tbuckley/cabot-search huggingface dataset:
NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in Multiple Myeloma.
Authors: Eve Blanquart, Rüçhan Ekren, Bineta Rigaud, Marie Veronique Joubert, virginie Baylot, Hélène Daunes, Marine Cuisinier, Marine Villard, Nadège Carrié, Celine Mazzotti, Liliana E Lucca, Aurore Perrot, Jill Corre, Thierry Walzer, Hervé Avet-Loiseau, Pierre-Paul Axisa, Ludovic Martinet
Journal: Blood (2024)

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as natural killer (NK) cells that are mandatory for MM surveillance and therapy. Here, we performed a single-cell RNA sequencing analysis of NK cells from 10 patients with MM and 10 age/sex-matched healthy donors that revealed important transcriptomic changes in the NK cell landscape affecting both the bone marrow (BM) and peripheral blood compartment. The frequency of mature cytotoxic CD56dim NK cell subsets was reduced in patients with MM at the advantage of late-stage NK cell subsets expressing NF-κB and interferon-I inflammatory signatures. These NK cell subsets accumulating in patients with MM were characterized by low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced lymphocyte function-associated antigen 1 (LFA-1) integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM-infiltrating NK cells in a retrospective cohort of 177 patients with MM from the Intergroupe Francophone du Myélome (IFM) 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively affect patients' clinical outcomes. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.
Reply to J.A. Garcia et al
Authors: Susan Halabi, Siyuan Guo, Akash Roy, Larysa E. Rydzewska, Peter Godolphin, Maha Hussain, Catherine Tangen, Ian Thompson, Wanling Xie, Michael A. Carducci, Michael J. Morris, Matthew R. Smith, Gwenaelle Gravis, David P. Dearnaley, Paul J. Verhagen, Takayuki J. Goto, Nick D. James, Marc E. Buyse, Jayne F. Tierney, Christopher J. Sweeney
Journal: Journal of Clinical Oncology (2024)
Early-life infection depletes preleukemic cells in a mouse model of hyperdiploid B-cell acute lymphoblastic leukemia
Authors: Ali Farrokhi, Tanmaya Atre, Samuel Salitra, Maryam Aletaha, Ana Citlali Márquez, Matthew Gynn, Mario Fidanza, Sumin Jo, Nina Rolf, Karen Simmons, Jesus Duque-Afonso, Michael L. Cleary, Alix E. Seif, Tobias Kollmann, Soren Gantt, Gregor S. D. Reid
Journal: Blood (2024)
When I use a word . . . The languages of medicines—umbrella terms
Authors: Jeffrey K Aronson
Journal: BMJ (2024)

In the world of medicines, proprietary names are the brand names or trade names that pharmaceutical manufacturers give to their medicinal products. They are distinct from the generic names of the active ingredients they contain. Here I discuss the 2019 regulatory guidelines issued by the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK and the 2020 guidelines, published by the US Food and Drug Administration (FDA), on the desiderata governing a manufacturer's choice of a proprietary name for a medicinal product. I specifically highlight what the former calls an "umbrella segment," defined as "a section of [an] invented name that is used in more than one medicinal name to create a brand or range of products," and the latter a "brand name extension," defined as "a naming strategy that uses a proprietary name that is already associated with one or more marketed drug products, with or without a modifier, for a product that does not share any active ingredient(s) or active moiety(ies) with the marketed product(s)." Umbrellas, originally intended to give shade from the sun and now more commonly used to give shelter from the rain, do not appear to give shelter from the possibility of medication errors through confusion of proprietary names of medicinal products. Simplification of the rules governing the formulation of these types of names would be welcome to consumers and healthcare professionals alike.
Targeting T cell plasticity in kidney and gut inflammation by pooled single-cell CRISPR screening
Authors: Leon U. B. Enk, Malte Hellmig, Kristoffer Riecken, Christoph Kilian, Paul Datlinger, Saskia L. Jauch-Speer, Tobias Neben, Zeba Sultana, Varshi Sivayoganathan, Alina Borchers, Hans-Joachim Paust, Yu Zhao, Nariaki Asada, Shuya Liu, Theodora Agalioti, Penelope Pelczar, Thorsten Wiech, Christoph Bock, Tobias B. Huber, Samuel Huber, Stefan Bonn, Nicola Gagliani, Boris Fehse, Ulf Panzer, Christian F. Krebs
Journal: Science Immunology (2024)

