tbuckley/cabot-search huggingface dataset:
Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites
Authors: Sophie Lanciano, Claude Philippe, Arpita Sarkar, David Pratella, Cécilia Domrane, Aurélien J. Doucet, Dominic van Essen, Simona Saccani, Laure Ferry, Pierre-Antoine Defossez, Gael Cristofari
Journal: Cell Genomics (2024)

Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- and long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, and individual loci and elucidate key principles involved. We find that the youngest primate L1 families are specifically hypomethylated in pluripotent stem cells and the placenta but not in most tumors. Locally, intronic L1 methylation is intimately associated with gene transcription. Conversely, the L1 methylation state can propagate to the proximal region up to 300 bp. This phenomenon is accompanied by the binding of specific transcription factors, which drive the expression of L1 and chimeric transcripts. Finally, L1 hypomethylation alone is typically insufficient to trigger L1 expression due to redundant silencing pathways. Our results illuminate the epigenetic and transcriptional interplay between retrotransposons and their host genome.
Antibody–Drug Conjugates: Advancing from Magic Bullet to Biological Missile
Authors: Ana C. Veneziani, Suku Sneha, Amit M. Oza
Journal: Clinical Cancer Research (2024)

Summary Precision drug development is focusing on targeting tumor cell surface proteins for therapeutic delivery, maximizing biomarker identified on-target damage to the tumor while minimizing toxicity. A recent article demonstrated high expression of B7-H4 antigen on resistant ovarian cancer cells and described preclinical activity of B7-H4–directed antibody–drug conjugate. See related article by Gitto et al., p. 1567
Topology-Optimized Splints vs Casts for Distal Radius Fractures
Authors: Honghong Ma, Beite Ruan, Jian Li, Jiahui Zhang, Changgui Wu, Hao Tian, Yichen Zhao, Debing Feng, Wei Yan, Xiaobing Xi
Journal: JAMA Network Open (2024)

Importance To date, there is currently no evidence-based medical support for the efficacy of topology-optimized splints in treating distal radius fractures. Objective To assess the clinical efficacy and complication rates of topology-optimized splints in the treatment of distal radius fractures after closed manual reduction. Design, Setting, and Participants This 12-week, multicenter, open-label, analyst-blinded randomized clinical trial (comprising a 6-week intervention followed by a 6-week observational phase) was carried out from December 3, 2021, to March 10, 2023, among 110 participants with distal radius fractures. Statistical analysis was performed on an intention-to-treat basis between June 3 and 30, 2023. Intervention Participants were randomly assigned to 2 groups: the intervention group received topology-optimized splint immobilization and the control group received cast immobilization after closed manual reduction for 6weeks. After this period, immobilization was removed, and wrist rehabilitation activities commenced. Main Outcomes and Measures The primary outcome was the Gartland-Werley (G-W) wrist score at 6 weeks (where higher scores indicate more severe wrist dysfunction). Secondary outcomes encompassed radiographic parameters, visual analog scale scores, swelling degree grade, complication rates, and 3 dimensions of G-W wrist scores. Results A total of 110 patients (mean [SD] age, 64.1 [12.7] years; 89 women [81%]) enrolled in the clinical trial, and complete outcome measurements were obtained for 101 patients (92%). Median G-W scores at 6 weeks were 15 (IQR, 13-18) for the splint group and 17 (IQR, 13-18) for the cast group (mean difference, −2.0 [95% CI, −3.4 to −0.6]; P = .03), indicating a statistically significant advantage for the splint group. At 12 weeks, no clinically significant differences in G-W scores between the 2 groups were observed. Complication rates, including shoulder-elbow pain and dysfunction and skin irritation, were less common in the splint group (shoulder-elbow pain and dysfunction: risk ratio, 0.28 [95% CI, 0.08-0.93]; P = .03; skin irritation: risk ratio, 0.30 [95% CI, 0.10-0.89]; P = .02). Conclusions and Relevance Findings of this randomized clinical trial suggest that patients with distal radius fractures that were managed with topology-optimized splints had better wrist functional outcomes and fewer complications at 6 weeks compared with those who received casting, with no difference at week 12. Therefore, topology-optimized splints with improved performance have the potential to be an advisable approach in the management of distal radius fractures. Trial Registration Chinese Clinical Trial Registry: ChiCTR2000036480
Prevalence of Technology-Facilitated Abuse Among Sexual and Gender Minority Youths
Authors: Heather A. Turner, David Finkelhor, Kimberly Mitchell, Deirdre Colburn
Journal: JAMA Network Open (2024)

