tbuckley/cabot-search huggingface dataset:
Moss-Produced, Glycosylation-Optimized Human Factor H for Therapeutic Application in Complement Disorders
Authors: Stefan Michelfelder, Juliana Parsons, Lennard L. Bohlender, Sebastian N.W. Hoernstein, Holger Niederkrüger, Andreas Busch, Nicola Krieghoff, Jonas Koch, Benjamin Fode, Andreas Schaaf, Thomas Frischmuth, Martin Pohl, Peter F. Zipfel, Ralf Reski, Eva L. Decker, Karsten Häffner
Journal: Journal of the American Society of Nephrology (2016)

Genetic defects in complement regulatory proteins can lead to severe renal diseases, including atypical hemolytic uremic syndrome and C3 glomerulopathies, and age-related macular degeneration. The majority of the mutations found in patients with these diseases affect the glycoprotein complement factor H, the main regulator of the alternative pathway of complement activation. Therapeutic options are limited, and novel treatments, specifically those targeting alternative pathway activation, are highly desirable. Substitution with biologically active factor H could potentially treat a variety of diseases that involve increased alternative pathway activation, but no therapeutic factor H is commercially available. We recently reported the expression of full-length recombinant factor H in moss ( Physcomitrella patens ). Here, we present the production of an improved moss-derived recombinant human factor H devoid of potentially immunogenic plant–specific sugar residues on protein N -glycans, yielding approximately 1 mg purified moss–derived human factor H per liter of initial P. patens culture after a multistep purification process. This glycosylation-optimized factor H showed full in vitro complement regulatory activity similar to that of plasma-derived factor H and efficiently blocked LPS-induced alternative pathway activation and hemolysis induced by sera from patients with atypical hemolytic uremic syndrome. Furthermore, injection of moss-derived factor H reduced C3 deposition and increased serum C3 levels in a murine model of C3 glomerulopathy. Thus, we consider moss-produced recombinant human factor H a promising pharmaceutical product for therapeutic intervention in patients suffering from complement dysregulation.
Detection of biomarkers for esophageal cancer pathologic complete response (pathCR) in OE33 and NCI-H460 control cell lines using a clinical standard operating procedure (SOP) protocol.
Authors: Robert W. Cook, Jaffer A. Ajani, Landon Inge
Journal: Journal of Clinical Oncology (2012)

20 Background: The standard of care for esophageal cancer (EC) patients is a trimodality approach that includes chemo− and radiotherapy followed by surgery. Approximately 25% of EC patients exhibit pathCR to chemoradiotherapy, but undergo unnecessary surgical resection procedures. A set of three protein biomarkers (NF−kB, SHH, and Gli−1) able to effectively identify pathCR status from diagnostic patient biopsies was discovered at M. D. Anderson Cancer Center (uncorrected ROC=0.97; corrected ROC=0.96). To translate that discovery to the clinical laboratory, a standardized protocol utilizing clinical grade reagents and instrumentation for biomarker detection has been developed. PathCR determination with this clinical procedure would be a significant step toward individualized therapeutic options for EC patients. Methods: OE33 and NCI−H460 cells were grown to confluence, collected, and fixed with PFA as a cell pellet. Fixed cell pellets were paraffin embedded, sectioned, and adhered to microscope slides. IHC detection of NF−kB, SHH, and Gli-1 proteins was performed in each cell line using clinical grade reagents and instrumentation, and protein localization was determined by microscopy to verify concordance with research laboratory techniques and results. Results: The clinical SOP allowed for efficient staining of each pathCR biomarker. Nuclear localization of activated NF-kB and Gli-1 was observed in OE33 and NCI-H460 cells, respectively, and SHH localization to the cytoplasm of NCI-H460 cells was also confirmed. The results correlate well with staining protocols utilized during research laboratory procedures. Conclusions: The clinical SOP for IHC detection of EC pathCR biomarkers can efficiently detect NF-kB, SHH, and Gli−1 in the control cell lines OE33 and NCI-H460. The protocols presented should be adaptable to EC patient tumor biopsies, providing an effective method for determining pathCR that will facilitate an individualized approach to treatment methods for people suffering from EC.
Effect of 2G8, a TGF-beta-R2 inhibitor, on TGF-beta signaling and migration in an immunocompetent pancreatic cancer model.
Authors: Katherine Ostapoff, Bercin Cenik, Roderich Schwarz, Rolf A. Brekken
Journal: Journal of Clinical Oncology (2012)

