tbuckley/cabot-search huggingface dataset:
Modeling the Cellular Response of Lung Cancer to Radiation Therapy for a Broad Range of Fractionation Schedules
Authors: Jeho Jeong, Jung Hun Oh, Jan-Jakob Sonke, Jose Belderbos, Jeffrey D. Bradley, Andrew N. Fontanella, Shyam S. Rao, Joseph O. Deasy
Journal: Clinical Cancer Research (2017)

Abstract Purpose: To demonstrate that a mathematical model can be used to quantitatively understand tumor cellular dynamics during a course of radiotherapy and to predict the likelihood of local control as a function of dose and treatment fractions. Experimental Design: We model outcomes for early-stage, localized non–small cell lung cancer (NSCLC), by fitting a mechanistic, cellular dynamics-based tumor control probability that assumes a constant local supply of oxygen and glucose. In addition to standard radiobiological effects such as repair of sub-lethal damage and the impact of hypoxia, we also accounted for proliferation as well as radiosensitivity variability within the cell cycle. We applied the model to 36 published and two unpublished early-stage patient cohorts, totaling 2,701 patients. Results: Precise likelihood best-fit values were derived for the radiobiological parameters: α [0.305 Gy−1; 95% confidence interval (CI), 0.120–0.365], the α/β ratio (2.80 Gy; 95% CI, 0.40–4.40), and the oxygen enhancement ratio (OER) value for intermediately hypoxic cells receiving glucose but not oxygen (1.70; 95% CI, 1.55–2.25). All fractionation groups are well fitted by a single dose–response curve with a high χ2 P value, indicating consistency with the fitted model. The analysis was further validated with an additional 23 patient cohorts (n = 1,628). The model indicates that hypofractionation regimens overcome hypoxia (and cell-cycle radiosensitivity variations) by the sheer impact of high doses per fraction, whereas lower dose-per-fraction regimens allow for reoxygenation and corresponding sensitization, but lose effectiveness for prolonged treatments due to proliferation. Conclusions: This proposed mechanistic tumor-response model can accurately predict overtreatment or undertreatment for various treatment regimens. Clin Cancer Res; 23(18); 5469–79. ©2017 AACR.
The interplay between adaptive and innate immunity promotes cancer development
Authors: Karin E. De Visser, Lisa M. Coussens
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1751 

Recent clinical and experimental data suggest a strong promoting role for inflammatory cells during early neoplastic development, however, the mechanisms by which inflammatory cells are recruited towards (pre-) malignant lesions and the mechanisms by which they contribute to neoplastic progression are still largely unknown. Utilizing a transgenic mouse model of multi-stage squamous cell carcinogenesis, e.g. HPV16 mice we have previously shown that specific subsets of immune cells, in particular mast cells, are crucial modifiers of early epithelial carcinogenesis. The aims of this study are to understand the mechanisms regulating recruitment of these infiltrating leukocytes towards premalignant epithelial lesions and how they functionally contribute to neoplastic development. Taking a genetic approach, we have revealed that specific elimination of the adaptive immune system in HPV16 mice results in a dramatic reduction in the number of infiltrating mast cells at all stages of neoplastic progression. Moreover, neoplastic progression in the absence of functional T and B cell responses results in decreased infiltration of premalignant tissue by neutrophils, attenuated angiogenesis and reduced characteristic keratinocyte hyperproliferation. In addition, our preliminary data suggest that elimination of the adaptive immune response in HPV16 mice results in a reduction in overall tumor incidence. Since genetic elimination of either CD4+ and CD8+ T cells alone does not result in reduced mast cell infiltration or altered characteristics of angiogenesis in early premalignant tissue, and since neoplastic progression in HPV16 mice is characterized by abundant deposition of IgG and IgM antibodies in the neoplastic environment, we hypothesize that antibodies, and specifically activated B cells play a crucial role in the recruitment pathway regulating mast cell infiltration and mast cell potentiation of squamous carcinogenesis. The implications of these findings support a model in which inhibition of mast cell recruitment into premalignant neoplastic stroma significantly alters the characteristics of neoplastic development and suggests that pharmacological intervention targeting either activation of B cells, antibody deposition or mast cell recruitment may represent a viable therapeutic anti-cancer strategy. (Supported by a fellowship from the Dutch Cancer Society).
Empirical MRSA Coverage for Nonpurulent Cellulitis
Authors: Emily K. Shuman, Preeti N. Malani
Journal: JAMA (2017)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Association Between Skin and Aortic Vascular Inflammation in Patients With Psoriasis
Authors: Amit K. Dey, Aditya A. Joshi, Abhishek Chaturvedi, Joseph B. Lerman, Tsion M. Aberra, Justin A. Rodante, Heather L. Teague, Charlotte L. Harrington, Joshua P. Rivers, Jonathan H. Chung, Mohammad Tarek Kabbany, Balaji Natarajan, Joanna I. Silverman, Qimin Ng, Gregory E. Sanda, Alexander V. Sorokin, Yvonne Baumer, Emily Gerson, Ronald B. Prussick, Alison Ehrlich, Lawrence J. Green, Benjamin N. Lockshin, Mark A. Ahlman, Martin P. Playford, Joel M. Gelfand, Nehal N. Mehta
Journal: JAMA Cardiology (2017)

