A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.

PURPOSE: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis. EXPERIMENTAL DESIGN: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR. RESULTS: HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF. CONCLUSIONS: Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies.

5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-ß-SMAD4 signaling.

Disseminated cancer cells (DCCs) in secondary organs can remain dormant for years to decades before reactivating into overt metastasis. Microenvironmental signals leading to cancer cell chromatin remodeling and transcriptional reprogramming appear to control onset and escape from dormancy. Here, we reveal that the therapeutic combination of the DNA methylation inhibitor 5-azacytidine (AZA) and the retinoic acid receptor ligands all-trans retinoic acid (atRA) or AM80, an RARα-specific agonist, promotes stable dormancy in cancer cells. Treatment of head and neck squamous cell carcinoma (HNSCC) or breast cancer cells with AZA+atRA induces a SMAD2/3/4-dependent transcriptional program that restores transforming growth factor ß (TGF-ß)-signaling and anti-proliferative function. Significantly, either combination, AZA+atRA or AZA+AM80, strongly suppresses HNSCC lung metastasis formation by inducing and maintaining solitary DCCs in a SMAD4+/NR2F1+ non-proliferative state. Notably, SMAD4 knockdown is sufficient to drive resistance to AZA+atRA-induced dormancy. We conclude that therapeutic doses of AZA and RAR agonists may induce and/or maintain dormancy and significantly limit metastasis development.

Molecular identification of Austrodiplostomum sp., an eye parasite among farmed tambaqui in Amazonia.

Austrodiplostomum Szidat & Nani, 1951 is a genus of parasitic digenetic trematodes widely distributed in the Neotropical region. Infects a wide variety of species, families and requests for freshwater fish. We identify samples of Austrodiplostomum sp, based on metacercariae isolates from eyes of tambaqui (Colossoma macropomum), a fish of high commercial importance in Brazil, and widely consumed by the population of the northern region. The sequences obtained clustered with A. compactum. This is the first report of the occurrence of diplostomids in farmed tambaqui in Amazonia.

Longitudinal study comparing IgG antibodies induced by heterologous prime­boost COVID­19 vaccine

ABSTRACT: Vaccines are critical cost­effective tools to control the COVID­19 pandemic. The heterologous prime­boost vaccination has been used by many countries to overcome supply issues, so the effectiveness and safety of this strategy need to be better clarified. This study aims to verify the effect of heterologous prime­boost COVID­19 vaccination on healthcare professionals from Dante Pazzanese Hospital in Brazil. It was performed serological assays of vaccinated individuals after 2­dose of CoronaVac (Sinovac; n = 89) or ChAdOx1 nCoV­19 (Oxford­AstraZeneca; n = 166) followed by a BNT162b2 booster (Pfizer­BioNTech; n = 255). The serum antibodies anti­S (spike), anti­N (nucleocapsid), and anti­RBD (receptor binding domain) were assessed by enzyme­linked immunosorbent assay. The heterologous booster dose induced a 10­fold higher anti­Spike antibody regardless of the 2­dose of a prime vaccine. It was strikingly observed that BNT162b2 enhanced levels of anti­spike antibodies, even in those individuals who did not previously respond to the 2­dose of CoronaVac. In conclusion, the heterologous scheme of vaccination using mRNA as a booster vaccine efficiently enhanced the antibody response against SARS­CoV­2, especially benefiting those elderly who were seronegative with a virus­inactivated vaccine.

IGF1R Inhibition Enhances the Therapeutic Effects of Gq/11 Inhibition in Metastatic Uveal Melanoma Progression.

