tbuckley/cabot-search huggingface dataset:
A role for FOXO1 in BCR–ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia
Authors: M Wagle, A M Eiring, M Wongchenko, S Lu, Y Guan, Y Wang, M Lackner, L Amler, G Hampton, M W Deininger, T O'Hare, Y Yan
Journal: Leukemia (2016)

Chronic myeloid leukemia (CML) patients who relapse on imatinib due to acquired ABL1 kinase domain mutations are successfully treated with second-generation ABL1-tyrosine kinase inhibitors (ABL-TKIs) such as dasatinib, nilotinib or ponatinib. However, ~40% of relapsed patients have uncharacterized BCR-ABL1 kinase-independent mechanisms of resistance. To identify these mechanisms of resistance and potential treatment options, we generated ABL-TKI-resistant K562 cells through prolonged sequential exposure to imatinib and dasatinib. Dual-resistant K562 cells lacked BCR-ABL1 kinase domain mutations, but acquired other genomic aberrations that were characterized by next-generation sequencing and copy number analyses. Proteomics showed that dual-resistant cells had elevated levels of FOXO1, phospho-ERK and BCL-2, and that dasatinib no longer inhibited substrates of the PI3K/AKT pathway. In contrast to parental cells, resistant cells were sensitive to growth inhibition and apoptosis induced by the class I PI3K inhibitor, GDC-0941 (pictilisib), which also induced FOXO1 nuclear translocation. FOXO1 was elevated in a subset of primary specimens from relapsed CML patients lacking BCR-ABL1 kinase domain mutations, and these samples were responsive to GDC-0941 treatment ex vivo. We conclude that elevated FOXO1 contributes to BCR-ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with BCR-ABL1 inhibition may represent a novel therapeutic approach.
Renal radionuclide studies
Authors: K. E. Britton, M. N. Maisey, A. J. W. Hilson
Journal: Clinical Nuclear Medicine (1991)

The easiest way to locate the kidneys is to feel for the lumbar spine and the costal margins following the line of the ribs medially and cranially. A disc 10 cm in diameter may then be set with its medial edge towards the lumbar spine and the lowest rib overlying a quarter of its surface. The kidneys move with respiration and with change of posture, falling forward in the prone and sitting forward positions, so investigations are best performed with the patient reclining. In this position the two kidneys are at approximately equal depths, less than 1 cm difference in 75% of cases. The actual depth of the kidney in any individual varies from 4 cm–11 cm, therefore it is usual to calculate individual renal function as a fraction or percentage of the total, and measure the total function separately to avoid the need to measure the absolute radiotracer content of each kidney. To correct for tissue attenuation, renal depth may be estimated directly or indirectly.
Vancomycin-resistant enterococcus (VRE) in pediatric oncology patients: An analysis of potential consequences of colonization and infection
Authors: I. J. Dunkel, A. Kosack, E. Riedel, T. E. Kiehn, T. N. Small, L. H. Wexler
Journal: Journal of Clinical Oncology (2007)

9537 Background: VRE colonization and infection have emerged as an issue for pediatric oncology patients, but little is known about the long-term risks following initial VRE positivity in this population. The purpose of this study was to determine the risk of subsequent VRE infection in colonized or infected pediatric oncology patients and to try to identify risk factors. Methods: A retrospective analysis was performed of the 57 pediatric oncology patients who had a positive VRE culture at MSKCC from 1996–2000 and subsequently received chemotherapy and/or radiation therapy. Patients whose only subsequent treatment was allogeneic stem cell transplantation were excluded. The incidence of subsequent VRE infection was calculated using a competing risk analysis accounting for death from non-VRE causes as a competing risk. Data regarding hypothesized risk factors for subsequent VRE infections were collected. Results: Ten of the 57 patients had subsequent VRE infection, but none was the primary cause of death. The cumulative incidence of subsequent infection was 14% (7–27%, 95% confidence interval) at 1 year and 16% (9–29%, 95% confidence interval) at 2 years. Eight developed their subsequent infection within 3 months; the other 2 occurred at 15 and 30 months. A formal analysis of risk factors was not attempted due to the small number of events; however, none of the hypothesized risk factors (initial VRE colonization versus infection, number of chemotherapy or radiation therapy regimens, number of neutropenic or mucositis episodes, number of hospitalizations, number of abdominal surgeries or stem cell transplantations) appeared to differ between those who developed a subsequent infection and those who did not. Conclusions: Pediatric oncology patients with VRE colonization or initial infection are at risk for subsequent VRE infection, particularly within the first 3 months of initial diagnosis of VRE positivity. No significant financial relationships to disclose.
Taking the biscuit
Authors: Tony Delamothe
Journal: BMJ (2016)

Connoisseurs of the perverse will need to look elsewhere for their kicks: England’s Cancer Drugs Fund ceases to exist in its current form from next month. The realisation of an election promise made in 2010, the fund has racked up costs of £1.27bn (€1.64bn; $1.8bn) in its possibly useless life. No data exist to show whether this sum has been spent wisely, both the House of Commons Public Accounts Committee and the National Audit Office concluded.

