tbuckley/cabot-search huggingface dataset:
MQ232, A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases
Authors: Goran Stanajic-Petrovic, Mathilde Keck, Peggy Barbe, Apolline Urman, Evelyne Correia, Pierre Isnard, Jean-Paul Duong Van Huyen, Khawla Chmeis, Sékou Siramakan Diarra, Stefano Palea, Frederic Theodoro, Anvi-Laëtitia Nguyen, Florence Castelli, Alain Pruvost, Wenchao Zhao, Christiane Mendre, Bernard Mouillac, Frank Bienaimé, Philippe Robin, Pascal Kessler, Catherine Llorens-Cortes, Denis Servent, Hervé Nozach, Bernard Maillère, Dong Guo, Charles Truillet, Nicolas Gilles
Journal: Journal of the American Society of Nephrology (2024)

Background: Vaptans were developed at the end of the previous century as V2R antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and the autosomal polycystic kidney disease (ADPKD). However, its use is not as widespread as it should be due to price issues, a narrow therapeutic window and some side effects. With the aim of discovering new efficient and safer V2R antagonists, we screened animal venoms and identified several interesting peptide toxins. Among them, MQ1 displayed such unique biological properties in that regard that it was the starting point for the development of a potential drug candidate. Methods: Human T-cell assays and bioinformatics was used to mitigate MQ1 immunogenicity risk. The MQ232 biodistribution in mice was done by positron emission tomography (PET). Pharmacodynamics, pharmacokinetics, acute and chronic toxicity tests were performed on control rats. A rat experimental model of dDAVP-induced hyponatremia, an ex vivo mice model of renal cysts and a mice orthologous model of ADPKD were used to validate MQ232 efficacy in these pathologies. Results: Three mutations were introduced in MQ1 to mitigate its immunogenicity risk. A fourth gain-of-function mutation was added to generate MQ232. MQ232’s safety was demonstrated by a first toxic dose as high as 3,000 nmol/kg and a strong kidney organ selectivity by PET imaging, while showing almost no interaction with the liver. MQ232’s efficacy was first demonstrated with an effective dose of 3 nmol/kg in a hyponatremic model, and then in polycystic kidney models on which MQ232 significantly reduced cyst growth. Conclusions: We demonstrated, employing diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD.
Replication Stress is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors
Authors: Asuka Kawai-Kawachi, Madison M. Lenormand, Clémence Astier, Noé Herbel, Meritxell B. Cutrona, Carine Ngo, Marlène Garrido, Thomas Eychenne, Nicolas Dorvault, Laetitia Bordelet, Fei Fei Song, Ryme Bouyakoub, Anastasia Loktev, Antonio Romo-Morales, Clémence Henon, Léo Colmet-Daage, Julien Vibert, Marjorie Drac, Rachel Brough, Etienne Schwob, Oliviano Martella, Guillaume Pinna, Janet M. Shipley, Sibylle Mittnacht, Astrid Zimmermann, Aditi Gulati, Olivier Mir, Axel Le Cesne, Matthieu Faron, Charles Honoré, Christopher J. Lord, Roman M. Chabanon, Sophie Postel-Vinay
Journal: Cancer Research (2024)

