tbuckley/cabot-search huggingface dataset:
One thousand patients with essential thrombocythemia: the Mayo Clinic experience
Authors: Naseema Gangat, Omer Karrar, Aref Al-Kali, Kebede H. Begna, Michelle A. Elliott, Alexandra P. Wolanskyj-Spinner, Animesh Pardanani, Curtis A. Hanson, Rhett P. Ketterling, Ayalew Tefferi
Journal: Blood Cancer Journal (2024)

Abstract We describe 1000 patients with essential thrombocythemia seen at the Mayo Clinic between 1967 and 2023: median age 58 years (18–90), females 63%, JAK2 / CALR / MPL -mutated 62%/27%/3%, triple-negative (TN) 8%, extreme thrombocytosis (ExT; platelets ≥1000 × 10 9 /L) 26%, leukocytosis (leukocyte count &gt;11 × 10 9 /L) 20%, and abnormal karyotype 6%. JAK2 -mutated patients were older (median 71 years), and CALR mutated (52 years), and TN (50 years) younger ( p &lt; 0.01). Female gender clustered with TN (73%) and JAK2 (69%) vs. CALR / MPL (49%/47%) mutations ( p &lt; 0.01). ExT clustered with CALR (type-2 more than type-1) and TN and leukocytosis with JAK2 mutation ( p &lt; 0.01). In multivariable analysis, risk factors for overall survival were older age ( p &lt; 0.01), male gender (HR 1.8), absolute neutrophil count (ANC) ≥ 8 × 10 9 /L (HR 1.6), absolute lymphocyte count (ALC) &lt; 1.7 × 10 9 /L (HR 1.5), hypertension (HR 1.7), and arterial thrombosis history (HR 1.7); for leukemia-free survival, ExT (HR 2.3) and abnormal karyotype (HR 3.1); for myelofibrosis-free survival, ANC ≥ 8 × 10 9 /L (HR 2.3) and MPL mutation (HR 3.9); for arterial thrombosis-free survival, age ≥60 years (HR 1.9), male gender (HR 1.6), arterial thrombosis history (HR 1.7), hypertension (HR 1.7), and JAK2 mutation (HR 1.8); for venous thrombosis-free survival, male gender (HR 1.8) and venous thrombosis history (HR 3.0). Associations between ExT and leukemic transformation and between ANC and fibrotic progression were limited to JAK2 -mutated cases. Aspirin therapy appeared to mitigate both arterial (HR 0.4) and venous (HR 0.4) thrombosis risk. HR-based risk models delineated patients with median survivals ranging from 10 years to not reached and 20-year leukemia/myelofibrosis incidences from 3%/21% to 12.8%/49%. The current study provides both novel and confirmatory observations of essential thrombocythemia.
One thousand patients with essential thrombocythemia: the Florence-CRIMM experience
Authors: Giuseppe G. Loscocco, Francesca Gesullo, Giulio Capecchi, Alessandro Atanasio, Chiara Maccari, Francesco Mannelli, Alessandro M. Vannucchi, Paola Guglielmelli
Journal: Blood Cancer Journal (2024)

