The Major Pre- and Postmenopausal Estrogens Play Opposing Roles in Obesity-Driven Mammary Inflammation and Breast Cancer Development

Many inflammation-associated diseases, including cancers, increase in women after menopause and with obesity. In contrast to anti-inflammatory actions of 17β-estradiol, we find estrone, which dominates after menopause, is pro-inflammatory. In human mammary adipocytes, cytokine expression increases with obesity, menopause, and cancer. Adipocyte:cancer cell interaction stimulates estrone- and NFκB-dependent pro-inflammatory cytokine upregulation. Estrone- and 17β-estradiol-driven transcriptomes differ. Estrone:ERα stimulates NFκB-mediated cytokine gene induction; 17β-estradiol opposes this. In obese mice, estrone increases and 17β-estradiol relieves inflammation. Estrone drives more rapid ER+ breast cancer growth in vivo. HSD17B14, which converts 17β-estradiol to estrone, associates with poor ER+ breast cancer outcome. Estrone and HSD17B14 upregulate inflammation, ALDH1 activity, and tumorspheres, while 17β-estradiol and HSD17B14 knockdown oppose these. Finally, a high intratumor estrone:17β-estradiol ratio increases tumor-initiating stem cells and ER+ cancer growth in vivo. These findings help explain why postmenopausal ER+ breast cancer increases with obesity, and offer new strategies for prevention and therapy.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 84510

Polycystin-1 Expression in Fetal, Adult and Autosomal Dominant Polycystic Kidney

The mutation of the PKD1 gene causes autosomal dominant polycystic kidney disease (ADPKD), and the PKD1 gene encodes polycystin-1 (PC-1). PC-1 is thought to be a cell-cell/matrix adhesion receptor molecule at the cell surface that is widely expressed in the kidney. However, there are controversies about the role of PC-1 protein and its expression when using different antibodies to detect it. We used two PC-1 antibodies; C-20 (Santa Cruz, sc-10372) as the C-terminal antibody, and P-15 (Santa Cruz, sc-10307) as the N-terminal antibody. We evaluated the PC-1 expression by performing immunoblotting on the human embryonic kidney (HEK) 293 cells and the renal proximal tubular epithelial cell (RPTEC) lysates. We characterized the expression of PC-1 in the fetal, adult and polycystic kidneys tissues by performing immunohistochemistry. We confirmed the PC-1 expression in the HEK 293 cells and the RPTEC lysates, but the expression was very low. The PC-1 proteins were diffusely expressed in the tubular epithelial cells cytoplasm in the fetal and adult kidneys, and the PC-1 expression was more prominent in the proximal tubules of the fetal kidney. In the ADPKD kidney, the PC-1 proteins were heterogenously and weakly expressed in the tubular or cyst lining epithelial cells. Our data suggests that the development of the kidney may regulate the expression of PC-1, and an altered PC-1 expression may contribute to cyst formation in ADPKD

Comparison of carnivore, omnivore, and herbivore mammalian genomes with a new leopard assembly.

BACKGROUND: There are three main dietary groups in mammals: carnivores, omnivores, and herbivores. Currently, there is limited comparative genomics insight into the evolution of dietary specializations in mammals. Due to recent advances in sequencing technologies, we were able to perform in-depth whole genome analyses of representatives of these three dietary groups. RESULTS: We investigated the evolution of carnivory by comparing 18 representative genomes from across Mammalia with carnivorous, omnivorous, and herbivorous dietary specializations, focusing on Felidae (domestic cat, tiger, lion, cheetah, and leopard), Hominidae, and Bovidae genomes. We generated a new high-quality leopard genome assembly, as well as two wild Amur leopard whole genomes. In addition to a clear contraction in gene families for starch and sucrose metabolism, the carnivore genomes showed evidence of shared evolutionary adaptations in genes associated with diet, muscle strength, agility, and other traits responsible for successful hunting and meat consumption. Additionally, an analysis of highly conserved regions at the family level revealed molecular signatures of dietary adaptation in each of Felidae, Hominidae, and Bovidae. However, unlike carnivores, omnivores and herbivores showed fewer shared adaptive signatures, indicating that carnivores are under strong selective pressure related to diet. Finally, felids showed recent reductions in genetic diversity associated with decreased population sizes, which may be due to the inflexible nature of their strict diet, highlighting their vulnerability and critical conservation status. CONCLUSIONS: Our study provides a large-scale family level comparative genomic analysis to address genomic changes associated with dietary specialization. Our genomic analyses also provide useful resources for diet-related genetic and health research

