Background: Cervical cancer incidence and mortality rates are high among women from Appalachia, y... more Background: Cervical cancer incidence and mortality rates are high among women from Appalachia, yet data do not exist on human papillomavirus (HPV) prevalence among these women. We examined the prevalence of genital HPV among Appalachian women and identified correlates of HPV detection. Methods: We report data from a case-control study conducted between January 2006 and December 2008 as part of the Community Awareness, Resources, and Education (CARE) Project. We examined HPV prevalence among 1116 women (278 women with abnormal Pap tests at study entry [cases], 838 women with normal Pap tests [controls]) from Appalachian Ohio. Analyses used multivariable logistic regression to identify correlates of HPV detection. Results: The prevalence of HPV was 43.1% for any HPV type, 33.5% for high-risk HPV types, 23.4% for low-risk HPV types, and 12.5% for vaccine-preventable HPV types. Detection of any HPV type was more common among women who were ages 18-26 (OR = 2.09, 95% CI: 1.26-3.50), current smokers (OR = 1.86, 95% CI: 1.26-2.73), had at least five male sexual partners during their lifetime (OR = 2.28, 95% CI: 1.56-3.33), or had multiple male sexual partners during the last year (OR = 1.98, 95% CI: 1.25-3.14). Similar correlates were identified for detection of a high-risk HPV type. Conclusions: HPV was prevalent among Appalachian women, with many women having a high-risk HPV type detected. Results may help explain the high cervical cancer rates observed among Appalachian women and can help inform future cervical cancer prevention efforts in this geographic region.
Purpose: Computed tomographic (CT) imaging was used to determine the displacement of stranded see... more Purpose: Computed tomographic (CT) imaging was used to determine the displacement of stranded seeds between day 0 and day 30 following prostate seed implants. Post-plan dosimetry was used to assess the dosimetric consequence of strand displacement. Methods and Materials: Between March 2006 and December 2009, 86 prostate seed implant patients had day 0 and day 30 post-plan CT imaging. Migrated strands were first identified by inspection of day 0 and day 30 scans. The exact distance of displacement was measured using 3-dimensional fusion software. Post-plan dosimetric analysis was performed using CMS software. Results: Of the 1550 strands placed, 23 strands exhibited substantial movement and these displacements occurred in 21 of the 86 cases. The measured distance of strand movement ranged from 0.31 cm to 3.44 cm, with mean displacement of 2.75 cm. Of the displaced strands, 15 strands moved away from the implant center while 8 strands moved toward the implant center. A comparison of changes in dosimetric parameters between day 0 and day 30 revealed expected increases in D90 related to resolution of prostate edema. When cases of strand displacement were compared with cases without displacement, there were no differences in D90 or V100 at day 0. At day 30, however, statistically significant decreases in D90 (96.8% vs 89.5%; P = .0061) and V100 (85.9% vs 82.2%; P = .046) were noted for cases with strand displacement. When the data were analyzed by looking at the change in dosimetric parameters over time for each individual case (eg, comparing the difference in D90 from day 0 to day 30 per patient) there was a trend toward decrease in D90 with displacement of the strands but this did not achieve statistical significance (P = .09). Conclusions: Stranded seeds show unexpected spatial instability in the craniocaudal dimension. Strand displacement may occur in approximately 1.5% of stranded sources placed and about 25% of Practical Radiation Oncology (2011) xx, xxx-xxx cases. One may expect mean decreases in D90 and V100 of about 7% and 3%, respectively, among cases exhibiting strand migration in the first month following seed implant. Resolution of prostate edema during the same time period accounts for an approximately 30% increase in D90 and V100.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2015
Highly conserved Inhibitors of DNA-Binding (ID1-ID4) genes encode multi-functional proteins whose... more Highly conserved Inhibitors of DNA-Binding (ID1-ID4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, ID2 and ID3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, ID2 and ID3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, ID2 and ID3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promote stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western world. The tran... more Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western world. The transition of androgen-dependent PCa to castration-resistant (CRPC) is a major clinical manifestation during disease progression and presents a therapeutic challenge. Our studies have shown that genetic ablation of inhibitor of differentiation 4 (Id4), a dominant-negative helix loop helix protein, in mice results in prostatic intraepithelial neoplasia lesions and decreased Nkx3.1 expression without the loss of androgen receptor (Ar) expression. ID4 is also epigenetically silenced in the majority of PCa. However, the clinical relevance and molecular pathways altered by ID4 inactivation in PCa are not known. This study investigates the effect of loss of ID4 in PCa cell lines on tumorigenicity and addresses the underlying mechanism. Stable silencing of ID4 in LNCaP cells (L-ID4) resulted in increased proliferation, migration, invasion, and anchorage-independent growth. An increase in the rate o...
As transcriptional regulators of basic helix-oop-helix (bHLH) transcription and non-bHLH factors,... more As transcriptional regulators of basic helix-oop-helix (bHLH) transcription and non-bHLH factors, the inhibitor of differentiation (Id1, Id2, Id3, and Id4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id1 regulates prostate cancer (PCa) cell proliferation, apoptosis, and androgen independence, but its clinical significance in PCa remains controversial. Moreover, there is lack of evidence on the expression of Id2 and Id3 in PCa progression. In this study we investigated the expression of Id2 and Id3 and reevaluated the expression of Id1 in PCa. We show that increased Id1 and Id3 protein expression is strongly associated with increasing grade of PCa. At the molecular level, we report that silencing either Id1 or Id3 attenuates cell cycle. Although structurally and mechanistically similar, our results show that both these proteins are noncompensatory at least in PCa progression. Moreover, through gene silencing approaches we show that Id1 and Id3 primarily attenuates CDKN1A (p21) and CDKN1B (p27), respectively. We also demonstrate that silencing Id3 alone significantly attenuates proliferation of PCa cells as compared with Id1. We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype.