Abstract We describe 1000 patients with essential thrombocythemia seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Florence, Italy, between 1980 and 2023: median age 59 years (18–95), females 65%, JAK2 / CALR / MPL -mutated 66%/19%/4%, triple-negative (TN) 11%. Extreme thrombocytosis (ExT, platelets ≥1000 × 10 9 /L) in 16%, leukocytosis (leukocytes &gt;11 × 10 9 /L) in 16%, and at least one cardiovascular risk factor in 52% of cases. JAK2 -mutated patients were older (median 62 years) and CALR -mutated and TN (53 years for both) younger ( p &lt; 0.001). Female gender clustered with TN (76%) and JAK2 (67%) vs CALR (46%) mutations ( p &lt; 0.001). ExT clustered with CALR (type-2 more than type-1), TN and MPL , and leukocytosis with JAK2 mutation ( p &lt; 0.001). In multivariable analysis, risk factors for arterial thrombosis-free survival were age ≥60 years (HR 2.0; p &lt; 0.001) and JAK2 mutation (HR 1.3; p = 0.02) with borderline significance for male gender ( p = 0.08) and cardiovascular risk factors ( p = 0.08); for venous thrombosis-free survival, JAK2 mutation (HR 1.9; p = 0.03) with borderline significance for venous thrombosis history ( p = 0.07); for overall survival, older age ( p &lt; 0.001), male gender (HR 1.9; p &lt; 0.001), absolute neutrophil count (ANC) ≥ 8 × 10 9 /L (HR 1.8; p = 0.01), absolute lymphocyte count (ALC) &lt; 1.7 × 10 9 /L (HR 1.2; p = 0.03); for myelofibrosis-free survival, CALR mutation (HR 2.7; p &lt; 0.001, particularly for CALR type 1/1-like, HR 3.3) and MPL mutation (HR 3.9; p = 0.001); for leukemia-free survival, older age ( p = 0.03). Cytoreductive therapy appeared to mitigate both venous (HR 0.3; p = 0.01) and arterial thrombosis (HR 4; p = 0.04); there was a trend for aspirin in preventing arterial thrombosis recurrence. The current study provides real-world observations in essential thrombocythemia, representing a valid source document for interpreting current literature and planning future studies.
Equity in patient care in the intensive care unit
Authors: Katarzyna Kotfis, Segun Olusanya, Lucy Modra
Journal: Intensive Care Medicine (2024)

Intensive care physicians use key interventions like mechanical ventilation or vasopressor support in response to physiological deterioration, aiming to give each patient their best chance to not only survive critical illness, but to return back to their pre-admission lives.However, it is recognised that the provision of intensive care interventions cannot be explained entirely by physiological or other clinical factors like patient comorbidities [1,2].Instead, many large-scale retrospective studies found that the treatment provided to critically ill patients is independently associated with sociodemographic factors including patient race, gender and socioeconomic status [2][3][4][5][6].This suggests possible inequity in intensive care unit (ICU) interventions across sociodemographic groups.Understanding these sociodemographic differences in critical illness and intensive care interventions could better ensure we provide equitable care to our patients.
The contribution of age-related changes in the gut-brain axis to neurological disorders
Authors: Romeesa Khan, Claudia M. Di Gesù, Juneyoung Lee, Louise D. McCullough
Journal: Gut Microbes (2024)

Trillions of microbes live symbiotically in the host, specifically in mucosal tissues such as the gut. Recent advances in metagenomics and metabolomics have revealed that the gut microbiota plays a critical role in the regulation of host immunity and metabolism, communicating through bidirectional interactions in the microbiota-gut-brain axis (MGBA). The gut microbiota regulates both gut and systemic immunity and contributes to the neurodevelopment and behaviors of the host. With aging, the composition of the microbiota changes, and emerging studies have linked these shifts in microbial populations to age-related neurological diseases (NDs). Preclinical studies have demonstrated that gut microbiota-targeted therapies can improve behavioral outcomes in the host by modulating microbial, metabolomic, and immunological profiles. In this review, we discuss the pathways of brain-to-gut or gut-to-brain signaling and summarize the role of gut microbiota and microbial metabolites across the lifespan and in disease. We highlight recent studies investigating 1) microbial changes with aging; 2) how aging of the maternal microbiome can affect offspring health; and 3) the contribution of the microbiome to both chronic age-related diseases (e.g., Parkinson's disease, Alzheimer's disease and cerebral amyloidosis), and acute brain injury, including ischemic stroke and traumatic brain injury.
VLDL Biogenesis and Secretion: It Takes a Village
Authors: Willemien van Zwol, Bart van de Sluis, Henry N. Ginsberg, Jan Albert Kuivenhoven
Journal: Circulation Research (2024)

