A Phase I trial of talazoparib in patients with advanced hematologic malignancies

Aim: The objective of this study was to establish the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of talazoparib. Patients & methods: This Phase I, two-cohort, dose-escalation trial evaluated talazoparib monotherapy in advanced hematologic malignancies (cohort 1: acute myeloid leukemia/myelodysplastic syndrome; cohort 2: chronic lymphocytic leukemia/mantle cell lymphoma). Results: Thirty-three (cohort 1: n = 25; cohort 2: n = 8) patients received talazoparib (0.1-2.0 mg once daily). The MTD was exceeded at 2.0 mg/day in cohort 1 and at 0.9 mg/day in cohort 2. Grade ≥3 adverse events were primarily hematologic. Eighteen (54.5%) patients reported stable disease. Conclusion: Talazoparib is relatively well tolerated in hematologic malignancies, with a similar MTD as in solid tumors, and shows preliminary anti leukemic activity.Clinical trial registration: NCT01399840 (ClinicalTrials.gov)

Posterior Mediastinal Hematoma after a Fall from Standing Height: A Case Report

Posterior Mediastinal Hematomas (PMHs) secondary to a fall from standing height are uncommon, with only one previous case reported in the literature. We describe a case of a 78-year-old male with multiple medical comorbidities, who was transferred to Montreal General Hospital (MGH) with a posterior mediastinal hematoma (PMH) after sustaining a fall from standing height. On initial assessment, the patient was hemodynamically stable and complained of mild chest pain, dyspnea, fatigue, and diaphoresis. The patient's airway was secured via endotracheal intubation fearing impending respiratory compromise secondary to an enlarging PMH. The patient was admitted to ICU where over the next 3 days he was managed conservatively via careful monitoring of his hemodynamic and hematologic indices. Repeat CT scanning indicated reduction in size of the PMH. The patient was discharged on hospital day eight. This case describes the assessment, evaluation, and conservative management of PMH in a complicated patient receiving prior anticoagulation. A review of the literature regarding the epidemiology of PMH and the management of both unstable and stable PMHs is also presented

Expression of Growth Factors and Growth Factor Receptor in Non-healing and Healing Ischaemic Ulceration

AbstractObjectivesTo characterise the histological and cytokinetic characteristics of purely ischaemic ulcers and the processes that underpin healing following successful revascularisation.DesignProspective observational study.Materials and methodsBiopsies were taken immediately pre- and 6 weeks following successful revascularisation of solely ischaemic ulceration. They were evaluated for morphological differences using H&E staining for the platelet derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), TGFβreceptorIII (TGFβRIII), transforming growth factor beta 1 and 3 (TGFβ1 and TGFβ3) and von Willebrand factor (vWF) expression using immunohistochemistry. Localisation and quantification of these growth factors and receptors was assessed systematically by three independent investigators who were blinded to the timing of biopsy.ResultsPre-operatively, small vessel vasculitis, necrosis and infection with a profuse neutrophil and macrophage infiltrate was observed in all samples. Post-operative biopsies revealed a proliferation of new capillaries in and around the ulcer edge and base. vWF staining confirmed an endothelial layer within these new vessels. Following successful revascularisation there was less infection and inflammation with minimal vasculitis. These newly formed capillaries had increased staining for TGFβ3, PDGFR and TGFβRIII with staining for PDGFR also localised to dermal fibroblasts which were larger and more numerous. Accelerated epithelial cell proliferation was observed with detachment from the underlying dermis.ConclusionsHealing of purely ischaemic ulcers is characterised by vasculogenesis associated with increased presence of the proangiogenic cytokines PDGF and TGFβ3. These findings show promise for the use of growth factor manipulation to aid healing in ischaemic ulcers

Artificially Intelligent Technology for the Margins: A Multidisciplinary Design Agenda

There has been increasing interest in socially just use of Artificial Intelligence (AI) and Machine Learning (ML) in the development of technology that may be extended to marginalized people. However, the exploration of such technologies entails the development of an understanding of how they may increase and/or counter marginalization. The use of AI/ML algorithms can lead to several challenges, such as privacy and security concerns, biases, unfairness, and lack of cultural awareness, which especially affect marginalized people. This workshop will provide a forum to share experiences and challenges of developing AI/ML health and social wellbeing technologies with/for marginalized people and will work towards developing design methods to engage in the re-envisioning of AI/ML technologies for and with marginalized people. In doing so we will create cross-research area dialogues and collaborations. These discussions build a basis to (1) explore potential tools to support designing AI/ML systems with marginalized people, and (2) develop a design agenda for future research and AI/ML technology for and with marginalized people

Optimality and distortionary lobbying: regulating tobacco consumption

We examine policies directed at regulating tobacco consumption through three types of instruments: (i) an excise tax hindering consumption by increasing the price of cigarettes, (ii) prevention programs helping consumers to make choices that are more time consistent when trading-off the current pleasure from smoking and its future health harms, and (iii) smoking bans directly restricting consumption. First, on normative grounds, we focus on the optimal design of public policies maximizing the economy’s surplus. Second, in a positive perspective, we investigate how the lobbying activities of the tobacco industry, of smokers, and of anti-tobacco organizations may distort government intervention

