Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X

Context  Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown. Objective  To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities. Design, Setting, and Participants  Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses. Main Outcome Measures  Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. Results  Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001). Conclusions  Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.      

Antiangiogenic properties of fibstatin, an extracellular FGF-2-binding polypeptide

By using the two-hybrid system with basic fibroblast growth factor (FGF-2) as bait, we isolated and characterized fibstatin, an endogenous M(r) 29,000 human basement membrane-derived inhibitor of angiogenesis and tumor growth. Fibstatin, a fragment containing the type III domains 12-14 of fibronectin, was produced as a recombinant protein and was shown to inhibit the proliferation, migration, and differentiation of endothelial cells in vitro. Antiangiogenic activity of fibstatin was confirmed in a Matrigel angiogenesis assay in vivo, and electrotransfer of the fibstatin gene into muscle tissue resulted in reduced B16F10 tumor growth. Taken together, these results suggest that fibstatin could act as a powerful molecule for antiangiogenic therapy.     

Loss of N‐WASP drives early progression in an Apc model of intestinal tumourigenesis

N‐WASP (WASL) is a widely expressed cytoskeletal signalling and scaffold protein also implicated in regulation of Wnt signalling and homeostatic maintenance of skin epithelial architecture. N‐WASP mediates invasion of cancer cells in vitro and its depletion reduces invasion and metastatic dissemination of breast cancer. Given this role in cancer invasion and universal expression in the gastrointestinal tract, we explored a role for N‐WASP in the initiation and progression of colorectal cancer. While deletion of N‐wasp is not detectably harmful in the murine intestinal tract, numbers of Paneth cells increased, indicating potential changes in the stem cell niche, and migration up the crypt–villus axis was enhanced. Loss of N‐wasp promoted adenoma formation in an adenomatous polyposis coli (Apc) deletion model of intestinal tumourigenesis. Thus, we establish a tumour suppressive role of N‐WASP in early intestinal carcinogenesis despite its later pro‐invasive role in other cancers. Our study highlights that while the actin cytoskeletal machinery promotes invasion of cancer cells, it also maintains normal epithelial tissue function and thus may have tumour suppressive roles in pre‐neoplastic tissues. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors

The neurotrophin brain-derived neurotrophic factor (BDNF) is required for the maintenance of cardiac vessel wall stability during embryonic development through direct angiogenic actions on endothelial cells expressing the tropomysin receptor kinase B (TrkB). However, the role of BDNF and a related neurotrophin ligand, neurotrophin-4 (NT-4), in the regulation of revascularization of the adult tissues is unknown. To study the potential angiogenic capacity of BDNF in mediating the neovascularization of ischemic and non-ischemic adult mouse tissues, we utilized a hindlimb ischemia and a subcutaneous Matrigel model. Recruitment of endothelial cells and promotion of channel formation within the Matrigel plug by BDNF and NT-4 was comparable to that induced by VEGF-A. The introduction of BDNF into non-ischemic ears or ischemic limbs induced neoangiogenesis, with a 2-fold increase in the capillary density. Remarkably, treatment with BDNF progressively increased blood flow in the ischemic limb over 21 days, similar to treatment with VEGF-A. The mechanism by which BDNF enhances capillary formation is mediated in part through local activation of the TrkB receptor and also by recruitment of Sca-1+CD11b+ pro-angiogenic hematopoietic cells. BDNF induces a potent direct chemokinetic action on subsets of marrow-derived Sca-1+ hematopoietic cells co-expressing TrkB. These studies suggest that local regional delivery of BDNF may provide a novel mechanism for inducing neoangiogenesis through both direct actions on local TrkB-expressing endothelial cells in skeletal muscle and recruitment of specific subsets of TrkB+ bone marrow-derived hematopoietic cells to provide peri-endothelial support for the newly formed vessels.     

Prevalence and characteristics of moderate to severe pulmonary hypertension in systemic sclerosis with and without interstitial lung disease

OBJECTIVE: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD). METHODS: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH. RESULTS: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD. CONCLUSION: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.     

Complex functions of phosphatidylinositol 4,5-bisphosphate in regulation of TRPC5 cation channels

The canonical transient receptor potential (TRPC) proteins have been recognized as key players in calcium entry pathways activated through phospholipase-C-coupled receptors. While it is clearly demonstrated that members of the TRPC3/6/7 subfamily are activated by diacylglycerol, the mechanism by which phospholipase C activates members of the TRPC1/4/5 subfamily remains a mystery. In this paper, we provide evidence for both negative and positive modulatory roles for membrane polyphosphoinositides in the regulation of TRPC5 channels. Depletion of polyphosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate (PIP₂) through inhibition of phosphatidylinositol 4-kinase activates calcium entry and membrane currents in TRPC5-expressing but not in TRPC3- or TRPC7-expressing cells. Inclusion of polyphosphatidylinositol 4-phosphate or PIP₂, but not phosphatidylinositol 3,4,5-trisphosphate, in the patch pipette inhibited TRPC5 currents. Paradoxically, depletion of PIP₂ with a directed 5-phosphatase strategy inhibited TRPC5. Furthermore, when the activity of single TRPC5 channels was examined in excised patches, the channels were robustly activated by PIP₂. These findings indicate complex functions for regulation of TRPC5 by PIP₂, and we propose that membrane polyphosphoinositides may have at least two distinct functions in regulating TRPC5 channel activity. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Mohamed Trebak and Loic Lemonnier contributed equally to this work.     

