tbuckley/cabot-search huggingface dataset:
PI3K/mTOR is a therapeutically targetable genetic dependency in diffuse intrinsic pontine glioma
Authors: Ryan J. Duchatel, Evangeline R. Jackson, Sarah G. Parackal, Dylan Kiltschewskij, Izac J. Findlay, Abdul Mannan, Dilana E. Staudt, Bryce C. Thomas, Zacary P. Germon, Sandra Laternser, Padraic S. Kearney, M. Fairuz B. Jamaluddin, Alicia M. Douglas, Tyrone Beitaki, Holly P. McEwen, Mika L. Persson, Emily A. Hocke, Vaibhav Jain, Michael Aksu, Elizabeth E. Manning, Heather C. Murray, Nicole M. Verrills, Claire Xin Sun, Paul Daniel, Ricardo E. Vilain, David A. Skerrett-Byrne, Brett Nixon, Susan Hua, Charles E. de Bock, Yolanda Colino-Sanguino, Fatima Valdes-Mora, Maria Tsoli, David S. Ziegler, Murray J. Cairns, Eric H. Raabe, Nicholas A. Vitanza, Esther Hulleman, Timothy N. Phoenix, Carl Koschmann, Frank Alvaro, Christopher V. Dayas, Christopher L. Tinkle, Helen Wheeler, James R. Whittle, David D. Eisenstat, Ron Firestein, Sabine Mueller, Santosh Valvi, Jordan R. Hansford, David M. Ashley, Simon G. Gregory, Lindsay B. Kilburn, Javad Nazarian, Jason E. Cain, Matthew D. Dun
Journal: Journal of Clinical Investigation (2024)

Diffuse midline glioma (DMG), including tumors diagnosed in the brainstem (diffuse intrinsic pontine glioma – DIPG), are uniformly fatal brain tumors that lack effective treatment. Analysis of CRISPR-Cas9 loss-of-function gene deletion screens identified PIK3CA and MTOR as targetable molecular dependencies across DIPG patient models, highlighting the therapeutic potential of the blood-brain barrier penetrant PI3K/Akt/mTOR inhibitor, paxalisib. At the human equivalent maximum tolerated dose, mice treated with paxalisib experienced systemic glucose feedback and increased insulin levels commensurate with patients using PI3K inhibitors. To exploit genetic dependence and overcome resistance whilst maintaining compliance and therapeutic benefit, we combined paxalisib with the anti-hyperglycemic drug, metformin. Metformin restored glucose homeostasis and decreased phosphorylation of the insulin receptor in vivo, a common mechanism of PI3K-inhibitor resistance, extending survival of orthotopic models. DIPG models treated with paxalisib increased calcium-activated PKC signaling. The brain penetrant PKC inhibitor enzastaurin in combination with paxalisib, synergistically extended the survival of multiple orthotopic patient-derived and immunocompetent syngeneic allograft models; benefits potentiated in combination with metformin and standard-of-care radiotherapy. Therapeutic adaptation was assessed using spatial transcriptomics and ATAC-sequencing, identifying changes in myelination and tumor immune microenvironment crosstalk. Together, we have identified a clinically relevant DIPG therapeutic combinatorial approach.
Landscape Heterogeneity Explains the Genetic Differentiation of a Forest Bird across the Sino-Himalayan Mountains
Authors: Xiaolu Jiao, Lei Wu, Dezhi Zhang, Huan Wang, Feng Dong, Le Yang, Shangyu Wang, Hitoha E Amano, Weiwei Zhang, Chenxi Jia, Frank E Rheindt, Fumin Lei, Gang Song
Journal: Molecular Biology and Evolution (2024)

