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Russell Lewis, Jan Philipp Bewersdorf, Amer M Zeidan Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USACorrespondence: Amer M ZeidanDepartment of Medicine, Section of Hematology, Smilow Cancer Center at Yale New Haven Hospital, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028, USAEmail amer.zeidan@yale.eduAbstract: For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.Keywords: myelodysplastic syndrome, erythropoiesis-stimulating agents, novel agents, clinical trials

Jan Philipp Bewersdorf,1 Sara Mohamed Jaszczur,2 Salma Afifi,2 Jennifer C Zhao,2 Amer M Zeidan1,3 1Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT, USA; 2Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA; 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT, USACorrespondence: Amer M ZeidanSection of Hematology, Department of Internal Medicine, Yale University, 37 College Street, PO Box 208028, New Haven, CT 06520-8028, USATel +1 203-737-7103Fax +1 203-785-7232Email amer.zeidan@yale.eduAbstract: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke’s encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.Keywords: fedratinib, ruxolitinib, myelofibrosis, MF, JAK2

The axial ( z-) resolution of ∼100 nm provided by 4Pi and I5M fluorescence microscopy relies on the coherent addition of spherical wavefronts of two opposing high aperture angle lenses. Both microscopes feature a point-spread function (PSF) with a sharp central spot that is accompanied by axially shifted sidelobes which leads to replication artefacts in the raw image data. In a 4Pi-microscope the sidelobes are less pronounced than in I5M and without relevant lateral ( x, y) substructure, making their posterior removal in the image reliable and fast. On the other hand, high speeds of raw data acquisition are more easily gained by I5M. Moreover, I5M features a stronger signal as compared to the commonly employed two-photon excitation (2PE) 4Pi-imaging mode. We investigate here the capability of both techniques to image (aqueous) specimens without artefacts. To this end, we consider the optical transfer function (OTF) of the two microscopes in conjunction with the signal-to-noise-ratio (SNR) of the object to be imaged. The imaging of E. coli bacteria with an interconvertable setup enabled a direct comparison of the two imaging modes. As both systems rely on high aperture angles, water-immersion lenses of the largest numerical aperture available (NA = 1.2) were employed. The experimental results are corroborated by simulations assuming the signal strength encountered in the experiment. The comparison of the theoretical with the experimental PSFs/OTFs showed that our setup operated close to theory in both imaging modes. Although I5M provided about 10 times brighter raw image data as compared to (2PE) 4Pi-microscopy, the I5M data could not be entirely cleared of artefacts. In conclusion, with the current aperture angles and fluorescence signal strengths, it is not advisable to trade in the suppression of the sidelobes for a larger image signal. [ABSTRACT FROM AUTHOR]

We demonstrate theoretically, experimentally, and in an imaging application the possibility to generate a single predominant sharp diffraction maximum in the effective point-spread function of a fluorescence microscope that coherently uses two opposing lenses. This is achieved through binary pupil filters that preclude the origination of the unfavorable strong interference side maxima that are otherwise present in these systems. Mathematical postprocessing, which has so far been a prerequisite to gain artifact-free images, is now optional or obsolete. © 2001 American Institute of Physics. [ABSTRACT FROM AUTHOR]