Therapeutic Potential of Clusterin Inhibition in Human Cancer.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease.

Biomarker Identification through Proteomics in Colorectal Cancer.

Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer.

Clusterin Expression in Colorectal Carcinomas.

Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer.

The Use of SP/Neurokinin-1 as a Therapeutic Target in Colon and Rectal Cancer.

Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation, proliferation, and migration as well as angiogenesis and metastasis of a wide range of solid tumors including colorectal cancer. Until now, the selective high-affinity antagonist of human SP/NK1-R aprepitant (Emend) has been authorized by the Food and Drug Administration as a low dosage medication to manage and treat chemotherapy-induced nausea. However, increasing evidence in recent years support the potential utility of high doses of aprepitant as an antitumor agent and thus, opening the possibility to the pharmacological repositioning of SP/NK1-R antagonists as an adjuvant therapy to conventional cancer treatments. In this review, we summarize current knowledge on the molecular basis of colorectal cancer as well as the pathophysiological importance of SP/NK1-R and the potential utility of SP/NK-1R axis as a therapeutic target in this malignancy.

Calcium Homeostasis in the Development of Resistant Breast Tumors.

Cancer is one of the main health problems worldwide. Only in 2020, this disease caused more than 19 million new cases and almost 10 million deaths, with breast cancer being the most diagnosed worldwide. Today, despite recent advances in breast cancer treatment, a significant percentage of patients will either not respond to therapy or will eventually experience lethal progressive disease. Recent studies highlighted the involvement of calcium in the proliferation or evasion of apoptosis in breast carcinoma cells. In this review, we provide an overview of intracellular calcium signaling and breast cancer biology. We also discuss the existing knowledge on how altered calcium homeostasis is implicated in breast cancer development, highlighting the potential utility of Ca2+ as a predictive and prognostic biomarker, as well as its potential for the development of new pharmacological treatments to treat the disease.

The effect of rapid and delayed insemination on reproductive outcome in conventional insemination and intracytoplasmic sperm injection in vitro fertilization cycles.

PURPOSE: The precise timing of insemination after oocyte retrieval is sometimes challenging. In this study, we have assessed the effect of the variation in insemination timing on reproductive outcome for both conventional insemination (CI) and intracytoplasmic sperm injection (ICSI) cycles. METHODS: A single-center retrospective cohort data analysis was performed on 6559 patients (9575 oocyte retrievals) from January 2017 to July 2019. The main outcome measured was live birth rates. Secondary outcomes included fertilization rate per all oocytes retrieved, blastocyst utilization, clinical pregnancy, and miscarriage rates. The time interval between oocyte retrieval and insemination was analyzed in eight categories: 0 (0- < 0.5 h), 1 (0.5- < 1.5 h), 2 (1.5- < 2.5 h), 3 (2.5- < 3.5 h), 4 (3.5- < 4.5), 5 (4.5- < 5.5), 6 (5.5-6.5), and 7 (6.5- < 8 h). The number of retrievals in each group (0-7) was 586, 1594, 1644, 1796, 1836, 1351, 641, and 127 respectively. RESULTS: The mean fertilization rate for CI ranged from 54.1 to 64.9% with a significant difference between time categories 0 and 5 (p < 0.001) and 1 and 5 (p < 0.0.001). The mean fertilization rate for ICSI ranged from 52.8 to 67.3% with no significant difference between time categories. Blastocyst rate for CI and ICSI was not significantly different. Miscarriage and clinical pregnancy rates in CI and ICSI were not significantly different. Live birth rates differed significantly (p < 0.05) in CI with time categories 0 and 7 representing the lowest rates, but not in the ICSI group. CONCLUSION: If performing CI or ICSI before 1.5 h and > 6.5 h, any detrimental effects are moderate on fertilization but do not affect blastocyst usage and birth rates. TRIAL REGISTRATION: Institutional Review Board Approval from the Beth Israel Deaconess Medical Centre [IRB Protocol #: 2015P000122].

Reproductive Outcomes in Lesbian Couples Undergoing Reception of Oocytes from Partner Versus Autologous In Vitro Fertilization/Intracytoplasmic Sperm Injection.