Journal of Epidemiology and Community Health, 2004
To identify a credible explanation for the excessively high mortality associated with general pra... more To identify a credible explanation for the excessively high mortality associated with general practitioners who were flagged up by the Shipman inquiry. Retrospective analysis of routine data. Primary care. Two general practitioners in the West Midlands who were associated with an unacceptably high mortality of patients during 1993-2000. Observed and expected number of deaths and deaths in nursing homes. Preliminary discussions with the general practitioners highlighted deaths in nursing homes as a possible explanatory factor. No relation was found between the expected number of deaths and deaths in nursing homes in each year during 1993-2000 for either general practitioner. In contrast, the magnitude and shape of the curves of a cumulative sum plot for excess number of deaths (observed minus expected) in each year were closely mirrored by the magnitude and shape of the curves of the number of patients dying in nursing homes; and this was reflected in the high correlations (R2 = 0.87 and 0.89) between excess mortality and the number of deaths in nursing homes in each year for the general practitioners. These findings were supported by administrative data. The excessively high mortality associated with two general practitioners was credibly explained by a nursing home effect. General practitioners associated with high patient mortality, albeit after sophisticated statistical analysis, should not be labelled as having poor performance but instead should be considered as a signal meriting scientific investigation.
Data on near-elderly (ages 55-64) women&a... more Data on near-elderly (ages 55-64) women's access to and use of health care have been limited. In this study, we sought to examine the status of near-elderly women's health insurance coverage in the United States and how it may influence their use of health care services. A nationwide random sample of women aged 55-64 was drawn from the 2002 wave of the Health and Retirement Study. Descriptive statistics were calculated and multivariable regression analyses were performed to quantify the impact of insurance coverage on near-elderly women's use of outpatient services, inpatient services, and prescription medication over a 2-year period. In 2002, 9.4% of near-elderly women in the United States were uninsured and 15.4% had public coverage. Those who had coverage for a particular service were significantly more likely to use that service compared to women without coverage, with odds ratios ranging from 2.0-6.7 for services such as a physician visit, hospital stay, dental visit, and use of prescription medication. Among those who had at least one physician visit, near-elderly women who had some of the cost covered by insurance reported significantly more visits than women without coverage. Likewise, for near-elderly women regularly taking prescription medications, having more extensive coverage significantly increased their likelihood of medication adherence. The frequency of hospitalization was also higher for women who had complete coverage for the cost. The nature of a near-elderly woman's insurance coverage significantly affects her use of health care services. More attention is needed to improve the health care of near-elderly women with inadequate insurance coverage.
Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is a... more Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.
The complex mycobacterial cell envelope is recognized as a critical factor in our failure to cont... more The complex mycobacterial cell envelope is recognized as a critical factor in our failure to control tuberculosis, leprosy and other non-tuberculous pathogens. Although its composition has been extensively determined, many details regarding the organization of the envelope remain uncertain. This is particularly so for the non-covalently bound lipids, whose natural distribution may be disrupted by conventional biochemical or cytological techniques. In order to study the native organization of lipid domains in the mycobacterial envelope, we have applied a range of fluorescent lipophilic probes to live mycobacteria, including Mycobacterium smegmatis, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium gadium and Mycobacterium aurum, and analysed the resultant signals by fluorescence microscopy and digital image processing. Five key features were observed: (i) the presence of both envelope and intracellular lipid domains; (ii) differential localization of probes into these domains influenced predominantly by their hydrophobicity, as modelled by their calculated octanol:water partition coefficients and by their amphiphilicities; (iii) uneven distribution of lipophilic material in the envelope; (iv) selective labelling of septal regions of the envelope; and (v) modification of labelling patterns by additional treatments such as fluorescence quenching antibodies, detergents and solvents. Using this last approach, a coherent cell envelope lipid domain was demonstrated outside the cytoplasmic membrane and, for the first time, the proposed covalently linked mycolyl-arabinogalactan-peptidoglycan macromolecular complex was imaged directly. The use of fluorescent probes and high-resolution fluorescence microscopy has enabled us to obtain a coherent view of distinct lipid domains in mycobacteria. Further application of this approach will facilitate understanding of the role of lipids in the physiology of these organisms.
Background: The mechanisms that can restore biological activity of mutant p53 are an area of high... more Background: The mechanisms that can restore biological activity of mutant p53 are an area of high interest given that mutant p53 expression is observed in one third of prostate cancer. Here we demonstrate that Id4, an HLH transcriptional regulator and a tumor suppressor, can restore the mutant p53 transcriptional activity in prostate cancer cells. Methods: Id4 was over-expressed in prostate cancer cell line DU145 harboring mutant p53 (P223L and V274F) and silenced in LNCaP cells with wild type p53. The cells were used to quantitate apoptosis, p53 localization, p53 DNA binding and transcriptional activity. Immuno-precipitation/-blot studies were performed to demonstrate interactions between Id4, p53 and CBP/p300 and acetylation of specific lysine residues within p53.