The production and secretion of VLDLs (very-low-density lipoproteins) by hepatocytes has a direct impact on liver fat content, as well as the concentrations of cholesterol and triglycerides in the circulation and thus affects both liver and cardiovascular health, respectively. Importantly, insulin resistance, excess caloric intake, and lack of physical activity are associated with overproduction of VLDL, hepatic steatosis, and increased plasma levels of atherogenic lipoproteins. Cholesterol and triglycerides in remnant particles generated by VLDL lipolysis are risk factors for atherosclerotic cardiovascular disease and have garnered increasing attention over the last few decades. Presently, however, increased risk of atherosclerosis is not the only concern when considering today’s cardiometabolic patients, as they often also experience hepatic steatosis, a prevalent disorder that can progress to steatohepatitis and cirrhosis. This duality of metabolic risk highlights the importance of understanding the molecular regulation of the biogenesis of VLDL, the lipoprotein that transports triglycerides and cholesterol out of the liver. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL by hepatocytes, which has led to many exciting new molecular insights that are the topic of this review. Increasing our understanding of the biology of this pathway will aid to the identification of novel therapeutic targets to improve both the cardiovascular and the hepatic health of cardiometabolic patients. This review focuses, for the first time, on this duality.
Meet the First Authors
Authors: Shancy Jacob
Journal: Circulation Research (2024)

In 2020, Shancy joined Dr Rowley's laboratory with a research emphasis on comprehending the role of platelet mitochondrial dynamics in hemostasis and thrombosis.Currently, she is investigating genetic and mitochondrial aspects regulating platelet function in cardiovascular diseases and beyond, with the goal of developing new therapeutic strategies.In addition to her scientific pursuits, she enjoys playing piano, dancing and hula hooping.Atherogenic CD147 in Inflammation and Efferocytosis (p 165)
History and Iatrogenic Effects of Conversion Therapy
Authors: Gerald C. Davison, Kyla-Rose Walden
Journal: Annual Review of Clinical Psychology (2024)

Research indicates that sexual orientation change efforts (SOCEs) are not effective and furthermore commonly lead to iatrogenic effects such as depression, anxiety, and even suicide. Negative attitudes toward homosexuality derive from most formal religions and are incarnated in medical and psychological theories that support and encourage SOCEs. Oppression of sexual minorities makes it unlikely that change requests by patients are voluntary. Recently there has been a dramatic change as the field moves from reparative to affirmative approaches. Here, we review the history of SOCEs, their consequences, current affirmative treatments, and future directions in the field as they pertain to the well-being of the queer community. From an institutional community psychology perspective, we argue that even if true conversion were possible, such efforts are unethical and should not be pursued even if requested. As is the case with all psychological/psychiatric interventions, the issue is not "can" but "ought."
Femicide, intimate partner femicide, and non-intimate partner femicide in South Africa: An analysis of 3 national surveys, 1999–2017
Authors: Naeemah Abrahams, Shibe Mhlongo, Esnat Chirwa, Bianca Dekel, Asiphe Ketelo, Carl Lombard, Nwabisa Shai, Leane Ramsoomar, Shanaaz Mathews, Gérard Labuschagne, Richard Matzopoulos, Megan Prinsloo, Lorna J. Martin, Rachel Jewkes
Journal: PLoS Medicine (2024)

Background In most countries, reliable national statistics on femicide, intimate partner femicide (IPF), and non-intimate partner femicide (NIPF) are not available. Surveys are required to collect robust data on this most extreme consequence of intimate partner violence (IPV). We analysed 3 national surveys to compare femicide, IPF, and NIPF from 1999 to 2017 using age-standardised rates (ASRs) and incidence rate ratios (IRRs). Methods and findings We conducted 3 national mortuary-based retrospective surveys using weighted cluster designs from proportionate random samples of medicolegal laboratories. We included females 14 years and older who were identified as having been murdered in South Africa in 1999 ( n = 3,793), 2009 ( n = 2,363), and 2017 ( n = 2,407). Further information on the murdered cases were collected from crime dockets during interviews with police investigating officers. Our findings show that South Africa had an IPF rate of 4.9/100,000 female population in 2017. All forms of femicide among women 14 years and older declined from 1999 to 2017. For IPF, the ASR was 9.5/100,000 in 1999. Between 1999 and 2009, the decline for NIPF was greater than for IPF (IRR for NIPF 0.47 (95% confidence interval (CI) 0.42 to 0.53) compared to IRR for IPF 0.69 (95% CI 0.63 to 0.77). Rates declined from 2009 to 2017 and did not differ by femicide type. The decline in IPF was initially larger for women aged 14 to 29, and after 2009, it was more pronounced for those aged 30 to 44 years. Study limitations include missing data from the police and having to use imputation to account for missing perpetrator data. Conclusions In this study, we observed a reduction in femicide overall and different patterns of change in IPF compared to NIPF. The explanation for the reductions may be due to social and policy interventions aimed at reducing IPV overall, coupled with increased social and economic stability. Our study shows that gender-based violence is preventable even in high-prevalence settings, and evidence-based prevention efforts must be intensified globally. We also show the value of dedicated surveys in the absence of functional information systems.
Understudied and underaddressed: Femicide, an extreme form of violence against women and girls
Authors: Chen Reis, Sarah R. Meyer
Journal: PLoS Medicine (2024)

