tbuckley/cabot-search huggingface dataset:
Chemotherapy with irradiation in salivary gland carcinomas (SGC): A Rare Cancer Network study (RCN).
Authors: Juliette Thariat, Dawn Aranguren, Yazici Gozde, Gabriela Studer, Marco Krengli, Pirus Ghadjar, Candan Demiroz, Onal Cem, Sefik Igdem, Hale Basak Ozkok, Serap Akyurek, Kaouthar Khanfir, xu Shan Sun, Robert Clell Miller
Journal: Journal of Clinical Oncology (2013)

e17019 Background: To report the role of combined chemotherapy in SGT. Methods: 251 patients with SGC treated in 2001-2011 were included in a collaborative IRB-approved retrospective RCN study. Chemotherapy is empirically administered based on extrapolation from conventional head and neck squamous cell carcinoma (Ca) (SCC) and data on systemic treatment in localized SGC are lacking. Results: Median age was 60 yo with 2/5 females/males. Tumor sites were the parotid 74.9%, submandibular 16%, sublingual 2.8% or minor gland 4%. Histologic findings were adenoid cystic (ACC) 17.3%, mucoepidermoid (MEC) 19.8%, adenoCa 15.6%, salivary duct (SDC) 10.3%, acinic cell (Aci) 6.2%, ex-pleomorphic 7.8%, undifferentiated 4.9%, myoepithelial 3.3%, epithelial myoepithelial 1.6%, basal cell 1.2%, lymphoepithelial 1.2%, others 4.0%. Surgery was performed in 95.1% (complete resection 38.1%). T stages 1, 2, 3 and 4 were 17.2%, 41.2%, 18.1% and 23.5% respectively. N stages were N0 61%, N1 13%, N2 24%, N3 2%. Perineural, vascular or lymphatic emboli were present in 47%, 24%, 27% respectively. Irradiation was performed postoperatively 96% or exclusively 4% (unilateral 84%, performed w/ photons only 78%, IMRT 41%). Chemotherapy was administered in 18%, dependent on grade, N stage, and emboli (p ≤ .05). None of 17 ex-pleomorphic, 25% of undifferentiated, 36% of SDC, and 66.7% of lymphoepithelial Ca received chemotherapy (p NS). With a median follow-up of 42 months for living patients, crude local, regional, metastatic relapse rates were 112% (in field 85%), 10%, 25%, respectively. Crude death rate was 28% including 77% from SGC. 5-year survival (5y OS) was 63%. The only prognostic factor was nodal involvement (p .002). However, 5y OS differed by histology: ACC 79%, MEC 84%, Aci 67%, SCC 43%, adenoCa NOS 40%, SDC 37%. Chemotherapy did not improve survival whatever histology. Conclusions: Further prospective studies are warranted to define the role of chemotherapy by histology in the setting of localized SGT. Also molecular profile-driven systemic treatments should be investigated.
CTLA-4 and PD-1 dual blockade induces SIV reactivation without control of rebound after antiretroviral therapy interruption
Authors: Justin Harper, Shari Gordon, Chi Ngai Chan, Hong Wang, Emily Lindemuth, Cristin Galardi, Shane D. Falcinelli, Samuel L. M. Raines, Jenna L. Read, Kevin Nguyen, Colleen S McGary, Michael Nekorchuk, Kathleen Busman-Sahay, James Schawalder, Colin King, Maria Pino, Luca Micci, Barbara Cervasi, Sherrie Jean, Andrew Sanderson, Brian Johns, A. Alicia Koblansky, Heather Amrine-Madsen, Jeffrey Lifson, David M. Margolis, Guido Silvestri, Katharine J. Bar, David Favre, Jacob D. Estes, Mirko Paiardini
Journal: Nature Medicine (2020)
Rewiring of gene networks underlying mite allergen‐induced CD4 + Th‐cell responses during immunotherapy
Authors: Anya C. Jones, Denise Anderson, Niamh M. Troy, Dominic Mallon, Rochelle Hartmann, Michael Serralha, Barbara Holt, Anthony Bosco, Patrick G. Holt
Journal: Allergy (2020)

