Decrease in drug accumulation and in tumour aggressiveness marker expression in a fenretinide-induced resistant ovarianumour cell line

We investigated whether the efficacy of fenretinide (HPR) against ovarian tumours may be limited by induction of resistance. The human ovarian carcinoma cell line A2780, which is sensitive to a pharmacologically achievable HPR concentration (IC 50= 1 μM), became 10-fold more resistant after exposure to increasing HPR concentrations. The cells (A2780/HPR) did not show cross-resistance to the synthetic retinoid 6-[3-adamantyl-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and were not sensitive, similarly to the parent line, to all- trans -retinoic acid, 13- cis -retinoic acid or N-(4-methoxyphenyl)retinamide. A2780/HPR cells showed, compared to parental cells, a 3-fold reduction in colony-forming ability in agar. The development of HPR resistance was associated with a marked increase in retinoic acid receptor β (RARβ) mRNA and protein levels, which decreased, together with drug resistance, after drug removal. The expression of cell surface molecules associated with tumour progression including HER-2, laminin receptor and β1 integrin was markedly reduced. The increase in the levels of reactive oxygen species is not involved in HPR-resistance because it was similar in parental and resistant cells. Conversely differences in pharmacokinetics may account for resistance because, in A2780/HPR cells, intracellular peak drug levels were 2 times lower than in A2780 cells and an as yet unidentified polar metabolite was present. These data suggest that acquired resistance to HPR is associated with changes in marker expression, suggestive of a more differentiated status and may be explained, at least in part, by reduced drug accumulation and increased metabolism. © 2001 Cancer Research Campaign http://www.bjcancer.co

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

Intra-operative MRI facilitates tumour resection during trans-sphenoidal surgery for pituitary adenomas

Background During trans-sphenoidal microsurgical resection of pituitary adenomas, the extent of resection may be difficult to assess, especially when extensive suprasellar and parasellar growth has occurred. In this prospective study, we investigated whether intra-operative magnetic resonance imaging (iMRI) can facilitate tumour resection. Methods Twenty patients with macroadenomas, (16 non-functioning, three growth-hormone secreting and one pharmaco-resistant prolactinoma) were selected for surgery in the iMRI. The mean tumour diameter was 27 mm (range 11–41). The mean parasellar grade, according to the Knosp classification, was 2.3. Pre-operative coronal and sagittal T1-weighted and T2-weighted images were obtained. The trans-sphenoidal tumour resection was performed at the edge of the tunnel of a Signa SP 0.5-Tesla MRI. The surgeon aimed at a radical tumour resection that was followed by a peri-operative MRI scan. When a residual tumour was visualised and deemed resectable, an extended resection was performed, followed by another MRI scan. This procedure was repeated until the imaging results were satisfactory. In all patients, we were able to obtain images to assess the extent of resection and to classify the resection as either total or subtotal. Results After primary resection, eight out of 20 cases were classified as total resections. A second resection was performed in 11 of 12 cases classified as subtotal resections, and in four of these, total resection was achieved. A third resection was performed in three of the remaining seven cases with subtotal resections, but we did not achieve total resection in any of these cases. Therefore, the use of iMRI increased the number of patients with total resection from 8/20 (40%) to 12/20 (60%). The only observed complication was a transient spinal fluid leakage. Conclusion Intra-operative MRI during trans-sphenoidal microsurgery is useful in selected patients for a safe and more complete resection. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited

Is there a role for postoperative radiotherapy following open partial laryngectomy when prognostic factors on the pathological specimen are unfavourable? A survey of head and neck surgical/radiation oncologists

Our aim was to survey the opinions of Italian radiation and ENT oncologists regarding the role of postoperative radiotherapy (PRT) and the appropriate dose to be given to patients with remnant larynx (RL) after open partial laryngectomy (OPL). The radio-oncologists (RO s) of the Italian Radiation-Oncologist Association (AIRO) and the ENTs of the Head-Neck Oncology Society (AIOCC-IHNS) were contacted through a SurveyMonkey online interface questionnaire. There were 148 usable responses. The majority of RO s recommended PRT in the case of positive/close margins (R(+)/Rclose) or in the case of initial involvement of thyroid cartilage (pT3tci). In the same cases, ENTs prefer a "watch and wait" policy (w&w). Both disciplines recommended w&w in the case of negative margins (R(-)). Finally, the majority of RO s recommended irradiating RL with 62-66 Gy in R(+), with 56-66 Gy (61.4%) in Rclose and with 56-60 Gy (34%) in pT3tci. In Conclusion, OPL raises new considerations about PRT

Validity of the Postoperative Morbidity Survey after abdominal aortic aneurysm repair—a prospective observational study

BACKGROUND: Currently, there is no standardised tool used to capture morbidity following abdominal aortic aneurysm (AAA) repair. The aim of this prospective observational study was to validate the Postoperative Morbidity Survey (POMS) according to its two guiding principles: to only capture morbidity substantial enough to delay discharge from hospital and to be a rapid, simple screening tool. METHODS: A total of 64 adult patients undergoing elective infrarenal AAA repair participated in the study. Following surgery, the POMS was recorded daily, by trained research staff with the clinical teams blinded, until hospital discharge or death. We modelled the data using Cox regression, accounting for the competing risk of death, with POMS as a binary time-dependent (repeated measures) internal covariate. For each day for each patient, ‘discharged’ (yes/no) was the event, with the elapsed number of days post-surgery as the time variable. We derived the hazard ratio for any POMS morbidity (score 1–9) vs. no morbidity (zero), adjusted for type of repair (endovascular versus open), age and aneurysm size. RESULTS: The hazard ratio for alive discharge with any POMS-recorded morbidity versus no morbidity was 0.130 (95 % confidence interval 0.070 to 0.243). The median time-to-discharge was 13 days after recording any POMS morbidity vs. 2 days after scoring zero for POMS morbidity. Compliance with POMS completion was 99.5 %. CONCLUSIONS: The POMS is a valid tool for capturing short-term postoperative morbidity following elective infrarenal AAA repair that is substantial enough to delay discharge from hospital. Daily POMS measurement is recommended to fully capture morbidity and allow robust analysis. The survey could be a valuable outcome measure for use in quality improvement programmes and future research

Visual imagery and false memory for pictures:a functional magnetic resonance imaging study in healthy participants

BACKGROUND: Visual mental imagery might be critical in the ability to discriminate imagined from perceived pictures. Our aim was to investigate the neural bases of this specific type of reality-monitoring process in individuals with high visual imagery abilities. METHODS: A reality-monitoring task was administered to twenty-six healthy participants using functional magnetic resonance imaging. During the encoding phase, 45 words designating common items, and 45 pictures of other common items, were presented in random order. During the recall phase, participants were required to remember whether a picture of the item had been presented, or only a word. Two subgroups of participants with a propensity for high vs. low visual imagery were contrasted. RESULTS: Activation of the amygdala, left inferior occipital gyrus, insula, and precuneus were observed when high visual imagers encoded words later remembered as pictures. At the recall phase, these same participants activated the middle frontal gyrus and inferior and superior parietal lobes when erroneously remembering pictures. CONCLUSIONS: The formation of visual mental images might activate visual brain areas as well as structures involved in emotional processing. High visual imagers demonstrate increased activation of a fronto-parietal source-monitoring network that enables distinction between imagined and perceived pictures