Mahant, Sunil Kumar, Sanju Nanda, Rekha Rao
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Dermatological disorders have a huge psychosocial impact, causing significant impairment of patient's life. Topical therapy plays a pivotal role in management of such disorders. Conventional topical delivery systems result in overmedication/undermedication, leading to adverse effects and reduction in therapeutic efficacy. Consequently, researchers have been striving towards the development of alternative delivery systems for dermatological applications. In the last decade, microsponges emerged as an attractive option for topical delivery. Their characteristic particle size offers enhanced benefits, making them superior to the contemporary microcarriers. The present review furnishes a comprehensive account of state of the art, important factors affecting the performance and mechanism of drug release from topically applied microsponges, along with characterization techniques. Further, a list of marketed products and their applications for common dermatological disorders has been presented. All in all, this paper is an attempt to lay a bibliographic foundation for researchers working in this field and foster further investigations in this arena.
Abstract 167: CT Calcium Scoring Detects Coronary Artery Pathology In Patients With A Remote History Of Kawasaki Disease
Authors: Andrew M Kahn, Lori B Daniels, John B Gordon, Matthew J Budoff, Matthew Vejar, Jane C Burns
Journal: Circulation (2015)

Background: As a result of the acute vasculitis associated with Kawasaki disease (KD), subsets of patients with a remote history of KD have coronary artery aneurysms and may develop coronary artery stenoses with associated risks of late morbidity. Hence, there is a need for effective non-invasive testing to detect coronary artery pathology and risk stratify patients with a remote history of KD. In a pilot study we previously showed that computed tomography (CT) coronary artery calcium (CAC) scoring with relatively low radiation doses detects late CAC in patients with aneurysms and a remote history of KD. Methods: We performed CT calcium volume scoring in 166 subjects (median age 19.5 years) with a remote history of KD (median interval from onset of KD to CT 15.1 years). Coronary arteries were classified as normal (n = 100), transiently dilated (n = 23), persistently dilated (n = 10), resolved aneurysm (n = 9), or aneurysm (n = 24) based on the initial echocardiograms. We defined coronary artery pathology as the presence of a coronary artery aneurysm or stenosis. Results: All subjects with coronary arteries classified as normal, persistently dilated, or resolved aneurysm had zero CAC. All but one of the subjects with transiently dilated coronary arteries had zero CAC (the one subject with a CAC score of 666 mm 3 had a history of severe left main coronary artery stenosis requiring bypass surgery). Of the 24 subjects with coronary aneurysms, all but 5 had CAC (median volume score 542 mm 3 ; range 17 mm 3 to 8,218 mm 3 ). Four of the 5 subjects with aneurysms and no CAC were imaged within 6 years of their episode of acute KD. For subjects imaged 9 or more years after their acute KD (n=144), the presence of CAC on CT had a sensitivity of 95% and a specificity of 100% for detecting coronary artery pathology. Conclusions: For patients with a remote history of KD, CT calcium scoring is a sensitive and specific test for detecting coronary artery pathology. Patients with coronary artery aneurysms secondary to KD develop late CAC, which may be severe. The pathophysiology and clinical significance of this calcification are currently unknown.
Sprinkle formulations—A review of commercially available products
Authors: Han Sol Lee, Jeong-Jun Lee, Myeong-Gyu Kim, Ki-Taek Kim, Cheong-Weon Cho, Dae-Duk Kim, Jae-Young Lee
Journal: Asian Journal of Pharmaceutical Sciences (2019)

Currently, sixty-five original sprinkle drug products are available in various dosage forms including tablets, powders, granules, immediate-release capsules, extended-release capsules, delayed-release capsules, and multiparticulate drug delivery systems. By sprinkling on soft food vehicles, these products provide dosing flexibility and convenience of administration, which potentially improve the compliance of patients with dysphagia. Due to these advantages, the growth of sprinkle products picked up since the 1990s, and several regulatory issues regarding this dosage form have been raised and documented. In this article, the types of sprinkle formulations were discussed by dividing them into seven categories, and the commercial products were summarized in terms of the drug substance, pharmaceutical excipients, storage conditions and administration methods. In addition, several US Food and Drug Administration guidelines related to the regulatory issues of sprinkle formulations were reviewed, which led to the conclusion that the future development of this promising dosage form demands integrated guidance for industry rather than scattered information in various documents.
Toxicity and Outcomes of Autologous Stem Cell Transplant in Multiple Myeloma Patients with Renal Insufficiency: An Institutional Comparison between Two Eras
Authors: Amanda Li, Eshetu G Atenafu, Rosanne St. Bernard, Esther Masih-Khan, Donna Reece, Norman Anthony Franke, Rodger Tiedemann, Anca Prica, Suzanne Trudel, Vishal Kukreti, Christine I Chen
Journal: Blood (2017)
Heat-Damaged Red Blood Cell Scintigraphy in Helping Interpretation of 68Ga-DOTATATE PET/CT
Authors: Zhe Wen, Kevin W. Edwards, Lisa J. States, Hongming Zhuang
Journal: Clinical Nuclear Medicine (2019)