Uveal melanoma (UM) is the most common intraocular tumor in adults, and up to 50% of patients develop metastatic disease, which remains uncurable. Because patients with metastatic UM have an average survival of less than 1 year after diagnosis, there is an urgent need to develop new treatment strategies. Although activating mutations in Gαq or Gα11 proteins are major drivers of pathogenesis, the therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating UM, possibly due to alternative signaling pathways and/or resistance mechanisms. Activation of the insulin-like growth factor 1 (IGF1) signaling pathway promotes cell growth, metastasis, and drug resistance in many types of cancers, including UM, where expression of the IGF1 receptor (IGF1R) correlates with a poor prognosis. In this article, we show that direct inhibition of Gαq/11 by the cyclic depsipeptide YM-254890 in combination with inhibition of IGF1R by linsitinib cooperatively inhibits downstream signaling and proliferation of UM cells. We further demonstrate that a 2-week combination treatment of 0.3 to 0.4 mg/kg of YM-254890 administered by intraperitoneal injection and 25 to 40 mg/kg linsitinib administered by oral gavage effectively inhibits the growth of metastatic UM tumors in immunodeficient NOD scid gamma (NSG) mice and identifies the IGF1 pathway as a potential resistance mechanism in response to Gαq/11 inhibition in UM. These data suggest that the combination of Gαq/11 and IGF1R inhibition provides a promising therapeutic strategy to treat metastatic UM.

Longitudinal study comparing IgG antibodies induced by heterologous prime-boost COVID-19 vaccine.

Vaccines are critical cost-effective tools to control the COVID-19 pandemic. The heterologous prime-boost vaccination has been used by many countries to overcome supply issues, so the effectiveness and safety of this strategy need to be better clarified. This study aims to verify the effect of heterologous prime-boost COVID-19 vaccination on healthcare professionals from Dante Pazzanese Hospital in Brazil. It was performed serological assays of vaccinated individuals after 2-dose of CoronaVac (Sinovac; n = 89) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca; n = 166) followed by a BNT162b2 booster (Pfizer-BioNTech; n = 255). The serum antibodies anti-S (spike), anti-N (nucleocapsid), and anti-RBD (receptor binding domain) were assessed by enzyme-linked immunosorbent assay. The heterologous booster dose induced a 10-fold higher anti-Spike antibody regardless of the 2-dose of a prime vaccine. It was strikingly observed that BNT162b2 enhanced levels of anti-spike antibodies, even in those individuals who did not previously respond to the 2-dose of CoronaVac. In conclusion, the heterologous scheme of vaccination using mRNA as a booster vaccine efficiently enhanced the antibody response against SARS-CoV-2, especially benefiting those elderly who were seronegative with a virus-inactivated vaccine.

Sequential IgG antibody monitoring for virus-inactivated and adenovirus-vectored COVID-19 vaccine in Brazilian healthcare workers.

Vaccination certainly is the best way to fight against the COVID-19 pandemic. In this study, the seroconversion effectiveness of two vaccines against severe acute respiratory syndrome coronavirus 2 was assessed in healthcare workers: virus-inactivated CoronaVac (CV, n = 303), and adenovirus-vectored Oxford-AstraZeneca (AZ, n = 447). The immunoglobulin G (IgG) antibodies anti-spike glycoprotein and anti-nucleocapsid protein were assessed by enzyme-linked immunosorbent assay at the time before vaccination (T1), before the second dose (T2), and 30 days after the second dose (T3). Of all individuals vaccinated with AZ, 100% (n = 447) exhibited seroconversion, compared to 91% (n = 276) that were given CV vaccine. Among individuals who did not respond to the CV, only three individuals showed a significant increase in the antibody level 4 months later the booster dose. A lower seroconversion rate was observed in elders immunized with the CV vaccine probably due to the natural immune senescence, or peculiarity of this vaccine. The AZ vaccine induced a higher humoral response; however, more common side effects were also observed. Nonvaccinated convalescent individuals revealed a similar rate of anti-spike IgG to individuals that were given two doses of CV vaccine, which suggests that only a one-shot COVID-19 vaccine could produce an effective immune response in convalescents.