The authors examined college students&amp... more The authors examined college students' perceptions regarding emergency contraception (EC) provision in light of the then pending U.S. Food and Drug Administration (FDA) decision about the over-the-counter (OTC) status of EC. We randomly sampled 7000 male and female students who were enrolled full-time at the University of Michigan during the winter 2006 semester. A total of 1585 (22.6%) students responded to our web-based survey and were included in these descriptive analyses. Nearly all (94%) respondents knew of EC. When asked whether EC should be made available OTC, 60% of respondents agreed, 23% disagreed, and 17% were unsure. If EC were to be made available OTC, 34% of respondents indicated that they (or their partner) would purchase EC in advance of need, and 44% stated that they would purchase it only after unprotected sexual intercourse or contraceptive failure. Advance discussion and provision of EC is underused. Only 10% of all female respondents indicated that their current healthcare provider had spoken to them about EC in a routine health visit, and just 5% of female respondents were offered a supply of EC in advance of need. Continued efforts are needed to ensure timely access to EC in this population.
Objective: Despite the controversy over expanding delivery options for emergency contraceptive pi... more Objective: Despite the controversy over expanding delivery options for emergency contraceptive pills (ECP), little is known about physicians' attitudes toward over-the-counter (OTC) provision of ECP, and prior research on physicians' practices often has focused on a single specialty. This study examined the attitudes and practices regarding advance provision and OTC status of ECP among physicians in five medical specialties likely to encounter patients in need of ECP.
Obstetrician/gynecologists (Ob/Gyn) and nurse practitioners (NP) are essential providers of prima... more Obstetrician/gynecologists (Ob/Gyn) and nurse practitioners (NP) are essential providers of primary and preventive care for their female patients. Therefore, colorectal cancer (CRC) screening should be part of their routine preventive practices. The purpose of our study is to evaluate the CRC screening practices of these providers. A self-administered survey was mailed to a national sample of 1130 Ob/Gyns and NPs to assess providers' demographics, current CRC screening practices, and familiarity with CRC guidelines. Three hundred thirty-six providers (29.7%) returned our survey (54% Ob/Gyns and 46% NPs). Three fourths of providers routinely performed screening for CRC, compared with 95% for breast and cervical cancer. Routine CRC screening was more common among Ob/Gyns (87.2%) than NPs (61.7%) (p < 0.001). Slightly over half of providers correctly identified the recommended age to begin CRC screening for the average-risk patient, with no significant difference between provider types. Overall, Ob/Gyns scored higher than NPs on a series of questions assessing CRC screening (p < 0.03). Several provider factors were found to be significantly associated with screening practices, including practicing >10 years (p < 0.01), practicing in a multispecialty group (2.62 times more likely), and having an older patient population (p < 0.001). Ob/Gyns and NPs underuse CRC screening compared with breast and cervical cancer screening and lack knowledge about appropriate use of CRC screening modalities. Opportunities to further educate Ob/Gyns and NPs should be sought to improve compliance with current CRC screening guidelines.
Background: The potential benefit in preventing pelvic floor disorders (PFDs) is a frequently cit... more Background: The potential benefit in preventing pelvic floor disorders (PFDs) is a frequently cited reason for requesting or performing cesarean delivery on maternal request (CDMR). However, for primigravid women without medical=obstetric indications, the lifetime cost-effectiveness of CDMR remains unknown, particularly with regard to lifelong pelvic floor consequences. Our objective was to assess the cost-effectiveness of CDMR in comparison to trial of labor (TOL) for primigravid women without medical=obstetric indications with a single childbirth over their lifetime, while explicitly accounting for the management of PFD throughout the lifetime. Methods: We used Monte Carlo simulation of a decision model containing 249 chance events and 101 parameters depicting lifelong maternal and neonatal outcomes in the following domains: actual mode of delivery, emergency hysterectomy, transient maternal morbidity and mortality, perinatal morbidity and mortality, and the lifelong management of PFDs. Parameter estimates were obtained from published literature. The analysis was conducted from a societal perspective. All costs and quality-adjusted life-years (QALYs) were discounted to the present value at childbirth. Results: The estimated mean cost and QALYs were $14,259 (95% confidence interval [CI] $8,964-$24,002) and 58.21 (95% CI 57.43-58.67) for CDMR and $13,283 (95% CI $7,861-$23,829) and 57.87 (95% CI 56.97-58.46) for TOL over the combined lifetime of the mother and the child. Parameters related to PFDs play an important role in determining cost and quality of life. Conclusions: When a woman without medical=obstetric indications has only one childbirth in her lifetime, costeffectiveness analysis does not reveal a clearly preferable mode of delivery.
