tbuckley/cabot-search huggingface dataset:
Ptk7 as a direct and tumor stroma target in multiple solid malignancies
Authors: Jonathan Terrett, Vidusha Devasthali, Chin Pan, Sanjeev Gangwar, David King, Lisheng Lu, Pina Cardarelli, Orville Cortez, Colin Ching, Rory Dai, Chetana Rao-Naik, Mary Huber, Sarah Pogue, Rozanne Lee, David Passmore, Haichun Huang, Vangipuram Rangan, Allen Zhang, Bilal Sufi, Vincent Guerlavais, Liang Chen
Journal: Cancer Research (2008)

1526  Ptk7 shares homology with the receptor tyrosine kinases and contains extracellular immunoglobulin like domains. It is predicted to lack kinase activity as it is missing one of the conserved catalytic amino acids and is therefore classified as a pseudokinase. Ptk7 clearly has a role in embryonic development as seen in mouse knock-out and expression analyses. There have been sporadic reports of the expression of ptk7 in cancers, mostly through mRNA analyses. We identified ptk7 as a potential target for multiple solid malignancies through proteomic analyses of cancer cell lines where it was identified in cell lines representing different tumor types. mRNA studies showed ptk7 to be upregulated in many clinical cancer specimens and virtually absent from normal adult organs except fibroblasts in some tissues. This observation was confirmed by IHC which showed ptk7 to be highly expressed in many cancer types including lung, ovarian, pancreatic, colon, renal and breast. Interestingly the staining of cancer tissues occurs either in the cancer cells themselves, or in the tumor activated stroma, but very rarely in both. The clinical prevalence of ptk7 in these solid malignancies is >80% for all types when both regions of positive staining are considered. Furthermore, over-expression of ptk7 enhances the invasive properties of cells. Thus ptk7 represents an extremely attractive protein for targeted anti cancer therapies. To exploit this we have developed a panel of fully human antibodies specific for ptk7. These antibodies are internalized on receptor binding and, when conjugated to toxins, effectively kill cancer cells in vitro. The ptk7 antibodies cross-react with the mouse protein and preliminary toxicity studies with antibody drug conjugates in mice show no adverse target related events. We are developing 2 types of in vivo models to examine activity of anti ptk7 antibody-drug-conjugates : 1) where ptk7 is expressed on the cancer cells, and 2) where ptk7 is expressed on tumor associated stromal cells.
Early specialist palliative care for all hospitalized, advanced cancer patients (ACP)? Better outcomes with “up-front” versus “on-demand” palliative care.
Authors: Monica Malec, Fay J. Hlubocky, Stacie K. Levine, Kristen Wroblewski, Bradford Lane, Ashley Thomas, William Dale, Christopher Daugherty
Journal: Journal of Clinical Oncology (2017)

10026 Background: Palliative care improves outcomes for cancer patients, especially those with advanced disease. Optimal timing for initiation of specialist palliative care remains undetermined. We created a Supportive Oncology inpatient service that integrates immediate “up-front” palliative care (IPC) consultation for selected ACP to supplement our usual oncologic care (UOC) service, which continued to utilize “on-demand” palliative care consultation. Here, we compare ACP populations and selected outcomes between these two versions of in-patient cancer care. Methods: A retrospective cohort analysis of ACP receiving either IPC or UOC between Jan 2015-Dec 2015 (N = 809). ACP were compared for age, gender, race, and ethnicity. Disease severity was determined by APR DRG weight, Risk of Mortality (ROM), and Severity score. Outcomes included examining differences between groups for: Length of stay (LOS), Cost, and 30 day readmission rate. Univariate and multivariate analysis were employed. Results: 468 ACP were admitted to IPC and 341 to UOC. Compared with UOC, ACP assigned to IPC were significantly younger (61.1±13.2 vs 63.3±13.0, p = 0.02); more likely female (50% vs 40%, P = 0.005); and more likely to be AA (47% vs 35%, P = 0.005). After adjusting for gender, age, race, and encounter type, ACP receiving IPC had higher ROM (52% v 47%, p = 0.03). There were no differences in APR DRG weight (p = 0.30) or Severity scores (p = 0.34). IPC had significantly lower costs ($12,050 vs $15,990, p = 0.003), less 30-day readmissions (16% vs 23%, p = 0.03), and a trend toward shorter LOS (5.6 ± 4.9 vs 6.2 ± 6.5, p = 0.10). Conclusions: Our data provides additional evidence for the benefits of earlier specialist palliative care consultation services, including patients traditionally identified as underserved.
Taken to task: what is and is not an appropriate response to an ERS guidelines task force?
Authors: Guy Joos, Andrew Bush, Otto Chris Burghuber, Carlos Robalo Cordeiro, Mina Gaga, G. John Gibson, Christina Gratziou, David Rigau, Gernot Rohde, Dan Smyth, Daiana Stolz, Thomy Tonia, Jørgen Vestbo, Tobias Welte, Guy Brusselle, Marc Miravitlles
Journal: European Respiratory Journal (2017)