230 Background: TGF-beta functions as a tumor suppressor early in the development of pancreatic ductal adenocarcinoma (PDAC) but during tumor progression after undefined molecular changes TGF-beta switches to a promoter of metastasis, tumor angiogenesis and epithelial to mesenchymal transition (EMT.) A potential strategy is to target TGF-beta-R2, one of the major signaling receptors for TGF-beta. 2G8 is a anti-rat monoclonal antibody that binds specifically to and blocks murine TGF-beta-R2. Methods: Protein expression was analyzed using Western Blot. Cell proliferation was analyzed using Cell Titer Blue Assay and migration was determined using transwell migration assay. EMT protein expression was determined by ICC. PanO2-HY cells were used to establish an orthotopic and splenic metastasis model. In an orthotopic model, mice received saline, gemcitabine (Gem), 2G8 or 2G8 + Gem. For splenic metastasis model,mice received 2G8 on post injection day −1, +1 or +7 days or control IgG. Results: At baseline, PanO2-HY cells express TGF-beta-R2, alk5 and alk1 and express high levels of zeb1 and beta-catenin. 2G8 inhibits phosphorylation of smad2, ERK1/2 and p38 but not smad1/5 in vitro. 2G8 did not inhibit cell proliferation but did inhibit cell migration in vitro. After 7 days of treatment with 2G8, PanO2-HY cells had reduction in nuclear zeb1 staining by ICC. In the orthotopic model, 2G8 significantly inhibited metastasis to liver, peritoneum and gastrointestinal tract(p=0.02). In splenic metastasis assay, 2G8 treated mice livers weighed significantly less than control treated mice (p=0.0005). In the group of mice treated prior to tumor cell injection, none of them developed a primary tumor. Conclusions: Inhibition of TGF-beta-R2 with 2G8, results in inhibition of smad2 dependent pathways as well as non-canonical TGF-beta signaling in vitro. By inhibiting tumor cell migration in vitro and reducing EMT transcription factors, 2G8 may result in delayed tumor progression. In vivo data in both orthotopic and metastatic models suggest that inhibition of TGF-beta signaling via TGF-beta-R2 inhibits tumor cell metastasis. Further analysis are being conducted to understand changes within primary tumor and metastasis within this model.
Flow Cytometry and Cytogenetics of Fine Needle Aspiration Biopsy Samples Is a Reliable Method for Diagnosing Burkitt Lymphoma. Evaluation of 78 Cases from a Single-Institution
Authors: Rymkiewicz Grzegorz, Katarzyna Blachnio, Beata Grygalewicz, Zbigniew Bystydzienski, Renata Woroniecka, Beata Sledz-Gawronska, Joanna Romejko-Jarosinska, Katarzyna Domanska-Czyz, Michalina Zajdel, Kinga Sikorska-Mali, Jan Konrad Siwicki, Barbara Pienkowska-Grela, Monika Prochorec-Sobieszek, Jan Walewski
Journal: Blood (2014)
Does removal of the primary tumor in patients with metastatic breast cancer improve either local control or overall survival?
Authors: S. Samiee, P. Berardi, N. Bouganim, L. Vandermeer, A. Arnaout, D. Mirsky, S. Dent, J. Caudrelier, M. R. Chasen, M. Clemons
Journal: Journal of Clinical Oncology (2011)

e11511 Background: Approximately 10% of new breast cancer patients will present with concurrent metastatic disease. Controversy exists about the optimal local management of these patients as some retrospective studies suggest a survival benefit to removing the primary. In the absence of prospective data many physicians will recommend surgery for, “local control”. We decided to assess the impact of surgery on the incidence of uncontrolled local disease in this patient population. Methods: We reviewed case records of all patients seen with primary breast cancer and concurrent distant metastases during 2007. Data was collected on patient, primary/metastasis tumour characteristics, local and systemic treatments. The primary endpoint was to compare local progression and uncontrolled local disease rates between patients who had removal of the primary tumour and those that did not. Uncontrolled disease was defined as local progression that did not respond to either local or systemic therapy. Results: 50 patients were identified. Median follow-up 30 months (1-46 months). Patients were divided into two groups: Group 1: Patients who did not undergo surgical excision of their primary tumour (n = 29) and Group 2: Patients who had breast surgery (n=21) (13/21 had surgery immediately prior to diagnosis of metastases). Local progression occurred in 10/29 (34%) in Group 1 and 3/21 (14%) of Group 2 (P=0.037). Uncontrolled local disease was seen in 9/29 in Group 1 and 3/21 in Group 2 at last follow up or time of death. Median OS for Group 1 was 21 months (5-41) and 34 months (1-46) for Group 2 (p=0.49). Conclusions: The optimal management of local disease in patients with metastatic breast cancer is unknown. Current local treatment recommendations are prone to many physician and patient selection biases – in this and other small retrospective studies. We showed that surgical resection of the primary tumor was associated with reduced risk of local progression. Importantly when local progression occurs it is often not controllable. These results confirm the need for prospective studies using local control and quality of life endpoints in this setting.
Preoperative chemoradiation therapy for localized retroperitoneal soft tissue sarcoma (RSTS): A phase II study from the Italian Sarcoma Group.
Authors: A. Gronchi, A. De Paoli, C. Dani, F. Merlo, V. Quagliuolo, G. Grignani, G. Bertola, P. Navarria, A. P. Dei Tos, P. G. Casali
Journal: Journal of Clinical Oncology (2011)