Purpose: This study aimed to compare reproductive outcomes after Reception of Oocytes from Partner (ROPA; also called reciprocal in vitro fertilization) with those after in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) with autologous oocytes, in lesbian couples. Methods: This was a retrospective matched cohort study of couples performing a first cycle of either ROPA (n = 60) or autologous IVF/ICSI (n = 120) between February 2012 and May 2018. Couples were matched 1:2 by age of the oocyte provider, day of embryo transfer (ET), and number of embryos transferred. Pregnancy and live birth rates after the first ET and cumulative results after all subsequent ETs performed until June 2019 were evaluated. Results: Reproductive outcomes were significantly better after ROPA at first ET: biochemical pregnancy 70.0% versus 47.5% (p = 0.004), clinical pregnancy 60.0% versus 40.0% (p = 0.011), ongoing pregnancy 60.0% versus 36.7% (p = 0.003), and live birth 57.1% versus 29.8% (p = 0.001). After adjusting for age, body mass index, and number of mature oocytes, we still observed a significant improvement across all outcomes in ROPA (live birth rate odds ratio [OR]: 3.05, 95% confidence interval [CI] 1.42-6.57). Cumulative pregnancy and live birth rates were also higher after ROPA (live birth 66.1% vs. 43.4% [p = 0.005]). The adjusted analysis result for cumulative live birth was OR: 2.51, 95% CI: 1.14-5.54. Conclusion: When medically indicated, ROPA can potentially improve reproductive outcomes for lesbian couples through the possibility of selecting the best combination between two oocyte providers and two gestational mothers, provided that both women wish to participate in the pregnancy plan.

Perinatal outcomes in singleton pregnancies after in vitro fertilization cycles over 24 years.

OBJECTIVE: To determine how a shift in clinical practice along with laboratory changes has impacted singleton perinatal outcomes after autologous in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort. SETTING: Single academic fertility clinic. PATIENT(S): Singleton live births resulting from all IVF cycles (n = 14,424) from August 1, 1995 to October 31, 2019. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth weight, large for gestational age (GA), small for GA, and preterm birth. RESULT(S): The entire cohort consisted of 9,280 fresh and 5,144 frozen IVF cycles. Maternal age, parity, body mass index, neonatal sex, and GA at delivery were similar in both groups. There was a decrease in adjusted birth weight per year over the study period for the entire cohort of IVF cycles (-4.42g, 95% confidence interval [CI]: -6.63g to -2.22g). Rates of large for GA newborns decreased by 1.7% (95% CI: 2.9% to 0.6%) annually across the entire cohort of IVF cycles. Furthermore, there was a decrease in annual rates of preterm birth before 32 weeks by 3.2% (95% CI: 5.9% to 0.5%) across the entire cohort of IVF cycles. Trends were also seen in annual reduction of rates of preterm birth before 37 and 28 weeks. CONCLUSION(S): With the gradual evolution of clinical and IVF laboratory practices, there has been a decrease in birth weight over 24 years for the entire cohort of IVF cycles. Concurrently, noteworthy practice changes have resulted in an improvement in IVF outcomes with decreased rates of large for GA newborns and preterm birth before 32 weeks for the entire cohort of IVF cycles.

Research priorities in infertility and assisted reproductive technology treatments - a James Lind Alliance priority setting partnership with brazilian patients.

OBJECTIVE: To identify the main research interests of Brazilian patients in the field of infertility and assisted reproductive technology (ART) treatments. METHODS: This prospective multicenter cross-sectional study was carried out in Brazil. Patients attending five fertility centers from the Huntington Group between October and December 2018 were invited to join the study, which consisted of answering an anonymous survey online. Two hundred and twenty-seven patients signed the informed consent form and were emailed the survey link. The survey was designed based on the James Lind Alliance Priority Setting Partnership protocol. In the area of infertility, patients were probed on issues such as somatic and psychological effects of treatment, prevention, assisted reproductive technology (medications and procedures), success rates, risks, and emotional aspects. RESULTS: The response rate (RR) was 47.58% (108 patients; 88 women - RR 51.46% and 20 men - RR 35.71%). Patient mean age was 36.5 years (SD 4.6). The top ten research priorities listed were 1) short- and long-term side effects of treatment; 2) how to cope with infertility; 3) risks associated with ART; 4) success rates in ART; 5) impact of diet on ART and fertility; 6) healthy habits; 7) alternative therapies; 8) impact of exercise on fertility and ART success; 9) oocyte quality and ovarian reserve; and 10) genetic or inherited causes of infertility. CONCLUSION: To better cater to the needs of patients and develop patient-centered care in the field of infertility and ART treatment, clinicians, healthcare providers, and the scientific community must identify patient concerns and priorities and make efforts to address them.

Identification of research priorities in infertility and assisted reproduction: an international, multicentre study.

