Galectin-3 inhibition suppresses drug resistance, motility, invasion and angiogenic potential in ovarian cancer.

OBJECTIVE: Ovarian cancer is the most deadly gynecologic malignancy worldwide. Since the pathogenesis of ovarian cancer is incompletely understood, and there are no available screening techniques for early detection, most patients are diagnosed with advanced, incurable disease. In an effort to develop innovative and effective therapies for ovarian cancer, we tested the effectiveness of Galecti-3C in vitro. This is a truncated, dominant negative form of Galectin-3, which is thought to act by blocking endogenous Galectin-3. METHODS: We produced a truncated, dominant-negative form of Galectin-3, namely Galetic-3C. Ovarian cancer cell lines and primary cells from ovarian cancer patients were treated with Galectin-3C, and growth, drug sensitivity, and angiogenesis were tested. RESULT: We show, for the first time, that Galectin-3C significantly reduces the growth, motility, invasion, and angiogenic potential of cultured OC cell lines and primary cells established from OC patients. CONCLUSIONS: Our findings indicate that Galectin-3C is a promising new compound for the treatment of ovarian cancer.

Inclusion of women in FDA-regulated premarket clinical trials: A call for innovative and recommended action.

Women were historically excluded from clinical trials. Despite numerous guidance and policy, we are still seeing this exclusion throughout the research pipeline more than 40 years later. The progress that has been made to include women in clinical trials and to report data disaggregated by sex continues to be limited due to multiple factors. In this paper, we aim to review some of the current FDA funding, policies, and practice in regard to inclusion of biological sex and sociocultural gender variables. This paper provides some recommendations and actionable policies to ensure that women as well as men can benefit from the updated biomedical research and clinical trials designed to take these variables into account. Strong regulations and mandates should be in place to direct pharmaceutical companies and industry toward the inclusion of women in biomedical research instead of a series of guidelines and recommendations that have not led to sufficient progress. Additionally, regulatory agencies should be completely independent in their decision-making process. Provision of Food and Drug Administration (FDA) funding by industry user fee for instance, might compromise FDA's impartiality in the approval process. Finally, better oversight is needed by the FDA for the labeling of drugs. FDA has made a significant contribution to the progress that has been made to this date, however, some of the current action plans including the Drug Trial Snapshots need to be refined to be more responsive to the current needs.

Closing the gap: How women can benefit more from science, research, policies, and health services.

The consequences of the systemic errors in policies, research, and education that exclude women are still being faced. Consequently, women have higher morbidity and mortality rates in many conditions with high public health significance. Here we discuss important gaps in policy, research, and education that result in worse health outcomes for women.

Tracking human multiple myeloma xenografts in NOD-Rag-1/IL-2 receptor gamma chain-null mice with the novel biomarker AKAP-4.

BACKGROUND: Multiple myeloma (MM) is a fatal malignancy ranking second in prevalence among hematological tumors. Continuous efforts are being made to develop innovative and more effective treatments. The preclinical evaluation of new therapies relies on the use of murine models of the disease. METHODS: Here we describe a new MM animal model in NOD-Rag1null IL2rgnull (NRG) mice that supports the engraftment of cell lines and primary MM cells that can be tracked with the tumor antigen, AKAP-4. RESULTS: Human MM cell lines, U266 and H929, and primary MM cells were successfully engrafted in NRG mice after intravenous administration, and were found in the bone marrow, blood and spleen of tumor-challenged animals. The AKAP-4 expression pattern was similar to that of known MM markers, such as paraproteins, CD38 and CD45. CONCLUSIONS: We developed for the first time a murine model allowing for the growth of both MM cell lines and primary cells in multifocal sites, thus mimicking the disease seen in patients. Additionally, we validated the use of AKAP-4 antigen to track tumor growth in vivo and to specifically identify MM cells in mouse tissues. We expect that our model will significantly improve the pre-clinical evaluation of new anti-myeloma therapies.

Food and Drug Administration Beyond the 2001 Government Accountability Office Report: Promoting Drug Safety for Women.