Nick Timmins identifies the fund as “the biggest single thing that has undermined the …
Profilin modulates sarcomeric organization and mediates cardiomyocyte hypertrophy
Authors: Viola Kooij, Meera C. Viswanathan, Dong I. Lee, Peter P. Rainer, William Schmidt, William A. Kronert, Sian E. Harding, David A. Kass, Sanford I. Bernstein, Jennifer E. Van Eyk, Anthony Cammarato
Journal: Cardiovascular Research (2016)

AimsHeart failure is often preceded by cardiac hypertrophy, which is characterized by increased cell size, altered protein abundance, and actin cytoskeletal reorganization. Profilin is a well-conserved, ubiquitously expressed, multifunctional actin-binding protein, and its role in cardiomyocytes is largely unknown. Given its involvement in vascular hypertrophy, we aimed to test the hypothesis that profilin-1 is a key mediator of cardiomyocyte-specific hypertrophic remodelling.
Bacterial Peptidoglycan Traverses the Placenta to Induce Fetal Neuroproliferation and Aberrant Postnatal Behavior
Authors: Jessica Humann, Beth Mann, Geli Gao, Philip Moresco, Joseph Ramahi, Lip Nam Loh, Arden Farr, Yunming Hu, Kelly Durick-Eder, Sophie A. Fillon, Richard J. Smeyne, Elaine I. Tuomanen
Journal: Cell Host & Microbe (2016)
Cell Damage by Near Ultraviolet Radiation: Role of DNA-Protein Cross-links&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: A. Eisenstark, S. Kovacs, J. Terry
Journal: JNCI Journal of the National Cancer Institute (1982)

Near UV radiation and hydrogen peroxide were found to act synergistically to damage bacteriophage (which contains only DNA and protein) and mammalian cells. DNA-protein cross-links are being considered as the critical molecular alteration that leads to biological damage.
Randomised crossover trial of telemonitoring in chronic respiratory patients (TeleCRAFT trial)
Authors: M Chatwin, G Hawkins, L Panicchia, A Woods, A Hanak, R Lucas, E Baker, E Ramhamdany, B Mann, J Riley, M R Cowie, A K Simonds
Journal: Thorax (2016)

<h3>Objective</h3> To assess the impact of home telemonitoring on health service use and quality of life in patients with severe chronic lung disease. <h3>Design</h3> Randomised crossover trial with 6 months of standard best practice clinical care (control group) and 6 months with the addition of telemonitoring. <h3>Participants</h3> 68 patients with chronic lung disease (38 with COPD; 30 with chronic respiratory failure due to other causes), who had a hospital admission for an exacerbation within 6 months of randomisation and either used long-term oxygen therapy or had an arterial oxygen saturation (SpO<sub>2</sub>) of &lt;90% on air during the previous admission. Individuals received telemonitoring (second-generation system) via broadband link to a hospital-based care team. <h3>Outcome measures</h3> Primary outcome measure was time to first hospital admission for an acute exacerbation. Secondary outcome measures were hospital admissions, general practitioner (GP) consultations and home visits by nurses, quality of life measured by EuroQol-5D and hospital anxiety and depression (HAD) scale, and self-efficacy score (Stanford). <h3>Results</h3> Median (IQR) number of days to first admission showed no difference between the two groups—77 (114) telemonitoring, 77.5 (61) control (p=0.189). Hospital admission rate at 6 months increased (0.63 telemonitoring vs 0.32 control p=0.026). Home visits increased during telemonitoring; GP consultations were unchanged. Self-efficacy fell, while HAD depression score improved marginally during telemonitoring. <h3>Conclusions</h3> Telemonitoring added to standard care did not alter time to next acute hospital admission, increased hospital admissions and home visits overall, and did not improve quality of life in chronic respiratory patients. <h3>Trial registration number</h3> NCT02180919 (ClinicalTrials.gov).
A trial of combination chemotherapy followed by hormonal therapy for previously untreated metastatic carcinoma of the prostate.
Authors: E J Seifter, P A Bunn, M H Cohen, R W Makuch, N R Dunnick, N Javadpour, H Bensimon, J L Eddy, J D Minna, D C Ihde
Journal: Journal of Clinical Oncology (1986)

We administered combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin to 25 previously untreated patients with metastatic prostate cancer in order to assess the efficacy of chemotherapy before any hormonal manipulation. Hormonal therapy was administered only after progression of disease to chemotherapy. All 25 patients were followed until time of death and all were able to receive hormonal therapy. We did not find substantially improved response rates when combination chemotherapy was applied before endocrine treatment since the 33% objective response rate to chemotherapy was only minimally higher than the response in our patients who had failed hormonal therapy and then received identical or similar chemotherapy. Furthermore, the introduction of intensive combination chemotherapy before hormonal therapy in our study did not result in any striking improvement in overall survival compared with patients who received initial hormonal therapy in many other studies. Responses to chemotherapy were not attributable to suppression of serum testosterone since all 12 patients with partial response (PR) or stable disease (SD) and four of seven patients with no response (NR) had normal testosterone levels at the time of response assessment. The initial use of chemotherapy did not adversely affect the expected high percentage of objective responses (68%) to subsequent hormonal manipulation. The frequency, duration, and quality of responses to hormonal therapy exceeded the responses to chemotherapy. The disappointing responses to chemotherapy reflect the very modest efficacy of even aggressively delivered cytotoxic agents.
Symposium: Current and future issues in hepatitis C treatment : Current and future issues in hepatitis C treatment: Non-responders and relapsers
Authors: Mark S Sulkowski
Journal: Clinical and Molecular Hepatology (2009)

The management of persons non-responsive to peginterferon and RBV therapy requires careful assessment of the liver disease stage and prior treatment course with respect to virologic response and tolerability. Re-treatment with interferon and RBV should be considered in persons with inadequate prior treatment andcorrectable factors as well as those with partial response to prior therapy (>2 log10 at week 12). However, during re-treatment, the milestone measure of treatment effectiveness is the achievement of an undetectable HCV RNA at re-treatment week 12; patients who do not have an undetectable HCV RNA level at this milestone should discontinue therapy. For patients who become undetectable, longer therapy (72 weeks) may increase the likelihood of SVR by reducing the rate of relapse. For patients who remain detectable, long-term interferon therapy is not uniformly recommended but may be considered in persons with baseline portal hypertension based on the findings of the EPIC3study. Persons with treatment failure should be referred to clinical trials of novel therapeutic agents.
Cervical cancer risk with the use of tumour necrosis factor inhibitors in rheumatoid arthritis: to worry or not to worry?
Authors: Jasvinder A Singh
Journal: Annals of the Rheumatic Diseases (2016)

Wadstrom et al studied whether tumour necrosis factor (TNF) inhibitors (TNFi) increase the risk of cervical neoplasia in patients with rheumatoid arthritis (RA)? 1 Study authors performed a nationwide study using Swedish databases.The main findings from the study were that biologicnaive women with RA had more screenings (HR=1.08;95% CI 1.06 to 1.10), were at greater risk of cervical intraepithelial neoplasia (CIN) 1 (HR=1.53;95% CI 1.23 to 1.89) and CIN 2-3 (HR=1.39;95% CI 1.16 to 1.66), but not of invasive cervical cancer (HR=1.09;95% CI 0.71 to 1.65), compared with the general Swedish female population without RA.Patients who initiated TNFi therapy had similar screening patterns (HR=1.01;95% CI 0.98 to 1.05), were not at increased risk of CIN 1 (HR=1.23;95% CI 0.87 to 1.74), but were at increased risk of CIN 2-3 (HR=1.36;95% CI 1.01 to 1.82), and invasive cervical cancer (HR=2.10;95% CI 1.04 to 4.23) compared with biologic-naive women with RA.The estimates for the association of TNFi use (incident or ongoing) with invasive cervical cancer were attenuated when the study period was restricted to 2006-2012 and the biologic-naive comparator restricted to those individuals who had received dispensing of two or more different conventional disease-modifying antirheumatic drugs (DMARDs), HR=1.36 (95% CI 0.59 to 3.13) and was absent when restricted to the new users of TNFi 2006 or later (only one case during 18 110 person-years).Study strengths were the use of Swedish national databases making it a populationbased study, linkage between various
Peroral endoscopic pyloromyotomy for primary pyloric stenosis
Authors: Khanh Pham, Asgaut Viste, Aly Dicko, Trygve Hausken, Jan Hatlebakk
Journal: Endoscopy (2015)