Pro-inflammatory CD4 + T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (T H 17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody–associated glomerulonephritis on the basis of single-cell (sc) T cell receptor analysis and scRNA velocity. To uncover molecules driving T cell polarization and plasticity, we established an in vivo pooled scCRISPR droplet sequencing (iCROP-seq) screen and applied it to mouse models of glomerulonephritis and colitis. CRISPR-based gene targeting in T H 17 cells could be ranked according to the resulting transcriptional perturbations, and polarization biases into T helper 1 (T H 1) and regulatory T cells could be quantified. Furthermore, we show that iCROP-seq can facilitate the identification of therapeutic targets by efficient functional stratification of genes and pathways in a disease- and tissue-specific manner. These findings uncover T H 17 to T H 1 cell plasticity in the human kidney in the context of renal autoimmunity.
Schlafen 11 triggers innate immune responses through its ribonuclease activity upon detection of single-stranded DNA
Authors: Peng Zhang, Xiaoqing Hu, Zekun Li, Qian Liu, Lele Liu, Yingying Jin, Sizhe Liu, Xiang Zhao, Jianqiao Wang, Delong Hao, Houzao Chen, Depei Liu
Journal: Science Immunology (2024)

Nucleic acids are major structures detected by the innate immune system. Although intracellular single-stranded DNA (ssDNA) accumulates during pathogen infection or disease, it remains unclear whether and how intracellular ssDNA stimulates the innate immune system. Here, we report that intracellular ssDNA triggers cytokine expression and cell death in a CGT motif–dependent manner. We identified Schlafen 11 (SLFN11) as an ssDNA-activated RNase, which is essential for the innate immune responses induced by intracellular ssDNA and adeno-associated virus infection. We found that SLFN11 directly binds ssDNA containing CGT motifs through its carboxyl-terminal domain, translocates to the cytoplasm upon ssDNA recognition, and triggers innate immune responses through its amino-terminal ribonuclease activity that cleaves transfer RNA (tRNA). Mice deficient in Slfn9, a mouse homolog of SLFN11, exhibited resistance to CGT ssDNA–induced inflammation, acute hepatitis, and septic shock. This study identifies CGT ssDNA and SLFN11/9 as a class of immunostimulatory nucleic acids and pattern recognition receptors, respectively, and conceptually couples DNA immune sensing to controlled RNase activation and tRNA cleavage.
Overexpression of <i>Malat1</i> drives metastasis through inflammatory reprogramming of the tumor microenvironment
Authors: Elena Martinez-Terroba, Leah M. Plasek-Hegde, Ioannis Chiotakakos, Vincent Li, Fernando J. de Miguel, Camila Robles-Oteiza, Antariksh Tyagi, Katerina Politi, Jesse R. Zamudio, Nadya Dimitrova
Journal: Science Immunology (2024)

Expression of the long noncoding RNA (lncRNA) metastasis–associated lung adenocarcinoma transcript 1 ( MALAT1 ) correlates with tumor progression and metastasis in many tumor types. However, the impact and mechanism of action by which MALAT1 promotes metastatic disease remain elusive. Here, we used CRISPR activation (CRISPRa) to overexpress MALAT1/Malat1 in patient-derived lung adenocarcinoma (LUAD) cell lines and in the autochthonous K-ras/p53 LUAD mouse model. Malat1 overexpression was sufficient to promote the progression of LUAD to metastatic disease in mice. Overexpression of MALAT1/Malat1 enhanced cell mobility and promoted the recruitment of protumorigenic macrophages to the tumor microenvironment through paracrine secretion of CCL2/Ccl2. Ccl2 up-regulation was the result of increased global chromatin accessibility upon Malat1 overexpression. Macrophage depletion and Ccl2 blockade counteracted the effects of Malat1 overexpression. These data demonstrate that a single lncRNA can drive LUAD metastasis through reprogramming of the tumor microenvironment.
Waking the sleeping giant: Single-stranded DNA binds Schlafen 11 to initiate innate immune responses
Authors: Stephanie A. Ragland, Jonathan C. Kagan
Journal: Science Immunology (2024)

Single-stranded DNA containing CGT/A motifs binds to the helicase domain of Schlafen 11 (SLFN11) to initiate cell death and cytokine production via SLFN11 ribonuclease activity (see related Research Article by Zhang et al. ).
Liver cancer initiation requires translational activation by an oncofetal regulon involving LIN28 proteins
Authors: Meng-Hsiung Hsieh, Yonglong Wei, Lin Li, Liem H. Nguyen, Yu-Hsuan Lin, Jung M. Yong, Xuxu Sun, Xun Wang, Xin Luo, Sarah K. Knutson, Christina Bracken, George Q. Daley, John T. Powers, Hao Zhu
Journal: Journal of Clinical Investigation (2024)