10020 Background: Local recurrence after complete surgical resection represents the leading cause of death in retroperitoneal soft tissue sarcoma (RSTS). Radiation therapy (RT) is widely used in STS of the extremities, but is problematic post-operatively in RSTS. High dose long-infusion Ifosfamide (HLI) as a single agent is known to be active in advanced sarcoma and may be a radiosensitizer. We then decided to study the feasibility, safety and activity of the combination of HLI and RT as preoperative treatment for resectable localized RSTS. Methods: Patients received 3 cycles of HLI (14 g/m2), given as a continuous infusion in 14 days. RT was started in combination with the onset of the 2nd cycle and administered up to a total dose of 50.4 Gy in 28 fractions. Response rate was evaluated by RECIST at the time of surgery. Surgery was scheduled 4-6 weeks after the end of RT. An intra-operative boost (IORT) was allowed when clinically indicated. 3-yr local relapse-free survival (LRFS), distant recurrence-free survival (DRFS) and overall survival (OS) were calculated from the time of surgery. Results: Between December 2003 and December 2010, 86 patients were recruited. 2 patients were ineligible following central pathological review. The overall preoperative treatment plan was completed in 61 patients. CT was completed in 65 patients, while RT in 74 patients. A partial response was obtained in 7 patients, while stable disease was observed in 62. One patient had systemic progression during preoperative therapy and was not operated. 79 patients underwent surgery (macroscopically complete in 70). IORT was delivered in 15 patients (median dose 12,0 Gy). At a median follow-up of 1.8 years (IQ range = 0.6-3.7), 3-yr LRFS, DRFS and OS were 66%, 79% and 80%, respectively. Conclusions: The combination of preoperative HDI and RT is feasible and relatively safe, although 1/3 of the patients could not complete it. Pts had to suspend HDI more often than RT. A formal phase III study should preferably address the role of RT alone.
Goodbyes Are Not Forever
Authors: Michele Y. F. Kong
Journal: JAMA Pediatrics (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Teaching medical ethics: useful or useless?
Authors: Daniel Sokol
Journal: BMJ (2016)

Including ethics in the medical curriculum sends an important message



Probably for the first time in history, UK trained doctors at all levels, and in all specialties, now receive formal ethics training at medical school. This raises an important but uncomfortable question for those who teach the subject: has it made any difference? If not, should we replace it with another course on pharmacology, clinical skills, or the interpretation of scans?

An “ethics” sceptic will point to the vast increase in numbers of complaints against doctors to the UK General Medical Council in the past 10 years and the growth of clinical negligence claims in that same period. More ethics, more complaints and law suits.

This sceptic may say that any improvement in “ethics” arises not from any teaching …
Is Interim/Mid-Treatment PET (interim PET, i-PET) Scan Predictive of Outcome in Diffuse Large B-Cell Lymphoma?.
Authors: Dushyant Verma, Amol Takalkar, Runhua Shi, Glenn M. Mills, Srikanth Paladugu, Diana Veillon, Reinhold Munker, Gerhard Hildebrandt, Binu S. Nair, Nebu Koshy
Journal: Blood (2012)
HLA Mismatched/Haploidentical Haematopoietic Stem Cell Transplantation for the Treatment of Chronic Myelogenous Leukemia.
Authors: Xiao Jun Huang, Lan-ping Xu, Kai-yan Liu, Dai-hong Liu, Huan Chen, Wei Han, Yu-hong Chen, Jing-zhi Wang, Yao Chen, Xiao-hui Zhang, Hong-xia Shi, Dao-pei Lu
Journal: Blood (2006)
Early outcomes with neoadjuvant high-dose intensity methotrexate, vinblastine, doxorubicin, and cisplatin (HD-MVAC) or gemcitabine and cisplatin (GC) in muscle-invasive urothelial carcinoma of the bladder: A single-institution experience.
Authors: N. Mitra, J. P. Monk, K. S. Pohar, A. Shabsigh, D. S. Sharp, R. Abaza, G. N. Box, D. L. Zynger, S. K. Clinton, A. Mortazavi
Journal: Journal of Clinical Oncology (2011)

