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Malek, S.

Publications and source records attributed to Malek, S..

2 recordsLinked to original sources

Impact of long-term storage on mid-infrared spectral patterns of serum and synovial fluid samples of dogs with osteoarthritis

ObjectiveTo evaluate impact of long-term storage on mid-infrared (MIR) spectral patterns of serum and synovial fluid (SF) of dogs with knee OA and controls. DesignSerum (52 OA and 49 control) and SF (51 OA and 51 control) samples from dogs that had been in short-term (<3 years) frozen state (-80{degrees}C) had their MIR spectra obtained. The remaining aliquots were maintained in long-term (>5 years) frozen state before having MIR spectra acquired under the same testing conditions. Multi-level simultaneous component analysis was used to evaluate the effect of time. Partial least squares discriminant analysis was used to compare performance of predictive models built for discriminating OA from control spectra from each time point. ResultsMedian interval of storage between sample measurements was 5.7 years. Spectra obtained at two time points were significantly different (P <0.0001), however, contribution of sample aging accounted for only 1.61% and 2.98% of serum and SF profiles variability, respectively. Predictive models for discriminating serum of OA from controls for short-term storage showed 87.3{+/-}3.7% sensitivity, 88.9{+/-}2.4% specificity and 88.1{+/-}2.3% accuracy, while, for long-term storage, values of the same figures of merit were 92.5{+/-}2.6%, 97.1{+/-}1.7% and 94.8{+/-}1.4%, respectively. Predictive models based on short-term stored SF spectra had 97.3{+/-}1.6% sensitivity, 89.4{+/-}2.6% specificity and 93.4{+/-}1.6% accuracy, while the values for long-term storage 95.7{+/-}2.1%, 95.7{+/-}0.8% and 95.8{+/-}1.1%, respectively. ConclusionsLong-term storage of serum and SF results in significant differences in spectral variables, however, these changes do not significantly alter the performance of predictive algorithms for discriminating OA samples from controls.

biochemistry↗

RTK-dependent inducible degradation of mutant PI3K alpha drives GDC-0077 (Inavolisib) efficacy

PIK3CA is one of the most frequently mutated oncogenes; the p110 protein it encodes plays a central role in tumor cell proliferation and survival. Small molecule inhibitors targeting the PI3K p110 catalytic subunit have entered clinical trials, with early-phase GDC-0077 (Inavolisib) studies showing anti-tumor activity and a manageable safety profile in patients with PIK3CA-mutant, hormone receptor-positive breast cancer as a single agent or in combination therapy. Despite this, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression, resulting in enhanced apoptosis and greater efficacy. This unique mechanism against mutant p110 reveals a new strategy for creating inhibitors that specifically target mutant tumors with selective degradation of the mutant oncoprotein and also provide a strong rationale for pursuing PI3K degraders in patients with HER2-positive breast cancer.

cancer biology↗