Post-surgery statin use contributes to favorable outcomes in patients with early breast cancer.

BACKGROUND: Statins are a group of lipid-lowering drugs with pleiotropic effects that include, but are not limited to the inhibition of cholesterol synthesis resulting in a wide range of anti-inflammatory, anti-tumor, immunomodulatory, and anti-thrombotic properties. This study aimed to determine the impact of the prior to- or after- breast surgery usage of statins on the tumor prognosis in breast cancer (BC) patients. METHODS: A cohort of patients diagnosed with early invasive ductal BC (n=301) at the Hospital Italiano de Buenos Aires, Argentina, with a minimum follow-up period of 10 years after the surgical procedure were included and stratified according to the time of use of statins and type of statin used. Then, local relapse-free survival (RFS), metastasis-free survival (MFS), bone metastasis-free survival (BMFS), visceral metastasis-free (VMFS), mixed metastasis (bone and visceral)-free survival (mix-MFS) and overall survival (OS) were analyzed. RESULTS: Statins usage after breast surgery was related with lesser metastatic occurrence (p=0.017), lower number of metastatic foci (p=0.034) and fewer dead events (p=0.041), as well as longer MFS (p=0.013) and OS (p=0.027). When stratified by the nature of statins (hydrophilic or lipophilic), only the relatively hydrophilic statin rosuvastatin (ROSU) had an impact on the increase of MFS and OS (p=0.018 and p=0.030, respectively). CONCLUSION: Post-surgery statins usage was associated with increased MFS and OS, with increased benefits of ROSU over simvastatin (SIM) or atorvastatin (ATOR). These results set the rationale for additional studies addressing the use of statins, and particularly, rosuvastatin, to improve the outcome of BC patients.

Adoptive T cell therapy for solid tumors: current landscape and future challenges.

Adoptive cell therapy (ACT) comprises different strategies to enhance the activity of T lymphocytes and other effector cells that orchestrate the antitumor immune response, including chimeric antigen receptor (CAR) T-cell therapy, T-cell receptor (TCR) gene-modified T cells, and therapy with tumor-infiltrating lymphocytes (TILs). The outstanding results of CAR-T cells in some hematologic malignancies have launched the investigation of ACT in patients with refractory solid malignancies. However, certain characteristics of solid tumors, such as their antigenic heterogeneity and immunosuppressive microenvironment, hamper the efficacy of antigen-targeted treatments. Other ACT modalities, such as TIL therapy, have emerged as promising new strategies. TIL therapy has shown safety and promising activity in certain immunogenic cancers, mainly advanced melanoma, with an exciting rationale for its combination with immune checkpoint inhibitors. However, the implementation of TIL therapy in clinical practice is hindered by several biological, logistic, and economic challenges. In this review, we aim to summarize the current knowledge, available clinical results, and potential areas of future research regarding the use of T cell therapy in patients with solid tumors.

Role of hydroxymethylglutharyl-coenzyme A reductase in the induction of stem-like states in breast cancer.

PURPOSE: De novo synthesis of cholesterol and its rate-limiting enzyme, 3-hydroxy-3-methylglutharyl-coenzyme A reductase (HMGCR), is deregulated in tumors and critical for tumor cell survival and proliferation. However, the role of HMGCR in the induction and maintenance of stem-like states in tumors remains unclear. METHODS: A compiled public database from breast cancer (BC) patients was analyzed with the web application SurvExpress. Cell Miner was used for the analysis of HMGCR expression and statin sensitivity of the NCI-60 cell lines panel. A CRISPRon system was used to induce HMGCR overexpression in the luminal BC cell line MCF-7 and a lentiviral pLM-OSKM system for the reprogramming of MCF-7 cells. Comparisons were performed by two-tailed unpaired t-test for two groups and one- or two-way ANOVA. RESULTS: Data from BC patients showed that high expression of several members of the cholesterol synthesis pathway were associated with lower recurrence-free survival, particularly in hormone-receptor-positive BC. In silico and in vitro analysis showed that HMGCR is expressed in several BC cancer cell lines, which exhibit a subtype-dependent response to statins in silico and in vitro. A stem-like phenotype was demonstrated upon HMGCR expression in MCF-7 cells, characterized by expression of the pluripotency markers NANOG, SOX2, increased CD44 +/CD24low/ -, CD133 + populations, and increased mammosphere formation ability. Pluripotent and cancer stem cell lines showed high expression of HMGCR, whereas cell reprogramming of MCF-7 cells did not increase HMGCR expression. CONCLUSION: HMGCR induces a stem-like phenotype in BC cells of epithelial nature, thus affecting tumor initiation, progression and statin sensitivity.

