Automated patient monitoring system

Radio-linked patient monitoring system collects several channels of physiological data from as many as 64 hospital patients and transmits the data in digital form to a central control station. The system consists of a central control station and battery-operated patient units comprising small strap-on electronics packages

Study on the neuronal circuits implicated in postural tremor and hypokinesia

The effect of various tegmentary lesions at the level of the pontomesenchphalon in monkeys on motor function was observed. The importance of the monoaminergic mechanisms of the brainstem is discussed. The results also show the importance of the descending tegmentary rubral system and the rubroolivocerebellar circuit in controlling peripheral motor activity. The destruction of the sensory motor cortex proves to be a more effective way of eliminating spontaneous or harmaline induced tremor than the complete interruption of the pyramidal system on the level of the cerebral peduncle

Real-time phase-shift detection of the surface plasmon resonance

We investigate a method to directly measure the phase of a laser beam reflected from a metallic film after excitation of surface plasmon polaritons. This method permits real time access to the phase information, it increases the possible speed of data acquisition, and it may thus prove useful for increasing the sensitivity of surface plasmon based sensors

Personalized medicine for metastatic breast cancer

Cel przeglądu. Dzięki nowym technikom sekwencjonowania DNA można identyfikować w materiale biopsyjnymu chorych na raka piersi z przerzutami powtarzające się zmiany w genomie, co może prowadzić do molekularnego selekcjonowania przypadków do badań klinicznych nad lekami ukierunkowanymi. W niniejszym przeglądzie przedstawiano aktualne dane dotyczące powtarzających się zmian w genomie w raku piersi z przerzutami, a także podsumowano wyniki badań klinicznych wczesnej fazy dotyczących nowych leków ukierunkowanych.Najnowsze odkrycia. Postęp kliniczny w zakresie personalizacji leczenia obejmuje zastosowanie leków ukierunkowanych na szlak PI3K/mTOR, receptor czynnika wzrostu fibroblastów, receptor typu drugiego ludzkiego naskórkowego czynnika wzrostu, szlaki naprawy DNA oraz szlaki regulujące cykl komórkowy. Leki ukierunkowane na szlak PI3K/mTOR wykazują aktywność w raku piersi opornym na leczenie hormonalne i trastuzumab. W podgrupie chorych na raka piersi z przerzutami, po preselekcji w kierunku aberracji w zakresie wymienionych szlaków, wykazano potencjalną aktywność leków ukierunkowanych na szlak PI3K/mTOR, FGFR i polimerazę poli(ADP-rybozy). Prowadzone są również badania oceniające skuteczność leczenia skojarzonego z udziałem leków ukierunkowanych, hormonoterapii, leków przeciw HER-2 lub też chemioterapii w grupach chorych z określonymi zmianami genomu w zakresie genów receptorów hormonalnych, szlaku HER-2 czy też pozostałych istotnych szlaków sygnałowych.Podsumowanie. Obecnie wdrażane jest nowe podejście do spersonalizowanego leczenia chorych na raka piersi z przerzutami. Uwzględnia ono selekcję molekularną mającą na celu identyfikację istotnych klinicznie zmian w genomie oraz leczenie ukierunkowane molekularnie. Konieczne jest prowadzenie badań klinicznych, które pozwolą wykazać, czy dane subpopulacje chorych na raka piersi z przerzutami mogą odnieść rzeczywistą korzyść z leczenia dobranego według zmian w genomie.Purpose of review. With recent advances in DNA sequencing technology, recurrent genomic alterations can be identified in tumor samples from patients with metastatic breast cancer (MBC) to enrich clinical trials testing targeted therapies. This review provides an overview of clinically relevant genomic alterations in MBC and summarizes the recent clinical data from early phase trials of novel targeted treatments.Recent findings. The clinical development of personalized treatment includes targeted agents directed against PI3K/mTOR, fibroblast growth factor receptor (FGFR), human epidermal growth factor receptor 2 (HER2), DNA repair, and cell cycle pathways. PI3K/mTOR pathway drugs are active in endocrine and trastuzumab-resistant disease. Drugs targeted at PI3K/mTOR, FGFR, and poly(ADP-ribose) polymerase show early signs of efficacy in MBC subpopulations enriched with relevant pathway aberrancies. Regimens combining targeted agents with either endocrine, anti-HER2, or chemotherapy treatments are also being studied in hormone receptor-definedand HER2-defined or pathway-enriched subgroups.Summary. A new approach to personalized medicine for MBC that involves molecular screening for clinically relevant genomic alterations and genotype-targeted treatments is emerging. Clinical trials are needed to determine whether rare subpopulations of MBC benefit from genotype-targeted treatments

