Fibroblast growth factor-mediated crosstalk in cancer etiology and treatment.

It is becoming increasingly evident that multiple cell types within the tumor work together to drive tumour progression and impact on both the response to therapy and the dissemination of tumour cells throughout the body. Fibroblast growth factor signalling (FGF) is perturbed in a number of tumors, serving to drive tumor cell proliferation and migration, but also has a central role in orchestrating the plethora of cells that comprise the tumor microenvironment. This review focuses on how this family of signalling molecules can influence the interactions between tumor cells and their surrounding environment. Unraveling the complexities of FGF signalling between the distinct cell types of a tumor may identify additional opportunities for FGF-targeted compounds in therapy and could help combat drug resistance. Developmental Dynamics 246:493-501, 2017. © 2017 Wiley Periodicals, Inc.

Accelerated re-epithelialization in beta3-integrin-deficient- mice is associated with enhanced TGF-beta1 signaling.

The upregulation of TGF-beta1 and integrin expression during wound healing has implicated these molecules in this process, but their precise regulation and roles remain unclear. Here we report that, notably, mice lacking beta(3)-integrins show enhanced wound healing with re-epithelialization complete several days earlier than in wild-type mice. We show that this effect is the result of an increase in TGF-beta1 and enhanced dermal fibroblast infiltration into wounds of beta(3)-null mice. Specifically, beta(3)-integrin deficiency is associated with elevated TGF-beta receptor I and receptor II expression, reduced Smad3 levels, sustained Smad2 and Smad4 nuclear localization and enhanced TGF-beta1-mediated dermal fibroblast migration. These data indicate that alpha(v)beta(3)-integrin can suppress TGF-beta1-mediated signaling, thereby controlling the rate of wound healing, and highlight a new mechanism for TGF-beta1 regulation by beta(3)-integrins.

TGF-α and IL-6 plasma levels selectively identify CML patients who fail to achieve an early molecular response or progress in the first year of therapy.

Early molecular response (EMR, BCR-ABL1 (IS)⩽10% at 3 months) is a strong predictor of outcome in imatinib-treated chronic phase chronic myeloid leukemia (CP-CML) patients, but for patients who transform early, 3 months may be too late for effective therapeutic intervention. Here, we employed multiplex cytokine profiling of plasma samples to test newly diagnosed CP-CML patients who subsequently received imatinib treatment. A wide range of pro-inflammatory and angiogenesis-promoting cytokines, chemokines and growth factors were elevated in the plasma of CML patients compared with that of healthy donors. Most of these normalized after tyrosine kinase inhibitor treatment while others remained high in remission samples. Importantly, we identified TGF-α and IL-6 as novel biomarkers with high diagnostic plasma levels strongly predictive of subsequent failure to achieve EMR and deep molecular response, as well as transformation to blast crisis and event-free survival. Interestingly, high TGF-α alone can also delineate a poor response group raising the possibility of a pathogenic role. This suggests that the incorporation of these simple measurements to the diagnostic work-up of CP-CML patients may enable therapy intensity to be individualized early according to the cytokine-risk profile of the patient.

Right ventricular function in valvular heart disease: relation to pulmonary artery pressure.

Right ventricular angiography was performed in 46 patients with acquired valvular heart disease and 8 normal subjects. Right ventricular ejection fraction (RVEF) correlated highly only with right ventricular peak systolic pressure (RVPSP) and mean pulmonary artery pressure, both in patients with and without tricuspid insufficiency. For the group, RVEF = -0.33 RVPSP + 63 (correlation coefficient [r] = -0.76, probability [p] less than 0.001). Of 20 patients with moderate or severe elevation of pulmonary artery pressure, 17 (85%) had an abnormally low ejection fraction (less than 47%), while 19 (73%) of 26 patients with normal or mildly elevated pulmonary artery pressure had a normal right ventricular ejection fraction. In seven patients with elevated pulmonary artery pressure, a second ventriculogram was performed during intravenous nitroglycerin administration. Nitroglycerin produced a significant decrease in right ventricular peak systolic pressure (59 +/- 22 to 49 +/- 18 mm Hg, mean +/- standard deviation) (p less than 0.05) and in end-systolic volume (71 +/- 16 to 59 +/- 11 m1/m2) (p less than 0.05), and an increase in ejection fraction (43 +/- 9 to 48 +/- 7%) (p less than 0.05). Thus, at least part of the depression of ejection fraction in patients with elevated pulmonary pressure is reversible with a decrease in pulmonary artery pressure.