Sequential IgG antibody monitoring for virus­inactivated and adenovirus­vectored COVID­19 vaccine in Brazilian health care workers

Vaccination certainly is the best way to fight against the COVID­19 pandemic. In this study, the seroconversion effectiveness of two vaccines against severe acute respiratory syndrome coronavirus 2 was assessed in healthcare workers: virus­inactivated CoronaVac (CV, n= 303), and adenovirus­vectored Oxford­AstraZeneca (AZ, n= 447). The immunoglobulin G (IgG) antibodies anti­spike glycoprotein and anti­nucleocapsid protein were assessed by enzyme­linked immunosorbent assay at the time before vaccination (T1), before the second dose (T2), and 30 days after the second dose (T3). Of all individuals vaccinated with AZ, 100% (n= 447) exhibited seroconversion, compared to 91% (n= 276) that were given CV vaccine. Among individuals who did not respond to the CV, only three individuals showed a significant increase in the antibody level 4 months later the booster dose. A lower seroconversion rate was observed in elders immunized with the CV vaccine probably due to the natural immune senescence, or peculiarity of this vaccine. The AZ vaccine induced a higher humoral response; however, more common side effects were also observed. Nonvaccinated convalescent individuals revealed a similar rate of anti­spike IgG to individuals that were given two doses of CV vaccine, which suggests that only a one­shot COVID­19 vaccine could produce an effective immune response in convalescents.

A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy.

Cancer cells disseminate and seed in distant organs, where they can remain dormant for many years before forming clinically detectable metastases. Here we studied how disseminated tumor cells sense and remodel the extracellular matrix (ECM) to sustain dormancy. ECM proteomics revealed that dormant cancer cells assemble a type III collagen-enriched ECM niche. Tumor-derived type III collagen is required to sustain tumor dormancy, as its disruption restores tumor cell proliferation through DDR1-mediated STAT1 signaling. Second-harmonic generation two-photon microscopy further revealed that the dormancy-to-reactivation transition is accompanied by changes in type III collagen architecture and abundance. Analysis of clinical samples revealed that type III collagen levels were increased in tumors from patients with lymph node-negative head and neck squamous cell carcinoma compared to patients who were positive for lymph node colonization. Our data support the idea that the manipulation of these mechanisms could serve as a barrier to metastasis through disseminated tumor cell dormancy induction.

An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy.

We describe the discovery of an agonist of the nuclear receptor NR2F1 that specifically activates dormancy programs in malignant cells. The agonist led to a self-regulated increase in NR2F1 mRNA and protein and downstream transcription of a novel dormancy program. This program led to growth arrest of an HNSCC PDX line, human cell lines, and patient-derived organoids in 3D cultures and in vivo. This effect was lost when NR2F1 was knocked out by CRISPR-Cas9. RNA sequencing revealed that agonist treatment induces transcriptional changes associated with inhibition of cell cycle progression and mTOR signaling, metastasis suppression, and induction of a neural crest lineage program. In mice, agonist treatment resulted in inhibition of lung HNSCC metastasis, even after cessation of the treatment, where disseminated tumor cells displayed an NR2F1hi/p27hi/Ki-67lo/p-S6lo phenotype and remained in a dormant single-cell state. Our work provides proof of principle supporting the use of NR2F1 agonists to induce dormancy as a therapeutic strategy to prevent metastasis.

Invasive phenotype in triple negative breast cancer is inhibited by blocking SIN3A-PF1 interaction through KLF9 mediated repression of ITGA6 and ITGB1.

SIN3A, a scaffold protein has regulatory functions in tumor biology. Through its Paired amphipathic helix (PAH2) domain, SIN3A interacts with PHF12 (PF1), a protein with SIN3 interaction domain (SID) that forms a complex with MRG15 and KDM5A/B. These components are often overexpressed in cancer. In the present study, we evaluated the role of SIN3A and its interacting partner PF1 in mediating inhibition of tumor growth and invasion in triple negative breast cancer (TNBC). We found profound inhibition of invasion, migration, and induction of cellular senescence by specific disruption of the PF1/SIN3A PAH2 domain interaction in TNBC cells expressing PF1-SID transcript or peptide treatment. Genome-wide transcriptomic analysis by RNA-seq revealed that PF1-SID downregulates several gene sets and pathways linked to invasion and migration. Integrin α6 (ITGA6) and integrin ß1 (ITGB1) and their downstream target proteins were downregulated in PF1-SID cells. We further determined increased presence of SIN3A and transcriptional repressor, KLF9, on promoters of ITGA6 and ITGB1 in PF1-SID cells. Knockdown of KLF9 leads to re-expression of ITGA6 and ITGB1 and restoration of the invasive phenotype, functionally linking KLF9 to this process. Overall, these data demonstrate that specific disruption of PF1/SIN3A, inhibits tumor growth, migration, and invasion. Also, PF1-SID not only inhibits tumor growth by senescence induction and reduced proliferation, but it also targets cancer stem cell gene expression and blocks mammosphere formation. Overall, these data demonstrate a mechanism whereby invasion and metastasis of TNBC can be suppressed by inhibiting SIN3A-PF1 interaction and enhancing KLF9 mediated suppression of ITGA6 and ITGB1.