Abstract 68 Ga-DOTATATE PET/CT was performed to determine the cause of endogenous Cushing syndrome in a 10-year-old boy whose MRI studies did not reveal pituitary or adrenal gland abnormality. The PET/CT images demonstrated an intense activity in a small soft tissue nodule in the left upper abdomen where splenules are commonly located. Heat-damaged 99m Tc-labeled red blood cell imaging showed that this soft tissue nodule did not have increased red blood cell activity, which indicated that this lesion was a true somatostatin receptor–rich lesion. The pathology result following surgical resection of the lesion confirmed adrenocorticotropic hormone–producing neuroendocrine tumor.
Global Expression Changes of Malignant Plasma Cells over Time Reveals the Evolutionary Development of Signatures of Aggressive Clinical Behavior
Authors: Eileen M Boyle, Adam Rosenthal, Yan Wang, Phil Farmer, Michael W Rutherford, Cody Ashby, Michael A Bauer, Sarah K Johnson, Christopher P. Wardell, Niels Weinhold, Antje Hoering, Charles Dumontet, Thierry Facon, Carolina D. Schinke, Sharmilan Thanendrarajan, Frits van Rhee, Maurizio Zangari, Bart Barlogie, Faith E. Davies, Brian A Walker, Gareth Morgan
Journal: Blood (2018)
Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis
Authors: Justin Taylor, Maria Sendino, Alexander N. Gorelick, Alessandro Pastore, Matthew T. Chang, Alexander V. Penson, Elena I. Gavrila, Connor Stewart, Ella M. Melnik, Florisela Herrejon Chavez, Lillian Bitner, Akihide Yoshimi, Stanley Chun-Wei Lee, Daichi Inoue, Bo Liu, Xiao J. Zhang, Anthony R. Mato, Ahmet Dogan, Michael G. Kharas, Yuhong Chen, Demin Wang, Rajesh K. Soni, Ronald C. Hendrickson, Gorka Prieto, Jose A. Rodriguez, Barry S. Taylor, Omar Abdel-Wahab
Journal: Cancer Discovery (2019)

Altered expression of XPO1, the main nuclear export receptor in eukaryotic cells, has been observed in cancer, and XPO1 has been a focus of anticancer drug development. However, mechanistic evidence for cancer-specific alterations in XPO1 function is lacking. Here, genomic analysis of 42,793 cancers identified recurrent and previously unrecognized mutational hotspots in XPO1. XPO1 mutations exhibited striking lineage specificity, with enrichment in a variety of B-cell malignancies, and introduction of single amino acid substitutions in XPO1 initiated clonal, B-cell malignancy in vivo. Proteomic characterization identified that mutant XPO1 altered the nucleocytoplasmic distribution of hundreds of proteins in a sequence-specific manner that promoted oncogenesis. XPO1 mutations preferentially sensitized cells to inhibitors of nuclear export, providing a biomarker of response to this family of drugs. These data reveal a new class of oncogenic alteration based on change-of-function mutations in nuclear export signal recognition and identify therapeutic targets based on altered nucleocytoplasmic trafficking. SIGNIFICANCE: Here, we identify that heterozygous mutations in the main nuclear exporter in eukaryotic cells, XPO1, are positively selected in cancer and promote the initiation of clonal B-cell malignancies. XPO1 mutations alter nuclear export signal recognition in a sequence-specific manner and sensitize cells to compounds in clinical development inhibiting XPO1 function.This article is highlighted in the In This Issue feature, p. 1325.
How to spot ocular abnormalities in progressive supranuclear palsy? A practical review
Authors: Onanong Phokaewvarangkul, Roongroj Bhidayasiri
Journal: Translational Neurodegeneration (2019)