To examine the incidence of meningococcal disease in a defined geographic area and relate this to... more To examine the incidence of meningococcal disease in a defined geographic area and relate this to rural/urban residence and material deprivation. Retrospective review of statutory notifications, laboratory records and death registrations from 1 January 1996 through 31 December 2001 in an English health area. Incidence of disease was analysed in two populations residing within the area, one rural and one urban. Deprivation was measured using the Townsend material deprivation score. Altogether, 183 cases of meningococcal disease were identified. Average annual incidence was significantly higher (P=0.019) in the urban area (8.8/10(5)) compared to the rural area (6.2/10(5)). In 1996, the relative risk (RR) was greater in the urban area (RR 3.20 95% CI 1.40-7.32) compared to the rural area. During the study period a significant upward trend in disease incidence in the rural area (chi2 for trend P=0.018) was identified whereas a non-significant decrease was observed in the urban area. In the urban area, but not in the rural area, increasing deprivation was strongly associated with increasing disease incidence (chi2 for trend P=0.00010). Meningococcal disease places a disproportionate disease burden on certain populations. Further research is required to identify measures to address the inequalities identified.
International Journal of Radiation Oncology*Biology*Physics, 2005
Purpose/Objective: Preoperative PSA velocity (PSAV), or the rate of PSA rise prior to diagnosis, ... more Purpose/Objective: Preoperative PSA velocity (PSAV), or the rate of PSA rise prior to diagnosis, has recently been shown to predict for risk of cancer death after radical prostatectomy (RP). We test the relative merit of known preoperative variables, including biopsy tumor volume indices and preoperative PSAV, to predict for relapse following RP. Materials/Methods: We reviewed the outcomes of 202 men with available preoperative annual PSAV data who underwent RP between 1989 and 2001. No patient received adjuvant androgen suppression prior to RP and all patients were pN0. Biopsy and surgical specimens were reviewed by a single pathologist: JEM. Univariate and multivariate analyses were performed for all clinical and biopsy variables with respect to relapse-free survival after RP. Results: Thirty-one patients relapsed after RP defined as biochemical failure (PSA Ն0.2 ng/mL) with a median time to failure of 16 months. Median follow-up was 48 months. Kaplan-Meier estimates of relapse-free survival at 5 years were 97% for patients with an annual PSAV Յ1.0 ng/mL compared to 75% for those with an annual PSAV Ͼ1.0 ng/mL (pϭ0.01), 89% compared to 73% for PSAV Յ2 vs. Ͼ2 (pϭ0.003) and 88% compared to 68% for PSAV Յ3 vs. Ͼ3 (pϭ0.005). Only PSAV and biopsy Gleason grade remained significant on multivariate analysis as a clinical predictor of relapse after RP . Patients with a pre-op PSAV Ͼ2 ng/mL/yr were more likely to be pT3 (28% vs. 13%; pϭ0.007), have positive margins (18% vs. 7%; pϭ0.01), have tumors Ͼ1cc (86% vs. 74%; pϭ0.05) and possess Ͼ10% grade 4/5 tumors (60% vs. 44%; pϭ0.04). Conclusions: The preoperative PSA velocity is a significant independent clinical factor, overpowering all other clinical factors but the biopsy Gleason grade in predicting for relapse after RP, and it also predicts for larger, more aggressive and more locally advanced tumors. Inclusion of preoperative PSAV will be useful in risk stratification and in patient selection for neo-adjuvant or adjuvant therapies as part of randomized clinical trials.
International Journal of Gynecology & Obstetrics, 2008
To determine general attitudes and approaches to complementary and alternative medicine (CAM) amo... more To determine general attitudes and approaches to complementary and alternative medicine (CAM) among physicians who care for gynecologic oncology patients. Surveys were mailed to members of the Society of Gynecologic Oncologists and the Michigan Oncology Group. Physicians were asked to rate their general attitude toward CAM. Surveys were obtained from 462 physicians. Gynecologic oncologists and female physicians were more likely to have positive attitudes toward CAM, and to believe that clinical care should integrate conventional and CAM practices, compared with other oncologists and male physicians. Discrepancies exist among oncologists regarding attitude and use of CAM in their practice. Education of physicians regarding the safety and efficacy of CAM modalities may ultimately improve patient care.
Introduction: Minnesota has the largest concentration of Somali refugees in the US, with populati... more Introduction: Minnesota has the largest concentration of Somali refugees in the US, with population estimates ranging from 25,000 to 60,000. In Somalia, the total fertility rate is high, at approximately seven live births, due in part to the high infant mortality rate of 125 per 1000 births. In Minnesota, Somali women experience lower infant mortality rates due to improved access to prenatal and postpartum care. With this trend, family planning has become a critical reproductive health issue for Somali women and the health care providers that serve them.
Background: Cervical cancer incidence and mortality rates are high among women from Appalachia, y... more Background: Cervical cancer incidence and mortality rates are high among women from Appalachia, yet data do not exist on human papillomavirus (HPV) prevalence among these women. We examined the prevalence of genital HPV among Appalachian women and identified correlates of HPV detection. Methods: We report data from a case-control study conducted between January 2006 and December 2008 as part of the Community Awareness, Resources, and Education (CARE) Project. We examined HPV prevalence among 1116 women (278 women with abnormal Pap tests at study entry [cases], 838 women with normal Pap tests [controls]) from Appalachian Ohio. Analyses used multivariable logistic regression to identify correlates of HPV detection. Results: The prevalence of HPV was 43.1% for any HPV type, 33.5% for high-risk HPV types, 23.4% for low-risk HPV types, and 12.5% for vaccine-preventable HPV types. Detection of any HPV type was more common among women who were ages 18-26 (OR = 2.09, 95% CI: 1.26-3.50), current smokers (OR = 1.86, 95% CI: 1.26-2.73), had at least five male sexual partners during their lifetime (OR = 2.28, 95% CI: 1.56-3.33), or had multiple male sexual partners during the last year (OR = 1.98, 95% CI: 1.25-3.14). Similar correlates were identified for detection of a high-risk HPV type. Conclusions: HPV was prevalent among Appalachian women, with many women having a high-risk HPV type detected. Results may help explain the high cervical cancer rates observed among Appalachian women and can help inform future cervical cancer prevention efforts in this geographic region.
