bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A033: The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in ovarian cancer
Authors: Suzuki Tise , Chen Wanqiu , Wang Charles , Unternaehrer Juli
Published: March 2024

High-grade serous ovarian cancer (HGSOC) remains the deadliest cancer of the female reproductive system. Among the many treatment alternatives, platinum-based therapies have been ubiquitous. However, even though initial response is favorable, most patients experience relapse and chemoresistance. Many studies have highlighted the role of epithelial-mesenchymal transition (EMT) in contributing to chemoresistance. In fact, the EMT transcription factor SNAI1 (Snail) has been associated with the development of aggressive disease. Nevertheless, further studies are necessary to understand the underlying mechanisms by which Snail contributes to recurrence and resistance. Thus, our goal is to develop a clinically relevant model of chemoresistance in which to study the transcriptional landscape and gene signatures related to EMT, platinum resistance, and recurrence in HGSOC. After acquisition and characterization of a HGSOC patient sample, cells were continuously exposed to increasing concentrations of cisplatin in vitro, until approximately a tenfold increase in IC-50 relative to parental cells was achieved. RNA-seq analysis comparing the patient-derived sensitive and resistant cell line pair identified over 4,000 genes that were differentially expressed. Furthermore, gene expression was evaluated against a database of genes associated with platinum resistance, revealing 273 genes linked with mechanisms of apoptosis, extracellular matrix signaling, immune response, cancer stemness, EMT, among others. Additionally, we analyzed previously published chromatin immunoprecipitation-sequencing (ChIP-seq) studies for Snail to determine the potential mechanism of EMT-induced therapy resistance. Our results indicate that most of the genes associated with platinum resistance mechanisms were identified by more than two Snail ChIP-seq studies, indicating their potential for being regulated. Furthermore, to establish whether such genes could also be regulated in HGSOC, we compared our findings to ATAC-seq studies done in ovarian cancer cell lines. Data obtained from these analyses will be used in the future assessment of Snail’s direct regulation of these pathways and functions.

Citation Format: Tise Suzuki, Wanqiu Chen, Charles Wang, Juli Unternaehrer. The transcriptional landscape of cisplatin resistance and its relationship with epithelial mesenchymal transition in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A033.
Abstract A084: AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment
Authors: Chauvin Maeva Y.
Published: March 2024

Introduction: Cancer-associated mesothelial cells (CAMCs) have emerged as significant contributors to the tumor microenvironment, influencing tumor growth and immune evasion. Mesothelial cells represent the first point of contact of ovarian cancer cells during their peritoneal spread. Normal omental mesothelial cells have been reported to play a role in immune surveillance of the peritoneal cavity. However, beyond their initial involvement during the seeding of cancer cells to the omentum, the role of omental mesothelial cells in the subsequent development of the tumor microenvironment and the immune evasion of the tumor remains poorly understood. Methods: To study the role of mesothelial cells in the tumor microenvironment, we recently generated novel syngeneic mouse models of high grade serous ovarian cancer, which were derived from Fallopian tube epithelium, and bear human-relevant mutational genotypes. We analysed one such model, the CCNE1-amplified KPCA cell line, using single cell transcriptomics in omental metastases to survey the pattern of expression of the anti-Müllerian hormone (Amh) and its receptor Amhr2 across tumor cell types. Results: Single-cell transcriptomics revealed specific expression of Amhr2 in cancer-associated mesothelial cells, but not normal omental mesothelium. The co-culture of cancer cells with normal omental mesothelial cells induced AMHR2 expression along with a pro-tumorigenic cancer-associated mesothelial cell transcriptomic signature. Overexpression of AMHR2 in a human immortalized mesothelial cell line (Met5a) significantly modulated the expression of genes involved in immune response pathways, remodeling of extra-cellular matrix, and secretion of growth factors. Furthermore, we showed that AMH was secreted by ovarian cancer cells and downregulated key immunomodulatory cytokines (Ccl2, Cxcl2/3, Il1a/b) secreted by CAMCs, thus promoting immunosuppression within the tumor. Finally, implantation of ovarian cancer cells into syngeneic Amhr2−/− hosts produced tumors that grew significantly slower than in wild type hosts, which contained significantly reduced populations of exhausted T cells as marked by PD1 and CTLA4 expression. Conclusion: Together these data suggest that AMHR2 expression is necessary for the reprogramming of mesothelial cells into CAMCs and represents a specific marker of CAMCs in ovarian cancer. The AMH-AMHR2 paracrine axis between cancer cells and CAMCs modulates the tumor microenvironment to promote growth and immune evasion and may represent a novel target for immunotherapy in ovarian cancer.