Multiple regulatory mechanisms have been identified employing conventional hypothesis-driven approaches as contributing to allergen-specific immunotherapy outcomes, but understanding of how these integrate to maintain immunological homeostasis is incomplete.To explore the potential for unbiased systems-level gene co-expression network analysis to advance understanding of immunotherapy mechanisms.We profiled genome-wide allergen-induced Th-cell responses prospectively during 24 months subcutaneous immunotherapy (SCIT) in 25 rhinitis, documenting changes in immunoinflammatory pathways and associated co-expression networks and their relationships to symptom scores out to 36 months.Prior to immunotherapy, mite-induced Th-cell response networks involved multiple discrete co-expression modules including those related to Th2-, type1 IFN-, inflammation- and FOXP3/IL2-associated signalling. A signature comprising 109 genes correlated with symptom scores, and these mapped to cytokine signalling/T-cell activation-associated pathways, with upstream drivers including hallmark Th1/Th2- and inflammation-associated genes. Reanalysis after 3.5 months SCIT updosing detected minimal changes to pathway/upstream regulator profiles despite 32.5% symptom reduction; however, network analysis revealed underlying merging of FOXP3/IL2-with inflammation-and Th2-associated modules. By 12 months SCIT, symptoms had reduced by 41% without further significant changes to pathway/upstream regulator or network profiles. Continuing SCIT to 24 months stabilized symptoms at 47% of baseline, accompanied by upregulation of the type1 IFN-associated network module and its merging into the Th2/FOXP3/IL2/inflammation module.Subcutaneous immunotherapy stimulates progressive integration of mite-induced Th cell-associated Th2-, FOXP3/IL2-, inflammation- and finally type1 IFN-signalling subnetworks, forming a single highly integrated co-expression network module, maximizing potential for stable homeostatic control of allergen-induced Th2 responses via cross-regulation. Th2-antagonistic type1 IFN signalling may play a key role in stabilizing clinical effects of SCIT.
Ranolazine Preserves and Improves Left Ventricular Ejection Fraction and Autonomic Measures when wdded to Guideline-Driven Therapy in Chronic Heart Failure
Authors: Gary L. Murray, Joseph Colombo
Journal: Clinical Cardiology and Cardiovascular Interventions (2020)

Background: Ranolazine (RAN) reduces cardiac sodium channel 1.5’s late sodium current in congestive heart failure (CHF), reducing myocardial calcium overload, potentially improving left ventricular (LV) function. RAN blocks neuro- nal sodium channel 1.7, potentially altering parasympathetic and sympathetic (P&amp;S) activity. The effects of RAN on LV ejection fraction (LVEF) and P&amp;S function in CHF were studied. Methods: Matched CHF patients were given open-label RAN (1000 mg po-bid) added to guideline-driven therapy (RANCHF, 41 systolic, 13 diastolic) or no adjuvant therapy (control, NORANCHF, 43 systolic, 12 diastolic). Echocar- diographic LVEF and P&amp;S measures were obtained at baseline and follow-up (mean 23.7 months). Results: LVEF increased in 70% of RANCHF patients, an average of 11.3 units. Mean LVEF remained unchanged in NORANCHF patients. P&amp;S measures indicated cardiovascular autonomic neuropathy (P≤0.1 bpm2) in 20% of NORANCHF patients at baseline and in 29% at follow-up (increasing in both groups). At baseline, 28% of patients had high sympathovagal balance (SB), RAN normalized SB over 50% of these; in contrast, the NORANCHF group had a 20% increase in patients with high SB. Conclusions: RAN preserves or improves LVEF and decreases high SB in CHF.
EFFECT OF SEVOFLURANE ON CKMB RELEASE AFTER PCI WITH DRUG-ELUTING STENTS: A RANDOMISED TRIAL
Authors: Jose de Ribamar Costa, Ronaldo Rossi, Caetano Nigro, J. Italo França, Sergio Braga, Adélia Bergwerk, Marcelo A Goncalves, Edna Valeria da Silva, Maria Helena de Almeida, Amanda Sousa, Fausto Feres, Alexandre Abizaid
Journal: Journal of the American College of Cardiology (2020)
Cortical Neurons form a Functional Neuronal Network in a 3D Printed Reinforced Matrix
Authors: Dieter Janzen, Ezgi Bakirci, Annalena Wieland, Corinna Martin, Paul D. Dalton, Carmen Villmann
Journal: Advanced Healthcare Materials (2020)