Importance Digital communication and imaging technologies have created new opportunities for technology-facilitated abuse (TFA) and necessitate a better understanding of how and why the risk for TFA varies across different groups of youths. Objectives To compare the prevalence of TFA among youths across 5 different sexual and gender identity groups, and to identify risk factors that may explain variations in TFA risk. Design, Setting, and Participants A US nationally representative online survey was conducted among 2639 young adults recruited from the KnowledgePanel online panel from November 19 to December 29, 2021. Individuals aged 18 to 28 years were asked retrospectively about TFA and a variety of other youth experiences in childhood (aged &amp;amp;lt;18 years). Main Outcomes and Measures Participants were asked about their sexual and gender identities, 11 types of TFA occurring before the age of 18 years, and several potential risk factors. Prevalence rates of any TFA were compared across sexual and gender identity groups, and analyses were conducted to identify risk factors that help explain group differences. Weights were developed to compensate for gender, education, race and ethnicity, household income, census region, and metropolitan status disproportions. Results Among the 2510 respondents (mean [SD] age, 24.8 [2.8] years) who provided gender and sexual identity information, 46.5% (95% CI, 41.9%-51.1%) were cisgender heterosexual females, 25.2% (95% CI, 21.6%-29.1%) were cisgender sexual minority females, 18.3% (95% CI, 14.4%-22.9%) were cisgender heterosexual males, 6.8% (95% CI, 4.6%-9.9%) were cisgender sexual minority males, and 3.3% (95% CI, 2.0%-5.4%) were gender minority individuals. The prevalence of TFA occurring before the age of 18 years was highest among sexual minority females (55.3%; 95% CI, 48.0%-62.4%) and gender minority individuals (53.4%; 95% CI, 33.5%-72.2%). Rates of sexting were highest among cisgender sexual minority females (38.8%; 95% CI, 19.1%-58.8%) and gender minority individuals (36.7%; 95% CI, 19.1%-58.8%) and represented the strongest risk factor for TFA exposure (odds ratio, 5.7; 95% CI, 4.0-8.0). However, it explained little variation in TFA across groups once early in-person adversity, sexual abuse, bullying, and maltreatment were taken into account. Conclusions and Relevance This study demonstrates the risk of TFA among sexual and gender minority youths and the need to target prevention efforts toward these vulnerable groups. In addition to strategies to reduce risky behavior, efforts to lower the risk of early sexual abuse, bullying, and maltreatment are likely to also be effective in decreasing TFA among these marginalized groups.
mRNA delivery systems for cancer immunotherapy: Lipid nanoparticles and beyond
Authors: Mariona Estapé Senti, Lucía García del Valle, Raymond M. Schiffelers
Journal: Advanced Drug Delivery Reviews (2024)

mRNA-based vaccines are emerging as a promising alternative to standard cancer treatments and the conventional vaccines. Moreover, the FDA-approval of three nucleic acid based therapeutics (Onpattro, BNT162b2 and mRNA-1273) has further increased the interest and trust on this type of therapeutics. In order to achieve a significant therapeutic efficacy, the mRNA needs from a drug delivery system. In the last years, several delivery platforms have been explored, being the lipid nanoparticles (LNPs) the most well characterized and studied. A better understanding on how mRNA-based therapeutics operate (both the mRNA itself and the drug delivery system) will help to further improve their efficacy and safety. In this review, we will provide an overview of what mRNA cancer vaccines are and their mode of action and we will highlight the advantages and challenges of the different delivery platforms that are under investigation.
Compliance With US Federal Regulations on Waterpipe Tobacco Warnings on Packaging
Authors: Jennifer Cornacchione Ross, Alexandra R. Zizzi, Cynthia K. Suerken, Caroline Kimes, Eric Soule, Erin L. Sutfin
Journal: JAMA Network Open (2024)

