tbuckley/cabot-search huggingface dataset:
Induction of PDGF-B expression in HUVECs by growth factors and conditioned medium derived from lung cancer cells.
Authors: Niels Reinmuth, Sonja Rensinghoff, Heike Hintelmann, Guido Bisping, Frank Hilberg, Gerald J. Roth, Wolfgang E. Berdel, Michael Thomas, Rolf M. Mesters
Journal: Cancer Research (2004)

3595  Introduction: PDGF-B (platelet derived growth factor) affects tumor angiogenesis in multiple ways, e.g. by migration of perivascular cells, and is secreted by numerous cells including endothelial cells. In contrast to its known biological functions, the induction of PDGF-B expression is only poorly understood. Methods: Human umbilical vascular endothelial cells (HUVECs) were cultured in standard medium up to 80% confluence. After incubation of the cells in 10%MEM over night, the medium was changed to 0.5% MEM, and the cells were stimulated by 20 ng/ml VEGF (vascular endothelial growth factor) and/or 20 ng/ml bFGF (basic fibroblastic growth factor). The small molecule BIBF1000 (1 μM) was used as a tyrosine kinase inhibitor for the VEGF and bFGF receptors. PDGF-B RNA and protein expression levels were analysed using real-time PCR and ELISA assays, respectively. For RNA analyses, 18S was used as a reference gene. Results: Under serum-free conditions, VEGF and bFGF induced a significant increase in PDGF-B RNA expression up to 4-times which was time- and dose-dependent (p
Skin-infiltrating, interleukin-22–producing T cells differentiate pediatric psoriasis from adult psoriasis
Authors: Kelly M. Cordoro, Maria Hitraya-Low, Keyon Taravati, Priscila Munoz Sandoval, Esther Kim, Jeffrey Sugarman, Mariela L. Pauli, Wilson Liao, Michael D. Rosenblum
Journal: Journal of the American Academy of Dermatology (2017)
Transplantation related toxicity and mortality in older autologous hematopoietic cell transplantation recipients
Authors: Hewan Belete, Linda J. Burns, Ryan Shanley, Manju Nayar, Brian McClune, Aleksandr Lazaryan, Veronika Bachanova, Nelli Bejanyan, Celalettin Ustun, Claudio Brunstein, Daniel J. Weisdorf, Mukta Arora
Journal: American Journal of Hematology (2017)

With advances in supportive care, autologous hematopoietic cell transplant (AHCT) is increasingly being performed for patients older than 60 years. We analyzed patients receiving an AHCT for multiple myeloma or lymphoma in a contemporary cohort (2010-2012), with consistent treatment and supportive care and compared outcomes [CTCAE grade 3-5 toxicities, nonrelapse mortality (NRM) and overall-survival (OS)] of younger (40-59 years, n = 77) versus older (≥60 years, n = 67) recipients. The proportion of patients with neutropenic infections was higher in the older group (64% vs. 44%; P = 0.02). The proportion of patients with any grade 3-5 toxicity was also higher in the older group (84% vs. 67%, P = 0.03). In multivariate analysis, older age was significantly associated with higher odds (OR: 2.57, 95% CI:1.09-6.05) of grade 3-5 toxicity. The NRM was 3% (older) vs. 0% (younger) at 1 year. The probability of OS at 2 years was lower in the older group (76% vs. 90%, P = 0.04). Though AHCT can be performed safely in older recipients, the higher toxicity and slightly higher NRM in this population needs attention. Studies focusing on risk-stratification in older patients would further help predict toxicity. Further studies addressing enhanced supportive care needs for older patients who are most likely to benefit are indicated.
Response to: ‘Does IL-38 act on macrophages and/or dendritic cells in arthritis?’ by Jiang <i>et al</i>
Authors: Marie-Astrid Boutet, Frédéric Blanchard, Benoît Le Goff
Journal: Annals of the Rheumatic Diseases (2017)

We appreciate the comments by Jiang et al 1 on our study showing that IL-38 overexpression has anti-inflammatory effects in experimental arthritis presumably through decreased production of proinflammatory cytokines by macrophages.2 Jiang et al point out that the Iba1 marker used in our immunohistochemistry analysis is also expressed by dendritic cells (DCs) and that IL-23, whose expression is reduced by IL-38, is also highly expressed by DCs. Therefore, IL-38 could target DCs in addition to macrophages.