Abstract Impairments in neuronal circuits underly multiple neurodevelopmental and neurodegenerative disorders. 3D cell culture models enhance the complexity of in vitro systems and provide a microenvironment closer to the native situation than with 2D cultures. Such novel model systems will allow the assessment of neuronal network formation and their dysfunction under disease conditions. Here, mouse cortical neurons are cultured from embryonic day E17 within in a fiber‐reinforced matrix. A soft Matrigel with a shear modulus of 31 ± 5.6 Pa is reinforced with scaffolds created by melt electrowriting, improving its mechanical properties and facilitating the handling. Cortical neurons display enhance cell viability and the neuronal network maturation in 3D, estimated by staining of dendrites and synapses over 21 days in vitro, is faster in 3D compared to 2D cultures. Using functional readouts with electrophysiological recordings, different firing patterns of action potentials are observed, which are absent in the presence of the sodium channel blocker, tetrodotoxin. Voltage‐gated sodium currents display a current–voltage relationship with a maximum peak current at −25 mV. With its high customizability in terms of scaffold reinforcement and soft matrix formulation, this approach represents a new tool to study neuronal networks in 3D under normal and, potentially, disease conditions.
SYNCOPE RELATES TO A HIGHER BASELINE RISK STATUS, PULMONARY ARTERY OBSTRUCTIVE BURDEN AND MORTALITY IN ACUTE PULMONARY EMBOLISM
Authors: Berhan Keskin, Ozgur Yasar Akbal, Seda Tanyeri, Aykun Hakgor, Hacer Tokgoz, Ali Karagoz, Cem Dogan, Rezzan Deniz Acar, Zübeyde Bayram, Ismail Balaban, Dogancan Ceneli, Cagrı Kafkas, Seyhmus Kulahcıoglu, Halil Tanboga, Nihal Ozdemir, Cihangir Kaymaz
Journal: Journal of the American College of Cardiology (2020)
Pre-existing antitherapeutic antibodies against the Fc region of the hu14.18K322A mAb are associated with outcome in patients with relapsed neuroblastoma
Authors: Jacob L Goldberg, Fariba Navid, Jacquelyn A Hank, Amy K Erbe, Victor Santana, Jacek Gan, Fenna de Bie, Amal M Javaid, Anna Hoefges, Michael Merdler, Lakeesha Carmichael, KyungMann Kim, Michael W Bishop, Michael M Meager, Stephen D Gillies, Janardan P Pandey, Paul M Sondel
Journal: Journal for ImmunoTherapy of Cancer (2020)

Purpose Patients with cancer receiving tumor-reactive humanized monoclonal antibody (mAb) therapy can develop a human antihuman antibody (HAHA) response against the therapeutic mAb. We evaluated for HAHA in patients with neuroblastoma treated in a phase I study of humanized anti-GD2 mAb (immunoglobulin (Ig)G1 isotype), hu14.18K322A ( NCT00743496 ). The pretreatment sera (collected prior to mAb treatment) from 9 of 38 patients contained antitherapeutic antibodies, even though they had no prior mAb exposure. We sought to characterize these pre-existing antitherapeutic antibodies (PATA). Experimental design The PATA+ pretreatment samples were characterized via ELISA; clinical associations with PATA status were evaluated. Results Pretreatment sera from eight of nine PATA+ patients also bound rituximab and demonstrated preferential ELISA reactivity against the Fc portions of hu14.18K322A and rituximab as compared with the Fab portions of these mAbs. These PATA+ sera also recognized dinutuximab (human IgG1 isotype) and mouse IgG2a isotype mAbs, but not a mouse IgG1 isotype or the fully human panitumumab (IgG2 isotype) mAb. Of the 38 treated patients, only 4 patients (all in the PATA+ cohort) demonstrated no disease progression for &gt; 2.5 years without receiving further therapy (p=0.002). Conclusions This study demonstrates an association between clinical outcome and the presence of PATA against determinant(s) on the Fc component of the therapeutic mAb, suggesting that the PATA may be playing a role in augmenting mAb-based antitumor effects. Further analyses for the presence of PATA in a larger cohort of patients with relapsed neuroblastoma, analyses of their clinical correlates, identification of their immunological targets, and potential antitumor mechanisms are warranted.
The pan-cancer landscape of prognostic germline variants in 10,582 patients
Authors: Ajay Chatrath, Roza Przanowska, Shashi Kiran, Zhangli Su, Shekhar Saha, Briana Wilson, Takaaki Tsunematsu, Ji-Hye Ahn, Kyung Yong Lee, Teressa Paulsen, Ewelina Sobierajska, Manjari Kiran, Xiwei Tang, Tianxi Li, Pankaj Kumar, Aakrosh Ratan, Anindya Dutta
Journal: Genome Medicine (2020)