Citation Format: Maeva Y. Chauvin. AMH paracrine signaling between cancer and mesothelial cells modulates the ovarian tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A084.
Abstract A088: Tumor innervation as a novel driver of ovarian cancer progression
Authors: Knarr Matthew , Reavis Hunter , Lippert Timothy , Rawat Priyanka , Vermeer Paola , Drapkin Ronny
Published: March 2024

One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment.

Citation Format: Matthew Knarr, Hunter Reavis, Timothy Lippert, Priyanka Rawat, Paola Vermeer, Ronny Drapkin. Tumor innervation as a novel driver of ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A088.
Abstract A101: A novel ovarian cancer organotypic tumor slice culture model
Authors: Pourcel Violaine , Létourneau Emile , Jean Dominique , Labrie Marilyne
Published: March 2024

High-grade serous ovarian carcinoma (HGSOC) is the most common form of ovarian cancer (OC). This heterogeneous disease is associated with various molecular alterations influencing the disease course. Unfortunately, the impact of those molecular alterations on the response to therapy is still misunderstood. Few OC models allow control of genetic background in the cancer cells while preserving the tumor's architecture and microenvironment, including the immune cells. Furthermore, there is currently no high-throughput model that retains those characteristics and is suitable for drug screens. This project aims to develop a high-throughput syngeneic murine organotypic tumor slice culture model to study the impact of common HGSOC molecular alterations on anticancer drug responses. The pre-established Trp53−/− syngeneic OC mouse model has been genetically engineered to represent molecular alterations frequently found in HGSC. Ten variants were produced by overexpressing Tp53R172h and overexpressing oncogenes such as Ccne, Brd4, Myc, Ndrg1, and Pik3ca and/or deleting Brca1, Pten, and Nf1. After validation and characterization of the cells in vitro, we performed allografts in immunocompetent C57/bl6 mice and obtained tumors with HGSOC histology. The tumors were used to develop an organotypic tumor slice culture model. Briefly, each tumor is collected and thinly sliced with a vibratome. Each slice can be cultured for several days without significant cell death induction and can be used for a drug screen. Our preliminary data shows that the model preserves the HGSOC histology over six days and remains viable. A viability assay has also been developed to assess the sensitivity of the tumor slices to various anticancer drugs. In conclusion, this project will allow the development of a platform for screening anticancer therapies against HGSOC and will lead to a better understanding of the relationship between HGSOC's common molecular alterations and the responses to therapy.

Citation Format: Violaine Pourcel, Emile Létourneau, Dominique Jean, Marilyne Labrie. A novel ovarian cancer organotypic tumor slice culture model [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A101.
Abstract A114: Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium
Authors: Ho Victor , Chan Maggie , Chehal Manreet , Liang Alice , Eaves Allen C , Louis Sharon A , Stingl John
Published: March 2024

High-grade serous ovarian cancer (HGSOC) is the most prevalent subtype of epithelial ovarian cancer. Despite its name, HGSOC originates in the fallopian tube (FT), but metastasizes quickly in the adnexal region and is the most lethal gynecological cancer worldwide. Organoid culture is emerging as a powerful model for studying normal FT cell biology and ovarian cancer. To standardize primary human FT and HGSOC organoid culture, we have developed GyneCult Fallopian Tube Organoid Medium (FTOM), an optimized serum-free medium and a workflow that supports robust and representative FT organoid culture from freshly isolated or cryopreserved primary human FT cells. FT cultures were initiated by seeding 4000 fresh or cryopreserved single cells (8 donors) directly into 20 µL Corning® Matrigel® domes and overlaying them with FT Organoid Medium. Cultures were maintained with full-medium changes every 3 - 4 days and were passaged every 8 - 14 days into new 20 µL Matrigel® droplets, either at a passage ratio of 1:3 or by seeding at 4000 cells per droplet. Cultures were analyzed by immunocytochemistry (ICC) to detect secretory markers keratin 7 (KRT7), oviductal glycoprotein 1 (OVGP1), and PAX8, as well as ciliated cell markers acetylated alpha tubulin (TUBA1A) and FOXJ1. Across all donors, 16 ± 8% (mean ± SD) of dissociated EpCAM+ FT cells formed 50 - 300 µm diameter cystic organoids within 14 days of seeding (n = 8). Cultures can be maintained for at least 5 passages with 14 - 20 cumulative population doublings, at 3 - 4 doublings per passage. ICC analysis confirmed that organoids contained both polarized secretory cells (i.e., KRT7+, OVGP1+, PAX8+) and ciliated cells (i.e. acetylated TUBA1A+, FOXJ1+), indicating multilineage capacity (n = 5). We also tested the compatibility of GyneCult FTOM with culturing HGSOC samples and observed that one of three tumor samples tested generated organoids. These tumour organoids had a solid and irregular shaped morphology and were composed of PAX8+ cells. These cells underwent ≥ 5 cumulative population doublings over 5 passages, with 0.5 - 2 doublings per passage; this performance is consistent with recently published HGSOC organoid culture methods. These results demonstrate that GyneCult Fallopian Tube Organoid Medium is a robust medium for initiating and culturing FT epithelium as organoids, can support HGSOC organoid culture, and is a valuable tool for studying FT biology.