On the Determinants and Effects of Political Influence

This paper uses a large cross-country survey of business firms to assess their influence on government policies. It is found that influence is associated with larger, government-owned firms that have a high degree of ownership concentration. In contrast, foreign ownership matters little. It is also found that the extent to which government policies and legislation are viewed as impeding firm growth decreases with political influence and, independently, with a country's level of institutional quality

Subcutaneous emphysema in a case of infective sinusitis: a case report

<p>Abstract</p> <p>Introduction</p> <p>Subcutaneous emphysema with pneumomediastinum is a rare phenomenon with a high morbidity and may occur spontaneously.</p> <p>Case presentation</p> <p>A 30-year-old Caucasian man presented with sudden onset of a painful, swollen neck and was found, via clinical and radiological examination to have subcutaneous emphysema. A swallow study showed no oesophageal perforation. Computed tomography of his neck and thorax demonstrated pneumomediastinum but no other pathology. Management was conservative with intravenous antibiotics, fluids and no oral intake. He had a history of a productive cough and a flexible nasoendoscopy found purulent sinusitis which was treated with topical nasal washes. The patient was discharged after 72 hours and will be followed up by the otolaryngology-head and neck service.</p> <p>Conclusions</p> <p>Infective sinusitis is a rare cause of subcutaneous emphysema and pneumomediastinum. It may be managed conservatively provided there is early recognition and exclusion of more serious pathology, such as a ruptured trachea or oesophagus.</p

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations

Risdiplam in Type 1 Spinal Muscular Atrophy

BACKGROUND: Type 1 spinal muscular atrophy is a rare, progressive neuromuscular disease that is caused by low levels of functional survival of motor neuron (SMN) protein. Risdiplam is an orally administered, small molecule that modifies SMN2 pre-messenger RNA splicing and increases levels of functional SMN protein. METHODS: We report the results of part 1 of a two-part, phase 2-3, open-label study of risdiplam in infants 1 to 7 months of age who had type 1 spinal muscular atrophy, which is characterized by the infant not attaining the ability to sit without support. Primary outcomes were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and the selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included the ability to sit without support for at least 5 seconds. RESULTS: A total of 21 infants were enrolled. Four infants were in a low-dose cohort and were treated with a final dose at month 12 of 0.08 mg of risdiplam per kilogram of body weight per day, and 17 were in a high-dose cohort and were treated with a final dose at month 12 of 0.2 mg per kilogram per day. The baseline median SMN protein concentrations in blood were 1.31 ng per milliliter in the low-dose cohort and 2.54 ng per milliliter in the high-dose cohort; at 12 months, the median values increased to 3.05 ng per milliliter and 5.66 ng per milliliter, respectively, which represented a median of 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively. Serious adverse events included pneumonia, respiratory tract infection, and acute respiratory failure. At the time of this publication, 4 infants had died of respiratory complications. Seven infants in the high-dose cohort and no infants in the low-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg per kilogram per day) was selected for part 2 of the study. CONCLUSIONS: In infants with type 1 spinal muscular atrophy, treatment with oral risdiplam led to an increased expression of functional SMN protein in the blood. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02913482.)

PI3Kδ and PI3Kγ isoforms have distinct functions in regulating pro-tumoural signalling in the multiple myeloma microenvironment

Phosphoinositide-3-kinase and protein kinase B (PI3K-AKT) is upregulated in multiple myeloma (MM). Using a combination of short hairpin RNA (shRNA) lentivirus-mediated knockdown and pharmacologic isoform-specific inhibition we investigated the role of the PI3K p110γ (PI3Kγ) subunit in regulating MM proliferation and bone marrow microenvironment-induced MM interactions. We compared this with inhibition of the PI3K p110δ (PI3kδ) subunit and with combined PI3kδ/γ dual inhibition. We found that MM cell adhesion and migration were PI3Kγ-specific functions, with PI3kδ inhibition having no effect in MM adhesion or migration assays. At concentration of the dual PI3Kδ/γ inhibitor duvelisib, which can be achieved in vivo we saw a decrease in AKT phosphorylation at s473 after tumour activation by bone marrow stromal cells (BMSC) and interleukin-6. Moreover, after drug treatment of BMSC/tumour co-culture activation assays only dual PI3kδ/γ inhibition was able to induce MM apoptosis. shRNA lentiviral-mediated targeting of either PI3Kδ or PI3Kγ alone, or both in combination, increased survival of NSG mice xeno-transplanted with MM cells. Moreover, treatment with duvelisib reduced MM tumour burden in vivo. We report that PI3Kδ and PI3Kγ isoforms have distinct functions in MM and that combined PI3kδ/γ isoform inhibition has anti-MM activity. Here we provide a scientific rationale for trials of dual PI3kδ/γ inhibition in patients with MM