The European Respiratory Society (ERS) management group have discussed the worrying recent trend for outside interference by a small number of pharmaceutical and other companies in the Society's processes for generating, publishing, disseminating and/or implementing clinical practice guidelines. Recently, some companies have targeted their unwanted attentions very aggressively on particular individuals who are chairs or members of task forces developing guidelines. This is unacceptable, and the purpose of this manuscript is to remind all concerned of our guideline procedures, the proper way of responding and expressing comments, and how the Society will regard any future attempts to manipulate outcomes. Task forces use rigorous methodology, and the ERS will not tolerate interference with the processes by outsiders <http://ow.ly/WwIe30cyhDO> The authors acknowledge the members of the ERS Guidelines Working Group for their contribution to facilitate the development of clinical practice guidelines within ERS and for reviewing the current document.
Erratum: Expression cloning of a cDNA for the major Fanconi anaemia gene, FAA (Nature Genetics (1996) 14 (320-323))
Authors: J. R L T Foe, M. A. Rooimans, L. Bosnoyan-Collins, N. Alon, M. Wijker, L. Parker, J. Lightfoot, M. Carreau, D. F. Callen, A. Savoia, N. C. Cheng, C. G M Van Berkel, M. H P Strunk, J. J P Gille, G. Pals, F. A E Kruyt, J. C. Pronk, F. Arwert, M. Buchwald, H. Joenje
Journal: Nature Genetics (1996)
MCPIP1 Downregulation in Clear Cell Renal Cell Carcinoma Promotes Vascularization and Metastatic Progression
Authors: Paulina Marona, Judyta Górka, Zofia Mazurek, Waclaw Wilk, Janusz Rys, Marcin Majka, Jolanta Jura, Katarzyna Miekus
Journal: Cancer Research (2017)

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer and it forms highly vascularized tumors. The monocyte endoribonuclease MCPIP1 negatively regulates inflammation by degrading mRNA encoding proinflammatory cytokines, such as IL6, IL1, and IL12. MCPIP1 is also a negative regulator of NFκB and AP1 activity and it influences a broad range of miRNA activities. Here we report that MCPIP1 protein levels are decreased during renal cancer progression. In patient-derived tumors and xenografts established in NOD-SCID or nude mice, low MCPIP1 levels correlated strongly with increased proliferation, tumor outgrowth, and vascularity. MCPIP1 activity regulated secretion of VEGF, IL8, and CXCL12 leading to chemotaxis of microvascular endothelial cells, phosphorylation of VE-cadherin, and increased vascular permeability. Mechanistic investigations showed that MCPIP1 regulated ccRCC cell motility, lung metastasis, and mesenchymal phenotype by regulating key elements in the EMT signaling axis. Overall, our results illuminate how MCPIP1 serves as a key nodal point in coordinating tumor growth, angiogenesis, and metastatic spread in ccRCC. Cancer Res; 77(18); 4905–20. ©2017 AACR.
Risk of post-pregnancy hypertension in women with a history of hypertensive disorders of pregnancy: nationwide cohort study
Authors: Ida Behrens, Saima Basit, Mads Melbye, Jacob A Lykke, Jan Wohlfahrt, Henning Bundgaard, Baskaran Thilaganathan, Heather A Boyd
Journal: BMJ (2017)