Citation Format: Victor Ho, Maggie Chan, Manreet Chehal, Alice Liang, Allen C Eaves, Sharon A Louis, John Stingl. Robust establishment and expansion of multilineage human fallopian tube organoids in serum-free medium [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr A114.
Abstract B003: A multi-omic analysis to identify epigenetic drivers of platinum-resistance in high-grade serous ovarian carcinoma models
Authors: Adams Kristin , Moreno Ryan , Wendt Jae-Rim , Wood Josie , Roopra Avtar , Lang Jessica D.
Published: March 2024

Despite being rare cancers, ovarian cancer rank as the fifth leading cause of cancer mortalities in women in the United States. Most patients are detected late, with most patients diagnosed in Stages 3 and 4. While patients often initially respond to standard of care chemotherapy, which includes platinum-based chemotherapy such as cisplatin and carboplatin, they recur with resistant phenotypes. While a large effort has characterized mechanisms of resistance to platinum-based chemotherapy, it is still challenging to identify these patients and identify more promising therapies. While the field understands that a quiescent, stem cell-like state can serve as an intermediate from which chemoresistant recurrences can arise, the epigenetics of this state are less well understood. In fact, we do know that embryonic and pluripotent stem cells differ significantly in enhancers and other epigenetic features that contribute significantly to their phenotypes. We performed histone post-translational modifications by CUT&Tag, as well as ATACseq and RNA-seq, on four isogenic cell line models of cisplatin resistance. We show that these models are resistant to both cisplatin and carboplatin. While we see paradoxical quiescent cell markers in these isogenic lines, we have characterized differential features of their epigenetics that may contribute to the resistant phenotype. We are continuing to explore transcription factors that may drive this resistance. We are also examining super-enhancers that are altered between chemo-sensitive and -resistant cell lines. Similarly, we have examined whether inhibitors of components of super-enhancers may be a viable therapeutic option for platinum-resistant high-grade serous ovarian cancer patients. We see moderate synergy between triptolide (targets TFIIH subunit XPB1) and JQ-1 (targets BRD4) with cisplatin in resistant models. Together, we hope our studies can contribute to the knowledge of how epigenetic features might contribute and be targets for chemoresistance in ovarian cancer.

Citation Format: Kristin Adams, Ryan Moreno, Jae-Rim Wendt, Josie Wood, Avtar Roopra, Jessica D. Lang. A multi-omic analysis to identify epigenetic drivers of platinum-resistance in high-grade serous ovarian carcinoma models [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B003.
Abstract B007: NAD+ metabolism drives PARPi resistance in ovarian cancer cells
Authors: Myong Subin , Shah Hardik , Nagele Benedikt , Rajesh Reshma , Challa Sridevi
Published: March 2024

NAD+ is a coenzyme for redox reactions and a cofactor for enzymes such as PARPs and Sirtuins. The nuclear enzyme PARP1 is a major consumer of NAD+, which is cleaved during the catalytic activation of PARP1 in response to DNA damage. PARP1 inhibitors compete with NAD+ for the catalytic site of PARP1 and reduce the catalytic activity of PARP1 and impair DNA damage repair. Recently PARP inhibitors (PARPi) have shown efficacy in the treatment of ovarian cancers and most patients with defects in homologous repair of DNA damage are now on PARPi maintenance. But, heterogeneous responses to PARPi is limiting their clinical efficacy. To identify the mechanisms of PARPi resistance, we generated a panel of ovarian cancer cells with acquired resistance to niraparib (PARPiR), an FDA approved PARP inhibitor. We demonstrated that the PARPiR cells are also resistant to other FDA approved PARP inhibitors rucaparib and olaparib. This data suggested that a common mechanism of resistance underlies poor response to the FDA approved PARP inhibitors. Since PARP1 activity is tightly controlled by the cellular NAD+ levels, we next investigated the role of NAD+ biosynthesis in PARPi resistance. Metabolomic profiling of the parental and PARPiR cells demonstrated that PARPiR cells have elevated levels of NAD+ metabolism. Indeed, treating the PARPiR cells with inhibitors of NAD+ synthesis restored the sensitivity to PARP inhibitors. Moreover, culturing the previously sensitive parental ovarian cancer cells in NAD+ precursors decreased their sensitivity to PARP inhibitors. These data collectively demonstrated that high levels of NAD+ metabolism causes PARP inhibitor resistance in ovarian cancer cells. Complementary to the metabolomic analysis, results from phenotypic assays in PARPiR cells revealed that high levels of NAD+ maintain cellular quiescence in PARPiR cells. In summary, our results demonstrated that high levels of NAD+ biosynthesis causes PARPi resistance by maintaining cellular quiescence. There is an urgent need to identify the mechanisms of resistance to PARP inhibitors to increase their clinical efficacy. Our study identified that maintenance of quiescence is a fundamental mechanism of PARPi resistance. We also demonstrated that inhibiting NAD+ biosynthesis reverses PARP inhibitor resistance.