Abstract Mountains are the world's most important centers of biodiversity. The Sino-Himalayan Mountains are global biodiversity hotspot due to their extremely high species richness and endemicity. Ample research investigated the impact of the Qinghai–Tibet Plateau uplift and Quaternary glaciations in driving species diversification in plants and animals across the Sino-Himalayan Mountains. However, little is known about the role of landscape heterogeneity and other environmental features in driving diversification in this region. We utilized whole genomes and phenotypic data in combination with landscape genetic approaches to investigate population structure, demography, and genetic diversity in a forest songbird species native to the Sino-Himalayan Mountains, the red-billed leiothrix (Leiothrix lutea). We identified 5 phylogeographic clades, including 1 in the East of China, 1 in Yunnan, and 3 in Tibet, roughly consistent with differences in song and plumage coloration but incongruent with traditional subspecies boundaries. Isolation-by-resistance model best explained population differentiation within L. lutea, with extensive secondary contact after allopatric isolation leading to admixture among clades. Ecological niche modeling indicated relative stability in the extent of suitable distribution areas of the species across Quaternary glacial cycles. Our results underscore the importance of mountains in the diversification of this species, given that most of the distinct genetic clades are concentrated in a relatively small area in the Sino-Himalayan Mountain region, while a single shallow clade populates vast lower-lying areas to the east. This study highlights the crucial role of landscape heterogeneity in promoting differentiation and provides a deep genomic perspective on the mechanisms through which diversity hotspots form.
Age-, sex- and proximal–distal-resolved multi-omics identifies regulators of intestinal aging in non-human primates
Authors: Xinyuan Wang, Yaru Luo, Siyu He, Ying Lu, Yanqiu Gong, Li Gao, Shengqiang Mao, Xiaohui Liu, Na Jiang, Qianlun Pu, Dan Du, Yang Shu, Shan Hai, Shuangqing Li, Hai-Ning Chen, Yi Zhao, Dan Xie, Shiqian Qi, Peng Lei, Hongbo Hu, Heng Xu, Zong-Guang Zhou, Biao Dong, Huiyuan Zhang, Yan Zhang, Lunzhi Dai
Journal: Nature Aging (2024)

The incidence of intestinal diseases increases with age, yet the mechanisms governing gut aging and its link to diseases, such as colorectal cancer (CRC), remain elusive. In this study, while considering age, sex and proximal-distal variations, we used a multi-omics approach in non-human primates (Macaca fascicularis) to shed light on the heterogeneity of intestinal aging and identify potential regulators of gut aging. We explored the roles of several regulators, including those from tryptophan metabolism, in intestinal function and lifespan in Caenorhabditis elegans. Suggesting conservation of region specificity, tryptophan metabolism via the kynurenine and serotonin (5-HT) pathways varied between the proximal and distal colon, and, using a mouse colitis model, we observed that distal colitis was more sensitive to 5-HT treatment. Additionally, using proteomics analysis of human CRC samples, we identified links between gut aging and CRC, with high HPX levels predicting poor prognosis in older patients with CRC. Together, this work provides potential targets for preventing gut aging and associated diseases.
ABCB1-dependent collateral sensitivity of multidrug-resistant colorectal cancer cells to the survivin inhibitor MX106-4C
Authors: Zi-Ning Lei, Najah Albadari, Qiu-Xu Teng, Hadiar Rahman, Jing-Quan Wang, Zhongzhi Wu, Dejian Ma, Suresh V. Ambudkar, John N.D. Wurpel, Yihang Pan, Wei Li, Zhe-Sheng Chen
Journal: Drug Resistance Updates (2024)
Life and disease status of patients with Parkinson’s disease during and after zero-COVID in China: an online survey
Authors: Pei Huang, Yu-Yan Tan, Biao Chen, Hui-Fang Shang, Li-Juan Wang, Chun-Feng Liu, Ling Chen, Ying Chang, Han Wang, Xue-Lian Wang, Xiao-Guang Lei, Li-Fen Yao, Yang Yu, Zheng Ye, Hai-Bo Chen, Sheng-Di Chen
Journal: Translational Neurodegeneration (2024)

Little is known about the impact of the COVID-19 pandemic on patients with Parkinson's disease (PD) at different stages of the pandemic. This study aims to assess the lives and disease status of PD patients during the zero-COVID policy period and after ending the zero-COVID policy.
Efficacy and immune modulation associated with the addition of IMiDs to Daratumumab backbone in multiple myeloma patients refractory to both drug classes: resetting synergistic activity
Authors: Ioannis V. Kostopoulos, Despina Fotiou, Maria Gavriatopoulou, Pantelis Rousakis, Ioannis Ntanasis-Stathopoulos, Chrysanthi Panteli, Panagiotis Malandrakis, Magdalini Migkou, Nikolaos Angelis, Nikolaos Kanellias, Evangelos Eleutherakis-Papaiakovou, Foteini Theodorakakou, Maria Krevvata, Evangelos Terpos, Meletios-Athanasios Dimopoulos, Ourania Tsitsilonis, Efstathios Kastritis
Journal: Blood Cancer Journal (2024)

