Symposium Agenda: 2016 University of Massachusetts and New England Area Librarian e-Science Symposium
Agenda for the 8th annual University of Massachusetts and New England Area Librarian e-Science Symposium, held Wednesday, April 6, 2016 at the University of Massachusetts Medical School, Worcester, MA.
Occurrence and predictors of recurrence after a first episode of acute venous thromboembolism: population-based Worcester Venous Thromboembolism Study
Venous thromboembolism (VTE) has multiple risk factors and tends to recur. Despite the benefits of anticoagulation, the prevalence of, and case-fatality rate associated with, recurrent VTE remains a concern after an acute episode; it is particularly high during the acute treatment phase. We sought to quantify the magnitude, identify predictors, and develop risk score calculator of recurrence within 3 years after first-time VTE. This was a population-based surveillance study among residents of central Massachusetts (MA), USA, diagnosed with an acute first-time pulmonary embolism and/or lower-extremity deep vein thrombosis from 1999 to 2009 in hospital and ambulatory settings in all 12 central MA hospitals. Medical records were reviewed and validated. The 2989 study patients were followed for 5836 person-years [mean follow-up 23.4 (median 30) months]. Mean age was 64.3 years, 44 % were men, and 94 % were white. The cumulative incidence rate of recurrent VTE within 3 years after an index VTE was 15 % overall, and 25, 13, and 13 % among patients with active cancer, provoked, or unprovoked VTE, respectively. Multivariable regression indicated that active cancer, varicose vein stripping, and inferior vena cava filter placement were independent predictors of recurrence during both 3-month and 3-year follow-up. A risk score calculator was developed based on the 3-month prognostic model. In conclusion, the rate of VTE recurrence over 3 years of follow-up remained high. The risk score calculator may assist clinicians at the index encounter in determining the frequency of clinical surveillance and appropriate outpatient treatment of VTE during the acute treatment phase.
Diet-responsive Gene Networks Rewire Metabolism in the Nematode Caenorhabditis elegans to Provide Robustness against Vitamin B12 Deficiency: A Dissertation
Maintaining cellular homeostasis is a complex task, which involves monitoring energy states and essential nutrients, regulating metabolic fluxes to accommodate energy and biomass needs, and preventing buildup of potentially toxic metabolic intermediates and byproducts. Measures aimed at maintaining a healthy cellular economy inherently depend on the composition of nutrients available to the organism through its diet. We sought to delineate links between dietary composition, metabolic gene regulation, and physiological responses in the model organism C. elegans.
As a soil-dwelling bacterivore, C. elegans encounters diverse bacterial diets. Compared to a diet of E. coli OP50, a diet of Comamonas aquatica accelerates C. elegans developmental rate, alters egg-laying dynamics and shortens lifespan. These physiological responses are accompanied by gene expression changes. Taking advantage of this natural, genetically tractable predator-prey system, we performed genetic screens i) in C. elegans to identify regulators of diet-responsive genes, and ii) in E. coli and Comamonas to determine dietary factors driving transcriptional responses in C. elegans. We identified a C. elegans transcriptional program that regulates metabolic genes in response to vitamin B12 content in the bacterial diet. Interestingly, several B12- repressed metabolic genes of unknown function are highly activated when B12- dependent propionyl-CoA breakdown is impaired, and inactivation of these genes renders animals sensitive to propionate-induced toxicity. We provide genetic and metabolomic evidence in support of the hypothesis that these genes form a parallel, B12-independent, β-oxidation-like propionate breakdown shunt in C. elegans, similar to the pathway utilized by organisms like yeast and plants that do not use vitamin B12.
Transcriptional Regulation of the Drosophila Peptidoglycan Sensor PGRP-LC by the Steroid Hormone Ecdysone: A Masters Thesis
Drosophila is host to the steroid hormone ecdysone, which regulates development and immune functions using a common group of transcription factors. Developmentally-induced ecdysone pulses activate the expression of the EcR, BR-C, HR46, Eip74EF, Eip75B, Eip78C, and Eip93F, which assume control of hundreds of other genes involved in the transition from larva to pupa stage. Many of the transcription factors are related to mammalian nuclear hormone receptors by homology. In addition to these transcription factors, the ecdysoneregulated GATA factors SRP and PNR are required for the proper expression of the peptidoglycan sensor PGRP-LC, which belongs to a conserved class of proteins in innate immunity. Although the transcriptional network has been elucidated in development, it is unclear why ecdysone control of PGRP-LC gene activity involves these nine transcription factors and how ecdysone is regulated in the context of an infection in vivo.