Citation Format: Subin Myong, Hardik Shah, Benedikt Nagele, Reshma Rajesh, Sridevi Challa. NAD+ metabolism drives PARPi resistance in ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B007.
Abstract B046: Lack of ER/PR expression and unresponsiveness to oral contraceptives in fallopian tube stem/progenitor cell states: reevaluating the mechanism of cancer prevention
Authors: Ritting Megan , Aalam Syed Mohammed Musheer , Bettencourt Manny , Jalagam Kinnera , Kaufmann Scott , Weroha John , Sherman Mark , Bakkum-Gamez Jamie , Kannan Nagarajan
Published: March 2024

Objective: Prolonged use of oral contraceptives (OC) has been associated with a reduced risk of ovarian cancer, yet the underlying mechanism remains elusive. Long-lived self-renewing fallopian tube epithelial stem cells (SCs) capable of cilio-secretory differentiation are considered a potential cell-of-origin for ovarian cancers. Using innovative stem cell methodologies, our objective is to gain insights into the mechanism by which OC exert their protective action. Methods: This research is supported by Mayo Clinic’s clinically annotated regenerative fallopian tube biobank. RNA was isolated from the SC-enriched cell fraction and differentiated cilio-secretory organoids. Absolute mRNA copies of OC targets estrogen receptor-alpha (ESR1; ER) and progesterone receptor (PGR; PR) were determined using optimum RT-ddPCR assay. OC effects on SC-enriched growth in 2D was measured using live-cell imaging. Our primary tubal cells and organoids as well as public single-cell transcriptomics datasets were analyzed for ESR1/PGR expression across tubal cell states. Results: The panel of OCs tested exhibited no growth response in patient-derived cultures enriched with stem cells, and there was an absence of ESR1/PGR expression. Clonal organoid differentiation exhibited high ESR1 levels and lack of PGR, while growth factor cocktail-dependent PGR induction was achieved. Single-cell transcriptomics identified molecular signatures associated with ER/PR-positive OC sensor cells. Conclusions: Based on our findings, we propose a model wherein ER/PR-negative SC differentiate into ER/PR-positive OC-sensors and control SC development through paracrine signals. Our in-vitro conditions to differentiate SC into OC-sensors provide an opportunity to study complex paracrine signaling and explore targets for prevention of ovarian cancers.

Citation Format: Megan Ritting, Syed Mohammed Musheer Aalam, Manny Bettencourt, Kinnera Jalagam, Scott Kaufmann, John Weroha, Mark Sherman, Jamie Bakkum-Gamez, Nagarajan Kannan. Lack of ER/PR expression and unresponsiveness to oral contraceptives in fallopian tube stem/progenitor cell states: reevaluating the mechanism of cancer prevention [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B046.
Abstract B096: Targeting RNA splicing factor RBM39 improves therapy responses in ovarian high-grade serous carcinoma
Authors: Xu Yuewei , Spear Sarah , Ma Yurui , Lorentzen Marc , Gruet Michael , McKinney Flora , Xu Yitao , Wickremesinghe Chiharu , McNeish Iain , Keun Hector , Nijhuis Anke
Published: March 2024

Ovarian high-grade serous carcinoma (HGSC) is the most common subtype of ovarian cancer with limited therapeutic options and poor prognosis. In recent years, PARP inhibitors have demonstrated significant clinical benefits, especially in patients with BRCA1/2 mutations. However, acquired drug resistance and relapse is a major challenge. Indisulam (E7070) has been identified as a molecular glue that brings together splicing factor RBM39 and DCAF15 E3 ubiquitin ligase resulting in polyubiquitination, degradation and subsequent RNA splicing defects. We demonstrate that RBM39 degradation results in large scale mis-splicing events that are enriched for DNA damage repair genes, including BRCA1, RAD51 and ATM. These events lead to a reduction of these targets at protein level, aberrant cell cycle progression and replication fork stalling. The treatment with indisulam leads to increased sensitivity to platinum and PARP inhibitors in-vitro as well as improved responses to olaparib in mice bearing PARP inhibitor-resistant tumors. In summary, our work demonstrates that combining RBM39 degrading molecular glues with PARP inhibitors is a promising therapeutic approach to improve PARP inhibitor response in ovarian HGSC.