280 Background: Compared to MVAC, HD-MVAC achieves significantly higher complete response rates in patients (pts) with metastatic bladder cancer. Based on current literature, 7%-38% of pts with muscle-invasive bladder cancer achieve pathological down-staging (pT0) with neoadjuvant chemotherapy (NC), which correlates with improved disease-free and overall survival. The role of HD-MVAC has not been evaluated in the neoadjuvant setting. In this retrospective study, we present our data in pts who received NC with HD-MVAC or GC followed by radical cystectomy (RC). Methods: From July 2008 to August 2010, 38 (pts) received 4 cycles of NC with either HD-MVAC or GC for at least T2 bladder cancer followed by RC. The endpoints of interest of this study were the complete pathologic response (pT0) or down-staging to &lt; pT2 (pT0, pTis, and pT1) at RC; and median interval to RC from the time of diagnosis of muscle-invasive bladder cancer and start of NC. Results: Median age at the time of diagnosis was 66 years (35-80 years). Fifteen pts received neoadjuvant HD-MVAC, and 23 received neoadjuvant GC. Clinical T stage at the time of diagnosis was T2 in 29 (76%), T3 in 3 (8%), and T4 in 6 (16%) pts. Down-staging to &lt; pT2 was achieved in 8 (53%) of HD-MVAC pts and 10 (43%) of GC pts. pT0 was achieved in 5 (33%) of HD-MVAC pts and 9 (39%) of GC pts. The median interval from time of diagnosis to RC was 129 days (range 84-154) for the HD-MVAC pts, and 145 days (range 108-252) for the GC pts. The median interval from initiation of NC to RC was 85 days (range 53-122) for the HD-MVAC pts and 107 days (range 60-126) for the GC pts. Overall, NC was well tolerated with 80% of HD-MVAC pts and 78% of GC pts completing the planned chemotherapy. To this date, none of the pT0 pts had recurrence. Conclusions: Both neoadjuvant HD-MVAC and GC appear to be well tolerated, with very promising rate of pathological down-staging. Longer follow-up is needed for the survival outcomes of these patients. A shorter interval from diagnosis and initiation of NC to RC might be responsible for our better outcomes comparing to some historical data. No significant financial relationships to disclose.
Efficacy analysis of high-risk breast cancer patients treated with accelerated partial breast irradiation from a single institution.
Authors: P. Y. Chen, F. A. Vicini, C. Mitchell, M. Wallace, P. Benitez, N. Dekhne, C. Shah, J. B. Wilkinson, A. Martinez
Journal: Journal of Clinical Oncology (2011)

111 Background: We present the results of an analysis of high-risk breast cancer patients as defined by the NSABP B-39/RTOG 0413 phase III trial, all treated with accelerated partial breast irradiation (APBI) from a single institution. Methods: Between July 1993 and August 2010, 130 patients with any combination of at least one of the high-risk features of estrogen receptor (ER) negativity, age &lt; 50, and/or axillary nodal positivity were treated with 1 of 3 forms of APBI. Sixty-seven patients were treated with interstitial needle-catheter brachytherapy, 44 balloon-based brachytherapy and 19 with 3D conformal external beam radiation therapy. Aside from the high-risk features, general eligibility criteria included infiltrating ductal carcinoma, with inclusion of invasive lobular and DCIS since 2003, margins &gt; 2 mm, and surgically staged axilla. One-hundred eighteen patients had one high-risk factor, 11 had two, and 1 had all three factors. The median tumor size was 12.0 mm with margins &gt; 2 mm in 80% of patients. Greater than 75% had T1 tumors and 50% were ER negative. Thirty-one percent of patients were node positive. Based upon the ASTRO Consensus Guidelines for use of APBI (2009) none of these patients were suitable, 38% cautionary and 62% were unsuitable. Results: Median age was 56.5 yrs (range 40-90). With a median follow-up of 5.3 yrs (0.02-16.9) the 5-yr actuarial local recurrence rate (LR) was 4.2%; regional recurrence (RR) was 2.1%. Median time to LR and RR were 1.2 and 2.8 yrs, respectively. On univariate analysis, the only factor significant for LR was a close/positive margin (p=0.031), as ER/PR, age, nodal status, tumor size, histology, grade, hormonal or chemotherapy were all NS. The 5-yr actuarial cause specific, disease-free, and overall survivals as well as distant metastasis were 94%, 91%, 90%, and 6.4%, respectively. Conclusions: This cohort of NSABP B-39/RTOG 0413 identified high-risk patients who have undergone APBI has yielded local-regional control rates and survival outcomes comparable to standard risk patients undergoing partial breast irradiation. Continued follow-up will be needed to assess the long-term efficacy of such high-risk breast cancer patients treated with APBI.
Stimulation of prostate cancer cell proliferation by bone-derived factors.
Authors: P. Sluka, G. Whitty, I. D. Davis
Journal: Journal of Clinical Oncology (2011)