Inter-laboratory proficiency testing scheme for tumour next-generation sequencing in Ontario: A pilot study

Background A pilot inter-laboratory proficiency scheme for 5 Ontario clinical laboratories testing tumour samples for the Ontario-wide Cancer Targeted Nucleic Acid Evaluation (OCTANE) study was undertaken to assess proficiency in the identification and reporting of next-generation sequencing (NGS) test results in solid tumour testing from archival formalin-fixed, paraffin-embedded (FFPE) tissue. Methods One laboratory served as the reference centre and provided samples to 4 participating laboratories. An analyte-based approach was applied: each participating laboratory received 10 FFPE tissue specimens profiled at the reference centre, with tumour site and histology provided. Laboratories performed testing per their standard NGS tumour test protocols. Items returned for assessment included genes and variants that would be typically reported in routine clinical testing and variant call format (VCF) files to allow for assessment of NGS technical quality. Results Two main aspects were assessed: Technical quality and accuracy of identification of exonic variants Site-specific reporting practices Technical assessment included evaluation of exonic variant identification, quality assessment of the VCF files to evaluate base calling, variant allele frequency, and depth of coverage for all exonic variants. Concordance at 100% was observed from all sites in the technical identification of 98 exonic variants across the 10 cases. Variability between laboratories in the choice of variants considered clinically reportable was significant. Of the 38 variants reported as clinically relevant by at least 1 site, only 3 variants were concordantly reported by all participating centres as clinically relevant. Conclusions Although excellent technical concordance for NGS tumour profiling was observed across participating institutions, differences in the reporting of clinically relevant variants were observed, highlighting reporting as a gap where consensus on the part of Ontario laboratories is needed

Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor

CLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation

Quantitative Analysis of Dynamic Protein Interactions during Transcription Reveals a Role for Casein Kinase II in Polymerase-associated Factor (PAF) Complex Phosphorylation and Regulation of Histone H2B Monoubiquitylation

Using affinity purification MS approaches, we have identified a novel role for casein kinase II (CKII) in the modification of the polymerase associated factor complex (PAF-C). Our data indicate that the facilitates chromatin transcription complex (FACT) interacts with CKII and may facilitate PAF complex phosphorylation. Posttranslational modification analysis of affinity-isolated PAF-C shows extensive CKII phosphorylation of all five subunits of PAF-C, although CKII subunits were not detected as interacting partners. Consistent with this, recombinant CKII or FACT-associated CKII isolated from cells can phosphorylate PAF-C in vitro, whereas no intrinsic kinase activity was detected in PAF-C samples. Significantly, PAF-C purifications combined with stable isotope labeling in cells (SILAC) quantitation for PAF-C phosphorylation from wild-type and CKII temperature-sensitive strains (cka1Δ cka2–8) showed that PAF-C phosphorylation at consensus CKII sites is significantly reduced in cka1Δ cka2–8 strains. Consistent with a role of CKII in FACT and PAF-C function, we show that decreased CKII function in vivo results in decreased levels of histone H2B lysine 123 monoubiquitylation, a modification dependent on FACT and PAF-C. Taken together, our results define a coordinated role of CKII and FACT in the regulation of RNA polymerase II transcription through chromatin via phosphorylation of PAF-C