Efficacy and immune modulation associated
The Ip6k1 and Ip6k2 Kinases Are Critical for Normal Renal Tubular Function
Authors: Betül Haykir, Seraina Olivia Moser, Eva Maria Pastor-Arroyo, Udo Schnitzbauer, Zsuzsa Radvanyi, Isabel Prucker, Danye Qiu, Dorothea Fiedler, Adolfo Saiardi, Henning J. Jessen, Nati Hernando, Carsten A. Wagner
Journal: Journal of the American Society of Nephrology (2024)

Significance Statement Kidneys are gatekeepers of systemic inorganic phosphate balance because they control urinary phosphate excretion. In yeast and plants, inositol hexakisphosphate kinases (IP6Ks) are central to regulate phosphate metabolism, whereas their role in mammalian phosphate homeostasis is mostly unknown. We demonstrate in a renal cell line and in mice that Ip6k1 and Ip6k2 are critical for normal expression and function of the major renal Na + /Pi transporters NaPi-IIa and NaPi-IIc. Moreover, Ip6k1/2 −/− mice also show symptoms of more generalized kidney dysfunction. Thus, our results suggest that IP6Ks are essential for phosphate metabolism and proper kidney function in mammals. Background Inorganic phosphate is an essential mineral, and its plasma levels are tightly regulated. In mammals, kidneys are critical for maintaining phosphate homeostasis through mechanisms that ultimately regulate the expression of the Na + /Pi cotransporters NaPi-IIa and NaPi-IIc in proximal tubules. Inositol pyrophosphate 5-IP 7 , generated by IP6Ks, is a main regulator of phosphate metabolism in yeast and plants. IP6Ks are conserved in mammals, but their role in phosphate metabolism in vivo remains unexplored. Methods We used in vitro (opossum kidney cells) and in vivo (renal tubular-specific Ip6k1/2 −/− mice) models to analyze the role of IP6K1/2 in phosphate homeostasis in mammals. Results In both systems, Ip6k1 and Ip6k2 are responsible for synthesis of 5-IP 7 . Depletion of Ip6k1/2 in vitro reduced phosphate transport and mRNA expression of Na + /Pi cotransporters, and it blunts phosphate transport adaptation to changes in ambient phosphate. Renal ablation of both kinases in mice also downregulates the expression of NaPi-IIa and NaPi-IIc and lowered the uptake of phosphate into proximal renal brush border membranes. In addition, the absence of Ip6k1 and Ip6k2 reduced the plasma concentration of fibroblast growth factor 23 and increased bone resorption, despite of which homozygous males develop hypophosphatemia. Ip6k1/2 −/− mice also show increased diuresis, albuminuria, and hypercalciuria, although the morphology of glomeruli and proximal brush border membrane seemed unaffected. Conclusions Depletion of renal Ip6k1/2 in mice not only altered phosphate homeostasis but also dysregulated other kidney functions.
Uncertainty-aware deep-learning model for prediction of supratentorial hematoma expansion from admission non-contrast head computed tomography scan
Authors: Anh T. Tran, Tal Zeevi, Stefan P. Haider, Gaby Abou Karam, Elisa R. Berson, Hishan Tharmaseelan, Adnan I. Qureshi, Pina C. Sanelli, David J. Werring, Ajay Malhotra, Nils H. Petersen, Adam de Havenon, Guido J. Falcone, Kevin N. Sheth, Seyedmehdi Payabvash
Journal: npj Digital Medicine (2024)

