Paracrine signaling from breast cancer cells causes activation of ID4 expression in tumor-associated macrophages

Background: Tumor-associated macrophages (TAMs) constitute a major portion of the leukocyte infiltrate found in breast cancer (BC). BC cells may reprogram TAMs in a pro-angiogenic and immunosuppressive sense. We previously showed that high expression of the ID4 protein in triple-negative BC cells leads to the induction of a proangiogenic program in TAMs also through the downregulation of miR-107. Here, we investigated the expression and function of the ID4 protein in TAMs. Methods: Human macrophages obtained from peripheral blood-derived monocytes (PBDM) and mouse RAW264.7 cells were used as macrophage experimental systems. ID4-correlated mRNAs of the TCGA and E-GEOD-18295 datasets were analyzed. Results: We observed that BC cells determine a paracrine induction of ID4 expression and activation of the ID4 promoter in neighboring macrophages. Interestingly, ID4 expression is higher in macrophages associated with invasive tumor cells compared to general TAMs, and ID4-correlated mRNAs are involved in various pathways that were previously reported as relevant for TAM functions. Selective depletion of ID4 expression in macrophages enabled validation of the ability of ID4 to control the expression of YAP1 and of its downstream targets CTGF and CYR61. Conclusion: Collectively, our results show that activation of ID4 expression in TAMs is observed as a consequence of BC cell paracrine activity and could participate in macrophage reprogramming in BC

Association between proton-pump inhibitors (PPI) and metronomic capecitabine (MCAP) as salvage treatment for patients with advanced gastro-intestinal tumoursa. A randomized phase II study

Background: Several researches have shown that acidification of tumor microenvironment is the basis for tumor invasiveness, ability to metastasize S382 Abstracts and cytotoxic agents resistance; therefore proton pump inhibitors (PPI) could significantly increase the chemosensitivity. In our retrospective work we have investigated the role of capecitabine (mCAP) at metronomic dosage of 1500 mg/die as salvage chemotherapy in patients with metastatic colorectal cancer, showing a moderately activity and well tolerability. In this prospective study we evaluated safety and activity of mCAP in the advanced gastro-intestinal patients and the putative chemosensitizing activity of a specific PPI (Rabeprazole) in association to this therap

Quaternary geographical sibling speciation and population structuring in the Eastern Atlantic skates (suborder Rajoidea) Raja clavata and R. straeleni

To access the final version, follow the next link. http://www.springerlink.com/content/t1809472211lk67q/Aim Geographical (allopatric) speciation is a dynamic process whose footprints in the living world are a continuum of stages of increasing divergence. Geographical speciation can also contribute to the evolution of marine taxa. This study looked for two of these evolutionary stages (i.e. structured populations and sibling species) in the diversification patterns of two Atlantic skates (Raja, suborder Rajoidea) which exhibited high morphological and ecological conservativism(undefined

Combination therapy of high-dose rabeprazole plus metronomic capecitabine in advanced gastrointestinal cancer: a randomized phase II trial

Abstract: Background: In recent years, proton pump inhibitors (PPIs) have been investigated at high-dose tomodulate tumormicroenvironment acidification thus restoring chemotherapeutic sensitivity. This is the first trial to study activity and safety of repurposing high dose rabeprazole combined with metronomic capecitabine (mCAP). Methods: A phase II study in which patients with gastrointestinal cancer, refractory to standard treatments, who had a life expectancy >3 months, were blind randomized 1:1 to mCAP, 1500 mg/daily, continuously with or without rabeprazole 1.5 mg/kg bid, three days a week. The primary endpoint was 3-months progression-free survival (PFS). The secondary endpoints were clinical benefit (CB) and overall survival (OS). Safety and plasma concentrations of capecitabine and its metabolites (50-DFUR and 5-FU) were also evaluated. Results: Sixty-seven (median age 69 years; 63% male; 84% colorectal cancer, 76% ECOG-PS 1; 84% pretreated with two or more lines of chemotherapy) out of 90 patients screened for eligibility, were randomized to receive mCAP+rabeprazole (n = 32) vs. mCAP (n = 35). All patients were evaluable for response. No significant dierence between mCAP+rabeprazole vs. mCAP, in terms of 3-months PFS rate (HR = 1.43, 95%CI 0.53–3.85; p = 0.477), median PFS (HR = 1.22, 95%CI 0.75–2.00, p = 0.420), CB (RR = 0.85, 95%CI 0.29–2.44; p = 0.786) and median OS (HR = 0.89, 95%CI 0.54–1.48; p = 0.664) was observed. However, a 3-year OS rate of 10% and 12% was reported in the mCAP-rabeprazole and mCAP groups, respectively. Overall, no grade 3 or 4 toxicity occurred but grade 1 or 2 adverse event of any type were more frequently in the mCAP+rabeprazole group than in the mCAP (OR 2.83, 95%CI 1.03–7.79; p = 0.043). Finally, there was not statistically significant dierence in the plasma concentration of capecitabine and its metabolites between the two groups. Conclusions: Although the adjunct of high dose rabeprazole to mCAP was not shown to aect mCAP activity, as PPI are being investigated worldwide as drugs to be repositioned in cancer treatment and also considering the limited sample size as well as the favorable safety profile of the combination in the present study, further clinical investigations are desirable

Correlation between visual field index and quality of life in glaucoma patients: a new tool to screen quality of life perception?

