Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia.

RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.

Contagion to unrest: Investigating the link between disease and civil unrest in Africa.

Scholars, policymakers, and citizens alike remain invested in the impact of infectious diseases worldwide. Studies have found that emerging diseases and disease outbreaks burden global economies and public health goals. This article explores the potential link between measles outbreaks and various forms of civil unrest, such as demonstrations, riots, strikes, and other anti-government violence, in four central African countries from 1996 to 2005. Using a difference-in-differences model, we examine whether disease outbreaks have a discernible impact on the prevalence of civil unrest. While our findings indicate that the relationship between disease and civil unrest is not as strong as previously suggested, we identify a notable trend that warrants further investigation. These results have significant implications for health and policy officials in understanding the complex interplay between state fragility, civil unrest, and the spread of disease.

Clinical and Pathological Characteristics and Outcomes Among Patients With Subcutaneous Panniculitis-like T-Cell Lymphoma and Related Adipotropic Lymphoproliferative Disorders.

Importance: There is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date. Objective: To generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions. Design, Setting, and Participants: This retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation. Exposures: Cases of SPTCL diagnosed between 1998 and 2018. Main Outcomes and Measures: The main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis. Results: The cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH. Conclusions and Relevance: In this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Morphology of Mycosis Fungoides and Sézary Syndrome in Skin of Color.

Although mycosis fungoides (MF) and Sézary syndrome (SS) commonly affect Black patients, dermatologic educational resources primarily describe the appearance of these conditions in lighter skin types. Skin of color (SoC) patients with Fitzpatrick skin types (FSTs) IV to VI tend to have variable morphologies compared to the erythematous patches, plaques, or tumors in non-sun-exposed areas seen in non-SoC patients (FSTs I-III). We performed a single-institution review of clinical photographs of patients with FSTs I to VI with the primary outcome of determining the frequency of various morphologic features of MF/SS in SoC vs non-SoC patients. Providers need to be familiar with the differences in morphologic features across skin types to ensure early diagnosis and treatment.

High-Altitude Pulmonary Edema in Ohio at an Elevation of 339 Meters.

BACKGROUND: HAPE (High-Altitude Pulmonary Edema) is a life-threatening form of high-altitude illness caused by noncardiogenic pulmonary edema. It has been most commonly reported in individuals who live at lower elevations and travel to elevations above 2500 m, typically in those who do so without any acclimatization. It can also occur in residents of high altitudes who descend to lower altitudes and then return to their native altitude without acclimatization. HAPE is more common in individuals with a history of prior HAPE, very rapid rates of ascent, upper respiratory illness, extreme exertion and cold environmental temperatures, Down's Syndrome, obesity and congenital pulmonary anomalies. CASE PRESENTATION: Our case discusses a patient presenting to an emergency department in Ohio with severe respiratory distress, hypoxia and a radiograph that showed pulmonary edema without cardiomegaly. Additional history revealed the patient had recently returned from Breckenridge, Colorado (an elevation of approximately 2926 m). The diagnosis of HAPE was recognized and he was appropriately treated. He was educated and will not be returning to high altitude without acclimatization in the future. CONCLUSION: Upon literature review, there has never been a prior documented case of a patient in Ohio with HAPE. Providers must consider altitude illness when evaluating travelers from high altitude destinations, even when traveling to a very low altitude like Ohio, as symptoms may be unresolved by descent alone. This case emphasizes the importance of obtaining relevant historical data including a travel history. It also emphasizes the importance of avoiding early closure of the diagnostic process by only considering common conditions. Finally, the case emphasizes the potential danger of anchoring bias to previously encountered conditions.

High incidence of adnexotropism in cytotoxic cutaneous lymphomas.

BACKGROUND: Primary cutaneous gamma-delta T-cell lymphoma (PCγδTCL) and primary cutaneous aggressive epidermotropic T-cell lymphomas (PCAETCL) are rare aggressive cytotoxic cutaneous lymphomas (CyCL) often difficult to diagnose. Histopathologically, PCAETCL and PCγδTCL may resemble mycosis fungoides (MF) and the presence of adnexotropism in CyCL (CyCL) contributes to this diagnostic challenge, especially in the setting of atypical and double-negative phenotypes. METHODS: In this retrospective study clinical data and histopathological section of 91 patients were analyzed for signs of clinical and histopathological signs adnexotropism. RESULTS: Adnexotropism was identified in 48.4% (44/91) of cases, including PCAETCL (40.9%, 18/44), PCγδTCL and cytotoxic cutaneous lymphomas, not otherwise specified (CyCTCL, NOS) (43.2%, 19/44 and 15.9%, 7/44). Comparison between disease-related mortality with Kaplan-Meier survival analysis of non-adnexotropic vs adnexotropic CyCL did not show any significant difference between the two groups (P = 0.8). Clinically they present with patches, plaques, and tumors and commonly with ulceration, but follicular prominence or alopecia are rare. Clinical signs of adnexotropism such as alopecia and hypo- or anhidrosis were rarely seen. CONCLUSION: Adnexotropism is a common finding in CyCL, especially in PCAETCL. Adnexotropic CyCL may be histopathologically difficult to distinguish from folliculotropic mycosis fungoides. A comprehensive IHC panel should be routinely performed in such cases.

