tbuckley/cabot-search huggingface dataset:
Loss of human ICOSL results in combined immunodeficiency
Authors: Lucie Roussel, Marija Landekic, Makan Golizeh, Christina Gavino, Ming-Chao Zhong, Jun Chen, Denis Faubert, Alexis Blanchet-Cohen, Luc Dansereau, Marc-Antoine Parent, Sonia Marin, Julia Luo, Catherine Le, Brinley R. Ford, Mélanie Langelier, Irah L. King, Maziar Divangahi, William D. Foulkes, André Veillette, Donald C. Vinh
Journal: The Journal of Experimental Medicine (2018)

Primary immunodeficiencies represent naturally occurring experimental models to decipher human immunobiology. We report a patient with combined immunodeficiency, marked by recurrent respiratory tract and DNA-based viral infections, hypogammaglobulinemia, and panlymphopenia. He also developed moderate neutropenia but without prototypical pyogenic infections. Using whole-exome sequencing, we identified a homozygous mutation in the inducible T cell costimulator ligand gene (ICOSLG; c.657C&amp;gt;G; p.N219K). Whereas WT ICOSL is expressed at the cell surface, the ICOSLN219K mutation abrogates surface localization: mutant protein is retained in the endoplasmic reticulum/Golgi apparatus, which is predicted to result from deleterious conformational and biochemical changes. ICOSLN219K diminished B cell costimulation of T cells, providing a compelling basis for the observed defect in antibody and memory B cell generation. Interestingly, ICOSLN219K also impaired migration of lymphocytes and neutrophils across endothelial cells, which normally express ICOSL. These defects likely contributed to the altered adaptive immunity and neutropenia observed in the patient, respectively. Our study identifies human ICOSLG deficiency as a novel cause of a combined immunodeficiency.
Abstract 12736: Increased Arterial Stiffness Predicts Cardiovascular Events in Patients with Heart Failure with Reduced Left Ventricular Ejection Fraction
Authors: Kenichiro Otsuka, Shota Fukuda, Kenei Shimada, Ryoko Kitada, Koki Nakanishi, Minoru Yoshiyama, Junichi Yoshikawa
Journal: Circulation (2013)

Background: Impaired arterial stiffness reflects intrinsic stiffness of the aortic wall, attributed to it being the earliest detectable manifestations of adverse structural and functional damages w...
Safety and efficacy of depatuxizumab mafodotin + temozolomide in patients with<i>EGFR</i>-amplified, recurrent glioblastoma: results from an international phase I multicenter trial
Authors: Andrew B Lassman, Martin J van den Bent, Hui K Gan, David A Reardon, Priya Kumthekar, Nicholas Butowski, Zarnie Lwin, Tom Mikkelsen, Louis B Nabors, Kyriakos P Papadopoulos, Marta Penas-Prado, John Simes, Helen Wheeler, Tobias Walbert, Andrew M Scott, Erica Gomez, Ho-Jin Lee, Lisa Roberts-Rapp, Hao Xiong, Peter J Ansell, Earle Bain, Kyle D Holen, David Maag, Ryan Merrell
Journal: Neuro-Oncology (2018)

Patients with glioblastoma (GBM) have a dismal prognosis. Nearly all will relapse with no clear standard of care for recurrent disease (rGBM). Approximately 50% of patients have tumors harboring epidermal growth factor receptor (EGFR) amplification. The antibody-drug conjugate depatuxizumab mafodotin (depatux-m) binds cells with EGFR amplification, is internalized, and releases a microtubule toxin, killing the cell. Here we report efficacy, safety and pharmacokinetics (PK) of depatux-m + temozolomide (TMZ) in patients with EGFR-amplified rGBM.M12-356 (NCT01800695) was an open-label study encompassing patients with newly diagnosed or rGBM across 3 treatment arms. Results are reported for adults with EGFR-amplified, measurable rGBM who received depatux-m (0.5-1.5 mg/kg) on days 1 and 15, and TMZ (150-200 mg/m2) on days 1-5 in a 28-day cycle. Patients were bevacizumab and nitrosourea naïve.There were 60 patients, median age 56 years (range, 20-79). Fifty-nine patients previously received TMZ. Common adverse events (AEs) were blurred vision (63%), fatigue (38%), and photophobia (35%). Grades 3/4 AEs were split between ocular and non-ocular AEs, occurring in 22% of patients each. Systemic PK exposure of depatux-m was dose proportional. The objective response rate was 14.3%, the 6-month progression-free survival rate was 25.2%, and the 6-month overall survival rate was 69.1%.Depatux-m + TMZ displayed an AE profile similar to what was described previously. Antitumor activity in this TMZ-refractory population was encouraging. Continued study of depatux-m in patients with EGFR-amplified, newly diagnosed, or recurrent GBM is ongoing in 2 global, randomized trials (NCT02573324, NCT02343406).
REVERCE: a randomized phase II study of regorafenib followed by cetuximab versus the reverse sequence for previously treated metastatic colorectal cancer patients
Authors: K. Shitara, T. Yamanaka, T. Denda, Y. Tsuji, K. Shinozaki, Y. Komatsu, Y. Kobayashi, J. Furuse, H. Okuda, M. Asayama, K. Akiyoshi, Y. Kagawa, T. Kato, E. Oki, T. Ando, Y. Hagiwara, Y. Ohashi, T. Yoshino
Journal: Annals of Oncology (2018)