Abstract Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma subtype that is driven by the EWS-WT1 chimeric transcription factor. The prognosis for DSRCT is poor, and major advances in treating DSCRT have not occurred for over two decades. To identify effective therapeutic approaches to target DSRCT, we conducted a high-throughput drug sensitivity screen in a DSRCT cell line assessing chemosensitivity profiles for 79 small-molecule inhibitors. DSRCT cells were sensitive to PARP and ATR inhibitors (PARPi, ATRi), as monotherapies and in combination. These effects were recapitulated using multiple clinical PARPi and ATRi in three biologically distinct, clinically-relevant models of DSRCT, including cell lines, a patient-derived xenograft (PDX)-derived organoid model, and a cell line-derived xenograft mouse model. Mechanistically, exposure to a combination of PARPi and ATRi caused increased DNA damage, G2/M checkpoint activation, micronuclei accumulation, replication stress, and R-loop formation. EWS-WT1 silencing abrogated these phenotypes and was epistatic with exogenous expression of the R-loop resolution enzyme RNase H1 in reversing the sensitivity to PARPi and ATRi monotherapies. The combination of PARPi and ATRi also induced EWS-WT1-dependent cell-autonomous activation of the cGAS/STING innate immune pathway and cell surface expression of PD-L1. Taken together, these findings point towards a role for EWS-WT1 in generating R-loop-dependent replication stress that leads to a targetable vulnerability, providing a rationale for the clinical assessment of PARPi and ATRi in DSRCT.
The EP3–ZNF488 Axis Promotes Self-Renewal of Glioma Stem-like Cells to Induce Resistance to Tumor Treating Fields
Authors: Dongjiang Chen, Son B. Le, Harshit Manektalia, Tianyi Liu, Tarun E. Hutchinson, Adam O'Dell, Bodour Salhia, David D. Tran
Journal: Cancer Research (2024)

Tumor Treating Fields (TTFields) employ low-intensity, alternating electric fields to exert antitumor activity and have demonstrated efficacy against multiple cancers, including glioblastoma (GBM). Unfortunately, cancer cells inevitably develop resistance to TTFields, highlighting the need to elucidate the underlying mechanisms to develop approaches to induce durable responses. Using a gene network-based machine-learning algorithm, we interrogated TTFields-resistant GBM cells and uncovered a regulatory axis anchored by the prostaglandin E receptor 3 (EP3) and the transcription factor zinc finger 488 (ZNF488). Mechanistically, TTFields induced EP3 upregulation and nuclear envelope localization, where it formed a complex with ZNF488 to induce resistance to TTFields by promoting self-renewal of glioma stem-like cells (GSC). Overexpression of EP3 and/or ZNF488 in TTFields-sensitive GSC conferred resistance and enhanced self-renewal, while expression of non-interacting mutants of these proteins abrogated formation of the nuclear complex and prevented resistance. Inhibition of either partner in this protein complex in resistant GSC, including those freshly isolated from TTFields-resistant GBM tumors, re-sensitized cells to the cytotoxic effects of TTFields, concomitant with reduced self-renewal and in vivo tumorigenicity. Importantly, inhibition of EP3 in TTFields-sensitive GSC preemptively halted the development of resistance. The EP3-ZNF488 axis was significantly upregulated in TTFields-resistant GBM tumors, and co-expression of EP3 and ZNF488 in other cancers correlated with lower survival rates. Collectively, these results indicate that the nuclear EP3-ZNF488 axis is necessary and sufficient to establish TTFields resistance, underscoring the potential to target this axis to prevent or reverse resistance in GBM and possibly other cancers.
KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition
Authors: Sigrid K. Fey, Arafath K. Najumudeen, Dale M. Watt, Laura M. Millett, Catriona A. Ford, Kathryn Gilroy, Rosalin J. Simpson, Kathy McLay, Rosanna Upstill-Goddard, David Chang, William Clark, Colin Nixon, Joanna L. Birch, Simon T. Barry, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. While the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrated that wild-type KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of wild-type KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of wild-type Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of wild-type KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of wild-type KRAS in both tumor progression and therapeutic response in pancreatic cancer.
Authors' Reply: The Potential Outcome-Modification Influences Introduced by ESKD Life Plan on eGFR Slopes
Authors: Abdel-Hay Tabcheh, Julie Boucquemont, Roberto Pecoits-Filho, Natalia Alencar De Pinho
Journal: Journal of the American Society of Nephrology (2024)