Ionised calcium-binding adaptor molecule 1 (Iba1) also known as allograft inflammatory factor 1 (AIF-1) is widely accepted as a pan-macrophage marker expressed in …
Recombinant Staphylokinase Variants With Altered Immunoreactivity
Authors: De´sire´ Collen, Huberte Moreau, Luc Stockx, Steven Vanderschueren
Journal: Circulation (1996)

Background The substitution variants K35A,E38A,K74A,E75A,R77A (SakSTAR.M38) and K74A,E75A,R77A,E80A,D82A (SakSTAR.M89) of recombinant staphylokinase (SakSTAR) with reduced antibody reactivity were assayed for thrombolytic potency and antibody induction in animal models and in patients. Methods and Results In a 125 I-fibrin–labeled pulmonary embolism model in the hamster, the doses giving 50% clot lysis in 90 minutes were 25 μg/kg for SakSTAR, 85 μg/kg for SakSTAR.M38, and 90 μg/kg for SakSTAR.M89. In rabbits with 125 I-fibrin–labeled plasma clots incorporated into extracorporeal arteriovenous loops, lysis within 2 hours was 76±18% (mean±SD, n=28) with 400 μg/kg SakSTAR, 53±13% (n=8) with 1000 μg/kg SakSTAR.M38, and 39±13% (n=6) with 800 μg/kg SakSTAR.M89. When groups of eight rabbits were immunized by intravenous administration of 0.2 to 1.0 mg/kg compound followed by subcutaneous injection of 0.4 mg in Freund's adjuvant at 2, 3, and 5 weeks, SakSTAR.M38 and SakSTAR.M89 elicited markedly less circulating neutralizing activity, compared with SakSTAR, when determined at 6 weeks (neutralizing 6.1±3.0 and 4.9±1.3 μg compound/mL plasma, respectively, versus 20±17 μg/mL; P =.02 and P =.01, respectively) and induced significantly less resistance to thrombolysis (residual thrombolytic potency producing 59±25% and 39±12% lysis, respectively, versus 8.5±5.7%; P =.008 and P =.006, respectively). In patients with peripheral arterial occlusion, intra-arterial administration of SakSTAR.M38 (n=4) or SakSTAR.M89 (n=4) induced significantly fewer circulating neutralizing antibodies ( P =.03) and specific IgG ( P =.01) at 2 to 3 weeks than SakSTAR (n=8). Conclusions SakSTAR.M38 and SakSTAR.M89 induce less antibody formation and might constitute preferred agents for thrombolytic therapy in humans.
Abstract 086: Estrogen Replacement Downregulates Cardiac Angiotensin II in an ACE-independent Manner in Oophorectomized mRen2.Lewis Rats
Authors: Hao Wang, Zhuo Zhao, Jewell Jessup, Marina Lin, Lindsay MacNamara, Sarfaraz Ahmad, Carlos Ferrario, Leanne Groban
Journal: Circulation Research (2013)