Objectives To determine how soon after delivery the risk of post-pregnancy hypertension increases in women with hypertensive disorders of pregnancy and how the risk evolves over time.Design Nationwide register based cohort study.Setting Denmark.Populations 482 972 primiparous women with a first live birth or stillbirth between 1995 and 2012 (cumulative incidence analyses), and 1 025 118 women with at least one live birth or stillbirth between 1978 and 2012 (Cox regression analyses).Main outcome measures 10 year cumulative incidences of post-pregnancy hypertension requiring treatment with prescription drugs, and hazard ratios estimated using Cox regression.Results Of women with a hypertensive disorder of pregnancy in a first pregnancy in their 20s, 14% developed hypertension in the first decade post partum, compared with 4% of women with normotensive first pregnancies in their 20s. The corresponding percentages for women with a first pregnancy in their 40s were 32% and 11%, respectively. In the year after delivery, women with a hypertensive disorder of pregnancy had 12-fold to 25-fold higher rates of hypertension than did women with a normotensive pregnancy. Rates in women with a hypertensive disorder of pregnancy were threefold to 10-fold higher 1-10 years post partum and remained twice as high even 20 or more years later.Conclusions The risk of hypertension associated with hypertensive disorders of pregnancy is high immediately after an affected pregnancy and persists for more than 20 years. Up to one third of women with a hypertensive disorder of pregnancy may develop hypertension within a decade of an affected pregnancy, indicating that cardiovascular disease prevention in these women should include blood pressure monitoring initiated soon after pregnancy.
Advanced Gene Manipulation Methods for Stem Cell Theranostics
Authors: Christopher Rathnam, Sy-Tsong Dean Chueng, Letao Yang, Ki-Bum Lee
Journal: Theranostics (2017)

In the field of tissue engineering, autologous cell sources are ideal to prevent adverse immune responses; however, stable and reliable cell sources are limited.To acquire more reliable cell sources, the harvesting and differentiation of stem cells from patients is becoming more and more common.To this end, the need to control the fate of these stem cells before transplantation for therapeutic purposes is urgent.Since transcription factors orchestrate all of the gene activities inside of a cell, researchers have developed engineered and synthetic transcription factors to precisely control the fate of stem cells allowing for safer and more effective cell sources.Engineered transcription factors, mutant fusion proteins of naturally occurring proteins, comprise the three main domains of natural transcription factors including DNA binding domains, transcriptional activation domains, and a linker domain.Several key advancements of engineered zinc finger proteins, transcriptional activator-like effectors, and deficient cas9 proteins have revolutionized the field of engineered transcription factors allowing for precise control of gene regulation.Synthetic transcription factors are chemically made transcription factor mimics that use small molecule based moieties to replicate the main functions of natural transcription factors.These include hairpin polyamides, triple helix forming oligonucleotides, and nanoparticle-based methods.Synthetic transcription factors allow for non-viral delivery and greater spatiotemporal control of gene expression.The developments in engineered and synthetic transcription factors have lowered the risk of tumorigenicity and improved differentiation capability of stem cells, as well as facilitated many key discoveries in the fields of cancer and stem cell biology, thus providing a stepping stone to advance regenerative medicine in the clinic for cell replacement therapies.
Investigations into molecular alterations present in ductal carcinoma in situ of the breast using a murine mammary tumor model
Authors: Stephen D. Buttars, Wenben Qiao, Nona C. R. Arneson, Susan J. Done
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

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Ductal carcinoma in situ (DCIS), an alleged precursor of invasive breast cancer, is characterized by neoplastic epithelial cells growing within mammary ducts. One of the most critical stages in the development of breast cancer is the progression from DCIS to invasive carcinoma, when the basement membrane of the duct is breached and tumour cells spill out into the surrounding stroma. Clinical prognostication for DCIS is challenging, as the likelihood of progression to invasion by low-grade DCIS and the potential for low-grade lesions to evolve to high-grade both remain unclear. The small size of lesions, coupled with variations in time to invasion and rates of post-treatment recurrence, have complicated the study of DCIS in humans. The MMTV- neu 202Mul mouse model has been reported to develop DCIS-like lesions in the mammary fat pads. When a tumour is detected by manual palpation, the animal is sacrificed and the mammary fat pads are removed. Tissues are prepared as both snap-frozen and formalin-fixed paraffin-embedded (FFPE) blocks, sectioned, stained with haematoxylin and eosin, and assessed for quality. Immunohistochemical staining for smooth muscle actin (SMA) reveals the myoepithelial cells which are wrapped around the basement membrane of the ducts. Assessing the continuity of the myoepithelial cell line permits classification of tumours as either DCIS, invasive, or focally invasive. FFPE sections of DCIS and fully invasive samples are then microdissected. DNA is extracted and examined using array comparative genomic hybridization. Analysis has revealed differing patterns of genomic amplification and deletion between the two tumour types. Copy numbers of Gas6 and Psmb3 have been found amplified in invasive carcinoma. To assess gene expression levels, RNA is extracted from frozen DCIS and fully invasive tumours and analysed via expression microarray. Array profiling has revealed altered expression of genes including Tsga2 , Grb7 , Arl1 , and Phka2 . Preliminary data indicate that these genes have higher expression in DCIS. Gene copy number and gene expression differentials will be further analyzed using quantitative polymerase chain reaction (Q-PCR). Immunohistochemistry is being employed to develop a profile of the tumour types. Targets including Ki67, Laminin, Activated Caspase 3, E-Cadherin, and CD31 have been assessed. These data indicate differences in the expression of certain markers between tumour types. In comparison to DCIS tumours, invasive tumours have shown an increase in expression of Ki67 but a decreased expression of Activated Caspase 3. Additional immunohistochemistry is ongoing, as is collection and analysis of microarray data. Through comparison of data from mouse and human cases, we plan to identify a subset of genes which could be used as prognostic markers and/or therapeutic targets to improve clinical management of human DCIS cases.
Low dose metronomic cyclophosphamide, methotrexate (LDCM) and aspirin for patients with residual disease after neoadjuvant chemotherapy for stage II-III breast cancer.
Authors: Jose Ignacio Ruades Ninfea, Susan Burdette-Radoux, Melissa of Sands, Jamie E Levis, Mercedes Rincon, Chris E. Holmes, Marie Wood
Journal: Journal of Clinical Oncology (2016)