The objective of this randomized phase II trial was to evaluate efficacy and safety of the therapeutic sequence of regorafenib followed by cetuximab, compared with cetuximab followed by regorafenib, as the current standard sequence for metastatic colorectal cancer patients.
Rationale for Study of the Deep Subfascial Lymphatic Vessels During Lymphoscintigraphy for the Diagnosis of Peripheral Lymphedema
Authors: Corrado Cesare Campisi, Melissa Ryan, Giuseppe Villa, Pietro Di Summa, Mario Cherubino, Francesco Boccardo, Corradino Campisi
Journal: Clinical Nuclear Medicine (2018)

The current study aimed to determine the utility of including the study of deep subfascial lymphatic vessels in a 2-compartment lymphoscintigraphy for the diagnosis of lymphedema in patients with limb swelling. Lymphoscintigraphy is a valuable imaging tool for the timely diagnosis of peripheral lymphedema. However, there is a lack of standardization in its application, especially regarding which type of lymphatic vessels to examine (superficial, deep, or both).Two hundred fifty-eight patients with lymphedema underwent segmental lymphoscintigraphy. The transport index (TI) was calculated to categorize the flow of the superficial and deep vessels as normal (<10) or pathological (≥10). The scores from 248 patients (48 unilateral arm, 86 unilateral leg, 114 bilateral leg) were tested with a 3-way analysis of variance to examine the relationship between affected limb, deep or superficial pathways, and primary or secondary lymphedema. The relationship between clinical presentation and TI was also investigated.In general, primary and secondary lymphedema patients had similar patterns of lymphoscintigraphic lymphatic abnormalities. Patients with unilateral clinical presentation can have bilateral TI abnormalities. The vast majority of patients (88%-98%) had either the deep subfascial vessels alone, or both the superficial and deep vessels, with a pathological TI.A 2-compartment lymphoscintigraphy is able to accurately detect lymphatic flow abnormalities in patients with limb swelling. Given that the vast majority of patients had deep lymphatic vessels abnormalities, inclusion of these vessels in the lymphoscintigraphic diagnostic protocol is recommended.
6-gingerol induces cell cycle arrest and apoptosis through multiple mechanisms in human colorectal cancer cells
Authors: Seong-Ho Lee, Maria Cekanova, Seung Joon Baek
Journal: Cancer Research (2007)

4971  6-gingerol, natural product of ginger, has been known to possess the anti-tumorigenic and pro-apoptotic activity although the mechanisms by which it prevents cancer growth are not well understood. Nonsteroidal anti-inflammatory drug activatedgene (NAG-1) is a novel gene associated with pro-apoptoticand anti-tumorigenic activities. In the present study, we examined whether 6-gingerol altered cyclin D1 and NAG-1 expression and determined cell growth in human colorectal cancer cells. 6-gingerol suppressed cell growth and induced G1 cell cycle arrest. 6-gingerol also inhibited cyclin D1 expression and induced NAG-1 expression. Transient transfection and promoter assay revealed that 6-gingerol inhibited β-catenin activity as well as cyclin D1 transactivation. In addition, 6-gingerol increased proteosomal degradation of cyclin D1. The induction of NAG-1 by 6-gingerol is mediated by GSK-3β pathway and PKC epsilon. The results suggest that 6-gingerol stimulates apoptosis through up-regulation of NAG-1 and G1 arrest through downregulation of cyclin D1.
Role of the PI3K/Akt pathway in promoting drug resistance of human pancreatic cells
Authors: Ellis Wt Wong, Shrikanth A. G. Reddy, Jose R. Garcia, James McCubrey
Journal: Cancer Research (2006)

