tbuckley/cabot-search huggingface dataset:
Leveraging the Benefits of Systemic Therapy to Tailor Surgery
Authors: Monica Morrow
Journal: JAMA Surgery (2017)

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Anthracyclines in Early Breast Cancer: The ABC Trials—USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology)
Authors: Joanne L. Blum, Patrick J. Flynn, Greg Yothers, Lina Asmar, Charles E. Geyer, Samuel A. Jacobs, Nicholas J. Robert, Judith O. Hopkins, Joyce A. O'Shaughnessy, Chau T. Dang, Henry Leonidas Gómez, Louis Fehrenbacher, Svetislava J. Vukelja, Alan P. Lyss, Devchand Paul, Adam M. Brufsky, Jong-Hyeon Jeong, Linda H. Colangelo, Sandra M. Swain, Eleftherios P. Mamounas, Stephen E. Jones, Norman Wolmark
Journal: Journal of Clinical Oncology (2017)

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was &gt; 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer compared with the TC6 regimen.
Reproductive factors and subtypes of breast cancer defined by hormone receptor and histology
Authors: Giske Ursin, Leslie Bernstein, Sarah J. Lord, Roksana Karim, Dennis Deapen, Michael F. Press, Janet R. Daling, Sandra A. Norman, Jonathan M. Liff, Polly A. Marchbanks, Suzanne G. Folger, Michael S. Simon, Brian L. Strom, Ronald T. Burkman, Linda K. Weiss, Robert Spirtas
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3206 

Introduction: Certain reproductive factors are known to protect against breast cancer, but less is known about whether they provide differential protection against subtypes of breast cancer. If reproductive factors act through hormonal mechanisms, they should protect predominantly against cancers expressing estrogen and progesterone receptors. Methods: We examined the effect of selected reproductive factors on subgroups of tumors defined by hormone receptor status as well as histology using data from the National Institute of Child Health and Human Development Women’s Contraceptive and Reproductive Experiences (CARE) study, a multicenter case-control study of breast cancer among White and African-American women aged 35-64. The current analyses are based on data from 3,764 cases with known tumor hormone receptor status and 4,668 controls. The data were analyzed using unconditional logistic regression models with adjustment for potential confounders. Results: Multiparity and early age at first birth were associated with a lower relative risk for ER+PR+ tumors (p for trend=0.0001 and 0.01 respectively) but not for ER-PR- tumors (p for trend=0.27 and 0.85), whereas duration of breastfeeding was associated with lower relative risk for both receptor negative (p for trend=0.0002) and receptor positive tumors (p=0.004). Our results were consistent across subgroups of women defined by age (< 50 versus ≥50) and race. We found few significant differences by histologic subtype, although the strongest protective effect of multiparity was seen for mixed ductolobular tumors. Conclusion: Our results suggest that parity or multiparity and early age at first birth, but possibly not lactation, protect against breast cancer through hormonal mechanisms. These reproductive factors have similar protective effects on breast tumors of lobular and ductal origin.
Delays in Emergency Care and Mortality during Major U.S. Marathons
Authors: Anupam B. Jena, N. Clay Mann, Leia N. Wedlund, Andrew Olenski
Journal: New England Journal of Medicine (2017)