Immunotherapeutic Approaches in Ovarian Cancer

Ovarian cancer (OC) is gynecological cancer, and diagnosis and treatment are continuously advancing. Next-generation sequencing (NGS)-based diagnoses have emerged as novel methods for identifying molecules and pathways in cancer research. The NGS-based applications have expanded in OC research for early detection and identification of aberrant genes and dysregulation pathways, demonstrating comprehensive views of the entire transcriptome, such as fusion genes, genetic mutations, and gene expression profiling. Coinciding with advances in NGS-based diagnosis, treatment strategies for OC, such as molecular targeted therapy and immunotherapy, have also advanced. Immunotherapy is effective against many other cancers, and its efficacy against OC has also been demonstrated at the clinical phase. In this review, we describe several NGS-based applications for therapeutic targets of OC, and introduce current immunotherapeutic strategies, including vaccines, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cell transplantation, for effective diagnosis and treatment of OC

Fatty Acid Metabolism in Ovarian Cancer: Therapeutic Implications

Ovarian cancer is the most malignant gynecological tumor. Previous studies have reported that metabolic alterations resulting from deregulated lipid metabolism promote ovarian cancer aggressiveness. Lipid metabolism involves the oxidation of fatty acids, which leads to energy generation or new lipid metabolite synthesis. The upregulation of fatty acid synthesis and related signaling promote tumor cell proliferation and migration, and, consequently, lead to poor prognosis. Fatty acid-mediated lipid metabolism in the tumor microenvironment (TME) modulates tumor cell immunity by regulating immune cells, including T cells, B cells, macrophages, and natural killer cells, which play essential roles in ovarian cancer cell survival. Here, the types and sources of fatty acids and their interactions with the TME of ovarian cancer have been reviewed. Additionally, this review focuses on the role of fatty acid metabolism in tumor immunity and suggests that fatty acid and related lipid metabolic pathways are potential therapeutic targets for ovarian cancer

Integration of Genomic Profiling and Organoid Development in Precision Oncology

Precision oncology involves an innovative personalized treatment strategy for each cancer patient that provides strategies and options for cancer treatment. Currently, personalized cancer medicine is primarily based on molecular matching. Next-generation sequencing and related technologies, such as single-cell whole-transcriptome sequencing, enable the accurate elucidation of the genetic landscape in individual cancer patients and consequently provide clinical benefits. Furthermore, advances in cancer organoid models that represent genetic variations and mutations in individual cancer patients have direct and important clinical implications in precision oncology. This review aimed to discuss recent advances, clinical potential, and limitations of genomic profiling and the use of organoids in breast and ovarian cancer. We also discuss the integration of genomic profiling and organoid models for applications in cancer precision medicine

Immunotherapeutic Approaches in Ovarian Cancer

Ovarian cancer (OC) is gynecological cancer, and diagnosis and treatment are continuously advancing. Next-generation sequencing (NGS)-based diagnoses have emerged as novel methods for identifying molecules and pathways in cancer research. The NGS-based applications have expanded in OC research for early detection and identification of aberrant genes and dysregulation pathways, demonstrating comprehensive views of the entire transcriptome, such as fusion genes, genetic mutations, and gene expression profiling. Coinciding with advances in NGS-based diagnosis, treatment strategies for OC, such as molecular targeted therapy and immunotherapy, have also advanced. Immunotherapy is effective against many other cancers, and its efficacy against OC has also been demonstrated at the clinical phase. In this review, we describe several NGS-based applications for therapeutic targets of OC, and introduce current immunotherapeutic strategies, including vaccines, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cell transplantation, for effective diagnosis and treatment of OC

Role of Klotho as a Modulator of Oxidative Stress Associated with Ovarian Tissue Cryopreservation

Ovarian tissue cryopreservation is the only option for preserving fertility in adult and prepubertal cancer patients who require immediate chemotherapy or do not want ovarian stimulation. However, whether ovarian tissue cryopreservation can ameliorate follicular damage and inhibit the production of reactive oxygen species in cryopreserved ovarian tissue remains unclear. Oxidative stress is caused by several factors, such as UV exposure, obesity, age, oxygen, and cryopreservation, which affect many of the physiological processes involved in reproduction, from maturation to fertilization, embryonic development, and pregnancy. Here, freezing and thawing solutions were pre-treated with N-acetylcysteine (NAC) and klotho protein upon the freezing of ovarian tissue. While both NAC and klotho protein suppressed DNA fragmentation by scavenging reactive oxygen species, NAC induced apoptosis and tissue damage in mouse ovarian tissue. Klotho protein inhibited NAC-induced apoptosis and restored cellular tissue damage, suggesting that klotho protein may be an effective antioxidant for the cryopreservation of ovarian tissue