tbuckley/cabot-search huggingface dataset:
A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor–Naïve <i>EGFR</i> -Mutant Metastatic Non–Small Cell Lung Cancer (RAMOSE trial)
Authors: Xiuning Le, Jyoti D. Patel, Elaine Shum, Christina Baik, Rachel E. Sanborn, Catherine A. Shu, Chul Kim, Mary Jo Fidler, Richard Hall, Yasir Y. Elamin, Janet Tu, George Blumenschein, Jianjun Zhang, Don Gibbons, Carl Gay, Nisha A. Mohindra, Young Chae, Yanis Boumber, Joshua Sabari, Rafael Santana-Davila, Shane Rogosin, Benjamin Herzberg, Ben Creelan, Bruna Pellini, Tawee Tanvetyanon, Simon Heeke, Mike Hernandez, Jhanelle E. Gray, Andreas Saltos, John V. Heymach
Journal: Journal of Clinical Oncology (2024)

PURPOSE Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS). METHODS The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334 , HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR -mutant non–small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for evaluable patients; secondary end points include objective response rates (ORRs), disease control rate (DCR), overall survival, and safety. The stratification criteria were EGFR mutation type and the presence of CNS metastasis. RESULTS At data cutoff on August 29, 2023, 160 patients consented, 147 patients received treatment, and 139 patients were evaluable with at least one scan. In this preplanned interim analysis, the median follow-up was 16.6 months. Among the evaluable patients, 57 PFS events occurred. The median PFS was 24.8 (A) versus 15.6 (B) months (hazard ratio, 0.55 [95% CI, 0.32 to 0.93]; log-rank P = .023), 12-month PFS rate was 76.7% (A) versus 61.9% (B; P = .026). No significant difference was observed in the ORRs and DCRs between arms. Any-grade (G) adverse events (AEs) occurred in 100% (A) and 98% (B) of patients, with no G5 treatment-related AE (TRAE), one G4 TRAE (hyponatremia, A), and 53% (A) versus 41% (B) G3 TRAEs. AE-related discontinuation occurred in 13 patients (9.7% in A and 8.7% in B). The safety profile was in line with known safety of each drug. CONCLUSION Ramucirumab plus osimertinib significantly prolonged PFS compared with osimertinib alone in patients with TKI-naïve EGFR -mutant NSCLC. The combination is safe and well tolerated.
OPAR: A Randomized Trial of Partial Breast Irradiation in Five Fractions Once Daily for Early Breast Cancer
Authors: Do-Hoon Kim, Valerie Théberge, Sameer Parpia, Iwa Kong, Sawyna Provencher, Michael Yassa, Francisco Perera, Sophie Lavertu, Pierre Rousseau, Justin Lee, Irene Karam, Kenneth Schneider, Mark N. Levine, Timothy J. Whelan, Christiaan Stevens, Ramana Rachakonda, Tarek Hijal
Journal: Journal of Clinical Oncology (2024)

PURPOSE Previous studies suggest that external-beam partial breast irradiation (PBI) delivered twice a day can lead to increased adverse cosmesis (AC). The objective of our trial was to determine whether two regimens for PBI given once daily over 1 week resulted in acceptable AC to inform a phase III trial. METHODS Patients age ≥50 years with invasive breast cancer or ductal carcinoma in situ, ≤3 cm in size treated by lumpectomy with negative axillary nodes were randomly assigned to external-beam PBI of 30 Gy or 27.5 Gy, each given in five fractions once daily. The primary outcome was AC (fair or poor) by photographic assessment at 2 years. Secondary outcomes included AC assessed by nurse at 2 years, by patient self-assessment at 3 years, and late toxicity. On the basis of a 17% risk of AC with whole-breast irradiation, the upper bound of a two-sided 90% CI, 23% was set as the tolerance margin (OPAR, ClinicalTrials.gov identifier: NCT02637024 ). RESULTS In total, 142 patients were randomly assigned to 30 Gy and 139 to 27.5 Gy. The median follow-up was 5 years. The mean age was 65 years, and the mean tumor size was 1.2 cm. Both schedules met acceptability criteria by photographic assessment (AC, 12.1% [90% CI, 8.2 to 17.6] for 30 Gy and 15.2% [90% CI, 10.8 to 21.1] for 27.5 Gy) and by nurse assessment. AC by patient self-assessment exceeded the 90% CI for the 30 Gy regimen. At 5 years, 16 (11.3%, 90% CI, 7.6 to 16.4) patients treated with 30 Gy and eight (5.8%, 90% CI, 3.3 to 9.9) patients treated with 27.5 Gy were observed to have grade 2 or more late toxicity. CONCLUSION According to the study design, 30 Gy and 27.5 Gy resulted in acceptable cosmetic outcomes. In light of recent studies, a lower dose was chosen for the phase III trial.
Estimating Long-Term Survivorship Rates Among Patients With Resected Stage III/IV Melanoma: Analyses From CheckMate 238 and European Organization for Research and Treatment of Cancer 18071 Trials
Authors: Jeffrey S. Weber, Mark R. Middleton, Georgia Yates, Daniel J. Sharpe, Murat Kurt, Maurice Lobo, Andriy Moshyk, Jacqueline Vanderpuye-Orgle, Peter Mohr
Journal: Journal of Clinical Oncology (2024)

