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Ovarian cancer (OvCa), while accounting for only 3% of all women’s cancer, is the fifth leading cause of cancer death among women. One of the most significant obstacles to successful OvCa treatment is chemoresistance. The current lack of understanding of the driving mechanisms underlying chemoresistance hinders the development of effective therapeutics against this obstacle. Adipocytes are key components of the OvCa microenvironment and have been shown to be involved in OvCa cell proliferation, however, little is known about their impact on OvCa chemoresistance. In the current study, we found that adipocytes, of both subcutaneous and visceral origin, secrete factors that enhance the resistance of OvCa cells against chemotherapeutic drugs by activating the Akt pathway. Importantly, we have demonstrated that secreted lipids mediate adipocyte-induced chemoresistance. Through a comprehensive lipidomic analysis, we have identified this chemo-protective lipid mediator as arachidonic acid (AA). AA acts on OvCa cells directly, not through its downstream derivatives such as prostaglandins, to activate Akt and inhibit cisplatin-induced apoptosis. Taken together, our study has identified adipocytes and their secreted AA as important mediators of OvCa chemoresistance. Strategies that block the production of AA from adipocytes or block its anti-apoptotic function may potentially inhibit chemoresistance in OvCa patients.

Obesity is associated with an increased risk of, and a poor prognosis for, postmenopausal (PM) breast cancer (BC). Our goal was to determine whether diet-induced obesity (DIO) promotes 1) shorter tumor latency, 2) an escape from tumor dormancy, and 3) an acceleration of tumor growth and to elucidate the underlying mechanism(s). We have developed in vitro assays and PM breast tumor models complemented by a noninvasive imaging system to detect vascular invasion of dormant tumors and have used them to determine whether obesity promotes the escape from breast tumor dormancy and tumor growth by facilitating the switch to the vascular phenotype (SVP) in PM BC. Obese mice had significantly higher tumor frequency, higher tumor volume, and lower overall survival compared with lean mice. We demonstrate that DIO exacerbates mammary gland hyperplasia and neoplasia, reduces tumor latency, and increases tumor frequency via an earlier acquisition of the SVP. DIO establishes a local and systemic proangiogenic and inflammatory environment via the up-regulation of lipocalin-2 (LCN2), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) that may promote the escape from tumor dormancy and tumor progression. In addition, we show that targeting neovascularization via a multitargeted receptor tyrosine kinase inhibitor, sunitinib, can delay the acquisition of the SVP, thereby prolonging tumor latency, reducing tumor frequency, and increasing tumor-free survival, suggesting that targeting neovascularization may be a potential therapeutic strategy in obesity-associated PM BC progression. This study establishes the link between obesity and PM BC and, for the first time to our knowledge, bridges the dysfunctional neovascularization of obesity with the earliest stages of tumor development.

Background Breast cancer (BC) is a complex heterogenous disease that is a leading cause of death in women. For patients with early stage disease following primary BC therapy, approximately 30% will develop metastatic BC (MBC). The median survival of MBC patients is ~ 2–3 yr. While the early detection and monitoring of BC progression have improved prognosis and reduced BC-related mortality, there is a lack of long-term surveillance strategies for monitoring patients for recurrence of MBC. The aim of our study was to identify non-invasive urinary biomarkers for detection and monitoring of MBC. Methods We have conducted a comparative label-free LC–MS/MS analysis of the urinary proteome of patients with MBC and healthy age-matched, sex-matched controls (HC). A hybrid quadrupole time of flight (Q-Tof™) mass spectrometer was used for urine analysis via liquid chromatography (LC) with tandem mass spectrometry (MS/MS). Retrospective analysis of urine samples from MBC and locally invasive breast cancer (IBC) patients as well as HC was conducted. Diagnostic accuracies of candidate markers were validated using independent training and validation sets according to the REMARK criteria. Results Using this approach, we have identified 212 urinary proteins of which 83 and 25 were unique to the MBC and HC groups, respectively. Upregulated proteins in the MBC cohort were associated with angiogenesis, Ca 2+ homeostasis, apoptosis, proteolysis, extracellular matrix regulation, cell adhesion and protein synthesis pathways. A specific non-invasive metastasis signature comprised of candidate biomarkers (urinary CALB1, S100A8, ZAG, VTN and TN) were validated and analyzed via monospecific ELISA assays. Urinary vitronectin (uVTN) levels correlated with disease status and were significantly higher in samples from MBC compared to those from IBC patients and HC. uVTN alone (cutoff > 500 ng/ml) could discriminate between HC and MBC groups ( AUC  = 0.782, P  < 0.001). Longitudinal analysis of samples from MBC patients indicated a strong correlation between uVTN levels and disease status. Conclusions Our findings suggest that uVTN is a promising and non-invasive biomarker for the diagnosis and monitoring of MBC. While future validation in larger cohorts should be done, these results identify a novel urinary protein that represents the first non-invasive diagnostic test for monitoring BC progression and recurrence.