Clinical Trial of High-Dose Pegylated-Interferon-Alfa-2b Combined With Phototherapy in Advanced Stage Mycosis Fungoides.

The combination of Interferon-α-2b (IFN-α-2b) and phototherapy is highly effective in treating mycosis fungoides (MF) but side effects often lead to discontinuation of therapy.1.

What are the highest yielding search strategy terms for systematic reviews in atopic dermatitis? A systematic review.

The impact of search strategies on systematic reviews (SR) of atopic dermatitis (AD) is unknown. The purpose of this review was to evaluate search strategies used in SR of AD and their impact on the frequency of manuscripts identified. MEDLINE and EMBASE were searched for SR related to AD. Simulations were performed by running combinations of search terms in MEDLINE and EMBASE. Overall, 250 SR met inclusion criteria, of which 225 specified search strategies. SR using 5-6 terms (20.0% to 12.1%) or ≥ 7 (40.0% to 18.8%) terms decreased, whereas SR using 3-4 terms numerically increased (18.8% to 30.2%) and 1-2 terms remained similar (37.5% to 38.9%) from 1999-2009 to 2015-2019. The most commonly searched terms were "atopic dermatitis" (n = 166), followed by "eczema" (n = 156), "dermatitis atopic'" (n = 81), "atopic eczema" (n = 74), "neurodermatitis" (n = 59), "Besniers prurigo" (n = 29), "infantile eczema" (n = 27), and "childhood eczema" (n = 19). Simulations revealed that "eczema" and "atopic dermatitis" yielded the most hits. The number of search terms that maximized hits in MEDLINE and EMBASE was 5 and 4, respectively. Search strategies for AD were heterogeneous, with high proportions of search strategies providing few search hits. Future studies should use standardized and optimized search terms.

Pericardial effusion and cardiac tamponade requiring pericardial window in an otherwise healthy 30-year-old patient with COVID-19: a case report.

BACKGROUND: This case report demonstrates pericardial effusion, acute pericarditis, and cardiac tamponade in an otherwise healthy woman who had a positive test result for coronavirus disease 2019. Few case reports have been documented on patients with this presentation, and it is important to share novel presentations of the disease as they are discovered. CASE PRESENTATION: A Caucasian patient with coronavirus disease 2019 returned to the emergency department of our hospital 2 days after her initial visit with worsening chest pain and shortness of breath. Imaging revealed new pericardial effusion since the previous visit. The patient became hypotensive, was taken for pericardial window for cardiac tamponade with a drain placed, and was treated for acute pericarditis. CONCLUSION: Much is still unknown about the implications of coronavirus disease 2019. With the novel coronavirus disease 2019 pandemic, research is still in process, and we are slowly learning about new signs and symptoms of the disease. This case report documents a lesser-known presentation of a patient with coronavirus disease 2019 and will help to further understanding of a rare presentation.

CtIP-Mediated Fork Protection Synergizes with BRCA1 to Suppress Genomic Instability upon DNA Replication Stress.

Protecting stalled DNA replication forks from degradation by promiscuous nucleases is essential to prevent genomic instability, a major driving force of tumorigenesis. Several proteins commonly associated with the repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) have been implicated in the stabilization of stalled forks. Human CtIP, in conjunction with the MRE11 nuclease complex, plays an important role in HR by promoting DSB resection. Here, we report an unanticipated function for CtIP in protecting reversed forks from degradation. Unlike BRCA proteins, which defend nascent DNA strands from nucleolytic attack by MRE11, we find that CtIP protects perturbed forks from erroneous over-resection by DNA2. Finally, we uncover functionally synergistic effects between CtIP and BRCA1 in mitigating replication-stress-induced genomic instability. Collectively, our findings reveal a DSB-resection- and MRE11-independent role for CtIP in preserving fork integrity that contributes to the survival of BRCA1-deficient cells.

Receptor Activity Modifying Proteins Have Limited Effects on the Class B G Protein-Coupled Receptor Calcitonin Receptor-Like Receptor Stalk.