Primary pyloric stenosis (PPS) in adults is a rare condition. The symptoms are those of gastric outlet obstruction. The standard treatment is balloon dilation, pyloroplasty, or occasionally surgical distal gastrectomy [1]. Peroral endoscopic pyloromyotomy (POP) has been used to improve gastric emptying in selected patients with refractory gastroparesis due to diabetes [2] [3] or with gastric outlet obstruction following esophagectomy [4]. To the best of our knowledge, this is the first case in which POP was used to treat PPS.
Intensive Supportive Care plus Immunosuppression in IgA Nephropathy
Authors: Thomas Robert, Alexandra Cambier, Alexandre Hertig
Journal: New England Journal of Medicine (2016)

To the Editor: In their report on the Supportive versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy (STOP-IgAN) trial, Rauen et al. (Dec. 3 issue)1 provide an important contribution to therapeutic management in IgA nephropathy. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines suggest the initiation of systemic glucocorticoids when proteinuria persists above 1 g of urinary protein excretion per day despite intensive supportive care. The investigators concluded that immunosuppressive treatment had many adverse effects without benefit in patients with moderate proteinuria and chronic kidney disease stages 1 through 3. Nevertheless, the trial was not designed to test the hypothesis in patients who would theoretically benefit the most from the use of glucocorticoids on the basis of the prognostic criteria that are now available in this disease — namely, MEST scores (which measure mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis or adhesion, and tubular atrophy or interstitial fibrosis)2 and the presence of circulating immune complexes (galactose-deficient IgA1, antibodies against IgG galactose-deficient IgA1,3 and soluble CD894).5 In addition, thin-basement-membrane nephropathy, which occurs in 20% of patients with IgA nephropathy and constitutes an overlapping syndrome, should be distinguished in future basic and clinical research in this field.6 IgA nephropathy is the leading form of primary glomerulonephritis associated with end-stage renal failure, dialysis, and renal transplantation. We believe that the use of glucocorticoids should not be systematically abandoned. Thomas Robert, M.D. Alexandra Cambier, M.D. Urgences Nephrologiques et Transplantation Renale Paris, France thomas . robert@ tnn . aphp . fr Alexandre Hertig, M.D., Ph.D.
Abstract 2500: Left Ventricular Recovery in Peripartum Cardiomyopathy: Impact of Beta Blockade
Authors: Brittany A Palmer, Karen M Janosko, Charles McTiernan, Fred Sherman, Dennis M McNamara
Journal: Circulation (2007)

Introduction : Peripartum cardiomyopathy (PPCM) remains a major cause of maternal morbidity and mortality. PPCM is associated with acute myocardial dysfunction with a high rate of spontaneous recovery. For subjects with chronic non-ischemic cardiomyopathy, beta blockade (BB) increases left ventricular ejection fraction (LVEF), reverses remodeling and improves survival. The impact of beta blockade (BB) on recovery in acute inflammatory cardiomyopathy is less certain. We investigated the impact of BB on left ventricular recovery in a single center series of women with PPCM. Method: Thirty-six subjects with PPCM referred within the first six months post partum from 1994 to 2006 to the University of Pittsburgh Heart Failure Program were retrospectively reviewed. LVEF and LV diastolic diameter (LVEDD) were assessed by echocardiography at the time of referral (entry) and at approximately 6 and 12 months post partum. Medical therapy was assessed and LV recovery compared by treatment subset. Results: The mean age was 29.7 ± 6.9 years, gravida 2.9 ± 1.9, and para 2.3 ± 0.9. LVEF at presentation was 0.23 ± 0.09. Therapy at entry included ACE inhibitors in 95% of subjects Overall 19 (53%) subjects were not on BB at entry (Group A) while 17 were treated with BB (Group B). BB use differed based on year of presentation with 12% prior to January of 2000 and 80% post on BB therapy. Significant recovery was evident by 12 months by LVEF(0.23 ± 0.09 to 0.41 ± 0.16, p = 0.03)and LVEDD( 5.8 ± 0.9 to 5.3 ± 0.9, p = 0.01). Of note, recovery did not differ significantly by year of presentation or BB therapy(table ). Conclusion : Similar recovery was evident in subjects with PPCM treated with BB and recent historical controls not on therapy. While BB clearly plays an important role in treatment of women with chronic PPCM, they do not appear to enhance the probablity of spontaneous resolution. Impact of Beta Bockade on LV remodeling in PPCM
“Weighing in” on screening mammography
Authors: W. M. Sikov, D. Berz, G. Colvin, E. McCormack, S. Weitzen
Journal: Journal of Clinical Oncology (2008)

6523 Background. Obesity is associated with an increased risk of breast cancer in postmenopausal women. In previous studies, obesity has been associated with decreased utilization of screening mammography (SM). We examined the association between Body Mass Index (BMI) and compliance with recommended SM using data from the 2004 Behavioral Risk Factor Surveillance Survey (BRFSS). Patients and Methods. The BRFSS included 130,185 female participants, aged 40 and older, who were randomly selected to participate in the world's largest telephone survey. After weighted analysis, this is believed to be representative of 56,226,220 non-institutionalized US women in this age group. The primary endpoint was the proportion of women who underwent SM within the two years preceding the survey. Utilization of SM in normal weight women (BMI 18.5–24.99) was compared with underweight (<18.5), overweight (25–29.99) and women with obesity class I (30–34.99), class II (35–39.99) and class III (≥40) using logistic regression analysis. Results. The sample included 1.91% underweight, 37.91% normal weight, 30.15% overweight and 14.36%, 5.44% and 3.49% women in obesity classes I, II, and III, respectively. Adjusting for age, race, smoking status, general health perception, level of education, and income level, underweight women were less likely to comply with regular SM than normal weight women (OR 0.57; 95% CI, 0.48–0.68). In contrast, overweight women had a significantly higher rate of appropriate SM utilization (OR 1.08; 95% CI 1.01–1.15). Women with class I and class II obesity showed a statistically non- significant trend towards a higher utilization of SM (OR 1.08; 95% CI 0.99–1.18) and (OR 1.10; 95% CI 0.98–1.25), respectively, while women with class III obesity showed a non-significant trend (OR 0.97; 95% CI, 0.84–1.13) towards under-utilization of SM. Conclusion. We present a weighted analysis of the BRFSS, evaluating the association of BMI and compliance with recommended SM among women 40 years and older. These results may be generalized to the US population of women in this age range. Previous studies reporting under-utilization of SM in higher risk, overweight and obese women were not confirmed in this large population-based analysis. No significant financial relationships to disclose.
Population-based study of the incidence, mortality and prognostic factors of small cell carcinoma of the cervix: Analysis of the Surveillance, Epidemiology and End Results database
Authors: J. Chen, O. K. MacDonald, D. K. Gaffney
Journal: Journal of Clinical Oncology (2007)

5546 Background: Small cell carcinoma (SmC) is a rare histology of the cervix uteri that is generally associated with a poor prognosis. This is a population-based study of SmC using the Surveillance, Epidemiology and End Results (SEER). Methods: From 1977 to 2003, 290 women with SmC of the cervix uteri were identified. In addition, 27,527 patients with squamous cell carcinoma (SC) and 5231 with adenocarcinoma (AC) of the cervix were identified for comparison. The annual incidence of each histology was determined and examined for trend. The patient and disease characteristics at diagnosis were examined for each histology, and prognostic factors were evaluated for SmC. Mortality rates of SmC and other histologies were compared via log-rank tests. Results: Mean annual incidence of SmC was 0.03 per 100,000 women compared to 3.5 and 0.62 for SC and AC. A significant change in incidence was identified for SC and AC (p&lt;0.05), but not for SmC (p=0.595). Patients with SmC were more likely to be treated with radiotherapy and to present with more advanced stage, lymph node involvement and distant metastasis than SC and AC (p&lt;0.05). Survival rates for SmC at 2 and 5 years were 46.8% and 35.7%, which were worse compared to SC (HR 0.45; 95% CI: 0.36–0.57) and AC (HR 0.31; 95% CI: 0.25–0.39). The difference in survival is predominantly in patients with early stage, localized disease, and those treated with surgery ( Table ). Multivariate analysis of SmC, race, FIGO stage, age and hysterectomy alone significantly impacted prognosis (p&lt;0.05), while year of diagnosis, lymph node involvement, tumor size, marital status and other treatment modality did not. Conclusions: SmC is an uncommon histologic variant of cervix cancer associated with a worse prognosis compared to SC and AC with a predilection for metastasis at diagnosis. FIGO stage, age and race are prognostic factors for survival. [Table: see text] No significant financial relationships to disclose.