Inflammation is critical in the development of atherosclerosis. Psoriasis is a chronic inflammatory skin disease that is associated with increased vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography in vivo and future cardiovascular events. It provides a human model to understand the effect of treating inflammation in a target organ (eg, the skin) on vascular diseases.To investigate the association between change in skin disease severity and change in vascular inflammation at 1 year and to characterize the impact of 1 year of anti-tumor necrosis factor therapy on vascular inflammation.In this prospective cohort study, 220 participants from outpatient practices were recruited at the US National Institutes of Health. A total of 115 consecutively recruited patients with psoriasis were followed up at 1 year. The study was conducted from January 1, 2013, through October 31, 2016, with data analyzed in November 2016.Skin inflammation measured as Psoriasis Area and Severity Index (PASI) score.Vascular inflammation assessed as target-to-background ratio by 18fluorodeoxyglucose positron emission tomography/computed tomography.Among the 115 patients, the mean (SD) age at 1-year follow-up was 50.8 (12.8) years and 68 were men (59%). The cohort had a low cardiovascular risk by Framingham risk score and mild-to-moderate psoriasis, with a median PASI score of 5.2 (interquartile range, 3.0-8.9). At follow-up, the total cohort had a median improvement in PASI score of 33%, with use of topical therapy (60%), biological therapy (66%, mostly anti-tumor necrosis factor) and phototherapy (15%) (P < .001). Moreover, improvement in PASI score was associated with improvement in target-to-background ratio of 6%, mainly driven by those with higher responses in PASI score (P < .001). This association persisted beyond traditional risk factors (β = 0.19; 95% CI, 0.012-0.375; P = .03) and was the strongest in those initiated with anti-tumor necrosis factor therapy (β = 0.79; 95% CI, 0.269-1.311; P = .03).Improvement in psoriasis skin disease severity was associated with improvement in aortic vascular inflammation by 18fluorodeoxyglucose positron emission tomography/computed tomography, with greater improvement in aortic vascular inflammation observed in those who had higher than 75% reduction in skin disease severity. These findings suggest that controlling remote target organ inflammation (eg, in the skin) may improve vascular diseases; however, randomized clinical trials are needed to confirm these findings.
Bcl-2 antisense oligonucleotide (G3139, Genasense) chemosensitizes human nasopharyngeal carcinoma to cisplatin in vivo in a SCID xenotransplantation model
Authors: Hadas Dvory-Sobol, Meirav Rozenblat, Diana Kazanov, Shahar Lev-Ari, Nadir Arber
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2928 

Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV), and EBV latent membrane protein 1 (LMP-1) is expressed in the majority of NPCs. LMP-1 upregulates anti-apoptotic genes, including bcl-2, and Bcl-2 protein is co-expressed with LMP-1 in NPC. Given the anti-apoptotic and chemoprotective effects of Bcl-2, it represents a rational therapeutic target in NPC. We have investigated the anti-tumor and chemosensitizing effects in NPC of G3139 (Genasense; Genta, Inc), a phosphorothioated antisense oligodeoxynucleotide targeted to the first six codons of Bcl-2 mRNA. In previous in vitro studies in C666-1, a stably infected NPC-derived line which co-expresses LMP-1 and bcl-2, we have shown that G3139 treatment caused sequence-dependent inhibition of growth and depletion of Bcl-2 protein. Although G3139 had anti-tumor effects in vivo, delaying establishment and inhibiting growth of C666-1 engrafted s.c. in SCID mice, G3139 did not prevent establishment or extend survival compared to untreated and control oligonucleotide-treated animals. Since Bcl-2 mediates chemoresistance, and G3139 enhances sensitivity to chemotherapy, we sought to determine whether G3139 sensitizes NPC to cisplatin (CDDP) in our NPC xenotransplantation model. Animals were injected with 5 million C666-1 cells on day 1 and randomized to treatment arms (n = 5-6). Tumor volumes were measured at 3 day intervals and mean tumor volumes were compared using Student’s t test. EBV DNA load in serum was measured serially by real-time quantitative PCR. Results: In the first experiment, G3139 (25 mg/kg i.p. q 3 days x 5 starting on day 7) + CDDP (8 mg i.p. on day 14) prevented tumor establishment in 80% of animals compared to CDDP alone (0%) or CDDP + a reverse control oligonucleotide (RV) (0%). CDDP + RV had no effect on tumor establishment or growth compared to CDDP alone. Tumor burden correlated directly with EBV DNA load in serum. In a second experiment, treatment was delayed until tumor was established. On day 21, animals with measurable tumor were randomized and treated as above with CDDP, G3139 + CDDP, or CDDP + MM (two base mismatch control oligonucleotide). In contrast to CDDP or CDDP + MM, G3139 + CDDP resulted in partial tumor regressions in 4 of 6 animals, and significantly inhibited tumor growth. Survival analysis and correlative studies on tumor tissue to assess in vivo mechanisms are in progress. Conclusions: These studies demonstrate that the pro-apoptotic bcl-2 antisense oligonucleotide G3139 sensitizes EBV-positive NPC to CDDP in vivo. The sequence-dependency of this effect is consistent with an antisense mechanism. Moreover, these studies support the use of this animal model of EBV-positive NPC to test novel targeted therapies for NPC, including anti-viral agents.
Global DNA methylation analysis in breast tumors using promoter microarray
Authors: Anna Christina M. Salim, Luiz Paulo Camargo, Yipeng Wang, Helena Paula Brentani, Michael McClelland, Dirce Maria Carraro, Anamaria Aranha Camargo
Journal: Cancer Research (2006)