32 Background: Interactions between cancer cells and their microenvironment affect the establishment and metastasis of cancer. The most common site of prostate cancer (PC) metastasis is bone. This study examined the effects of selected factors known to be produced by bone stroma (EGF, aFGF, HGF, β-NGF, TGF-β, and TNFα) on the proliferation of PC cells. The effect of cell culture medium (CM) conditioned by osteoblasts (OBCM) was also examined. Methods: The PC-derived cell lines PC3, LNCaP, and DU145 were used. Expression of receptors for the above-mentioned cytokines was assessed using real-time RT-PCR. After 5 days of continuous cytokine treatment, proliferation was assessed by MTS conversion, and cell survival and apoptosis was assessed by 7-AAD staining and flow cytometry. OBCM was generated using the HOS, MG63, and SaOs2 cell lines. CM from the HT1080 fibrosarcoma cell line was used as a non-bone control. Results: The PC cell lines expressed receptors for all of the cytokines examined at the mRNA level. LNCaP cell proliferation was increased by aFGF and decreased by TGF-β. Treatment with TNFα decreased proliferation of all PC cell lines. These effects were not due to apoptosis. EGF, HGF, and β-NGF did not affect proliferation of any line despite receptor expression. OBCM increased proliferation of PC3 and DU145 cells but not LNCaP cells, while HT1080 CM did not affect proliferation of any line. Conclusions: PC cells are able to respond to defined bone-derived factors and that the nature of this response varies between individual cancers. Acidic FGF increased proliferation of LNCaP cells while TGF-β and TNFα decreased proliferation of LNCaP and all cell lines, respectively; an effect not mediated by apoptosis. Current studies are examining the effect of these cytokines on other functional parameters (cell survival, adhesion and migration) and on primary PC epithelial cells. No significant financial relationships to disclose.
The novel cytotoxicity of neutrophils in the peripheral blood of breast cancer patients versus women without breast cancer.
Authors: Z. Granot, E. A. Comen, L. Norton, R. Benezra
Journal: Journal of Clinical Oncology (2011)

44 Background: Using murine mammary tumor models, recent research conducted by our laboratory at the Sloan-Kettering Institute indicates that select neutrophils are mobilized and entrained by a primary breast tumor and uniquely have the capacity to inhibit metastatic seeding in the lung (Granot Z et al. unpublished). We sought to determine whether entrainment of cytotoxic neutrophils also occurs in blood samples from women with newly diagnosed breast cancer as contrasted to those garnered from healthy women. Methods: Subjects were 21 newly diagnosed pre-operative breast cancer patients without evidence of metastatic disease, 9 healthy female volunteers with no history of any cancer, and 3 patients with newly diagnosed DCIS. Neutrophils were purified from the blood samples. Cytotoxicity was evaluated by incubating isolated neutrophils with luciferase labeled MDA-MB-231 cells. Luciferase activity, as a reflection of % cell kill, was measured using a Bio-Tek microplate luminescence reader. Results: Significant cytotoxicity was notably observed when MDA-MB-231 cells were co-cultured with neutrophils purified from patients with invasive tumors. Pre-operative breast cancer patients (n=21) had a cell kill range of 0-30% (mean = 12.1%), whereas healthy subjects (n=9) had a cell kill range of 0.2-8% (mean = 2.6%), p&lt;0.004. DCIS patients (N=3) had a cell kill range of 3-4% (mean = 2.7). Conclusions: To date, this preliminary work is the first to demonstrate the cytotoxic role of select neutrophils in the peripheral blood of breast cancer patients as contrasted with those from women without breast cancer. Further studies are needed to evaluate the prognostic and therapeutic role of cytotoxic neutrophils.