This cohort study reports the rate and degree of compliance with the Food and Drug Administration–mandated warning labels among waterpipe tobacco brands and products.
STAR Has Better Discrimination for Mortality than ERS/ATS COPD Severity Classification
Authors: Surya P Bhatt, Arie Nakhmani, Spyridon Fortis, Matthew J. Strand, Edwin K Silverman, Carla G. Wilson, Frank C. Sciurba, Sandeep Bodduluri
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"STAR Has Better Discrimination for Mortality than ERS/ATS COPD Severity Classification." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Let's move forward: Image-computable models and a common model evaluation scheme are prerequisites for a scientific understanding of human vision – CORRIGENDUM
Authors: James J. DiCarlo, Daniel L. K. Yamins, Michael E. Ferguson, Evelina Fedorenko, Matthias Bethge, Tyler Bonnen, Martin Schrimpf
Journal: Behavioral and Brain Sciences (2024)

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Abstract A007: Ser/Thr kinase BUB1 stabilizes DNAPKcs in response to radiation induced DNA double strand break repair
Authors: Sushmitha Sriramulu, Shivani Thoidingjam, Stephen Brown, Farzan Siddiqui, Benjamin Movsas, Michael Green, Corey Speers, Shyam Nyati
Journal: Cancer Research (2024)

Abstract Ser/Thr kinase BUB1 is known to regulate chromosomal segregation during mitosis. However, its exact role in DNA damage repair in response to radiotherapy remained elusive. Here, we demonstrate that inhibition of BUB1 kinase activity (BAY1816032) or genomic depletion (CRISPR) lead to radiation sensitization in triple negative breast cancer and lung cancer cell lines and in TNBC tumor xenograft models. Mechanistic studies demonstrated reduced DNA-DSB repair (γ-H2AX foci assay), and effect on the NHEJ pathway by the bioluminescent DNA repair reporter (BLRR). Gene expression analysis show that BUB1 expression correlates tightly with key members of the NHEJ machinery including H2AX, ATM, 53BP1, DNAPKcs, Ku70, Ku80, Lig4 among others. Cycloheximide-chase experiments demonstrate that BUB1 ablation (pharmacological or genomic) stabilizes DNAPKcs after irradiation. The half-lives (t1/2) of total-DNAPK, phospho-DNAPK could not be estimated in BUB1 ablated cells post radiotherapy. Conversely, we observed BUB1 stabilization following radiotherapy alone while pre-treatment with BUB1i or DNAPKi caused robust degradation of BUB1 (significantly shorter t1/2). Nuclear and chromatin fractionation assays revealed an increase in the phospho- and total- DNAPK, ATM, and KAP1 in nuclear fractions and in chromatin enriched fractions in BUB1 inhibited or depleted cells. There was no significant change in the levels of Ku70 and Ku80 in the nuclear fractions or in the chromatin enriched fractions. This data indicates that BUB1 may be involved in the activation and recruitment of key NHEJ proteins (ATM, DNAPKcs) to DSBs. Further experiments are underway to determine how BUB1 stabilizes DNAPKcs and regulate chromatin loading of key NHEJ factors following radiation. Additionally, we demonstrate that BUB1 mediate apoptotic cell death of cancer cells post-radiation. Our findings suggest that BUB1 may serve as a novel molecular target for radiosensitization in various solid cancers including TNBC. Citation Format: Sushmitha Sriramulu, Shivani Thoidingjam, Stephen Brown, Farzan Siddiqui, Benjamin Movsas, Michael Green, Corey Speers, Shyam Nyati. Ser/Thr kinase BUB1 stabilizes DNAPKcs in response to radiation induced DNA double strand break repair [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr A007.
PTEN Lipid Phosphatase Activity Suppresses Melanoma Formation by Opposing an AKT/mTOR/FRA1 Signaling Axis
Authors: Xiaonan Xu, Ilah Bok, Neel Jasani, Kaizhen Wang, Manon Chadourne, Nicol Mecozzi, Ou Deng, Eric A. Welsh, Fumi Kinose, Uwe Rix, Florian A. Karreth
Journal: Cancer Research (2024)