Systemic and coronary effects of intravenous milrinone and dobutamine in congestive heart failure.

The effects of dobutamine and intravenous milrinone on systemic hemodynamics, coronary blood flow and myocardial metabolism were studied in 11 patients with severe congestive heart failure. Although milrinone and dobutamine similarly increased cardiac index from 1.9 +/- 0.4 to 2.5 +/- 0.4 liters/min per m2 (p less than 0.001) and from 1.9 +/- 0.4 to 2.8 +/- 0.8 liters/min per m2 (p less than 0.001), respectively, milrinone decreased left ventricular end-diastolic pressure to a greater extent than dobutamine, that is, from 26 +/- 6 to 12 +/- 8 mm Hg (p less than 0.001) versus 26 +/- 8 to 20 +/- 8 mm Hg (p less than 0.001). In contrast to dobutamine, milrinone significantly reduced mean systemic arterial and right atrial pressures. Dobutamine increased the first derivative of left ventricular pressure (dP/dt) from 1,013 +/- 309 to 1,360 +/- 538 mm Hg/s (p less than 0.01) but milrinone did not. Similarly, blood flow and myocardial oxygen consumption were increased by dobutamine from 152 +/- 87 to 187 +/- 118 ml/min (p less than 0.05) and from 17.7 +/- 10.9 to 21.5 +/- 14.9 ml O2/min (p less than 0.05), respectively, but were unchanged by milrinone. Both drugs significantly decreased coronary vascular resistance and myocardial oxygen extraction but did not change myocardial lactate extraction. Thus, dobutamine and milrinone produce similar improvement in cardiac index. However, dobutamine increases myocardial oxygen consumption, whereas milrinone does not. This difference can probably be explained by the substantial vasodilating properties of milrinone.

Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries.

Subgroups of patients with angina pectoris and normal coronary arteries are known to have pacing-induced lactate production and, therefore, myocardial ischemia. To examine the mechanism of this pacing-induced ischemia, the effect of incremental atrial pacing on coronary blood flow and metabolism was studied in 27 patients with angina and normal coronary arteries. Seventeen patients continued to exhibit normal lactate extraction even at heart rates up to 160 beats/min (Group 1), whereas in 10 patients (Group 2) lactate extraction changed to production at the highest pacing rate. Coronary blood flow increased in Group 1 patients by 18, 41 and 75%, respectively, as heart rate was increased by 20 beat/min increments from 100 to 160 beats/min. In contrast, coronary blood flow increased by only 8, 7 and 14%, at the three respective pacing rates in Group 2. Between the heart rates of 100 and 160 beats/min, coronary vascular resistance decreased 32% in Group 1 patients but was unchanged in Group 2 patients. There was no significant change in the ratio of myocardial O2 consumption/rate-pressure product in Group 1 patients, but this ratio decreased from 0.91 +/- 0.26 ml O2 X min-1 X (mm Hg X beats/min)-1 to 0.53 +/- 0.11 (p less than 0.05) in Group 2 patients as heart rate increased from baseline to 160 beats/min. Thus, patients with angina and normal coronary arteries who develop ischemia with pacing have a decreased coronary vasodilator response that interferes with their ability to increase myocardial oxygen supply to match the higher demand.

The Thrombolysis in Myocardial Infarction (TIMI) phase II pilot study: tissue plasminogen activator followed by percutaneous transluminal coronary angioplasty.

The Thrombolysis in Myocardial Infarction (TIMI) Study Group is investigating whether percutaneous transluminal coronary angioplasty or intravenous beta-receptor blockers, or both, are useful adjuncts to recombinant tissue-type plasminogen activator (rt-PA) in the treatment of patients with acute myocardial infarction (TIMI II study). A total of 317 patients with acute myocardial infarction were treated an average of 2.7 hours after the onset of chest pain during the course of a nonrandomized pilot investigation with 150 mg of rt-PA given over 6 hours. This dose of rt-PA resulted in a high rate of infarct-related coronary artery patency (82 and 87% of patients catheterized an average of either 1 or 32 hours after entry, respectively) and a low 21 day mortality rate of 4.4%. Coronary angioplasty was performed successfully in greater than 90% of patients with appropriate anatomy and in greater than 50% of those treated with rt-PA. In 75 patients treated within 2 hours of the onset of chest pain only 2 (2.7%) were dead by 6 weeks. However, five cases of intracranial hemorrhage were noted, and the rt-PA dose was subsequently reduced to 100 mg given over 6 hours. The TIMI II design and the results of the TIMI II pilot study are discussed.

Angiographic and hemodynamic correlations in hypertrophic cardiomyopathy with intracavitary systolic pressure gradients.

To correlate angiographic and hemodynamic events in hypertrophic cardiomyopathy (HC), 14 patients with HC were investigated using pressure recordings and caudocranial left anterior oblique contrast angiography. Patients were separated into 2 groups on the basis of the presence (group I) or absence (group II) of systolic anterior motion of the anterior mitral leaflet on caudocranial angiography. In group I (10 patients), the pressure gradient could be recorded with the left ventricular (LV) catheter in the nonobliterated inflow region of the left ventricle. Simultaneous micromanometer tracings and caudocranial angiography revealed that contact between the anterior mitral leaflet and the ventricular septum was an early systolic event (occurring 136 +/- 33 ms after the R wave of the electrocardiogram) and was coincident with the onset of the pressure gradient. Cavitary obliteration was present in only 7 of 10 patients in group I, and occurred late in systole well after the peak gradient (292 +/- 28 ms after the R wave). In group II (4 patients), the pressure gradients could be recorded only from the obliterated portion of the ventricle distal to the level of the papillary muscles. Total LV cavitary obliteration was present in all group II patients. In 1 patient, simultaneous micromanometer pressure recording and caudocranial angiography revealed that cavitary obliteration preceded the peak gradient by 40 ms. Thus, in group I patients the onset of the pressure gradient is coincident with mitral leaflet-septal contact, while cavitary obliteration is an inconsistent late systolic event.(ABSTRACT TRUNCATED AT 250 WORDS)

Review article: the pathophysiology and pharmacological treatment of portal hypertension.

The pathogenesis of portal hypertension remains poorly understood. Similarly, pharmacological manipulation for the prevention and treatment of variceal haemorrhage has not fulfilled the promise of the 1980s. This article reviews current concepts in the pathophysiology of portal hypertension and considers pharmacotherapy for the treatment of variceal bleeding.

Early postoperative angiographic assessment of radial grafts used for coronary artery bypass grafting.

UNLABELLED: Despite a revival of interest in using the radial artery as an alternative conduit for myocardial revascularization, little angiographic documentation of early postoperative results has been presented, particularly in North America. Accordingly, 60 of 150 patients who underwent coronary artery bypass with radial arteries from November 1993 to July 1995 have had postoperative cardiac catheterization at our institution. The patency rate of the radial artery grafts was 95.7% (90 of 94 grafts patent) with an average internal diameter of 2.51 mm. Four radial artery grafts showed diffuse narrowing. The patency rate of the internal thoracic artery grafts was 100% with an average internal diameter of 2.25 mm. Three of 62 grafts demonstrated diffuse narrowing. Two of 24 (7.7%) saphenous vein grafts were occluded; the average internal diameter was 3.23 mm. The internal thoracic artery, the radial artery, and saphenous vein grafts were, respectively, 7.5%, 19.5%, and 53.3% larger than the anastomosed native coronary arteries. Graft-dependent flow was found in 81.1% of the radial artery grafts. CONCLUSION: The results of this study demonstrate that the short-term patency rate of radial artery grafts is excellent.

