Chronic myeloproliferative neoplasms with concomitant CALR mutation and BCR::ABL1 translocation: diagnostic and therapeutic implications of a rare hybrid disease.

Myeloproliferative neoplasms (MPNs) are subdivided into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is essential for the development and diagnosis of CML; on the other hand, the majority of Ph-negative MPNs are characterized by generally mutually exclusive mutations of Janus kinase 2 (JAK2), calreticulin (CALR), or thrombopoietin receptor/myeloproliferative leukemia (MPL). CALR mutations have been described essentially in JAK2 and MPL wild-type essential thrombocythemia and primary myelofibrosis. Rarely coexisting CALR and MPL mutations have been found in Ph-negative MPNs. BCR::ABL1 translocation and JAK2 mutations were initially considered mutually exclusive genomic events, but a discrete number of cases with the combination of these genetic alterations have been reported. The presence of BCR::ABL1 translocation with a coexisting CALR mutation is even more uncommon. Herein, starting from a routinely diagnosed case of CALR-mutated primary myelofibrosis subsequently acquiring BCR::ABL1 translocation, we performed a comprehensive review of the literature, discussing the clinicopathologic and molecular features, as well as the outcome and treatment of cases with BCR::ABL1 and CALR co-occurrence.

HELLS regulates transcription in T-cell lymphomas by reducing unscheduled R-loops and by facilitating RNAPII progression.

Chromatin modifiers are emerging as major determinants of many types of cancers, including Anaplastic Large Cell Lymphomas (ALCL), a family of highly heterogeneous T-cell lymphomas for which therapeutic options are still limited. HELLS is a multifunctional chromatin remodeling protein that affects genomic instability by participating in the DNA damage response. Although the transcriptional function of HELLS has been suggested, no clues on how HELLS controls transcription are currently available. In this study, by integrating different multi-omics and functional approaches, we characterized the transcriptional landscape of HELLS in ALCL. We explored the clinical impact of its transcriptional program in a large cohort of 44 patients with ALCL. We demonstrated that HELLS, loaded at the level of intronic regions of target promoters, facilitates RNA Polymerase II (RNAPII) progression along the gene bodies by reducing the persistence of co-transcriptional R-loops and promoting DNA damage resolution. Importantly, selective knockdown of HELLS sensitizes ALCL cells to different chemotherapeutic agents, showing a synergistic effect. Collectively, our work unveils the role of HELLS in acting as a gatekeeper of ALCL genome stability providing a rationale for drug design.

Precise cortical contributions to sensorimotor feedback control during reactive balance.

The role of the cortex in shaping automatic whole-body motor behaviors such as walking and balance is poorly understood. Gait and balance are typically mediated through subcortical circuits, with the cortex becoming engaged as needed on an individual basis by task difficulty and complexity. However, we lack a mechanistic understanding of how increased cortical contribution to whole-body movements shapes motor output. Here we use reactive balance recovery as a paradigm to identify relationships between hierarchical control mechanisms and their engagement across balance tasks of increasing difficulty in young adults. We hypothesize that parallel sensorimotor feedback loops engaging subcortical and cortical circuits contribute to balance-correcting muscle activity, and that the involvement of cortical circuits increases with balance challenge. We decomposed balance-correcting muscle activity based on hypothesized subcortically- and cortically-mediated feedback components driven by similar sensory information, but with different loop delays. The initial balance-correcting muscle activity was engaged at all levels of balance difficulty. Its onset latency was consistent with subcortical sensorimotor loops observed in the lower limb. An even later, presumed, cortically-mediated burst of muscle activity became additionally engaged as balance task difficulty increased, at latencies consistent with longer transcortical sensorimotor loops. We further demonstrate that evoked cortical activity in central midline areas measured using electroencephalography (EEG) can be explained by a similar sensory transformation as muscle activity but at a delay consistent with its role in a transcortical loop driving later cortical contributions to balance-correcting muscle activity. These results demonstrate that a neuromechanical model of muscle activity can be used to infer cortical contributions to muscle activity without recording brain activity. Our model may provide a useful framework for evaluating changes in cortical contributions to balance that are associated with falls in older adults and in neurological disorders such as Parkinson's disease.

Skin Involvement by Hematological Neoplasms with Blastic Morphology: Lymphoblastic Lymphoma, Blastoid Variant of Mantle Cell Lymphoma and Differential Diagnoses.

Hematological neoplasms sharing a blastic morphology may involve the skin. The skin may be either the primary site of occurrence of hematological malignancies with blastic features or cutaneous lesions are the first manifestation of an underlying systemic malignancy. The assessment of skin biopsies of hematological neoplasms with blastic features poses diagnostic problems and requires expert hematopathologists considering a wide range of differential diagnoses. The precise diagnosis of diseases sharing blastic features but with different outcomes and requiring distinct therapies is essential for patient management. The present paper mainly focuses on cutaneous involvement of the blastoid variant of mantle cell lymphoma and lymphoblastic lymphoma of B-cell or T-cell origin. The relevant literature has been reviewed and the clinical aspects, pathological features, prognosis, and therapy of both blastoid mantle cell lymphoma and lymphoblastic lymphoma involving the skin are discussed. A focus on other hematological entities with blastic features, which may involve the skin, to be taken into consideration in differential diagnosis is also given.

Long non-coding RNA mitophagy and ALK-negative anaplastic lymphoma-associated transcript: a novel regulator of mitophagy in T-cell lymphoma.

Long non-coding RNA (lncRNA) are emerging as powerful and versatile regulators of transcriptional programs and distinctive biomarkers of progression of T-cell lymphoma. Their role in the aggressive anaplastic lymphoma kinase-negative (ALK-) subtype of anaplastic large cell lymphoma (ALCL) has been elucidated only in part. Starting from our previously identified ALCL-associated lncRNA signature and performing digital gene expression profiling of a retrospective cohort of ALCL, we defined an 11 lncRNA signature able to discriminate among ALCL subtypes. We selected a not previously characterized lncRNA, MTAAT, with preferential expression in ALK- ALCL, for molecular and functional studies. We demonstrated that lncRNA MTAAT contributes to an aberrant mitochondrial turnover restraining mitophagy and promoting cellular proliferation. Functionally, lncRNA MTAAT acts as a repressor of a set of genes related to mitochondrial quality control via chromatin reorganization. Collectively, our work demonstrates the transcriptional role of lncRNA MTAAT in orchestrating a complex transcriptional program sustaining the progression of ALK- ALCL.

Voluntary muscle coactivation in quiet standing elicits reciprocal rather than coactive agonist-antagonist control of reactive balance.

Muscle coactivation increases in challenging balance conditions as well as with advanced age and mobility impairments. Increased muscle coactivation can occur both in anticipation of (feedforward) and in reaction to (feedback) perturbations, however, the causal relationship between feedforward and feedback muscle coactivation remains elusive. Here, we hypothesized that feedforward muscle coactivation would increase both the body's initial mechanical resistance due to muscle intrinsic properties and the later feedback-mediated muscle coactivation in response to postural perturbations. Young adults voluntarily increased leg muscle coactivation using visual biofeedback before support-surface perturbations. In contrast to our hypothesis, feedforward muscle coactivation did not increase the body's initial intrinsic resistance to perturbations, nor did it increase feedback muscle coactivation. Rather, perturbations with feedforward muscle coactivation elicited a medium- to long-latency increase of feedback-mediated agonist activity but a decrease of feedback-mediated antagonist activity. This reciprocal rather than coactivation effect on ankle agonist and antagonist muscles enabled faster reactive ankle torque generation, reduced ankle dorsiflexion, and reduced center of mass (CoM) motion. We conclude that in young adults, voluntary feedforward muscle coactivation can be independently modulated with respect to feedback-mediated muscle coactivation. Furthermore, our findings suggest feedforward muscle coactivation may be useful for enabling quicker joint torque generation through reciprocal, rather than coactivated, agonist-antagonist feedback muscle activity. As such our results suggest that behavioral context is critical to whether muscle coactivation functions to increase agility versus stability.NEW & NOTEWORTHY Feedforward and feedback muscle coactivation are commonly observed in older and mobility impaired adults and are considered strategies to improve stability by increasing body stiffness prior to and in response to perturbations. In young adults, voluntary feedforward coactivation does not necessarily increase feedback coactivation in response to perturbations. Instead, feedforward coactivation enabled faster ankle torques through reciprocal agonist-antagonist muscle activity. As such, coactivation may promote either agility or stability depending on the behavioral context.

CIC-rearranged sarcoma presenting with superior vena cava syndrome: case report.

CIC-rearranged sarcomas are rare mesenchymal neoplasms belonging to the family of undifferentiated small round cell sarcomas. This report details the case of a 45-year-old man presenting with symptoms of mediastinal compression, radiological diagnosis of a mediastinal mass and rapid evolution to full-blown superior vena cava syndrome. The emergency was successfully managed with a pharmacological approach. Formulation of a pathological diagnosis of CIC-rearranged sarcoma was initially supported by fluorescence in situ hybridisation findings and later validated by next-generation sequencing, which showed CIC-DUX4 gene fusion. A chemotherapy regimen was started with immediate benefits for the patient. The spectrum of pathological entities able to cause superior vena cava syndrome is wide, and recognition of rare causes is important to tailor the therapeutic approach to the specific disease. This is, to the best of our knowledge, the first report of CIC-rearranged sarcoma presenting with superior vena cava syndrome.

Mast Cell Leukemia: An Update with a Practical Review.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Exoskeletons need to react faster than physiological responses to improve standing balance.

Maintaining balance throughout daily activities is challenging because of the unstable nature of the human body. For instance, a person's delayed reaction times limit their ability to restore balance after disturbances. Wearable exoskeletons have the potential to enhance user balance after a disturbance by reacting faster than physiologically possible. However, "artificially fast" balance-correcting exoskeleton torque may interfere with the user's ensuing physiological responses, consequently hindering the overall reactive balance response. Here, we show that exoskeletons need to react faster than physiological responses to improve standing balance after postural perturbations. Delivering ankle exoskeleton torque before the onset of physiological reactive joint moments improved standing balance by 9%, whereas delaying torque onset to coincide with that of physiological reactive ankle moments did not. In addition, artificially fast exoskeleton torque disrupted the ankle mechanics that generate initial local sensory feedback, but the initial reactive soleus muscle activity was only reduced by 18% versus baseline. More variance of the initial reactive soleus muscle activity was accounted for using delayed and scaled whole-body mechanics [specifically center of mass (CoM) velocity] versus local ankle-or soleus fascicle-mechanics, supporting the notion that reactive muscle activity is commanded to achieve task-level goals, such as maintaining balance. Together, to elicit symbiotic human-exoskeleton balance control, device torque may need to be informed by mechanical estimates of global sensory feedback, such as CoM kinematics, that precede physiological responses.

CD5-Negative Primary Mantle Cell Lymphoma Presenting with a Bilateral Conjunctival Mass: A Potential Diagnostic Pitfall.

Mantle cell lymphoma is a B-cell malignancy, which, in its classic form, usually involves lymph nodes and extranodal sites, and, among the extranodal sites, the gastrointestinal tract and the Waldeyer's ring are most prevalent. MCL is rarely reported in the ocular adnexa, a site more frequently affected by extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue, which is a form of low-grade malignancy. The diagnosis of MCL presenting in the ocular adnexa requires special attention as its rarity in this location combined with the not uncommon CD5 negativity of the disease when occurring in the ocular adnexa, may lead the pathologist to overlook the diagnosis and misinterpret MCL as marginal zone B cell lymphoma, which has a totally different behavior. Herein, we present a case of primary bilateral conjunctival CD5-negative MCL in a patient having no other sites affected by lymphoma and we discuss possible diagnostic pitfalls.

Myelodysplastic/myeloproliferative neoplasm with neutrophilia (atypical chronic myeloid leukemia-aCML).

A case of myelodysplastic/myeloproliferative neoplasm with neutrophilia (aCML) with SETBP1 and ASXL1 mutations.

A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas.

Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008 and 2017 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining diagnostic criteria of several diseases, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classifying proposals of lymphoid neoplasms, the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with focus on mature B-cell neoplasms. The main aim is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of lymphomas.

Co-occurrence of JAK2-V617 F mutation and BCR::ABL1 translocation in chronic myeloproliferative neoplasms: a potentially confounding genetic combination.

Myeloproliferative neoplasms (MPNs) are classified into Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and Ph-negative MPNs. BCR::ABL1 translocation is the key genetic event of CML, whereas JAK2/MPL/CALR mutations are molecular aberrations of Ph-negative MPNs. Despite initially considered mutually exclusive genetic aberrations, the co-occurrence of BCR::ABL1 and JAK2 has been reported in a limited number of cases. The two genetic alterations may be identified either at the same time or JAK2 aberration may be detected in patients with a previous CML treated with tyrosine kinase inhibitors or, finally, BCR::ABL1 translocation occurs in patients with a history of JAK2-positive MPN. This combination of genomic alterations is potentially confounding with clinical manifestations often misinterpreted either as disease progression or drug resistance, therefore leading to inappropriate patient's treatment. Our systematic review aims to improve hematologist and pathologist knowledge on this rare subset of patients. Starting from the presentation of two additional cases from our routine daily practice, we focus mainly on clinical, laboratory, and bone marrow histological findings, which may represent useful clues of BCR::ABL1 and JAK2 co-occurrence. The interaction between JAK2 and BCR::ABL1 clones during the disease course as well as therapy and outcome are presented.