Standard-of-care treatments for patients with resected stage III/IV melanoma include the immuno-oncology (IO) agents nivolumab (NIVO) and ipilimumab (IPI). This study used mixture cure models (MCMs) to estimate cure rates among patients treated with NIVO or IPI in the phase III CheckMate 238 (ClinicalTrials.gov identifier: NCT02388906) and European Organization for Research and Treatment of Cancer (EORTC) 18071 (ClinicalTrials.gov identifier: NCT00636168) trials, and to assess the impact of use of adjuvant immunotherapy on cure rates versus watchful waiting. MCMs were applied to patient-level recurrence-free survival data from CheckMate 238 and EORTC 18071. Cured patients were assumed to experience no disease recurrence and mortality risks similar to the general population. Uncured patients were at risk of disease recurrence and all-cause death. The survival trend of the cured patients was estimated using life expectancy data for a general population with the same baseline demographic characteristics. A regression model assessed the odds ratios (ORs) of cure across key subgroups on the basis of baseline characteristics of the study populations. In CheckMate 238, estimated cure rates were 48.3% (95% CI, 41.8 to 54.9) with NIVO and 38.2% (95% CI, 32.7 to 44.1) with IPI. In EORTC 18071, estimated cure rates were 38.0% (95% CI, 32.1 to 44.2) with IPI and 29.2% (95% CI, 24.4 to 34.6) with placebo. In the indirect comparison of the two trials, the odds of cure were significantly higher with NIVO than with placebo (OR, 2.33 [95% CI, 1.49 to 3.65]). Analyses involving two large phase III trials investigating adjuvant IO treatment for resected melanoma demonstrate higher cure rates for both NIVO and IPI than placebo, with NIVO providing the highest cure rate. Similar cure rates were estimated for patients treated with IPI in both trials, despite staging and dosing differences.
Elevated plasma and CSF neurofilament light chain concentrations are stabilized in response to mutant huntingtin lowering in the brains of Huntington’s disease mice
Authors: Nicholas S Caron, Lauren M Byrne, Fanny L Lemarié, Jeffrey N Bone, Amirah E-E Aly, Seunghyun Ko, Christine Anderson, Lorenzo L Casal, Austin M Hill, David J Hawellek, Peter McColgan, Edward J Wild, Blair R Leavitt, Michael R Hayden
Journal: Translational Neurodegeneration (2024)

Therapeutic approaches aimed at lowering toxic mutant huntingtin (mHTT) levels in the brain can reverse disease phenotypes in animal models of Huntington's disease (HD) and are currently being evaluated in clinical trials. Sensitive and dynamic response biomarkers are needed to assess the efficacy of such candidate therapies. Neurofilament light chain (NfL) is a biomarker of neurodegeneration that increases in cerebrospinal fluid (CSF) and blood with progression of HD. However, it remains unknown whether NfL in biofluids could serve as a response biomarker for assessing the efficacy of disease-modifying therapies for HD.
Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease
Authors: Qi Guo, Lingyan Ping, Eric B Dammer, Duc M Duong, Luming Yin, Kaiming Xu, Anantharaman Shantaraman, Edward J Fox, Todd E Golde, Erik C B Johnson, Blaine R Roberts, James J Lah, Allan I Levey, Nicholas T Seyfried
Journal: Molecular Neurodegeneration (2024)

Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer's disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches.
Environmental sustainability in intensive care: the path forward. An ESICM Green Paper
Authors: Jan J De Waele, Nicole Hunfeld, Heather Baid, Ricard Ferrer, Katerina Iliopoulou, Ana-Maria Ioan, Marc Leone, Marlies Ostermann, Gaetano Scaramuzzo, Maria Theodorakopoulou, Hugo Touw, Giuseppe Citerio, Lennie P G Derde, Katia Donadello, Nicole P Juffermans, Laura Galarza, Giacomo Grasselli, Salvatore Maurizio Maggiore, Ignacio Martin-Loeches, Joel Alexandre, Maurizio Cecconi, Elie Azoulay
Journal: Intensive Care Medicine (2024)

