tbuckley/cabot-search huggingface dataset:
MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in <i>BRAF-, NRAS</i>-, and <i>NF1</i>-Mutant Melanomas
Authors: Ophélia Maertens, Ryan Kuzmickas, Haley E. Manchester, Chloe E. Emerson, Alessandra G. Gavin, Caroline J. Guild, Terence C. Wong, Thomas De Raedt, Christian Bowman-Colin, Elodie Hatchi, Levi A. Garraway, Keith T. Flaherty, Shailja Pathania, Stephen J. Elledge, Karen Cichowski
Journal: Cancer Discovery (2019)

Abstract Although the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS- and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three RAS pathway–driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, in both models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, addition of entinostat triggers the concomitant suppression of nonhomologous end-joining genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together, these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker. Significance: BRAF/MEK inhibitors are not typically curative in BRAF-mutant melanomas and are ineffective in NRAS- and NF1-mutant tumors. We show that HDAC inhibitors dramatically enhance the efficacy of BRAF/MEK inhibitors in sensitive and insensitive RAS pathway–driven melanomas by coordinately suppressing two DNA repair pathways, and identify a clinical biomarker that predicts responsiveness. See related commentary by Lombard et al., p. 469. This article is highlighted in the In This Issue feature, p. 453
Malformations of Cerebral Cortex Development: Molecules and Mechanisms
Authors: Gordana Juric-Sekhar, Robert F. Hevner
Journal: Annual Review of Pathology Mechanisms of Disease (2019)

Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.
Annals Graphic Medicine - The Med Student
Authors: Mollie Kotzen
Journal: Annals of Internal Medicine (2019)

Web Exclusives5 February 2019Annals Graphic Medicine - The Med StudentFREEMollie Kotzen, MD, MPHMollie Kotzen, MD, MPHPennsylvania Hospital, Philadelphia, Pennsylvania (M.K.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G18-0006 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Susan Boiko MDUCSD Pediatric Dermatology/Rady Childrens29 March 2022 Awesome perspective Beautiful story and so important for all attendings to read, remember and share with colleagues and other medical students. If you're in the audience of a boring lecture, write something like this, even if it's just for you. Author, Article, and Disclosure InformationAffiliations: Pennsylvania Hospital, Philadelphia, Pennsylvania (M.K.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G18-0006.Author/Illustrator Information: Mollie Kotzen, MD, MPH, is an obstetrics and gynecology resident at Pennsylvania Hospital in Philadelphia (e-mail, mollie.[email protected]upenn.edu). PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAnnals Graphic Medicine - The Tale of a Wannabe Superhero Michelle Sayad Annals Graphic Medicine - Team Doctor Shruti Sudhakar Annals Graphic Medicine - What It Is Like Gazi M. Rashid Reimagining the Cape: Exploring New Metaphors for Emerging Medical Professionals Michael J. Green Reimagining the Cape: Exploring New Metaphors for Emerging Medical Professionals Michael J. Green Metrics Cited byReimagining the Cape: Exploring New Metaphors for Emerging Medical ProfessionalsMichael J. Green, MD, MS 5 February 2019Volume 170, Issue 3Page: W43-W53KeywordsConflicts of interestDisclosureHealth careObstetrics and gynecologyResidency ePublished: 5 February 2019 Issue Published: 5 February 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract 19941: CD8 T Cells With Constitutively Active PI3Kγ Increase Myogenic Tone of Resistance Arteries and Induce Hypertension in Mice
Authors: Daniela Carnevale, Manuel Casaburo, Iolanda Vinciguerra, Marialuisa Perrotta, Roberta Iacobucci, Daniele Iodice, Giuseppe Lembo
Journal: Circulation (2017)