Inactivating mutations in PTEN are prevalent in melanoma and are thought to support tumor development by hyperactivating the AKT/mTOR pathway. Conversely, activating mutations in AKT are relatively rare in melanoma, and therapies targeting AKT or mTOR have shown disappointing outcomes in preclinical models and clinical trials of melanoma. This has led to the speculation that PTEN suppresses melanoma by opposing AKT-independent pathways, potentially through noncanonical functions beyond its lipid phosphatase activity. In this study, we examined the mechanisms of PTEN-mediated suppression of melanoma formation through the restoration of various PTEN functions in PTEN-deficient cells or mouse models. PTEN lipid phosphatase activity predominantly inhibited melanoma cell proliferation, invasion, and tumor growth, with minimal contribution from its protein phosphatase and scaffold functions. A drug screen underscored the exquisite dependence of PTEN-deficient melanoma cells on the AKT/mTOR pathway. Furthermore, activation of AKT alone was sufficient to counteract several aspects of PTEN-mediated melanoma suppression, particularly invasion and the growth of allograft tumors. Phosphoproteomics analysis of the lipid phosphatase activity of PTEN validated its potent inhibition of AKT and many of its known targets, while also identifying the AP-1 transcription factor FRA1 as a downstream effector. The restoration of PTEN dampened FRA1 translation by inhibiting AKT/mTOR signaling, and FRA1 overexpression negated aspects of PTEN-mediated melanoma suppression akin to AKT. This study supports AKT as the key mediator of PTEN inactivation in melanoma and identifies an AKT/mTOR/FRA1 axis as a driver of melanomagenesis.
Abstract IA016: Replication-coupled and canonical DNA double strand breaks are processed by distinct mechanisms
Authors: Raphael Pavani, Veenu Tripathi, Dali Zong, Elsa Callen, Ajith Pankajam, Andre Nussenzweig, Wei Wu, Kyle Vrtis, Raj Chari, Johannes C Walter
Journal: Cancer Research (2024)

Abstract Single strand breaks (SSBs), including DNA nicks, are the most common form of endogenous DNA damage. If they are not resolved before the passage of a replication fork, current models suggest that SSBs are converted to single-ended double strand breaks (seDSBs) and repaired by homologous recombination (HR). Here we show that when a replication fork encounters a Cas9-induced nick on the leading strand, the replisome is rapidly dislodged, and a highly resected seDSB is generated. In contrast, a Cas9-induced nick on the lagging strand rarely gives rise to a resected seDSB, either because Cas9 is actively evicted and the nick sealed prior to the arrival of the fork or because the nick is concealed as the replisome traverses the lesion, resulting in a double ended DSB (deDSB). Unlike canonical DSBs, end-resection at collapsed forks is BRCA1-independent. Instead, BRCA1 antagonizes 53BP1 to promote RAD51 filament formation and recombination. In the absence of strand invasion, exemplified by BRCA1-, RAD51-, and BRCA2- deficiencies, replication-coupled seDSBs are converted deDSBs by a converging fork. Together, our results demonstrate how nicks can give rise to DSBs in a strand asymmetrical manner, with implications for cancer-associated rearrangements and therapies that target the replication fork. Citation Format: Raphael Pavani, Veenu Tripathi, Dali Zong, Elsa Callen, Ajith Pankajam, Andre Nussenzweig, Wei Wu, Kyle Vrtis, Raj Chari, Johannes C Walter. Replication-coupled and canonical DNA double strand breaks are processed by distinct mechanisms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr IA016.
Abstract B027: Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer
Authors: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Cancer Research (2024)

