OSI-906 is a novel, potent, selective and orally bioavailable dual IGF-1R/IR kinase inhibitor with favorable preclinical drug-like properties, which has demonstrated in vivo efficacy in tumor models and is currently in clinical testing.

Epidermal growth factor receptor (EGFR) and insulin-like growth factor

Aims This multicentre observational study aimed to prospectively assess the efficacy of left bundle branch area pacing (LBBAP) in heart failure patients with left bundle branch block (LBBB) and compare the 6-month outcomes between LBBAP and biventricular pacing (BVP). Methods and results Consecutive patients with LBBB and left ventricular ejection fraction (LVEF) ≤ 35% were prospectively recruited if they had undergone LBBAP as a primary or rescue strategy from three separate centres from March to December 2018. Patients who received BVP in 2018 were retrospectively selected by using 2 to 1 propensity score matching to minimize bias. Implant characteristics and echocardiographic parameters were assessed during the 6-month follow-up. LBBAP procedure succeeded in 81.1% (30/37) of patients, with selective LBBAP in 10 patients, and 3 of 20 patients combined non-selective LBBAP and LV lead pacing for further QRS narrowing. LBBAP resulted in significant QRS narrowing (from 178.2 ± 18.8 to 121.8 ± 10.8 ms, P < 0.001, paced QRS duration ≤ 130 ms in 27 patients) and improved LVEF (from 28.8 ± 4.5% to 44.3 ± 8.7%, P < 0.001) during the 6-month follow-up. The comparison between 27 patients with LBBAP alone and 54 of 130 matching patients with BVP showed that LBBAP delivered a greater reduction in the QRSd (58.0 vs. 12.5 ms, P < 0.001), a greater increase in LVEF (15.6% vs. 7.0%, P < 0.001), and greater echocardiographic (88.9% vs. 66.7%, P = 0.035) and super response (44.4% vs. 16.7%, P = 0.007) to cardiac resynchronization therapy. Conclusions LBBAP could deliver cardiac resynchronization therapy in most patients with heart failure and LBBB, and might be a promising alternative resynchronization approach to BVP.

The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC 50 values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Ka, PI3Kb, PI3Kg, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling.

Background-Vasovagal syncope (VVS) is the most common cause of recurrent syncope that can be debilitating despite optimal conventional therapy. The aim of this study was to evaluate the feasibility and efficacy of selective endocardial autonomic denervation in left atrium (LA) as an alternative treatment strategy in patients with highly symptomatic VVS. Methods and Results-Ten consecutive patients (mean age, 50.4Ϯ6.4 years; 7 women) with a medium of 3.5 (range, 2-20) recurrent episodes of VVS during the preceding year and positive head-up tilt testing in whom standard therapies were ineffective or poorly tolerated were enrolled. Ganglionated plexi (GP) in the LA, identified by high-frequency stimulation, was targeted by radiofrequency catheter ablation. The patients were then followed up at 3, 6, 12, 24, and 36 months, including repeated head-up tilt testing and Holter at 3 and 12 months. Radiofrequency energy was applied at the left superior GP in 10 patients, right anterior GP in 5, and left inferior GP in 3, using an 8-mm ablation catheter.

Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non -small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II -driven human tumor model. [Mol Cancer Ther 2007;6(8):2158 -67]

These findings suggest that significant titers of IL-1beta are present within the microenvironment of most breast carcinomas and that a high IL-1beta content is often associated with tumor invasiveness and with other pathologic features suggestive of an aggressive tumor biology.

BackgroundAutonomic modification through catheter ablation of ganglionated plexi (GPs) in the left atrium has been reported previously as a treatment for vasovagal syncope. This study aimed to observe the long‐term outcome in a larger cohort.Methods and ResultsA total of 57 consecutive patients (aged 43.2±13.4 years; 35 women) with refractory vasovagal syncope were enrolled, and high‐frequency stimulation and anatomically guided GP ablation were performed in 10 and 47 cases, respectively. A total of 127 GP sites with positive vagal response were successfully elicited and ablated, including 52 left superior, 19 left lateral, 18 left inferior, 27 right anterior, and 11 right inferior GPs. During follow‐up of 36.4±22.2 months (range 12–102 months), 52 patients (91.2%) remained free from syncope. Prodromes recurred in 16 patients. No statistical differences were found between the high‐frequency stimulation and anatomically guided ablation groups in either freedom from syncope (100% versus 89.4%, P=0.348) or recurrent prodromes (50% versus 76.6%, P=0.167). The deceleration capacity, heart rate, and heart rate variability measurements demonstrated a reduced vagal tone lasting for at least 12 months after the procedure, with improved tolerance of repeated head‐up tilt testing. No complications were observed except for transient sinus tachycardia that occurred in 1 patient.ConclusionsLeft atrial GP ablation showed excellent long‐term clinical outcomes and might be considered as a therapeutic option for patients with symptomatic vasovagal syncope.