An ecdysone-activated enhancer was located upstream of the PGRP-LC locus using a reporter plasmid. Female flies that lacked the enhancer had reduced PGRP-LC expression, but survived infection. Male flies did not experience these changes. Therefore, PGRP-LC enhancer appears to be a female-specific cis-regulatory element. The lack of survival phenotype could be caused by using an improper injection site. Bioinformatics software was used to identify putative individual and overlapping binding sites for some transcription factors. Site-directed mutations of the motifs reduced PGRP-LC promoter activity without abolishing the signal. These results suggest that the transcription factors assemble at multiple locations on the PGRP-LC enhancer and form strong protein-protein bonds. Septic injury led to elevated ecdysone in whole flies, which could be a neuroendocrine response to stress similar to the mammalian system. Steroid hormone regulation of immune receptors is a common theme in humans and flies, and these results could advance our understanding of the transcriptional regulation of related genes and gender differences observed in innate immune responses at the transcriptional level.
Exploring the Role of FUS Mutants from Stress Granule Incorporation to Nucleopathy in Amyotrophic Lateral Sclerosis: A Dissertation
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by preferential motor neuron death in the brain and spinal cord. The rapid disease progression results in death due to respiratory failure, typically within 3-5 years after disease onset. While ~90% of cases occur sporadically, remaining 10% of ALS cases show familial inheritance, and the number of genes linked to ALS has increased dramatically over the past decade.
FUS/TLS (Fused in Sarcoma/ Translocated to liposarcoma) is a nucleic acid binding protein that may regulate several cellular functions, including RNA splicing, transcription, DNA damage repair and microRNA biogenesis. More than 50 mutations in the FUS gene are linked to 4% of familial ALS, and many of these may disrupt the nuclear localization signal, leading to variable amounts of FUS accumulation in the cytoplasm. However, the mechanism by which FUS mutants cause motor neuron death is still unknown.
The studies presented in this dissertation focused on investigating the properties of FUS mutants in the absence and presence of stress conditions. We first examined how ALS-linked FUS mutants behaved in response to imposed stresses in both cell culture and zebrafish models of ALS. We found that FUS mutants were prone to accumulate in stress granules in proportion to their degree of cytoplasmic mislocalization under conditions of oxidative stress, ER stress, and heat shock.
However, many FUS missense mutants are retained predominantly in the nucleus, and this suggested the possibility that these mutants might also perturb one or more nuclear functions. In a human cell line expressing FUS variants and in human fibroblasts from an ALS patient, mutant FUS expression was associated with enlarged promyelocytic leukemia nuclear bodies (PML-NBs) under basal condition. Upon oxidative insult with arsenic trioxide (ATO), PML-NBs in control cells increased acutely in size and were turned over within 12-24 h, as expected. However, PML-NBs in FUS mutant cells did not progress through the expected turnover but instead continued to enlarge over 24 h. We also observed a persistent accumulation of the transcriptional repressor Daxx and the 11S proteasome regulator in association with these enlarged PML-NBs. Furthermore, the peptidase activities of the 26S proteasome were decreased in FUS mutant cells without any changes in the expression of proteasome subunits.
These results demonstrate that FUS mutant expression may alter cellular stress responses as manifested by (i) accumulation of mutant FUS into stress granules and (ii) inhibition of PML-NB dynamics. These findings suggest a novel nuclear pathology specific to mutant FUS expression that may perturb nuclear homeostasis and thereby contribute to ALS pathogenesis.