Large marathons frequently involve widespread road closures and infrastructure disruptions, which may create delays in emergency care for nonparticipants with acute medical conditions who live in proximity to marathon routes.We analyzed Medicare data on hospitalizations for acute myocardial infarction or cardiac arrest among Medicare beneficiaries (≥65 years of age) in 11 U.S. cities that were hosting major marathons during the period from 2002 through 2012 and compared 30-day mortality among the beneficiaries who were hospitalized on the date of a marathon, those who were hospitalized on the same day of the week as the day of the marathon in the 5 weeks before or the 5 weeks after the marathon, and those who were hospitalized on the same day as the marathon but in surrounding ZIP Code areas unaffected by the marathon. We also analyzed data from a national registry of ambulance transports and investigated whether ambulance transports occurring before noon in marathon-affected areas (when road closures are likely) had longer scene-to-hospital transport times than on nonmarathon dates. We also compared transport times on marathon dates with those on nonmarathon dates in these same areas during evenings (when roads were reopened) and in areas unaffected by the marathon.The daily frequency of hospitalizations was similar on marathon and nonmarathon dates (mean number of hospitalizations per city, 10.6 and 10.5, respectively; P=0.71); the characteristics of the beneficiaries hospitalized on marathon and nonmarathon dates were also similar. Unadjusted 30-day mortality in marathon-affected areas on marathon dates was 28.2% (323 deaths in 1145 hospitalizations) as compared with 24.9% (2757 deaths in 11,074 hospitalizations) on nonmarathon dates (absolute risk difference, 3.3 percentage points; 95% confidence interval, 0.7 to 6.0; P=0.01; relative risk difference, 13.3%). This pattern persisted after adjustment for covariates and in an analysis that included beneficiaries who had five or more chronic medical conditions (a group that is unlikely to be hospitalized because of marathon participation). No significant differences were found with respect to where patients were hospitalized or the treatments they received in the hospital. Ambulance scene-to-hospital transport times for pickups before noon were 4.4 minutes longer on marathon dates than on nonmarathon dates (relative difference, 32.1%; P=0.005). No delays were found in evenings or in marathon-unaffected areas.Medicare beneficiaries who were admitted to marathon-affected hospitals with acute myocardial infarction or cardiac arrest on marathon dates had longer ambulance transport times before noon (4.4 minutes longer) and higher 30-day mortality than beneficiaries who were hospitalized on nonmarathon dates. (Funded by the National Institutes of Health.).
Fas expression in osteosarcoma lung metastasis is correlated with chemotherapy prior to surgery
Authors: Nancy B. Gordon, Carola A. Arndt, Douglas S. Hawkins, Debra K. Doherty, Carrie Y. Inwards, Mark Munsell, Nadeshda Koshkina, Eugenie S. Kleinerman
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

4719 

Osteosarcoma (OS), a malignant bone tumor in children, metastasizes almost exclusively to the lung. Therapeutic options for patients with lung metastases are limited. Understanding the molecular mechanisms that contribute to the metastatic spread of OS in the lung is critical for the identification of new therapeutic approaches. Our previous investigations have shown that the Fas/FasL pathway plays an important role in the metastatic potential of OS cells. FasL is constitutively expressed in the pulmonary tissue. Thus, Fas+ cells appearing in the lung should be eliminated by engagement of FasL expressed on the surface of pneumocytes. Those tumor cells that do not express Fas can escape this internal defense mechanism. Using three different mouse model systems we have shown that OS lung metastases are Fas-. The purpose of this study was to determine the status of Fas expression in OS lung metastases from patients. Archived paraffin-embedded lung metastasis specimens from 38 OS patients were analyzed by immunohistochemistry. Patients were diagnosed initially with OS between January 1990 and December 2001, received multi-agent chemotherapy (most frequently consisting of cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide) and subsequently developed metastatic disease. Lung nodules from 23 of 38 (60%) patients were Fas-, those from 13 patients (34%) were weakly positive for Fas expression. The nodules from the remaining 2 patients were unable to be interpreted because of extensive necrosis. Eight patients had chemotherapy prior to metastatic tumor resection. Six of these 8 patients were among the weakly positive Fas group. There was a significant correlation between Fas expression and preoperative chemotherapy (p=0.0157). These data support our prior findings that Fas expression correlates inversely with metastatic potential. Similar to what we have observed in our mouse models, pulmonary metastases from OS patients were Fas-. Interestingly, the majority of patients that showed weakly positive Fas expression had received chemotherapy prior to lung resection. Indeed, cisplatin, etoposide, doxorubicin, and ifosfamide have all been shown to upregulate Fas expression in other tumor systems. Drug sensitivity has been shown to correlate with an intact Fas pathway. We, therefore, conclude that the ability of OS cells to metastasize to the lung (an organ that constitutively expresses FasL) may be linked to cell surface Fas. One mechanism by which chemotherapy may induce regression is through the upregulation of Fas.
Understanding the Role of Antibodies as Markers of Cancer-Associated Systemic Sclerosis: Comment on the Article by Shah et al
Authors: David Bernal‐Bello, Alfredo Guillén‐del Castillo, Albert Selva‐O'Callaghan, Vicent Fonollosa‐Pla, Jaime García de Tena, Carmen Pilar Simeón‐Aznar
Journal: Arthritis & Rheumatology (2017)
Separation of photoreceptor cell compartments in mouse retina for protein analysis
Authors: Kasey Rose, Steven T. Walston, Jeannie Chen
Journal: Molecular Neurodegeneration (2017)