We thank Hung and Chao1 for their insightful comments about the potential impact of life plan during the transition to kidney failure on the slowing of eGFR decline in patients with advanced CKD. Below, we provide additional hypotheses to explain why eGFR decline would start decelerating before preemptive arteriovenous (AV) access creation as shown in our study published in JASN.2 First, as highlighted in the letter to the editor, treatment adherence and lifestyle behavior change are key for slowing kidney function decline. During the Chronic Kidney Disease—Renal Epidemiology and Information Network (CKD-REIN) cohort follow-up (2013–2020), best practices for CKD management were summarized by the Kidney Disease Improving Global Outcomes 2012 guidelines, updated in 2024.3 In advanced CKD, recommendations included preparation to KRT but also measures aimed at delaying progression, including management of cardiovascular and CKD-associated comorbidities, patient education, and lifestyle modification including diet, exercise, and smoking cessation. The international CKD Outcomes and Practice Patterns Study (including France) previously showed that adherence to these recommendations was low in typical clinical settings.4 However, more frequent nephrology visits, as recommend by the Kidney Disease Improving Global Outcomes and the French Health Authority guidelines—a minimum of 2–4 visits per year in patients with CKD stages 4–5—provide an opportunity for improving symptom management and reducing adverse drug reactions. In a previous study, we showed that patients with more frequent nephrologist visits had lower likelihood of urgent dialysis start.5 Second, GFR estimated from serum creatinine (as in our study) may be overestimated in advanced CKD because of muscle mass loss and reduced protein intake, affecting eGFR trajectory estimation. Third, regression toward the mean—a statistical phenomenon related to random error in repeated measurements—cannot be excluded because the decision to create an AV access often follows a period of rapid decline. Finally, our results may simply be due to the natural history of CKD in advanced stages, which stabilizes after reaching a certain level of GFR. Preserving kidney function is paramount in all phases of CKD care, and further research is needed to clarify the potential contribution of the aforementioned factors. For decades, part of the nephrology community included AV access creation as one of the factors that could slow eGFR decline and delay KRT initiation. By showing a smooth eGFR trajectory around the moment of preemptive AV access creation, our study provides evidence against a causal role of AV access on CKD progression.
Toward a Restrictive Use of Plasma Exchanges in Thrombotic Microangiopathies
Authors: Marie Frimat, Nora Schwotzer, François Provôt, Fadi Fakhouri
Journal: Journal of the American Society of Nephrology (2024)

1Univ. Lille, CHU Lille, Nephrology Department, F-59000, Lille, France. 2Univ. Lille, Inserm, Institut Pasteur de Lille, U1167 - RID-AGE, F-59000 Lille, France. 3Service of Nephrology and Hypertension, CHUV, University of Lausanne, Lausanne, Switzerland aCorrespondence to: Fadi Fakhouri, Service of Nephrology and Hypertension, CHUV, Lausanne, Switzerland. Telephone: +41213141154, E-mail: [email protected]
Lead Acetate Exposure and Cerebral Amyloid Accumulation: Mechanistic Evaluations in APP/PS1 Mice
Authors: Huiying Gu, Luqing L. Liu, Alanna Wu, Yongqi Yu, Uzay Emir, Stephen J. Sawiak, Paul R. Territo, Matin R. Farlow, Wei Zheng, Yansheng Du
Journal: Environmental Health Perspectives (2024)

The role of environmental factors in Alzheimer's disease (AD) pathogenesis remains elusive. Mounting evidence suggests that acute and past exposure to the environmental toxicant lead (Pb) is associated with longitudinal decline in cognitive function, brain atrophy, and greater brain
Cytochrome P450 Enzymes: The Old Pandora’s Box with an Ever-Growing Hope for Therapy Optimization and Drug Development—Editorial
Authors: Ahmed F. El-Yazbi, Ali H. Eid
Journal: Pharmacological Reviews (2024)

In 1841, the notion of drug metabolism in the body was coined with the discovery of hippuric acid as a metabolite of benzoic acid in urine of human subjects ([Ure, 1841][1]). Since then, there has been an explosive growth in our knowledge of the chemical disposition of small molecules in the human
Summing Up<i>Pharmacological Reviews’</i>75th Anniversary Year and a Look to the Future
Authors: Lynette C. Daws
Journal: Pharmacological Reviews (2024)