Abstract Purpose: Ovarian cancer is the leading cause of death among cancers of the female reproductive system. Surgery and platinum-based adjuvant chemotherapy followed by PARP inhibitor (PARPi) maintenance therapy is standard treatment for most patients diagnosed with ovarian cancer. The mechanism of action of PARPi and platinum-based therapy involves the induction of DNA damage, which requires the Fanconi Anemia (FA)- BRCA pathway for repair, making these agents most beneficial in cancers with BRCA mutations. However, 75% of patients with ovarian cancer have BRCA wild type tumors and therefore their benefit from PARPi is limited. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cancer cell death. Recent research demonstrated TTFields induce a state of BRCAness in multiple cancer types, as well as anticancer effects in ovarian cancer preclinical models. This study investigated the impact of TTFields concomitant with carboplatin or PARPi in ovarian cancer cell lines. Methods: A2780 (BRCA wild type), OVCAR3 (BRCA mutated), and A2780cis (platinum-resistant) ovarian cancer cells were treated with TTFields (1 V/cm RMS, 200 kHz, 72 h), alone or concomitant with application of carboplatin or a PARPi (olaparib or niraparib). Efficacy assessments included cell count, colony formation, and apoptosis induction. The overall effect was calculated by multiplying the effects on cell count and colony formation. Results: TTFields treatment reduced cell count, increased overall effect, and elevated apoptosis. Carboplatin, olaparib, and niraparib exhibited dose-dependent effects in all cell lines. When TTFields were applied together with these drugs, a synergistic interaction was observed in the BRCA wild-type A2780 cells and platinum-resistant A2780cis cells, while an additive effect was noted in the BRCA mutant OVCAR-3 cells. Conclusions: This data implies potential advantages for TTFields concomitant with platinum-based chemotherapy and PARPi in ovarian cancer, even without underlying BRCA mutations. This aligns with the BRCAness state induced by TTFields and suggests a benefit in platinum resistant cancer. Overall, TTFields may augment the efficacy of ovarian cancer treatment in both adjuvant and maintenance settings. Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Roni Frechtel-Gerzi, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Preclinical efficacy of Tumor Treating Fields (TTFields) applied with PARP inhibitors or carboplatin in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B027.
Host genetic variants, Epstein-Barr virus subtypes, and the risk of nasopharyngeal carcinoma: Assessment of interaction and mediation
Authors: Miao Xu, Ruimei Feng, Zhonghua Liu, Xiang Zhou, Yanhong Chen, Yulu Cao, Linda Valeri, Zilin Li, Zhiwei Liu, Su-Mei Cao, Qing Liu, Shang-Hang Xie, Ellen T. Chang, Wei-Hua Jia, Jincheng Shen, Youyuan Yao, Yong-Lin Cai, Yuming Zheng, Zhe Zhang, Guangwu Huang, Ingemar Ernberg, Minzhong Tang, Weimin Ye, Hans-Olov Adami, Yi-Xin Zeng, Xihong Lin
Journal: Cell Genomics (2024)

Epstein-Barr virus (EBV) and human leukocyte antigen (HLA) polymorphisms are well-known risk factors for nasopharyngeal carcinoma (NPC). However, the combined effects between HLA and EBV on the risk of NPC are unknown. We applied a causal inference framework to disentangle interaction and mediation effects between two host HLA SNPs, rs2860580 and rs2894207, and EBV variant 163364 with a population-based case-control study in NPC-endemic southern China. We discovered the strong interaction effects between the high-risk EBV subtype and both HLA SNPs on NPC risk (rs2860580, relative excess risk due to interaction [RERI] = 4.08, 95% confidence interval [CI] = 2.03–6.14; rs2894207, RERI = 3.37, 95% CI = 1.59–5.15), accounting for the majority of genetic risk effects. These results indicate that HLA genes and the high-risk EBV have joint effects on NPC risk. Prevention strategies targeting the high-risk EBV subtype would largely reduce NPC risk associated with EBV and host genetic susceptibility.