bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator‐Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy
Authors: Keil Stefanie , Matter Hans , Schönafinger Karl , Glien Maike , Mathieu Magali , Marquette Jean‐Pierre , Michot Nadine , Haag‐Diergarten Silke , Urmann Matthias , Wendler Wolfgang 
Published: March 2011

AbstractCompounds that simultaneously activate the peroxisome proliferator‐activated receptor (PPAR) subtypes PPARγ and PPARδ have the potential to effectively target dyslipidemia and type II diabetes in a single pharmaceutically active molecule. The frequently observed side effects of selective PPARγ agonists, such as edema and weight gain, are expected to be overcome by using partial instead of full agonists for this nuclear receptor family. Herein we report the discovery, synthesis, and optimization of a novel series of sulfonylthiadiazoles that are active as partial agonists. The initial compound 6 was discovered by high‐throughput screening as a moderate partial PPARδ agonist; its optimization was based on the X‐ray crystal structure in complex with PPARδ. In contrast to other PPARδ agonists, this ligand does not interact directly with residues from the activation helix AF‐2, which might be linked to its partial agonistic effect. Interestingly, the thiadiazole moiety fills a novel subpocket, which becomes accessible after moderate conformational rearrangement. The optimization was focused on introducing conformational constraints and replacing intramolecular hydrogen bonding interactions. Highly potent molecules with activity as dual partial PPARγ/δ agonists in the low nanomolar range were then identified. One of the most active members, compound 20 a, displayed EC50 values of 1.6 and 336 nM for PPARδ and γ, respectively. The X‐ray crystal structure of its complex with PPARδ confirms our design hypothesis. Compound 20 a clearly displayed in vivo activity in two chronic mice studies. Lipids were modified in a beneficial way in normolipidemic mice, and the development of overt diabetes could be prevented in pre‐diabetic db/db mice. However, body weight gain was similar to that observed with the PPARγ agonist rosiglitazone. Hence, active compounds from this series can be considered as valuable tools to elucidate the complex roles of dual PPARγ/δ agonists for potential treatment of metabolic syndrome.
Keynote address: The past, the present, the future
Authors: Ho Reginald C. S. 
Published: March 2011

AbstractLung cancer in women has replaced uterine cancer among the cancers causing the highest mortality in women. However, breast cancer remains a leading cause of death because of increasing incidence. Potential causes for the increase in both these diseases in women will be explored.An exciting development in recent years has been the clarification of the role of oncogenes in carcinogenesis. It appears that some cancers require multiple sequential mutations for malignant transformation to occur. This may be the model for the study of carcinogenesis. These developments in molecular genetics have important implications in screening, diagnosis, prevention, and in treatment strategies.We may be witnessing the beginning of the era of cell differentiation therapy. Retinoids have a potential for impacting on the treatment of neoplasms such as promyelocytic leukemia and oropharyngeal cancers. Understanding of the mechanism of cell differentiation may be forthcoming although molecular genetic studies.
An overview of screening and early detection of gynecologic malignancies
Authors: White Linda N. 
Published: March 2011

AbstractReducing the toll of gynecologic cancer not only requires improving treatment, but also incorporating cancer prevention and detection strategies into clinical practice. Reviewing vulvar, cervical, endometrial, and ovarian cancer—their associated risk factors, means of prevention and early detection, and signs and symptoms—alerts patients to the potential risks and the detection methods available. Discussing what behaviors, personal characteristics, family history, and exposures increase their risk; what behaviors reduce their risk; and what self‐examinations and professional examinations may improve early detection permits health care professionals to write prescriptions for health. Neither major expenditure nor reorganization is required to incorporate cancer prevention and detection into existing clinical practice. Health care professionals who follow screening and detection recommendations appropriate in their own lives issue a consistent message and help bring patients into an active and responsibility‐sharing partnership for better health.
Controversies in the management of low‐grade cervical intraepithelial neoplasia
Authors: Richart Ralph M. , Wright Thomas C. 
Published: March 2011