Pharmacological prospection and structural characterization of two purified sulfated and pyruvylated homogalactans from green algae Codium isthmocladum.

Two sulfated polysaccharides (SPs), F2 and F3, isolated from Codium isthmocladum were found to contain galactose, sulfate, and pyruvate. The apparent molecular weights of F2 and F3 were determined to be 62 and 61 kDa, respectively. NMR spectroscopy combined with chemical analysis showed that F2 and F3 have the same structural features. However, F3 showed higher sulfate/sugar ratio (1/2.6) than F2 (1/4). F2 and F3 are essentially (1 → 3)-ß-D-galactans with some branching at C6. Pyruvylation occurs at O3 and O4, forming 3,4-O-(1-carboxyethylidene)-ß-D-Galp residues; some of these pyruvylated residues contain sulfate groups at C6. Some non-branching residues contain sulfate at C4. None of the SPs exhibited antioxidant activity. MTT results indicated that 1 mg/mL of both SPs about 40% of PANC-1 cell viability. At 10 µg/mL, F2 and F3 had 1.7-fold longer clotting times compared to that of Clexane® at the same concentration. The higher sulfate content of F3 is not a determining factor for pharmacological activities of galactans, considering that both F2 and F3 exerted the effects.

Use of Quality of Life in Cardiovascular Surgery in Coronary Artery Bypass Grafting: Validation, Reproducibility, and Quality of Life in One Year of Follow-Up.

BACKGROUND: The objectives of this study are to validate the Quality of Life in Cardiovascular Surgery (QLCS) questionnaire and to observe the evolution of quality of life in the first year of postoperative follow-up of patients who underwent coronary artery bypass grafting (CABG). METHODS: This was a prospective observational study of patients undergoing CABG from July 2016 to June 2017 who survived and answered the QLCS with 1, 6, and 12 months of follow-up. Validation was evaluated for internal consistency by Cronbach's alpha, test-retest reproducibility by correlation coefficient of concordance, and accuracy for interrater reliability by the kappa statistic. The nonparametric analysis of variance test was used for analysis of repeated measures, during follow-up, of the QLCS was considered significant at p < 0.05. RESULTS: Included were 360 patients, with a mean age of 63 years; 72% were men. Cronbach's alpha was 0.82, demonstrating adequate internal consistency. The correlation coefficient of concordance was 0.93 and accuracy 0.99, showing good precision and accuracy. The kappa statistic for questions ranged from 0.58 to 0.78, which ensures a moderate reproducibility. Scores of the QLCS in patients undergoing CABG of 17.69, 18.82, and 19.52 were found at 1, 6, and 12 months, respectively. Thus there was a progressive improvement in quality of life over the first year of follow-up (p < 0.0001). CONCLUSIONS: The QLCS proved to be a good questionnaire in this population, with adequate internal consistency and moderate reproducibility. Its use revealed a progressive and significant improvement in the quality of life of patients undergoing CABG.