3219  Aberrant DNA methylation of CpG sites in promoter regions is among the earliest and most frequent alterations in tumors and is emerging as an important molecular marker for disease diagnosis and prognosis. As a further step to understand the role of DNA methylation in tumorigenesis and to improve cancer diagnosis and treatment, abnormally methylated sequences occurring in the tumor genome need to be identified. Recently the microarray-based strategy was adapted to allow genome-wide assessment of methylation status of promoter regions. Human RefSeq promoter sequences were retrieved from GenBank and promoter fragments amplified by PCR were spotted onto glass slides resulting in a promoter microarray containing triplicate spots of 12.800 promoter sequences. Genomic DNA from a reference source (HB4a normal breast cell line) and a test source (MDA-MB-231 tumor breast cell line) were digested with the methylation sensitive enzyme HpaII. Oligonucleotide linkers were ligated to the digested fragments. Repetitive sequences were then removed by hybridization with biotin labeled Cot-1 DNA, followed by affinity capture with streptavidin magnetic particles. PCR using linker-specific primer was then used to separately amplify the test and reference DNA fragments. Test and reference DNA products were labeled with Cy5 and Cy3, respectively, and hybridized to the promoter microarray. 117 genes appeared to be differentially methylated between the HB4a normal cell line and the MDA-MB-231 tumor cell line. Among the differentially methylated genes, we were able to identify several genes that have already been reported to be hypermethylated in breast tumors (eg. RB1, RASSF5, EGFR, CDKN2C, WNT2B, BAX, CDC20 and GADD45G). Thus, the use of a method that directly amplifies the CpG regions of interest combined with a promoter microarray analysis seems to be a very useful strategy to genome-wide analysis of methylation patterns. We are now applying this technique to identify differentially methylated fragments between node positive and node negative breast tumors, which could be used in the future as molecular marker for disease management.
No renaissance for doctors in Shakespeare’s plays
Authors: Michele A Riva
Journal: BMJ (2017)

I greatly enjoyed the paper by Dholakia and colleagues on the interest of William Shakespeare (1564-1616) in medicine and surgery, commemorating the 400th anniversary of Shakespeare’s death.1 Even though the English playwright probably never formally studied medicine, he observed suffering and learnt from doctors and other figures in the healing arts.

In their conclusion, the authors focus on the representations of doctors in Renaissance plays …
Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages
Authors: Martin A. Bewley, Julie A. Preston, Mohammed Mohasin, Helen M. Marriott, Richard C. Budd, Julie Swales, Paul Collini, David R. Greaves, Ruth W. Craig, Christopher E. Brightling, Louise E. Donnelly, Peter J. Barnes, Dave Singh, Steven D. Shapiro, Moira K. B. Whyte, David H. Dockrell
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria.The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated.AMs were obtained from bronchoalveolar lavage from healthy donors or patients with COPD and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line in which the CD68 promoter ensures macrophage-specific expression of human induced myeloid leukemia cell differentiation protein Mcl-1 (CD68.hMcl-1) was used to model the molecular aspects of COPD.COPD AMs had elevated levels of Mcl-1, an antiapoptotic B-cell lymphoma 2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AMs phenocopied the microbicidal defect because transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages and human monocyte-derived macrophages generated mROS in response to pneumococci, which colocalized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected bone marrow-derived macrophages but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AMs also increased basal mROS expression, but they failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS/superoxide dismutase 2.Up-regulation of Mcl-1 and chronic adaption to oxidative stress alter mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD.
Multicenter analysis of the use of transjugular intrahepatic portosystemic shunt for management of MPN‐associated portal hypertension
Authors: Christopher R. Reilly, Daria V. Babushok, Karlyn Martin, Jerry L. Spivak, Michael Streiff, Ranjeeta Bahirwani, Jeffrey Mondschein, Brady Stein, Alison Moliterno, Elizabeth O. Hexner
Journal: American Journal of Hematology (2017)

Abstract BCR‐ABL1 ‐negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders defined by proliferation of one or more myeloid lineages, and carry an increased risk of vascular events and progression to myelofibrosis and leukemia. Portal hypertension (pHTN) occurs in 7‐18% of MPN patients via both thrombotic and nonthrombotic mechanisms and portends a poor prognosis. Transjugular intrahepatic portosystemic shunt (TIPS) has been used in the management of MPN‐associated pHTN; however, data on long‐term outcomes of TIPS in this setting is limited and the optimal management of medically refractory MPN‐associated pHTN is not known. In order to assess the efficacy and long‐term outcomes of TIPS in MPN‐associated pHTN, we performed a retrospective analysis of 29 MPN patients who underwent TIPS at three academic medical centers between 1997 and 2016. The majority of patients experienced complete clinical resolution of pHTN and its clinical sequelae following TIPS. One, two, three, and four‐year overall survival post‐TIPS was 96.4%, 92.3%, 84.6%, and 71.4%, respectively. However, despite therapeutic anticoagulation, in‐stent thrombosis occurred in 31.0% of patients after TIPS, necessitating additional interventions. In conclusion, TIPS can be an effective intervention for MPN‐associated pHTN regardless of etiology. However, TIPS thrombosis is a frequent complication in the MPN population and indefinite anticoagulation post‐TIPS should be considered.
Forecasted trends in disability and life expectancy in England and Wales up to 2025: a modelling study
Authors: Maria Guzman-Castillo, Sara Ahmadi-Abhari, Piotr Bandosz, Simon Capewell, Andrew Steptoe, Archana Singh-Manoux, Mika Kivimaki, Martin J Shipley, Eric J Brunner, Martin O'Flaherty
Journal: The Lancet Public Health (2017)