For parkinsonian disorders, progressive supranuclear palsy (PSP) continues to be significant for differential diagnosis. PSP presents a range of ocular abnormalities that have been suggested as optional tools for its early detection, apart from the principal characteristic of postural unsteadiness. Nonetheless, such symptoms may be difficult to identify, particularly during the early onset stage of the disorder. It may also be problematic to recognize these symptoms for general practitioners who lack the required experience or physicians who are not specifically educated and proficient in ophthalmology or neurology. Thus, here, a methodical evaluation was carried out to identify seven oculomotor abnormalities occurring in PSP, comprising square wave jerks, the speed and range of saccades (slow saccades and vertical supranuclear gaze palsy), 'round the houses' sign, decreased blink rate, blepharospasm, and apraxia of eyelid opening. Inspections were conducted using direct visual observation. An approach to distinguish these signs during a bedside examination was also established. When presenting in a patient with parkinsonism or dementia, the existence of such ocular abnormalities could increase the risk of PSP. For the distinction between PSP and other parkinsonian disorders, these signs hold significant value for physicians. The authors urge all concerned physicians to check for such abnormalities with the naked eye in patients with parkinsonism. This method has advantages, including ease of application, reduced time-consumption, and requirement of minimal resources. It will also help physicians to conduct efficient diagnoses since many patients with PSP could intially present with ocular symptoms in busy outpatient clinics.
68Ga-PSMA-617 Compared With 68Ga-RM2 and 18F-FCholine PET/CT for the Initial Staging of High-Risk Prostate Cancer
Authors: Romain Schollhammer, Henri de Clermont Gallerande, Grégoire Robert, Mokrane Yacoub, Delphine Vimont, Elif Hindié, Philippe Fernandez, Clément Morgat
Journal: Clinical Nuclear Medicine (2019)

Abstract 68 Ga-labeled prostate-specific membrane antigen inhibitors and 68 Ga-labeled gastrin-releasing peptide receptor antagonists showed interesting results for staging biochemically recurrent prostate cancer. In this case, 68 Ga–prostate-specific membrane antigen-617 PET/CT, 68 Ga-RM2 PET/CT, and 18 F-choline PET/CT were performed in a patient (66-year-old man, prostate-specific antigen = 6.7 ng/mL) with biopsy-proven Gleason 9 (5 + 4) prostate cancer, candidate for radical prostatectomy and lymph node dissection.
A multimodality test to guide the management of patients with a pancreatic cyst
Authors: Simeon Springer, David L. Masica, Marco Dal Molin, Christopher Douville, Christopher J. Thoburn, Bahman Afsari, Lu Li, Joshua D. Cohen, Elizabeth Thompson, Peter J. Allen, David S. Klimstra, Mark A. Schattner, C. Max Schmidt, Michele Yip-Schneider, Rachel E. Simpson, Carlos Fernandez-Del Castillo, Mari Mino-Kenudson, William Brugge, Randall E. Brand, Aatur D. Singhi, Aldo Scarpa, Rita Lawlor, Roberto Salvia, Giuseppe Zamboni, Seung-Mo Hong, Dae Wook Hwang, Jin-Young Jang, Wooil Kwon, Niall Swan, Justin Geoghegan, Massimo Falconi, Stefano Crippa, Claudio Doglioni, Jorge Paulino, Richard D. Schulick, Barish H. Edil, Walter Park, Shinichi Yachida, Susumu Hijioka, Jeanin van Hooft, Jin He, Matthew J. Weiss, Richard Burkhart, Martin Makary, Marcia I. Canto, Michael G. Goggins, Janine Ptak, Lisa Dobbyn, Joy Schaefer, Natalie Sillman, Maria Popoli, Alison P. Klein, Cristian Tomasetti, Rachel Karchin, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Christopher L. Wolfgang, Ralph H. Hruban, Anne Marie Lennon
Journal: Science Translational Medicine (2019)

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.
Use of 18F-Fluciclovine to Diagnose Recurrent Prostate Carcinoma in a Patient With Beta-Thalassemia
Authors: Chelsea R. Schmitt, Christian T. Schmitt, Peter R. Hinds, Kevin J. Sawyer
Journal: Clinical Nuclear Medicine (2019)

Abstract We present a case demonstrating increased diagnostic difficulty in interpretation of 18 F-flucyclovine PET/CT in a patient with beta-thalassemia. 18 F-flucyclovine PET/CT demonstrated diffuse increased marrow activity. Additional findings of extramedullary hematopoiesis including intrasplenic extramedullary hematopoiesis are presented. Despite the background marrow activity, an osseous metastatic lesion representing recurrent metastatic prostate carcinoma was identified. This case demonstrates a spectrum of findings of 18 F-flucyclovine uptake in thalassemia, which increased the difficulty of identifying recurrent disease.
The Combination of Radium-223 Dichloride and Bortezomib Effectively Reduces Tumor Burden and Lesion Area in the Syngeneic, Systemic 5TGM1 Multiple Myeloma Mouse Model
Authors: Mari Suominen, Tiina Kähkönen, Jenni Mäki-Jouppila, Jukka P Rissanen, Anniina Luostarinen, Katja M Fagerlund, Birgitta Sjöholm, Esa Alhoniemi, Sanna Kakonen, Gerhard Siemeister, Dominik Mumberg, Jussi M Halleen, Karl Ziegelbauer, Arne Scholz
Journal: Blood (2017)
Response to Comment on “PP2A inhibition sensitizes cancer stem cells to ABL tyrosine kinase inhibitors in BCR-ABL <sup>+</sup> human leukemia”
Authors: Damian Lai, Min Chen, Jiechuang Su, Xiaohu Liu, Katharina Rothe, Kaiji Hu, Donna L. Forrest, Connie J. Eaves, Gregg B. Morin, Xiaoyan Jiang
Journal: Science Translational Medicine (2019)