Citation Format: Yuewei Xu, Sarah Spear, Yurui Ma, Marc Lorentzen, Michael Gruet, Flora McKinney, Yitao Xu, Chiharu Wickremesinghe, Iain McNeish, Hector Keun, Anke Nijhuis. Targeting RNA splicing factor RBM39 improves therapy responses in ovarian high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B096.
Abstract IA017: A liquid biopsy fingerprint of disease via nanoengineering
Authors: Heller Daniel A. , Kim Mijin , Ramanathan Lakshmi , Roche Kara Long
Published: March 2024

Serum biomarkers are often insufficiently sensitive or specific to facilitate cancer screening or diagnostic testing. In many cancers, including high-grade serous carcinoma (HGSC), biomarkers fail to detect early-stage cancer detection or to substantially impact mortality rates. We developed a perception-based sensing method that captures a biomarker-agnostic ‘disease fingerprint’ of HGSC using serum. Instead of measuring individual biomarkers, the method collects large data sets of molecular binding interactions to a diverse array of moderately-selective sensors, which were used to train machine learning algorithms. In an initial study using serum from 264 patients, we built a prediction model of nanosensor responses that reliably identified HGSC substantially better than CA125. We believe that the improvement of such a method, using larger nanosensor arrays, more sophisticated AI algorithms, and larger patient cohorts, could improve the detection of HGSC and facilitate biomarker discovery efforts.

Citation Format: Daniel A. Heller, Mijin Kim, Lakshmi Ramanathan, Kara Long Roche. A liquid biopsy fingerprint of disease via nanoengineering [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr IA017.
Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene–Environment Interactions
Authors: Cobaleda Cesar , Godley Lucy A. , Nichols Kim E. , Wlodarski Marcin W. , Sanchez-Garcia Isidro
Published: March 2024

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.
Biodiversity Medicine: New Horizon and New Opportunity for Cancer
Authors: Hong Jing Han , Lim Abner Herbert , Kaewnarin Khwanta , Chan Jason Yongsheng , Ng Cedric Chuan Young , Teh Bin Tean
Published: March 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.
FIGURE 7 from Identification and Characterization of a Small Molecule Bcl-2 Functional Converter
Authors: Kopparapu Prasad R. , Pearce Martin C. , Löhr Christiane V. , Duong Cathy , Jang Hyo Sang , Tyavanagimatt Shanthakumar , O'Donnell Edmond F. , Nakshatri Harikrishna , Kolluri Siva K.
Published: March 2024

Inhibition of breast cancer lung metastasis by BFC1108. A, BFC1108 suppresses the growth of lung metastasis in vivo. LMD-231 cells (200,000) stably expressing luciferase were injected into the tail vein of 6-week-old nude mice. Lung metastasis was detected in 2 weeks. Mice were randomized and were treated four times a week with vehicle or 100 mg/kg BFC1108 by intraperitoneal route (n = 8 for vehicle treatment and n = 9 for BFC1108 treatment). Bioluminescent imaging was performed once a week and quantified. *, P < 0.05; **, P < 0.01; ***, P < 0.001. Bioluminescent imaging data for individual mouse treated with vehicle or BFC1108 are shown in Supplementary Fig. S2. B, Representative mouse image from vehicle and BFC treatment is shown. C, Treatment with BFC1108 does not alter body weight of mice. Body weights were measured each time the mice were imaged. D, Suppression of lung metastasis by BFC1108. H&E staining showed increased number of tumor cells in lung tissue of mice with vehicle treatment, compared with BFC1108 treatment, at the end of the study. E, BFC1108 reduces proliferation of lung metastatic TNBC cells. Detection of Ki-67 indicating proliferating tumor cells in lung tissue from vehicle and BFC1108-treated mice.
Supplementary Figure 7 from Establishment and Characterization of an Epstein-Barr Virus–positive Cell Line from a Non-keratinizing Differentiated Primary Nasopharyngeal Carcinoma
Authors: Chai Annie Wai Yeeng , Yee Shi Mun , Lee Hui Mei , Abdul Aziz Norazlin , Yee Pei San , Marzuki Marini , Wong Ka Wo , Chiang Alan K.S. , Chow Larry Ka-Yue , Dai Wei , Liu Teng Fei , Tan Lu Ping , Khoo Alan Soo Beng , Lo Kwok Wai , Lim Paul V.H. , Rajadurai Pathmanathan , Lightfoot Howard , Barthorpe Syd , Garnett Mathew J. , Cheong Sok Ching
Published: March 2024

