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The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

BackgroundIn the developed countries, uveal melanoma is the most common primary intraocular malignancy in adults. Little is known about the epidemiological and geographical distribution of uveal melanoma in Canada.MethodsTo determine the incidence patterns and geographical distribution of uveal melanoma cases in Canada, we conducted the first comprehensive, population-based national study of this malignancy across all Canadian provinces and territories during 1992–2010 years. We examined two independent population-based registries: the Canadian Cancer Registry and Le Registre Québécois du Cancer using corresponding International Classification of Diseases for Oncology-3rd edition codes for all histological subtypes of uveal melanoma.ResultsWe report that 2215 patients were diagnosed with uveal melanoma, of which 52.1% were males. The average -annual incidence rate of uveal melanoma in Canada was 3.75 cases per million individuals per year (95% CI 3.60 to 3.91). Overall, we report a steady increase in uveal melanoma incidence with an annual increase of 0.074 cases per million individuals per year. Significant differences in the incidence rates of uveal melanoma between Canadian provinces and territories were noted, where the highest crude incidence was in British Columbia and Saskatchewan with rates of 6.38 and 5.47 cases per million individuals per year, respectively.ConclusionsThis work, for the first time, defines the disease burden of uveal melanoma in Canada and highlights important longitudinal, geographical and spatial differences in the distribution of uveal melanoma in Canada.

ARS-CoV-2 is an enveloped positive-sense RNA coronavirus belonging to the Coronaviridae family, and its cellular entry depends mainly on the binding of S protein 1,2 to angiotensin-converting enzyme 2, a specific cellular receptor located at the surface of the host cells. 3,4 The SARS-CoV-2 viral particles' presence in the retina of deceased patients with COVID-19 has been suggested through the real-time polymerase chain reaction (PCR) and immunological methods to detect its main proteins. The eye is affected by COVID-19 infection, 5,6 and retinal changes were attributed to secondary microvascular and immunological changes. The aim of this study was to detect the presence of presumed SARS-CoV-2 viral particles in the retina of individuals who died of COVID-19 using fluorescence microcopy of tissues immunostained for S1 and nucleocapsid proteins and transmission electron microscopy of thin sections. MethodsThis investigational study was approved by the ethical and research committee at the Federal University of São Paulo in São Paulo, Brazil, and all patients' representatives agreed to participate through written consent applied after the patient's death. They were informed of the procedure and potential benefits and risks, and no compensation was received for agreeing to participate. Detailed demographic, medical history, concomitant events, medication history, hospitalization details, IMPORTANCE The presence of the SARS-CoV-2 virus in the retina of deceased patients with COVID-19 has been suggested through real-time reverse polymerase chain reaction and immunological methods to detect its main proteins. The eye has shown abnormalities associated with COVID-19 infection, and retinal changes were presumed to be associated with secondary microvascular and immunological changes.OBJECTIVE To demonstrate the presence of presumed SARS-CoV-2 viral particles and its relevant proteins in the eyes of patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe retina from enucleated eyes of patients with confirmed COVID-19 infection were submitted to immunofluorescence and transmission electron microscopy processing at a hospital in São Paulo, Brazil, from June 23 to July 2, 2020. After obtaining written consent from the patients' families, enucleation was performed in patients deceased with confirmed SARS-CoV-2 infection. All patients were in the intensive care unit, received mechanical ventilation, and had severe pulmonary involvement by COVID-19. MAIN OUTCOMES AND MEASURESPresence of presumed SARS-CoV-2 viral particles by immunofluorescence and transmission electron microscopy processing.RESULTS Three patients who died of COVID-19 were analyzed. Two patients were men, and 1 was a woman. The age at death ranged from 69 to 78 years. Presumed S and N COVID-19 proteins were seen by immunofluorescence microscopy within endothelial cells close to the capillary flame and cells of the inner and the outer nuclear layers. At the perinuclear region of these cells, it was possible to observe by transmission electron microscopy dou...