Little is known about the prevalence and dynamics of femicide, a persistent form of violence against women and girls, due to challenges associated with its documentation. Research by Abrahams and colleagues comparing rates of femicide in South Africa over 18 years, however, suggests that femicide is preventable.
“ <i>The third table where I would sit comfortably</i> ”: narratives of nonbinary identity routes
Authors: B. Di Giannantonio, K. Milanese, M. Mirabella, F. Rosati, M. M. Lorusso, J. Pistella, R. Baiocco, V. Lingiardi, G. Giovanardi
Journal: International Journal of Transgender Health (2024)

Background Research on nonbinary people has been growing steadily. However, most studies have focused on gender identity development in binary cisgender or transgender populations, and there is a lack of knowledge about the experiences and milestones of nonbinary identification, including the many challenges of living in a binary world. In Italy, nonbinary individuals are exposed to various forms of discrimination and face multiple forms of invisibility—linguistic, social, and legal.
Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK–induced cancer cell plasticity
Authors: Sanam Peyvandi, Manon Bulliard, Alev Yilmaz, Annamaria Kauzlaric, Rachel Marcone, Lisa Haerri, Oriana Coquoz, Yu-Ting Huang, Nathalie Duffey, Laetitia Gafner, Girieca Lorusso, Nadine Fournier, Qiang Lan, Curzio Rüegg
Journal: Journal of Clinical Investigation (2024)

Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unravelling the underlying cues may provide novel strategies to manage metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we showed that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1high Ly6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+(Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted OSM and IL6. JAK inhibition prevented OSM/IL6-induced SCA1+ population enrichment while OSM/IL6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL6 production and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter OS, RFS and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL6-JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
Preschool impulse oscillometry predicts active asthma and impaired lung function at school age
Authors: Hanna M Knihtilä, Benjamin J Stubbs, Vincent J Carey, Nancy Laranjo, Robert S Zeiger, Leonard B Bacharier, George T O'Connor, Scott T Weiss, Augusto A Litonjua
Journal: Journal of Allergy and Clinical Immunology (2024)
Targeting mitochondrial dynamics of morphine-responsive dopaminergic neurons ameliorates opiate withdrawal
Authors: Changyou Jiang, Han Huang, Xiao Yang, Qiumin Le, Xing Liu, Lan Ma, Feifei Wang
Journal: Journal of Clinical Investigation (2024)