Uncropped western blot images
Associations between Proton-Pump Inhibitor Usage, Allergy, and Asthma: An Analysis of NHANES 2005–2006
Authors: Yu Ruili , Wang Xueyan , Wang Hongtian , Lu Xuechun , Yang Bo
Published: March 2024

Introduction: Acid suppression medications, such as proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists, are commonly prescribed for the treatment of gastroesophageal reflux disease and other gastrointestinal disorders. However, concerns regarding potential long-term side effects are brought up by the overuse of PPIs. This study aimed to investigate the relationship between PPI usage, allergy, and asthma in the general US population. Methods: Data of individuals aged ≥20 years who had information on PPI use and questionnaires on allergy and asthma in the US National Health and Nutrition Examination Survey (NHANES) 2005–2006 were analyzed. Univariate and multivariable logistic regression analyses were performed to determine the associations between PPI use, prevalent allergy, and asthma. Results: A total of 4,481 participants (representing 198,543,007 US individuals after weighting) were included in the analyses. PPI use was not significantly associated with the presence of allergy or asthma in the general study population after adjustment. However, in females without steroid exposure, PPI use was significantly associated with increased odds of allergy (adjusted odds ratio [aOR] = 1.69, 95% confidence interval [CI]: 1.002–2.86), among which esomeprazole use was significantly associated with increased odds of allergy (aOR = 2.68, 95% CI: 1.30–5.54) and lansoprazole with increased odds of asthma (aOR = 3.44, 95% CI: 1.50–7.87) as compared to no PPI use. Duration of PPI use was not significantly associated with allergy or asthma. Conclusions: In US women without steroid exposure, PPI use is associated with increased likelihood of prevalent allergy and asthma.
COVID-19 Pandemic and Hospitalizations due to Abortion among 10- to 14-Year-Old Girls in Brazil
Authors: do Nascimentoa Maria Isabel , Rabelo Silva Thalys Gabriel , de Aguiar Mello Nascimento Victor Joshua , Ortiz Flores Luis Patricio , McBenedict Billy
Published: March 2024

Introduction: Various non-pharmacological interventions to prevent coronavirus dissemination were implemented during the COVID-19 pandemic, including school closures. The effect of these interventions on particular aspects of people’s lives such as sexual and reproductive health outcomes has not been adequately discussed. The objective of the study was to compare the monthly hospital admission rates due to abortion before and during school closure. Methods: We used an interrupted time series (IES) design to estimate the hospital admission rates before and during the school closure (intervention in March 2020) period. The analysis was performed considering all girls from age groups of interest and by stratifying the age groups according to skin color (white and non-white) in which the non-white category comprised both the black and mixed ethnicity together. Coefficients and 95% confidence intervals (95% CIs) were calculated using segmented linear regression models. Results: The results showed positive and statistically significant coefficients, suggesting post-intervention trend changes both in the population as a whole (coefficient: 0.07; 95% CI: 0.02; 0.11) and the non-white population group (coefficient: 0.07; 95% CI: 0.03; 0.11), indicating that the monthly hospital admission rates increased over the post-intervention period compared to baseline pre-intervention period. The ITS analysis did not detect statistically significant trend changes (coefficient: 0.02; 95% CI: −0.01; 0.05) in abortion admission rates in the white girl population group. Conclusion: The hospitalizations in Brazil due to abortions in 10- to 14-year-old girls increased during the COVID-19 pandemic in 2020 compared to 2019, and the number of abortions was higher in the non-white population than the white population. Furthermore, recognizing that the implementation of school closure has affected the minority population differentially can help develop more effective actions to face other future similar situations.
Preventing Sudden Cessation of Implantable Pulse Generators in Deep Brain Stimulation: A Systematic Review and Protocol Proposal
Authors: Oslin Spencer J. , Shi Helen H. , Conner Andrew K.
Published: March 2024

Introduction: Deep brain stimulation (DBS) requires a consistent electrical supply from the implantable pulse generator (IPG). Patients may struggle to monitor their IPG, risking severe complications in battery failure. This review assesses current literature on DBS IPG battery life management and proposes a protocol for healthcare providers. Methods: A literature search using four databases identified best practices for DBS IPG management. Studies were appraised for IPG management guidelines, categorized as qualitative, quantitative, or both. Results: Of 408 citations, only seven studies were eligible, none providing clear patient management strategies. Current guidelines lack specificity, relying on clinician suggestions. Conclusion: Limited guidelines exist for IPG management. Specificity and adaptability to emerging technology are crucial. The findings highlight the need for specificity in patients’ needs and adaptability to emerging technology in future studies. To address this need, we developed a protocol for DBS IPG management that we have implemented at our own institution. Further research is needed for effective DBS IPG battery life management, preventing therapy cessation complications.
Kodamaea ohmeri Leg Skin Ulcer Infection in an Immunocompetent Patient: A Case Report
Authors: Aita Angelo , Lelli Diana , Gherardi Giovanni , Pedone Claudio , Antonelli Incalzi Raffaele
Published: March 2024

