NF-κB contributes to MMP1 expression in breast cancer spheroids causing paracrine PAR1 activation and disintegrations in the lymph endothelial barrier in vitro

RELA, RELB, CREL, NFKB1 and NFKB2, and the upstream regulators NEMO and NIK were knocked-down in lymph endothelial cells (LECs) and in MDA-MB231 breast cancer spheroids to study the contribution of NF-κB in vascular barrier breaching. Suppression of RELA, NFKB1 and NEMO inhibited “circular chemo-repellent induced defects” (CCIDs), which form when cancer cells cross the lymphatic vasculature, by ~20–30%. Suppression of RELB, NFKB2 and NIK inhibited CCIDs by only ~10–15%. In MDA-MB231 cells RELA and NFKB1 constituted MMP1 expression, which caused the activation of PAR1 in adjacent LECs. The knock-down of MMP1 in MDA-MB231 spheroids and pharmacological inhibition of PAR1 in LECs inhibited CCID formation by ~30%. Intracellular Ca²⁺ release in LECs, which was induced by recombinant MMP1, was suppressed by the PAR1 inhibitor {"type":"entrez-protein","attrs":{"text":"SCH79797","term_id":"1052762130","term_text":"SCH79797"}}SCH79797, thereby confirming a functional intercellular axis: RELA/NFKB1 – MMP1 (MDA-MB231) – PAR1 (LEC). Recombinant MMP1 induced PAR1-dependent phosphorylation of MLC2 and FAK in LECs, which is indicative for their activity and for directional cell migration such as observed during CCID formation. The combined knock-down of the NF-κB pathways in LECs and MDA-MB231 spheroids inhibited CCIDs significantly stronger than knock-down in either cell type alone. Also the knock-down of ICAM-1 in LECs (a NF-κB endpoint with relevance for CCID formation) and knock-down of MMP1 in MDA-MB231 augmented CCID inhibition. This evidences that in both cell types NF-κB significantly and independently contributes to tumour-mediated breaching of the lymphatic barrier. Hence, inflamed tumour tissue and/or vasculature pose an additional threat to cancer progression.     

Need for diagnostic-centric care in dentistry: A case study from the Marshfield Clinic Health System

Background

The study objective was to evaluate the workflow of dental providers who use the existing electronic dental record (EDR) system at a large regional health care system to establish a diagnostic-centric culture as part of their dental practice. A further goal focused on identifying when improvements to the workflow and design of the EDR may be indicated.

Successful development and clinical translation of a novel anterior lamellar artificial cornea

Blindness due to corneal diseases is a common pathology affecting up to 23 million individuals worldwide. The tissue‐engineered anterior human cornea, which is currently being tested in a Phase I/II clinical trial to treat severe corneal trophic ulcers with preliminary good feasibility and safety results. This bioartificial cornea is based on a nanostructured fibrin–agarose biomaterial containing human allogeneic stromal keratocytes and cornea epithelial cells, mimicking the human native anterior cornea in terms of optical, mechanical, and biological behavior. This product is manufactured as a clinical‐grade tissue engineering product, fulfilling European requirements and regulations. The clinical translation process included several phases: an initial in vitro and in vivo preclinical research plan, including preclinical advice from the Spanish Medicines Agency followed by additional preclinical development, the adaptation of the biofabrication protocols to a good manufacturing practice manufacturing process, including all quality controls required, and the design of an advanced therapy clinical trial. The experimental development and successful translation of advanced therapy medicinal products for clinical application has to overcome many obstacles, especially when undertaken by academia or SMEs. We expect that our experience and research strategy may help future researchers to efficiently transfer their preclinical results into the clinical settings.     

Morphological changes in disc herniation in the lower cervical spine: an ultrastructural study

Introduction

The basis of disc degeneration is still unknown, but is believed to be a cell-mediated process. Apoptosis might play a major role in degenerative disc disease (DDD). The aim of this study was to correlate the viability of disc cells with the radiological degeneration grades (rDG) in disc herniation.

Materials and methods

Forty anterior IVD’s (C4–C7) from 39 patients with DDD were studied histologically and ultrastructurally to quantify healthy, “balloon”, chondroptotic, apoptotic and necrotic cells. Patients were classified to their rDG, as having either prolapse (P: DGII + III) and/or osteochondrosis (O: DGIV + V). Similar studies were undertaken on eight control discs.

Results

Cell death by necrosis (mean 35%) was common but differed not significantly in both groups. All patients with a disc prolapse DGII + III revealed balloon cells (iAF: mean 32%). All appeared alive and sometimes were hypertrophic. However, significantly less balloon cells were found in the O-Group. Control samples revealed no evidence of “balloon” cells in DGII and only a minor rate in DGIII.

