tbuckley/cabot-search huggingface dataset:
Tyrosine phosphatase SHP2 aggravates tumor progression and glycolysis by dephosphorylating PKM2 in gastric cancer
Authors: Peiyun Wang, Yueting Han, Wen Pan, Jian Du, Duo Zuo, Yi Ba, Haiyang Zhang
Journal: MedComm (2024)

Abstract Gastric cancer (GC) is among the most lethal human malignancies, yet it remains hampered by challenges in fronter of molecular‐guided targeted therapy to direct clinical treatment strategies. The protein tyrosine phosphatase Src homology 2 domain‐containing phosphatase 2 (SHP2) is involved in the malignant progression of GC. However, the detailed mechanisms of the posttranslational modifications of SHP2 remain poorly understood. Herein, we demonstrated that an allosteric SHP2 inhibitor, SHP099, was able to block tumor proliferation and migration of GC by dephosphorylating the pyruvate kinase M2 type (PKM2) protein. Mechanistically, we found that PKM2 is a bona fide target of SHP2. The dephosphorylation and activation of PKM2 by SHP2 are necessary to exacerbate tumor progression and GC glycolysis. Moreover, we demonstrated a strong correlation between the phosphorylation level of PKM2 and adenosine 5‘‐monophosphate (AMP)‐activated protein kinase (AMPK) in GC cells. Notably, the low phosphorylation expression of AMPK was negatively correlated with activated SHP2. Besides, we proved that cisplatin could activate SHP2 and SHP099 increased sensitivity to cisplatin in GC. Taken together, our results provide evidence that the SHP2/PKM2/AMPK axis exerts a key role in GC progression and glycolysis and could be a viable therapeutic approach for the therapy of GC.
Roles of reactive oxygen species in inflammation and cancer
Authors: Yunfei Yu, Shengzhuo Liu, Luchen Yang, Pan Song, Zhenghuan Liu, Xiaoyang Liu, Xin Yan, Qiang Dong
Journal: MedComm (2024)

Abstract Reactive oxygen species (ROS) constitute a spectrum of oxygenic metabolites crucial in modulating pathological organism functions. Disruptions in ROS equilibrium span various diseases, and current insights suggest a dual role for ROS in tumorigenesis and the immune response within cancer. This review rigorously examines ROS production and its role in normal cells, elucidating the subsequent regulatory network in inflammation and cancer. Comprehensive synthesis details the documented impacts of ROS on diverse immune cells. Exploring the intricate relationship between ROS and cancer immunity, we highlight its influence on existing immunotherapies, including immune checkpoint blockade, chimeric antigen receptors, and cancer vaccines. Additionally, we underscore the promising prospects of utilizing ROS and targeting ROS modulators as novel immunotherapeutic interventions for cancer. This review discusses the complex interplay between ROS, inflammation, and tumorigenesis, emphasizing the multifaceted functions of ROS in both physiological and pathological conditions. It also underscores the potential implications of ROS in cancer immunotherapy and suggests future research directions, including the development of targeted therapies and precision oncology approaches. In summary, this review emphasizes the significance of understanding ROS‐mediated mechanisms for advancing cancer therapy and developing personalized treatments.
Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
Authors: Freddie Bray, Mathieu Laversanne, Hyuna Sung, Jacques Ferlay, Rebecca L. Siegel, Isabelle Soerjomataram, Ahmedin Jemal
Journal: CA A Cancer Journal for Clinicians (2024)

