tbuckley/cabot-search huggingface dataset:
Abstract B014: Patient-derived organoid models for drug screening in molecular subtypes of endometrial cancer
Authors: Dongli Liu, Elyse Powell, King Man Wan, Ramanand Athavale, Christine Loo, Caroline E. Ford
Journal: Clinical Cancer Research (2024)

Abstract Introduction: The lack of reliable pre-clinical models has significantly impeded the progress of drug discovery for specific molecular subtypes of endometrial cancer. This study aimed to develop patient-derived organoid models for use in preclinical screening of novel and repurposed therapies in endometrial cancer molecular subtypes. Method: Endometrial cancer tissue (n=27) and ascites fluid (n=1) were collected for this study (ethics approval SESLHD HREC 2021_ETH11975 and 19/001) from patients of various subtypes (17 endometrioid, 3 high grade serous, 2 carcinosarcoma, 2 clear cell, 3 mixed) undergoing treatment at the Royal Hospital for Women and Prince of Wales Private Hospital in Sydney, Australia. Tumor cells were isolated, embedded in 70% Matrigel and cultured in defined culture medium to form organoids. Molecular subtyping of organoids and matched parental tissue was undertaken by mismatch repair (MMR) and p53 immunohistochemistry (IHC), and sequencing of POLE exonuclease domain mutations (EDMs). A unique matched two-dimensional (2D) cell line and three-dimensional (3D) organoid culture derived from ascites isolated from a high grade serous endometrial cancer patient was established. These molecularly stratified pre-clinical models were then used to test drug activity. As a proof of principle, response to paclitaxel and carboplatin was undertaken. Result: 20 organoids representing all major molecular subtypes were established (71% success rate), including one derived from ascites fluid. Organoids are presented with either a cystic or solid structure that highly resembles the morphology of the original tissue. Organoid culture can faithfully retain key features including MMR, p53 status as well as POLE EDMs of the parental tissue. The drug screening results identified contrasting responses of 2D and 3D models obtained from the same patient tissue, highlighting the importance of selecting appropriate pre-clinical models for drug development and testing. Conclusion: This study demonstrated that patient-derived organoids can successfully recapitulate the molecular characterization of endometrial cancer. Molecularly defined organoids represent a promising preclinical resource for drug screening in endometrial cancer. In addition, the model structure should be taken into account while conducting drug screening. Citation Format: Dongli Liu, Elyse Powell, King Man Wan, Ramanand Athavale, Christine Loo, Caroline E. Ford. Patient-derived organoid models for drug screening in molecular subtypes of endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B014.
Abstract B016: Novel curcumin analogues as therapies for endometrial cancer with <i>TP53</i> mutations
Authors: Kimberly K. Leslie, Alex Goss, Jamie Padilla, Lane E. Smith
Journal: Clinical Cancer Research (2024)

Abstract The protein p53 is designated as the guardian of the genome because it is the principal tumor suppressor and functions to surveil the genome, enforce cell cycle checkpoints, and trigger apoptosis when genomic instability is beyond repair. Mutations in TP53 are found in &amp;gt;50% of human tumors and in 25% of the deadliest endometrial malignancies. Yet, few studies have targeted the mutant protein to restore its wild type (WT) tumor suppressor functions. Curcumin, a turmeric derivative, has been shown to help return WT function to mutant p53. However, curcumin is not bioavailable to most of the body because of its water insolubility, hydrophobic nature and rapid metabolization. Our laboratory is testing novel, more bioavailable analogs of curcumin including HO-3867 and AKT-100. In these studies, we tested these agents in preclinical models of serous endometrial cancer to assess their effects on cell growth and p53-dependent signaling. We used CyQUANT cell proliferation assay to identify IC50 values for HO-3867 and AKT-100 in ECC-1 and KLE endometrial cancer cell lines. We performed RNA sequencing to elucidate mechanisms of action and verified p53 expression changes via Western blotting. IC50 values ranged from 100 nanomolar (AKT-100) to low micromolar (HO-3867). RNA sequencing data revealed the re-enforcement of cell cycle checkpoints including the upregulation of CDKN1A (p21) and GADD45 (Gadd45). Proliferative signaling downstream of ATM, an important protein kinase stimulating cell growth, was downregulated by both agents. Western blotting confirmed the classic negative feedback loop of p53, where total p53 levels decreased after drug treatment. Taken together, our findings show that AKT-100 and HO-3867 are able to restore WT tumor suppressor function in otherwise oncogenic mutant p53 by reducing cell replication and promoting apoptosis. Thus, curcumin analogues such as AKT-100 and HO-3867 show promise in the treatment of a subset of endometrial tumors expressing mutant p53 by returning WT p53 functionality, and future studies will move to in vivo analyses of curcumin analogue function. Citation Format: Kimberly K. Leslie, Alex Goss, Jamie Padilla, Lane E. Smith. Novel curcumin analogues as therapies for endometrial cancer with TP53 mutations [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B016.
Abstract IA015: Epigenetic approaches for endometrial cancer
Authors: Rugang Zhang
Journal: Clinical Cancer Research (2024)