Introduction: Despite it is clearly recognized that CD8 effector T cells are critical players in colonization of target organs of hypertension, the intracellular signaling pathways responsible for the acquisition of effectors functions still remain unidentified. Phosphatidylinositol-3-kinase gamma (PI3Kγ), a lipid kinase mainly distributed in immune and cardiovascular systems, is a typical signaling downstream of G protein-coupled receptors that regulates cell trafficking and plays a selective role in regulating the migration of effector CD8 T cells. Hypothesis and Methods: In the past, we described a crucial role of PI3Kγ in hypertension. Here we tested the hypothesis that this signaling could be a critical regulator of immune cells trafficking in hypertension. By taking advantage of a knock-in mouse model, expressing a constitutively active PI3Kγ isoform (PI3KγCX/CX), we conceived different experimental settings allowing to assess the role of PI3Kγ in the crosstalk between immune cells and vasculature a...
Abstract 16123: Drug Eluting Stent Implantation in Multivessel Coronary Artery Disease Reduces the Adverse Effect of Diabetes on Late Outcomes When Compared to Bare Metal Stent
Authors: Sanaa A Badour, Kamellia R Dimitrova, Yumiko Kanei, Robert F Tranbaugh, Mark M Hajjar, Ameer Kabour, Thomas A Schwann, Robert H Habib
Journal: Circulation (2014)

OBJECTIVE: Diabetes mellitus (DM) portends an increased risk of adverse early and late outcomes in patients undergoing percutaneous coronary intervention (PCI), especially in case of multivessel co...
Multicenter Compliance Study of Asthma Medication for Children in Korea
Authors: Chang-Keun Kim, Zak Callaway, Jungi Choi, Hyo-Bin Kim, Eun-Mi Kwon, Yoon-Seok Chang, Yeong-Ho Rha, Soo-Jong Hong, Jae-Won Oh, Hyun Hee Kim, Dae Hyun Lim, Sung Won Kim, Kang-Seo Park, Yong Hoon Cho, Hai Lee Chung, Hee Ju Park, Sang-Gun Jung, Im-Joo Kang, Myung Chul Hyun, Mu Young Oh, Jin-A. Jung, Myung Sung Kim, Jung Yeon Shim, Jin-Tack Kim, Young Yull Koh
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 17614: Predictors of Mitral Annular Calcification Progression
Authors: Rayji S Tsutsui, Kinjal Banerjee, James D Thomas, Samir Kapadia, Zoran Popovic
Journal: Circulation (2017)

Background: Various risk factors are known to be associated with development of mitral annular calcification (MAC). However, little is known about risk factors that are associated with its progression. In this study, we aimed to identify clinical and echocardiographic risk factors for progression. Methods: We searched our echocardiogram database for patients who had MAC from year 1996-2013. MAC was reported in a semi-quantitative, visual manner by at least experienced echocardiographers at our institution for each study. Patients were included in the study population if they had MAC at their index study and underwent more than two studies in the period of two years or more. Patients with prior mitral valve surgery, rheumatic heart disease, or other identifiable mitral disease were excluded from the study. Results: A total of 2927 patients (18487 studies) met the criteria and was included in the study. Mean age of our study population was 71 ± 11 years and the mean follow up time was 4.8 ± 2.8 years. Avera...
Early Infectious Complications after Autologous Hematopoietic Cell Transplantation (AHCT) for Lymphoma
Authors: Shafia Rahman, Lisa Rybicki, Eric Cober, Robert M. Dean, Betty K. Hamilton, Deepa Jagadeesh, Brian T. Hill, Brad Pohlman, Ronald Sobecks, Matt Kalaycio, Sherif Mossad, Navneet S. Majhail
Journal: Blood (2018)
Combined immune checkpoint inhibition (ICI) with tremelimumab and durvalumab in patients with advanced hepatocellular carcinoma (HCC) or biliary tract carcinomas (BTC).
Authors: Charalampos S. Floudas, Changqing Xie, Gagandeep Brar, Maria Pia Morelli, Suzanne Fioravanti, Melissa Walker, Donna Mabry-Hrones, Brad J. Wood, Elliot B Levy, Venkatesh P Krishnasamy, Tim F. Greten
Journal: Journal of Clinical Oncology (2019)