The cardioprotective effects of estrogen are well recognized, but the mechanisms remain poorly understood. Accumulating evidence suggests that the local cardiac renin-angiotensin system (RAS) is involved in the development and progression of left ventricle (LV) remodeling and diastolic dysfunction (LVDD). Estrogen attenuates the effects of an activated circulating RAS, however, its role in regulating the cardiac RAS is unclear. We hypothesized that estrogen replacement limits the development of the LVDD phenotype after ovarian hormone loss by shifting the RAS from the pro-fibrotic angiotensin II (Ang II)/ Ang II type 1 receptor (AT1R)/converting enzyme (ACE) and aldosterone pathway to the anti-fibrotic, Ang-(1-7)/Mas/ACE2 pathway. Bilateral oophorectomy (OVX; n=17) or sham-operation (Sham; n=13) was performed in 4-week-old, female mRen2.Lewis rats. At 11 weeks of age, after the development of exacerbated hypertension, the rats were randomized and received either 17 β-estradiol (E2, 36 μg/pellet, 60 day release, n=8) or vehicle (OVX-V, n=9) for 4 weeks. E2 treatment attenuated the adverse effects of estrogen loss on tissue Doppler-derived diastolic indices, e′ and E/e′, without changing blood pressure. E2 treatment minimized the rise in circulating Ang II and aldosterone, following OVX. Chronic E2 also attenuated OVX-associated increases in cardiac Ang II, Ang-(1-7), and chymase expression, and in mast cell number as determined by real-time PCR, western blot, and immunohistochemical analyses. Neither OVX nor OVX+E2 altered cardiac expression of AT1R, or gene expression and activity of cardiac ACE. E2 treatment in OVX rats significantly decreased gene expression of MMP-9, ACE2, and Ang-(1-7) mas receptor, in comparison to sham-operated, intact and OVX littermates. In conclusion, E2 treatment inhibits upsurges in cardiac Ang II expression in the OVX-mRen2 rat, possibly in a non-ACE-dependent manner. Further studies are warranted to determine whether an E2-mediated reduction in cardiac chymase directly contributes to this response in OVX rats.
The Authors' reply: Figure 1
Authors: Dirk Roggenbuck, Dirk Reinhold, Thomas Wex, Ulrike von Arnim, Peter Malfertheiner, Andreas Sturm, Lael Werner, Dimitrios P Bogdanos, Martin W Laass, Karsten Conrad
Journal: Gut (2011)

The Authors' reply We would like to thank Op De Beeck et al 1 for their interest in the evaluation of antibodies to the zymogen granule membrane glycoprotein 2 (GP2) in patients with inflammatory bowel disease (IBD). Their meticulous investigation of a large, well-characterised cohort of patients and controls revealed good reproducibility, linearity and robustness of the anti-GP2 assays, confirming the assay performance reported in a recent study by our group.2 Both studies found a comparable, high specificity of anti-GP2 for Crohn's disease (CD). On testing 100 patients with ulcerative colitis (UC) and 162 blood donors (BDs) as controls in our study, the specificity reached a value of 94.3% (95% CI 90.7% to 96.8%). This value is similar to the specificity of 93.9% reported by Op De Beeck et al , including 118 UC …
Micromanaging Tolerance in Hemophilia A Gene Therapy
Authors: Jennielle Jobson, Brian D. Brown
Journal: Molecular Therapy (2017)

Due to the successes of hemophilia B gene therapy, there has been a great interest in using similar strategies to treat hemophilia A. Data presented at international meetings suggest there are promising early-stage clinical results showing high levels of circulating factor VIII (FVIII) and substantial reductions in bleeding following treatment of severe hemophilia A patients with an adeno-associated virus (AAV) vector encoding FVIII. However, development of neutralizing antibodies against FVIII ("inhibitors") is viewed as a risk for hemophilia A gene therapy.
A memorable patient: A colleague's referral
Authors: G Manojkrishnan
Journal: BMJ (2001)

I am a general practitioner in a small town in India. One night, at about 8 pm, I received a house call from a witchcraft practitioner. He told me that a woman aged about 20 years had been brought to him to drive away the evil spirit in her.