Abstract The past decade has brought unprecedented progress in understanding the genetics of endometrial cancer, but cures remain elusive due to the lack of insights into mechanisms that can be leveraged to develop new therapies. Endometrial cancer is genetically heterogeneous and, therefore, it is imperative that therapeutic strategies become personalized by targeting distinct molecular subsets of endometrial cancer. Despite the importance of epigenetic regulators in endometrial cancer, the mechanism of action for these epigenetic regulators and the associated vulnerabilities exposed by their dysregulations have remained elusive for most of them. Here we will discuss our recent work on how to leverage epigenetic mechanisms to address unmet clinical needs in endometrial cancer through integrated approaches. Citation Format: Rugang Zhang. Epigenetic approaches for endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA015.
Active vitamin D treatment in the prevention of sarcopenia in adults with prediabetes (DPVD ancillary study): a randomised controlled trial
Authors: Tetsuya Kawahara, Gen Suzuki, Shoichi Mizuno, Naoki Tominaga, Mikio Toda, Nagahiro Toyama, Tetsuya Inazu, Chie Kawahara, Yosuke Okada, Yoshiya Tanaka
Journal: The Lancet Healthy Longevity (2024)

BackgroundObservational studies show inverse associations between serum 25-hydroxyvitamin D concentrations and sarcopenia incidence; however, it remains unclear whether treatment with vitamin D prevents its development. We aimed to assess whether treatment with active vitamin D (eldecalcitol [0·75 μg per day]) can reduce the development of sarcopenia among adults with prediabetes.MethodsThis randomised, double-blind, placebo-controlled, multicenter trial as an ancillary study was conducted at 32 clinics and hospital sites in Japan. Participants were assigned (1:1) by using a central randomisation method in which a randomisation list was made for each hospital separately using a stratified permuted block procedure. The primary endpoint was sarcopenia incidence during 3 years in the intention-to-treat population defined as weak handgrip strength (<28 kg for men and <18 kg for women) and low appendicular skeletal muscle index (<7·0 kg/m2 for men and <5·7 kg/m2 for women in bioelectrical impedance analysis). Although the usual criterion of hypercalcaemia was 10·4 mg/dL (2·6 mmol/L) or higher, hypercalcaemia that was enough to discontinue the study was defined as 11·0 mg/dL or higher. This study is registered with the UMIN clinical trials registry, UMIN000005394.FindingsA total of 1094 participants (548 in the eldecalcitol group and 546 in the placebo group; 44·2% [484 of 1094] women; mean age 60·8 [SD 9·2] years) were followed up for a median of 2·9 (IQR 2·8–3·0) years. Eldecalcitol treatment as compared with placebo showed statistically significant preventive effect on sarcopenia incidence (25 [4·6%] of 548 participants in the eldecalcitol group and 48 [8·8%] of 546 participants in the placebo group; hazard ratio 0·51; 95% CI 0·31 to 0·83; p=0·0065). The incidence of adverse events did not differ between the two groups.InterpretationWe found that treatment with eldecalcitol has the potential to prevent the onset of sarcopenia among people with prediabetes via increasing skeletal muscle volume and strength, which might lead to a substantial risk reduction of falls.FundingKitakyushu Medical Association.TranslationFor the Japanese translation of the abstract see Supplementary Materials section.
Abstract B023: The role of ribosomal protein L22 in regulating the immune landscape in mismatch repair deficient endometrial cancers
Authors: Macy L. Osborne, Hannah Atkins, Andrew B. Gladden, Russell R. Broaddus
Journal: Clinical Cancer Research (2024)

