bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Oncogenic Transformation Drives DNA Methylation Loss and Transcriptional Activation at Transposable Element Loci
Authors: Kanholm Tomas , Rentia Uzma , Hadley Melissa , Karlow Jennifer A. , Cox Olivia L. , Diab Noor , Bendall Matthew L. , Dawson Tyson , McDonald James I. , Xie Wenbing , Crandall Keith A. , Burns Kathleen H. , Baylin Stephen B. , Easwaran Hari , Chiappinelli Katherine B.
Published: August 2023

Abstract
Transposable elements (TE) are typically silenced by DNA methylation and repressive histone modifications in differentiated healthy human tissues. However, TE expression increases in a wide range of cancers and is correlated with global hypomethylation of cancer genomes. We assessed expression and DNA methylation of TEs in fibroblast cells that were serially transduced with hTERT, SV40, and HRASR24C to immortalize and then transform them, modeling the different steps of the tumorigenesis process. RNA sequencing and whole-genome bisulfite sequencing were performed at each stage of transformation. TE expression significantly increased as cells progressed through transformation, with the largest increase in expression after the final stage of transformation, consistent with data from human tumors. The upregulated TEs were dominated by endogenous retroviruses [long terminal repeats (LTR)]. Most differentially methylated regions (DMR) in all stages were hypomethylated, with the greatest hypomethylation in the final stage of transformation. A majority of the DMRs overlapped TEs from the RepeatMasker database, indicating that TEs are preferentially demethylated. Many hypomethylated TEs displayed a concordant increase in expression. Demethylation began during immortalization and continued into transformation, while upregulation of TE transcription occurred in transformation. Numerous LTR elements upregulated in the model were also identified in The Cancer Genome Atlas datasets of breast, colon, and prostate cancer. Overall, these findings indicate that TEs, specifically endogenous retroviruses, are demethylated and transcribed during transformation.
Significance:
Analysis of epigenetic and transcriptional changes in a transformation model reveals that transposable element expression and methylation are dysregulated during oncogenic transformation.
Data from Deficiency of the Polycomb protein RYBP and TET methylcytosine oxidases promotes extensive CpG island hypermethylation and malignant transformation
Authors: Cui Wei , Huang Zhijun , Jin Seung-Gi , Johnson Jennifer , Lau Kin H. , Hostetter Galen , Pfeifer Gerd P.
Published: August 2023

Abstract
Hypermethylation of CpG islands is a common feature of cancer cells and predominantly affects Polycomb-associated genomic regions. Elucidating the underlying mechanisms leading to DNA hypermethylation in human cancer could help identify chemoprevention strategies. Here, we evaluated the role of Polycomb complexes and 5-methylcytosine oxidases in protecting CpG islands from DNA methylation and observed that four genes coding for components of Polycomb repressive complex 1 (PRC1) are downregulated in tumors. Inactivation of RYBP, a key activator of variant PRC1 complexes, in combination with all three 5-methylcytosine oxidases (TET proteins) in nontumorigenic bronchial epithelial cells led to widespread hypermethylation of Polycomb-marked CpG islands affecting almost 4,000 target genes, which closely resembled the DNA hypermethylation landscape observed in human squamous cell lung tumors. The RYBP- and TET-deficient cells showed methylation-associated aberrant regulation of cancer-relevant pathways, including defects in the Hippo tumor suppressor network. Notably, the quadruple knockout cells acquired a transformed phenotype, including anchorage-independent growth and formation of squamous cell carcinomas in mice. This work provides a mechanism promoting hypermethylation of CpG islands and shows that such hypermethylation can lead to cell transformation. The breakdown of a two-pronged protection mechanism can be a route towards genome-wide hypermethylation of CpG islands in tumors.
Data from Functional and clinical characterization of variants of uncertain significance identifies a hotspot for inactivating missense variants in RAD51C
Authors: Hu Chunling , Belur Nagaraj Anil , Shimelis Hermela , Montalban Gemma , Lee Kun Y. , Huang Huaizhi , Lumby Carolyn A. , Na Jie , Susswein Lisa R. , Roberts Maegan E. , Marshall Megan L. , Hiraki Susan , LaDuca Holly , Chao Elizabeth , Yussuf Amal , Pesaran Tina , Neuhausen Susan L. , Haiman Christopher A. , Kraft Peter , Lindström Sara , Palmer Julie R. , Teras Lauren R. , Vachon Celine M. , Yao Song , Ong Irene , Nathanson Katherine L. , Weitzel Jeffrey N. , Boddicker Nicholas , Gnanaolivu Rohan , Polley Eric C. , Mer Georges , Cui Gaofeng , Karam Rachid , Richardson Marcy E. , Domchek Susan M. , Yadav Siddhartha , Hruska Kathleen S. , Dolinsky Jill , Weroha S. John , Hart Steven N. , Simard Jacques , Masson Jean-Yves , Pang Yuan-Ping , Couch Fergus J.
Published: August 2023