Purpose: Computed tomographic (CT) imaging was used to determine the displacement of stranded see... more Purpose: Computed tomographic (CT) imaging was used to determine the displacement of stranded seeds between day 0 and day 30 following prostate seed implants. Post-plan dosimetry was used to assess the dosimetric consequence of strand displacement. Methods and Materials: Between March 2006 and December 2009, 86 prostate seed implant patients had day 0 and day 30 post-plan CT imaging. Migrated strands were first identified by inspection of day 0 and day 30 scans. The exact distance of displacement was measured using 3-dimensional fusion software. Post-plan dosimetric analysis was performed using CMS software. Results: Of the 1550 strands placed, 23 strands exhibited substantial movement and these displacements occurred in 21 of the 86 cases. The measured distance of strand movement ranged from 0.31 cm to 3.44 cm, with mean displacement of 2.75 cm. Of the displaced strands, 15 strands moved away from the implant center while 8 strands moved toward the implant center. A comparison of changes in dosimetric parameters between day 0 and day 30 revealed expected increases in D90 related to resolution of prostate edema. When cases of strand displacement were compared with cases without displacement, there were no differences in D90 or V100 at day 0. At day 30, however, statistically significant decreases in D90 (96.8% vs 89.5%; P = .0061) and V100 (85.9% vs 82.2%; P = .046) were noted for cases with strand displacement. When the data were analyzed by looking at the change in dosimetric parameters over time for each individual case (eg, comparing the difference in D90 from day 0 to day 30 per patient) there was a trend toward decrease in D90 with displacement of the strands but this did not achieve statistical significance (P = .09). Conclusions: Stranded seeds show unexpected spatial instability in the craniocaudal dimension. Strand displacement may occur in approximately 1.5% of stranded sources placed and about 25% of Practical Radiation Oncology (2011) xx, xxx-xxx cases. One may expect mean decreases in D90 and V100 of about 7% and 3%, respectively, among cases exhibiting strand migration in the first month following seed implant. Resolution of prostate edema during the same time period accounts for an approximately 30% increase in D90 and V100.
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2015
Highly conserved Inhibitors of DNA-Binding (ID1-ID4) genes encode multi-functional proteins whose... more Highly conserved Inhibitors of DNA-Binding (ID1-ID4) genes encode multi-functional proteins whose transcriptional activity is based on dominant negative inhibition of basic helix-loop-helix (bHLH) transcription factors. Initial animal models indicated a degree of compensatory overlap between ID genes such that deletion of multiple ID genes was required to generate easily recognizable phenotypes. More recently, new model systems have revealed alterations in mice harboring deletions in single ID genes suggesting complex gene and tissue specific functions for members of the ID gene family. Because ID genes are highly expressed during development and their function is associated with a primitive, proliferative cellular phenotype there has been significant interest in understanding their potential roles in neoplasia. Indeed, numerous studies indicate an oncogenic function for ID1, ID2 and ID3. In contrast, the inhibitor of differentiation 4 (ID4) presents a paradigm shift in context of well-established role of ID1, ID2 and ID3 in development and cancer. Apart from some degree of functional redundancy such as HLH dependent interactions with bHLH protein E2A, many of the functions of ID4 are distinct from ID1, ID2 and ID3: ID4 proteins a) regulate distinct developmental processes and tissue expression in the adult, b) promote stem cell survival, differentiation and/or timing of differentiation, c) epigenetic inactivation/loss of expression in several advanced stage cancers and d) increased expression in some cancers such as those arising in the breast and ovary. Thus, in spite of sharing the conserved HLH domain, ID4 defies the established model of ID protein function and expression. The underlying molecular mechanism responsible for the unique role of ID4 as compared to other ID proteins still remains largely un-explored. This review will focus on the current understanding of ID4 in context of development and cancer.
Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western world. The tran... more Prostate cancer (PCa) is the most commonly diagnosed cancer in men in the Western world. The transition of androgen-dependent PCa to castration-resistant (CRPC) is a major clinical manifestation during disease progression and presents a therapeutic challenge. Our studies have shown that genetic ablation of inhibitor of differentiation 4 (Id4), a dominant-negative helix loop helix protein, in mice results in prostatic intraepithelial neoplasia lesions and decreased Nkx3.1 expression without the loss of androgen receptor (Ar) expression. ID4 is also epigenetically silenced in the majority of PCa. However, the clinical relevance and molecular pathways altered by ID4 inactivation in PCa are not known. This study investigates the effect of loss of ID4 in PCa cell lines on tumorigenicity and addresses the underlying mechanism. Stable silencing of ID4 in LNCaP cells (L-ID4) resulted in increased proliferation, migration, invasion, and anchorage-independent growth. An increase in the rate o...