Donor height in combination with islet donor score improves pancreas donor selection for pancreatic islet isolation and transplantation.

To maximize the islet isolation yield for successful islet transplantation, the key task has been to identify an ideal pancreas donor. Since implementation of the islet donor score in donor selection, we have consistently obtained higher islet yields and transplantation rates. In this study, we tested whether assessing donor height as an independent variable in combination with the donor score could improve the pancreas donor selection. Donor and islet isolation information (n = 22) were collected and studied between 2011 and 2012. Pearson correlation analysis was used in statistical analysis. Donor height as an independent variable was significantly correlated to the weight of the pancreas, pre-Islet Equivalents (pre-IEQ), post-IEQ, and IDS (P < .05). When donor with height of 179 cm ± 3 was selected in combination with IDS > 80, the clinical islet transplantation rate reached 80%.

Improved coating of pancreatic islets with regulatory T cells to create local immunosuppression by using the biotin-polyethylene glycol-succinimidyl valeric acid ester molecule.

BACKGROUND: We showed that T regulatory (Treg) cells can be attached to the surface of pancreatic islets providing local immunoprotection. Further optimization of the method can improve coating efficiency, which may prolong graft survival. In this study, we compared the effectiveness of two different molecules used for binding of the Tregs to the surface of pancreatic islets. Our aim was to increase the number of Treg cells attached to islets without compromising islets viability and function. METHODS: The cell surface of human Treg cells and pancreatic islets was modified using biotin-polyethylene glycol-N-hydroxylsuccinimide (biotin-PEG-NHS) or biotin-PEG-succinimidyl valeric acid ester (biotin-PEG-SVA). Then, islets were incubated with streptavidin as islet/Treg cells binding molecule. Treg cells were stained with CellTracker CM-DiL dye and visualized using a Laser Scanning Confocal Microscope. The number of Treg cells attached per islets surface area was analyzed by Imaris software. The effect of coating on islet functionality was determined using the glucose-stimulated insulin response (GSIR) assay. RESULTS: The coating procedure with biotin-PEG-SVA allowed for attaching 40% more Treg cells per 1 µm(2) of islet surface. Although viability was comparable, function of the islets after coating using the biotin-PEG-SVA molecule was better preserved than with NHS molecule. GSIR was 62% higher for islets coated with biotin-PEG-SVA compared to biotin-PEG-NHS. CONCLUSION: Coating of islets with Treg cells using biotin-PEG-SVA improves effectiveness with better preservation of the islet function. Improvement of the method of coating pancreatic islets with Treg cells could further facilitate the effectiveness of this novel immunoprotective approach and translation into clinical settings.

The autophagy-associated factors DRAM1 and p62 regulate cell migration and invasion in glioblastoma stem cells.

The aggressiveness of glioblastoma multiforme (GBM) is defined by local invasion and resistance to therapy. Within established GBM, a subpopulation of tumor-initiating cells with stem-like properties (GBM stem cells, GSCs) is believed to underlie resistance to therapy. The metabolic pathway autophagy has been implicated in the regulation of survival in GBM. However, the status of autophagy in GBM and its role in the cancer stem cell fraction is currently unclear. We found that a number of autophagy regulators are highly expressed in GBM tumors carrying a mesenchymal signature, which defines aggressiveness and invasion, and are associated with components of the MAPK pathway. This autophagy signature included the autophagy-associated genes DRAM1 and SQSTM1, which encode a key regulator of selective autophagy, p62. High levels of DRAM1 were associated with shorter overall survival in GBM patients. In GSCs, DRAM1 and SQSTM1 expression correlated with activation of MAPK and expression of the mesenchymal marker c-MET. DRAM1 knockdown decreased p62 localization to autophagosomes and its autophagy-mediated degradation, thus suggesting a role for DRAM1 in p62-mediated autophagy. In contrast, autophagy induced by starvation or inhibition of mTOR/PI-3K was not affected by either DRAM1 or p62 downregulation. Functionally, DRAM1 and p62 regulate cell motility and invasion in GSCs. This was associated with alterations of energy metabolism, in particular reduced ATP and lactate levels. Taken together, these findings shed new light on the role of autophagy in GBM and reveal a novel function of the autophagy regulators DRAM1 and p62 in control of migration/invasion in cancer stem cells.