When I reached his village he guided me to the dimly lit hut where the woman was lying on a cot. She was surrounded by at least a dozen women, and I was told by them that the woman was behaving normally when lying …
Molecular characterization of EZH2 mutant patients with myelodysplastic/myeloproliferative neoplasms
Authors: J Rinke, J P Müller, M F Blaess, A Chase, M Meggendorfer, V Schäfer, N Winkelmann, C Haferlach, N C P Cross, A Hochhaus, T Ernst
Journal: Leukemia (2017)
Risk of Second Malignancies in Solid Organ Transplant Recipients Who Develop Keratinocyte Cancers
Authors: Rachel D. Zamoiski, Elizabeth Yanik, Todd M. Gibson, Elizabeth K. Cahoon, Margaret M. Madeleine, Charles F. Lynch, Sally Gustafson, Marc T. Goodman, Melissa Skeans, Ajay K. Israni, Eric A. Engels, Lindsay M. Morton
Journal: Cancer Research (2017)

Abstract Solid organ transplant recipients have increased risk for developing keratinocyte cancers, including cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), in part as a result of immunosuppressive medications administered to prevent graft rejection. In the general population, keratinocyte cancers are associated with increased risks of subsequent malignancy, however, the risk in organ transplant populations has not been evaluated. We addressed this question by linking the U.S. Scientific Registry of Transplant Recipients, which includes data on keratinocyte cancer occurrence, with 15 state cancer registries. Risk of developing malignancies after keratinocyte cancer was assessed among 118,440 Caucasian solid organ transplant recipients using multivariate Cox regression models. Cutaneous SCC occurrence (n = 6,169) was associated with 1.44-fold increased risk [95% confidence interval (CI), 1.31–1.59] for developing later malignancies. Risks were particularly elevated for non-cutaneous SCC, including those of the oral cavity/pharynx (HR, 5.60; 95% CI, 4.18–7.50) and lung (HR, 1.66; 95% CI, 1.16–2.31). Cutaneous SCC was also associated with increased risk of human papillomavirus-related cancers, including anal cancer (HR, 2.77; 95% CI, 1.29–5.96) and female genital cancers (HR, 3.43; 95% CI, 1.44–8.19). In contrast, BCC (n = 3,669) was not associated with overall risk of later malignancy (HR, 0.98; 95% CI, 0.87–1.12), including any SCC. Our results suggest that transplant recipients with cutaneous SCC, but not BCC, have an increased risk of developing other SCC. These findings somewhat differ from those for the general population and suggest a shared etiology for cutaneous SCC and other SCC in the setting of immunosuppression. Cutaneous SCC occurrence after transplantation could serve as a marker for elevated malignancy risk. Cancer Res; 77(15); 4196–203. ©2017 AACR.
Tumor Antigen and Receptor Densities Regulate Efficacy of a Chimeric Antigen Receptor Targeting Anaplastic Lymphoma Kinase
Authors: Alec J. Walker, Robbie G. Majzner, Ling Zhang, Kelsey Wanhainen, Adrienne H. Long, Sang M. Nguyen, Paola Lopomo, Marc Vigny, Terry J. Fry, Rimas J. Orentas, Crystal L. Mackall
Journal: Molecular Therapy (2017)

We explored the utility of targeting anaplastic lymphoma kinase (ALK), a cell surface receptor overexpressed on pediatric solid tumors, using chimeric antigen receptor (CAR)-based immunotherapy. T cells expressing a CAR incorporating the single-chain variable fragment sequence of the ALK48 mAb linked to a 4-1BB-CD3ζ signaling domain lysed ALK-expressing tumor lines and produced interferon-gamma upon antigen stimulation but had limited anti-tumor efficacy in two xenograft models of human neuroblastoma. Further exploration demonstrated that cytokine production was highly dependent upon ALK target density and that target density of ALK on neuroblastoma cell lines was insufficient for maximal activation of CAR T cells. In addition, ALK CAR T cells demonstrated rapid and complete antigen-induced loss of receptor from the T cell surface via internalization. Using a model that simultaneously modulated antigen density and CAR expression, we demonstrated that CAR functionality is regulated by target antigen and CAR density and that low expression of either contributes to limited anti-tumor efficacy of the ALK CAR. These data suggest that stoichiometric relationships between CAR receptors and target antigens may significantly impact the anti-tumor efficacy of CAR T cells and that manipulation of these parameters could allow precise tuning of CAR T cell activity.
HER-2/neu expression is associated with increased tumor cell proliferation, loss of hormone receptors and an aggressive phenotype in a population based setting of endometrial carcinomas
Authors: Ingeborg Engelsen, Ingunn Stefansson, Rameen Beroukhim, Matthew Meyerson, William Sellers, Lars Akslen, Helga Salvesen
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