As transcriptional regulators of basic helix-oop-helix (bHLH) transcription and non-bHLH factors,... more As transcriptional regulators of basic helix-oop-helix (bHLH) transcription and non-bHLH factors, the inhibitor of differentiation (Id1, Id2, Id3, and Id4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id1 regulates prostate cancer (PCa) cell proliferation, apoptosis, and androgen independence, but its clinical significance in PCa remains controversial. Moreover, there is lack of evidence on the expression of Id2 and Id3 in PCa progression. In this study we investigated the expression of Id2 and Id3 and reevaluated the expression of Id1 in PCa. We show that increased Id1 and Id3 protein expression is strongly associated with increasing grade of PCa. At the molecular level, we report that silencing either Id1 or Id3 attenuates cell cycle. Although structurally and mechanistically similar, our results show that both these proteins are noncompensatory at least in PCa progression. Moreover, through gene silencing approaches we show that Id1 and Id3 primarily attenuates CDKN1A (p21) and CDKN1B (p27), respectively. We also demonstrate that silencing Id3 alone significantly attenuates proliferation of PCa cells as compared with Id1. We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype.
Journal of Epidemiology and Community Health, 2004
To identify a credible explanation for the excessively high mortality associated with general pra... more To identify a credible explanation for the excessively high mortality associated with general practitioners who were flagged up by the Shipman inquiry. Retrospective analysis of routine data. Primary care. Two general practitioners in the West Midlands who were associated with an unacceptably high mortality of patients during 1993-2000. Observed and expected number of deaths and deaths in nursing homes. Preliminary discussions with the general practitioners highlighted deaths in nursing homes as a possible explanatory factor. No relation was found between the expected number of deaths and deaths in nursing homes in each year during 1993-2000 for either general practitioner. In contrast, the magnitude and shape of the curves of a cumulative sum plot for excess number of deaths (observed minus expected) in each year were closely mirrored by the magnitude and shape of the curves of the number of patients dying in nursing homes; and this was reflected in the high correlations (R2 = 0.87 and 0.89) between excess mortality and the number of deaths in nursing homes in each year for the general practitioners. These findings were supported by administrative data. The excessively high mortality associated with two general practitioners was credibly explained by a nursing home effect. General practitioners associated with high patient mortality, albeit after sophisticated statistical analysis, should not be labelled as having poor performance but instead should be considered as a signal meriting scientific investigation.
Data on near-elderly (ages 55-64) women&a... more Data on near-elderly (ages 55-64) women's access to and use of health care have been limited. In this study, we sought to examine the status of near-elderly women's health insurance coverage in the United States and how it may influence their use of health care services. A nationwide random sample of women aged 55-64 was drawn from the 2002 wave of the Health and Retirement Study. Descriptive statistics were calculated and multivariable regression analyses were performed to quantify the impact of insurance coverage on near-elderly women's use of outpatient services, inpatient services, and prescription medication over a 2-year period. In 2002, 9.4% of near-elderly women in the United States were uninsured and 15.4% had public coverage. Those who had coverage for a particular service were significantly more likely to use that service compared to women without coverage, with odds ratios ranging from 2.0-6.7 for services such as a physician visit, hospital stay, dental visit, and use of prescription medication. Among those who had at least one physician visit, near-elderly women who had some of the cost covered by insurance reported significantly more visits than women without coverage. Likewise, for near-elderly women regularly taking prescription medications, having more extensive coverage significantly increased their likelihood of medication adherence. The frequency of hospitalization was also higher for women who had complete coverage for the cost. The nature of a near-elderly woman's insurance coverage significantly affects her use of health care services. More attention is needed to improve the health care of near-elderly women with inadequate insurance coverage.
Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is a... more Purpose: A germline microRNA binding site-disrupting variant, the KRAS-variant (rs61764370), is associated with an increased risk of developing several cancers. Because this variant is most strongly associated with ovarian cancer risk in patients from hereditary breast and ovarian families (HBOC), and with the risk of premenopausal triple negative breast cancer, we evaluated the association of the KRAS-variant with women with personal histories of both breast and ovarian cancer, referred to as double primary patients.
The complex mycobacterial cell envelope is recognized as a critical factor in our failure to cont... more The complex mycobacterial cell envelope is recognized as a critical factor in our failure to control tuberculosis, leprosy and other non-tuberculous pathogens. Although its composition has been extensively determined, many details regarding the organization of the envelope remain uncertain. This is particularly so for the non-covalently bound lipids, whose natural distribution may be disrupted by conventional biochemical or cytological techniques. In order to study the native organization of lipid domains in the mycobacterial envelope, we have applied a range of fluorescent lipophilic probes to live mycobacteria, including Mycobacterium smegmatis, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium gadium and Mycobacterium aurum, and analysed the resultant signals by fluorescence microscopy and digital image processing. Five key features were observed: (i) the presence of both envelope and intracellular lipid domains; (ii) differential localization of probes into these domains influenced predominantly by their hydrophobicity, as modelled by their calculated octanol:water partition coefficients and by their amphiphilicities; (iii) uneven distribution of lipophilic material in the envelope; (iv) selective labelling of septal regions of the envelope; and (v) modification of labelling patterns by additional treatments such as fluorescence quenching antibodies, detergents and solvents. Using this last approach, a coherent cell envelope lipid domain was demonstrated outside the cytoplasmic membrane and, for the first time, the proposed covalently linked mycolyl-arabinogalactan-peptidoglycan macromolecular complex was imaged directly. The use of fluorescent probes and high-resolution fluorescence microscopy has enabled us to obtain a coherent view of distinct lipid domains in mycobacteria. Further application of this approach will facilitate understanding of the role of lipids in the physiology of these organisms.