Abstract This article presents global cancer statistics by world region for the year 2022 based on updated estimates from the International Agency for Research on Cancer (IARC). There were close to 20 million new cases of cancer in the year 2022 (including nonmelanoma skin cancers [NMSCs]) alongside 9.7 million deaths from cancer (including NMSC). The estimates suggest that approximately one in five men or women develop cancer in a lifetime, whereas around one in nine men and one in 12 women die from it. Lung cancer was the most frequently diagnosed cancer in 2022, responsible for almost 2.5 million new cases, or one in eight cancers worldwide (12.4% of all cancers globally), followed by cancers of the female breast (11.6%), colorectum (9.6%), prostate (7.3%), and stomach (4.9%). Lung cancer was also the leading cause of cancer death, with an estimated 1.8 million deaths (18.7%), followed by colorectal (9.3%), liver (7.8%), female breast (6.9%), and stomach (6.8%) cancers. Breast cancer and lung cancer were the most frequent cancers in women and men, respectively (both cases and deaths). Incidence rates (including NMSC) varied from four‐fold to five‐fold across world regions, from over 500 in Australia/New Zealand (507.9 per 100,000) to under 100 in Western Africa (97.1 per 100,000) among men, and from over 400 in Australia/New Zealand (410.5 per 100,000) to close to 100 in South‐Central Asia (103.3 per 100,000) among women. The authors examine the geographic variability across 20 world regions for the 10 leading cancer types, discussing recent trends, the underlying determinants, and the prospects for global cancer prevention and control. With demographics‐based predictions indicating that the number of new cases of cancer will reach 35 million by 2050, investments in prevention, including the targeting of key risk factors for cancer (including smoking, overweight and obesity, and infection), could avert millions of future cancer diagnoses and save many lives worldwide, bringing huge economic as well as societal dividends to countries over the forthcoming decades.
“I was largely unguided trying to figure it out on my own”: experiences of genital tucking among transfeminine and gender diverse individuals
Authors: Sangeeta Subedi, Jessica Kant, Noah Miranda, Rebecca Anacheka-Nasemann, Joseph Martinez, Oren Ganor
Journal: International Journal of Transgender Health (2024)

Background Genital tucking, defined as the use of any nonsurgical method to reduce the appearance of the penis and/or testes to align with one's gender expression, is a common gender-affirming practice among transfeminine and gender diverse (TFGD) individuals. However, little is known about TFGD individuals' experiences of genital tucking beyond limited research on its fertility impacts.
Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease
Authors: Yajie Zhao, Maria Chukanova, Katherine A. Kentistou, Zammy Fairhurst-Hunter, Anna Maria Siegert, Raina Y. Jia, Georgina K. C. Dowsett, Eugene J. Gardner, Katherine Lawler, Felix R. Day, Lena R. Kaisinger, Yi-Chun Loraine Tung, Brian Yee Hong Lam, Hsiao-Jou Cortina Chen, Quanli Wang, Jaime Berumen-Campos, Pablo Kuri-Morales, Roberto Tapia-Conyer, Jesus Alegre-Diaz, Inês Barroso, Jonathan Emberson, Jason M. Torres, Rory Collins, Danish Saleheen, Katherine R. Smith, Dirk S. Paul, Florian Merkle, I. Sadaf Farooqi, Nick J. Wareham, Slavé Petrovski, Stephen O’Rahilly, Ken K. Ong, Giles S. H. Yeo, John R. B. Perry
Journal: Nature Genetics (2024)

Abstract Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes ( BSN and APBA1 ) with effects substantially larger than those of well-established obesity genes such as MC4R . In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.
Therapy-induced senescent tumor cell-derived extracellular vesicles promote colorectal cancer progression through SERPINE1-mediated NF-κB p65 nuclear translocation
Authors: Dan Zhang, Jian-Wei Zhang, Hui Xu, Xin Chen, Yu Gao, Huan-Gang Jiang, You Wang, Han Wu, Lei Yang, Wen-Bo Wang, Jing Dai, Ling Xia, Jin Peng, Fu-Xiang Zhou
Journal: Molecular Cancer (2024)