336 Background: Prognosis in advanced HCC and BTC is unfavorable, and 5-year overall survival (OS) rate is less than 20% and 10%, respectively. Single agent ICI in HCC has response rates (RR) of 20%, while early data in BTC reported 17.4% RR. Dual ICI has increased RR in other malignancies. The purpose of this study was to explore the efficacy of the combination of anti-CTLA4 (tremelimumab) with anti-PD-L1 (durvalumab) in advanced HCC and BTC. Methods: Eligible patients with advanced HCC or BTC who had received (or refused) at least one prior therapy, received monthly tremelimumab 75 mg in combination with durvalumab 1500 mg for 4 doses followed by monthly durvalumab 1500 mg monotherapy until progression of disease or unacceptable toxicity. Response was assessed with CT scan every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint is 6-month progression free survival (PFS). Results: Twenty-two patients were enrolled, 10 with advanced HCC and 12 with advanced BTC. Male to female ratio was 14:8, with median age of 62.5 years (range 19-80). Grade 3/4 treatment-related AEs included lymphocytopenia, hyponatremia, bullous dermatitis, maculopapular rash, mucositis, hypophosphatemia, anaphylaxis, dyspnea, pleural effusion, and pain. Twenty patients were evaluable for response analysis. Two patients (2/10, 20%) achieved a confirmed partial response (both with HCC, lasting 6.9 and 17.6 months), while 9 patients (4 [40%] with HCC and 5 [41.7%] with BTC) had stable disease, with the longest duration of 9.3 months (in an HCC patient). Disease control rate is 60% in HCC and 41.7% in BTC, respectively. In this small pilot cohort, median PFS was 3.1 months (95% CI 0.8 to 4.6 months) and median OS was 5.45 months (95% CI 4.60 to 8.3 months) among BTC patients, while HCC patients median PFS was 7.8 months (95% CI 2.6 to 10.6 months) and median OS was 15.9 (95% CI 7.1 to 16.3 months). Conclusions: Combined ICI with tremelimumab and durvalumab is well tolerated and demonstrates promising activity in patients with advanced HCC and BTC. Clinical trial information: NCT02821754.
Loss of SMAD4 Promotes Colorectal Cancer Progression by Recruiting Tumor-Associated Neutrophils via the CXCL1/8–CXCR2 Axis
Authors: Ryotaro Ogawa, Takamasa Yamamoto, Hideyo Hirai, Keita Hanada, Yoshiyuki Kiyasu, Gen Nishikawa, Rei Mizuno, Susumu Inamoto, Yoshiro Itatani, Yoshiharu Sakai, Kenji Kawada
Journal: Clinical Cancer Research (2019)

Abstract Purpose: SMAD4 is a key transcriptional factor of TGFβ signaling and acts as a tumor suppressor in colorectal cancer. In the present study, we explored the immunologic effect of SMAD4 on the tumor microenvironment. Experimental Design: Using 99 clinical specimens and human colorectal cancer cell lines, we investigate the relationship between SMAD4 expression and neutrophil accumulation. We immunohistochemically analyzed expression of SMAD4, CXCL1, CXCL8, CXCR2, and other proteins with clinical specimens. Finally, we determined the serum levels of CXCL1 and CXCL8 in 125 patients with colorectal cancer. Results: SMAD4 knockdown from human colorectal cancer cells upregulated the expression of CXCL1 and CXCL8, which recruited neutrophils to colorectal cancer tumor via CXCR2. In turn, when neutrophils were exposed to the supernatant of SMAD4-negative colorectal cancer cells, they produced a large amount of CXCL1 and CXCL8 by themselves in vitro. In human clinical specimens, we found that neutrophil infiltration into the peritumoral stroma was more marked in SMAD4-negative colorectal cancer compared with that in SMAD4-positive colorectal cancer, and that both CXCL1 and CXCL8 were abundantly expressed in the tumor-infiltrating neutrophils. Neutrophils isolated from primary colorectal cancer expressed significantly higher levels of CXCL1 and CXCL8 than did those isolated from peripheral blood. Furthermore, tumor-infiltrating neutrophils expressed MMP2 and MMP9 in addition to ARG1 and IDO. Serum CXCL8 level was significantly higher in colorectal cancer patients, especially those at stage II/III, and statistical analysis indicated a high CXCL8 level was associated with a shorter overall survival and relapse-free survival. Conclusions: Blockade of the CXCL1/8–CXCR2 axis could be a novel therapeutic approach against SMAD4-negative colorectal cancer.
Comparative Genomic and Expression Analysis of Chronic and Blast-Phase Cells in Patients with Myeloproliferative Neoplasms
Authors: Paola Guglielmelli, Tiziana Fanelli, Valentina Ariu, Giada Rotunno, Annalisa Pacilli, Elisa Contini, Alberto Magi, Roberto Semeraro, Simona Salati, Alberto Bosi, Francesco Mannelli, Rossella Manfredini, Alessandro M. Vannucchi
Journal: Blood (2018)
Abstract B078: Expression of activated STAT3 in the epithelial cells of hormone-naïve prostate cancer
Authors: Agnieszka Krzyzanowska, Nicholas Don-Doncow, Felicia-Elena Marginean, William Watson, Rebecka Hellsten, Anders Bjartell
Journal: Cancer Research (2018)