A 2001 U.S. Government Accountability Office (GAO) report indicated 8 of 10 drugs withdrawn from the U.S. market between 1997 and 2000 posed greater risk to women than men. We examined drugs withdrawn from the market for safety-related reasons from January 1, 2001, to January 1, 2018. To be included, drugs must be listed as discontinued on Drugs@FDA and either listed in the Federal Register or cited in literature as being withdrawn for safety-related reasons. Biologics, over-the-counter products, and medical devices were excluded. During the 17-year time span, 19 drugs were withdrawn from the market for safety-related reasons, fewer drugs per year compared to the 3-year period examined in the GAO report. Food and Drug Administration (FDA) has not recommended the market removal of any drug approved since 2005 due to the time from the start of the Q wave to the end of the T wave (QT) interval prolongation resulting in torsades de pointes (TdP) or other abnormal heart rhythms. Furthermore, no drugs approved after the implementation of FDA's 2009 guidance on drug-induced liver injury (DILI) have been withdrawn because of hepatoxicity. All, but one of the drugs discontinued from the market for safety-related reasons during the period examined were approved between 1957 and 2002. TdP and DILI are two relevant examples of drug-induced adverse events posing greater risk to women than men. FDA has made measurable progress incorporating consideration of sex and gender differences into drug trial development and FDA review of these data, supporting inclusion of women in clinical trials, providing a comprehensive drug safety review, and advancing postmarket surveillance and risk assessment, thus strengthening FDA's ability to protect public health.

Nanotechnology and human health: risks and benefits.

Nanotechnology is expected to be promising in many fields of medical applications, mainly in cancer treatment. While a large number of very attractive exploitations open up for the clinics, regulatory agencies are very careful in admitting new nanomaterials for human use because of their potential toxicity. The very active research on new nanomaterials that are potentially useful in medicine has not been counterbalanced by an adequate knowledge of their pharmacokinetics and toxicity. The different nanocarriers used to transport and release the active molecules to the target tissues should be treated as additives, with potential side effects of themselves or by virtue of their dissolution or aggregation inside the body. Only recently has a systematic classification of nanomaterials been proposed, posing the basis for dedicated modeling at the nanoscale level. The use of in silico methods, such as nano-QSAR and PSAR, while highly desirable to expedite and rationalize the following stages of toxicological research, are not an alternative, but an introduction to mandatory experimental work.

Evaluation of Technical Competency in Healthcare Simulation (E-TeCHS) tool: a modified Delphi study.

Background: Graduates of simulation fellowship programmes are expected to have the ability to perform a variety of simulation specific skills at the time of graduation. Currently, simulation fellowship directors have access to tools to assess the ability of a fellow to debrief learners. However, there is no tool to assess a simulation fellow's competency in technical skills. The purpose of our manuscript was to develop and obtain content validation of a novel instrument designed to assess a simulation fellow's ability to perform the five core simulation technical skills. Methods: The study protocol was based on a methodology for content validation of curriculum consensus guidelines. This approach involves a three-step process, which includes the initial delineation of the curricular content. This was then followed by the validation of the curricular content using survey methodology and lastly obtaining consensus on modifications using Delphi methodology. Results: Two rounds of modified Delphi methodology were performed. Seventy-four respondents provided feedback on the round 1 survey and 45 respondents provided feedback on round 2. The final assessment tool has five elements and 16 subitems with four optional subitems. Conclusion: The Evaluation of Technical Competency in Healthcare Simulation tool provides an instrument developed from a national consensus of content experts. This tool provides simulation fellowship directors a method to evaluate fellows' competency in technical skills.

Generic and Brand-Name Thyroid Hormone Drug Use Among Commercially Insured and Medicare Beneficiaries, 2007 Through 2016.