Abstract Background Cellular senescence frequently occurs during anti-cancer treatment, and persistent senescent tumor cells (STCs) unfavorably promote tumor progression through paracrine secretion of the senescence-associated secretory phenotype (SASP). Extracellular vesicles (EVs) have recently emerged as a novel component of the SASP and primarily mediate the tumor-promoting effect of the SASP. Of note, the potential effect of EVs released from STCs on tumor progression remains largely unknown. Methods We collected tumor tissues from two cohorts of colorectal cancer (CRC) patients to examine the expression of p16, p21, and SERPINE1 before and after anti-cancer treatment. Cohort 1 included 22 patients with locally advanced rectal cancer (LARC) who received neoadjuvant therapy before surgical resection. Cohort 2 included 30 patients with metastatic CRC (mCRC) who received first-line irinotecan-contained treatment. CCK-8, transwell, wound-healing assay, and tumor xenograft experiments were carried out to determine the impacts of EVs released from STCs on CRC progression in vitro and in vivo. Quantitative proteomic analysis was applied to identify protein cargo inside EVs secreted from STCs. Immunoprecipitation and mass spectrometer identification were utilized to explore the binding partners of SERPINE1. The interaction of SERPINE1 with p65 was verified by co-immunoprecipitation, and their co-localization was confirmed by immunofluorescence. Results Chemotherapeutic agents and irradiation could potently induce senescence in CRC cells in vitro and in human CRC tissues. The more significant elevation of p16 and p21 expression in patients after anti-cancer treatment displayed shorter disease-free survival (DFS) for LARC or progression-free survival (PFS) for mCRC. We observed that compared to non-STCs, STCs released an increased number of EVs enriched in SERPINE1, which further promoted the progression of recipient cancer cells. Targeting SERPINE1 with a specific inhibitor, tiplaxtinin, markedly attenuated the tumor-promoting effect of STCs-derived EVs. Additionally, the patients with greater increment of SERPINE1 expression after anti-cancer treatment had shorter DFS for LARC or PFS for mCRC. Mechanistically, SERPINE1 bound to p65, promoting its nuclear translocation and subsequently activating the NF-κB signaling pathway. Conclusions We provide the in vivo evidence of the clinical prognostic implications of therapy-induced senescence. Our results revealed that STCs were responsible for CRC progression by producing large amounts of EVs enriched in SERPINE1. These findings further confirm the crucial role of therapy-induced senescence in tumor progression and offer a potential therapeutic strategy for CRC treatment.
Strengthening primary health care to achieve universal health coverage
Authors: None The Lancet Regional Health – Europe
Journal: The Lancet Regional Health - Europe (2024)

Health systems worldwide are grappling with a critical challenge: the pursuit of universal health coverage (UHC), wherein all individuals can access a comprehensive range of quality health services without experiencing financial hardship. Globally, 4.5 billion people lack full coverage of essential health services. A robust primary health care system is essential to realising UHC. Encompassing health promotion, disease prevention, treatment, rehabilitation, and palliative care, primary health care serves as the cornerstone of a sustainable and resilient health system.
Redefining hyperviscosity in acute leukemia: Potential implications for red cell transfusions in the microvasculature
Authors: Jamie O. Musick, Evelyn K. Williams, Kirby S. Fibben, Dan Y. Zhang, Christina Caruso, Yumiko Sakurai, Reginald Tran, Melissa L. Kemp, Wilbur A. Lam
Journal: American Journal of Hematology (2024)

Abstract Hyperleukocytosis is an emergency of acute leukemia leading to blood hyperviscosity, potentially resulting in life‐threatening microvascular obstruction, or leukostasis. Due to the high number of red cells in the circulation, hematocrit/hemoglobin levels (Hct/Hgb) are major drivers of blood viscosity, but how Hct/Hgb mediates hyperviscosity in acute leukemia remains unknown. In vivo hemorheological studies are difficult to conduct and interpret due to issues related to visualizing and manipulating the microvasculature. To that end, a multi‐vessel microfluidic device recapitulating the size‐scale and geometry of the microvasculature was designed to investigate how Hct/Hgb interacts with acute leukemia to induce “in vitro” leukostasis. Using patient samples and cell lines, the degree of leukostasis was different among leukemia immunophenotypes with respect to white blood cell (WBC) count and Hct/Hgb. Among lymphoid immunophenotypes, severe anemia is protective against in vitro leukostasis and Hct/Hgb thresholds became apparent above which in vitro leukostasis significantly increased, to a greater extent with B‐cell acute lymphoblastic leukemia (ALL) versus T‐cell ALL. In vitro leukostasis in acute myeloid leukemia was primarily driven by WBC with little interaction with Hct/Hgb. This sets the stage for prospective clinical studies assessing how red cell transfusion may affect leukostasis risk in immunophenotypically different acute leukemia patients.
Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction – Results from the <scp>EMPULSE</scp> trial
Authors: Jasper Tromp, Mikhail N. Kosiborod, Christiane E. Angermann, Sean P. Collins, John R. Teerlink, Piotr Ponikowski, Jan Biegus, João Pedro Ferreira, Michael E. Nassif, Mitchell A. Psotka, Martina Brueckmann, Jonathan P Blatchford, Dominik Steubl, Adriaan A. Voors
Journal: European Journal of Heart Failure (2024)