Though symptoms such as loss of vision, decline in cognition and memory are evident during aging, the underlying processes that affect neuronal function during aging are not well understood. Unlike changes in other tissues and organs, age-related changes in the nervous system affect the overall physical, mental as well as social state of human beings. To start elucidating the molecular mechanisms underlying normal age-dependent brain decline, we have characterized structural neuronal changes occurring during Caenorhabditis elegans aging. Our analysis reveals distinct neuronal alterations that arise with age and that the types of changes and their age of onset are neuronal-type specific, highlighting the differential susceptibility of neurons to the stresses of life. We also find that these age-dependent neuronal changes are largely uncoupled from lifespan. As a first step towards understanding the neuropathological conditions manifested during senescence, we have characterized the role of the neuronal maintenance gene sax-7/L1CAM in normal C. elegans aging. Our comparison of age-related structural changes in the wild-type nervous system with that of sax-7 mutants, indicates that loss of function of sax-7 results in accelerated neuronal deterioration that mimics alterations occurring during normal aging. Conversely, overexpressing wild-type copies of SAX-7 delays some of the neuronal changes that accompany normal aging, indicating that SAX-7 plays a neuroprotective role. Additionally we find that x mechanical stress from body movements impacts the neuronal changes during adulthood. Taken together, our results give an entry point into the mechanisms of age-related neuroanatomical changes and neuronal protection.
Roles of Protein Arginine Methyltransferase 7 and Jumonji Domain-Containing Protein 6 in Adipocyte Differentiation: A Dissertation
Regulation of gene expression comprises a wide range of mechanisms that control the abundance of gene products in response to environmental and developmental changes. These biological processes can be modulated by posttranslational modifications including arginine methylation. Among the enzymes that catalyze the methylation, protein arginine methyltransferase 7 (PRMT7) is known to modify histones to repress gene expression. Jumonji domain-containing protein 6 (JMJD6) is a putative arginine demethylase that potentially antagonize PRMT7. However, the biological significance of these enzymes is not well understood. This thesis summarizes the investigation of both PRMT7 and JMJD6 in cell culture models for adipocyte differentiation. The results suggest that PRMT7 is not required for the differentiation, whereas JMJD6 is necessary for the differentiation by promoting the expression of the lineage determining transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancerbinding proteins (C/EBPs). The underlying mechanisms by which JMJD6 regulate differentiation involve transcriptional and post-transcriptional control of gene expression. Unexpectedly, the adipogenic function of JMJD6 is independent of its enzymatic activity. Collectively, the present research reveals a novel role of JMJD6 in gene regulation during the differentiation of adipocytes.
Insights into Melanocyte Regeneration and Melanoma Initiation Using the Zebrafish Model System: A Dissertation
During regeneration, cells must coordinate proliferation and differentiation to rebuild tissues that are lost. Understanding how source cells execute the regeneration process has been a longstanding goal in regenerative biology with implications in wound healing and cell replacement therapies. Melanocytes are pigment-producing cells in the skin of vertebrates that can be lost during hair graying, injury and disease-related depigmentation. Melanoma is an aggressive skin cancer that develops from melanocytes, and it is hypothesized that melanoma cells have properties that are similar to melanocyte stem cells.
To gain insight into melanocyte regeneration we set out to identify the source of regeneration melanocytes in adult zebrafish and the path through which progenitor cells reconstitute the pigment pattern. Using targeted cell ablation and single cell lineage-tracing analyses we identified that a majority of regeneration melanocytes arise through direct differentiation of mitfa-expressing progenitor cells. Concurrently, other mitfa-expressing cells divide symmetrically to generate additional mitfa-positive progenitors, thus maintaining regeneration capability. Using reporter assays and drug studies, we found that Wnt signaling gets turned on in progenitor cells during regeneration and Wnt inhibition after melanocyte ablation blocks regeneration. Based on our finding that Wnt signaling is active in differentiated melanocytes but not in the progenitor cells, we explored the role of Wnt signaling in tumor initiation. We found that approximately half of the melanomas are Wnt silent, and overexpression of dkk1b, a negative regulator of canonical Wnt signaling, accelerates melanoma onset.
This work defines an unappreciated contribution by direct differentiation in melanocyte regeneration and suggests a broader role for this process in the maintenance of epithelial sheets. This study also identifies a shared pathway between melanocyte progenitors and melanoma cells, which could be applicable to other cancers.