CONTEXT: Generic drugs account for 9 out of 10 prescriptions dispensed in the United States but for a lower proportion of commonly prescribed thyroid hormone replacement therapies. OBJECTIVE: Characterize temporal patterns of generic and brand-name thyroid hormone drug use, including patient and prescriber characteristics associated with brand-name use. DESIGN AND SETTING: Cross-sectional longitudinal analysis of national data from a large administrative claims database from January 2007 through December 2016. PATIENTS: Adults with insurance coverage through commercial, Medicare Advantage, and Medicare Part D health plans. MAIN OUTCOME MEASURES: Generic and brand-name thyroid hormone drug use. RESULTS: From 2007 to 2016, the annual number of thyroid hormone treatment pharmacy fills increased from 8,905,836 in 2007 to 11,613,923 in 2016, 73.6% of which were for generic levothyroxine, 23.4% for brand-name levothyroxine, and the remaining for other formulations. Dispensing of generic thyroid hormone drugs increased from 59.8% in 2007 to 84.9% in 2016 and was consistently higher among Medicare Advantage and Medicare Part D when compared with the commercial beneficiary population. For all three beneficiary populations, use of brand-name products was less common among older adults and more common among women and those receiving prescriptions from endocrinologists and was more common among those of white race and with greater household income for the Medicare Advantage and commercial beneficiary populations (P < 0.001). CONCLUSIONS: Brand-name thyroid hormone product use declined from 2007 to 2016 among three large, national insurer beneficiary populations. Although certain patient characteristics were associated with brand-name use, prescriber specialty was the strongest predictor.

The pituitary tumor transforming gene 1 (PTTG-1): an immunological target for multiple myeloma.

BACKGROUND: Multiple Myeloma is a cancer of B plasma cells, which produce non-specific antibodies and proliferate uncontrolled. Due to the potential relapse and non-specificity of current treatments, immunotherapy promises to be more specific and may induce long-term immunity in patients. The pituitary tumor transforming gene 1 (PTTG-1) has been shown to be a novel oncogene, expressed in the testis, thymus, colon, lung and placenta (undetectable in most other tissues). Furthermore, it is over expressed in many tumors such as the pituitary adenoma, breast, gastrointestinal cancers, leukemia, lymphoma, and lung cancer and it seems to be associated with tumorigenesis, angiogenesis and cancer progression. The purpose was to investigate the presence/rate of expression of PTTG-1 in multiple myeloma patients. METHODS: We analyzed the PTTG-1 expression at the transcriptional and the protein level, by PCR, immunocytochemical methods, Dot-blot and ELISA performed on patient's sera in 19 multiple myeloma patients, 6 different multiple myeloma cell lines and in normal human tissue. RESULTS: We did not find PTTG-1 presence in the normal human tissue panel, but PTTG-1 mRNA was detectable in 12 of the 19 patients, giving evidence of a 63% rate of expression (data confirmed by ELISA). Four of the 6 investigated cell lines (66.6%) were positive for PTTG-1. Investigations of protein expression gave evidence of 26.3% cytoplasmic expression and 16% surface expression in the plasma cells of multiple myeloma patients. Protein presence was also confirmed by Dot-blot in both cell lines and patients. CONCLUSION: We established PTTG-1's presence at both the transcriptional and protein levels. These data suggest that PTTG-1 is aberrantly expressed in multiple myeloma plasma cells, is highly immunogenic and is a suitable target for immunotherapy of multiple myeloma.

Smoking status as a predictor of hip fracture risk in postmenopausal women of northwest Texas.

INTRODUCTION: The purpose of this study was to determine the effect of cigarette smoking on the risk of hip fracture for postmenopausal women living in rural and urban areas of Northwest Texas. METHODS: Using an unmatched case-control design, we compared postmenopausal women who had recently experienced osteoporotic hip fracture with women who had not. Both study groups completed a questionnaire on demographic, clinical, and behavioral risk factors for osteoporotic hip fracture. We categorized smoking status as never smoked, former smoker, and current smoker. Covariates included age, weight, age at menopause, physical activity, estrogen replacement, calcium supplementation, and rurality. We used univariate and multivariate logistic regressions to test the associations between hip fracture and the independent variables of interest. RESULTS: We found an increased risk of hip fracture for former smokers (adjusted odds ratio [OR], 2.27; 95% confidence interval [CI], 1.22-4.21) and current smokers (adjusted OR, 3.72; 95% CI, 1.59-8.70). Residence in a rural county (population <100,000) also was associated with increased risk (adjusted OR, 2.71; 95% CI, 1.48-4.95). CONCLUSION: Former and current smoking increased the risk of hip fracture in this population of postmenopausal women.

Update on nonhormonal approaches to menopausal management.

The risk-benefit evaluation for managing vasomotor symptoms and other menopause-related health issues should be tailored to each individual woman, taking into account her own assessment of the most bothersome symptom(s) and her personal weighting of risks versus quality of life. For most symptomatic menopausal women, hormone therapy (HT) remains the best treatment, but various nonhormonal options are available for treating menopausal symptoms and bone loss in women who are unable or unwilling to take HT. Low doses of local vaginal estrogen remain an option for treatment of vaginal atrophy in these women. This article reviews alternatives to systemic HT for treating menopausal symptoms and related health issues.

Working Together to Address Women's Health in Research and Drug Development: Summary of the 2017 Women's Health Congress Preconference Symposium.

Historically, women have been underrepresented in clinical research, requiring physicians to extrapolate medical recommendations for women from clinical research done in cohorts consisting predominantly of male participants. While government-funded clinical research has achieved gender parity in phase-3 clinical trials across many biomedical disciplines, improvements are still needed in several facets of women's health research, such as the inclusion of women in early-phase clinical trials, the inclusion of pregnant women and women with physical and intellectual disabilities, the consideration of sex as a biological variable in preclinical research, and the analysis and reporting of sex and gender differences across the full biomedical research continuum. The National Institutes of Health (NIH) Office of Research on Women's Health and the Office of Women's Health of the U.S. Food and Drug Administration (FDA) cosponsored a preconference symposium at the 25th Annual Women's Health Congress, held in Arlington, VA in April, 2017, to highlight gains made and remaining needs regarding the representation of women in clinical research, to introduce innovative procedures and technologies, and to outline revised policy for future studies. Six speakers presented information on a range of subjects related to the representation of women in clinical research and federal initiatives to advance precision medicine. Topics included the following: the return on investment from the NIH-funded Women's Health Initiative; progress in including women in clinical trials for FDA-approved drugs and products; the importance of clinical trials in pregnant women; FDA initiatives to report drug safety during pregnancy; the NIH-funded All of Us Research Program; and efforts to enhance FDA transparency and communications, including the introduction of Drug Trials Snapshots. This article summarizes the major points of the presentations and the discussions that followed.

Participation of Women in Clinical Trials Supporting FDA Approval of Cardiovascular Drugs.

BACKGROUND: Concerns exist that women are underrepresented in trials of cardiovascular medications. OBJECTIVES: The authors sought to examine women's participation and the reported safety and efficacy by gender for pivotal cardiovascular disease (CVD) trials submitted to the U.S. Food and Drug Administration (FDA) supporting marketing applications. METHODS: On the basis of publicly available FDA reviews, the authors assessed enrollment of women in trials supporting 36 drug approvals from 2005 to 2015. Prevalence-corrected estimates for the participation of women were calculated as the percentage of women among trial participants divided by the percentage of women in the disease population (participation to prevalence ratio [PPR]), with a range between 0.8 and 1.2 reflecting similar representation of women in the trial and disease population. Sex differences in efficacy and safety were assessed. RESULTS: The proportion of women enrolled ranged from 22% to 81% (mean 46%). The calculated PPR by disease area was within or above the desirable range for atrial fibrillation (0.8 to 1.1), hypertension (0.9), and pulmonary arterial hypertension (1.4); PPR was <0.8 for heart failure (0.5 to 0.6), coronary artery disease (0.6), and acute coronary syndrome/myocardial infarction (0.6). The authors found little indication of clinically meaningful gender differences in efficacy or safety. Gender differences in efficacy or safety were described in labeling for 4 drugs. CONCLUSIONS: Women were well represented in trials of drugs for hypertension and atrial fibrillation, and overrepresented for pulmonary arterial hypertension. Representation of women fell below a PPR of 0.8 for trials in heart failure, coronary artery disease, and acute coronary syndrome. Minimal gender differences in drug efficacy and safety profiles were observed.

Improving Medical Education Using a Sex- and Gender-Based Medicine Lens.

Sex- and Gender-Based Medicine (SGBM) is an emerging discipline within healthcare research, education, and practice. It addresses both the similarities and differences in men and women and it considers both biological and sociocultural factors that impact on the health of all individuals. On a basic level, sex refers to biology and gender refers to sociocultural factors. SGBM emerged after a body of knowledge had been established about health differences between women and men. However, these differences are not consistently considered and misperceptions are propagated when translations from the bench to the bedside are based on a predominantly one-sex model. Medical curricula are not yet integrating the evidence of sex and gender across students' educational experiences. We propose adopting a sex and gender lens to enable physicians and students to critically examine the scientific evidence and assess its applicability to specific patients. A Sex and Gender Medical Education Summit was held in 2015 to create a roadmap for integrating SGBM into medical education. We present examples that led to successful integration of SGBM in U.S. medical schools, as well as resources for medical educators and researchers, so that the health of both women and men can be positively impacted.

Development of a PubMed Based Search Tool for Identifying Sex and Gender Specific Health Literature.

BACKGROUND: An effective literature search strategy is critical to achieving the aims of Sex and Gender Specific Health (SGSH): to understand sex and gender differences through research and to effectively incorporate the new knowledge into the clinical decision making process to benefit both male and female patients. The goal of this project was to develop and validate an SGSH literature search tool that is readily and freely available to clinical researchers and practitioners. METHODS: PubMed, a freely available search engine for the Medline database, was selected as the platform to build the SGSH literature search tool. Combinations of Medical Subject Heading terms, text words, and title words were evaluated for optimal specificity and sensitivity. The search tool was then validated against reference bases compiled for two disease states, diabetes and stroke. RESULTS: Key sex and gender terms and limits were bundled to create a search tool to facilitate PubMed SGSH literature searches. During validation, the search tool retrieved 50 of 94 (53.2%) stroke and 62 of 95 (65.3%) diabetes reference articles selected for validation. A general keyword search of stroke or diabetes combined with sex difference retrieved 33 of 94 (35.1%) stroke and 22 of 95 (23.2%) diabetes reference base articles, with lower sensitivity and specificity for SGSH content. CONCLUSIONS: The Texas Tech University Health Sciences Center SGSH PubMed Search Tool provides higher sensitivity and specificity to sex and gender specific health literature. The tool will facilitate research, clinical decision-making, and guideline development relevant to SGSH.

Sex and gender in medical education: a national student survey.

BACKGROUND: Gender- and sex-specific medicine is defined as the practice of medicine based on the understanding that biology (dictated by sex chromosomes) and social roles (gender) are important in and have implications for prevention, screening, diagnosis, and treatment in men and women. In light of the many ways that sex and gender influence disease presentation and patient management, there have been various initiatives to improve the integration of these topics into medical education curriculum. Although certain schools may include the topics, their impact on the student body's knowledge has not been as fully studied. By studying the opinions of US allopathic and osteopathic-enrolled students on the extent to which their schools address these topics and their understanding of these topics, this study examined the role of gender specific medicine in the US medical school curriculum. METHODS: An email solicitation with link to an anonymous survey was sent to approximately 35,876 student members of five US medical student organizations. The survey instrument consisted of yes/no, multiple choice, and attitude awareness questions. Data was analyzed as a complete data set to evaluate national trends and via subset analysis using chi-square, paired t test, and one-way anova. RESULTS: A total of 1097 students responded. The majority of respondents strongly agreed that sex and gender medicine (SGBM) improves patient management (96.0 %) and should be included as a part of the medical school curriculum (94.4 %). Only 2.4 % of participants agreed that SGBM is the same as Women's Health. When asked specifically about inclusion of an identified sex and gender-based medicine curriculum at their institution, students answered not sure at 40.8, 25.1, 19.1, and 20.3 % from first year to fourth year, respectively. Males reported a higher rate of exposure to SGBM content areas (in medical history taking, domestic violence) than women. CONCLUSIONS: Medical students recognize the differentiation between SGBM principles and women's health, and understand the translational value of sex and gender-specific principles in the clinical setting. However, current curricular offerings fall short of providing students with adequate coverage of specific evidence-based health differences.