Hematoma expansion (HE) is a modifiable risk factor and a potential treatment target in patients with intracerebral hemorrhage (ICH). We aimed to train and validate deep-learning models for high-confidence prediction of supratentorial ICH expansion, based on admission non-contrast head Computed Tomography (CT). Applying Monte Carlo dropout and entropy of deep-learning model predictions, we estimated the model uncertainty and identified patients at high risk of HE with high confidence. Using the receiver operating characteristics area under the curve (AUC), we compared the deep-learning model prediction performance with multivariable models based on visual markers of HE determined by expert reviewers. We randomly split a multicentric dataset of patients (4-to-1) into training/cross-validation (n = 634) versus test (n = 159) cohorts. We trained and tested separate models for prediction of ≥6 mL and ≥3 mL ICH expansion. The deep-learning models achieved an AUC = 0.81 for high-confidence prediction of HE
Nuclear miR-204-3p mitigates metabolic dysfunction-associated steatotic liver disease in mice
Authors: Zhaowei Zou, Xiu Liu, Jie Yu, Tao Ban, Ziyi Zhang, Peiqi Wang, Renli Huang, Fuxin Zheng, Yafei Chang, Wanli Peng, Yubo Tang, Xiaoqing Feng, Ziying Zhao, Xiaofei Lv, Shuai Huang, Jiawei Guo, Yonghua Tuo, Zhijun Zhou, Sijia Liang
Journal: Journal of Hepatology (2024)
Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding
Authors: Ashley S. Williams, Scott B. Crown, Scott P. Lyons, Timothy R. Koves, Rebecca J. Wilson, Jordan M. Johnson, Dorothy H. Slentz, Daniel P. Kelly, Paul A. Grimsrud, Guo-Fang Zhang, Deborah M. Muoio
Journal: Cell Metabolism (2024)
Dopamine transients follow a striatal gradient of reward time horizons
Authors: Ali Mohebi, Wei Wei, Lilian Pelattini, Kyoungjun Kim, Joshua D. Berke
Journal: Nature Neuroscience (2024)

Abstract Animals make predictions to guide their behavior and update those predictions through experience. Transient increases in dopamine (DA) are thought to be critical signals for updating predictions. However, it is unclear how this mechanism handles a wide range of behavioral timescales—from seconds or less (for example, if singing a song) to potentially hours or more (for example, if hunting for food). Here we report that DA transients in distinct rat striatal subregions convey prediction errors based on distinct time horizons. DA dynamics systematically accelerated from ventral to dorsomedial to dorsolateral striatum, in the tempo of spontaneous fluctuations, the temporal integration of prior rewards and the discounting of future rewards. This spectrum of timescales for evaluative computations can help achieve efficient learning and adaptive motivation for a broad range of behaviors.
Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results
Authors: Sergio Crespo-Garcia, Frédérik Fournier, Roberto Diaz-Marin, Sharon Klier, Derek Ragusa, Lauren Masaki, Gael Cagnone, Guillaume Blot, Ikhlas Hafiane, Agnieszka Dejda, Rana Rizk, Rachel Juneau, Manuel Buscarlet, Sarah Chorfi, Priyanka Patel, Pedro J. Beltran, Jean-Sebastien Joyal, Flavio A. Rezende, Masayuki Hata, Alex Nguyen, Lynne Sullivan, Jason Damiano, Ariel M. Wilson, Frédérick A. Mallette, Nathaniel E. David, Anirvan Ghosh, Pamela R. Tsuruda, Jamie Dananberg, Przemyslaw Sapieha
Journal: Nature Medicine (2024)
Itaconate impairs immune control of Plasmodium by enhancing mtDNA-mediated PD-L1 expression in monocyte-derived dendritic cells
Authors: Theresa Ramalho, Patricia A. Assis, Ogooluwa Ojelabi, Lin Tan, Brener Carvalho, Luiz Gardinassi, Osvaldo Campos, Philip L. Lorenzi, Katherine A. Fitzgerald, Cole Haynes, Douglas T. Golenbock, Ricardo T. Gazzinelli
Journal: Cell Metabolism (2024)

Severe forms of malaria are associated with systemic inflammation and host metabolism disorders; however, the interplay between these outcomes is poorly understood. Using a Plasmodium chabaudi model of malaria, we demonstrate that interferon (IFN) γ boosts glycolysis in splenic monocyte-derived dendritic cells (MODCs), leading to itaconate accumulation and disruption in the TCA cycle. Increased itaconate levels reduce mitochondrial functionality, which associates with organellar nucleic acid release and MODC restraint. We hypothesize that dysfunctional mitochondria release degraded DNA into the cytosol. Once mitochondrial DNA is sensitized, the activation of IRF3 and IRF7 promotes the expression of IFN-stimulated genes and checkpoint markers. Indeed, depletion of the STING-IRF3/IRF7 axis reduces PD-L1 expression, enabling activation of CD8+ T cells that control parasite proliferation. In summary, mitochondrial disruption caused by itaconate in MODCs leads to a suppressive effect in CD8+ T cells, which enhances parasitemia. We provide evidence that ACOD1 and itaconate are potential targets for adjunct antimalarial therapy.
Reductions in smoking due to ratification of the Framework Convention for Tobacco Control in 171 countries
Authors: Guillermo Paraje, Mauricio Flores Muñoz, Daphne C. Wu, Prabhat Jha
Journal: Nature Medicine (2024)

Abstract Smoking globally kills over half of long-term smokers and causes about 7 million annual deaths. The World Health Organization Framework Convention for Tobacco Control (FCTC) is the main global policy strategy to combat smoking, but its effectiveness is uncertain. Our interrupted time series analyses compared before- and after-FCTC trends in the numbers and prevalence of smokers below the age of 25 years (when smoking initiation occurs and during which response to interventions is greatest) and on cessation at 45–59 years (when quitting probably occurs) in 170 countries, excluding China. Contrasting the 10 years after FCTC ratification with the income-specific before-FCTC trends, we observed cumulative decreases of 15.5% (95% confidence interval = −33.2 to −0.7) for the numbers of current smokers and decreases of −7.5% (95% CI = −10.6 to −4.5) for the prevalence of smoking below age 25 years. The quit ratio (comparing the numbers of former and ever smokers) at 45–59 years increased by 1.8% (1.2 to 2.3) 10 years after FCTC ratification. Countries raising taxes by at least 10 percentage points concurrent with ratification observed steeper decreases in all three outcomes than countries that did not. Over a decade across 170 countries, the FCTC was associated with 24 million fewer young smokers and 2 million more quitters.
Severe disease during both primary and secondary dengue virus infections in pediatric populations
Authors: Charu Aggarwal, Hasan Ahmed, Pragati Sharma, Elluri Seetharami Reddy, Kaustuv Nayak, Mohit Singla, Deepti Maheshwari, Yadya M. Chawla, Harekrushna Panda, Ramesh Chandra Rai, Sivaram Gunisetty, Lalita Priyamvada, Siddhartha Kumar Bhaumik, Syed Fazil Ahamed, Rosario Vivek, Priya Bhatnagar, Prabhat Singh, Manpreet Kaur, Kritika Dixit, Sanjeev Kumar, Kamal Gottimukkala, Keshav Saini, Prashant Bajpai, Gopinathan Pillai Sreekanth, Shobha Mammen, Anand Rajan, Valsan Philip Verghese, Asha Mary Abraham, Paresh Shah, Kalichamy Alagarasu, Tianwei Yu, Carl W. Davis, Jens Wrammert, Aftab Ansari, Rustom Antia, Sushil Kumar Kabra, Guruprasad R. Medigeshi, Rafi Ahmed, Rakesh Lodha, Anita Shet, Anmol Chandele, Kaja Murali-Krishna
Journal: Nature Medicine (2024)
MYC targeting by OMO-103 in solid tumors: a phase 1 trial
Authors: Elena Garralda, Marie-Eve Beaulieu, Víctor Moreno, Sílvia Casacuberta-Serra, Sandra Martínez-Martín, Laia Foradada, Guzman Alonso, Daniel Massó-Vallés, Sergio López-Estévez, Toni Jauset, Elena Corral de la Fuente, Bernard Doger, Tatiana Hernández, Raquel Perez-Lopez, Oriol Arqués, Virginia Castillo Cano, Josefa Morales, Jonathan R. Whitfield, Manuela Niewel, Laura Soucek, Emiliano Calvo
Journal: Nature Medicine (2024)