Eukaryotic DNA is incorporated into the nucleoprotein structure of chromatin. This structure is essential for the proper storage, maintenance, regulation, and function of the genomes’ constituent genes and genomic sequences. Importantly, cells generate discrete types of chromatin that impart distinct properties on genomic loci; euchromatin is an open and active compartment of the genome, and heterochromatin is a restricted and inactive compartment. Heterochromatin serves many purposes in vivo, from heritably silencing key gene loci during embryonic development, to preventing aberrant DNA repeat recombination. Despite this generally repressive role, the DNA contained within heterochromatin must still be repaired and replicated, creating a need for regulated dynamic access into silent heterochromatin. In this work, we discover and characterize activities that the ATP-dependent chromatin remodeling enzyme SWI/SNF uses to disrupt repressive heterochromatin structure.
First, we find two specific physical interactions between the SWI/SNF core subunit Swi2p and the heterochromatin structural protein Sir3p. We find that disrupting these physical interactions results in a SWI/SNF complex that can hydrolyze ATP and slide nucleosomes like normal, but is defective in its ability to evict Sir3p off of heterochromatin. In vivo, we find that this Sir3p eviction activity is required for proper DNA replication, and for establishment of silent chromatin, but not for SWI/SNF’s traditional roles in transcription. These data establish new roles for ATP-dependent chromatin remodeling in regulating heterochromatin.
Second, we discover that SWI/SNF can disrupt heterochromatin structures that contain all three Sir proteins: Sir2p, Sir3p and Sir4p. This new disruption activity requires nucleosomal contacts that are essential for silent chromatin formation in vivo. We find that SWI/SNF evicts all three heterochromatin proteins off of chromatin. Surprisingly, we also find that the presence of Sir2p and Sir4p on chromatin stimulates SWI/SNF to evict histone proteins H2A and H2B from nucleosomes. Apart from discovering a new potential mechanism of heterochromatin dynamics, these data also establish a new paradigm of chromatin remodeling enzyme regulation by nonhistone proteins present on the substrate.
Fireflies are beetles that generate yellow-green light when their luciferase enzyme activates and oxidizes its substrate, D-luciferin. This bioluminescent reaction is widely used as a sensitive reporter both in vitro and in vivo. However, the light-emitting chemistry is limited by the properties of the small molecule D-luciferin. Our lab has developed a panel of synthetic luciferin analogs that improve on the inherent characteristics of D-luciferin. My thesis work focuses on harnessing these novel substrates to further expand the utility and molecular understanding of firefly bioluminescence.
The first part of my thesis focuses on using synthetic luciferins to improve bioluminescence imaging beyond what is possible with D-luciferin. Our substrates emit red-shifted light compared to D-luciferin, bringing the wavelength to a range that is more able to penetrate through tissue, but at a cost of lower signal intensity. I developed mutant luciferases that increase the maximal photon flux with the synthetic luciferins over what is achievable with the wild-type luciferase, and furthermore discriminate between substrates based on their chemical structures. Additionally, I have expanded the bioluminescence toolkit by harnessing the intrinsic properties of the luciferins to non-invasively and specifically assay the activity of a single enzyme (fatty acid amide hydrolase) in live mice. Therefore, my work presents an effective way to generally improve upon bioluminescent reporters, but also to measure the activity of a specific enzyme of interest in the context of a living organism.
The second part of my thesis employs synthetic luciferins to more deeply probe the light-emitting chemistry of bioluminescence. Our synthetic substrates reveal latent luciferase activity from multiple luciferase homologs that are inactive with D-luciferin. These enzymes, the fatty acyl-CoA synthetases, are predicted to be luciferase’s evolutionary predecessors, but it was not clear how the light emitting chemistry originated. My work shows that the luciferase must activate the luciferin and provide oxygen access, but the light emitting chemistry is a fundamental property of that activated intermediate. In summary, the work described herein not only expands our understanding of firefly bioluminescence, but also broadens its practical applications to shine bioluminescent light on the dark corners of biology.