Introduction: Kodamaea ohmeri is an emerging fungus recognised as an important pathogen in immunocompromised hosts, responsible for life-threatening infections. Case Presentation: We describe a case of a 69-year-old immunocompetent man with a long history of leg skin ulcers infected by K. ohmeri. This is the first case of leg wounds infected by K. ohmeri in an immunocompetent patient. The infection was successfully treated with voriconazole 200 mg daily. Conclusion: Though rare, K. ohmeri should be considered in patients with skin ulcers that are poorly responsive to medical treatment, even if not immunocompromised.
Implications of the Co-Dominance Model for Hardy-Weinberg Testing in Genetic Association Studies
Authors: Wellek Stefan , Mueller-Nurasyid Martina , Strauch Konstantin
Published: March 2024

Introduction: The standard way of using tests for compatibility of genetic markers with
the Hardy-Weinberg equilibrium (HWE) assumptionvas a means of quality control in genetic
association studies (GAS) is to vcarry out this step of preliminary data analysis with the sample of
non-diseased vindividuals only. We show that this strategy has no rational basis whenever the
genotype--phenotype relation for avmarker under consideration satisfies the assumption of co-dominance.
Methods/Results: The justification of this statement is the fact rigorously shown here that under
co-dominance, the genotype distribution of a diallelic marker is in HWE among the
controls if and only if the same holds true for the cases.
Conclusion: The major practical consequence of that theoretical result is
that under the co-dominance model, testing for HWE should be done both for cases
and controls aiming to establish the combined (intersection) hypothesis of
compatibility of both underlying genotype distributions with the HWE assumption.
A particularly useful procedure serving this purpose is obtained through applying the
confidence-interval inclusion rule derived by Wellek, Goddard and Ziegler (Biom J.
2010; 52:253-270) to both samples separately and combining these two tests by
means of the intersection-union principle.
Characterization of Transthyretin Mutation G47V Associated with Hereditary Cardiac Amyloidosis
Authors: He Xiaopeng , Wang Mengdie , Sun Jialu , Yu Zhengyang , Hu Xinyang , Liu Yu , Lin Xiaoping
Published: March 2024

Introduction: Amyloidosis caused by TTR mutations (ATTRv) is a rare inherited and autosomal dominant disease. More than 150 mutants of TTR have been reported, whereas some of them remain to be investigated. Methods: A 52-year-old male presented with heart failure and clinically diagnosed ATTR cardiac amyloidosis (ATTR-CA) was recruited. Whole-exome sequencing (WES) was performed. Biochemical and biophysical experiments characterized protein stability using urea-mediated tryptophan fluorescence. Drug response was analyzed by fibril formation assay. Finally, tetramer TTR concentration in patient’s serum sample was measured by ultra-performance liquid chromatography (UPLC). Results: For the proband, WES revealed a mutation (c.200G>T; p.Gly67Val and referred to as G47V) in TTR gene. Biochemical and biophysical kinetics study showed that the thermodynamic stability of G47V-TTR (Cm = 2.4 m) was significantly lower than that of WT-TTR (Cm = 3.4 m) and comparable to that of L55P-TTR (Cm = 2.3 m), an early age-of-onset mutation. G47V:WT-TTR heterozygous tetramer kinetic stability (t1/2 = 1.4 h) was further compromised compared to that of the homozygous G47V-TTR (t1/2 = 3.1 h). Among three small molecule stabilizers, AG10 exhibited the best inhibition of the fibrillation of G47V-TTR homozygous protein. Using a UPLC assay, nearly 40% of TTR in this patient was calculated to be non-tetrameric. Conclusion: In this work, we reported a patient presented early onset of clinically typical ATTR-CA due to G47V-TTR mutation. Our work for the first time not only characterized the biochemical properties of G47V-TTR mutation, but also provided hints for the pathogenicity of this mutation.
Effects of Cerebellar Repetitive Transcranial Magnetic Stimulation in the Treatment of Post-Stroke Dysphagia: A Meta-Analysis and Systematic Review of Randomized Controlled Trials
Authors: Liu Ying , Yin Shao , Yang Xinwei , Luo Shanshan , Zhu Fengya , Zeng Zijian , Hu Qian , Xu Li , Yu Qian
Published: March 2024