Deficiency of invariant natural killer T cells in coeliac disease.

BACKGROUND: Immunoregulatory invariant natural killer (iNK) T cells rapidly produce interleukin (IL)-4 and other cytokines that suppress a Th1 response and are deficient in some autoimmune diseases. AIM: The aim of this study was to investigate any deficiency of iNK T cells in coeliac disease. METHODS: Blood was collected from 86 subjects with coeliac disease and from 152 healthy control subjects for investigation of Valpha24+ T cells by flow cytometry. iNK T cells were assessed by Valpha24 and alpha-galactosylceramide/CD1d tetramer markers in 23 normal controls and 13 subjects with coeliac disease. Intracellular IL-4 was measured after anti-CD3 antibody stimulation. Duodenal biopsies were obtained in a subgroup of subjects with coeliac disease and control subjects for Valpha24 mRNA expression using relative PCR and for Valpha24+ T cells by immunofluorescence. RESULTS: The mean numbers of circulating Valpha24+ T cells and iNK T cells in coeliac disease were 27% (p<0.001) and 16% (p<0.001), respectively, of levels in control subjects. After in vitro anti-CD3 stimulation, numbers of IL-4+ producing iNK T cells from subjects with coeliac disease were unchanged but increased by 21% in control subjects. In subjects with coeliac disease, Valpha24 mRNA intestinal expression was reduced to 17% (p<0.001) by relative PCR and numbers of intestinal Valpha24+ T cells were 16% (p<0.01) of levels in control subjects. CONCLUSIONS: We conclude that Valpha24+ T cells and iNK T cells are deficient in coeliac disease. We speculate that this deficiency could contribute to the failure of immunological oral tolerance that seems to underlie this disease.

Right ventricular dysfunction in acute ventricular septal defect.

Eight patients with acute ventricular septal defect (VSD) receiving early intra-aortic balloon augmentation, cardiac catheterization, and open-heart surgery are described. Because of the large shunts in this group of patients, there was visualization of the right ventricle during left ventriculography which was adequate for qualitative analysis. The following were noted: (1) All patients had severe right ventricular (RV) dysfunction angiographically. (2) RV akinesis noted on angiography was more extensive than the surgical description of RV infarction, although all patients had biventricular infarction at surgery. (3) The RV dysfunction was the major cause of death (two cases) or a contributing factor (three cases). (4) RV papillary muscle rupture was identified in one case.

Pulmonary arterial V waves in mitral regurgitation: clinical and experimental observations.

Pulmonary arterial early diastolic waves (V waves) were investigated in patients and experimental animals with mitral regurgitation. V waves exceeding systolic pressure in the pulmonary artery were recorded in the main pulmonary artery with micromanometer catheters both in patients and animals, eliminating the possibility of catheter artifact. In experimental animals, aortic closure preceded pulmonic closure by 33 +/- 12 msec at baseline. With the creation of acute mitral insufficiency, a pulmonary arterial V wave occurred in six of eight animals. Early pulmonic valve closure occurred only in the six animals with a pulmonary arterial V wave. In these animals, pulmonic closure preceded aortic closure by 28 +/- 7 msec during mitral insufficiency (p less than .05). Of 70 patients with severe mitral regurgitation at cardiac catheterization, 14 had a pulmonary arterial V wave. In five patients recordings with micromanometer catheters were made and early pulmonic closure was also observed in four of these patients who had pulmonary arterial V waves at rest or upon provocation. Patients with pulmonary arterial V waves had a more acute onset of symptoms, shorter duration of mitral regurgitation, higher pulmonary capillary wedge V waves, and lower pulmonary arterial resistances than patients without them and were more likely to have nonrheumatic mitral regurgitation.