It is unknown which post-transcriptional regulatory mechanisms are required for oncogenic competence. Here, we show that the LIN28 family of RNA-binding proteins (RBPs), which facilitate post-transcriptional RNA metabolism within ribonucleoprotein networks, are essential for the initiation of diverse oncotypes of hepatocellular carcinoma (HCC). In HCC models driven by NRASG12V/Tp53, CTNNB1/YAP/Tp53, or AKT/Tp53, mice without Lin28a and Lin28b were markedly impaired in cancer initiation. We biochemically defined an oncofetal regulon of 15 factors connected to Lin28 through direct mRNA and protein interactions. Interestingly, all were RBPs and only 1 of 15 is a Let-7 target. Polysome profiling and reporter assays showed that LIN28B directly increased the translation of 8 of these 15 RBPs. As expected, overexpression of LIN28B and IGFBP1-3 were able to genetically rescue cancer initiation. Using this platform to probe components downstream of LIN28, we found that 8 target RBPs were able to restore NRASG12V/Tp53 cancer formation in Lin28a/b deficient mice. Furthermore, these LIN28B targets promote cancer initiation through an increase in protein synthesis. LIN28B, central to an RNP regulon that increases translation of RBPs, is important for tumor initiation in the liver.
Dabrafenib and trametinib in patients with tumors with <i>BRAF V600E/k</i> mutations: Updated results from NCI-MATCH arm H.
Authors: April K.S. Salama, Victoria Wang, Erin Renee Macrae, Jong-In Park, Helen X. Chen, Robert James Gray, Lisa McShane, Lawrence Rubinstein, P. Mickey Williams, Stanley R. Hamilton, Deborah Kay Armstrong, James V. Tricoli, Barbara A. Conley, Carlos L. Arteaga, Lyndsay Harris, Peter J. O'Dwyer, Alice P. Chen, Keith Flaherty
Journal: Journal of Clinical Oncology (2024)

3110 Background: The NCI-MATCH precision medicine trial assigns patients (pts) with solid tumors, lymphomas or multiple myeloma to a targeted therapy based on genetic alterations identified in pretreatment biopsies. Arm H (EAY131-H) evaluated the combination of the BRAF inhibitor (inh) dabrafenib (DAB), and the MEK inh, trametinib (TRM), in pts with BRAF V600E/K mutations. Thirty-five pts in the primary cohort (PC) were enrolled from Jan 2016-Feb 2018, with 30 patients included in the primary efficacy analysis (1). The trial reactivated for an expansion cohort (EC) in October 2020. Methods: Pts could enroll based on molecular results from approved local CLIA labs; central confirmation was required to be included in primary efficacy analyses. Pts with melanoma, thyroid, or colorectal cancer were excluded. Pts with NSCLC were excluded after the US Food and Drug Administration (FDA) approved DAB/TRM in 2017. Pts received DAB 150 mg po BID and TRM 2 mg PO daily on 28-day cycles until disease progression or intolerable toxicity, with restaging every 2 cycles. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), 6-month (mo) PFS, and overall survival (OS). Results: An additional 9 pts were accrued to the EC; 6 pts were eligible, started treatment and molecularly confirmed. One pt never started therapy and 2 pts had inadequate tissue for central molecular confirmation, resulting in a combined cohort (CC) population of 36 pts. The trial closed to accrual in Jan 2023. In the CC, 17 different histologies were represented. In the EC, 38% of pts were female, with a median age of 60; &gt; 50% had received at least 3 lines of prior therapy. In the 6 pts with central assay results, 1 pt with a pilocytic astrocytoma had a CR, with a PFS &gt;18 mo and 1 pt with GBM had a PR, with a PFS of &gt;12 mo. The 2 pts without central assay results had PRs, both were alive and free of progression for &gt;7 mo. Median OS in the EC is 19.8 mo. For the CC, the confirmed ORR is 36.1% (90% CI 22.9-51.2%); the estimated 6 mo PFS is 67.6% (90% CI 54.5-80.8%). Median OS for the CC is 28.6 mo. At the time of data cutoff (Nov 2023) 2 pts in the PC and 1 pt in the EC are still on therapy. Adverse events were comparable to previously reported profiles of DAB/TRM. Conclusions: In this pretreated cohort of BRAF V600 mutated solid tumors, the combination of DAB/TRM showed clinically meaningful activity with durable responses seen in pts across multiple histologies, further supporting the disease agnostic approval by the FDA for this regimen. 1. J Clin Oncol. 2020;38[33]. Clinical trial information: NCT04439292 .
Open-label, dose-escalation phase 1a study of SPH5030, a tyrosine kinase inhibitor (TKI) targeting HER2, in patients with HER2 positive advanced solid tumors.
Authors: Jiayu Wang, Wenna Wang, Zhongsheng Tong, Yehui Shi, Yanxia Shi, Qiufan Zheng, Shunjiang Yu, Yuanyuan Cao, Ning Xie, Jianru Fan, Binghe Xu
Journal: Journal of Clinical Oncology (2024)

3117 Background: Although existing HER2-targeted agents have driven treatment strategies of HER2-overexpressed advanced solid tumor, unmet need still occurred in clinical setting. SPH5030, is a novel tyrosine kinase inhibitor targeting HER2, with a modified structure from tucatinib and pyrotinib. It has advantages such as target selectivity of tucatinib and the irreversible inhibitory effect of pyrotinib. Methods: This Phase Ia, open-label, multi-center study was conducted to evaluate the safety, pharmacokinetics and preliminary activity of SPH5030 in patients (pts) with HER2-positive advanced solid tumor. A 3+3 dose-escalation was conducted with six dose levels of SPH5030 (50,100,200,300,400,600 mg) administered orally once every day (QD) to evaluate dose limiting toxicity (DLT). Adverse events were assessed using CTCAE V5.0; tumor response per RECIST 1.1 every 6 weeks. Results: As of Feb 2, 2024, 30 pts were enrolled with a median age of 51 years, including 28 (93.3%) pts with breast cancer (BC) and 2 (6.7%) pts with colorectal cancer (CRC). All pts were heavily treated with a median of 4 (range, 1-9) prior lines of therapy. All the 28 BC pts received previous anti-HER2 therapy, and 23 of them received anti-HER2-TKI therapy. Treatment-emerged adverse events (TEAEs) and ≥grade (G) 3 TEAEs occurred in 30 pts (100.0%) and 10 pts (33.3%), respectively. Treatment-related adverse events (TRAEs) and ≥G3 TRAEs occurred in 28 pts (93.3%) and 8 pts (26.7%), respectively; the most common TRAEs (≥20%) were diarrhea (66.7%, 16.7% ≥ G3), creatinine increased (30.0%, 0% ≥ G3), hypokalemia (23.3%, 3.3% ≥ G3), fatigue (23.3%, 3.3% ≥ G3), AST increased (20.0%, 0% ≥ G3), and bilirubin increased (20.0%, 0% ≥ G3). One in 6 pts receiving 600 mg dose experienced a DLT (diarrhea, G3). SPH5030 plasma exposures from single-dose and steady-state showed a proportional dose increase, but absorption of SPH5030 was found to reach a plateau from 400 to 600mg. Of the 28 evaluable pts for efficacy (BC = 26, CRC = 2),6 pts (21.4%) achieved partial response (PR, BC = 5, CRC = 1), while 16 pts (57.1%) achieved stable disease (4 pts SD≥ 24 weeks,14.3%). Objective response rate (ORR) was 21.4%, disease control rate was 78.6%, and clinical benefit rate was 35.7%. Three pts in the 600 mg dose group achieved PR, with ORR of 50.0%. Conclusions: This study demonstrated that SPH5030 was well tolerated at doses ranging from 50 to 600mg. A dose of 600 mg QD regimen could be considered for further clinical trials. Clinical trial information: NCT05245058 .
Targeting rare variants of a pan-cancer target: The landscape of <i>BRAF</i> non-v600 mutations and <i>BRAF</i>fusions from 172,005 adult patients with cancer.
Authors: Niamh Coleman, Vivek Subbiah
Journal: Journal of Clinical Oncology (2024)