Introduction: This study aimed to comprehensively evaluate the therapeutic efficacy of cerebellar repetitive transcranial magnetic stimulation (rTMS) in the rehabilitation of post-stroke dysphagia (PSD). Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Cochrane Library, Embase, and Web of Science to identify relevant randomized controlled trials (RCTs) investigating the application of cerebellar rTMS in the treatment of PSD. Inclusion and exclusion criteria were rigorously applied during the screening process, and pertinent characteristics of the included RCTs were meticulously extracted. The I2 statistic was employed to assess heterogeneity, and meta-analysis was conducted using Stata 17 software. The Cochrane Risk of Bias 2 tool and PEDro scale were utilized to evaluate bias risk and literature quality. Results: Our analysis encompassed a total of 5 RCTs involving 673 patients with dysphagia who met the inclusion criteria. The findings indicated a significant positive impact of cerebellar rTMS when combined with traditional swallowing exercises on PSD, demonstrating superior efficacy compared to conventional swallowing exercises in isolation. Furthermore, the study revealed no statistically significant differences based on stimulation site (unilateral vs. bilateral cerebellum), stimulation mode (rTMS vs. intermittent theta-burst stimulation), and stimulation frequency (5 Hz vs. 10 Hz). Conclusion: The amalgamation of cerebellar rTMS with conventional swallowing exercises demonstrates notable efficacy, surpassing the outcomes achievable with traditional exercises alone. The sustained effectiveness observed underscores the potential of cerebellar rTMS as an innovative avenue in the field of neurorehabilitation for PSD. This study contributes valuable insights into the prospect of utilizing cerebellar rTMS as an adjunctive therapeutic strategy in the management of PSD, emphasizing its relevance for further exploration and clinical application.
Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke
Authors: Shimada Yuki , Todo Kenichi , Doijiri Ryosuke , Yamazaki Hidekazu , Sonoda Kazutaka , Koge Junpei , Iwata Tomonori , Ueno Yuji , Yamagami Hiroshi , Kimura Naoto , Morimoto Masafumi , Kondo Daisuke , Koga Masatoshi , Nagata Eiichiro , Miyamoto Nobukazu , Kimura Yoko , Gon Yasufumi , Okazaki Shuhei , Sasaki Tsutomu , Mochizuki Hideki , Sugiyama Shintaro , Ohara Mariko , Ikegami Takeshi , Wadayama Tomoya , Murakami Yasutaka , Sakurai Rei , Moriyama Takuya , Oi Kiyotaka , Ikenouchi Hajime , Yamaguchi Eriko , Egashira Shuhei , Takizawa Shunya , Honma Kazunari , Nakayama Taira , Kadokura Ayana , Hanano Hideyuki , Yamamoto Shiro
Published: March 2024

BACKGROUND:

Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM).

METHODS:

We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS
2
score.

RESULTS:

Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5–76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397–827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend
P
<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24–3.58) and 3.23 (95% CI, 2.07–5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14–5.74) and 4.25 (2.14–8.47), respectively.

CONCLUSIONS:

The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.
Impact of Monocular Retinal Lesions on Blob Size in Adult Human V1
Authors: Marcondes Marco , Farias Mariana F. , Pary Luis F. , Fiorani Mario , Lima Bruss , Amorim Ana Karla J. , Gattass Ricardo
Published: March 2024

We studied the attributes of cytochrome c oxidase (CytOx)-rich blobs and ocular dominance columns (OD) in human V1 associated with monocular retinal lesions. Interblob distance, blob cross-sectional area, OD width, and OD arrangement pattern were analyzed in CytOx-reacted tangential sections of flat-mounted V1 preparations. Monocular deprivation induces differential expression of CytOx in the corresponding ODs in V1. We were thereby able to identify the V1 regions associated with the lesioned area in the retina, assign which OD was associated with each eye, and assign the corresponding blob in Layer III as deprived or nondeprived of visual input. We found that nondeprived blobs are more conspicuously stained than blobs outside the lesioned area. Notably, we found a selective expansion of blobs associated with the nonlesioned eye, whereas blobs associated with the deprived eye showed no significant change in size. Blob size in the latter condition was similar to the one observed in normal participants. These effects were present throughout the representation of the lesion in V1, suggesting that the underlying plasticity mechanisms do not depend on eccentricity. Retinal lesion caused no change in interblob distance, which was comparable to the normal brain (i.e., participants with no retinal lesion). This indicates that blob center is a stable hallmark of cortical organization. Finally, the width of ODs associated with the nonlesioned eye tended to be larger compared with ODs of the lesioned eye. However, this effect did not reach statistical significance. The stability of ODs thereby contrasts with blob plasticity, suggesting that the retinal lesion-triggered imbalance in the thalamocortical projection to Layer IVc has a limited impact on OD CytOx reactivity. On the other hand, we argue that ocular imbalance supports intracortical lateral competition that increases CytOx reactivity in the periblob region associated with the nonlesioned eye, accounting for the blob expansion we observe.