RESEARCH QUESTION: What are the main research interests among patients of assisted reproductive technologies (ART)? DESIGN: Cross-sectional study consisting of an anonymous online survey sent to 2112 patients from eight centres in four countries in 2018. Patients were asked to identify research questions relevant to them in the field of infertility and ART. Answers were categorized into topics and ranked by frequency. A long list of the top 30 research topics was extracted from the aggregate results, from which a short list of the top 10 research topics was created. Ten research questions were finally formulated. RESULTS: A total of 945 responses were analysed. Main interests were side-effects, success rates, infertility prevention and emotional support. The 10 research questions were: 1. What are the side-effects of drugs used in ART treatments? (51.6%). 2. What are the most effective methods to cope with infertility from the psychological point of view? (35.7%). 3. What effects could diet have on fertility? (25.9%). 4. What are ART success rates per clinical profile? (24.8%). 5. Are there some habits and lifestyle factors that could prevent infertility? (20.0%). 6. What are the long-term risks associated with ART in mother and child? (18.5%). 7. Are alternative therapies such as acupuncture, yoga and meditation effective to treat/prevent infertility? (18.5%). 8. What is the impact of exercise on fertility? (15.4%). 9. How does oocyte quantity and quality affect fertility? (9.5%). 10. What are the genetic patterns or hereditary conditions causing/related to infertility? (9.5%). CONCLUSIONS: Researchers and clinicians should keep in mind that, in addition to success rates and safety, patients greatly value research into causes, prevention and emotional aspects of infertility.

Single women and motherhood: right now or maybe later?

Purpose: The decision to have a child might be postponed by the lack of partner, and elective egg freezing (EEF) can afford single women more time to find a suitable companion to reach the desired family structure. Alternatively, some women decide to have a child on their own thorough in vitro fertilization (IVF) or intrauterine insemination (IUI) with donor sperm. This study investigates the motivations and personal characteristics of single women undergoing IVF/IUI or EEF.Materials and methods: This is a cross-sectional study including 281 heterosexual single women who underwent either IVF/IUI with donor sperm for solo motherhood (208) or EEF (73) in 2015 at a large fertility center. An anonymous electronic survey was sent after starting the treatment.Results: The most common reason for not having fulfilled the motherhood desire was lack of partner (72.4% IVF/IUI and 65.9% EEF). We found that women undergoing IVF/IUI report a longer motherhood desire, >10 years (71.3% vs. 54.3%), live closer to their families (75.5% vs. 56.5%), and perceive a stronger family support than women undergoing EEF (85.4% vs. 68.8%). Finally, 100% of EEF obviously knew about the possibility of IVF/IUI with donor sperm, while 59.9% of IVF/IUI knew about EEF.Conclusion: Our results underscore the relevance of family ties in the decision to undergo IVF/IUI as single women. Moreover, these women might not be fully informed about social freezing as an option to postpone motherhood. Health professionals should be aware of these differences when counseling single women on fertility choices.

Mapping research in assisted reproduction worldwide.

RESEARCH QUESTION: What are the current research trends in human assisted reproduction around the world? DESIGN: An analysis of 26,000+ scientific publications (articles, letters and reviews) produced worldwide between 2005 and 2016. The corpus of publications indexed in PubMed was obtained by combining the Medical Subject Heading (MeSH) terms: 'Reproductive techniques', 'Reproductive medicine', 'Reproductive health', 'Fertility', 'Infertility' and 'Germ cells'. An analysis was then carried out using text mining algorithms to obtain the main topics of interest. RESULTS: A total of 44 main topics were identified, which were then further grouped into 11 categories: 'Laboratory techniques', 'Male factor', 'Quality of ART, ethics and law', 'Female factor', 'Public health and infectious diseases', 'Basic research and genetics', 'Pregnancy complications and risks', 'General - infertility & ART', 'Psychosocial aspects', 'Cancer' and 'Research methodology'. The USA was the leading country in terms of number of publications, followed by the UK, China and France. Research content in high-income countries is fairly homogeneous across categories and it is dominated by 'Laboratory techniques' in Western-Southern Europe, and by 'Quality of ART, ethics and law' in North America, Australia and New Zealand. 'Laboratory techniques' is also the most abundant category on a yearly basis. CONCLUSIONS: This study identifies the current hot topics on human assisted reproduction worldwide and their temporal trends for 2005-2016. This provides an innovative picture of the current research that could help explore the areas where further research is needed.

Vaginal microbiota profile at the time of embryo transfer does not affect live birth rate in IVF cycles with donated oocytes.

