Bone-Induced Expression of Integrin β3 Enables Targeted Nanotherapy of Breast Cancer Metastases

Bone metastases occur in approximately 70% of metastatic breast cancer patients, often leading to skeletal injuries. Current treatments are mainly palliative and underscore the unmet clinical need for improved therapies. In this study, we provide preclinical evidence for an antimetastatic therapy based on targeting integrin β3 (β3), which is selectively induced on breast cancer cells in bone by the local bone microenvironment. In a preclinical model of breast cancer, β3 was strongly expressed on bone metastatic cancer cells, but not primary mammary tumors or visceral metastases. In tumor tissue from breast cancer patients, β3 was significantly elevated on bone metastases relative to primary tumors from the same patient (n = 42). Mechanistic investigations revealed that TGFβ signaling through SMAD2/SMAD3 was necessary for breast cancer induction of β3 within the bone. Using a micelle-based nanoparticle therapy that recognizes integrin αvβ3 (αvβ3-MPs of ∼12.5 nm), we demonstrated specific localization to breast cancer bone metastases in mice. Using this system for targeted delivery of the chemotherapeutic docetaxel, we showed that bone tumor burden could be reduced significantly with less bone destruction and less hepatotoxicity compared with equimolar doses of free docetaxel. Furthermore, mice treated with αvβ3-MP-docetaxel exhibited a significant decrease in bone-residing tumor cell proliferation compared with free docetaxel. Taken together, our results offer preclinical proof of concept for a method to enhance delivery of chemotherapeutics to breast cancer cells within the bone by exploiting their selective expression of integrin αvβ3 at that metastatic site

The Allantois and Chorion, when Isolated before Circulation or Chorio-Allantoic Fusion, have Hematopoietic Potential

The chorio-allantoic placenta forms through the fusion of the allantois (progenitor tissue of the umbilical cord), with the chorionic plate. The murine placenta contains high levels of hematopoietic stem cells, and is therefore a stem cell niche. However, it is not known whether the placenta is a site of hematopoietic cell emergence, or whether hematopoietic cells originate from other sites in the conceptus and then colonize the placenta. Here, we show that the allantois and chorion, isolated prior to the establishment of circulation, have the potential to give rise to myeloid and definitive erythroid cells following explant culture. We further show that the hematopoietic potential of the allantois and chorion does not require their union, indicating that it is an intrinsic property of these tissues. These results suggest that the placenta is not only a niche for, but also a source of, hematopoietic cells

A systematic review and meta-analysis on the comorbidity of premenstrual dysphoric disorder or premenstrual syndrome with mood disorders:prevalence, clinical and neurobiological correlates

BACKGROUND: Mood disorders are among the leading causes of disease burden worldwide, with 20-70% of affected individuals experiencing comorbid premenstrual disorders. This systematic review and meta-analysis investigated the comorbidity of premenstrual dysphoric disorder (PMDD) or premenstrual syndrome (PMS) with non-reproductive mood disorders.AIMS: We aimed to determine the pooled prevalence of PMDD/PMS with adult mood disorders, assess the impact of comorbidity on clinical course and summarise the associated neurobiological findings.METHOD: Eligible studies were identified through Embase, MEDLINE and APA PsycINFO from inception to 22 January 2024 (PROSPERO, no. CRD42021246796). Studies on women ('females') with diagnoses of PMDD/PMS and mood disorders were included. Risk of bias was assessed using National Institutes of Health quality assessment tools. A random-effects, pooled-prevalence meta-analysis was conducted using the Comprehensive Meta-Analysis software, categorising diagnostic sampling strategies as follows: mood disorders diagnosed first, PMDD/PMS diagnosed first or concurrent diagnoses. A narrative synthesis explored secondary outcomes, including illness course and biomarkers.RESULTS: A total of 39 studies were included, with 36 of these ( n = 3646) contributing to the meta-analysis. Seven studies focused on bipolar disorders, 18 on unipolar depressive disorders and 14 on mixed samples of bipolar and unipolar disorders. Random-effects pooled-prevalence meta-analyses showed consistently high comorbidity rates between PMDD/PMS and mood disorders, ranging from 42% (95% CI: 30%, 55%) to 49% (95% CI: 38%, 60%) across sampling strategies. Risk of bias varied, with methodological heterogeneity noted. CONCLUSIONS: This review underscores high comorbidity rates between PMDD/PMS and mood disorders, regardless of sampling strategy, and highlights the need for research into clinical and neurobiological characteristics specific to this comorbidity. Limitations include study heterogeneity, reliance on cross-sectional designs and provisional PMDD/PMS diagnoses. Future research should address these gaps to inform diagnostic and therapeutic advancements tailored to this population.</p

Hepatic lipids promote liver metastasis

Obesity predisposes to cancer and a virtual universality of nonalcoholic fatty liver disease (NAFLD). However, the impact of hepatic steatosis on liver metastasis is enigmatic. We find that while control mice were relatively resistant to hepatic metastasis, those which were lipodystrophic or obese, with NAFLD, had a dramatic increase in breast cancer and melanoma liver metastases. NAFLD promotes liver metastasis by reciprocal activation initiated by tumor-induced triglyceride lipolysis in juxtaposed hepatocytes. The lipolytic products are transferred to cancer cells via fatty acid transporter protein 1, where they are metabolized by mitochondrial oxidation to promote tumor growth. The histology of human liver metastasis indicated the same occurs in humans. Furthermore, comparison of isolates of normal and fatty liver established that steatotic lipids had enhanced tumor-stimulating capacity. Normalization of glucose metabolism by metformin did not reduce steatosis-induced metastasis, establishing the process is not mediated by the metabolic syndrome. Alternatively, eradication of NAFLD in lipodystrophic mice by adipose tissue transplantation reduced breast cancer metastasis to that of control mice, indicating the steatosis-induced predisposition is reversible

Effect of gender on the co-occuring manic symptoms in depression

10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders -- JUN 13-16, 2013 -- Miami Beach, FL[Anstract Not Available]Int Soc Bipolar Disorder

Exploratory factor analysis of mixed depression utilizing a modified version of Hypomania Checklist 32 (mHCL-32)

10th International Conference on Bipolar Disorder of the International-Society-for-Bipolar-Disorders -- JUN 13-16, 2013 -- Miami Beach, FL[Anstract Not Available]Int Soc Bipolar Disorder