BackgroundReliable estimation of future trends in life expectancy and the burden of disability is crucial for ageing societies. Previous forecasts have not considered the potential impact of trends in disease incidence. The present prediction model combines population trends in cardiovascular disease, dementia, disability, and mortality to forecast trends in life expectancy and the burden of disability in England and Wales up to 2025.MethodsWe developed and validated the IMPACT-Better Ageing Model—a probabilistic model that tracks the population aged 35–100 years through ten health states characterised by the presence or absence of cardiovascular disease, dementia, disability (difficulty with one or more activities of daily living) or death up to 2025, by use of evidence-based age-specific, sex-specific, and year-specific transition probabilities. As shown in the English Longitudinal Study of Ageing, we projected continuing declines in dementia incidence (2·7% per annum), cardiovascular incidence, and mortality. The model estimates disability prevalence and disabled and disability-free life expectancy by year.FindingsBetween 2015 and 2025, the number of people aged 65 years and older will increase by 19·4% (95% uncertainty interval [UI] 17·7–20·9), from 10·4 million (10·37–10·41 million) to 12·4 million (12·23–12·57 million). The number living with disability will increase by 25·0% (95% UI 21·3–28·2), from 2·25 million (2·24–2·27 million) to 2·81 million (2·72–2·89 million). The age-standardised prevalence of disability among this population will remain constant, at 21·7% (95% UI 21·5–21·8) in 2015 and 21·6% (21·3–21·8) in 2025. Total life expectancy at age 65 years will increase by 1·7 years (95% UI 0·1–3·6), from 20·1 years (19·9–20·3) to 21·8 years (20·2–23·6). Disability-free life expectancy at age 65 years will increase by 1·0 years (95% UI 0·1–1·9), from 15·4 years (15·3–15·5) to 16·4 years (15·5–17·3). However, life expectancy with disability will increase more in relative terms, with an increase of roughly 15% from 2015 (4·7 years, 95% UI 4·6–4·8) to 2025 (5·4 years, 4·7–6·4).InterpretationThe number of older people with care needs will expand by 25% by 2025, mainly reflecting population ageing rather than an increase in prevalence of disability. Lifespans will increase further in the next decade, but a quarter of life expectancy at age 65 years will involve disability.FundingBritish Heart Foundation.
Chlorambucil PLUS Rituximab As FRONT-LINE Therapy for Elderly and/or Unfit CLL Patients. LONG-TERM Follow-up and Correlation with Biologic-Based Risk Stratification
Authors: Luca Laurenti, Idanna Innocenti, Francesco Autore, Raffaella Pasquale, Barbara Vannata, Stefania Ciolli, Francesca Romana Mauro, Donato Mannina, Giovanni Del Poeta, Giovanni D'Arena, Massimo Massaia, Marta Coscia, Stefano Molica, Gabriele Pozzato, Dimitar G Efremov, Roberto Marasca, Piero Galieni, Antonio Cuneo, Sonia Orlando, Alfonso Piciocchi, Riccardo Boncompagni, Donatella Iolanda Vincelli, Anna Marina Liberati, Filomena Russo, Robin Foa
Journal: Blood (2016)