BRAF Inhibitors in Metastatic Colorectal Cancer and Mechanisms of Resistance: A Review of the Literature.

Metastatic colorectal cancer (mCRC) with mutated BRAF exhibits distinct biological and molecular features that set it apart from other subtypes of CRC. Current standard treatment for these tumors involves a combination of chemotherapy (CT) and VEGF inhibitors. Recently, targeted therapy against BRAF and immunotherapy (IT) for cases with microsatellite instability (MSI) have been integrated into clinical practice. While targeted therapy has shown promising results, resistance to treatment eventually develops in a significant portion of responsive patients. This article aims to review the available literature on mechanisms of resistance to BRAF inhibitors (BRAFis) and potential therapeutic strategies to overcome them.

Current Landscape of Immunotherapy for Advanced Sarcoma.

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine-kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research.

Peritumoral adipose tissue promotes lipolysis and white adipocytes browning by paracrine action.

Background: Stromal adipocytes and tumor breast epithelial cells undergo a mutual metabolic adaptation within tumor microenvironment. Therefore, browning and lipolysis occur in cancer associated adipocytes (CAA). However, the paracrine effects of CAA on lipid metabolism and microenvironment remodeling remain poorly understood. Methods: To analyze these changes, we evaluated the effects of factors in conditioned media (CM) derived from explants of human breast adipose tissue from tumor (hATT) or normal (hATN) on morphology, degree of browning, the levels of adiposity, maturity, and lipolytic-related markers in 3T3-L1 white adipocytes by Western blot, indirect immunofluorescence and lipolytic assay. We analyzed subcellular localization of UCP1, perilipin 1 (Plin1), HSL and ATGL in adipocytes incubated with different CM by indirect immunofluorescence. Additionally, we evaluated changes in adipocyte intracellular signal pathways. Results: We found that adipocytes incubated with hATT-CM displayed characteristics that morphologically resembled beige/brown adipocytes with smaller cell size and higher number of small and micro lipid droplets (LDs), with less triglyceride content. Both, hATT-CM and hATN-CM, increased Pref-1, C/EBPß LIP/LAP ratio, PPARγ, and caveolin 1 expression in white adipocytes. UCP1, PGC1α and TOMM20 increased only in adipocytes that were treated with hATT-CM. Also, hATT-CM increased the levels of Plin1 and HSL, while decreased ATGL. hATT-CM modified the subcellular localization of the lipolytic markers, favoring their relative content around micro-LDs and induced Plin1 segregation. Furthermore, the levels of p-HSL, p-ERK and p-AKT increased in white adipocytes after incubation with hATT-CM. Conclusions: In summary, these findings allow us to conclude that adipocytes attached to the tumor could induce white adipocyte browning and increase lipolysis as a means for endocrine/paracrine signaling. Thus, adipocytes from the tumor microenvironment exhibit an activated phenotype that could have been induced not only by secreted soluble factors from tumor cells but also by paracrine action from other adipocytes present in this microenvironment, suggesting a "domino effect".

Burnout in nursing: A vision of gender and "invisible" unrecorded care.

AIM: To reflect on how characteristics inherent in the nursing profession might be related to burnout syndrome among the nursing collective. BACKGROUND: Most people are unaware of the tasks and responsibilities of the nursing profession, as well as the burnout rates suffered by nurses. The nursing profession is a feminized profession, and this feminization may lead to the assignment of gender stereotypes and roles traditionally attributed to women. Much of the care provided by nurses is unrecorded, "invisible" and could be seen as an extension of their role as caregivers. METHODS: This is a discussion paper. The literature on gender stereotypes, unrecorded (invisible) care in nursing and burnout are the argumentative basis of this work. DISCUSSION: Stereotypes and gender roles may explain the lack of recognition of some of the carework carried out by nurses. Care, which is the essence of the profession, continues to be largely invisible and is not valued. This lack of recognition of invisible care, coupled with gender stereotypes, may help to understand burnout syndrome in nursing. IMPACT FOR NURSING: Health organizations should take into account the history of the nursing profession and the stereotypes associated with it. It is necessary to recognize and make visible much of the care provided by nurses which are not recorded (invisible care), since this would facilitate the visibilization of the workload and could reduce the possibility of suffering burnout. If we want quality care and staff who enjoy the greatest possible well-being, it will be necessary to take these variables into consideration. One purpose should be: to care for them so that they can provide quality care to others. NO PATIENT OR PUBLIC CONTRIBUTION: This is a discussion paper.

Receptor Tyrosine Kinase Inhibitors for the Treatment of Recurrent and Unresectable Bone Sarcomas.

Bone sarcomas are a heterogeneous group of rare tumors with a predominance in the young population. Few options of systemic treatment are available once they become unresectable and resistant to conventional chemotherapy. A better knowledge of the key role that tyrosine kinase receptors (VEGFR, RET, MET, AXL, PDGFR, KIT, FGFR, IGF-1R) may play in the pathogenesis of these tumors has led to the development of multi-target inhibitors (TKIs) that are progressively being incorporated into our therapeutic arsenal. Osteosarcoma (OS) is the most frequent primary bone tumor and several TKIs have demonstrated clinical benefit in phase II clinical trials (cabozantinib, regorafenib, apatinib, sorafenib, and lenvatinib). Although the development of TKIs for other primary bone tumors is less advanced, preclinical data and early trials have begun to show their potential benefit in advanced Ewing sarcoma (ES) and rarer bone tumors (chondrosarcoma, chordoma, giant cell tumor of bone, and undifferentiated pleomorphic sarcoma). Previous reviews have mainly provided information on TKIs for OS and ES. We aim to summarize the existing knowledge regarding the use of TKIs in all bone sarcomas including the most recent studies as well as the potential synergistic effects of their combination with other systemic therapies.

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates.

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

Periprostatic Adipose Tissue Microenvironment: Metabolic and Hormonal Pathways During Prostate Cancer Progression.

The periprostatic adipose tissue (PPAT) is a site of invasion of prostate cancer (PCa) and is part of the microenvironment. It was shown that PPAT secretes factors and fatty acids (FAs) that alter the microenvironment of the PCa. The PPAT secretome of patients with PCa-T3 stage (PPAT-T3) has a metabolic profile enriched in several pathways related to energy production, indicating a greater energy requirement by the tumor, when compared to that of patients in the PCa-T2 stage (PPAT-T2). PPAT-T3 also shows enrichment in pathways related to hormone response, polyamine synthesis, and control of protein synthesis, through amino acid, RNA, and nucleotide metabolism. PPAT-T2 and PPAT-BPH secretomes have less complex metabolic profile, both related with energy balance, while PPAT-BPH has hormone response through insulin pathway. Undoubtedly, a deeper characterization of the human PPAT will lead to a better understanding of the disease and possibly allow new stratification factors and the design of a specific therapy that targets crucial components of the tumor microenvironment as another way to treat or control the disease.

Renal peritumoral adipose tissue undergoes a browning process and stimulates the expression of epithelial-mesenchymal transition markers in human renal cells.

Tumor cells can interact with neighboring adipose cells and adipocyte dedifferentiation appears to be an important aspect of tumorigenesis. We evaluated the size of adipocytes in human adipose explants from normal (hRAN) and kidney cancer (hRAT); changes in the expression of WAT and BAT/beige markers in hRAN and hRAT; the expression of epithelial-mesenchymal transition (EMT) cell markers in human kidney tumor (786-O, ACHN and Caki-1); and non-tumor (HK-2) epithelial cell lines incubated with the conditioned media (CMs) of hRAN and hRAT. We observed that hRAT adipocytes showed a significantly minor size compared to hRAN adipocytes. Also, we observed that both Prdm16 and Tbx1 mRNA and the expression of UCP1, TBX1, PPARγ, PCG1α, c/EBPα LAP and c/EBPα LIP was significantly higher in hRAT than hRAN. Finally, we found an increase in vimentin and N-cadherin expression in HK-2 cells incubated for 24 h with hRAT-CMs compared to hRAN- and control-CMs. Furthermore, desmin and N-cadherin expression also increased significantly in 786-O when these cells were incubated with hRAT-CMs compared to the value observed with hRAN- and control-CMs. We observed a significant decrease in E-cadherin expression in the ACHN cell line incubated with hRAT-CMs versus hRAN- and control-CMs. However, we did not observe changes in E-cadherin expression in HK-2, 786-O or Caki-1. The results obtained, together with the results previously published by our group, allow us to conclude that perirenal white adipose tissue browning contributes to tumor development in kidney cancer. In addition, hRAT-CMs increases the expression of mesenchymal markers in renal epithelial cells, which could indicate a regulation of EMT due to this adipose tissue.

Paternal alcohol consumption has intergenerational consequences in male offspring.

PURPOSE: Alcoholism is a heterogeneous set of disorders caused by ethanol intake. Harmful effects of paternal consumption on the offspring are poorly explored and not fully understood. We analyzed the effect of paternal alcohol consumption on both their own reproductive capacity and that of their male offspring. METHODS: We used a model of ethanol consumption (15% v/v in drinking water) for 12 days in adult CF-1 male mice. DNA integrity and post-translational modifications of histones were assessed in sperm; testicular weight, histology, and DNA fragmentation were analyzed. Treated or untreated male mice were mated with non-treated females to obtain two cell embryos that were cultured for 7 days; morphology and embryonic cell death were evaluated. Males of both groups were mated with non-treated females. Adult male offspring was euthanized, and sperm and testicular parameters determined. RESULTS: Paternal ethanol consumption caused histological and epigenetic changes, as well as damage in DNA integrity in the testicular germline and sperm. These alterations gave rise to deleterious effects on embryonic development and to testicular and spermatic changes in the offspring. CONCLUSION: This study provides critical information on reproductive disturbances brought about by paternal alcohol consumption and the profound impact these could have on the male progeny. The need to explore the effects of paternal alcohol consumption in detail and warn about the importance of controlling alcohol intake for the well-being of future generations should not be underscored.

Oral health conditions and self-reported presence of pain in rowers: an epidemiology study / Condiciones de salud bucodental y presencia de dolor autodeclarado en remeros: un estudio epidemiológico / Condições de saúde bucal e autorrelato de dor em remadores: um estudo epidemiológico

ABSTRACT Introduction: Rowers are especially prone to oral health problems due to the massive consumption of supplements and isotonic drinks that lead eating disorders, due to the need for weight control, and to the development of teeth clenching caused by the constant activation of the chewing muscles during sports activity. Objective: To evaluate the oral health status of a group of Brazilian rowers and to identify the main risk factors influencing their oral health. Methods: One hundred and twenty rowers (84 men and 36 women) with an age of 24.16 ± 5.74 years participated in this study; an average height of 1.79 ± 0.09 cm and body mass of 75.02 ± 11.64 kg were detected by means of a questionnaire focused on the main factors that influence the deterioration in athletes' oral health. Results: The dental results revealed a significant number of rowers with the oral breathing pattern (46.7%), malocclusion (65.8%), bruxism (33.3%) and noise and/or pain in the TMJ (temporomandibular joint) (20.8%). The use of supplements and isotonic drinks (48.3%) and the incidence of bleeding gums (30.83%) were also found. Conclusion: The results show the importance of making rowers aware of the relevance of oral health and the need for prevention systems, ideally including sports dentistry specialists within the sports medicine departments of rowing clubs. Level of evidence II; Retrospective study.

RESUMEN Introducción: Los remeros son especialmente propensos a sufrir problemas de salud bucodental debido al uso masivo de suplementos e isotónicos, con tendencia a trastornos alimentarios por la exigencia de control de peso y el apretamiento dental, por la constante activación de los músculos masticatorios durante la actividad deportiva. Objetivo: Evaluar el estado bucal de un grupo de remeros brasileños e identificar los principales factores de riesgo para la salud bucal de estos deportistas. Material y método: En este estudio participaron 120 remeros (84 hombres y 36 mujeres) con una edad de 24,16 ± 5,74 años; una altura de 1,79 ± 0,09 cm y una masa corporal de 75,02 ± 11,64 kg, por medio de un cuestionario que indagó sobre los principales problemas de la salud bucodental de los deportistas. Resultados: Los resultados relativos al área dental revelaron un número significativo de remeros con patrón de respiración oral (46,7%), con historia de maloclusión (65,8%), con parafunción de bruxismo (33,3%) y con ruido y/o dolor de la ATM (articulación temporomandibular) (20,8%). El uso de suplementos e isotónicos (48,3%) y la incidencia de sangrado gingival (30,83%) son también datos relevantes encontrados. Conclusión: Los resultados obtenidos muestran la importancia de concientizar a esta categoría deportiva sobre la relevancia de la salud bucodental y establecer sistemas de prevención, preferiblemente con la inclusión de un especialista en odontología deportiva en el departamento de medicina deportiva de los clubes de remo. Nivel de evidencia II; Estudio retrospectivo.

RESUMO Introdução: Os remadores são particularmente propensos a problemas de saúde oral devido ao uso generalizado de suplementos e isotônicos, tendência a distúrbios alimentares pela exigência do controle de peso e ao cerramento dos dentes causado pela ativação constante dos músculos mastigatórios durante a atividade esportiva. Objetivo: Avaliar os distúrbios orais dos remadores brasileiros e identificar os principais fatores de risco de saúde bucal desses atletas. Métodos: Participaram deste estudo 120 remadores (84 homens e 36 mulheres) com idade de 24,16 ± 5,74 anos, estatura de 1,79 ± 0,09 cm e massa corporal de 75,02 ± 11,64 kg, que foram avaliados com um questionário que investigou os principais problemas de comprometimento da saúde oral dos atletas. Resultados: Os resultados odontológicos revelaram um número significativo de remadores com padrão respiratório oral (46,7%), com histórico de maloclusão (65,8%), com parafunção oclusal de bruxismo (33,3%) e com ruído e/ou dor na ATM (articulação temporomandibular) (20,8%). O uso de suplementos e isotônicos (48,3%) e a incidência de sangramento gengival (30,83%) também são achados relevantes. Conclusão: Os resultados obtidos mostram a importância de conscientizar essa categoria esportiva sobre a relevância da saúde oral e de estabelecer sistemas de prevenção, de preferência, com a inclusão de um especialista em odontologia do esporte no departamento de medicina esportiva dos clubes de remo. Nível de evidência II; Estudo retrospectivo.

Beige adipocytes contribute to breast cancer progression.

Adipocytes are the main stromal cells in the mammary microenvironment, and crosstalk between adipocytes and breast cancer cells may play a critical and important role in cancer maintenance and progression. Tumor­induced differentiation to beige/brown adipose tissue is an important contribution to the hypermetabolic state of breast cancer. However, the effect of epithelial cell­beige adipocyte communication on tumor progression remains unclear. To contribute to the understanding of this phenomenon, we characterized components present in conditioned media (CM) from beige adipocytes (BAs) or white adipocytes (WAs), and evaluated the effects of BA­ and WA­CM on both adhesion and migration of tumor (LM3, 4T1 and MC4­L1) and non­tumor (NMuMG) mouse mammary epithelial cell lines. Additionally, we analyzed the expression of ObR, CD44, vimentin, MMP­9, MCT1 and LDH in tumor and non­tumor mouse mammary epithelial cell lines incubated with BA­CM, WA­CM or Ctrol­CM (control conditioned media). 3T3­L1 preadipocytes differentiated into beige adipocytes upon PPARγ activation (rosiglitazone) displaying characteristics that morphologically resembled brown/beige adipocytes. Levels of UCP1, CIDEA, GLUT4, leptin, MCT4 and FABP4 were increased, while adiponectin, caveolin 1 and perilipin 1 levels were decreased in BAs with respect to WAs. Tumor cell lines revealed lower cell adhesion and increased cell migration after incubation with BA­ and WA­CM vs. Ctrol­CM. ObR and MMP­9 in MC4­L1 cells were significantly increased after incubation with BA­CM vs. WA­ and Ctrol­CM. In addition, MC4­L1 and LM3 cells significantly increased their migration in the presence of BAs, suggesting that new signals originating from the crosstalk between BAs and tumor cells, could be responsible for this change. Our results indicate that beige adipocytes are able to regulate the behavior of both tumor and non­tumor mouse mammary epithelial cells, favoring tumor progression.