Abstract Background While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions. Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors. Methods We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models. Results We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers. The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness. Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences. Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers. Conclusions Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone. The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology. Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.
Evaluation of SRC-family kinases in gastrointestinal stromal tumors
Authors: S. Bauer, G. D. Demetri, J. A. Fletcher
Journal: Journal of Clinical Oncology (2006)

9529 Background: Inhibition of KIT oncoproteins by imatinib mesylate (IM) induces clinical responses in most GIST patients. However, many patients develop IM-resistance and novel KIT-Inhibitors show clinical benefit in only a minority of patients. SRC-family kinases (SFK) are important participants in kinase oncoprotein signaling pathways in ALL and CML, and dual-specificity SRC/ABL-inhibitors show promising activity in IM-resistant CML in vitro. However, little is known about SFK functional roles in IM-resistant GIST. Methods: GIST were analyzed for SFK expression and activation by western blotting. Biological consequences of KIT inhibition alone (IM), SFK inhibition (SU6656) and combined KIT/SFK inhibition (PP1, PP2, SU6656+IM) were determined by immunoblotting for protein activation, and—in GIST cell lines—by luminescence assays for cell proliferation. Results: Primary GIST and GIST cell lines showed weak SFK activation compared to Jurkat (T-cell ALL) controls. Variable expression of the SFK proteins FYN, LYN and SRC (but not BLK and LCK) was shown in the cell lines and primary GIST. Expression of SFK proteins HCK and FGR was found in 2 primary GIST only. KIT and KIT signaling pathways (pAKT, pS6, pSTAT3) were affected by IM and combined KIT inhibitors but not by SU6656 at 1μM in GIST882 (IM-sensitive cell line) and GIST48 (IM-resistant cell line). SRC phosphorylation (Y418) was not affected by IM or SFK-inhibitors at 1μM. IM showed superior inhibition of proliferation compared to PP1 and PP2 (1μM) in GIST882 (IM: 67%, PP1: 1%, PP2: 0%) and comparable inhibition in GIST48 (IM:30%, PP1: 29%, PP2: 29%). No effects on proliferation were seen with SU6656 alone or in combination with IM; no antagonistic effects were observed. Conclusions: Our analysis showed expression and weak activation of several SFK in GIST. Expression of heme-associated SFKs in primary GIST may be explained by lymphocellular infiltration. Biochemical inhibition of SFK alone does not have antiproliferative effects in GIST cell lines, and no synergies or antagonisms were found in combination with IM or with combined KIT/SFK inhibitors. Therefore, targeting of SFK may be of less therapeutic value in GIST than in kinase-driven haematological cancers. No significant financial relationships to disclose.
Phase I, first-in-human trial of an oral VEGFR tyrosine kinase inhibitor (TKI) x-82 in patients (pts) with advanced solid tumors.
Authors: Kathleen N. Moore, Suzanne Fields Jones, Carla Kurkjian, Hendrik-Tobias Arkenau, Jeffrey R. Infante, Shubham Pant, Howard A. Burris, D. Scott McMeekin, Jay Gibbons, Kimberly Harrow, Chris Liang, Sara Ramsey, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2012)