Light exposure triggers movement of certain signaling proteins within the cellular compartments of the highly polarized rod photoreceptor cell. This redistribution of proteins between the inner and outer segment compartments affects the performance and physiology of the rod cell. In addition, newly synthesized phototransduction proteins traverse from the site of their synthesis in the inner segment, through the thin connecting cilium, to reach their destination in the outer segment. Processes that impede normal trafficking of these abundant proteins lead to cell death. The study of movement and unique localization of biomolecules within the different compartments of the rod cell would be greatly facilitated by techniques that reliably separate these compartments. Ideally, these methods can be applied to the mouse retina due to the widespread usage of transgenic mouse models in the investigation of basic visual processes and disease mechanisms that affect vision. Although the retina is organized in distinct layers, the small and highly curved mouse retina makes physical separation of retinal layers a challenge. We introduce two peeling methods that efficiently and reliably isolate the rod outer segment and other cell compartments for Western blots to examine protein movement across these compartments.The first separation method employs Whatman® filter paper to successively remove the rod outer segments from isolated, live mouse retinas. The second method utilizes ScotchTM tape to peel the rod outer segment layer and the rod inner segment layer from lyophilized mouse retinas. Both procedures can be completed within one hour.We utilize these two protocols on dark-adapted and light-exposed retinas of C57BL/6 mice and subject the isolated tissue layers to Western blots to demonstrate their effectiveness in detecting light-induced translocation of transducin (GNAT1) and rod arrestin (ARR1). Furthermore, we provide evidence that RGS9 does not undergo light-induced translocation.These results demonstrate the effectiveness of the two different peeling protocols for the separation of the layered compartments of the mouse retina and their utility for investigations of protein compositions within these compartments.
Idiopathic atrophoderma of Pasini and Pierini: A case study of collagen and elastin texture by multiphoton microscopy
Authors: Gislaine Vieira-Damiani, Denise Lage, Patrícia Érica Christofoletti Daldon, Caroline Romanelli Tibúrcio Alves, Maria Letícia Cintra, Konradin Metze, Javier Adur, Vitor B. Pelegati, Hernandes F. Carvalho, Carlos Lenz Cesar
Journal: Journal of the American Academy of Dermatology (2017)
Medical charity will help GPs defy government’s immigration crackdown
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The medical charity Doctors of the World is urging GPs to defy the government’s controversial push to make it easier for immigration officials to access NHS patients’ personal details. GPs should advise some patients not to register at practices with their home address, it says.

A new toolkit sets out how GPs and practice staff can keep their patients’ addresses off NHS records and act in line with NHS and General Medical Council rules on confidentiality (https://www.doctorsoftheworld.org.uk/news/medics-mobilise-against-nhs-patient-data-sharing).

Doctors of the World said that it had launched the “safe surgeries” toolkit amid growing concern that the government’s policy was deterring patients from seeking medical help and forcing doctors to act …
Abstract 205: Differing Cardiac Phenotypes Between PP1α and PP1β Heart-Specific Gene-Deleted Mice
Authors: Mannix Messier, Ruijie Liu, Jeffery Molkentin
Journal: Circulation Research (2012)

Background: Protein phosphatase 1 is the major protein serine/threonine phosphatase in nearly all mammalian tissues, where it consists of three isoforms PP1α, PP1β, and PP1γ. However, the redundant or specific roles of each isoform in the heart is not known Methods: Each PP1 isoform was conditionally deleted in the mouse heart using a Cre-loxP approach. LoxP sites were introduced into intron 1 and 3 of each PP1α and PP1β. Both loxP-targeted lines were bred with mice expressing β-myosin heavy chain promoter driven Cre to achieve isoform specific gene deletion in the heart. Echocardiography was performed in these mice at different ages. We also investigated protein phosphorylation status of selected PP1 targets that underlie cardiac contraction and calcium handling from the hearts of these deleted mice. Results: Heart-specific deletion of PP1α caused a reduction of fractional shortening and worsening of cardiac function. Two weeks after transaortic constriction (TAC), PP1α deleted mice had greater increases in heart-weight to body-weight ratio compared with control mice, suggesting that PP1α was important for proper cardiac compensation. Interestingly, however, combined deletion of both PP1α and PP1β rescued the cardiac performance defects observed in PP1α deleted mice. Mechanistically, we found that deletion of PP1αβ led to increased phospholamban serine 16 and threonine 17 phosphorylation compared to that of PP1α. In conclusion, we showed that PP1 isoforms play distinct roles in the heart in regulating contractility and compensation after pressure overload stimulation.
Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver
Authors: Reiner K.W. Mailer, Anton Gisterå, Konstantinos A. Polyzos, Daniel F.J. Ketelhuth, Göran K. Hansson
Journal: Circulation Research (2017)

