The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway

BACKGROUND: Colorectal cancer (CRC) remains largely incurable when diagnosed at the metastatic stage. Despite some advances in precision medicine for this disease in recent years, new molecular targets, as well as prognostic/predictive markers, are highly needed. Neuroligin 1 (NLGN1) is a transmembrane protein that interacts at the synapse with the tumor suppressor adenomatous polyposis Coli (APC), which is heavily involved in the pathogenesis of CRC and is a key player in the WNT/β-catenin pathway. METHODS: After performing expression studies of NLGN1 on human CRC samples, in this paper we used in vitro and in vivo approaches to study CRC cells extravasation and metastasis formation capabilities. At the molecular level, the functional link between APC and NLGN1 in the cancer context was studied. RESULTS: Here we show that NLGN1 is expressed in human colorectal tumors, including clusters of aggressive migrating (budding) single tumor cells and vascular emboli. We found that NLGN1 promotes CRC cells crossing of an endothelial monolayer (i.e. Trans-Endothelial Migration or TEM) in vitro, as well as cell extravasation/lung invasion and differential organ metastatization in two mouse models. Mechanistically, NLGN1 promotes APC localization to the cell membrane and co-immunoprecipitates with some isoforms of this protein stimulates β-catenin translocation to the nucleus, upregulates mesenchymal markers and WNT target genes and induces an “EMT phenotype” in CRC cell lines CONCLUSIONS: In conclusion, we have uncovered a novel modulator of CRC aggressiveness which impacts on a critical pathogenetic pathway of this disease, and may represent a novel therapeutic target, with the added benefit of carrying over substantial knowledge from the neurobiology field. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02465-4

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study.

There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0-99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. Ki67 at diagnosis did not discriminate responders to PARPi

Peroneal nerve involvement as initial manifestation of primary systemic vasculitis

We report a case of two patients with foot drop due to peroneal nerve infarct as early sign of two different forms of primary systemic vasculitides: a predominantly small-vessel p-antineutrophil cytoplasmic antibody-positive vasculitis (microscopic polyangiitis) and a predominantly medium-vessel vasculitis (polyarteritis nodosa)

"Benign" metastatic meningioma: clinico-pathological analysis of one case metastasising to the lung and overview on the concepts of either primitive or metastatic meningiomas of the lung.

Lung '' metastases '' of benign meningiomas are rarely described events of biological and clinical interest. We, here, report of a 70-year-old healthy woman found by CT scan to have multiple lesions, the two largest in the right lung on routine examination. Anamnesis revealed that the patient underwent a surgical resection of cerebral meningioma 12 years before. The larger lung lesion was a 3-cm node located in the right lung and was removed by wedge resection. Macroscopically, it showed well-defined borders, whitish colour and firm consistency; histologically, it was uniformly composed by spindle meningothelial cells arranged in fascicules including psammoma bodies. The morphological and immunohistochemical features of this lesion, together with the similarity with the original cerebral tumour and its indolent evolution, led to a final diagnosis of '' benign '' meningioma metastatic to the lung. Lung metastatic meningiomas may be a diagnostic challenge because of their unusual site of presentation and the possible confusion with primitive lung meningiomas or primary mesenchymal lung lesions. They represent a typical example of '' benign '' tumours that may implant to the lung similar to other tumours, definitely considered benign but reported to rarely present unusual secondary localization

Widespread and widely widening? : Examining absolute socioeconomic health inequalities in northern Sweden across twelve health indicators

Background: Socioeconomic inequalities in health is a widely studied topic. However, epidemiological research tends to focus on one or a few outcomes conditioned on one indicator, overlooking the fact that health inequalities can vary depending on the outcome studied and the indicator used. To bridge this gap, this study aims to provide a comprehensive picture of the patterns of socioeconomic health inequalities in Northern Sweden over time, across a range of health outcomes, using an 'outcome-wide' epidemiological approach. Method: Cross-sectional data from three waves of the 'Health on Equal Terms' survey, distributed in 2006, 2010 and 2014 were used. Firstly, socioeconomic inequalities by income and education for twelve outcomes (self-rated health, self-rated dental health, overweight, hypertension, diabetes, long-term illness, stress, depression, psychological distress, smoking, risky alcohol consumption, and physical inactivity) were examined by calculating the Slope Index of Inequality. Secondly, time trends for each outcome and socioeconomic indicator were estimated. Results: Income inequalities increased for psychological distress and physical inactivity in men as well as for selfrated health, overweight, hypertension, long-term illness, and smoking among women. Educational inequalities increased for hypertension, long-term illness, and stress (the latter favouring lower education) in women. The only instance of decreasing income inequalities was seen for long-term illness in men, while education inequalities decreased for long-term illness in men and poor self-rated health, poor self-rated dental health, and smoking in women. Conclusion: Patterns of absolute socioeconomic inequalities in health vary by health and socioeconomic indicator, as well as between men and women. Overall, trends appear more stagnant in men while they fluctuate in women. Income inequalities seem to be generally greater than educational inequalities when looking across several different health indicators, a message that can only be derived from this type of outcome-wide study. These disparate findings suggest that generalised and universal statements about the development of health inequalities can be too simplistic and potentially misleading. Nonetheless, despite inequalities being complex, they do exist and tend to increase. Thus, an outcome-wide approach is a valuable method which should be utilised to generate evidence for prioritisations of policy decision

Extra-osseous Ewing sarcoma of the thyroid gland mimicking lymphoma recurrence: a case report

Extra-osseous Ewing sarcomas/peripheral primitive neuroectodermal tumors (EOES/pPNETs) are high-grade malignant tumors found in various organs, such as the lung, skin, intestine, kidney and female genital tract; however, to the best of our knowledge, only two cases have previously been identified in the thyroid gland. We describe a case of primary EOES/PNET of the thyroid gland in a 66-year-old man with a previous history of large B cell lymphoma. During a routine follow-up examination, the patient underwent an ultrasound cervical scan showing a solid nodule of the left thyroid lobe. The fine-needle aspiration biopsy of the nodule suggested a neuroendocrine tumor. Histological and immunohistochemical examination of the surgical specimen supported a diagnosis of EOES/PNET, which was further confirmed by the demonstration of EWSR1 gene translocation by means of fluorescent in situ hybridization and by the detection of glycogen particles and neurosecretory granules by means of electron microscopy. Total body computed tomography and magnetic resonance imaging excluded the involvement of other sites, and therefore a diagnosis of primary EOES/PNET of the thyroid gland was made.This paper also discusses the main differential diagnoses, including lymphoma recurrence, other small round cell tumors (primary or metastatic), and a thyroid localization of an EWS/PNET from another organ