3041 Background: VEGFR TKIs have shown benefit in the treatment of various tumor types. Side effects of the TKIs have affected the duration of therapy pts can tolerate, as well as the combinability with chemotherapy. X-82 is a highly potent VEGFR/PDGFR TKI with a smaller volume of distribution and limited tissue accumulation designed to minimize side effects while maintaining target effect. Methods: Pts with advanced solid tumors were enrolled using an accelerated titration scheme followed by 3+3 dose escalation design. X-82 was administered orally once daily (QD) or twice daily (BID) every 28 days. Safety, pharmacokinetic, clinical endpoints and blood-based biomarkers were evaluated. Results: 16 pts were treated across 8 dose levels: 20 (n=1), 40 (n=1), 80 (n=1), 160 (n=1), 300 (n=2), 400 mg QD (n=3), 140 mg BID (n=3) and 200 mg BID (n=4). The most common related adverse events (AEs) by pt were fatigue (4 G1, 1 G2), nausea (3 G1, 1 G2), diarrhea (3 G1), anorexia (1 G1, 1 G2), and vomiting (2 G1). G2 hypertension, resolved with treatment, was experienced by 1 patient. No &gt; G3 related AEs have been reported. Dose proportional exposure was observed with doses up to 160 mg QD, and BID dosing cohorts were added. At 160 mg QD X-82 has plasma concentrations &gt;100 ng/mL for at least 12 hours, the desired exposure predicted preclinically. Preliminary blood biomarker data (n=8) shows &gt;25% decrease in VEGFR1 in 62% of pts and in VEGFR2 in 25% of pts, including pts at 40 and 80 mg cohorts. Efficacy has also been noted, including 1 confirmed complete response lasting 24+ weeks (pancreatic adenocarcinoma), and 6 pts with stable disease lasting 8+ weeks (range 12.1+, 38.3+ weeks), including the pt at 20 mg with SCLC (25.1 weeks). Conclusions: X-82 is a well-tolerated VEGFR/PDFGR TKI designed to minimize side effects while inhibiting target receptors. No MTD has yet been defined, though preliminary biomarker data are encouraging and clinical efficacy has been noted.
Role of bone scan in routine practice for early recognition of bisphosphonate-related osteonecrosis of the jaws (ONJ): Pro and con.
Authors: Vittorio Fusco, Luigi Tommasi, Alfredo Muni, Hamed Rouhanifar, Ornella Testori, Antonella Fasciolo, Luca Benzi, Iolanda De Martino, Lorenza Randi, Pamela Francesca Guglielmini, Antonella Pertino
Journal: Journal of Clinical Oncology (2013)

e20694 Background: The literature on the role of 99m Tc-MDP bone scan (BS) in the diagnosis and follow-up of bisphosphonate-related ONJ is limited and unconsistent. Following data are in favour: a) BS is an imaging technique with high sensitivity; b) sporadic cases of early jawbone (maxilla or mandible) uptake have been reported, occasionally even months or years before the clinical evidence of ONJ (bone exposure); c) the jaw BS uptakes can change on different stages of ONJ disease (acute/symptomatic or less); d) the BS is performed periodically in patients with skeletal metastases to check out the status of disease activity and the response to specific treatments; consequently the research of ONJ does not involve additional costs. Vice versa, some limitations include: a) BS is a technique with low specificity; bone traumatic, inflammatory, degenerative lesions can determine an uptake; b) a non-negligible proportion of patients (even without any tumor disease) shows jaw uptakes, due to dental diseases widely seen in the general population (abscesses, denture ulcers,periodontal disease,etc.); c) even in BP-related ONJ suspected cases, jaw uptake may be due to infections that are not necessarily connected to the osteomyelitis component of ONJ; d) bone necrosis (sequestrum) is usually not uptaking at the BS, but it can appear as a downtaking area surrounded by an uptaking area. Methods: We conducted a retrospective study of 59 BS performed in 15 ONJ patients treated with BPs (8 with breast cancer,6 prostate cancer,1 renal cell carcinoma). Two Nuclear Medicine specialists reviewed 18 "baseline" BS (before treatment with BP), 14 BS in the 6-12 months prior to diagnosis of ONJ, 13 BS performed at the diagnosis time of ONJ (or within 6 months), 14 BS collected after the diagnosis of ONJ. Results: 6-12 months prior to diagnosis, 10 BS were positive (jaw uptakes in ONJ sites) and 4 negative. At the moment of ONJ diagnosis, 12 out of 13 exams resulted positive and one doubtful. Conclusions: These retrospective data will be used to design a case-control study with different patient groups, inluding ONJ cases, patients treated with BP and not suffering from ONJ, and cancer patients not receiving BPs.