AbstractDuring the last 30 years, there have been major changes in the methods used to diagnose and manage cervical cancer precursors. Early detection of precursors through mass cytologic screening programs and the eradication of these precursors when detected are currently the cornerstone of policies aimed at reducing cervical cancer. These policies have been successful, resulting in a marked reduction in both the number of cases and deaths from cervical cancer in North America and Western Europe. Recently, however, significant controversy has arisen over several aspects of the diagnosis and management of cervical intraepithelial neoplasia (CIN). Two of the most important of these controversies are whether all patients with low‐grade CIN lesions require therapy and what is the appropriate role for the newly introduced loop electrosurgical excision procedure in managing patients with CIN. In this article, these controversies are reviewed with emphasis placed on how these controversies affect the practicing gynecologist.
Radical hysterectomy for invasive cervical cancer: A 25‐year prospective experience with the Miami technique
Authors: Averette Hervy E. , Nguyen Hoa N. , Donato Daniel M. , Penalver Manuel A. , Sevin Bernd‐Uwe , Estape Ricardo , Little William A. 
Published: March 2011

AbstractBackground. The Miami modification of the traditional Wertheim–Meigs radical hysterectomy was used to treat Stage IB–IIA cervical cancer in a 25‐year prospective study involving 978 patients.Methods. The modifications included: vaginal reconstruction and closure using bladder and rectosigmoid serosa, retroperitoneal drainage through abdominal suction catheters, and suspension of the denuded ureters with the ipsilateral obliterated hypogastric artery.Results. The overall corrected 5‐year survival rate was 90.1%, with a surgical mortality rate of 1.4% and an overall urinary fistula rate of 1.4%. This fistula rate was significantly better than a 4.4% incidence rate in a literature survey. Although not measured, the Miami modification appeared to lengthen the vagina.Conclusions. Therefore, it was concluded that radical hysterectomy with the Miami modifications can be done safely in most patients with Stage IB–IIA cervical cancer.
International federation of gynecology and obstetrics staging of endometrial cancer 1988
Authors: Mikuta John J. 
Published: March 2011

AbstractIn 1988, the International Federation of Gynecology and Obstetrics (FIGO) Cancer Committee changed the staging of endometrial carcinoma from a clinical one to a surgicopathologic one. The emphasis in the new FIGO system was changed to the pathologic findings in the uterus, cervix, adnexa, and pelvic and/or periaortic nodes, and peritoneal cytologic findings. The major changes in this staging system were (1) the use of the depth of myometrial invasion and (2) the identification of tumor cells in peritoneal cytologic examination and of invasion in the retroperitoneal lymph nodes. Preoperative endocervical curettage was no longer necessary. Currently, the high level of operability of patients with endometrial carcinoma makes this staging system a viable one, which will provide information about the need for additional treatment. The use of the grading system for the tumor also was refined to upgrade nuclear changes that were inappropriate for the architectural grade. In serous adenocarcinomas, clear cell adenocarcinomas, and squamous cell carcinomas, nuclear grading took precedence. Adenocarcinomas with squamous differentiation were graded according to the nuclear grade of the glandular component.
Virulence factors in endometrial cancer
Authors: Gusberg S. B. 
Published: March 2011

AbstractThe majority of endometrial cancers are relatively benign and curable; there is a subset of virulent tumors that demands recognition. Factors that must be evaluated include: tumor grade, ploidy, steroid receptors, myometrial invasion, lymph node status, extrauterine disease or positive peritoneal fluid, and certain special tumors. These tumors of special virulence include: papillary adenocarcinoma, papillary serous adenocarcinoma, adenosquamous carcinoma, and clear cell carcinoma. Virulent tumors (approximately 20%) require special consideration and special treatment.
Prognostic significance of hormone receptors in endometrial cancer
Authors: Creasman William T. 
Published: March 2011

AbstractBackground. Endometrial carcinoma is the most common femalé pelvic genital malignancy. Many studies suggest that approximately 75% of all endometrial cancers are clinical Stage I. More than 50% of cancer deaths are in patients with clinical Stage I disease. As a result, prognostic factors have been evaluated in an attempt to identify those patients with presumed early stage disease who will be at high risk for recurrence. Recently, hormone receptor status (estrogen [ER], progesterone [PR]) in endometrial cancer has been suggested to be a prognostic factor.Methods. Two hundred seventeen patients with Stage I and II endometrial cancers were evaluated for cytoplasmic steroid‐receptor status. These results were compared with other prognostic factors in both univariant and multivariant analysis.Results. When ER and PR and combined ER/PR status were analyzed separately, patients with receptor‐positive lesions had significantly better disease‐free survival than those with receptor‐negative lesions. The receptor status was also a significant independent prognostic factor when evaluated by stepwise proportional hazards regression analysis.Conclusions. Hormone receptor status in endometrial cancer appears to be an important prognostic factor.
Hormone‐replacement therapy in patients with breast cancer: A reappraisal
Authors: Disaia Philip J. 
Published: March 2011

AbstractBackground. It has been common practice to prohibit hormone‐replacement therapy (HRT) in patients with breast cancer. A reappraisal of this practice is necessary because hundreds of reports have established the benefits of HRT in coronary artery disease, osteoporosis, the serum lipid profile, and quality of life.Methods. An argument is presented to support the safety of HRT use in such patients in the absence of a prospective randomized study addressing these issues. This argument relies primarily on historical data.Results. There is no direct evidence that the use of HRT adversely affects patients who have previously been afflicted with breast cancer.Conclusions. A prospective randomized study is essential to resolve this issue. In the meantime, patients should be counseled regarding the theoretical adverse effects of HRT versus the proven beneficial effects and the final decision for its use rests with the patient.
The estrogenic activity of synthetic progestins used in oral contraceptives
Authors: Jordan V. Craig , Jeng M. H. , Catherino W. H. , Parker C. J. 
Published: March 2011

AbstractBackground. Oral contraceptives (OC) contain an orally active estrogen in combination with an orally active synthetic progestin derived from 19‐nortestosterone. OC have had an enormous positive impact on public health for the past three decades, and in the main, there has been a remarkably low incidence of troublesome side effects. Although estrogens are implicated in an increased incidence of breast and endometrial cancer, epidemiologic studies have not provided convincing evidence to support a direct correlation between OC use and an increase in breast cancer incidence. By contrast, OC do cause a decrease in the incidence of endometrial and ovarian carcinoma. During the past decade, several isolated reports have linked an increased incidence of breast cancer with the use of synthetic progestins. No mechanism for the proliferative potential of progestins has been offered. Therefore, the authors investigated this problem to formulate a hypothesis, based on laboratory data, that might be evaluated in populations at risk.Methods. The synthetic progestins (19‐nortestosterone derivatives) chosen for the study were norethynodrel, norethindrone, norgestrel (levonorgestrel), and gestodene. These were compared with the actions of medroxyprogesterone acetate (MPA). To determine whether the progestins produced their effects via the ER, the cells were transfected with a chloramphenicol acetyl transferase (CAT) reporter gene containing an estrogen response element only activated by ER.Results. The 19‐nortestosterone derivatives all stimulated the growth of estrogen receptor (ER)‐positive but not ER‐negative breast cancer cells in culture. Antiestrogens, but not the antiprogestin mifepristone (also known as RU 486), inhibited progestin‐stimulated cell proliferation. MPA did not stimulate cell proliferation. All the synthetic progestins that increased replication also activated CAT. Activation was blocked by antiestrogens but not by mifepristone; the synthetic progestin MPA was inactive.Conclusions. These studies provided direct evidence that some synthetic progestins exert estrogenic effects through the ER. The results demonstrated that progestins can have a dual effect on estrogen target tissues either to stimulate or differentiate cells. The results suggest that some beneficial estrogen‐like effects could be produced by synthetic progestins (e.g., bone preservation), but epidemiologic studies of OC use should focus of the “total estrogen” content to establish whether some formulations place some groups of women at greater risk of having breast cancer.
Age‐specific differences in the relationship between oral contraceptive use and breast cancer
Authors: Wingo Phyllis A. , Lee Nancy C. , Ory Howard W. , Beral Valerie , Peterson Herbert B. , Rhodes Philip 
Published: March 2011

AbstractBackground. Nearly all studies have suggested that the use of oral contraceptives (OC) is not associated with the aggregate risk of breast cancer diagnosed in women aged 20–54 years. Because of age‐specific differences in the breast cancer–parity relationship and because of age‐specific differences in other breast cancer risk factors, the Centers for Disease Control reexamined data from the Cancer and Steroid Hormone Study (CASH) to assess whether OC use has different effects on the risk of breast cancer at different ages of diagnosis.Methods. This population‐based case–control study was designed to examine the relationship between the use of OC and the risk of breast, ovarian, and endometrial cancer. CASH was conducted in eight geographic areas in the United States during 1980–1982. All participants were interviewed at home with a pretested standardized questionnaire including a calendar of life events and a photograph book of all pills marketed in the United States.Results. We found that the relationship between the risk of breast cancer and OC use appeared to vary by the age at diagnosis. Among women aged 20–34 years at diagnosis or interview, those who had ever used OC had a slightly increased risk of breast cancer (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.0–2.1) compared with women of the same ages who had never used OC. Among these women, there were no trends of increasing or decreasing risk with any measure of OC use. Among women aged 35–44 years, there was no association between OC use and breast cancer. Among women aged 45–54 years, those who used OC had a slightly decreased risk of breast cancer (OR, 0.9; 95% CI, 0.8–1.0). Among these women, risk estimates decreased significantly with increasing time since first and last use.Conclusions. Although the slightly increased risk estimates for the youngest women were compatible with findings by other investigators, the decreased risk estimates for the oldest women have not been described in as many studies. Available data provide no reasons to change prescribing practices or the use of OC that are related to the breast cancer risk.
Ovarian cancer screening
Authors: van Nagell John R. , Depriest Paul D. , Gallion Holly H. , Pavlik Edward J. 
Published: March 2011

AbstractBackground. Despite advances in evaluation and treatment, ovarian cancer mortality has decreased minimally during the past two decades. Most patients have advanced‐stage disease at diagnosis, and the prognosis is poor. As a result, there has been increasing interest in the development of methods for the early detection of ovarian cancer. To benefit from screening, a disease should (1) be a significant cause of mortality, (2) have a high prevalence in the screened population, (3) have a preclinical phase that can be detected by screening, and (4) be amenable to therapy, such that the survival rate of patients with early‐stage disease is significantly higher than that of patients with advanced‐stage disease. Ovarian cancer fulfills all of these criteria.Methods. An optimal screening method should be safe, easy to do, time efficient, and acceptable to the patients being screened. Most importantly, it should have a high sensitivity and specificity.Results. Currently, the most effective screening methods for ovarian cancer are serum CA 125 levels and transvaginal sonography (TVS). In screening studies, the serum CA 125 level has had a reasonably high specificity but a low sensitivity. Currently, approximately 8000 asymptomatic women have been screened with TVS. Ten primary ovarian cancers were detected, and all were Stage I lesions. Patients whose tumors were detected by TVS all have been cured by conventional treatment. TVS screening has resulted in a significant reduction in stage at detection and in the case‐specific death rate from ovarian cancer. In these studies, TVS has had a high sensitivity but only a moderate specificity. CA 125 level, Doppler flow sonography, and the use of a morphology index are being evaluated as methods to increase the specificity of TVS.Conclusions. A large multiinstitutional study is indicated to determine if annual TVS screening will cause a significant decrease in site‐specific mortality from ovarian cancer.
Prophylaxis in ovarian cancer
Authors: Barber Hugh R. K. 
Published: March 2011

