Plexin-B1 plays a redundant role during mouse development and in tumour angiogenesis

<p>Abstract</p> <p>Background</p> <p>Plexins are a large family of transmembrane receptors for the Semaphorins, known for their role in the assembly of neural circuitry. More recently, Plexins have been implicated in diverse biological functions, including vascular growth, epithelial tissue morphogenesis and tumour development. In particular, PlexinB1, the receptor for Sema4D, has been suggested to play a role in neural development and in tumour angiogenesis, based on in vitro studies. However, the tissue distribution of PlexinB1 has not been extensively studied and the functional relevance of this receptor in vivo still awaits experimental testing. In order to shed light on PlexinB1 function in vivo, we therefore undertook the genomic targeting of the mouse gene to obtain loss of function mutants.</p> <p>Results</p> <p>This study shows that PlexinB1 receptor and its putative ligand, Sema4D, have a selective distribution in nervous and epithelial tissues during development and in the adult. PlexinB1 and Sema4D show largely complementary cell distribution in tissues, consistent with the idea that PlexinB1 acts as the receptor for Sema4D in vivo. Interestingly, PlexinB1 is also expressed in certain tissues in the absence of Sema4D, suggesting Sema4D independent activities. High expression of PlexinB1 was found in lung, kidney, liver and cerebellum.</p> <p>Mutant mice lacking expression of semaphorin receptor PlexinB1 are viable and fertile. Although the axon collapsing activity of Sema4D is impaired in PlexinB1 deficient neurons, we could not detect major defects in development, or in adult histology and basic functional parameters of tissues expressing PlexinB1. Moreover, in the absence of PlexinB1 the angiogenic response induced by orthotopically implanted tumours was not affected, suggesting that the expression of this semaphorin receptor in endothelial cells is redundant.</p> <p>Conclusion</p> <p>Our expression analysis suggests a multifaceted role of PlexinB1 during mouse development and tissue homeostasis in the adult. Nonetheless, the genetic deletion of PlexinB1 does not result in major developmental defects or clear functional abnormalities. We infer that PlexinB1 plays a redundant role in mouse development and it is not strictly required for tumour induced angiogenesis.</p

Post-Transplant Cyclophosphamide and Tacrolimus–Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors

Abstract Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571

Development of a 3D CZT Spectrometer System with Digital Readout for Hard X/Gamma-Ray Astronomy

We report on the development and of a complete X/γ rays detection system (10-1000 keV) based on CZT spectrometers with spatial resolution in three dimensions (3D) and a digital electronics acquisition chain. The prototype is made by packing four linear modules, each composed of one 3D CZT sensors. Each sensors is realized using a single spectroscopic graded CZT crystal of about 20×20×5 mm3. An electrode structure consisting of 12 collecting anodes with a pitch of 1.6 mm and 3 drift strips between each pair of anodes for 48 strips (0.15 mm wide) on the anodic side was adopted. The cathode is made of 10 strips with a pitch of 2 mm and orthogonal to anode side strips. Since the reading of the drift strips will carried out by putting in parallel all the strips that occupy the same place with respect to a collecting anode, the channels number for each sensors is only 25. The detector readout front-is based on custom designed low noise charge sensitive pre-amplifiers (CSP) implemented in hybrid 16 channels board. The CZT module and its CSP front-end provide the signals to a multichannel Digital Pulse Processing FPGA based system able to digitize and process continuously the signals. The digital system implement an innovative firmware that allow performing fine time-tagging, online pulse shape and height analysis with good energy resolution

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

A pilot study evaluating serum pro-prostate-specific antigen in patients with rising PSA following radical prostatectomy

[-2]pro-prostate-specific antigen (2pPSA), a proform of PSA, is a new marker in patients at risk of prostate cancer. We explored the potential role of 2pPSA in the identification of patients with metastatic progression following radical prostatectomy for prostate cancer. Seventy-six patients with biochemical (PSA) recurrence following radical prostatectomy were studied retrospectively. Diagnostic imaging performed at the time of biochemical recurrence confirmed metastatic disease in 31 of the 76 patients. Serum samples were collected and stored at the time of imaging-confirmed metastatic progression or at the most recent procedure for patients with negative imaging. Median values of PSA, free PSA (fPSA), %fPSA, 2pPSA and prostate health index (PHI) were compared between metastatic and non-metastatic patients by the Mann-Whitney U test. The results of each test were then correlated with metastatic status by univariate and multivariate logistic regression analysis. PSA, fPSA, %fPSA, 2pPSA serum concentrations and PHI values were statistically significantly higher in patients with metastatic disease. Results of the multivariate analysis revealed that 2pPSA remained a statistically significant predictor of imaging-proven metastatic prostate cancer among patients with biochemical recurrence. At a cut-off value of 12.25 pg/ml, 2pPSA outperformed the other markers in terms of sensitivity and specificity (97 and 80%, respectively) with respect to imaging-confirmed metastatic progression. This is the first study suggesting that 2pPSA predicts diagnostic imaging-proven metastatic disease in previously resected prostate cancer patients with biochemical recurrence. Our results merit validation in a prospective study