The threat of COVID-19 and its influence on nursing staff burnout.

AIMS: To evaluate whether the perceived threat of COVID-19 moderates the influence of work resources and demands on burnout. DESIGN: A cross-sectional study. METHODS: We used a convenience sample of 771 nurses working in 10 hospitals in northern Spain. The data on burnout, demand, and resources at work and the perceived threat of COVID-19 were compiled in the second fortnight of April 2020 using an online questionnaire. We used several hierarchical linear regression models. RESULTS: Work overload, material and human resources and social support at work were significant in explaining burnout. The perceived threat of COVID-19 variable was also significant and presented the highest regression coefficient (ß = 0.392). The perceived threat of COVID-19 moderated the relationship between social support at work and burnout. CONCLUSION: The perceived threat of COVID-19 helped to explain the degree of burnout in nurses and moderated the relationship between social support at work and burnout. IMPACT: Hospitals should implement strategies to ensure that health emergency situations are not perceived as a threat. In pandemics, the organization should maintain clear, fluid, and regular communication with the nursing staff, which would help increase staff members' confidence and sense of control.

Entrepreneurs' Capacity for Mentalizing: Its Influence on Burnout Syndrome.

Burnout is a mental disorder that leads to difficulties for the entrepreneur in controlling his or her personal and professional life. The most common consequences of entrepreneurial burnout include the subject experiencing low motivation, low organizational commitment, loss of energy, demoralization in connection with their work, poor quality of work, feeling of failure, and the perception that his or her company is performing poorly. We used a sample of 157 Spanish entrepreneurs selected at random from the Iberian Balance Sheet Analysis System database. We employed the Spanish version of the Reflective Functioning Questionnaire to measure mentalizing and the Spanish version of the Maslach-Burnout Inventory-General Survey (MBI-GS) to measure burnout. This research showed that entrepreneurial burnout could be avoided in part if the entrepreneur achieved a good capacity for mentalizing. Hypomentalizing contributed to explaining entrepreneurs' levels of professional efficacy, cynicism, and emotional exhaustion. In contrast, the explanatory power of hypermentalizing was not significant for any of the dimensions of burnout. This study provides new evidence of burnout in entrepreneurs; a professional group with an important economic, politic, and social role has been little studied.

Human renal adipose tissue from normal and tumor kidney: its influence on renal cell carcinoma.

Tumor cells can interact with neighboring adipose tissue. We evaluated components present in human adipose explants from normal (hRAN) and kidney cancer (hRAT) tissue, and we evaluated the effects of conditioned media (CMs) from hRAN and hRAT on proliferation, adhesion and migration of tumor and non-tumor human renal epithelial cell lines. In addition, we evaluated the expression of AdipoR1, ObR, CD44, vimentin, pERK and pPI3K on cell lines incubated with CMs. hRAN were obtained from healthy operated donors, and hRAT from patients who underwent a nephrectomy. hRAT showed increased levels of versican, leptin and ObR; and decreased levels of perilipin, adiponectin and AdipoR1, compared to hRAN. Cell lines showed a significant decrease in cell adhesion and increase in cell migration after incubation with hRAT-CMs vs. hRAN- or control-CMs. Surprisingly, HK-2, 786-O and ACHN cells showed a significant decrease in cell migration after incubation with hRAN-CMs vs. control-CMs. No difference in proliferation of cell lines was found after 24 or 48 h of treatment with CMs. AdipoR1 in ACHN and Caki-1 cells decreased significantly after incubation with hRAT-CMs vs. hRAN-CMs and control-CMs. ObR and CD44 increased in tumor line cells, and vimentin increased in non-tumor cells, after incubation with hRAT-CMs vs. hRAN-CMs and control-CMs. We observed an increase in the expression of pERK and pPI3K in HK-2, 786-O and ACHN, incubated with hRAT-CMs. In conclusion, results showed that adipose microenvironment can regulate the behavior of tumor and non tumor human renal epithelial cells.