What a fantastic year it has been at Pharmacological Reviews . We have done many things to celebrate our 75th anniversary, with this closing issue for 2024 arguably the pinnacle. This issue contains 16 total papers: a 75th Anniversary Celebration Collection Special Section in collaboration with
RE: Combining antivascular endothelial growth factor and anti-epidermal growth factor receptor antibodies: randomized phase II study of irinotecan and cetuximab with/without ramucirumab in second-line colorectal cancer (ECOG-ACRIN E7208)
Authors: Qiang Hu, Xingchen Zhou, Yuanshui Sun
Journal: JNCI Journal of the National Cancer Institute (2024)
Higher risk of proteinuria with atezolizumab plus bevacizumab than lenvatinib in first-line systemic treatment for hepatocellular carcinoma
Authors: Jiwon Yang, Won-Mook Choi, Hyung-Don Kim, Jonggi Choi, Changhoon Yoo, Danbi Lee, Ju Hyun Shim, Kang Mo Kim, Young-Suk Lim, Han Chu Lee
Journal: Liver Cancer (2024)

Proteinuria presents a challenging complication during systemic therapy for hepatocellular carcinoma (HCC). This study aims to identify risk factors for proteinuria in patients with HCC treated with atezolizumab plus bevacizumab (Atezo/Bev) or lenvatinib (LEN) as first-line systemic treatment. A retrospective analysis was conducted on 622 consecutive patients with unresectable HCC who received Atezo/Bev or LEN as first-line systemic treatment between October 2013 and October 2022. Cumulative incidence of proteinuria was estimated using Kaplan-Meier curves and compared using log-rank tests. Risk factors for proteinuria were identified using Cox proportional-hazard models, along with propensity score-matched and subgroup analyses. Among 367 patients treated with Atezo/Bev and 255 with LEN, the cumulative incidence of proteinuria at 12 months was 27.5%. In the multivariable analysis, Atezo/Bev treatment (adjusted HR [aHR]: 1.57; 95% CI: 1.03-2.42), diabetes (aHR: 1.64; 95% CI: 1.03-2.61), hypertension (aHR: 2.27; 95% CI: 1.04-4.97), Child-Pugh class B (aHR: 3.43; 95% CI: 1.34-8.78), macrovascular invasion (MVI; aHR: 1.58; 95% CI: 1.04-2.38), and an estimated glomerular filtration rate ≤60 mL/min/1.73 m2 (aHR: 3.21; 95% CI: 1.84-5.62) were identified as risk factors for proteinuria. A higher risk of proteinuria in Atezo/Bev patients compared with LEN was consistently observed in the PS-matched cohort, particularly pronounced in subgroups with MVI (HR: 2.84; 95% CI: 1.23-6.54) compared with those without MVI (HR: 1.31; 95% CI: 0.69-2.47). Patients treated with Atezo/Bev as first-line systemic treatment for HCC exhibited a higher risk of proteinuria compared with those with LEN, particularly when accompanied by MVI.
Seventy-Five Years of Interactions: The Department of Physiology and Pharmacology at Karolinska Institutet and<i>Pharmacological Reviews</i>
Authors: Gunnar Schulte
Journal: Pharmacological Reviews (2024)

This special issue emerged from an informal discussion at an editorial board meeting during 2023, where the 75th anniversaries of Pharmacological Reviews and the Department of Physiology and Pharmacology at Karolinska Institutet, Stockholm, Sweden were coincidentally discussed. The idea for the
FDA Approval Summary: Teclistamab – A Bispecific CD3 T-cell Engager for Patients with Relapsed or Refractory Multiple Myeloma
Authors: Andrea C. Baines, Bindu Kanapuru, Jay Zhao, Lauren S. L. Price, Nan Zheng, Robyn Konicki, Michael L. Manning, Brenda J. Gehrke, Marc R. Theoret, Nicole J. Gormley
Journal: Clinical Cancer Research (2024)