Abstract Among the ‘most wanted’ targets in cancer therapy is the oncogene MYC, which coordinates key transcriptional programs in tumor development and maintenance. It has, however, long been considered undruggable. OMO-103 is a MYC inhibitor consisting of a 91-amino acid miniprotein. Here we present results from a phase 1 study of OMO-103 in advanced solid tumors, established to examine safety and tolerability as primary outcomes and pharmacokinetics, recommended phase 2 dose and preliminary signs of activity as secondary ones. A classical 3 + 3 design was used for dose escalation of weekly intravenous, single-agent OMO-103 administration in 21-day cycles, encompassing six dose levels (DLs). A total of 22 patients were enrolled, with treatment maintained until disease progression. The most common adverse events were grade 1 infusion-related reactions, occurring in ten patients. One dose-limiting toxicity occurred at DL5. Pharmacokinetics showed nonlinearity, with tissue saturation signs at DL5 and a terminal half-life in serum of 40 h. Of the 19 patients evaluable for response, 12 reached the predefined 9-week time point for assessment of drug antitumor activity, eight of those showing stable disease by computed tomography. One patient defined as stable disease by response evaluation criteria in solid tumors showed a 49% reduction in total tumor volume at best response. Transcriptomic analysis supported target engagement in tumor biopsies. In addition, we identified soluble factors that are potential pharmacodynamic and predictive response markers. Based on all these data, the recommended phase 2 dose was determined as DL5 (6.48 mg kg −1 ). ClinicalTrials.gov identifier: NCT04808362 .
Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination
Authors: Matthew R. Lawrence-Paul, Tien-chi Pan, Dhruv K. Pant, Natalie N. C. Shih, Yan Chen, George K. Belka, Michael Feldman, Angela DeMichele, Lewis A. Chodosh
Journal: Genome Medicine (2024)

Abstract Background Evolutionary models of breast cancer progression differ on the extent to which metastatic potential is pre-encoded within primary tumors. Although metastatic recurrences often harbor putative driver mutations that are not detected in their antecedent primary tumor using standard sequencing technologies, whether these mutations were acquired before or after dissemination remains unclear. Methods To ascertain whether putative metastatic driver mutations initially deemed specific to the metastasis by whole exome sequencing were, in actuality, present within rare ancestral subclones of the primary tumors from which they arose, we employed error-controlled ultra-deep sequencing (UDS-UMI) coupled with FFPE artifact mitigation by uracil-DNA glycosylase (UDG) to assess the presence of 132 “metastasis-specific” mutations within antecedent primary tumors from 21 patients. Maximum mutation detection sensitivity was ~1% of primary tumor cells. A conceptual framework was developed to estimate relative likelihoods of alternative models of mutation acquisition. Results The ancestral primary tumor subclone responsible for seeding the metastasis was identified in 29% of patients, implicating several putative drivers in metastatic seeding including LRP5 A65V and PEAK1 K140Q. Despite this, 93% of metastasis-specific mutations in putative metastatic driver genes remained undetected within primary tumors, as did 96% of metastasis-specific mutations in known breast cancer drivers, including ERRB2 V777L, ESR1 D538G, and AKT1 D323H. Strikingly, even in those cases in which the rare ancestral subclone was identified, 87% of metastasis-specific putative driver mutations remained undetected. Modeling indicated that the sequential acquisition of multiple metastasis-specific driver or passenger mutations within the same rare subclonal lineage of the primary tumor was highly improbable. Conclusions Our results strongly suggest that metastatic driver mutations are sequentially acquired and selected within the same clonal lineage both before, but more commonly after, dissemination from the primary tumor, and that these mutations are biologically consequential. Despite inherent limitations in sampling archival primary tumors, our findings indicate that tumor cells in most patients continue to undergo clinically relevant genomic evolution after their dissemination from the primary tumor. This provides further evidence that metastatic recurrence is a multi-step, mutation-driven process that extends beyond primary tumor dissemination and underscores the importance of longitudinal tumor assessment to help guide clinical decisions.
Risk and Prevention of Cardiovacular Events after Exacerbations of Respiratory Symptoms in Patients with COPD
Authors: Bianca Beghe, Antonio Spanevello, Leonardo M. Fabbri
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Risk and Prevention of Cardiovascular Events After Exacerbations of Respiratory Symptoms." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.