TLR4 and MyD88 control protection and pulmonary granulocytic recruitment in a murine intranasal RSV immunization and challenge model

An intranasal vaccine composed of Toll-like receptor 2 (TLR2) ligand Neisseria meningitidis outer membrane proteins and Toll-like receptor 4 (TLR4) ligand Shigella flexneri lipopolysaccharide (LPS) (Protollin) and enriched respiratory syncytial virus (RSV) proteins (eRSV) has been demonstrated to promote balanced Th1/Th2 responses without eosinophil recruitment and to protect against challenge in mouse models. We used TLR2, TLR4 and myeloid differentiation factor 88 (MyD88) knock-out (-/-) mice to investigate the roles of these signalling pathways on immunogenicity, protection and pulmonary infiltrates following RSV immunization and challenge. Antigen-specific systemic and mucosal antibody production was significantly impaired only in TLR4-/- mice following Protollin–eRSV immunization. In contrast, an intact MyD88 pathway was crucial to elicit a balanced type 1:type 2 immune response, characterized by increased splenocyte production of antigen-induced IFNγ and IL-10 with concomitant reduction of IL5, IgG2a isotype switching and abrogation of pulmonary eosinophil recruitment following challenge. MyD88-dependent signalling also contributed to neutrophil recruitment to the lungs following immunization with eRSV antigen, in the presence or absence of Protollin, compared to a mock antigen or vaccine. Both TLR4 and MyD88-signalling were required for optimal protection against challenge. The upregulation of early signalling molecules IFN-β, TNFα, CD40 and CD86 were studied in splenocytes isolated from naïve TLR2, TLR4 and MyD88-/- mice following stimulation with vaccine components. Splenocytes from TLR4-/- mice displayed reduced IFN-β while those of MyD88-/- mice elicited less TNFα and lower expression of CD40 and CD86 on CD11c+ cells. Together, our results suggest that optimal immunogenicity and protection against RSV without risk of enhanced pulmonary inflammation requires intact TLR4/MyD88-dependent signalling.     

EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis

OBJECTIVES: To develop the European League Against Rheumatism (EULAR) recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis. METHODS: An expert consensus group was formed consisting of rheumatologists, nephrologists and specialists in internal medicine representing five European countries and the USA, a clinical epidemiologist and representatives from regulatory agencies. Using an evidence-based and expert opinion-based approach in accordance with the standardised EULAR operating procedures, the group identified nine topics for a systematic literature search through a modified Delphi technique. On the basis of research questions posed by the group, recommendations were derived for conducting clinical studies and/or clinical trials in systemic vasculitis. RESULTS: Based on the results of the literature research, the expert committee concluded that sufficient evidence to formulate guidelines on conducting clinical trials was available only for anti-neutrophil cytoplasm antibody-associated vasculitides (AAV). It was therefore decided to focus the recommendations on these diseases. Recommendations for conducting clinical trials in AAV were elaborated and are presented in this summary document. It was decided to consider vasculitis-specific issues rather than general issues of trial methodology. The recommendations deal with the following areas related to clinical studies of vasculitis: definitions of disease, activity states, outcome measures, eligibility criteria, trial design including relevant end points, and biomarkers. A number of aspects of trial methodology were deemed important for future research. CONCLUSIONS: On the basis of expert opinion, recommendations for conducting clinical trials in AAV were formulated. Furthermore, the expert committee identified a strong need for well-designed research in non-AAV systemic vasculitides.     

An underrecognized source of organ donors: patients with brain death after successfully resuscitated cardiac arrest

Objective To identify predictors of brain death after successful resuscitation of out-of-hospital cardiac arrest (OHCA), with the goal of improving the detection of brain death, and to evaluate outcomes of solid organs harvested from these patients. Design and setting Prospective observational cohort study in a medical and surgical unit of a nonuniversity hospital. Patients Patients with successfully resuscitated OHCA were prospectively included in a database over a 7-year period. We looked for early predictors of brain death and compared outcomes of organ transplants from these patients to those from patients with brain death due to head injury or stroke. Results Over the 7-year period 246 patients were included. No early predictors of brain death were found. Of the 40 patients (16%) who met criteria for brain death, after a median ICU stay of 2.5 days (IQR 2.0–4.2), 19 donated 52 solid organs (29 kidneys, 14 livers, 7 hearts, and 2 lungs). Outcomes of kidneys and livers did not differ between donors with and without resuscitated cardiac arrest. Conclusions Brain death may occur in about one-sixth of patients after successfully resuscitated OHCA, creating opportunities for organ donation. C. A. received a grant from the publicly funded organization Agence de Biomédecine which manages organ donor data in France.