Abstract The purpose of this study is to identify novel mechanisms of immune evasion in mismatch repair deficient endometrial cancers. Despite having a hypermutated phenotype that is proposed to lead to the accumulation of many neoantigens for immune recognition, our group has found that mismatch repair deficient endometrial cancers characterized by MLH1 protein loss display large variations in the number of tumors infiltrating CD8+ T cells (TILs) across different tumors. To better understand how variations in TILs arise in mismatch repair deficient endometrial cancers, we utilized human endometrial cancer samples from the UNCseq cohort. Immunohistochemistry (IHC) was used to identify expression patterns in proteins of interest across mismatch repair deficient endometrial cancers. To determine how expression patterns of proteins of interest correlate with TILs in our patient samples, Definiens Tissue Studio was utilized to quantify immunofluorescent CD8+ TILs in our mismatch repair deficient endometrial cancer cohort. Although upregulation of programmed death ligand 1 (PD-L1) expression is often cited as an explanation for low TILs, analysis of human data by our group shows that PD-L1 expression does not correlate with TIL numbers in mismatch repair deficient endometrial cancers. Interestingly, The Cancer Genome Atlas (TCGA) data reported that ribosomal protein L22 (RPL22) is mutated in ~50% of mismatch repair deficient endometrial cancers. We analyzed RPL22 by IHC and found that it was lost in 52% of our human mismatch repair deficient endometrial cancer cohort. Loss of various ribosomal proteins can alter translation efficiency of proteins critical for promoting immunosurveillance and the immune response in cancer. In our cohort, mismatch repair deficient endometrial cancers that have lost expression of RPL22 have lower numbers of CD8+ TILs. Preliminary data also show that human endometrial cancer cell lines that do not express RPL22 also do not express beta-2-microglobulin (β2M), a component of the major histocompatibility complex I (MHC-I) molecules that is necessary for neoantigen presentation to CD8+ T cells. Thus, we hypothesize that RPL22 loss in mismatch repair deficient endometrial cancers results in decreased translation of β2M and CD8+ T cell evasion. Moving forward, we speculate that RPL22 could be utilized as a predictive biomarker for immunotherapy response in mismatch repair deficient endometrial cancers. Citation Format: Macy L. Osborne, Hannah Atkins, Andrew B. Gladden, Russell R. Broaddus. The role of ribosomal protein L22 in regulating the immune landscape in mismatch repair deficient endometrial cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B023.
Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study
Authors: Peter M. K. de Blank, Katharine R. Lange, Mengqi Xing, Sedigheh Mirzaei Salehabadi, Deokumar Srivastava, Tara M. Brinkman, Kirsten K. Ness, Kevin C. Oeffinger, Joseph Neglia, Kevin R. Krull, Paul C. Nathan, Rebecca Howell, Lucie M. Turcotte, Wendy Leisenring, Gregory T. Armstrong, M. Fatih Okcu, Daniel C. Bowers
Journal: Nature Cancer (2024)
Biodiversity Medicine: New Horizon and New Opportunity for Cancer
Authors: Jing Han Hong, Abner Herbert Lim, Khwanta Kaewnarin, Jason Yongsheng Chan, Cedric Chuan Young Ng, Bin Tean Teh
Journal: Cancer Discovery (2024)