Interactions between 3´ untranslated regions (UTRs) and RNA-binding proteins (RBPs) play critical roles in post-transcriptional gene regulation. Metazoan genomes encode hundreds of RBPs and thousands of 3’ UTRs have been experimentally identified, yet the spectrum of interactions between 3´UTRs and RBPs remains largely unknown. Several methods are available to map these interactions, including protein-centered methods such as RBP immunoprecipitation (RIP) and cross-link immunoprecipitation (CLIP), yeast three-hybrid assays and RNAcompete. However, there is a paucity of RNA-centered approaches for assaying an RNA element of interest against multiple RBPs in a parallel, scalable manner.
Here, I present a strategy for delineating protein-RNA interaction networks using a gene centered approach. This approach includes annotating RBPs and identifying physical interactions between an RNA of interest and these RBPs using the Protein-RNA Interaction Mapping Assay (PRIMA). Few RBPs have been experimentally determined in most eukaryotic organisms. Therefore I show that existing RBP annotations can be supplemented using computational predictions of RNA binding domains (RBD) from protein sequences. A single RNA of interest can be tested using PRIMA against a library of RBPs constructed from these annotations. PRIMA utilizes the green fluorescent protein (GFP) in yeast as a reporter.
PRIMA is based on reconstitution of the interaction between the 5´ and 3´ ends of an mRNA, which increases mRNA stability and enhances translation. PRIMA recapitulates known and uncovers new interactions involving RBPs from human, Caenorhabditis elegans and bacteriophage with short RNA fragments and full-length 3´UTRs. The development of RBP prey libraries will enable the testing of 3´UTRs against the hundreds of RBPs, which is essential to gain broad insights into post-transcriptional gene regulation at a systems level.
Setting and Objectives: Carnegie Mellon University (CMU) recently planned and implemented a project to help CMU researchers get an Open Researcher and Contributor Identifier (ORCID) and to enable administrators to integrate the ORCIDs into university systems. This article describes and assesses the planning, performance, and outcome of this initiative, branded ORCID @ CMU.
Design and Methods: The article chronicles why and how ORCID was integrated at CMU, including the rationale for changes in strategic plans. It assesses researcher participation in the project using transaction log and content analyses, and the performance of the ORCID project team using recommendations in the Jisc ORCID project report, frankly reporting the team’s successes and failures. The article concludes with lessons learned that should inform ORCID integration projects and expectations at other institutions.
Results: The ORCID @ CMU web application was a great success. However, the project team did not allow enough time to prepare or devote enough attention to advocacy. The marketing message was not sufficiently persuasive and the marketing channels were not particularly effective. The overall participation rate in ORCID @ CMU was far below the target of 40%, though participation in many demographics exceeded the goal.
Conclusions: Strategic planning does not guarantee success. Secure more than lip service from senior administrators. Recruit champions from across the institution. Develop a message that resonates with researchers. Allow sufficient time to prepare. Empower the project manager. Start with the low hanging fruit. Develop special outreach to doctoral students and postdocs.
Low risk of ureteral obstruction with "deep" (dorsal/posterior) uterosacral ligament suture placement for transvaginal apical suspension
OBJECTIVE: Transvaginal uterosacral ligament fixation (USLF), often called "high" USLF, is associated with a 1.0% to 10.9% ureteral obstruction rate. Anatomic relations and pelvic rotation with positioning imply "high" (cephalad) suture placement may bring sutures closer to the ureter. We examined the ureteral obstruction rate with a "deep" (dorsal/posterior) uterosacral ligament suture placement modification of a standard USLF procedure.
STUDY DESIGN: At the University of Massachusetts and Tufts, 411 consecutive patients underwent Mayo culdoplasty utilizing > or = 3 uterosacral sutures placed "deep" bilaterally. Intraoperative cystoscopy was performed.
RESULTS: One patient (0.24% [.01%-1.35%]) had ureteral obstruction attributable to USLF. Two had obstruction secondary to concomitant procedures. Compared with previous published series, the odds of ureteral injury secondary to USLF was 4.6 times lower (95% CI 2.31-9.24; P < .0001).
CONCLUSION: Placement of USLF sutures "deep" (dorsal/posterior) increases the margin of safety for the ureter and, in this study, decreased the ureteral injury rate nearly 5-fold.