Background: The mechanisms that can restore biological activity of mutant p53 are an area of high... more Background: The mechanisms that can restore biological activity of mutant p53 are an area of high interest given that mutant p53 expression is observed in one third of prostate cancer. Here we demonstrate that Id4, an HLH transcriptional regulator and a tumor suppressor, can restore the mutant p53 transcriptional activity in prostate cancer cells. Methods: Id4 was over-expressed in prostate cancer cell line DU145 harboring mutant p53 (P223L and V274F) and silenced in LNCaP cells with wild type p53. The cells were used to quantitate apoptosis, p53 localization, p53 DNA binding and transcriptional activity. Immuno-precipitation/-blot studies were performed to demonstrate interactions between Id4, p53 and CBP/p300 and acetylation of specific lysine residues within p53.
The authors examined college students&amp... more The authors examined college students' perceptions regarding emergency contraception (EC) provision in light of the then pending U.S. Food and Drug Administration (FDA) decision about the over-the-counter (OTC) status of EC. We randomly sampled 7000 male and female students who were enrolled full-time at the University of Michigan during the winter 2006 semester. A total of 1585 (22.6%) students responded to our web-based survey and were included in these descriptive analyses. Nearly all (94%) respondents knew of EC. When asked whether EC should be made available OTC, 60% of respondents agreed, 23% disagreed, and 17% were unsure. If EC were to be made available OTC, 34% of respondents indicated that they (or their partner) would purchase EC in advance of need, and 44% stated that they would purchase it only after unprotected sexual intercourse or contraceptive failure. Advance discussion and provision of EC is underused. Only 10% of all female respondents indicated that their current healthcare provider had spoken to them about EC in a routine health visit, and just 5% of female respondents were offered a supply of EC in advance of need. Continued efforts are needed to ensure timely access to EC in this population.
Objective: Despite the controversy over expanding delivery options for emergency contraceptive pi... more Objective: Despite the controversy over expanding delivery options for emergency contraceptive pills (ECP), little is known about physicians' attitudes toward over-the-counter (OTC) provision of ECP, and prior research on physicians' practices often has focused on a single specialty. This study examined the attitudes and practices regarding advance provision and OTC status of ECP among physicians in five medical specialties likely to encounter patients in need of ECP.
Obstetrician/gynecologists (Ob/Gyn) and nurse practitioners (NP) are essential providers of prima... more Obstetrician/gynecologists (Ob/Gyn) and nurse practitioners (NP) are essential providers of primary and preventive care for their female patients. Therefore, colorectal cancer (CRC) screening should be part of their routine preventive practices. The purpose of our study is to evaluate the CRC screening practices of these providers. A self-administered survey was mailed to a national sample of 1130 Ob/Gyns and NPs to assess providers' demographics, current CRC screening practices, and familiarity with CRC guidelines. Three hundred thirty-six providers (29.7%) returned our survey (54% Ob/Gyns and 46% NPs). Three fourths of providers routinely performed screening for CRC, compared with 95% for breast and cervical cancer. Routine CRC screening was more common among Ob/Gyns (87.2%) than NPs (61.7%) (p < 0.001). Slightly over half of providers correctly identified the recommended age to begin CRC screening for the average-risk patient, with no significant difference between provider types. Overall, Ob/Gyns scored higher than NPs on a series of questions assessing CRC screening (p < 0.03). Several provider factors were found to be significantly associated with screening practices, including practicing >10 years (p < 0.01), practicing in a multispecialty group (2.62 times more likely), and having an older patient population (p < 0.001). Ob/Gyns and NPs underuse CRC screening compared with breast and cervical cancer screening and lack knowledge about appropriate use of CRC screening modalities. Opportunities to further educate Ob/Gyns and NPs should be sought to improve compliance with current CRC screening guidelines.
Background: The potential benefit in preventing pelvic floor disorders (PFDs) is a frequently cit... more Background: The potential benefit in preventing pelvic floor disorders (PFDs) is a frequently cited reason for requesting or performing cesarean delivery on maternal request (CDMR). However, for primigravid women without medical=obstetric indications, the lifetime cost-effectiveness of CDMR remains unknown, particularly with regard to lifelong pelvic floor consequences. Our objective was to assess the cost-effectiveness of CDMR in comparison to trial of labor (TOL) for primigravid women without medical=obstetric indications with a single childbirth over their lifetime, while explicitly accounting for the management of PFD throughout the lifetime. Methods: We used Monte Carlo simulation of a decision model containing 249 chance events and 101 parameters depicting lifelong maternal and neonatal outcomes in the following domains: actual mode of delivery, emergency hysterectomy, transient maternal morbidity and mortality, perinatal morbidity and mortality, and the lifelong management of PFDs. Parameter estimates were obtained from published literature. The analysis was conducted from a societal perspective. All costs and quality-adjusted life-years (QALYs) were discounted to the present value at childbirth. Results: The estimated mean cost and QALYs were $14,259 (95% confidence interval [CI] $8,964-$24,002) and 58.21 (95% CI 57.43-58.67) for CDMR and $13,283 (95% CI $7,861-$23,829) and 57.87 (95% CI 56.97-58.46) for TOL over the combined lifetime of the mother and the child. Parameters related to PFDs play an important role in determining cost and quality of life. Conclusions: When a woman without medical=obstetric indications has only one childbirth in her lifetime, costeffectiveness analysis does not reveal a clearly preferable mode of delivery.