5040 

OBJECTIVE: To investigate the distribution of HER-2/neu and EGFR expression in curettage material from a population based patient series with endometrial carcinoma in relation to clinico-pathologic characteristics, proliferative activity, receptor status in tumor and survival.

STUDY DESIGN: Preoperative curettage material was collected from a population based series of 316 endometrial carcinomas from Norway with long and complete follow-up. Curettage specimens were studied immunohistochemically for HER-2/neu, EGFR and Ki-67 expression.

RESULTS:

Positive expression of HER-2/neu was seen in 23% and was significantly correlated to high FIGO stage (p=0.03), serous /clear cell histological subtype (p=0.0001), high histologic grade (p=0.007) and aneuploidy (p=0.02). Patients with positive expression of HER-2/neu had 79% 5-year survival compared to 72% for low HER-2/neu expression (p=0.18). Positive HER-2/neu expression in tumors was significantly correlated to loss of estrogen (p=0.04) and progesterone receptors (p=0.001) and to high tumor proliferation (p=0.01). Expression of EGFR was examined with three different antibodies, but none showed significant correlation to any clinico-pathologic variables, other tumor markers or survival. Proliferative activity in curettage material and the corresponding hysterectomy specimens were significantly correlated. High proliferation estimated in tumor from the hysterectomy specimens showed the strongest correlation with high FIGO stage (p=0.01), serous /clear cell histological subtype (p=0.01), high histologic grade (p=0.002), other prognostic markers and prognosis (p=0.03).

CONCLUSION: Positive expression of HER-2/neu in curettage material is common in endometrial carcinomas and identifies tumors with aggressive phenotype, high proliferation and loss of hormonal receptors. These results motivate further clinical trials with trastuzumab based on molecular HER-2/neu status in tumors.
GEOMETRY <i>duo</i>-1: A phase (Ph) Ib/II, multicenter trial of oral cMET inhibitor capmatinib (INC280) ± erlotinib vs platinum + pemetrexed in adult patients (pts) with epidermal growth factor receptor (EGFR)-mutated, cMET-amplified, locally advanced/metastatic non-small cell lung cancer (NSCLC) with acquired resistance to prior EGFR tyrosine kinase inhibitor (TKI) therapy.
Authors: Egbert F. Smit, Hans-Georg Kopp, Dong-Wan Kim, Giampaolo Tortora, Alexander I. Spira, Alfredo Berruti, Dae Ho Lee, Noemi Reguart, Igor I. Rybkin, Mikhail Akimov, Karl Maria Schumacher, Allison Upalawanna, Cindy Xu, Matthew Squires, Daniel Shao-Weng Tan
Journal: Journal of Clinical Oncology (2016)