Intravascular NK/T-Cell Lymphoma: What We Know about This Diagnostically Challenging, Aggressive Disease.

Intravascular lymphoma is a form of lymphoid malignancy characterized by neoplastic cells growing almost exclusively within the lumina of small- to medium-sized blood vessels. Most cases are of B-cell origin with rare cases of natural killer or T-cell lineage. Extranodal sites are affected, mainly the skin and central nervous system, although any organ may be involved. Intravascular NK/T-cell lymphoma deserves special attention because of its clinicopathologic features and the need for adequate immunophenotyping combined with clonality test for a proper diagnosis. Moreover, intravascular NK/T-cell lymphoma is strongly linked to Epstein-Barr virus (EBV), which is considered to play a role in tumorigenesis and to be responsible for the aggressive behavior of the disease. In this paper, we review the current knowledge on this rare lymphoma and, in particular, the most recent advances about its molecular landscape. The main distinguishing features with other EBV-related entities, such as extranodal NK/T-cell lymphoma, EBV-positive primary nodal T/NK-cell lymphoma, and aggressive NK-cell leukemia, are discussed to help pathologists obtain the correct diagnosis and consequently develop an adequate and prompt therapy response.

Identification of RP-6685, an Orally Bioavailable Compound that Inhibits the DNA Polymerase Activity of Polθ.

DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.

Muscle synergy analysis yields an efficient and physiologically relevant method of assessing stroke.

The Fugl-Meyer Assessment is widely used to test motor function in stroke survivors. In the Fugl-Meyer Assessment, stroke survivors perform several movement tasks and clinicians subjectively rate the performance of each task item. The individual task items in the Fugl-Meyer Assessment are selected on the basis of clinical experience, and their physiological relevance has not yet been evaluated. In the present study, we aimed to objectively rate the performance of task items by measuring the muscle activity of 41 muscles from the upper body while stroke survivors and healthy participants performed 37 Fugl-Meyer Assessment upper extremity task items. We used muscle synergy analysis to compare muscle activity between subjects and found that 13 muscle synergies in the healthy participants (which we defined as standard synergies) were able to reconstruct all of the muscle activity in the Fugl-Meyer Assessment. Among the standard synergies, synergies involving the upper arms, forearms and fingers were activated to varying degrees during different task items. In contrast, synergies involving posterior trunk muscles were activated during all tasks, which suggests the importance of posterior trunk muscle synergies throughout all sequences. Furthermore, we noted the inactivation of posterior trunk muscle synergies in stroke survivors with severe but not mild impairments, suggesting that lower trunk stability and the underlying activity of posterior trunk muscle synergies may have a strong influence on stroke severity and recovery. By comparing the synergies of stroke survivors with standard synergies, we also revealed that some synergies in stroke survivors corresponded to merged standard synergies; the merging rate increased with the impairment of stroke survivors. Moreover, the degrees of severity-dependent changes in the merging rate (the merging rate-severity relationship) were different among different task items. This relationship was significant for 26 task items only and not for the other 11 task items. Because muscle synergy analysis evaluates coordinated muscle activities, this different dependency suggests that these 26 task items are appropriate for evaluating muscle coordination and the extent of its impairment in stroke survivors. Overall, we conclude that the Fugl-Meyer Assessment reflects physiological function and muscle coordination impairment and suggest that it could be performed using a subset of the 37 task items.

Discovery of an Orally Bioavailable and Selective PKMYT1 Inhibitor, RP-6306.

PKMYT1 is a regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its established synthetic lethal relationship with CCNE1 amplification. To date, no selective inhibitors have been reported for this kinase that would allow for investigation of the pharmacological role of PKMYT1. To address this need compound 1 was identified as a weak PKMYT1 inhibitor. Introduction of a dimethylphenol increased potency on PKMYT1. These dimethylphenol analogs were found to exist as atropisomers that could be separated and profiled as single enantiomers. Structure-based drug design enabled optimization of cell-based potency. Parallel optimization of ADME properties led to the identification of potent and selective inhibitors of PKMYT1. RP-6306 inhibits CCNE1-amplified tumor cell growth in several preclinical xenograft models. The first-in-class clinical candidate RP-6306 is currently being evaluated in Phase 1 clinical trials for treatment of various solid tumors.