RESEARCH QUESTION: What is the relationship between the vaginal microbiota profile at the time of embryo transfer and live birth rates in women undergoing IVF/intracytoplasmic sperm injection (ICSI) with donated oocytes? DESIGN: One hundred and fifty Caucasian women receiving donated oocytes were prospectively included in the study from March 2017 to January 2018. Samples of vaginal fluid were taken immediately before transfer of a fresh single blastocyst and genomic DNA (gDNA) was extracted. Bacterial load as well as the presence of four lactobacilli (L. crispatus, L. gasseri, L. jensenii and L. iners) and species associated with bacterial vaginosis (Gardnerella vaginalis, Atopobium vaginae, Mycoplasma hominis and Prevotella spp. - here collectively termed BVB) were determined by quantitative polymerase chain reaction. Vaginal microbiota profiles for each patient were characterized and correlated with reproductive results. RESULTS: Although bacterial load was variable, a majority of samples were dominated by a single species (80.7%, 121/150). Most samples (76.7%, 115/150) were dominated by Lactobacillus spp., while 23.3% (35/150) were dominated by bacteria associated with bacterial vaginosis. The distribution of microbiota profiles among women who achieved a live birth and women who did not was similar (P = 0.43). Interestingly, we found a significantly higher proportion of samples dominated by L. crispatus- in women achieving live birth compared with those who did not (P = 0.021); this correlation was also statistically significant for biochemical pregnancy (P = 0.039) and clinical pregnancy (P = 0.015). CONCLUSIONS: Our data suggest that bacterial vaginosis-like vaginal microbiota at the time of embryo transfer does not directly affect the live birth rate.

Functional Analysis of Human Pathological Semen Samples in an Oocyte Cytoplasmic Ex Vivo System.

Human fertilization and embryo development involve a wide range of critical processes that determine the successful development of a new organism. Although Assisted Reproduction Technologies (ART) may help solve infertility problems associated to severe male factor, the live birth rate is still low. A high proportion of ART failures occurs before implantation. Understanding the causes for these failures has been difficult due to technical and ethical limitations. Diagnostic procedures on human spermatozoa in particular have been limited to morphology and swimming behaviours while other functional requirements during early development have not been addressed due to the lack of suitable assays. Here, we have established a quantitative system based on the use of Xenopus egg extracts and human spermatozoa. This system provides novel possibilities for the functional characterization of human spermatozoa. Using clinical data we show that indeed this approach offers a set of complementary data for the functional evaluation of spermatozoa from patients.

Revisiting the association between smoking and female fertility using the oocyte donation model.

RESEARCH QUESTION: Is active smoking among donors, recipients and male partners associated with oocyte donation cycle outcomes, in donors and recipients? DESIGN: Retrospective cohort over a 4-year period including 4747 oocyte recipients and partners, and 3101 oocyte donors. All oocyte donation cycles were carried out between 2010 and 2014, and for whom donor, recipient and male partner smoking status at the time of treatment were known. RESULTS: Ovarian response was significantly reduced in oocyte donors who smoked compared with those who did not: 13.9 (SD 6.7) mature oocytes in heavy smokers versus 14.8 (SD 7.6) in non-smokers (P = 0.020). Nevertheless, biochemical, clinical and ongoing pregnancy rates and live birth rates were not affected by the degree of smoking among donors, recipients or recipients' partners. CONCLUSIONS: This study suggests that smoking is not associated with compromised oocyte quality or altered uterine receptivity in oocyte donation cycles.

Oocyte developmental competence is independent of ovarian reserve in women younger than 35 years.

RESEARCH QUESTION: Is higher antral follicle count (AFC) in healthy young women associated with higher oocyte developmental competence? DESIGN: Retrospective study of 1985 first oocyte donation cycles, corresponding to 3210 fresh embryo transfers in oocyte recipients, conducted between January 2010 and May 2014. RESULTS: Donors with higher AFC who underwent ovarian stimulation, produced both more cumulus-oocyte complexes (COC) (B coefficient = 0.47, 95% CI 0.41 to 0.53;P ≤ 0.001) and MII oocytes (B coefficient = 0.36, 95% CI 0.32 to 0.41;P ≤ 0.001) at linear regression analysis. Donors with low AFC had a higher risk of cancellation (OR 4.79, 95% CI 2.99 to 7.69;P < 0.001) or obtaining fewer than four metaphase II (MII) at ovum retrieval (OR 3.87, 95% CI 2.38 to 6.27;P < 0.001). No association was found between AFC and biochemical (OR 1.13, 95% CI 0.93 to 1.36), clinical (OR 1.05, 95% CI 0.87 to 1.28), ongoing pregnancy (OR 1.00, 95%, CI 0.82 to 1.21) or live birth rates (OR 0.97, 95% CI 0.8 to 1.19), when at least four MII were obtained at ovum retrieval. CONCLUSIONS: AFC does not relate to the developmental competence of oocytes in women younger than 35 years.