4262  The activation of the epidermal growth factor-receptor (EGF-R) by EGF induces the up-regulation of PI3K/Akt and Raf/MEK/ERK signaling pathways in human pancreatic carcinoma cells. These pathways play major roles in proliferation, survival, and drug resistance in many different cell types. Here we study the mechanism by which EGF-R activation increases drug resistance in human pancreatic carcinoma cells, using the BxPC3 human pancreatic cell line. Serum-starved cells and serum-starved cells stimulated with EGF and subsequently treated with doxorubicin or paclitaxel showed an increase in phosphorylation activity of both ERK and Akt. Combination treatments with LY294002 (a PI3K inhibitor) and chemotherapeutic drugs displayed a significant increase in apoptotic activity. However, treatments with U0126 (a MEK inhibitor which suppressed ERK activation) did not display any difference in the level of apoptosis. Hence, our data indicate that EGF and EGF-R mediate their effects on drug resistance through the PI3K/Akt and not through the Raf/MEK/ERK pathway in this pancreatic cancer cell line.
Chromatin remodeling ATPase BRG1 and PTEN are synthetic lethal in prostate cancer
Authors: Yufeng Ding, Ni Li, Baijun Dong, Wangxin Guo, Hui Wei, Qilong Chen, Huairui Yuan, Ying Han, Hanwen Chang, Shan Kan, Xuege Wang, Qiang Pan, Ping Wu, Chao Peng, Tong Qiu, Qintong Li, Dong Gao, Wei Xue, Jun Qin
Journal: Journal of Clinical Investigation (2018)

Loss of phosphatase and tensin homolog (PTEN) represents one hallmark of prostate cancer (PCa). However, restoration of PTEN or inhibition of the activated PI3K/AKT pathway has shown limited success, prompting us to identify obligate targets for disease intervention. We hypothesized that PTEN loss might expose cells to unique epigenetic vulnerabilities. Here, we identified a synthetic lethal relationship between PTEN and Brahma-related gene 1 (BRG1), an ATPase subunit of the SWI/SNF chromatin remodeling complex. Higher BRG1 expression in tumors with low PTEN expression was associated with a worse clinical outcome. Genetically engineered mice (GEMs) and organoid assays confirmed that ablation of PTEN sensitized the cells to BRG1 depletion. Mechanistically, PTEN loss stabilized BRG1 protein through the inhibition of the AKT/GSK3β/FBXW7 axis. Increased BRG1 expression in PTEN-deficient PCa cells led to chromatin remodeling into configurations that drove a protumorigenic transcriptome, causing cells to become further addicted to BRG1. Furthermore, we showed in preclinical models that BRG1 antagonist selectively inhibited the progression of PTEN-deficient prostate tumors. Together, our results highlight the synthetic lethal relationship between PTEN and BRG1 and support targeting BRG1 as an effective approach to the treatment of PTEN-deficient PCa.
NAMPT Inhibitor KPT-9274 Selectively Targets Self-Renewal Capacity in Acute Myeloid Leukemia
Authors: Shaneice Renee Mitchell, Nicole Grieselhuber, Yerdanos Asemelash, Matthew Cannon, Shelley Orwick, Pratibha Sharma, Virginia Goettl, Vinay K Puduvalli, Deepa Sampath, Alice S. Mims, James S. Blachly, Amy M. Lehman, Bonnie K. Harrington, Justin Breitbach, Erkan Baloglu, William Senapedis, Rosa Lapalombella, John C. Byrd
Journal: Blood (2018)
AB0119 Rheumatoid arthritis (RA)-associated autoantibodies are present in the periodontal exudate of patients with and without ra
Authors: M.J. de Smit, P.S. Rahajoe, G.J. Schuurmans, E. Eelsing, N. Kertia, A. Vissink, J. Westra
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Seropositivity for anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) is a hallmark of RA and can be present years before clinical disease onset. Environmental factors, including smoking and chronic inflamed mucosal tissues of the lungs, gastro-intestinal tract or oral cavity (i.e., the periodontium) are suggested to contribute to initiation of these autoantibodies. While it is known that the inflamed periodontium contains citrullinated proteins and peptides, only Harvey et al. (2013) showed that IgG ACPA is indeed present in periodontal exudate (n=9). <h3>Objectives</h3> As the IgA isotype is specific for mucosal immunity, we assessed in patients with and without RA whether IgA RF and IgA ACPA are present gingivocrevicular fluid (GCF), i.e., the periodontal inflammatory exudate. <h3>Methods</h3> RA patients fulfilling the ACR/<sup>EULAR 2010</sup> classification criteria were recruited at the Rheumatology department of the Dr. Sardjito General Hospital, Yogyakarta, Indonesia. Patients without RA (non-RA) were recruited from the Oral and Maxillofacial Surgery department of the same hospital. In both groups, patients with diabetes or cardiovascular disease were excluded. Periodontitis was defined as periodontal inflamed surface area (PISA) &gt;130 mm<sup>2</sup> (Leira et al. 2017). RF and ACPA were determined by ELISA in serum (IgM RF, IgA RF, IgG ACPA, IgA ACPA) and GCF (IgA RF, IgA ACPA). Total IgG and IgA were determined in GCF. IgA ACPA seropositivity and IgA RF- and IgA ACPA positivity in GCF were defined as &gt;mean +2 SD of healthy controls (non-RA patients, never smokers, no periodontitis, n=88). <h3>Results</h3> In non-RA patients (n=151), PISA was correlated with total IgG and IgA in GCF (p&lt;0.0001). IgA RF and IgA ACPA were present in GCF and correlated with total IgA in GCF (p&lt;0.05 and p&lt;0.01 respectively). In contrast to RA patients (n=72), IgA RF and IgA ACPA in GCF of non-RA patients did not correlate with IgA RF and IgA ACPA in serum. In non-RA patients, IgA ACPA positivity in GCF was more frequent in ever smokers (18%) than in never smokers (9.8%); the same held for presence or absence of periodontitis (18% and 9.3% IgA ACPA positivity, respectively). In non-RA patients PISA was correlated with IgA ACPA in serum (p&lt;0.01) and GCF (p=0.05) (figure 1). <h3>Conclusions</h3> RA-associated autoantibodies are present in GCF of patients with and without RA. In contrast to RA patients, in whom this presence is probably due to leakage from serum, presence of RA-associated autoantibodies in GCF of patients without RA is presumably the result of local formation of these autoantibodies due to periodontitis. <h3>References</h3> [1] Harvey, et al. J Periodontal Res2013;48:252–61. [2] Leira, et al. Acta Odontol Scand2017Nov 11:1–4. <h3>Disclosure of Interest</h3> None declared
Impact of a patient and family meeting program for patients with metastatic genitourinary cancer receiving treatment in the ambulatory care setting.
Authors: Michele Stayer Ochoa, Stefanie Mooney, Cristiane Decat Bergerot, Kathleen Burns, Finly Zachariah, Rupinder Kaur Sidhu, Jill Prudhomme-Hunter, Nellie Garcia, Sorin Buga, William Dale, Matthew J. Loscalzo, Sumanta K. Pal
Journal: Journal of Clinical Oncology (2018)