TPS9109 Background: Despite high overall response rates (ORR) to EGFR TKIs, most pts with EGFR-mutated NSCLC develop acquired resistance; secondary activation of cMET as gene amplification, occurs in ~20% of cases. Capmatinib (INC280) is a potent and selective cMET inhibitor. Preliminary clinical activity of INC280 + gefitinib was reported in pts with EGFR-mutated, cMET-amplified, EGFR TKI-resistant NSCLC. Methods: This multicenter, Ph Ib/II study (NCT02468661) will commence with a dose-escalation safety phase of INC280 + erlotinib. This will be followed by a randomized Ph II part, which will study the safety and efficacy of INC280 ± erlotinib compared with platinum + pemetrexed, in pts with EGFR TKI-resistant advanced NSCLC due to cMET amplification (EGFR T790M-negative). cMET gene copy number will be determined by fluorescence in situ hybridization. Eligible pts ( ≥ 18 years of age; ECOG PS 0–1) must have had prior therapy with a 1st/2nd-generation EGFR TKI ( ≥ 1 in Ph Ib: only 1 in Ph II). Pts in Ph II must be chemotherapy-naïve. In Ph Ib (N≈10–15), erlotinib 150 mg tablets once daily (QD), and increasing doses of INC280 with a starting dose of 200 mg tablets twice daily (BID), will be administered on a continuous dosing schedule. In Ph II (N≈120), pts will undergo central testing for cMET and T790M, and be randomized 1:1:1 in 3 arms: 1. INC280 (400 mg BID); 2. INC280 (recommended Ph II dose [RP2D]) + erlotinib (150 mg QD); 3. Cisplatin (75 mg/m2)/carboplatin (AUC 5 or 6) + pemetrexed (500 mg/m2; every 21 days). The primary objectives are to determine the maximum tolerated dose/RP2D of INC280 + erlotinib (Ph Ib), and to compare the investigator-assessed antitumor activity of INC280 ± erlotinib vs platinum + pemetrexed therapy, measured by progression-free survival (Ph II). Secondary objectives include investigator-assessed ORR, disease control rate, duration of response, overall survival, safety, and pharmacokinetics. Enrollment is ongoing. Clinical trial information: NCT02468661.
Musculoskeletal Disease in MDA5‐Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy
Authors: Luciana Martins de Carvalho, Gonza Ngoumou, Ji Woo Park, Nadja Ehmke, Nikolaus Deigendesch, Naoki Kitabayashi, Isabelle Melki, Flávio Falcäo L. Souza, Andreas Tzschach, Marcello H. Nogueira‐Barbosa, Virgínia Ferriani, Paulo Louzada‐Junior, Wilson Marques, Charles M. Lourenço, Denise Horn, Tilmann Kallinich, Werner Stenzel, Sun Hur, Gillian I. Rice, Yanick J. Crow
Journal: Arthritis & Rheumatology (2017)

To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy.
Core elements of general supportive care for patients with sepsis and septic shock in resource-limited settings
Authors: Mervyn Mer, Marcus J. Schultz, Neill K. Adhikari
Journal: Intensive Care Medicine (2017)

In this chapter, we outline important elements for the general supportive care for patients with sepsis in resource-limited settings. We discuss the use of corticosteroids, sedation, neuromuscular blocking agents, deep venous thrombosis (DVT) prophylaxis, gastric ulcer prevention, glucose control, enteral feeding, renal replacement therapy, and initial fluid resuscitation. Low-dose corticosteroids are recommended in septic patients with refractory shock, pending completion of current trials. Important issues around sedation include the availability of selected opiates and benzodiazepines, ways of administration, and availability of expertise and (human) resources essential for dosing and monitoring of sedation to care for mechanically ventilated patients with sepsis. Venous thromboembolism prophylaxis with proton-pump inhibitors and histamine-2 receptor antagonists is generally available for stress ulcer prophylaxis in resource-limited ICUs and can be delivered feasibly and safely. Critical illness-associated hyperglycemia is common, and short-acting insulin is widely available and inexpensive. However, stringent blood glucose control is not recommended, since this is dangerous in settings where continuous intravenous insulin with frequent monitoring is not feasible. Enteral feeding can be with hospital-prepared foods where commercial feeds are not available or expensive. Risk of aspiration pneumonia starts early in comatose non-intubated patients. Although not as effective as hemodialysis or hemofiltration methods, peritoneal dialysis is a feasible and cost-effective alternative for renal replacement therapy in very resource-limited settings. Initial fluid resuscitation in severe sepsis or septic shock should be more conservative in resource-limited settings where positive-pressure mechanical ventilation is not readily available.