Phase II clinical trial of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant ovarian or primary peritoneal cancer: a gynecologic oncology group study
PURPOSE: Ixabepilone (BMS-247550) is a microtubule-stabilizing epothilone B analog with activity in taxane-resistant metastatic breast cancer. The Gynecologic Oncology Group conducted a phase II evaluation of the efficacy and safety of ixabepilone in patients with recurrent or persistent platinum- and taxane-resistant primary ovarian or peritoneal carcinoma.
PATIENTS AND METHODS: Patients with measurable platinum- and taxane-resistant ovarian or peritoneal carcinoma, defined as progression during or within 6 months of one prior course of treatment with each agent, received intravenous ixabepilone 20 mg/m(2) administered over 1 hour on days 1, 8, and 15 of a 28-day cycle. Results Of 51 patients entered, 49 were eligible. The objective response rate was 14.3% (95% CI, 5.9% to 27.2%), with three complete and four partial responses. Twenty patients (40.8%) had stable disease, whereas sixteen (32.7%) had increasing disease. The median time to progression was 4.4 months (95% CI, 0.8 to 32.6+ months); median survival was 14.8 months (95% CI, 0.8 to 50.0) months. Patients received a median of two treatment cycles (range, 1 to 29 cycles), and 18.4% of patients received > or = six cycles. Adverse effects included peripheral grade 2 (28.5%) and grade 3 (6.1%) neuropathy, grades 3 to 4 neutropenia (20.4%), grade 3 fatigue (14.3%), grade 3 nausea/emesis (22%), grade 3 diarrhea (10%), and grade 3 mucositis (4%).
CONCLUSION: Ixabepilone 20 mg/m(2) over 1 hour on days 1, 8, and 15 of a 28-day cycle demonstrates antitumor activity and acceptable safety in patients with platinum- and taxane-resistant recurrent or persistent ovarian or primary peritoneal carcinoma.
OBJECTIVE: Paediatric and adolescent gynecology (PAG) is an evolving subspecialty, with patients often having to travel large distances to access care. The goal of the present study was to assess whether Telehealth (TH) would be appropriate for PAG services in a tertiary care centre and to determine patient/family interest.
METHODS: The present study was a prospective observational study of patients who attended PAG clinics over the course of one year. Patient data collected on each visit included postal code, diagnosis, availability of a local hospital with TH, patient appropriateness for TH and patient/family reasons for accepting TH. Visits were stratified by diagnosis to determine if certain conditions were more amenable to TH.
RESULTS: From the total visits through the year (July 15, 2008 to July 15, 2009), 1541 (79.6%) patients were approached for participation; 8 (0.5%) declined. The final sample size was 1533 patient visits. Four hundred sixty-nine visits (30.6%) were potentially appropriate for TH based on geography. According to clinic physicians, only 51 of these 469 visits (10.9%) were appropriate for TH. The main reasons for being inappropriate were the need for physical examination (n=238, 57.0%), imaging (n=57, 13.6%), or issues regarding sexuality/privacy (n=45, 10.8%). Of the 51 appropriate visits, 28 patients/families (55.0%) expressed interest in TH. Of those not interested in TH, the main reasons included the desire for a face-to-face encounter and the need to coordinate with other health care appointments.
CONCLUSION: Of the patient visits considered for TH (based on the fact that patients lived a considerable distance from the hospital), 10.9% were deemed appropriate for TH by the PAG team, but 45.0% of families/patients in this group said they would prefer a traditional clinic visit. Currently, TH appears to be appropriate for only a small subset of patients/families.
Umbilical cord blood, the blood remaining in the umbilical cord at birth, can be collected at birth and be a source of stem cells for a patient in need of a bone marrow transplant. Obstetricians and other health care practitioners are recognized as a patient's primary source for medical information affecting the mother and her neonate and frequently are asked to provide education and guidance regarding options of private and public cord blood banking. As the use of cord blood continues to grow in medicine and research uncovers more potential for cord blood, cord blood banking has become an important resource. The Stem Cell Therapeutic and Research Act has provided funding to expand public banking initiatives in the United States and to create a more ethnically diverse inventory of units. Private storage is not advocated unless there is an identified need in the family such that banked cord blood would offer a benefit. A recent report outlined the challenges of increasing participation and inventory, particularly among minority groups. Obstetricians and other health care practitioners should have a primary role in efforts to increase awareness of umbilical cord blood donation and be involved in initiatives to expand current public banking activities.