Converging studies demonstrate the dysfunction of the dopaminergic neurons following chronic opioid administration. However, the therapeutic strategies targeting opioid-responsive dopaminergic ensembles that contribute to the development of opioid withdrawal remain to be elucidated. Here, we used the neuronal activity-dependent Tet-Off system to label dopaminergic ensembles in response to initial morphine exposure (Mor-Ens) in the ventral tegmental area (VTA). Fiber optic photometry recording and transcriptome analysis revealed downregulated spontaneous activity, dysregulated mitochondrial respiratory, ultrastructure, and oxidoreductase signal pathways after chronic morphine administration in these dopaminergic ensembles. Mitochondrial fragmentation and the decreased mitochondrial fusion gene mitofusin 1 (Mfn1) were found in these ensembles after prolonged opioid withdrawal. Restoration of Mfn1 in the dopaminergic Mor-Ens attenuated excessive oxidative stress and the development of opioid withdrawal. Administration of Mdivi-1, a mitochondrial fission inhibitor, ameliorated the mitochondrial fragmentation and maladaptation of the neuronal plasticity in these Mor-Ens, accompanied by attenuated development of opioid withdrawal after chronic morphine administration, without affecting the analgesic effect of morphine. These findings highlighted the plastic architecture of mitochondria as a potential therapeutic target for opioid analgesic-induced substance use disorders.
Sterol biosynthesis regulates TLR signaling and the innate immune response in Smith-Lemli-Opitz syndrome model
Authors: Kristin Gabor, Emily V. Mesev, Jennifer Madenspacher, Julie Meacham, Prashant Rai, Sookjin Moon, Christopher A. Wassif, Saame Raza Shaikh, C.J. Tucker, Peer Karmaus, Simona Bianconi, Forbes D. Porter, Michael B. Fessler
Journal: Journal of Clinical Investigation (2024)
Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease
Authors: Maria Calvo-Rodriguez, Elizabeth K. Kharitonova, Austin C. Snyder, Steven S. Hou, Maria Virtudes Sanchez-Mico, Sudeshna Das, Zhanyun Fan, Hamid Shirani, K. Peter R. Nilsson, Alberto Serrano-Pozo, Brian J. Bacskai
Journal: Molecular Neurodegeneration (2024)

Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.
Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft-tissue Sarcomas: Clinical Outcomes and Biological Correlates
Authors: Candace L. Haddox, Michael J. Nathenson, Emanuele Mazzola, Jia-Ren Lin, Joanna Baginska, Allison Nau, Jason L. Weirather, Edwin Choy, Adrian Marino-Enriquez, Jeffrey A. Morgan, Gregory M. Cote, Priscilla Merriam, Andrew J. Wagner, Peter K. Sorger, Sandro Santagata, Suzanne George
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Eribulin modulates the tumor-immune microenvironment via cGAS-STING signaling in preclinical models. This non-randomized phase II trial evaluated the combination of eribulin and pembrolizumab in patients with soft-tissue sarcomas (STS). Patients and Methods: Patients enrolled in one of three cohorts: leiomyosarcoma (LMS), liposarcomas (LPS), or other STS that may benefit from PD-1 inhibitors, including undifferentiated pleomorphic sarcoma (UPS). Eribulin was administered at 1.4 mg/m2 i.v. (days 1 and 8) with fixed-dose pembrolizumab 200 mg i.v. (day 1) of each 21-day cycle, until progression, unacceptable toxicity, or completion of 2 years of treatment. The primary endpoint was the 12-week progression-free survival rate (PFS-12) in each cohort. Secondary endpoints included the objective response rate, median PFS, safety profile, and overall survival (OS). Pretreatment and on-treatment blood specimens were evaluated in patients who achieved durable disease control (DDC) or progression within 12 weeks [early progression (EP)]. Multiplexed immunofluorescence was performed on archival LPS samples from patients with DDC or EP. Results: Fifty-seven patients enrolled (LMS, n = 19; LPS, n = 20; UPS/Other, n = 18). The PFS-12 was 36.8% (90% confidence interval: 22.5–60.4) for LMS, 69.6% (54.5–89.0) for LPS, and 52.6% (36.8–75.3) for UPS/Other cohorts. All 3 patients in the UPS/Other cohort with angiosarcoma achieved RECIST responses. Toxicity was manageable. Higher IFNα and IL4 serum levels were associated with clinical benefit. Immune aggregates expressing PD-1 and PD-L1 were observed in a patient that completed 2 years of treatment. Conclusions: The combination of eribulin and pembrolizumab demonstrated promising activity in LPS and angiosarcoma.
Unmasking inadequate healthcare: Laser hair removal for transfemme adults in Germany
Authors: Lynhda Nguyen, Julika Heilberger, Anna S. Hartjen, Stefan W. Schneider, Timo O. Nieder, Katharina Herberger
Journal: International Journal of Transgender Health (2024)

Background Facial and body hair alterations are crucial for some transfemme individuals. To date, no data on the healthcare quality of permanent hair removal for transfemme adults are available for Germany.