Lupane Triterpenoids and New Derivatives as Antiproliferative Agents Against Prostate Cancer Cells.

BACKGROUND/AIM: This study examined the potential role of natural triterpenoids lupeol, calenduladiol and heliantriol B2, and a set of 19 derivatives, as antiproliferative and antimetastatic agents against prostate cancer cells. MATERIALS AND METHODS: Natural triterpenoids were isolated from Chuqiraga erinaceae. Analogs were obtained by transformations of lupeol and calenduladiol. The effects of compounds on PC-3 and LNCaP cells were determined using the MTT assay. Compounds with half-maximal inhibitory concentration <70 µM were evaluated as antimetastatic agents by a wound-healing assay. RESULTS: Lupeol-3ß-sulfate, a new semisynthetic lupane, was the most active compound. In general, sulfated derivatives displayed higher activity than the lead against both cell lines. A new analog, calenduladiol-3ß-monosulfate, inhibited the migration of PC-3 cells; heliantriol B2 and 3ß-aminolupane inhibited the migration of LNCaP cells in a concentration-dependent manner. CONCLUSION: Our study provides novel agents with cytotoxic effects on prostate cancer cells, which may represent a potential new therapeutic approach for prostate cancer.

Human Periprostatic Adipose Tissue: Secretome from Patients With Prostate Cancer or Benign Prostate Hyperplasia.

BACKGROUND/AIM: Periprostatic adipose tissue (PPAT) directs tumour behaviour. Microenvironment secretome provides information related to its biology. This study was performed to identify secreted proteins by PPAT, from both prostate cancer and benign prostate hyperplasia (BPH) patients. PATIENTS AND METHODS: Liquid chromatography-mass spectrometry-based proteomic analysis was performed in PPAT-conditioned media (CM) from patients with prostate cancer (CMs-T) (stage T3: CM-T3, stage T2: CM-T2) or benign disease (CM-BPH). RESULTS: The highest number and diversity of proteins was identified in CM-T3. Locomotion was the biological process mainly associated to CMs-T and reproduction to CM-T3. Immune responses were enriched in CMs-T. Extracellular matrix and structural proteins were associated to CMs-T. CM-T3 was enriched in proteins with catalytic activity and CM-T2 in proteins with defense/immunity activity. Metabolism and energy pathways were enriched in CM-T3 and those with immune system functions in CMs-T. Transport proteins were enriched in CM-T2 and CM-BPH. CONCLUSION: Proteins and pathways reported in this study could be useful to distinguish stages of disease and may become targets for novel therapies.

Comparative proteomics of soluble factors secreted by human breast adipose tissue from tumor and normal breast.

Tumor progression depends on the tumor-stroma interaction. In the breast, adipose tissue is the predominant stromal type. We have previously demonstrated that conditioned media (CMs) from explants of human adipose tissue of tumor breasts (hATT) increase proliferation and migration of breast cancer epithelial cells when compared to human adipose tissue from normal breasts (hATN). In this work, we aim to identify specific proteins and molecular/biological pathways associated with the secretion profile of hATT and hATN explants. hATT-CMs and hATN-CMs were separated by SDS-PAGE and analyzed by means of two-dimensional nano-liquid chromatography-mass spectrometry. The data was analyzed using ProteoIQ and FunRich software. In addition, 42 cytokines from hATT-CMs and hATN-CMs were assayed by a protein antibody assay. Compared to hATN-CMs, hATT-CMs showed greater protein diversity. We found that hATT-CMs presented a greater amount of proteins related to complement system activity, metabolism and immune system, as well as proteins involved in a variety of biological processes such as signal transduction and cell communication. Specifically, apolipoprotein AI and AII, complement component 3, and vimentin and desmin were significantly increased in hATT-CMs versus hATN-CMs. Moreover, a multivariate discriminant analysis of the cytokines detected by the array showed that IL-6, MCP-2 and GRO cytokines were sufficient and necessary to differentiate hATT-CMs from hATN-CMs. This analysis also showed that the levels of these three cytokines, taken together, correlated with stage and histological grade of the tumor in the hATT-CMs group, and with body mass index in the hATN-CMs group.