Conclusion

According to the different rDG, quantitative changes were obvious in healthy and “balloon” cells, but not for cell death. At the moment it can only be hypothesized if “balloon” cells are part of a repair strategy and/or cause of disc herniation.     

What's unique about unique entities? An fMRI investigation of the semantics of famous faces and landmarks

Famous people and artifacts are referred to as "unique entities" (UEs) due to the unique nature of the knowledge we have about them. Past imaging and lesion experiments have indicated that the anterior temporal lobes (ATLs) as having a special role in the processing of UEs. It has remained unclear which attributes of UEs were responsible for the observed effects in imaging experiments. In this study, we investigated what factors of UEs influence brain activity. In a training paradigm, we systematically varied the uniqueness of semantic associations, the presence/absence of a proper name, and the number of semantic associations to determine factors modulating activity in regions subserving the processing of UEs. We found that a conjunction of unique semantic information and proper names modulated activity within a section of the left ATL. Overall, the processing of UEs involved a wider left-hemispheric cortical network. Within these regions, brain activity was significantly affected by the unique semantic attributes especially in the presence of a proper name, but we could not find evidence for an effect of the number of semantic associations. Findings are discussed in regard to current models of ATL function, the neurophysiology of semantics, and social cognitive processing.     

T3+ and T4 Rectal Cancer Patients Seem to Benefit From the Addition of Oxaliplatin to the Neoadjuvant Chemoradiation Regimen

Background

To achieve T-downstaging and better resectability in locally advanced rectal cancer, neoadjuvant radiochemotherapy (RCT) has become the current standard of treatment. A variety of schemes have been used. This study investigates which scheme had the best effect on these parameters.

Methods

Our institution is a referral center for locally advanced rectal cancer. Different neoadjuvant radiochemotherapy regimens were administered: long course radiotherapy (RTH), 5-FU and leucovorin (5FUBolus), a combination of capecitabine and oxaliplatin (CORE), and capecitabine only (CAP). Selection of patients for 1 of the regimens was based on hospital policy rather than patient or tumor characteristics.

Results

The data of 504 consecutive patients (n?=?181 T3+, n?=?323 T4) without metastatic disease (cM0) who underwent surgery for advanced rectal carcinoma between 1994 and 2010 were reviewed. The RTH, 5FUBolus, CORE, and CAP scheme were administered to 106, 137, 155, and 106 patients, respectively. Odds ratios for downstaging were less effective for RTH, 5FUBolus, and CAP (0.31, 0.44, and 0.31; P?P?=?.003) or CRM+ resection (3.78, 2.73, 1.34; P?=?.001) were also in favor of the CORE. Hazard ratios for CSS were significantly better for the CORE scheme.

Conclusions

Downstaging with neoadjuvant treatment results in an increased number of radical resections. In our study, the combination of capecitabine and oxaliplatin appears to be the most effective regimen for locally advanced rectal cancer tumors. However, longer follow-up will be necessary to confirm this conclusion.     

Pulmonary nocardiosis in patients with COPD: characteristics and prognostic factors

IntroductionPulmonary nocardiosis (PN) is a severe infection with a high morbidity and mortality that mainly affects immunocompromised patients. In recent years, an increase in PN cases has been detected among patients with chronic obstructive pulmonary disease (COPD). The factors that are associated with its presence and determine its prognosis remain unknown.MethodsRetrospective study of COPD patients diagnosed with PN over the period from 1997 to 2009 at the Hospital de la Santa Creu i Sant Pau, in Barcelona (Spain). Demographic, clinical, microbiological and evolution data were evaluated in all cases.ResultsThirty patients were identified with PN and COPD. Mean age (standard deviation) was 76 (7) years and the mean FEV₁ was 40 (14)%. Chronic respiratory failure was observed in 56.7% patients and 51.7% had received systemic corticosteroid therapy previous to the PN diagnosis. The most common symptoms were cough and dyspnea (90%). Alveolar infiltrates were observed in 60% of the cases. The most frequently isolated Nocardia species was N. cyriacigeorgica (68%). The one-month mortality rate was 17%, while the one-year mortality rate was 33%. The factors associated with mortality within the first year included previous systemic corticosteroid treatment, less than three months of specific antibiotic therapy and active associated neoplasm.ConclusionsPN affects patients with moderate-severe COPD and has high short- and mid-term mortality rates. Previous corticosteroid treatment, specific antibiotic therapy for less than 3 months and active neoplasia were factors associated with mortality.