Antiestrogen therapy has been used successfully to prolong disease-free and overall survival of ER positive breast cancer patients. However, 50% of patients with ER+ tumors fail to respond to such therapy or eventually acquire resistance to endocrine therapy, resulting in tumor progression and mortality. It is imperative, therefore, to understand the mechanisms that lead to hormone refractory breast cancer in order to develop therapeutics that can modulate the resistance to antiestrogen therapy. The protease, ADAM12, can be detected in the urine of breast cancer patients and its levels correlate with disease status, stage, and cancer risk. Within the context of this study, the authors have investigated the role of the two distinct isoforms of ADAM12 in breast tumor cell proliferation and as potential mediators of endocrine resistance. Using stable clones of ADAM12-overexpressing MCF-7 cells, the authors analyzed proliferation rates of these ER+ breast tumor cells both in estrogen-depleted medium and in the presence of the antiestrogens, tamoxifen, and ICI 182,780. Acquired estrogen resistance in these cells was analyzed using phospho-RTK analysis. Upregulation and phosphorylation of proteins were detected via immunoprecipitation and immunoblotting. EGFR and MAPK inhibitors were used to explore the mechanism of acquired estrogen resistance in breast tumor cells. It was observed that overexpression of the two isoforms, transmembrane ADAM12-L, and secreted ADAM12-S, in breast tumor cells promoted estrogen-independent proliferation. In ADAM12-L-expressing cells, estrogen-independence was a direct result of increased EGFR expression and MAPK activation, whereas, the mechanism in ADAM12-S-expressing cells may be enhanced IGF-1R signaling. The importance of the EGFR signaling pathway in the estrogen-independent growth of ADAM12-L expressing cells was highlighted by the effect of EGFR inhibitors AG1478 and PD15035 or MAPK inhibitor U0126, each of which abolished the antiestrogen resistance in these cells. Taken together, these results demonstrate that ADAM12 isoforms confer a proliferative advantage to MCF-7 cells in the absence of estrogen stimulation, and suggest that downregulation of ADAM12 in combination with endocrine therapy may represent a useful pharmacological approach to breast cancer therapy.

Background The objective of this study was to discover and to validate novel noninvasive biomarkers that distinguish between benign prostate hyperplasia (BPH) and localized prostate cancer (PCa), thereby helping to solve the diagnostic dilemma confronting clinicians who treat these patients. Methods Quantitative iTRAQ LC/LC/MS/MS analysis was used to identify proteins that are differentially expressed in the urine of men with BPH compared with those who have localized PCa. These proteins were validated in 173 urine samples from patients diagnosed with BPH (N = 83) and PCa (N = 90). Multivariate logistic regression analysis was used to identify the predictive biomarkers. Results Three proteins, β2M, PGA3, and MUC3 were identified by iTRAQ and validated by immunoblot analyses. Univariate analysis demonstrated significant elevations in urinary β2M ( P  < 0.001), PGA3 ( P  = 0.006), and MUC3 ( P  = 0.018) levels found in the urine of PCa patients. Multivariate logistic regression analysis revealed AUC values ranging from 0.618 for MUC3 ( P  = 0.009), 0.625 for PGA3 ( P  < 0.008), and 0.668 for β2M ( P  < 0.001). The combination of all three demonstrated an AUC of 0.710 (95% CI: 0.631 – 0.788, P  < 0.001); diagnostic accuracy improved even more when these data were combined with PSA categories (AUC = 0.812, (95% CI: 0.740 – 0.885, P  < 0.001). Conclusions Urinary β2M, PGA3, and MUC3, when analyzed alone or when multiplexed with clinically defined categories of PSA, may be clinically useful in noninvasively resolving the dilemma of effectively discriminating between BPH and localized PCa.

Matrix metalloproteases (MMP) are a family of zinc‐ and calcium‐dependent proteolytic enzymes that play diverse roles in physiological and pathological processes. MMP‐mediated activities that have important physiological implications include cell migration and invasion, differentiation, proliferation, angiogenesis, apoptosis, inflammation, and platelet aggregation, which collectively contribute to diverse biological functions under normal and pathological conditions. By processing growth factors and cleaving cell adhesion molecules, MMPs serve as important regulators of epithelial to mesenchymal transition (EMT), an important process by which malignant tumor cells activate invasion and metastasis, one of the hallmarks of cancer. This chapter reviews the potential of MMPs as tools for cancer detection and prognosis and as monitors of disease progression and therapeutic efficacy. The many years spent identifying and characterizing the key functional roles of MMPs, disintegrin and metalloproteases (ADAMs), and their endogenous regulators, have provided the foundation for their current clinical relevance in a variety of human diseases.

This chapter contains sections titled: Introduction Cancer Biomarker Discovery Strategies Cancer Biomarkers Conclusions Summary Points Acknowledgments

Kans grass ( Saccharum spontaneum ) is a weed species that is frequently found in many heavy metal-enriched waste dumps including fly ash pond sites. In this study, among a collection of phosphate-solubilizing bacterial strains isolated from the rhizosphere of Saccharum spontaneum present in the abandoned ash pond site of Mejia Thermal Power Station (MTPS-DVC), three strains were characterized for their plant growth-promoting abilities. The isolates identified as Bacillus anthracis strain MHR2, Staphylococcus sp. strain MHR3 and Bacillus sp. strain MHR4 had phosphate solubilization indices of 2.86, 2.31 and 2.40 and they produced soluble phosphates of 700, 600 and 640 mg l −1 , respectively, in 4 days. In all the PSBs, pH significantly decreased, indicating the production of various organic acids. They showed other plant growth-promoting features like production of ammonia, siderophore, hydrocyanide and IAA. All of them were resistant to multiple heavy metals and antibiotics. Dry and fresh weight and shoot and root lengths of Brassica juncea L. increased in the presence of these isolates in pot cultures. The strains also increased phytoextraction ability of plants by enhancing the metal accumulation in plant tissues. Thus, the isolated indigenous and stress-adapted rhizobacteria may serve as potential biotechnological tool for the successful ecorestoration of various metal-contaminated sites.

Fly ash (FA), the major by-product of coal-fired thermal power plants, causes significant environmental degradation owing to its injurious heavy metal contents. Leaching of arsenic (As) from ash ponds is especially significant as As released from FA can increase As concentration of drinking water above maximum contaminant level of 10 ppb. The aim of this paper was demonstration of As bioremediation potential of indigenous As resistant bacteria present in the weathered pond ash sample. Ten isolates belonging to Bacillus, Micrococcus, Kytococcus and Staphylococcus genera were characterized. Biochemical tests showed reduction of relatively non toxic arsenate to more toxic arsenite by two strains while four strains showed oxidation of arsenite to arsenate. Two exoplolysaccharide producing strains were shown to absorb As within their biomass. Total heterotrophs versus As resistant heterotrophs counting performed showed that FA was enriched with As resistant heterotrophs. Column leaching based microcosm study revealed overall As detoxification potential of the isolated microbes.

This study evaluated the potential of a novel pre-validated “Picture Assisted Illustration Reinforcement” (PAIR) communication system and conventional verbal techniques for Oral Health Education (OHE) in terms of dentition status, gingival health, oral hygiene status, and practices in 7- to 18-year-old children with Autism Spectrum Disorder (ASD). A double-blind randomized controlled trial was undertaken in a school for children with autism from July to September 2022. A total of 60 children were randomly assigned into two groups: a PAIR group (n = 30) and a Conventional group (n = 30). Cognition and pre-evaluation of all the children were assessed by standardized scaling measures. A pre-validated closed-ended questionnaire was administered to caregivers of both groups. At a 12-week post-intervention, a clinical examination was performed using the World Health Organization (WHO) Oral Health Assessment form 2013, gingival and Oral Hygiene Index Simplified (OHI-S). The gingival scores in the PAIR group (0.35 ± 0.12) exhibited a statistically significant decline in scores as compared to Conventional group (0.83 ± 0.37), p = 0.043. Meanwhile, the oral hygiene scores in the PAIR group and Conventional group were 1.22 ± 0.14 and 1.94 ± 0.15, respectively (p < 0.05). A significant improvement in oral hygiene practices was observed in the PAIR group. Incorporating the PAIR technique resulted in significant progress in child cognitive ability and adaptive behavior, which reduced gingival scores and improved oral hygiene scores, consequently improving oral hygiene practices among children with ASD.