The calcitonin receptor-like receptor (CLR) is a class B G protein-coupled receptor (GPCR) that forms the basis of three pharmacologically distinct receptors, the calcitonin gene-related peptide (CGRP) receptor, and two adrenomedullin (AM) receptors. These three receptors are created by CLR interacting with three receptor activity-modifying proteins (RAMPs). Class B GPCRs have an N-terminal extracellular domain (ECD) and transmembrane bundle that are both important for binding endogenous ligands. These two domains are joined together by a stretch of amino acids that is referred to as the "stalk". Studies of other class B GPCRs suggest that the stalk may act as hinge, allowing the ECD to adopt multiple conformations. It is unclear what the role of the stalk is within CLR and whether RAMPs can influence its function. Therefore, this study investigated the role of this region using an alanine scan. Effects of mutations were measured with all three RAMPs through cell surface expression, cAMP production and, in select cases, radioligand binding and total cell expression assays. Most mutants did not affect expression or cAMP signaling. CLR C127A, N140A, F142A, and L144A impaired cell surface expression with all three RAMPs. T125A decreased the potency of all peptides at all receptors. N128A, V135A, and L139A showed ligand-dependent effects. While the stalk appears to play a role in CLR function, the effect of RAMPs on this region seems limited, in contrast to their effects on the structure of CLR in other receptor regions.

Role of CT Density in PET/CT-Based Assessment of Lymphoma.

PURPOSE: In patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL), primary staging, as well as intermediate and late response assessment, is often performed by integrated 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) positron emission tomography/X-ray computed tomography (PET/CT). The purpose of this analysis was to evaluate if findings in patients with histopathologically proven HL or NHL might correlate with semi-automated density measurements of target lesions (TLs) in the CT component of the integrated PET/CT examination. PROCEDURES: After approval by the institutional review board, 176 lymph nodes (LN) in 90 PET/CT examinations of 90 patients were retrospectively analyzed (HL, 108 TLs out of 55 patients; NHL, 68 TLs out of 35 patients). PET/CT was performed for reasons of primary staging, response evaluation as interim PET, or as final examination after therapy, according to the clinical schedule. Analyses of TLs were performed on the basis of tracer uptake (SUV) 60 min after tracer injection and volumetric CT histogram analysis in non-contrast-enhanced CT. RESULTS: All patients were diagnosed with HL or NHL in a pretreatment biopsy. Prior to therapy induction, staging of all patients was performed using contrast-enhanced CT of the neck to the pelvis, or by [18F]FDG PET/CT. Of the 176 TLs, 119 were classified as malignant, and 57 were benign. Malignant TLs had significantly higher CT density values compared to benign (p < 0.01). CONCLUSION: Density measurements of TLs in patients with HL and NHL correlate with the dignity of TLs and might therefore serve as a complementary surrogate parameter for the differentiation between malignant and benign TLs. A possible density threshold in clinical routine might be a 20-Hounsfield units (HU) cutoff value to rule out benignancy in TLs that are above the 20-HU threshold.

Worker brain development and colony organization in ants: Does division of labor influence neuroplasticity?

Brain compartment size allometries may adaptively reflect cognitive needs associated with behavioral development and ecology. Ants provide an informative system to study the relationship of neural architecture and development because worker tasks and sensory inputs may change with age. Additionally, tasks may be divided among morphologically and behaviorally differentiated worker groups (subcastes), reducing repertoire size through specialization and aligning brain structure with task-specific cognitive requirements. We hypothesized that division of labor may decrease developmental neuroplasticity in workers due to the apparently limited behavioral flexibility associated with task specialization. To test this hypothesis, we compared macroscopic and cellular neuroanatomy in two ant sister clades with striking contrasts in worker morphological differentiation and colony-level social organization: Oecophylla smaragdina, a socially complex species with large colonies and behaviorally distinct dimorphic workers, and Formica subsericea, a socially basic species with small colonies containing monomorphic workers. We quantified volumes of functionally distinct brain compartments in newly eclosed and mature workers and measured the effects of visual experience on synaptic complex (microglomeruli) organization in the mushroom bodies-regions of higher-order sensory integration-to determine the extent of experience-dependent neuroplasticity. We demonstrate that, contrary to our hypothesis, O. smaragdina workers have significant age-related volume increases and synaptic reorganization in the mushroom bodies, whereas F. subsericea workers have reduced age-related neuroplasticity. We also found no visual experience-dependent synaptic reorganization in either species. Our findings thus suggest that changes in the mushroom body with age are associated with division of labor, and therefore social complexity, in ants. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1072-1085, 2017.

Adaptive working memory training improved brain function in human immunodeficiency virus-seropositive patients.

OBJECTIVE: We aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A-rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls. METHODS: A total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near-transfer WM tests (Digit-Span, Spatial-Span), self-reported executive functioning, and functional magnetic resonance images during 1-back and 2-back tasks were performed at baseline and each follow-up visit, and LMX1A-rs4657412 was genotyped in all participants. RESULTS: Although HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p ≤ 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A-G carriers) also had poorer self-reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A-AA carriers (LMX1A genotype by HIV status, cluster-corrected-p < 0.0001). INTERPRETATION: Adaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV-LMX1A-AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17-34.

Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection.

Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity.