Lasofoxifene: Evidence of its therapeutic value in osteoporosis

Introduction: Osteoporosis is a skeletal disorder characterized by compromised bone strength and increased risk of fracture. It is a common disorder in elderly subjects and represents a major public health problem, affecting up to 40% postmenopausal women and 15% of men. Among the several therapeutical interventions, hormone replacement therapy (HRT) was traditionally seen as the gold standard for preventing osteoporotic fractures in postmenopausal women, as well as for the management of menopausal symptoms. However HRT, especially if administered long-term, may lead to an increased risk of breast and, when unopposed by progestins, endometrial cancers. Alternative therapies include bisphosphonates and raloxifene, a selective estrogen receptor modulator (SERM). While the former have been associated with suboptimal adherence, the latter was considerably less potent than estrogen and its effect in the prevention of nonvertebral fractures remain uncertain. Aims: The purpose of this article is to review the clinical trials of lasofoxifene, a new SERM for the treatment of postmenopausal osteoporosis. The medical literature was reviewed for appropriate articles containing the terms “lasofoxifene” and SERMs”. Evidence review: There are three (phase II or phase III) clinical trials that clearly demonstrate efficacy and safety of this new SERM in the suppression of bone loss and the prevention of vertebral and nonvertebral fractures. Moreover, lasofoxifene treatment also reduced breast cancer risk and the occurrence of vaginal atrophy. Place in therapy: With its increased potency and efficacy on the prevention of nonvertebral fractures lasofoxifene may be an alternative and cost-effective therapy for osteoporosis in postmenopausal women

Bazedoxifene for the prevention of postmenopausal osteoporosis

Bazedoxifene acetate is a novel, chemically distinct selective estrogen receptor modulator (SERM) that has been specifically developed after a stringent preclinical screening in order to obtain favorable effects on the skeleton and lipid metabolism with the additional improvement of a neutral effect on hot flushes and without stimulating the uterus or the breast. In both preclinical and clinical studies this SERM was shown to maintain BMD, prevent fractures, and reduce total cholesterol. Moreover, bazedoxifene also showed an improved uterine profile and demonstrated estrogen antagonistic activity on the endometrium. Importantly, this latter capacity has led to the development of a novel class of menopausal therapy called tissue selective estrogen complex (TSEC), in which bazedoxifene is combined with conjugated estrogen. The rationale for selecting bazedoxifene as the SERM in this TSEC combination is that it may offset estrogen stimulation of endometrial and breast tissue, without the necessity of using a progestin in women with an intact uterus, without aggravating menopausal vasomotor symptoms, but with an additive effect on bone. Preliminary data from phase 3 clinical trials appear to confirm this hypothesis, showing a greater effect of bazedoxifene on BMD with respect to raloxifene, coupled with efficacy on menopausal vasomotor symptoms not achieved by SERM alone. These properties and the safety profile of this combination, if confirmed long-term in ongoing phase 3 trials, might significantly affect the way women and physicians approach menopause and its related disorders

The Outcome of Cholangitis After Percutaneous Biliary Drainage in Neoplastic Jaundice

The purpose of this paper is to evaluate factors affecting the outcome of cholangitis after PTBD in jaundiced cancer patients. Twenty nine patients with neoplastic jaundice (male/female ratio 13/16, median age 55 years) with full clinical data, were treated by PTBD and developed cholangitis at a median of 9 days later. Four patients (14%) died of biliary sepsis a median of one month after PTBD while the other 25 survived a median of 6 months, with one week median duration of cholangitis. The probability of the cholangitis resolving was analyzed by time to resolution and it was found that 50% and 100% of the recoveries occurred 5 and 9 months respectively from the onset of the complication

Spatio-temporal dynamics of landscape use by the bumblebee Bombus pauloensis (Hymenoptera: Apidae) and its relationship with pollen provisioning