Abstract Aim The EMPULSE (EMPagliflozin in patients hospitalised with acUte heart faiLure who have been StabilizEd) trial showed that, compared to placebo, the sodium–glucose cotransporter 2 inhibitor empagliflozin (10 mg/day) improved clinical outcomes of patients hospitalized for acute heart failure (HF). We investigated whether efficacy and safety of empagliflozin were consistent across the spectrum of left ventricular ejection fraction (LVEF). Methods and results A total of 530 patients hospitalized for acute de novo or decompensated HF were included irrespective of LVEF. For the present analysis, patients were classified as HF with reduced (HFrEF, LVEF ≤40%), mildly reduced (HFmrEF, LVEF 41–49%) or preserved (HFpEF, LVEF ≥50%) ejection fraction at baseline. The primary endpoint was a hierarchical outcome of death, worsening HF events (HFE) and quality of life over 90 days, assessed by the win ratio. Secondary endpoints included individual components of the primary endpoint and safety. Out of 523 patients with baseline data, 354 (67.7%) had HFrEF, 54 (10.3%) had HFmrEF and 115 (22.0%) had HFpEF. The clinical benefit (hierarchical composite of all‐cause death, HFE and Kansas City Cardiomyopathy Questionnaire total symptom score) of empagliflozin at 90 days compared to placebo was consistent across LVEF categories (≤40%: win ratio 1.35 [95% confidence interval 1.04, 1.75]; 41–49%: win ratio 1.25 [0.66, 2.37)] and ≥50%: win ratio 1.40 [0.87, 2.23], p interaction = 0.96) with a favourable safety profile. Results were consistent across individual components of the hierarchical primary endpoint. Conclusion The clinical benefit of empagliflozin proved consistent across LVEF categories in the EMPULSE trial. These results support early in‐hospital initiation of empagliflozin regardless of LVEF.
FEV<sub>1</sub>Q: what (even) is normal lung function?
Authors: Arafa Aboelhassan, John R. Hurst
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>FEV<sub>1</sub>Q has real potential as a race-neutral assessment of lung function, but longitudinal data and data from diverse populations are required to support widespread implementation</b>https://bit.ly/48Y23v5
Response from the authors: As-needed ICS/formoterol or as-needed SABA in mild asthma?
Authors: Alberto Papi, Diogenes S. Ferreira, Thomy Tonia, Florence Schleich
Journal: European Respiratory Journal (2024)

<h3>Shareable abstract</h3> <b>The ERS guidelines do not ignore the increased risk of deaths associated with (over)use of as-needed SABA in mild asthma. The recommendation for as-needed ICS/formoterol <i>versus</i> as-needed SABA is strong, even if mortality was considered a critical outcome.</b>https://bit.ly/437bhnk
Next Directions in the Neuroscience of Cancers Arising outside the CNS
Authors: Moran Amit, Corina Anastasaki, Robert Dantzer, Ihsan Ekin Demir, Benjamin Deneen, Karen O. Dixon, Mikala Egeblad, Erin M. Gibson, Shawn L. Hervey-Jumper, Hubert Hondermarck, Claire Magnon, Michelle Monje, Shorook Na'ara, Yuan Pan, Elizabeth A. Repasky, Nicole N. Scheff, Erica K. Sloan, Sebastien Talbot, Kevin J. Tracey, Lloyd C. Trotman, Manuel Valiente, Linda Van Aelst, Varun Venkataramani, Humsa S. Venkatesh, Paola D. Vermeer, Frank Winkler, Richard J. Wong, David H. Gutmann, Jeremy C. Borniger
Journal: Cancer Discovery (2024)

Summary: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.
The Hallmarks of Precancer
Authors: Mary M. Stangis, Zhengyi Chen, Jimin Min, Sarah E. Glass, Jordan O. Jackson, Megan D. Radyk, Xen Ping Hoi, W. Nathaniel Brennen, Ming Yu, Huy Q. Dinh, Robert J. Coffey, Martha J. Shrubsole, Keith S. Chan, William M. Grady, Srinivasan Yegnasubramanian, Costas A. Lyssiotis, Anirban Maitra, Richard B. Halberg, Neelendu Dey, Ken S. Lau
Journal: Cancer Discovery (2024)

Summary: Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.
Glioblastoma: Not Just Another Cancer
Authors: Howard A. Fine
Journal: Cancer Discovery (2024)