Actions to increase knowledge about age-related fertility decline in women.

OBJECTIVE: There is a strong body of published data corroborating the current lack of awareness of age-related fertility decline (ARFD), but few studies have evaluated specific interventions aimed at increasing ARFD knowledge. Here, we review the literature examining the instruments developed and the educational interventions performed to date. METHODS: We carried out a narrative review based on a literature search in PubMed, Web of Science, PsycINFO and Scopus between January 2010 and December 2017. RESULTS: The instruments available comprise websites, paper brochures, slide presentations and tailored information, mainly developed with the input of university students. The eight interventions reviewed include surveys before and/or after a specific intervention, with and without a control group, in randomised and non-randomised designs. Overall, the interventions were effective in increasing ARFD knowledge and lowering the desired age for childbearing in the short term. These results were not always maintained, however, in the long term, possibly due to a lack of perceived risk of future infertility among those studied. CONCLUSION: Further interventions need to be targeted to both young people and health care providers, and should be as personalised as possible. A greater number of validated instruments are also needed to reliably measure the effectiveness of any intervention.

Knowledge of age-related fertility decline in women: A systematic review.

Age-related fertility decline (ARFD) knowledge has been evaluated in the past decade, showing that there is a general knowledge of the reduction of fertility with age. Here we review the studies published up to date which quantitatively measure this ARFD knowledge, to answer the question: how aware about ARFD is our society? We searched the terms "age", "fertility knowledge", "fertility awareness", "reproduction knowledge", "reproductive knowledge" and "reproductive health knowledge" in PubMed, Web of Science, PsychINFO and Scopus, within January 2000 and December 2016. We found 41 studies that quantitatively measured ARFD knowledge by asking for the most fertile age for a woman and/or when there are a slight and a marked decrease in female fertility. We obtained this searching for the questions: What is the most fertile age for a woman? (Q1). When there is a slight decrease in female fertility? (Q2) and, When there is a marked decrease in female fertility? (Q3). We further evaluated the knowledge increase in the 6 studies assessing an educational intervention, 4 of them randomized controlled trials (RCT). Participants reporting the most fertile age for women to be at 20-24 y.o. ranged 16%-89.4% (Q1); participants reporting a slight decrease in female fertility at 25-29 y.o. ranged 5.1%-83% (Q2), and those reporting that a marked decrease occurs between 35-39 y.o. ranged 5.6%-60% (Q3). On the whole, the studies included in this review conclude that ARFD knowledge is insufficient, particularly in determining when female fertility markedly decreases. ARFD knowledge can be increased through targeted campaigns, but few interventional studies have been performed up to date. In view of these results, ARFD campaigns targeted to reproductive age people and healthcare providers are necessary; this would help the society to make informed reproductive decisions throughout life.

Risk of preeclampsia in pregnancies resulting from double gamete donation and from oocyte donation alone.

INTRODUCTION: Pregnancies after gamete donation are at higher risk of developing pre-eclampsia (PE) than those achieved by IVF with patient's own gametes. We aim to assess whether pregnancies achieved with both oocyte and sperm donation (double donation, DD) are at an increased risk of developing PE and gestational hypertension (GH) compared to those achieved by oocyte donation alone (OD). MATERIALS AND METHODS: Retrospective cohort study of 433 patients who reached the 20th week of gestation with either DD (n = 81) or OD (n = 352) between March 2013 and April 2016 at a fertility clinic. The risk of preterm PE, term PE, and gestational hypertension (GH) are presented as unadjusted and adjusted odds ratio (OR). RESULTS: DD have a higher risk of preterm PE than OD, with an OR of 3.02 (95%CI 1.11-8.24; p = 0.031). We found no difference in the risk of term PE (OR 0.26, 95%CI 0.03-1.98; p = 0.19) or of GH (OR 1.23, 95% CI 0.63-2.43; p = 0.55). DISCUSSION: Pregnancies with DD are at higher risk of developing preterm PE than OD alone. Patients, and physicians treating them, should be made aware of the elevated risk of PE in these gestations, in order to start prophylactic measures during the first weeks of pregnancy.