Abstract Introduction: The Signal Transducer and Activator of Transcription 3 (STAT3) pathway is thought to be phosphorylated (pSTAT3) and constitutively activated in prostate cancer (PCa). Previous results from our laboratory showed high pSTAT3 levels in PCa metastases. In the present study we investigated the expression of pSTAT3 in tissue microarrays of two cohorts of localized hormone-naïve PCa patients and correlated it with disease outcome. Methods: The expression of pSTAT3 in the nuclei of epithelial cells of prostatic glands was examined in two TMAs of paraffin-embedded prostatic tissue. The TMAs consisted of tissue originated from hormone-naïve radical prostatectomy patients from two different sites: Malmö (n=300) and Dublin (n=99). Results: In the Malmö cohort, the average expression levels of pSTAT3 in the epithelial cells of benign glands were significantly higher than in the cancerous glands. Patients with low pSTAT3 levels in the epithelial cells of the cancerous glands showed reduced times to biochemical recurrence, compared to those with higher levels; however, adding the pSTAT3 expression data to Gleason score or pathologic T stage did not improve their prognostic values. The results for the Dublin cohort showed similar trends. Conclusions: Low pSTAT3 expression in epithelial cells of cancerous prostatic glands in hormone-naïve PCa was associated with faster disease progression; however, pSTAT3 is unlikely to be a good biomarker in the early stages of PCa. Citation Format: Agnieszka Krzyzanowska, Nicholas Don-Doncow, Felicia-Elena Marginean, William Watson, Rebecka Hellsten, Anders Bjartell. Expression of activated STAT3 in the epithelial cells of hormone-naïve prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B078.
Vector Integration and Efficacy of CD19-Directed CAR T Cell Therapy in Acute Lymphoblastic Leukemia (ALL) and Chronic Lymphocytic Leukemia (CLL)
Authors: Christopher L Nobles, John K Everett, Shantan Reddy, Joseph A Fraietta, David L. Porter, Noelle V. Frey, Stephan A. Grupp, Don L. Siegel, Simon F Lacey, Carl H June, Frederic D Bushman, J. Joseph Melenhorst
Journal: Blood (2018)
Efficacy and tolerability of sorafenib in unresectable/advanced hepatocellular carcinoma patients: Real-life experience in a Hong Kong tertiary liver cancer institute.
Authors: Thomas Cheung Yau, Vikki Tang, Roland Ching-Yu Leung, Gin Wai Kwok, Joanne Wing-Yan Chiu, Tan To Cheung
Journal: Journal of Clinical Oncology (2019)