3113 Background: BRAF is a recognized pan-cancer target, with dabrafenib in combination with trametinib receiving FDA accelerated approval for unresectable metastatic solid tumors with BRAF V600E mutation. BRAF fusions and mutations at codons aside from V600 (non-V600) activate the MAP kinase/ERK-signaling pathway, however the spectrum of these alterations is not yet well-defined. Preclinical data suggests that BRAF non-v600 mutations are diverse, with evidence of alternate signaling, requiring dimerization to function, while BRAFV600E tumors activate the pathway as monomers. We include a comprehensive analysis of non- BRAF V600 mutations and BRAF fusions in pan-cancer adult malignancies. Methods: 198,041 samples from 172,005 patients available from AACR Project GENIE v.15 (1) database were analyzed for the prevalence of non-V600 BRAF mutations, fusions and copy number alterations in a range of cancer types. Results: A total of 6374 separate non-V600 BRAF alterations were identified in 5876 samples (2.97%), including 1176 fusions (18.4%), 4435 missense mutations (69.6%), 299 truncating mutations (4.7%), and 245 in-frame mutations (3.8%), splice variants (3.4%). Most frequent tumors included lung (19%), melanoma (14%), colorectal (9.7%) glioma (5%), thyroid (1.4%). BRAF fusions were observed in 0.7% of tumor samples, most identified in glioma, prostate, lung, thyroid, and colorectal cancer (20%, 7.3%, 6.1%; 4%, 4% of identified BRAF fusions, respectively). Most fusions were considered driver events (1123, 95.5%); frequent fusion gene partners included KIAA1549, intragenic fusions, SND1, AGK, MKRN1 (39.9%, 15%, 4%, 3.3%, 2.4% of 1176 samples respectively). Of 4435 missense mutations identified, most were considered driver events (2734, 62%); 1701 missense mutations were variants of uncertain significance (VUS) using OncoKB database (38%). Missense mutations occurred across codons, most frequently involving codon 469 (n=584, 13.2%, G469A/V/R/E/S/L/K/I), 466 (n=310, 10.5%, G466V/E/A/R), 594 (n=506, 11.4%, D594G/N/A/E/H/Y/V/F), 601 (n=279, 6.3%, K601E/N/I/T/_S602delinsNT), 581 (n=231, 5.2%, N581S/I/Y/H/T/D/K) 597 (n=118; 2.7%, L597R/Q/S/V/P/H/I). BRAF amplification occurred in 0.14% of samples. Conclusions: While BRAF fusions are rare events across cancers, non-v600 BRAF alterations occur in 3% of malignancies. Atypical non-V600 BRAFalterations and BRAF fusions represent a distinct molecular cohort across cancers. Most BRAF fusion events and non-V600 missense mutations are characterized as oncogenic, underlining the spectrum of BRAF inhibition, and the urgent need to expand agents beyond the current BRAFV600 indications. Functional characterization of atypical BRAF variants is therefore crucial, together with enrolling patients with these rare alterations on rationally designed clinical trials. 1. Cancer Discov. 2017.
Non-invasive colorectal cancer detection using multimodal deep learning ensemble classifier.
Authors: Seung Wook Hong, Juntae Park, Junnam Lee, Chang-Seok Ki, Dasom Kim, Tae-Rim Lee, Jin Mo Ahn, Mengchi Wang, Andrew Carson, Byung-In Lee, Jeong-Sik Byeon, Eunhae Cho
Journal: Journal of Clinical Oncology (2024)

3066 Background: The demand for alternative, non-invasive methods for colorectal cancer (CRC) screening is substantial. Cell-free DNA (cfDNA) whole genome sequencing (WGS) offers a promising avenue, utilizing diverse fragmentomic data. We aimed to develop a new approach: integrating fragment end motif by size (FEMS) with genomic coverage (COV) of cfDNA to enhance CRC screening. Methods: Participants were comprised of 1,506 colonoscopy verified normal samples, 130 advanced adenoma (AA) patients, 302 CRC patients (stage I: 28.5%, stage II: 25.5%, stage III: 31.1%, stage IV: 14.2%, unknown: 0.7%). We generated low depth cfDNA-WGS data (a minimum 40 million reads per sample) using the Novaseq 6000 sequencer. We minimized batch bias by normalizing with the same samples for each experimental batch. The development set comprised 1,332 samples (1,023 normal, 103 AA, and 206 CRC), while the validation set consisted of 606 samples (483 normal, 27 AA, and 96 CRC). Results: Our new algorithm achieved 84.0% sensitivity (95% CI: 81%-86%) for CRC and 69.9% (95% CI: 66%-81%) for AA in the development set, with a specificity of 90.0%. These findings were consistent in the external set with 84.9% specificity (95% CI: 82%-88%) and sensitivities of 80.2% (95% CI: 72%-88%) and 63.0% (95% CI: 44%-82%) for CRC and AA, respectively. The sensitivities across stages (Stage I: 80%, Stage II: 86.8%, Stage III: 78.8%, Stage IV: 96.7%) were similarly reflected in the validation sets (Stage I: 74%, Stage II: 83%, Stage III: 79%, Stage IV: 92%). Conclusions: Our multimodal deep learning model shows promise for accurate non-invasive colon cancer and AA detection using low-coverage cfDNA WGS. Its strong performance in detecting not only CRC but also AA lesions suggests its potential for early intervention and improved patient outcomes. The use of colonoscopy-verified normal samples strengthens the study's credibility and paves the way for future clinical translation.