The European Society of Intensive Care Medicine (ESICM) Green Paper aims to address the challenge of environmental sustainability in intensive care and proposes actionable strategies for integrating sustainability into intensive care unit (ICU) stakeholder actions. The ESICM Executive Committee appointed a task force of topic experts and ESICM committee representatives to develop the ESICM Green Paper. The task force convened biweekly from January to June 2024, identifying key domains for environmental sustainability and prioritizing actions. Drafts were iteratively refined and approved by the ESICM Executive Committee. Climate change will impact activities in intensive care in many ways, but also the impact of ICU activities on the environment is considerable; drivers for this include extensive resource use and waste generation in ICUs from energy consumption, use of disposable items, and advanced therapies for critically ill patients. The ESICM Green Paper outlines a structured approach for ICUs to reduce their environmental impact, emphasizing energy efficiency, waste reduction, and sustainable procurement. Furthermore, it endorses the need for awareness and education among healthcare professionals, integration of sustainability into research, and sustainable policies within scientific societies. The ESICM Green Paper reviewed the relevance of climate change to intensive care and provided suggestions for clinical practice, research, education, and ESICM organizational domains. It underscores that reducing intensive care's ecological footprint can coexist with high-quality patient care. Promoting a resilient, responsible healthcare system is a joint responsibility of all ICU stakeholders.
Ultrasensitive detection of TDP-43 and amyloid-β protein aggregates using micelle-assisted seed amplification assay
Authors: Sora Sakamoto, Yuichi Riku, Teiko Komori Nomura, Akio Kimura, Naoki Yamahara, Kazuki Ohuchi, Mari Yoshida, Yasushi Iwasaki, Takayoshi Shimohata, Masatoshi Inden, Ryo Honda
Journal: Translational Neurodegeneration (2024)
Echocardiographic red flags of ATTR cardiomyopathy A single center validation
Authors: Michael Y Henein, Björn Pilebro, Per Lindqvist
Journal:  (2024)

Abstract Aims Echocardiography plays an important role in suspecting the presence of transthyretin cardiomyopathy (ATTR-CM) in patients with heart failure, based on parameters proposed as ‘red flags’ for the diagnosis of ATTR-CM. We aimed to validate those measurements in a group of patients with ATTR-CM including ATTRv and ATTRwt. Methods and results We tested a number of echocardiographic red flags in 118 patients with confirmed diagnosis of ATTR-CM. These variables were validated against healthy controls and patients with heart failure with left ventricular hypertrophy (LVH) but not ATTR-CM. The red flag measures outside the proposed cut-off values were also revalidated. In ATTR-CM, all conventional echocardiographic parameters were significantly abnormal compared with controls. Comparing ATTR-CM and LVH, LV wall thickness, LV diameter, E velocity, and relative apical sparing (RELAPS) were all different. Eighty-three per cent of ATTR-CM patients had RELAPS &amp;gt; 1.0, 73% had relative wall thickness (RWT) &amp;gt; 0.6, 72% had LVEF &amp;gt; 50%, 24% had global longitudinal strain (GLS) &amp;gt; −13%, 33% had LVEF/GLS &amp;gt; 4, and 54% had increased left atrial volume index (&amp;gt;34 mL/m2). Forty per cent of ATTR-CM patients had stroke volume index &amp;lt; 30 mL/m2 and 52% had cardiac index &amp;lt; 2.5 L/min/m2. RELAPS, LVEF, and RWT, in order of accuracy, were the three best measures for the presence ATTR-CM in the patient cohort, who all had thick myocardium. The concomitant presence of the three disturbances was found in only 50% but the combination of RELAPS &amp;gt; 1.0 and RWT &amp;gt; 0.6 was found in 72% of the patient cohort. Conclusion Increased relative apical sparing proved the most accurate independent marker of the presence of ATTR-CM followed by normal LV ejection fraction and then increased relative wall thickness. The other proposed red flags for diagnosing ATTR-CM did not feature as reliable disease predictors.
Nanopore sequencing with unique molecular identifiers enables accurate mutation analysis and haplotyping in the complex lipoprotein(a) KIV-2 VNTR
Authors: Stephan Amstler, Gertraud Streiter, Cathrin Pfurtscheller, Lukas Forer, Silvia Di Maio, Hansi Weissensteiner, Bernhard Paulweber, Sebastian Schönherr, Florian Kronenberg, Stefan Coassin
Journal: Genome Medicine (2024)