Use of quality of life in cardiovascular surgery in coronary artery bypass grafting: validation, reproducibility, and quality of life in one year of follow-up

BACKGROUND: The objectives of this study are to validate the Quality of Life in Cardiovascular Surgery (QLCS) questionnaire and to observe the evolution of quality of life in the first year of postoperative follow-up of patients who underwent coronary artery bypass grafting (CABG). METHODS: This was a prospective observational study of patients undergoing CABG from July 2016 to June 2017 who was evaluated for internal consistency by Cronbach's alpha, test-retest reproducibility by correlation coefficient of concordance, and accuracy for interrater reliability by the kappa statistic. The nonparametric analysis of variance test was used for analysis of repeated measures, during follow-up, of the QLCS was considered significant at p < 0.05. RESULTS: Included were 360 patients, with a mean age of 63 years; 72% were men. Cronbach's alpha was 0.82, demonstrating adequate internal consistency. The correlation coefficient of concordance was 0.93 and accuracy 0.99, showing good precision and accuracy. The kappa statistic for questions ranged from 0.58 to 0.78, which ensures a moderate reproducibility. Scores of the QLCS in patients undergoing CABG of 17.69, 18.82, and 19.52 were found at 1, 6, and 12 months, respectively. Thus there was a progressive improvement in quality of life over the first year of follow-up (p < 0.0001). CONCLUSIONS: The QLCS proved to be a good questionnaire in this population, with adequate internal consistency and moderate reproducibility. Its use revealed a progressive and significant improvement in the quality of life of patients undergoing CABG. (AU)

Ingestion of plastic fragments by the Guri sea catfish Genidens genidens (Cuvier, 1829) in a subtropical coastal estuarine system.

One of the most recognized anthropogenic impacts in marine environments is solid waste pollution, especially plastic, which can be ingested by fish, thus interfering with their health. In this context, the aim of this study is to describe the ingestion of plastic fragments and to identify the possible effect of this contamination in the condition factor of Genidens genidens in the Laguna Estuarine System. The stomach contents of 92 G. genidens (26 juveniles and 66 adults) were analyzed. The Index of Relative Importance was performed to identify the contribution of each prey item. Condition factor (CF) was used to analyze the effect of plastic ingestion on the fish's body condition (by comparing individuals in the same ontogenetic phase). For the juveniles, eight items were observed, the most important of which were Penaeidae, followed by Portunidae and plastic. For the adults, 12 items were observed, the most important of which were Penaeidae, Portunidae, Polychaeta, and plastic. The analysis of CF demonstrated higher values for individuals without plastic in the stomach, which indicated a better health condition. The CF of a fish may be affected by variations in the physiological condition, environmental stresses, and nutritional and biological variations, and could be used to compare the body condition or health of a fish species. The ingestion of plastic could significantly influence the worst body condition of the individuals that were analyzed in the present study. The plastic pollution in marine coastal waters is associated with the appropriate waste management levels.

Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma.

Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell-cycle arrest and induction of apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. IMPLICATIONS: Oncogenic Gαq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

Feeding ecology and ingestion of plastic fragments by Priacanthus arenatus: What's the fisheries contribution to the problem?

Atlantic Bigeye (Priacanthus arenatus) is a demersal species from the Priacanthidae family with little literature relating to its biology and catch aspects. Due to this lack of research, the focus of this effort was to describe the feeding preferences of Atlantic Bigeye and to evaluate the influence of plastic debris derived from the local fisheries activities on its diet. The most important items were Corophiidae, Penaeidae, Actinopterygii, Isopoda, Cephalopoda, Policheta and plastic. Plastic was present in 49.17% of the stomachs analyzed. A total of 210 plastic fragments were found, and 63% were derived from fishing. Of those, 55% were derived from paint fragments from vessels and 8% from synthetic fibers (PA). The results suggest that plastic fragments found in stomachs are related to the species' natural diet and that this debris is locally deposited in the coastal environment. Fishing resources appear to have been affected by this local marine pollution.

Influence of fishing activity over the marine debris composition close to coastal jetty.

