The extracellular matrix (ECM) from perilesional and colorectal carcinoma (CRC), but not healthy colon, sustains proliferation and invasion of tumor cells. We investigated the biochemical and physical diversity of ECM in pair-wised comparisons of healthy, perilesional and CRC specimens. Progressive linearization and degree of organization of fibrils was observed from healthy to perilesional and CRC ECM, and was associated with a steady increase of stiffness and collagen crosslinking. In the perilesional ECM these modifications coincided with increased vascularization, whereas in the neoplastic ECM they were associated with altered modulation of matrisome proteins, increased content of hydroxylated lysine and lysyl oxidase. This study identifies the increased stiffness and crosslinking of the perilesional ECM predisposing an environment suitable for CRC invasion as a phenomenon associated with vascularization. The increased stiffness of colon areas may represent a new predictive marker of desmoplastic region predisposing to invasion, thus offering new potential application for monitoring adenoma with invasive potential.

The interplay between tumor cells and the microenvironment has been recognized as one of the hallmarks of cancer biology. To assess the role of extracellular matrix (ECM) in the modulation of tissue homeostasis and tumorigenesis, we developed a protocol for the purification of tissue-derived ECM using mucosae from healthy human colon, perilesional area, and colorectal carcinoma (CRC). Matched specimens were collected from the left colon of patients undergoing CRC resection surgery. ECMs were obtained from tissues that were decellularized with hypotonic solutions containing ionic and nonionic detergents, hypertonic solution, and endonuclease in the absence of denaturing agents. Mucosae-derived ECMs maintained distribution and localization of proteins and glycoproteins typical of the original tissues, and showed different three-dimensional (3D) structures among normal versus perilesional and tumor-derived stroma. The three types of ECM differentially regulated the localization and organization of seeded monocytes and cancer cells that were located and organized as in the original tissue. Specifically, healthy, perilesional, and CRC-derived ECMs sustained differentiation and polarization of cancer epithelial cells. In addition, healthy, but not perilesional and CRC-derived ECM constrained invasion of cancer cells. All three ECMs sustained turnover between cell proliferation and death up to 40 days of culture, although each ECM showed different ability in supporting cell proliferation, with tumor > perilesional > healthy-derived ECMs. Healthy-, perilesional-and CRC-derived ECM differently modulated cell homeostasis, spreading in the stroma and turnover between proliferation and death, and equally supported differentiation and polarization of cancer epithelial cells, thus highlighting the contribution of different ECMs modulating some features of tissue homeostasis and tumorigenesis. Moreover, these ECMs provide competent scaffolds useful to assess efficacy of antitumor drugs in a 3D setting that more closely recapitulates the native microenvironment. Further, ECM-based scaffolds may also be beneficial for future studies seeking prognostic and diagnostic stromal markers and targets for antineoplastic drugs.

This study was designed to examine the importance of the underlying cardiac pathology on outcome of cardiac resynchronization therapy (CRT), hypothesizing that myocardial infarction scar and other noncontractile segments represent limitations to the ability to resynchronize cardiac contraction in patients with congestive heart failure associated with dilated cardiomyopathy. From October 1999 to April 2002, 158 patients (mean age 65 years, 121 men) were included in a single center, longitudinal, comparative study. All patients had dilated cardiomyopathy and indications for CRT with a mean QRS duration of 174 ms. The patient population was divided into a coronary artery disease (CAD) group that included patients with significant CAD, and no indication, or a contraindication for revascularization, and a non-CAD group that included patients with nonischemic dilated cardiomypopathy. Follow-up data were collected at 3, 6, and 12 months, and yearly thereafter. The median follow-up was 11.2 months. In the CAD group, the LVEF increased from 0.29 to 0.34 (P < 0.0001), the 6-minute walk test distance increased from 310 to 463 m (P < 0.0001), and the percentage of patients in NYHA functional Class III-IV decreased from 83% to 23% (P = 0.04). In the non-CAD group, LVEF increased from 29% to 42% (P < 0.0001), the 6-minute walk test distance increased from 332 to 471 m (P < 0.0001), and the percentage of patients in NYHA functional Class III-IV decreased from 79% to 5%, (P < 0.0001). Comparison of the two groups showed that patients in the non-CAD group had a significantly greater increase in LVEF (P = 0.007) and decrease in NYHA class (P < 0.05). Patients with CAD or non-CAD significantly improved clinically during CRT. Non-CAD patients had a greater increase in LVEF and decrease in NYHA functional class than patients with CAD.