To meet the challenges of providing affordable, efficient ultrasound training, a low-cost, portable personal ultrasound training simulator with structured curriculums and integrated assessment methods has been developed. By using extended image volumes for training, the realistic experience of scanning over a larger body surface is emulated.
Temsirolimus with or without megestrol acetate and tamoxifen for endometrial cancer: a gynecologic oncology group study
OBJECTIVES: To determine the response, toxicities, and progression free survival of a regimen of temsirolimus with or without hormonal therapy in the treatment of advanced, or recurrent endometrial carcinoma.
BACKGROUND: Preclinical evidence suggested that blockade of the PI3K/AKT/mTOR pathway might overcome resistance to hormonal therapy.
METHODS: We performed a randomized phase II trial of intravenous temsirolimus 25mg weekly versus the combination of weekly temsirolimus with a regimen of megestrol acetate 80 mg bid for three weeks alternating with tamoxifen 20mg bid for three weeks in women with recurrent or metastatic endometrial carcinoma.
RESULTS: There were 71 eligible patients who received at least one dose of therapy with 21 of these treated on the combination arm which was closed early because of an excess of venous thrombosis, with 5 episodes of deep venous thrombosis (DVT) and 2 pulmonary emboli. There were three responses observed in that arm (14%). A total of 50 eligible patients were treated on the single agent arm with 3 episodes of DVT and 11 responses (22%). Response rates were similar in patients with prior chemotherapy (7 of 29; 24%) and those with no prior chemotherapy (4 of 21; 19%). Two of four patients with clear cell carcinoma responded.
CONCLUSIONS: Adding the combination of megestrol acetate and tamoxifen to temsirolimus therapy did not enhance activity and the combination was associated with an excess of venous thrombosis. Temsirolimus activity was preserved in patients with prior adjuvant chemotherapy.
OBJECTIVES: Unplanned pregnancy is a public health problem in the United States, including in rural areas. Primary care physicians are the main providers of health care to women in rural areas and are uniquely positioned to help reduce unplanned pregnancy in rural women. This study documents provision of contraception by rural primary care physicians, focusing on the most effective, long acting methods, intrauterine devices (IUDs) and contraceptive implants.
METHODS: We surveyed all primary care physicians practicing in rural areas of Illinois and Wisconsin. Bivariate analysis was performed using chi squared and Fisher's exact test, and multivariable analysis was performed with logistic regression to determine factors associated with provision.
RESULTS: The response rate was 862 out of 2312 physicians (37%). Nine percent of respondents place implants and 35% place IUDs. Eighty-seven percent of physicians had not had training in implant placement, and 41% had not had training in IUD placement. In multivariable analysis, factors associated with placement of long acting contraception include provision of maternity care, and female gender of the physician. The most common reasons for not providing the methods were lack of training and perceived low demand from patients.
CONCLUSIONS: Many rural primary care providers do not place long acting contraceptive devices due to lack of training. Female physicians and those providing maternity care are the most likely to place these devices. Increased training for primary care physicians both during and after residency would help increase access to these options for women in rural areas.
Vulvar carcinoma is an uncommon tumor that is seen most often in older women. Subtle symptoms such as pruritus should prompt examination and targeted biopsy in all women as this disease can be successfully treated even in elderly, frail individuals. Vulvar cancer has a bimodal age distribution and is seen in both young and older women with risk factors including human papillomavirus (HPV) infection, smoking, and vulvar skin diseases (i.e., lichen sclerosus). This cancer is staged surgically, with an update in 2009 incorporating prognostic factors. The treatment of vulvar carcinoma has evolved to include more conservative surgical techniques that provide improved cure rates with emphasis on minimizing morbidity. Advanced and metastatic lesions are now treated with chemoradiation which produces substantial cure rates with decreased morbidity. Promising areas of research in vulvar cancer include refinement of sentinel lymph node biopsy, prevention of lymphedema, and preservation of sexual function following treatment.