PurposeTo evaluate the correlation between the visual field index (VFI) and vision-related quality of life (QoL) considering several confounding variables that may have a positive or negative effect.MethodsWe conducted a cross-sectional, mono-centric study on glaucoma patients. Quality of life was examined with the NEI-VFQ 25 and the Glaucoma Symptom Scale (GSS). The visual field was examined with the Humphrey Field Analyzer. The variables considered were age, gender, comorbidities, years (at diagnosis and duration of the illness), treatment and related active principles, intraocular pressure, and visual acuity. The analysis was performed on both the better and the worse eye. The linear regression univariate analysis and the multivariate analyses were performed.ResultsIn total, 193 patients enrolled in the study. The mean age was 70.8 ± 10.4 years. The mean follow-up period since diagnosis 11.4 ± 9.2 years. Approximately 50% of the patients suffered from primary open angle glaucoma (POAG) and 45% were on monotherapy. The mean VFI was 81.3 ± 26. Regarding QoL, the NEI-VFQ total mean was 80.4 ± 17.8 and the GSS total score was 77.2 ± 21. Regarding NEI-VFQ 25, the single linear regression analysis found the following relations: age at time of visit (r = −0.30, p = 0.016), years of illness (r = −0.32, p = 0.020), the minimum and maximal visual acuity (r = 2.04 and r = 3.96, p < 0.001), the IOP min (r = 1.13, p = 0.002) and max (r = −0.52, p = 0.017), and the number of previous surgeries (r = −3.94, p < 0.001). The multivariate analysis found the following relations: gender (r = 5.13, p = 0.019), visual acuity max (r = 3.16, p < 0.001), and previous surgeries (r = −1.80, p = 0.032). Regarding GSS, the single linear regression analysis found relations with visual acuity (r = 2.37, p < 0.001), VFI (r = 0.41, p < 0.001), previous surgeries in the eye considered (r = −7.27, p < 0.001), and number of instillations (r = −3.67, p = 0.031). Data confirmed that a higher VFI has a positive impact on the score of both the NEI-VFQ 25 (r = 0.22, p = < 0.001) and the GSS questionnaire (r = 0.36, p < 0.001).ConclusionsThe study demonstrated a correlation between the VFI and QoL of patients and their visual and non-visual ocular symptoms and function both in the worst and in the better eye, even when accounting for several clinical and demographic confounding variables. Our data support that the visual field index is an important metric instrument in the follow up of patients with glaucoma

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

BACKGROUND: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31. METHODS: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients. RESULTS: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio. CONCLUSION: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.We thank Professor Franco Locatelli for critical reading this paper and for his suggestions. We would also like to thank the children ’ s parents, who gave their informed consent for publication and “Il cuore grande di Flavio ”Onlus. Dr. Marta Colletti is a post-doctoral fellow of the Umberto Veronesi Founda- tion. To Valentina Polcini for proofreading.S

An exploratory study to identify risk factors for the development of capecitabine-induced palmar plantar erythrodysesthesia (PPE)

Aims: to identify pre-treatment risk factors for the development of Palmar Plantar Erythrodysesthesia in participants receiving capecitabine monotherapy. Specifically the hypothesis that avoidance of activities that cause friction and pressure cause Palmar Plantar Erythrodysesthesia was tested. Background. Previous literature showed contradictory evidence on the subject of predictors of chemotherapy-induced Palmar Plantar Erythrodysesthesia. There is a lack of empirical evidence to support the theory that Palmar Plantar Erythrodysesthesia is caused by damage to the microcapillaries due to everyday activities that cause friction or pressure to the hands or feet. Design. Prospective epidemiological study of risk factors. Methods. Prospective data collection. All patients prior to commencing capecitabine monotherapy between 11 June 2009–31 December 2010, were offered recruitment into the study and followed up for six cycles of treatment (n = 174). Data were collected during semi-structured interviews, from participants’ diaries, physical examination of the hands and feet and review of notes. Data relating to activities that cause friction, pressure or heat were collected. Data were analysed using bivariate (chi-square and independent groups Student’s t) tests where each independent variable was analysed against Palmar Plantar Erythrodysesthesia. Results. The only variables that were associated with an increased risk of Palmar Plantar Erythrodysesthesia were a tendency to have warm hands and pre-existing inflammatory disease. Conclusions. This study gives no support for the hypothesis that avoidance of activities that cause friction and pressure cause Palmar Plantar Erythrodysesthesia