382 Background: To evaluate the pattern and outcomes of sorafenib use in unresectable/advanced HCC in a real life setting in a tertiary Hong Kong liver cancer centre. Methods: A retrospective review of unresectable or advanced HCC patients treated with sorafenib at Queen Mary Hospital, Hong Kong from 2010-2015 was conducted. The objectives were to evaluate the sorafenib efficacy in overall treated population as well as different subgroups; and also reviewed the tolerability of sorafenib, especially its impact on liver function. Results: During the study period, 504 consecutive cases were identified and 493 cases with sufficient clinical data were analyzed. Consistent with Asia-Pacific etiologies, 79.3% patients had chronic hepatitis B. Sorafenib was mainly used in patients with high tumor burden (75.1% BCLC-C, 68.6% MVI or/and EHS). Two-third patients (68.2%) were pretreated, mostly with loco-regional therapies . While 70.2% patients had good baseline PS 0, one-quarter (26.6%) had Child-Pugh B/C cirrhosis state. The overall survival (OS) was 8.15 months, with no difference between HBV and non-HBV subgroups. Patients had Child-Pugh A(CP-A) had significantly better OS compared with those at CP-B/C (11.1m vs 3.29m vs 3.34m). About 36.1% patients received subsequent therapies. Safety profile was essentially consistent with literature with hand-foot-skin reaction (HFSR) being the most common AE (30.7% all-grade). Interestingly, the onset of HFSR was associated with significantly better OS (median: 14.59 vs 5.59 months, p &lt;0.001). Notably, there was no significant change in the on-treatment levels of liver function in terms of bilirubin and plasma albumin level. Conclusions: Our study confirms the efficacy and safety in using sorafenib to treat unresectable or advanced HCC patients in the real life setting. Our results are s comparable with those reported in literature. In addition, we found that 1) similar efficacy in treating HCC regardless of HBV status, 2) positive association of OS with HFSR onset, and 3) no compromised liver function during sorafenib therapy.
Abstract A43: Deficiency of PTPRH in pediatric solid tumors identifies a high-risk phenotype that can be overcome by combinatorial tyrosine kinase inhibition
Authors: Kathleen A. Scorsone, Siddhartha Tyagi, Mayra C. Orellana, Sonal Gahlawat, Amritha Nair, Tingting Sun, Thomas F. Westbrook, Ronald J. Bernardi
Journal: Cancer Research (2018)

Abstract As there is a paucity of targetable oncogenic drivers in pediatric solid tumors, we hypothesized that deficiency of select protein tyrosine phosphatases may allow proliferative signals to proceed unchecked in these cancers and that understanding these regulatory networks could inform therapy. In support of this possibility, the protein tyrosine phosphatase PTPRH has been previously reported to have a tumor-suppressive role in colon cancer and hepatocellular cancer. In the current study, we examine the role of PTPRH in pediatric solid tumors. Using multiple publicly available databases, we observed that low PTPRH expression is associated with significantly shorter survival in both neuroblastoma and osteosarcoma. Further, restoration of PTPRH expression in PTPRH-deficient neuroblastoma cells inhibits colony formation. In addition, we used a variety of biochemical approaches to identify novel PTPRH-binding partners and potential substrates. Moreover, we utilized these data to design combinatorial tyrosine kinase inhibitor therapies that target the cadre of receptor tyrosine kinases that are regulated by PTPRH. In particular, the combination of crizotinib and pazopanib inhibits proliferation of PTPRH-deficient neuroblastoma cells in vitro and reduces tumor growth in vivo. We are continuing to optimize the selection of tyrosine kinase inhibitors in order to most closely phenocopy restoration of PTPRH and maximize antitumor activity. Thus, we have shown that even for tumors that lack amplification or driver mutations of receptor tyrosine kinases, combinatorial tyrosine kinase inhibition can have substantial therapeutic activity and should be investigated further in the laboratory and the clinic. Citation Format: Kathleen A. Scorsone, Siddhartha Tyagi, Mayra C. Orellana, Sonal Gahlawat, Amritha Nair, Tingting Sun, Thomas F. Westbrook, Ronald J. Bernardi. Deficiency of PTPRH in pediatric solid tumors identifies a high-risk phenotype that can be overcome by combinatorial tyrosine kinase inhibition [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A43.
European recommendations and quality assurance for cytogenomic analysis of haematological neoplasms
Authors: K. A. Rack, E. van den Berg, C. Haferlach, H. B. Beverloo, D. Costa, B. Espinet, N. Foot, S. Jeffries, K. Martin, S. O’Connor, J. Schoumans, P. Talley, N. Telford, S. Stioui, Z. Zemanova, R. J. Hastings
Journal: Leukemia (2019)

Cytogenomic investigations of haematological neoplasms, including chromosome banding analysis, fluorescence in situ hybridisation (FISH) and microarray analyses have become increasingly important in the clinical management of patients with haematological neoplasms. The widespread implementation of these techniques in genetic diagnostics has highlighted the need for guidance on the essential criteria to follow when providing cytogenomic testing, regardless of choice of methodology. These recommendations provide an updated, practical and easily available document that will assist laboratories in the choice of testing and methodology enabling them to operate within acceptable standards and maintain a quality service.