31 Background: Palliative care in the ICU is recognized as a vital aspect of care delivery but less evidence exists regarding utilization in ambulatory care. Family meetings are considered a relevant strategy to discuss concerns around patients’ illness and treatment. This pilot study sought to describe preliminary results of the Patient and Family Meeting Program (FMP) implemented in October, 2017 in a genitourinary oncologic clinic. Methods: FMP is offered for high-risk patients with ≤ two year prognosis. Program includes: (1) patient identification, (2) orientation, (3) family meeting, and (4) post-meeting follow-up. After identification, social worker orients the patient/family, addresses advance directives, and assesses values regarding care. During the meeting, social worker introduces and elicits understanding of medical situation, physician provides medical information and recommendations, and social worker assists reconciling medical recommendations with patient values. During follow-up, educational materials are provided, referrals are made as indicated, and follow-up meetings are held by request. Results: 51 patients were identified. Most of them were male (69%) with a median age of 68 years, and diagnosed with renal cell carcinoma (47%), prostate cancer (27%), or urothelial cancer (26%). 48 orientations were conducted, and 18 family meetings were held. Hospice was recommended to 16 patients, and 69% were admitted. 6 cases were referred to supportive medicine. Oncologists spent on average 21 minutes with each family. In the inpatient setting, 3 family meetings were requested; all patients were referred to hospice, and 2 were enrolled. Conclusions: Findings indicate the feasibility/benefit of FMP; a high prevalence of patients were referred and enrolled in hospice. Meetings require little extra time for the physician. Also, this program favored better integration between the health care team and patient/family. Results provide support for expanding this program to other specialties. Extending the value of family meetings in ambulatory care is a unique opportunity to enhance essential psychosocial support to oncology patients with greatest need.
Antiangiogenic VEGF <sub>165</sub> b Regulates Macrophage Polarization via S100A8/S100A9 in Peripheral Artery Disease
Authors: Vijay Chaitanya Ganta, Min Choi, Charles R. Farber, Brian H. Annex
Journal: Circulation (2019)