The distribution of our sample is similar to the one reported by the American Forces Institute of Pathology (AFIP) in 1994. When we compare our sample to others coming from countries with high levels of sunlight exposure, we found a lower incidence of ocular surface squamous neoplasia, including squamous cell carcinomas in Canada.

BackgroundMelanoma is the most common primary malignancy of the eye in adults. While the epidemiology of uveal melanoma has recently been described in Canada, little is known about the epidemiology and geographic distribution of patients with conjunctival melanoma (CM) in Canada.MethodsWe conducted a population-based study of CM incidence across all Canadian provinces and territories during 1992–2010 using two independent population-based registries.Results190 patients were diagnosed with CM in Canada from 1992 to 2010. 55.3 % of these patients were men. The mean annual incidence rate of CM in Canada was 0.32 cases per million individuals (0.35 and 0.29 cases per million individuals for men and women, respectively). The incidence rates for Canadian provinces demonstrated that the eastern provinces of Nova Scotia and New Brunswick had higher age-adjusted incidence rates than the national average, with rates of 0.52 and 0.47 cases per million individuals per year, respectively.ConclusionsThis analysis demonstrates novel variations in CM incidence rates between different Canadian provinces. These results taken together with the data reported from the USA confirm the North-to-South geographic gradient of increasing CM incidence. This research highlights that the epidemiology of CM in North America is comparable to that of cutaneous malignant melanoma in contrast to the trends for uveal melanoma distribution.

Background Melanoma is a life‐threatening group of cancers mainly affecting the skin (cutaneous melanoma, CM) and the eyes (uveal melanoma, UM). Nearly half of patients with UM develop liver metastases regardless of the primary treatment. For this reason, adjuvant therapy to prevent disease progression is essential to improve survival of patients with melanoma. Beta‐adrenoceptors (β‐AR) have emerged as novel targets to inhibit tumor growth and dissemination in CM, but have not been investigated in UM. Methods The aim of this study was to comprehensively evaluate the effects of a non‐selective β‐blocker in UM and CM. Propranolol was tested on four UM and two CM cell lines to determine the effects of this beta‐blocker. The expression of β‐AR in UM was assessed in enucleated eyes of 36 patients. Results The results showed that propranolol exerts potent anti‐proliferative effects, attenuates migration, reduces VEGF and induces cell cycle arrest and apoptosis in both UM and CM in a dose‐dependent manner. Furthermore, levels of cell‐free DNA released from the cells correlated to propranolol treatment and may be an indicator of treatment response. Finally, immunohistochemical analysis revealed the expression of β1 and β2 adrenoceptors in all UM patients, with higher expression seen in the more aggressive epithelioid versus less aggressive spindle cells. Conclusions Collectively our data suggest that a nonselective beta‐blocker may be effective against melanoma. For the first time, we show potent anti‐tumor effects in UM cells following propranolol administration and expression of β1 and β2 adrenoceptors in patient tissue.

We reported on the ability of immortalized or oncosuppressor-mutated cells (OMCs) to uptake circulating cancer-factors and give tumors when transplanted into mice. This led to the first biological based liquid biopsy test, which we called MATER-D platform. In the present study, we showed for the first time that a different type of OMCs (PTEN-deficient human epithelial MCF10A cells) turn malignant when exposed to cancer patient’s sera, confirming the concept that different cells with diverse oncosuppressor mutations can uptake cancer factors and be used in biological based liquid biopsy tests. Our observations were confirmed in a large variety of solid and haematological malignancies. This test was able to detect dysplasia and carcinomas in situ lesions in different organs and circulating factors in cancer patients years after the removal of their lesions. To our knowledge, this ability is unique and not shared by other liquid biopsy platforms. Immunohistochemistry analysis of the xenotransplants revealed identical patterns of differentiation regardless of the cancer type, showing that differentiation through horizontal transfer might be dependent on the nature of the target cells rather than the type of cancer factors. These data strengthen the notion that OMC-based liquid biopsy tests might be promising platforms for cancer screening.