Worldwide, the marine debris emissions have been provoking impacts in ecosystems, generating massive mortality of different species with commercial interest. In South America, we have a lack of studies to verify the marine debris composition in transitional environments such as adjacent regions of coastal jetties. These are hydraulic engineering constructions used to maintain the navigation channel access between the sea-estuarine interface and are also used by teleost fishes, crustaceans, and mollusks like artificial shelters (reefs), being excellent fishing grounds. Therefore, the present study was devoted to qualitatively evaluate the composition of marine debris in an internal jetty portion of a Laguna Estuarine System (LES) located in South America (Brazil). Six hundred freediving were conducted to collect marine debris in the study region. The in situ campaigns were performed in 2016 during all spring season (sand substrata) in four distinct zones with 26,400 m2 each one covering almost all adjacent jetty extension, to evaluate possible spatial changes in the marine debris composition. All material obtained was identified, measured, weighed, and ordered in eight groups, with six groups being related to the fishing activity and two groups related to the tourism/community in the study region. So, it was possible to observe possible relations between the marine debris distribution to artisanal and recreational local fishing. After 600 freediving sampling efforts, 2142 marine debris items were obtained, totaling close to 100 kg of solid waste removed from the inner portion of the coastal jetty. Notably, 1752 units (50 kg) of fishing leads were collected being this item the main marine debris residue found in the four sampled areas, corresponding to nearly 50% of the total weight of the collected waste. Ninety-eight percent of marine debris were derived from the local fishing activities, and just 2% were derived from tourism/community. Considering the total contribution related to fishing, 83% of the marine debris were composed by lead (sinkers) adopted by recreational and artisanal fishing. Notably, the catch activity in this region has a close influence over the marine debris composition. Reductions of marine debris emissions derived from the fishing activities have been a global challenge, once this problem is occurring in practically all marine and estuarine environments under the anthropic action. The presence of marine debris changes the local landscape and can provoke serious environmental problems, such as ghost fishing that affects a wide variability of marine mammals, birds, and fishes. Most of marine debris collected came from recreational and artisanal fishing, being the fishing leads the most prominent material, especially in sector 4. This fact is possibly related to the intense mullet fishing using cast nets, usual in this sample area. In the other sectors, there was a great predominance of grapnel fishing leads, widely adopted by recreational fishermen in open water environments. The "fingernails" present in these fishing leads ensure the sinking of the line for a specific location independently of possible flow oscillations of the tidal current and/or currents generated by winds. The massive quantity of fishing leads into the sectors is a dangerous fact. Notably, lead is a heavy, non-biodegradable, and extremely toxic metal that, due to the anthropogenic activities, has been increasing around the world. Future efforts in our study region should evaluate the seasonal marine debris composition to observe possible changes along the different seasons of the year. In this way, it would be possible to infer quantitatively the emission of marine debris derived from the fishing activity, assessing its impacts and enabling the adoption of environmental management strategies. This effort adopted a qualitative analysis, serving to show the current situation of this region that we now know to be vulnerable to the presence of marine debris derived from the fishing activity.

Macrophages orchestrate breast cancer early dissemination and metastasis.

Cancer cell dissemination during very early stages of breast cancer proceeds through poorly understood mechanisms. Here we show, in a mouse model of HER2+ breast cancer, that a previously described sub-population of early-evolved cancer cells requires macrophages for early dissemination. Depletion of macrophages specifically during pre-malignant stages reduces early dissemination and also results in reduced metastatic burden at end stages of cancer progression. Mechanistically, we show that, in pre-malignant lesions, CCL2 produced by cancer cells and myeloid cells attracts CD206+/Tie2+ macrophages and induces Wnt-1 upregulation that in turn downregulates E-cadherin junctions in the HER2+ early cancer cells. We also observe macrophage-containing tumor microenvironments of metastasis structures in the pre-malignant lesions that can operate as portals for intravasation. These data support a causal role for macrophages in early dissemination that affects long-term metastasis development much later in cancer progression. A pilot analysis on human specimens revealed intra-epithelial macrophages and loss of E-cadherin junctions in ductal carcinoma in situ, supporting a potential clinical relevance.

Corrigendum: Mechanism of early dissemination and metastasis in Her2+ mammary cancer.

This corrects the article DOI: 10.1038/nature20609.