Repetitive genome regions, such as variable number of tandem repeats (VNTR) or short tandem repeats (STR), are major constituents of the uncharted dark genome and evade conventional sequencing approaches. The protein-coding LPA kringle IV type-2 (KIV-2) VNTR (5.6 kb per unit, 1-40 units per allele) is a medically highly relevant example with a particularly intricate structure, multiple haplotypes, intragenic homologies, and an intra-VNTR STR. It is the primary regulator of plasma lipoprotein(a) [Lp(a)] concentrations, an important cardiovascular risk factor. Lp(a) concentrations vary widely between individuals and ancestries. Multiple variants and functional haplotypes in the LPA gene and especially in the KIV-2 VNTR strongly contribute to this variance.
α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease
Authors: Fanni F. Geibl, Martin T. Henrich, Zhong Xie, Enrico Zampese, Jun Ueda, Tatiana Tkatch, David L. Wokosin, Elena Nasiri, Constantin A. Grotmann, Valina L. Dawson, Ted M. Dawson, Navdeep S. Chandel, Wolfgang H. Oertel, D. James Surmeier
Journal: Molecular Neurodegeneration (2024)

Abstract Background Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. Methods aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. Results In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Conclusions Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.
Autonomic Dysfunction Among Adult Survivors of Childhood Cancer in the St. Jude Lifetime Cohort Study
Authors: John D Groarke, Kirsten K Ness, Rikeenkumar Dhaduk, Juan C Plana, Jean Bernard Durand, Russell V Luepker, Vijaya M Joshi, Matthew Ehrhardt, Daniel A Mulrooney, Stephanie B Dixon, Anju Nohria, Daniel M Green, Rebecca M Howell, Deo Kumar Srivastava, John L Jefferies, Leslie L Robison, Melissa M Hudson, Gregory T Armstrong
Journal: JACC CardioOncology (2024)

The burden and functional significance of autonomic dysfunction among survivors of childhood cancer is unknown.
The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency
Authors: Mathew Sheridan, Muhammad Ahmad Maqbool, Anne Largeot, Liam Clayfield, Jingru Xu, Natalia Moncaut, Robert Sellers, Jessica Whittle, Jerome Paggetti, Mudassar Iqbal, Romain Aucagne, Laurent Delva, Syed Murtuza Baker, Michael Lie-A-Ling, Valerie Kouskoff, Georges Lacaud
Journal: Journal of Hematology & Oncology (2024)

The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors' self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs.
Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease
Authors: Sylvain Lehmann, Susanna Schraen-Maschke, Luc Buée, Jean-Sébastien Vidal, Constance Delaby, Christophe Hirtz, Frédéric Blanc, Claire Paquet, Bernadette Allinquant, Stéphanie Bombois, Audrey Gabelle, Olivier Hanon
Journal: Molecular Neurodegeneration (2024)

Abstract Background Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. Methods This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. Results As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. Conclusions The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.
Rare variant analyses in 51,256 type 2 diabetes cases and 370,487 controls reveal the pathogenicity spectrum of monogenic diabetes genes
Authors: Alicia Huerta-Chagoya, Philip Schroeder, Ravi Mandla, Jiang Li, Lowri Morris, Maheak Vora, Ahmed Alkanaq, Dorka Nagy, Lukasz Szczerbinski, Jesper G. S. Madsen, Silvia Bonàs-Guarch, Fanny Mollandin, Joanne B. Cole, Bianca Porneala, Kenneth Westerman, Josephine H. Li, Toni I. Pollin, Jose C. Florez, Anna L. Gloyn, David J. Carey, Inês Cebola, Uyenlinh L. Mirshahi, Alisa K. Manning, Aaron Leong, Miriam Udler, Josep M. Mercader
Journal: Nature Genetics (2024)

Type 2 diabetes (T2D) genome-wide association studies (GWASs) often overlook rare variants as a result of previous imputation panels' limitations and scarce whole-genome sequencing (WGS) data. We used TOPMed imputation and WGS to conduct the largest T2D GWAS meta-analysis involving 51,256 cases of T2D and 370,487 controls, targeting variants with a minor allele frequency as low as 5 × 10−5. We identified 12 new variants, including a rare African/African American-enriched enhancer variant near the LEP gene (rs147287548), associated with fourfold increased T2D risk. We also identified a rare missense variant in HNF4A (p.Arg114Trp), associated with eightfold increased T2D risk, previously reported in maturity-onset diabetes of the young with reduced penetrance, but observed here in a T2D GWAS. We further leveraged these data to analyze 1,634 ClinVar variants in 22 genes related to monogenic diabetes, identifying two additional rare variants in HNF1A and GCK associated with fivefold and eightfold increased T2D risk, respectively, the effects of which were modified by the individual's polygenic risk score. For 21% of the variants with conflicting interpretations or uncertain significance in ClinVar, we provided support of being benign based on their lack of association with T2D. Our work provides a framework for using rare variant GWASs to identify large-effect variants and assess variant pathogenicity in monogenic diabetes genes. Rare variant analyses identify a new type 2 diabetes risk allele near the LEP gene, which encodes leptin, and other risk alleles of intermediate penetrance in genes previously implicated in monogenic forms of diabetes.