High Cardiorespiratory Fitness Is Associated with Reduced Risk of Low Bone Density in Postmenopausal Women.

PURPOSE: The goal of this study was to determine the association between cardiorespiratory fitness (CRF) and bone mineral density (BMD) of the femoral neck (FN) in postmenopausal women using existing Cooper Center Longitudinal Study data. MATERIALS AND METHODS: A cohort of 1,720 predominantly healthy Caucasian women (57.1 ± 6.9 years) underwent preventive medical examinations that included CRF assessment by maximal Balke treadmill testing and measurement of BMD by dual-energy X-ray absorptiometry. CRF was estimated from total treadmill time and categorized into five categories of CRF (further defined as fitness category 1 = low fitness, 2-3 = moderate fitness, and 4-5 = high fitness). Logistic regression was used to characterize the association between CRF and BMD, adjusting for age, weight, and resistance activity level. RESULTS: Overall, the mean body-mass index (BMI) for all subjects was 25.0 ± 4.5 kg/m2, although BMI was in the obese range in the low fitness group. The prevalence of osteoporosis (T-score ≤ -2.5 at the FN) was greater in the low fit group than moderate or high fit (5.8% vs. 3.0% or 3.9%, respectively); with a similar pattern seen for prevalence of osteopenia (T-score > -2.5 and ≤ -1.0 at the FN) (47.5% vs. 46.4% or 44.8%, respectively). Higher age and lower weight were associated with low BMD. Fully adjusted logistic regression models showed an inverse association between CRF and low BMD of the FN. For T-score ≤ -1.0, the primary outcome, the odds ratio (OR) was 0.50 (95% confidence interval [CI] 0.32-0.79) for moderate fitness, and OR of 0.32 (95% CI 0.21-0.51) for high fitness was seen. For T-score ≤ -2.5 at the FN, OR was 0.30 (95% CI 0.11-0.80) for moderate fitness, and OR was 0.29 (95% CI 0.12-0.71) for high fitness. CONCLUSION: Increased CRF levels are associated with reduced risk for low bone density in postmenopausal women.

Women's health 2015: an update for the internist.

The field of women's health is varied and dynamic. Major studies in 2014 and the first half of 2015 suggest that selective serotonin reuptake inhibitors are not strongly associated with congenital heart defects, that paroxetine 7.5 mg is effective for treating menopausal symptoms, and that women with heart failure may benefit more from cardiac resynchronization therapy than men.

Sex-driven differences in immunological responses: challenges and opportunities for the immunotherapies of the third millennium.

PURPOSE OF THE STUDY: Male-based studies, both at the biochemical and at the pre-clinical/clinical trial levels, still predominate in the scientific community. Many studies are based on the wrong assumption that both sexes are fundamentally identical in their response to treatments. As a result, findings obtained mainly in males are applied to females, resulting in negative consequences female patients. In cancer immunotherapy, there is still a scarce focus on this topic. Here we review the main differences in immune modulation and immune system biology between males and females with a particular focus on how these differences affect cancer immunotherapy and cancer vaccines. METHODS: We reviewed articles published on PubMed from 1999 to 2014, using the keywords: sex hormones, immune response, estrogen, immunotherapy, testosterone, cancer vaccines, sex-based medicine. We also present new data wherein the expression of the cancer testis antigen, Ropporin-1, was determined in patients with multiple myeloma, showing that the expression of Ropporin-1 was influenced by sex. RESULTS: Male and female immune systems display radical differences mainly due to the immune regulatory effects of sex hormones. These differences might have a dramatic impact on the immunological treatment of cancer. Moreover, the expression of tumor antigens that can be targeted by anti-cancer vaccines is associated with sex. CONCLUSION: Future clinical trials focusing on cancer immunotherapy will need to take into account the differences in the immune response and in the frequency of target antigen expression between male and females, in order to optimize these anti-cancer immunotherapies of the third millennium.