Sunnybrook Health Sciences Centre

About: Sunnybrook Health Sciences Centre is a healthcare organization based out in Toronto, Ontario, Canada. It is known for research contribution in the topics: Population & Breast cancer. The organization has 7689 authors who have published 15236 publications receiving 523019 citations. The organization is also known as: Sunnybrook.

Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study

Abstract: Summary Background In the pivotal RESPONSE study, ruxolitinib, a Janus kinase (JAK)1 and JAK2 inhibitor, was superior to best available therapy at controlling haematocrit and improving splenomegaly and symptoms in patients with polycythaemia vera with splenomegaly who were inadequately controlled with hydroxyurea. In this study, we assessed the efficacy and safety of ruxolitinib in controlling disease in patients with polycythaemia vera without splenomegaly who need second-line therapy. Methods RESPONSE-2 is a randomised, open-label, phase 3b study assessing ruxolitinib versus best available therapy in patients with polycythaemia vera done in 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and North America. Eligible patients (aged ≥18 years) with polycythaemia vera, no palpable splenomegaly, and hydroxyurea resistance or intolerance were stratified by their hydroxyurea therapy status (resistance vs intolerance) and randomly assigned (1:1) by an interactive response technology provider using a validated system to receive either oral ruxolitinib 10 mg twice daily or investigator-selected best available therapy (hydroxyurea [at the maximum tolerated dose], interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or no cytoreductive treatment). Investigators and patients were not masked to treatment assignment; however, the study sponsor was masked to treatment assignment until database lock. The primary endpoint was the proportion of patients achieving haematocrit control at week 28. Analyses were done according to an intention-to-treat principle, including data from all patients randomly assigned to treatment. This study is registered with ClinicalTrials.gov (NCT02038036) and is ongoing but not recruiting patients. Findings Between March 25, 2014, and Feb 11, 2015, of 173 patients assessed for eligibility, 74 patients were randomly assigned to receive ruxolitinib and 75 to receive best available therapy. At randomisation, best available therapy included hydroxyurea (37 [49%] of 75 in the best available therapy group), interferon or pegylated interferon (ten [13%] of 75), pipobroman (five [7%] of 75), lenalidomide (one [1%] of 75), no treatment (21 [28%] of 75), and other (one [1%] of 75). Haematocrit control was achieved in 46 (62%) of 74 ruxolitinib-treated patients versus 14 (19%) of 75 patients who received best available therapy (odds ratio 7·28 [95% CI 3·43–15·45]; p vs two [3%] of 75 in the best available therapy group) and thrombocytopenia (two [3%] vs six [8%]). No cases of grade 3–4 anaemia or thrombocytopenia occurred with ruxolitinib; one patient (1%) reported grade 3–4 anaemia and three patients (4%) reported grade 3–4 thrombocytopenia in the group receiving best available therapy. Frequent grade 3–4 non-haematological adverse events were hypertension (five [7%] of 74 vs three [4%] of 75) and pruritus (0 of 74 vs two [3%] of 75). Serious adverse events occurring in more than 2% of patients in either group, irrespective of cause, included thrombocytopenia (none in the ruxolitinib group vs two [3%] of 75 in the best available therapy group) and angina pectoris (two [3%] of 74 in the ruxolitinib group vs none in the best available therapy group). Two deaths occurred, both in the best available therapy group. Interpretation RESPONSE-2 met its primary endpoint. The findings of this study indicate that ruxolitinib could be considered a standard of care for second-line therapy in this post-hydroxyurea patient population. Funding Novartis.

Brain-behavior correlations in hemispatial neglect using CT and SPECT The Sunnybrook Stroke Study

Abstract: Objective: Structural and functional lesion localization in patients with hemispatial neglect. Design: Location and severity of brain damage on CT and SPECT correlated with neglect performance as assessed with a battery of drawings, line bisection, and line and shape cancellation subtests. Patients: Participants included 120 consecutive stroke patients with a single right-hemisphere-damaged lesion on CT who were admitted to the Acute Stroke Care Unit at Sunnybrook Health Science Centre. Of these, 88 also had a SPECT. Results: On CT, 82 patients with neglect (compared with 38 without neglect) had more extensive damage in the parietal and sensorimotor cortex and white matter fiber bundles, including the posterior-superior longitudinal and inferior-frontal fasciculi ( p p p Conclusions: Damage in the parietal and anterior cingulate cortex and posterior white matter fiber bundles correlated with hemispatial neglect. Combining structural- and functional-imaging techniques with neurobehavioral analysis can elucidate brain-behavior relationships.

A GABAergic system in airway epithelium is essential for mucus overproduction in asthma

Abstract: Gamma-aminobutyric acid (GABA) is an important neurotransmitter that, through the subtype A GABA receptor (GABAAR), induces inhibition in the adult brain Here we show that an excitatory, rather than inhibitory, GABAergic system exists in airway epithelial cells Both GABAARs and the GABA synthetic enzyme glutamic acid decarboxylase (GAD) are expressed in pulmonary epithelial cells Activation of GABAARs depolarized these cells The expression of GAD in the cytosol and GABAARs in the apical membranes of airway epithelial cells increased markedly when mice were sensitized and then challenged with ovalbumin, an approach for inducing allergic asthmatic reactions Similarly, GAD and GABAARs in airway epithelial cells of humans with asthma increased after allergen inhalation challenge Intranasal application of selective GABAAR inhibitors suppressed the hyperplasia of goblet cells and the overproduction of mucus induced by ovalbumin or interleukin-13 in mice These findings show that a previously unknown epithelial GABAergic system has an essential role in asthma

Both mature miR-17-5p and passenger strand miR-17-3p target TIMP3 and induce prostate tumor growth and invasion

Abstract: MicroRNAs (miRNA) precursor (pre-miRNA) molecules can be processed to release a miRNA/miRNA* duplex. In the canonical model of miRNA biogenesis, one strand of the duplex is thought to be the biologically active miRNA, whereas the other strand is thought to be inactive and degraded as a carrier or passenger strand called miRNA* (miRNA star). However, recent studies have revealed that miRNA* strands frequently play roles in the regulatory networks of miRNA target molecules. Our recent study indicated that miR-17 transgenic mice could abundantly express both the mature miR-17-5p and the passenger strand miR-17-3p. Here, we showed that miR-17 enhanced prostate tumor growth and invasion by increasing tumor cell proliferation, colony formation, cell survival and invasion. miRNA target analysis showed that both miR-17-5p and miR-17-3p repressed TIMP metallopeptidase inhibitor 3 (TIMP3) expression. Silencing with small interfering RNA against TIMP3 promoted cell survival and invasion. Ectopic expression of TIMP3 decreased cell invasion and cell survival. Our results demonstrated that mature miRNA can function coordinately with its passenger strand, enhancing the repressive ability of a miRNA by binding the same target. Within an intricate regulatory network, this may be among the mechanisms by which miRNA can augment their regulatory capacity.