Accessibility to standard of care remains a challenge to patients in low- and middle-income countries (LMIC), hampering efforts to alleviate the burden of cancer and to improve overall health outcomes. In response to this pressing global health care issue, we propose here a new strategy to create affordable, easily accessible, and effective therapeutic solutions to address this inequity in cancer treatment: the use of science-based biodiversity medicine as an alternative to modern drug therapy, in which we will leverage and combine high-throughput omics technologies with artificial intelligence, to study local biodiversity, their potential anticancer properties, and short- and long-term clinical response and outcomes.
Systemic proteome adaptions to 7-day complete caloric restriction in humans
Authors: Maik Pietzner, Burulça Uluvar, Kristoffer J. Kolnes, Per B. Jeppesen, S. Victoria Frivold, Øyvind Skattebo, Egil I. Johansen, Bjørn S. Skålhegg, Jørgen F. P. Wojtaszewski, Anders J. Kolnes, Giles S. H. Yeo, Stephen O’Rahilly, Jørgen Jensen, Claudia Langenberg
Journal: Nature Metabolism (2024)
Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions
Authors: Cesar Cobaleda, Lucy A. Godley, Kim E. Nichols, Marcin W. Wlodarski, Isidro Sanchez-Garcia
Journal: Cancer Discovery (2024)

Summary: The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene–environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring. Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.
Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols
Authors: Oren Barboy, Akhiad Bercovich, Hanjie Li, Yaniv Eyal-Lubling, Adam Yalin, Yuval Shapir Itai, Kathleen Abadie, Mor Zada, Eyal David, Shir Shlomi-Loubaton, Yonatan Katzenelenbogen, Diego Adhemar Jaitin, Chamutal Gur, Ido Yofe, Tali Feferman, Merav Cohen, Rony Dahan, Evan W. Newell, Aviezer Lifshitz, Amos Tanay, Ido Amit
Journal: Nature Cancer (2024)
Epidemiology of gonorrhoea: systematic review, meta-analyses, and meta-regressions, World Health Organization European Region, 1949 to 2021
Authors: Omar Chidiac, Sawsan AlMukdad, Manale Harfouche, Emma Harding-Esch, Laith J Abu-Raddad
Journal: Eurosurveillance (2024)

Background Epidemiology of Neisseria gonorrhoeae (NG) infection remains inadequately understood. Aim We aimed to characterise NG epidemiology in Europe. Methods We used Cochrane and PRISMA guidelines to systematically review, report, synthesise and analyse NG prevalence data from 1949 to 30 September 2021. Random-effects meta-analyses estimated pooled prevalence. Meta-regression analyses investigated associations and sources of heterogeneity. Results The 844 included publications yielded 1,573 prevalence measures. Pooled prevalence of current urogenital infection was 1.0% (95% CI: 0.7–1.2%) among general populations, 3.2% (95% CI: 1.8–4.8%) among female sex workers, 4.9% (95% CI: 4.2–5.6%) among sexually transmitted infection clinic attendees and 12.1% (95% CI: 8.8–15.8%) among symptomatic men. Among men who have sex with men, pooled prevalence was 0.9% (95% CI: 0.5–1.4%), 5.6% (95% CI: 3.6–8.1%), and 3.8% (95% CI: 2.5–5.4%), respectively, for current urogenital, anorectal or oropharyngeal infection. Current urogenital, anorectal or oropharyngeal infection was 1.45-fold (95% CI: 1.19–1.77%), 2.75-fold (95% CI: 1.89–4.02%) and 2.64-fold (95% CI: 1.77–3.93%) higher among men than women. Current urogenital infection declined 0.97-fold (95% CI: 0.96–0.98%) yearly, but anorectal and oropharyngeal infection increased (1.02-fold; 95% CI: 1.01–1.04% and 1.02-fold; 95% CI: 1.00–1.04%), respectively. Conclusions Neisseria gonorrhoeae epidemiology in Europe has distinct and contrasting epidemiologies for vaginal sex transmission in heterosexual sex networks vs anal and oral sex transmission in MSM sexual networks. Increased transmission may facilitate drug-resistant strain emergence. Europe is far from achieving the World Health Organization target of 90% incidence reduction by 2030.
The Exosome‐Mediated Bone Regeneration: An Advanced Horizon Toward the Isolation, Engineering, Carrying Modalities, and Mechanisms
Authors: Fukang Zhu, Taiyou Wang, Guangjian Wang, Caiping Yan, Bin He, Bo Qiao
Journal: Advanced Healthcare Materials (2024)