Understanding how bees use resources at a landscape scale is essential for developing meaningful management plans that sustain populations and the pollination services they provide. Bumblebees are important pollinators for many wild and cultivated plants, and have experienced steep population declines worldwide. Bee foraging behavior can be influenced by resource availability and bees’ lifecycle stage. To better understand these relationships, we studied the habitat selection of Bombus pauloensis by tracking 17 queen bumblebees with radio telemetry in blueberry fields in Entre Ríos province, Argentina. To evaluate land use and floral resources used by bumblebees, we tracked bees before and after nest establishment and estimated home ranges using minimum convex polygons and kernel density methods. We also classified the pollen on their bodies to identify the floral resources they used from the floral species available at that time. We characterized land use for each bee as the relative proportion of GPS points inside of each land use. Bumblebees differed markedly in their movement behavior in relation to pre and post nest establishment. Bees moved over larger areas, and mostly within blueberry fields, before nest establishment. In contrast, after establishing the nest, the bees preferred the edges near forest plantations and they changed the nutritional resources to prefer wild floral species. Our study is the first to track queen bumblebee movements in an agricultural setting and relate movement changes across time and space with pollen resource availability. This study provides insight into the way bumblebee queens use different habitat elements at crucial periods in their lifecycle, showing the importance of mass flowering crops like blueberry in the first stages of queen’s lifecycle, and how diversified landscapes help support bee populations as their needs changes during different phases of their lifecycle.EEA ConcordiaFil: Cavigliasso, Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Concordia; ArgentinaFil: Phifer, Colin C. Michigan Technological University. School of Forest Resources and Environmental Science; Estados UnidosFil: Adams, Erika M. Michigan Technological University. School of Forest Resources and Environmental Science; Estados UnidosFil: Flaspohler, David J. Michigan Technological University. School of Forest Resources and Environmental Science; EstadosFil: Gennari, Gerardo Pablo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Famaillá; ArgentinaFil: Licata, Julián Andrés. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Concordia; ArgentinaFil: Chacoff, Natacha Paola. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Instituto de Ecología Regional. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Ecología Regional; Argentin

Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

Borbély AN, Figueras Agustí E, Martins A, et al. Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery. ChemistryOpen. 2019;8(6):737-742.RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin alphavbeta3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin alphavbeta3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin alphavbeta3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective alphavbeta3 integrin-mediated drug delivery

Cancer and fertility preservation: International recommendations from an expert meeting

In the last years, thanks to the improvement in the prognosis of cancer patients, a growing attention has been given to the fertility issues. International guidelines on fertility preservation in cancer patients recommend that physicians discuss, as early as possible, with all patients of reproductive age their risk of infertility from the disease and/or treatment and their interest in having children after cancer, and help with informed fertility preservation decisions. As recommended by the American Society of Clinical Oncology and the European Society for Medical Oncology, sperm cryopreservation and embryo/oocyte cryopreservation are standard strategies for fertility preservations in male and female patients, respectively; other strategies (e.g. pharmacological protection of the gonads and gonadal tissue cryopreservation) are considered experimental techniques. However, since then, new data have become available, and several issues in this field are still controversial and should be addressed by both patients and their treating physicians. In April 2015, physicians with expertise in the field of fertility preservation in cancer patients from several European countries were invited in Genova (Italy) to participate in a workshop on the topic of "cancer and fertility preservation". A total of ten controversial issues were discussed at the conference. Experts were asked to present an up-to-date review of the literature published on these topics and the presentation of own unpublished data was encouraged. On the basis of the data presented, as well as the expertise of the invited speakers, a total of ten recommendations were discussed and prepared with the aim to help physicians in counseling their young patients interested in fertility preservation. Although there is a great interest in this field, due to the lack of large prospective cohort studies and randomized trials on these topics, the level of evidence is not higher than 3 for most of the recommendations highlighting the need of further research efforts in many areas of this field. The participation to the ongoing registries and prospective studies is crucial to acquire more robust information in order to provide evidence-based recommendations