Background: Atherosclerotic occlusions decrease blood flow to the lower limbs, causing ischemia and tissue loss in patients with peripheral artery disease (PAD). No effective medical therapies are currently available to induce angiogenesis and promote perfusion recovery in patients with severe PAD. Clinical trials aimed at inducing vascular endothelial growth factor (VEGF)–A levels, a potent proangiogenic growth factor to induce angiogenesis, and perfusion recovery were not successful. Alternate splicing in the exon-8 of VEGF-A results in the formation of VEGFxxxa (VEGF 165 a) and VEGFxxxb (VEGF 165 b) isoforms with existing literature focusing on VEGF 165 b’s role in inhibiting vascular endothelial growth factor receptor 2–dependent angiogenesis. However, we have recently shown that VEGF 165 b blocks VEGF-A–induced endothelial vascular endothelial growth factor receptor 1 (VEGFR1) activation in ischemic muscle to impair perfusion recovery. Because macrophage-secreted VEGF 165 b has been shown to decrease angiogenesis in peripheral artery disease, and macrophages were well known to play important roles in regulating ischemic muscle vascular remodeling, we examined the role of VEGF 165 b in regulating macrophage function in PAD. Methods: Femoral artery ligation and resection were used as an in vivo preclinical PAD model, and hypoxia serum starvation was used as an in vitro model for PAD. Experiments including laser-Doppler perfusion imaging, adoptive cell transfer to ischemic muscle, immunoblot analysis, ELISAs, immunostainings, flow cytometry, quantitative polymerase chain reaction analysis, and RNA sequencing were performed to determine a role of VEGF 165 b in regulating macrophage phenotype and function in PAD. Results: First, we found increased VEGF 165 b expression with increased M1-like macrophages in PAD versus non-PAD (controls) muscle biopsies. Next, using in vitro hypoxia serum starvation, in vivo pre c linical PAD models, and adoptive transfer of VEGF 165 b-expressing bone marrow–derived macrophages or VEGFR1 +/– bone marrow–derived macrophages (M1-like phenotype), we demonstrate that VEGF 165 b inhibits VEGFR1 activation to induce an M1-like phenotype that impairs ischemic muscle neovascularization. Subsequently, we found S100A8/S100A9 as VEGFR1 downstream regulators of macrophage polarization by RNA-Seq analysis of hypoxia serum starvation-VEGFR1 +/+ versus hypoxia serum starvation-VEGFR1 +/– bone marrow–derived macrophages. Conclusions: In our current study, we demonstrate that increased VEGF 165 b expression in macrophages induces an antiangiogenic M1-like phenotype that directly impairs angiogenesis. VEGFR1 inhibition by VEGF 165 b results in S100A8/S100A9-mediated calcium influx to induce an M1-like phenotype that impairs ischemic muscle revascularization and perfusion recovery.
Screening colonoscopy for colorectal neoplasia in patients with sporadic fundic gland polyps of stomach
Authors: Byung-Wook Kim, Jeong-Seon Ji, Bo-In Lee, Hwang Choi, Kyu-Yong Choi, In-Sik Chung, Hiun-Suk Chae, Mary Bronner
Journal: Cancer Research (2008)

510  Background/Aim: Sporadic fundic gland polyp (SFGP) of stomach is known to be associated with increased risk of colorectal adenoma/adenocarcinoma (CRA). However, previous data were not analyzed with age and sex due to limited number of the patients. The aim of this study is to investigate a possible relationship between SFGP and CRA according to different age and sex group.  Methods: Patients who were confirmed SFGP pathologically and underwent colonoscopy six months within gastroscopy were reviewed retrospectively in Our Lady of Mercy Hospital, The Catholic University of Korea between July, 2001 and August, 2007. Control group included patients who underwent both gastroscopy and colonoscopy for general health examination without SFGP during same period in the same hospital.  Results: SFGP was found in 278 patients and 134 patients were underwent colonoscopy six months within gastroscopy. Control group included 2060 patients. CRA was found in 10.4% (14/134) of SFGP patients and 16.8% (347/2060) of control group. However, 61.5% (8/13) of 50 and over 50 years old male patients with SFGP had CRA compared to 33.5% (158/471) of control group (p