Abstract Exosomes, nanoparticles secreted by various cells, composed of a bilayer lipid membrane, and containing bioactive substances such as proteins, nucleic acids, metabolites, etc., have been intensively investigated in tissue engineering owing to their high biocompatibility and versatile biofunction. However, there is still a lack of a high‐quality review on bone defect regeneration potentiated by exosomes. In this review, the biogenesis and isolation methods of exosomes are first introduced. More importantly, the engineered exosomes of the current state of knowledge are discussed intensively in this review. Afterward, the biomaterial carriers of exosomes and the mechanisms of bone repair elucidated by compelling evidence are presented. Thus, future perspectives and concerns are revealed to help devise advanced modalities based on exosomes to overcome the challenges of bone regeneration. It is totally believed this review will attract special attention from clinicians and provide promising ideas for their future works.
Anterior Segment OCT Image of Vitreous Hernia
Authors: Ce Shi, Zhe Xu, Wen Xu
Journal: Ophthalmology (2024)

A 47-year-old male building maintenance worker was injured by the connection hook on a lanyard. A, The anterior chamber image reveals lens subluxation with the vitreous herniating into the anterior chamber around the lens edge as observed on anterior segment OCT (B). The herniated vitreous touched the corneal endothelium. C, The vitreous hernia was barely visible on slit-lamp biomicroscopy image; however, it could be observed on the retro-illumination image captured on the slit-lamp (D). (Magnified version of Figure A-D is available online at www.aaojournal.org).
Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy
Authors: Ana Töpf, Dan Cox, Irina T. Zaharieva, Valeria Di Leo, Jaakko Sarparanta, Per Harald Jonson, Ian M. Sealy, Andrei Smolnikov, Richard J. White, Anna Vihola, Marco Savarese, Munise Merteroglu, Neha Wali, Kristen M. Laricchia, Cristina Venturini, Bas Vroling, Sarah L. Stenton, Beryl B. Cummings, Elizabeth Harris, Chiara Marini-Bettolo, Jordi Diaz-Manera, Matt Henderson, Rita Barresi, Jennifer Duff, Eleina M. England, Jane Patrick, Sundos Al-Husayni, Valerie Biancalana, Alan H. Beggs, Istvan Bodi, Shobhana Bommireddipalli, Carsten G. Bönnemann, Anita Cairns, Mei-Ting Chiew, Kristl G. Claeys, Sandra T. Cooper, Mark R. Davis, Sandra Donkervoort, Corrie E. Erasmus, Mahmoud R. Fassad, Casie A. Genetti, Carla Grosmann, Heinz Jungbluth, Erik-Jan Kamsteeg, Xavière Lornage, Wolfgang N. Löscher, Edoardo Malfatti, Adnan Manzur, Pilar Martí, Tiziana E. Mongini, Nuria Muelas, Atsuko Nishikawa, Anne O’Donnell-Luria, Narumi Ogonuki, Gina L. O’Grady, Emily O’Heir, Stéphanie Paquay, Rahul Phadke, Beth A. Pletcher, Norma B. Romero, Meyke Schouten, Snehal Shah, Izelle Smuts, Yves Sznajer, Giorgio Tasca, Robert W. Taylor, Allysa Tuite, Peter Van den Bergh, Grace VanNoy, Nicol C. Voermans, Julia V. Wanschitz, Elizabeth Wraige, Kimihiko Yoshimura, Emily C. Oates, Osamu Nakagawa, Ichizo Nishino, Jocelyn Laporte, Juan J. Vilchez, Daniel G. MacArthur, Anna Sarkozy, Heather J. Cordell, Bjarne Udd, Elisabeth M. Busch-Nentwich, Francesco Muntoni, Volker Straub
Journal: Nature Genetics (2024)

Abstract In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3 , encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3 / TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish ( srpk3 −/− ; ttn.1 +/− ) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases.
Gene therapy approaches for obesity-induced adipose neuropathy: Device-targeted AAV-mediated neurotrophic factor delivery to adipocytes in subcutaneous adipose
Authors: Magdalena Blaszkiewicz, Tianyi Tao, Kofi Mensah-Arhin, Jake W Willows, Rhiannon Bates, Wei Huang, Lei Cao, Rosemary L Smith, Kristy L Townsend
Journal: Molecular Therapy (2024)