e12040 Background: The risk of recurrence for women who fail to achieve pathological complete response (pCR) to neoadjuvant chemotherapy is high (15-30% at 2 years). We investigated the effect of an all-oral regimen (LDCM + aspirin) in women who fail to achieve a pCR. We present 2 year follow up, toxicity and biomarker analysis. Methods: Patients with stage II-III HER-2 negative breast cancer with residual disease after neoadjuvant therapy were eligible, after completing radiotherapy and initiating hormonal therapy. Therapy consisted of 4 28-day cycles of cyclophosphamide 50 mg oral daily, and methotrexate 2.5 mg oral twice daily on days 1 and 2 each week. Aspirin 325 mg daily was added for cycles 3 and 4. Serum/plasma VEGF, IL-6 and TNF were obtained at baseline, after 2 and 4 cycles. The primary endpoint was safety with secondary endpoints of 2 year relapse free survival (RFS) and serum biomarkers. Results: 20 patients were enrolled between 5/2011 and 11/2015, 3 are excluded from this analysis (1 ineligible and 2 on treatment). Mean age was 51 (range 31-75), 70% had hormone receptor positive disease, stage at surgery ranged from T0N1 – T3N3 (18% had inflammatory breast cancer). The median follow up is 22 months (range 8-31). There were no grade 3 or 4 related toxicities. Worst hematology toxicity was grade 2 leukopenia in 6%. Worst non-hematologic toxicity includes grade 2 fatigue in 18% and nausea in 6%. Only 1 patient has relapsed (at 11 months after surgery). Post-treatment IL6 levels were higher than baseline (p = 0.02); with an increase after 2 cycles (p = 0.03) and non-significant decrease after cycle 4 (p = 0.89). No changes in TNF or VEGF levels were observed (TNF p = 0.65; Serum VEGF p = 0.83; Plasma VEGF p = 0.85). Analysis of biomarkers for receptor + and – groups is under way. Conclusions: This regimen is well tolerated in the post-neoadjuvant setting with low toxicity and 94% RFS at a median follow up of 22 months (significantly greater than expected). This may be a viable regimen for individuals at high risk of recurrence after neoadjuvant therapy. The modulation of IL6 by LDCM + aspirin is interesting and deserves further exploration. Clinical trial information: NCT 01612247.
Neonatal Caffeine Treatment and Respiratory Function at 11 Years in Children under 1,251 g at Birth
Authors: Lex W. Doyle, Sarath Ranganathan, Jeanie L. Y. Cheong
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Caffeine in the newborn period shortens the duration of assisted ventilation and reduces the incidence of bronchopulmonary dysplasia, but its effects on respiratory function in later childhood are unknown.To determine if children born with birth weight less than 1,251 g who were treated with neonatal caffeine had improved respiratory function at 11 years of age compared with children treated with placebo.Children enrolled in the CAP (Caffeine for Apnea of Prematurity) randomized controlled trial and assessed at the Royal Women's Hospital in Melbourne at 11 years of age had expiratory flow rates measured according to the standards of the American Thoracic Society. Values were converted to z-scores predicted for age, height, ethnicity, and sex. Parents completed questionnaires related to their child's respiratory health.A total of 142 children had expiratory flows measured. Expiratory flows were better in the caffeine group, by approximately 0.5 SD for most variables (e.g., FEV1; mean z-score, -1.00 vs. -1.53; mean difference, 0.54; 95% confidence interval, 0.14-0.94; P = 0.008). Fewer children in the caffeine group had values for FVC below the fifth centile (11% vs. 28%; odds ratio, 0.31; 95% confidence interval, 0.12-0.77; P = 0.012). When adjusted for bronchopulmonary dysplasia, the difference in flow rates between groups diminished.Caffeine treatment in the newborn period improves expiratory flow rates in midchildhood, which seems to be achieved by improving respiratory health in the newborn period. Follow-up lung function testing in adulthood is vital for these individuals. Future placebo-controlled randomized trials of neonatal caffeine are unlikely. Clinical trial registered with www.clinicaltrials.gov (NCT00182312).
Surgical Residents’ Work Hours and Well-Being in Year 2 of the FIRST Trial
Authors: Allison R Dahlke, Christopher M Quinn, Jeanette W Chung, Karl Y Bilimoria
Journal: New England Journal of Medicine (2017)