The liver is the central organ that responds to dietary cholesterol intake and facilitates the release and clearance of lipoprotein particles. Persistent hypercholesterolemia leads to immune responses against lipoprotein particles that drive atherosclerosis. However, the effect of hypercholesterolemia on hepatic T-cell differentiation remains unknown.To investigate hepatic T-cell subsets upon hypercholesterolemia.We observed that hypercholesterolemia elevated the intrahepatic regulatory T (Treg) cell population and increased the expression of transforming growth factor-β1 in the liver. Adoptive transfer experiments revealed that intrahepatically differentiated Treg cells relocated to the inflamed aorta in atherosclerosis-prone low-density lipoprotein receptor deficient (Ldlr-/-) mice. Moreover, hypercholesterolemia induced the differentiation of intrahepatic, but not intrasplenic, Th17 cells in wild-type mice, whereas the disrupted liver homeostasis in hypercholesterolemic Ldlr-/- mice led to intrahepatic Th1 cell differentiation and CD11b+CD11c+ leukocyte accumulation.Our results elucidate a new mechanism that controls intrahepatic T-cell differentiation during atherosclerosis development and indicates that intrahepatically differentiated T cells contribute to the CD4+ T-cell pool in the atherosclerotic aorta.
Strategies for monitoring and combating resistance to combination kinase inhibitors for cancer therapy
Authors: Leanne G. Ahronian, Ryan B. Corcoran
Journal: Genome Medicine (2017)

Targeted therapies such as kinase inhibitors and monoclonal antibodies have dramatically altered cancer care in recent decades. Although these targeted therapies have improved patient outcomes in several cancer types, resistance ultimately develops to these agents. One potential strategy proposed to overcome acquired resistance involves taking repeat tumor biopsies at the time of disease progression, to identify the specific molecular mechanism driving resistance in an individual patient and to select a new agent or combination of agents capable of surmounting that specific resistance mechanism. However, recent studies sampling multiple metastatic lesions upon acquired resistance, or employing "liquid biopsy" analyses of circulating tumor DNA, have revealed that multiple, heterogeneous resistance mechanisms can emerge in distinct tumor subclones in the same patient. This heterogeneity represents a major clinical challenge for devising therapeutic strategies to overcome resistance. In many cancers, multiple drug resistance mechanisms often converge to reactivate the original pathway targeted by the drug. This convergent evolution creates an opportunity to target a common signaling node to overcome resistance. Furthermore, integration of liquid biopsy approaches into clinical practice may allow real-time monitoring of emerging resistance alterations, allowing intervention prior to standard detection of radiographic progression. In this review, we discuss recent advances in understanding tumor heterogeneity and resistance to targeted therapies, focusing on combination kinase inhibitors, and we discuss approaches to address these issues in the clinic.
Margaret McCartney: Cool and cute—but cost effective?
Authors: Margaret McCartney
Journal: BMJ (2017)

Scandinavia: home of IKEA, cycling, good jumpers, excellent television dramas, and fika . Confident enough in nationhood to welcome refugees and to generally interact intelligently with the rest of the world. We all want a little bit of Sweden, Finland, or Denmark for ourselves.

Now, the Scottish government has pledged “baby boxes” for newborns, emulating the famous Finland scheme. These cardboard boxes come with a mattress so that they can double as a bed, as well as various other products—a toy, a book, a thermometer. Some clothes, too, which are Scandi-cool: no gender constraining pink for girls and blue for boys. …
Immunotherapy in hematologic malignancies: past, present, and future
Authors: Annie Im, Steven Z. Pavletic
Journal: Journal of Hematology & Oncology (2017)

The field of immunotherapy in cancer treatments has been accelerating over recent years and has entered the forefront as a leading area of ongoing research and promising therapies that have changed the treatment landscape for a variety of solid malignancies. Prior to its designation as the Science Breakthrough of the Year in 2013, cancer immunotherapy was active in the treatment of hematologic malignancies. This review provides a broad overview of the past, present, and potential future of immunotherapy in hematologic malignancies.