Short-term hemodynamic studies consistently report greater effects of cardiac resynchronization therapy (CRT) in patients stimulated from a LV lateral coronary sinus tributary (CST) compared to a septal site. The aim of the study was to compare the long-term efficacy of CRT when performed from different LV stimulation sites. From October 1999 to April 2002, 158 patients (mean age 65 years, mean LVEF 0.29, mean QRS width 174 ms) underwent successful CRT, from the anterior (A) CST in 21 patients, the anterolateral (AL) CST in 37 patients, the lateral (L) CST in 57 patients, the posterolateral (PL) CST in 40 patients, and the middle cardiac vein (MCV) CST in 3 patients. NYHA functional class, 6-minute walk test, and echocardiographic measurements were examined at baseline, and at 3, 6, and 12 months. Comparisons were made among all pacing sites or between lateral and septal sites by grouping AL + L + PL CST as lateral site (134 patients, 85%) and A + MC CST as septal site (24 patients, 15%). In patients stimulated from lateral sites, LVEF increased from 0.30 to 0.39 (P < 0.0001), 6-minute walk test from 323 to 458 m (P < 0.0001), and the proportion of NYHA Class III-IV patients decreased from 82% to 10% (P < 0.0001). In patients stimulated from septal sites, LVEF increased from 0.28 to 0.41 (P < 0.0001), 6-minute walk test from 314 to 494 m (P < 0.0001), and the proportion of NYHA Class III-IV patients decreased from 75% to 23% (P < 0.0001). A significant improvement in cardiac function and increase in exercise capacity were observed over time regardless of the LV stimulation sites, either considered singly or grouped as lateral versus septal sites.

Abstract-Mononuclear

No abstract

Congestive heart failure (CHF) patients with LBBB and QRS duration > 150 ms are considered the best candidates to biventricular pacing (Biv-P). However, patients with a narrow (120-150 ms) QRS may also benefit from Biv-P since true ventricular dyssynchrony may be underestimated by considering only QRS enlargement. From October 1999 to April 2002, 158 CHF patients (121 men, mean age 65 years, mean LVEF 0.29, mean QRS width 174 ms) underwent successful Biv-P implantation and were then followed for a mean time of 11.2 months. According to basal QRS duration, patients were divided in two groups, with wide QRS (> or = 150 ms, 128 patients, 81%) and with narrow QRS (< 150 ms, 30 patients, 19%). In the wide QRS group, LVEF improved from 29% to 39% (P < 0.0001), 6-minute walk test from 311 to 463 m (P < 0.0001), while NYHA Class III-IV patients decreased from 86% to 8% (P < 0.0001). In the narrow QRS group LVEF improved from 30% to 38% (P < 0.0001), 6-minute walk test from 370 to 506 m (P < 0.0001), and NYHA Class III-IV patients decreased from 60% to 0% (P < 0.0001). The data showed that in wide and narrow QRS patients, Biv-P significantly improved clinical parameters (NYHA class, 6-minute walk test, quality-of-life, and hospitalization rate) and main echocardiographic indicators. Furthermore, narrow QRS patients had a better survival rate, rapidly regained left ventricular function, and only a few patients remained in a higher NYHA class during follow-up. These patients should not be excluded "a priori" from cardiac resynchronization therapy.

The natural course of human immunodeficiency virus (HIV) infection is characterized by high viral load, depletion of immune cells, and immunodeficiency, ultimately leading to acquired immunodeficiency syndrome phase and the occurrence of opportunistic infections and diseases. Since the discovery of HIV in the early 1980s a naturally selected population of infected individuals has been emerged in the last years, characterized by being infected for many years, with viremia constantly below detectable level and poor depletion of immune cells. These individuals are classified as “elite controllers (EC) or suppressors” and do not develop disease in the absence of anti-retroviral therapy. Unveiling host factors and immune responses responsible for the elite status will likely provide clues for the design of therapeutic vaccines and functional cures. Scope of this review was to examine and discuss differences of the cell-mediated immune responses between HIV+ individuals with disease progression and EC.