In year 1, residents assigned to flexible duty hours were more likely to report negative effects on their well-being than those assigned to standard duty hours. In year 2, reports of negative effects in the former group decreased but remained more common than in the latter group.
Patient-reported outcomes and survival in multiple sclerosis: A 10-year retrospective cohort study using the Multiple Sclerosis Impact Scale–29
Authors: Joel Raffel, Alison Wallace, Djordje Gveric, Richard Reynolds, Tim Friede, Richard Nicholas
Journal: PLoS Medicine (2017)

Background There is increasing emphasis on using patient-reported outcomes (PROs) to complement traditional clinical outcomes in medical research, including in multiple sclerosis (MS). Research, particularly in oncology and heart failure, has shown that PROs can be prognostic of hard clinical endpoints such as survival time (time from study entry until death). However, unlike in oncology or cardiology, it is unknown whether PROs are associated with survival time in neurological diseases. The Multiple Sclerosis Impact Scale–29 (MSIS-29) is a PRO sensitive to short-term change in MS, with questions covering both physical and psychological quality of life. This study aimed to investigate whether MSIS-29 scores can be prognostic for survival time in MS, using a large observational cohort of people with MS. Methods and findings From 15 July 2004 onwards, MSIS-29 questionnaires were completed by people with MS registered with the MS Society Tissue Bank (n = 2,126, repeated 1 year later with n = 872 of the original respondents). By 2014, 264 participants (12.4%) had died. Higher baseline MSIS-29 physical (MSIS-29-PHYS) score was associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: hazard ratio [HR] 5.7, 95% CI 3.1–10.5, p < 0.001). Higher baseline MSIS-29 psychological score was also associated with reduced survival time (subgroup with highest scores versus subgroup with lowest scores: HR 2.8, 95% CI 1.8–4.4, p < 0.001). In those with high baseline MSIS-29 scores, mortality risk was even greater if the MSIS-29 score worsened over 1 year (HR 2.3, 95% CI 1.2–4.4, p = 0.02). MSIS-29-PHYS scores were associated with survival time independent of age, sex, and patient-reported Expanded Disability Status Scale score in a Cox regression analysis (per 1-SD increase in MSIS-29-PHYS score: HR 1.8, 95% CI 1.1–2.9, p = 0.03). A limitation of the study is that this cohort had high baseline age and disability levels; the prognostic value of MSIS-29 for survival time at earlier disease stages requires further investigation. Conclusions This study reports that PROs can be prognostic for hard clinical outcomes in neurological disease, and supports PROs as a meaningful clinical outcome for use in research and clinical settings.
UK adds hepatitis B to infant vaccination schedule
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Hepatitis B vaccine is being introduced for newborns from the autumn in the UK, making it one of the last countries in Europe to introduce a universal hepatitis B vaccination programme for infants.1

All babies born on or after 1 August 2017 will be eligible for Infanrix hexa, which protects against diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and disease caused by Haemophilus influenzae type b (Hib). This hexavalent vaccine will replace the pentavalent infant vaccines Infanrix-IPV+Hib and Pediacel used …