LB100 sensitizes resistant chronic phase CML stem and progenitor cells to TKIs and spares healthy bone marrow cells.
Treatment-free remission (TFR) following frontline (1L) nilotinib (NIL) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): 192-week data from the ENESTfreedom study.
Authors: Francis J. Giles, Tamas Masszi, María Teresa Gómez Casares, Andrzej Hellmann, Jesper Stentoft, Eibhlin Conneally, Valentin García Gutierrez, Norbert Gattermann, Phillipp D. Le Coutre, Bruno Martino, Susanne Saussele, Jerald P. Radich, David M. Ross, Giuseppe Saglio, Manu Sondhi, Suddhasatta Acharyya, Paola Aimone, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2019)

7013 Background: In ENESTfreedom (NCT01784068), which evaluated TFR following 1L NIL in CML-CP pts, 51.6% remained in TFR 48 wks after stopping treatment (primary endpoint) and durability of TFR was demonstrated at 144 wks. Data from longer follow-up (192 wks) evaluating maintenance of TFR are reported. Methods: Pts with MR 4.5 ( BCR-ABL1 IS ≤0.0032%) and ≥2y of 1L NIL entered a 1y consolidation; pts with sustained deep molecular response (MR) were eligible for TFR. NIL was resumed after loss of major MR (MMR; BCR-ABL1 IS ≤0.1%). At the latest data cut-off (Sep 17 2018), all pts had completed ≥192 wks of TFR, resumed NIL, or discontinued the study. Results: By the data cut-off, of 190 pts entering TFR, 87 were ongoing, 91 had resumed NIL, and 12 had permanently discontinued. The TFR rate at 192 wks was 44.2% (84/190, 95% CI: 37.0–51.6%). Of 89 pts with successful TFR at 144 wks, 5 were not assessable for TFR at 192 wks as 2 had discontinued by 192 wks due to pt/physician decision, and 3 with MR 4.5 previously did not have 192 wk PCR data. Of 91 pts who resumed NIL, 90 (98.9%) regained MMR and 84 (92.3%) regained MR 4.5 . 75/90 and 73/84 pts, respectively, had stable MMR and MR 4.5 at 48 wks later. There were no cases of disease progression or new deaths. 10 deaths were reported in the 144-wk analysis, none due to CML. The 192-wk treatment-free survival rate was 48.7% (95% CI 41.4–55.6%). Of 89 pts remaining in TFR for &gt; 144 wks (including 87 pts for &gt; 192 wks), all-grade AE rates during consolidation and each subsequent 48 wk period of TFR were 84.3%, 77.5%, 70.8%, 48.3%, and 52.8%, respectively. All-grade musculoskeletal pain AE rates were 15.7%, 40.4%, 9.0%, 3.4% and 3.4%, respectively; cardiovascular event rates were low across these periods. Among pts who resumed NIL, most common AEs were nasopharyngitis (18.7%) and pruritus, fatigue, and increased lipase (14.3% each); the majority of AEs were grade 1/2. Conclusions: Results continue to support the long-term durability and safety of TFR at 192 wks after stopping 1L NIL; overall AE rates declined during the TFR phase and musculoskeletal pain AEs were transient. Pts should continue to be regularly monitored during TFR. Clinical trial information: NCT01784068.
Dengue virus serotype 2 (DENV-2) outbreak, French Polynesia, 2019
Authors: Maite Aubry, Mihiau Mapotoeke, Anita Teissier, Tuterarii Paoaafaite, Elsa Dumas-Chastang, Marine Giard, Van-Mai Cao-Lormeau
Journal: Eurosurveillance (2019)

In 1996-97, the last dengue virus serotype 2 (DENV-2) outbreak occurred in French Polynesia. In February 2019, DENV-2 infection was detected in a traveller from New Caledonia. In March, autochthonous DENV-2 infection was diagnosed in two residents. A DENV-2 outbreak was declared on 10 April with 106 cases as at 24 June. Most of the population is not immune to DENV-2; a large epidemic could occur with risk of imported cases in mainland France.