Summary: This commentary urges a paradigm shift in how we approach research and drug development for glioblastoma, reimagining it as an aberrant brain-like organ, distinct from other cancers, to inspire innovative treatment strategies and interdisciplinary collaboration, addressing the minimal progress in extending glioblastoma patient survival despite years of research and investment.
Cancer Hallmarks: Piecing the Puzzle Together
Authors: Maria P. Alcolea, Direna Alonso-Curbelo, Chiara Ambrogio, Susan Bullman, Ana Luísa Correia, Aurélie Ernst, Christopher J. Halbrook, Gemma L. Kelly, Amanda W. Lund, Daniela F. Quail, Marcus Ruscetti, Efrat Shema, Ingunn M. Stromnes, Wai Leong Tam
Journal: Cancer Discovery (2024)
Phase-Separated Biomolecular Condensation in Cancer: New Horizons and Next Frontiers
Authors: Trever G. Bivona
Journal: Cancer Discovery (2024)

Summary: Beyond lipid membrane compartments, cells including cancer cells utilize various membraneless compartments, often termed biomolecular condensates, to regulate or organize key cellular processes underlying physiologic or pathologic phenotypes. In this commentary, the emergence of biomolecular condensation in cancer biology is highlighted, with a focus on key unanswered questions and with implications for improving the understanding of cancer pathogenesis and developing innovative cancer management strategies.
Cancer and the Metaorganism
Authors: Laurence Zitvogel, Guido Kroemer
Journal: Cancer Discovery (2024)

Summary: Pathogenic shifts in the gut microbiota are part of the “ecological” alterations that accompany tumor progression and compromise immunosurveillance. The future management of health and disease including cancer will rely on the diagnosis of such shifts and their therapeutic correction by general or personalized strategies, hence restoring metaorganismal homeostasis.
The Cancer Spectrum Theory
Authors: Hwa-Young Lee, Minkyo Song, Konrad H. Stopsack, Cheng Peng, Amanda I. Phipps, Molin Wang, Shuji Ogino, Naoko Sasamoto, Tomotaka Ugai
Journal: Cancer Discovery (2024)

Summary: Biological characteristics of tumors are heterogeneous, forming spectra in terms of several factors such as age at onset, anatomic spatial localization, tumor subtyping, and the degree of tumor aggressiveness (encompassing a neoplastic property spectrum). Instead of blindly using dichotomized approaches, the application of the multicategorical and continuous analysis approaches to detailed cancer spectrum data can contribute to a better understanding of the etiology of cancer, ultimately leading to effective prevention and precision oncology. We provide examples of cancer spectra and emphasize the importance of integrating the cancer spectrum theory into large-scale population cancer research.
Advancing Cancer Interception
Authors: Susan M. Domchek, Robert H. Vonderheide
Journal: Cancer Discovery (2024)

Summary: Rapid advances in technology and therapeutics, along with better methods to discern who is at risk for cancer by genetic testing and other means, has enabled the development of cancer interception. Targeted therapies and “immuno-interception” may eliminate premalignant lesions and require clinical trial and treatment paradigms altogether distinct from current approaches.
Elucidating the Cell Surfaceome to Accelerate Cancer Drug Development
Authors: Jacob B. Geri, William Pao
Journal: Cancer Discovery (2024)

Summary: Cell surface proteins represent ideal therapeutic targets because of their accessibility to antibodies, T cell–directed therapies, and radiotherapies, but there are only 25 therapeutically relevant cell surface targets for which cancer therapies are approved in the United States or European Union. This commentary calls for intensified research into mapping the universe of cell surface proteins – the cell surfaceome – in order to accelerate cancer drug development.
A Vision for Democratizing Next-Generation Oncology Clinical Trials
Authors: Vivek Subbiah, Denis Horgan, Ishwaria M. Subbiah
Journal: Cancer Discovery (2024)

Summary: Revolutionary advancements in oncology have transformed lives, but the clinical trials ecosystem encounters challenges, including restricted access to innovative therapies and a lack of diversity in participant representation. A vision emerges for democratized, globally accessible oncology trials, necessitating collaboration among researchers, clinicians, patients, and policymakers to shift from converting complex, exclusive trials into a dynamic, inclusive force against cancer.
Chemotherapy and the Extra-Tumor Immune Microenvironment: EXTRA-TIME
Authors: Tri Giang Phan, Katherine N. Weilbaecher, Rebecca Aft, Peter I. Croucher, Christine L. Chaffer
Journal: Cancer Discovery (2024)

Summary: Understandably, conventional therapeutic strategies have focused on controlling primary tumors. We ask whether the cost of such strategies is actually an increased likelihood of metastatic relapse.