Abstract On October 25, 2022, the FDA granted accelerated approval to teclistamab-cqyv (TECVAYLI; Janssen Biotech) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 mAb. Substantial evidence of effectiveness was obtained from the MajesTEC-1 trial, a phase I/II, single-arm, open-label, multicenter study. Patients received step-up doses of teclistamab at 0.06 and 0.3 mg/kg followed by 1.5 mg/kg subcutaneously once weekly until disease progression or unacceptable toxicity. An overall response rate of 61.8% was observed, with a complete response or better rate of 28.2%. Cytokine release syndrome occurred in 72% of patients, and neurologic toxicity occurred in 57%, including immune effector cell–associated neurotoxicity syndrome in 6%. Due to the risk of cytokine release syndrome and neurologic toxicity, including immune effector cell–associated neurotoxicity syndrome, the US Prescribing Information for teclistamab includes a boxed warning, and teclistamab is available only through a restricted program under a risk evaluation and mitigation strategy. Here, we summarize the data and FDA review supporting the accelerated approval of teclistamab, a B-cell maturation antigen–directed bispecific antibody that was the first bispecific CD3 T-cell engager approved for treatment of multiple myeloma.
Large Scale Comparative Analysis of Canine and Human Osteosarcomas Uncovers Conserved Clinically Relevant Tumor Microenvironment Subtypes
Authors: Sushant Patkar, Joshua Mannheimer, Stephanie A. Harmon, Christina J. Ramirez, Christina N. Mazcko, Peter L. Choyke, G. Thomas Brown, Baris Turkbey, Amy K. LeBlanc, Jessica A. Beck
Journal: Clinical Cancer Research (2024)

Osteosarcoma is an aggressive bone cancer lacking robust biomarkers for personalized treatment. Despite its scarcity in humans, it is relatively common in adult pet dogs. This study aimed to analyze clinically annotated bulk tumor transcriptomic datasets of canine and human osteosarcoma patients to identify potentially conserved patterns of disease progression.
Ironing Out the Mechanism of gp130 Signaling
Authors: Essam Eldin A Osman, Nouri Neamati
Journal: Pharmacological Reviews (2024)

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144's iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts. <h3>Significance Statement</h3> This perspective provides a timely and comprehensive analysis of advancements in gp130 signaling research, emphasizing the therapeutic implications of the currently available modulators. Bioinformatic analysis demonstrates potential interplay between gp130 and genes that regulate iron homeostasis, suggesting new therapeutic avenues. By combining original research findings with a broader discussion of gp1309s therapeutic potential, this perspective significantly contributes to the field.
The 75-Year Anniversary of the Department of Physiology and Pharmacology at Karolinska Institutet—Examples of Recent Accomplishments and Future Perspectives
Authors: Eddie Weitzberg, Magnus Ingelman-Sundberg, Jon O. Lundberg, Göran Engberg, Gunnar Schulte, Volker M. Lauschke
Journal: Pharmacological Reviews (2024)

Karolinska Institutet is a medical university encompassing 21 departments distributed across three departmental or campus groups. Pharmacological research has a long and successful tradition at the institute with a multitude of seminal findings in the areas of neuronal control of vasodilatation, cardiovascular pharmacology, neuropsychopharmacology, receptor pharmacology, and pharmacogenomics that resulted in, among many other recognitions, two Nobel prizes in Physiology and Medicine, one in 1970 to Ulf von Euler for his discovery of the processes involved in storage, release, and inactivation of neurotransmitters and the other in 1982 to Sune Bergström and Bengt Samuelsson for their work on prostaglandins and the discovery of leukotrienes. Pharmacology at Karolinska Institutet has over the last decade been ranked globally among the top 10 according to the QS World University Ranking. With the Department of Physiology and Pharmacology now celebrating its 75-year anniversary, we wanted to take this as an opportunity to showcase recent research achievements and how they paved the way for current activities at the department. We emphasize examples from preclinical and clinical research where the dpartment9s integrative environment and robust infrastructure have successfully facilitated the translation of findings into clinical applications and patient benefits. The close collaboration between preclinical scientists and clinical researchers across various disciplines, along with a strong network of partnerships within the department and beyond, positions us to continue leading world-class pharmacological research at the Department of Physiology and Pharmacology for decades to come. <h3>Significance Statement</h3> Pharmacological research at Karolinska Institutet has a long and successful history. Given the 75-year anniversary of the Department of Physiology and Pharmacology, this perspective provides an overview of recent departmental achievements and future trajectories. For these developments, interdisciplinary and intersectoral collaborations and a clear focus on result translation are key elements to continue its legacy of world-leading pharmacological research.