AbstractThe only prophylaxis for ovarian cancer is oophorectomy, except in the very rare case when an ovarian cancer appears to arise from the mesothelial tissue of the abdominal cavity.It has been shown that women who have taken the oral contraceptive pill for 4 or 5 years decreases the incidence of ovarian cancer by approximately 40%. It is estimated that the oral contraceptive pill can prevent approximately 1500 ovarian cancers each year.The postmenopausal palpable ovary syndrome is simply the palpation of what is interpreted as a normal‐sized ovary in the premenopausal woman represents an ovarian tumor in the postmenopausal woman. It addresses the size and consistency and has nothing to do with the small cysts reported by the sonographer.A patient who has two first‐degree blood relatives or a mother, sister, or daughter who has developed ovarian cancer premenopausally is at high risk to develop ovarian cancer.Because ovarian cancer is the leading cause of death from gynecologic cancer, it is important to explore all options for prophylaxis in the prevention of ovarian cancer.
Intraperitoneal chemotherapy in the management of ovarian cancer
Authors: Markman Maurie , Reichman Bonnie , Hakes Thomas , Curtin John , Jones Walter , Lewis John L. , Barakat Richard , Rubin Stephen , Mychalczak Borys , Saigo Patricia , Almadrones Lois , Hoskins William 
Published: March 2011

AbstractDuring the past decade, intraperitoneal therapy of ovarian cancer has evolved from a pharmacologic model into an established treatment technique for women with this malignancy. Approximately 40% of patients with small‐volume residual ovarian cancer (microscopic disease or macroscopic tumor, ≤ 0.5 cm in maximum tumor diameter), after an objective response to initial organoplatinum‐based systemic chemotherapy, may have a surgically documented complete response to platinum‐based intraperitoneal chemotherapy. Patients who have not responded to systemic platinum administration rarely will respond to the drug given intraperitoneally, despite the presence of only small‐volume residual disease when this regional treatment strategy is used. Other agents with antineoplastic activity after intraperitoneal administration in women with ovarian cancer include mitoxantrone, taxol, alpha‐interferon and gamma‐interferon, and interleukin‐2. Although intraperitoneal therapy currently is being examined as a component of the initial chemotherapeutic program for patients with ovarian cancer, a precise role for regional drug delivery in this clinical setting remains to be defined.
Update on malignant ovarian germ cell tumors
Authors: Gershenson David M. 
Published: March 2011

AbstractThe evolution of therapy for malignant ovarian germ cell tumors has been one of the true success stories in oncology. This article reviews the major advances in this field, with emphasis on more recent developments. During the past two decades, the nomenclature and histologic criteria for the major histologic subtypes have been standardized. Although the role of secondary debulking is uncertain, it probably has merit in selected patients. The use of second‐look laparotomy should be limited as much as possible. Chemotherapeutic regimens have evolved to the current “gold standard” —the combination of bleomycin, etoposide, and cisplatin, with overall disease‐free survival rates of greater than 95%. For patients with metastatic dysgerminoma, chemotherapy has replaced radiation therapy as the treatment of choice. For those few patients who do not respond to first‐line therapy, the combination of vinblastine, ifosfamide, and cisplatin is the most popular regimen for the subset of platinum‐sensitive tumors. For those with platinum‐resistant tumors, dose intensification with autologous bone marrow rescue or Phase II drugs are being investigated. Studies on the late effects of treatment reveal that reproductive potential can be preserved in most young patients. In summary, although the progress in this field has been phenomenal, small incremental advances will continue to occur during the 1990s.