To examine the incidence of meningococcal disease in a defined geographic area and relate this to... more To examine the incidence of meningococcal disease in a defined geographic area and relate this to rural/urban residence and material deprivation. Retrospective review of statutory notifications, laboratory records and death registrations from 1 January 1996 through 31 December 2001 in an English health area. Incidence of disease was analysed in two populations residing within the area, one rural and one urban. Deprivation was measured using the Townsend material deprivation score. Altogether, 183 cases of meningococcal disease were identified. Average annual incidence was significantly higher (P=0.019) in the urban area (8.8/10(5)) compared to the rural area (6.2/10(5)). In 1996, the relative risk (RR) was greater in the urban area (RR 3.20 95% CI 1.40-7.32) compared to the rural area. During the study period a significant upward trend in disease incidence in the rural area (chi2 for trend P=0.018) was identified whereas a non-significant decrease was observed in the urban area. In the urban area, but not in the rural area, increasing deprivation was strongly associated with increasing disease incidence (chi2 for trend P=0.00010). Meningococcal disease places a disproportionate disease burden on certain populations. Further research is required to identify measures to address the inequalities identified.
International Journal of Radiation Oncology*Biology*Physics, 2005
Purpose/Objective: Preoperative PSA velocity (PSAV), or the rate of PSA rise prior to diagnosis, ... more Purpose/Objective: Preoperative PSA velocity (PSAV), or the rate of PSA rise prior to diagnosis, has recently been shown to predict for risk of cancer death after radical prostatectomy (RP). We test the relative merit of known preoperative variables, including biopsy tumor volume indices and preoperative PSAV, to predict for relapse following RP. Materials/Methods: We reviewed the outcomes of 202 men with available preoperative annual PSAV data who underwent RP between 1989 and 2001. No patient received adjuvant androgen suppression prior to RP and all patients were pN0. Biopsy and surgical specimens were reviewed by a single pathologist: JEM. Univariate and multivariate analyses were performed for all clinical and biopsy variables with respect to relapse-free survival after RP. Results: Thirty-one patients relapsed after RP defined as biochemical failure (PSA Ն0.2 ng/mL) with a median time to failure of 16 months. Median follow-up was 48 months. Kaplan-Meier estimates of relapse-free survival at 5 years were 97% for patients with an annual PSAV Յ1.0 ng/mL compared to 75% for those with an annual PSAV Ͼ1.0 ng/mL (pϭ0.01), 89% compared to 73% for PSAV Յ2 vs. Ͼ2 (pϭ0.003) and 88% compared to 68% for PSAV Յ3 vs. Ͼ3 (pϭ0.005). Only PSAV and biopsy Gleason grade remained significant on multivariate analysis as a clinical predictor of relapse after RP . Patients with a pre-op PSAV Ͼ2 ng/mL/yr were more likely to be pT3 (28% vs. 13%; pϭ0.007), have positive margins (18% vs. 7%; pϭ0.01), have tumors Ͼ1cc (86% vs. 74%; pϭ0.05) and possess Ͼ10% grade 4/5 tumors (60% vs. 44%; pϭ0.04). Conclusions: The preoperative PSA velocity is a significant independent clinical factor, overpowering all other clinical factors but the biopsy Gleason grade in predicting for relapse after RP, and it also predicts for larger, more aggressive and more locally advanced tumors. Inclusion of preoperative PSAV will be useful in risk stratification and in patient selection for neo-adjuvant or adjuvant therapies as part of randomized clinical trials.
International Journal of Gynecology & Obstetrics, 2008
To determine general attitudes and approaches to complementary and alternative medicine (CAM) amo... more To determine general attitudes and approaches to complementary and alternative medicine (CAM) among physicians who care for gynecologic oncology patients. Surveys were mailed to members of the Society of Gynecologic Oncologists and the Michigan Oncology Group. Physicians were asked to rate their general attitude toward CAM. Surveys were obtained from 462 physicians. Gynecologic oncologists and female physicians were more likely to have positive attitudes toward CAM, and to believe that clinical care should integrate conventional and CAM practices, compared with other oncologists and male physicians. Discrepancies exist among oncologists regarding attitude and use of CAM in their practice. Education of physicians regarding the safety and efficacy of CAM modalities may ultimately improve patient care.
Introduction: Minnesota has the largest concentration of Somali refugees in the US, with populati... more Introduction: Minnesota has the largest concentration of Somali refugees in the US, with population estimates ranging from 25,000 to 60,000. In Somalia, the total fertility rate is high, at approximately seven live births, due in part to the high infant mortality rate of 125 per 1000 births. In Minnesota, Somali women experience lower infant mortality rates due to improved access to prenatal and postpartum care. With this trend, family planning has become a critical reproductive health issue for Somali women and the health care providers that serve them.
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Papers by Divya Patel