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Concomitant antithrombotic therapy (direct factor XA inhibitors, heparin anticoagulants, platelet aggregation inhibitors) at time of enrolment was permitted (excluding warfarin). COMPARISON OF BLEEDING-RELATED EVENTS IN PATIENTS WHO RECEIVED PIRTOBRUTINIB WITH AND WITHOUT ANTITHROMBOTIC AGENTS Pirtobrutinib, a non-covalent (reversible) BTKi FDA approved for treatment of R/R MCL after 2 lines of therapy including a BTKi, demonstrated efficacy and tolerability across B-cell malignancies. [Extracted from the article]

A deeper understanding of the role of autophagy, literally 'self-eating', in normal and cancer cell biology has emerged over the last few years. Autophagy serves as a vehicle for cells to respond to various stressors including genomic, hypoxic and nutrient stress, and to oppose mechanisms of 'programmed' cell death. Here, we review not only mechanisms of cell death and cell survival but also the early successes in applying autophagy inhibition strategies in solid tumors using the only currently available clinical inhibitor, oral hydroxychloroquine. In acute leukemia, currently available chemotherapy drugs promote cell death and demonstrate clinical benefit, but relapse and subsequent chemotherapy resistance is common. Increasing preclinical data suggest that autophagy is active in leukemia as a means of promoting cell survival in response to chemotherapy. We propose coupling autophagy inhibition strategies with current cytotoxic chemotherapy and discuss synergistic combinations of available anti-leukemic therapies with autophagy inhibition. Furthermore, novel autophagy inhibitors are in development and promise to provide new therapeutic opportunities for patients with leukemia. [ABSTRACT FROM AUTHOR]

The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34(+) cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term culture-initiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells. [ABSTRACT FROM AUTHOR]

Aim: To analyse the test characteristics of orthoptic screening for amblyopia or amblyogenic risk factors (target conditions) in kindergarten. Methods: 1180 three year old children were screened by orthoptists in 121 German kindergartens. Orthoptic screening consisted of cover tests, examination of eye motility and head posture, and monocular visual acuity testing with the Lea single optotype test. Children were re-examined in kindergarten by different orthoptists after 3-6 months using a more demanding pass threshold for visual acuity. All children with at least one positive orthoptic test result or an inconclusive re-examination were referred to an ophthalmologist for diagnosis. The gold standard was set positive if a target condition was diagnosed on ophthalmological examination. It was set negative if no target condition was found upon ophthalmological examination, or if a child who screened negative or inconclusive passed the orthoptic re-examination without any positive test result. Results: The gold standard was ascertained in 1114 children. 26 (2.3%) children had a "positive" gold standard. In 10.8% of the children the initial screening was "inconclusive," mostly due to lock of collaboration. Screening test sensitivity (based on conclusive results only) was 90.9% and specificity was 93.8%. Conclusions: Orthoptic vision screening of 3 year olds in kindergarten is sensitive and specific. However, owing to a substantial proportion of inconclusive screening results, rescreening of non-cooperative 3 year old children should be considered. [ABSTRACT FROM AUTHOR]

Discusses a simplified fabrication technology for laterally complex coupled distributed feedback (DFB) lasers by focused ion beam (FIB) implantation which combines an index grating with a self-aligned gain couples grating. Lateral implantation of grating to a ridge waveguide structure in the passive section of the device; Creation of an induced quantum well intermixing.