Abstract
Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 non-functional (deleterious) variants, including 18 in a hotspot within the ATP binding region. The deleterious variants conferred sensitivity to cisplatin and olaparib and disrupted formation of RAD51C/XRCC3 and RAD51B/RAD51C/RAD51D/XRCC2 complexes. Computational analysis indicated the deleterious variant effects were consistent with structural effects on ATP-binding to RAD51C. A subset of the variants displayed similar effects on RAD51C activity in reconstituted human RAD51C depleted cancer cells. Case-control association studies of deleterious variants in women with breast and ovarian cancer and non-cancer controls showed associations with moderate breast cancer risk (odds ratio (OR)=3.92; 95%CI:2.18-7.59) and high ovarian cancer risk (OR=14.8; 95%CI:7.71-30.36), similar to protein-truncating variants. This functional data supports the clinical classification of inactivating RAD51C missense variants as pathogenic or likely pathogenic, which may improve the clinical management of variant carriers.
Data from Hypoxia-Responsive lncRNA AC115619 Encodes a Micropeptide That Suppresses m6A Modifications and Hepatocellular Carcinoma Progression
Authors: Zhang Qiangnu , Wei Teng , Yan Lesen , Zhu Siqi , Jin Wen , Bai Yu , Zeng Yuandi , Zhang XiaoFei , Yin Zexin , Yang Jilin , Zhang Wenjian , Wu Meilong , Zhang Yusen , Liu Liping
Published: August 2023

Abstract
Long noncoding RNAs (lncRNA) regulate a number of aspects of cancer biology. Recent research has shown that lncRNAs can encode micropeptides that mediate their functions in tumors. Here, we revealed that the liver-specific putative lncRNA, AC115619, is expressed at low levels in hepatocellular carcinoma (HCC) and encodes a micropeptide, designated as AC115619–22aa. AC115619 played a crucial role in the regulation of tumor progression and was a prognostic indicator in HCC. The encoded micropeptide AC115619–22aa inhibited the progression of HCC by binding to WTAP and impeding the assembly of the N6-methyladenosine (m6A) methyltransferase complex, which regulates the expression of tumor-associated genes, such as SOCS2 and ATG14. AC115619 was cotranscribed with the adjacent upstream coding gene APOB, and hypoxia induced transcriptional repression of both APOB and AC115619 by controlling HIF1A/HDAC3 and HNF4A signaling. In animal and patient-derived models, AC115619–22aa reduced global m6A levels and suppressed tumor growth. In conclusion, this study establishes AC115619 and its encoded micropeptide as potential prognostic markers and therapeutic targets for patients with HCC.
Significance:
A micropeptide encoded by lncRNA AC115619 impedes formation of the m6A methylation complex to lower m6A levels and reduce the growth of hepatocellular carcinoma.
Data from Dying To Find Out: The Cost of Time at the Dawn of the Multicancer Early Detection Era
Authors: Klein Eric A. , Madhavan Sarina , Beer Tomasz M. , Bettegowda Chetan , Liu Minetta C. , Hartman Anne-Renee , Hackshaw Allan
Published: August 2023

Abstract
Cancer is a significant burden worldwide that adversely impacts life expectancy, quality of life, health care costs, and workforce productivity. Although currently recommended screening tests for individual cancers reduce mortality, they detect only a minority of all cancers and sacrifice specificity for high sensitivity, resulting in a high cumulative rate of false positives. Blood-based multicancer early detection tests (MCED) based on next-generation sequencing (NGS) and other technologies hold promise for broadening the number of cancer types detected in screened populations and hope for reducing cancer mortality. The promise of this new technology to improve cancer detection rates and make screening more efficient at the population level demands the development of novel trial designs that accelerate clinical adoption. Carefully designed clinical trials are needed to address these issues.
Data from Associations of Race and Ethnicity with Hepatocellular Carcinoma, Decompensation, and Mortality in US Veterans with Cirrhosis
Authors: VoPham Trang , Cravero Anne , Feld Lauren D. , Green Pamela , Feng Ziding , Berry Kristin , Kim Nicole J. , Vutien Philip , Mendoza Jason A. , Ioannou George N.
Published: August 2023

AbstractBackground:
Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology.
Methods:
US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).
Results:
Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24–1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42–1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41–2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63–0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33–0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29–2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68–0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients.
Conclusions:
Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality.
Impact:
Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.
Data from Sleep Behaviors, Genetic Predispositions, and Risk of Esophageal Cancer
Authors: Wang Xiaoyan , Tian Ruiyi , Zong Xiaoyu , Jeon Myung Sik , Luo Jingqin , Colditz Graham A. , Wang Jean S. , Tsilidis Konstantinos K. , Ju Yo-El S. , Govindan Ramaswamy , Puri Varun , Cao Yin
Published: August 2023

AbstractBackground:
Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC).
Methods:
We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006–2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI).
Results:
We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18–3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06–1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13–1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24–2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32–5.88).
Conclusions:
Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk.
Impact:
Sleep behaviors may serve as modifiable factors for the prevention of EAC.
Data from Prediagnostic 25-Hydroxyvitamin D in Association with Cancer-specific and All-cause Mortality among Low-income, Non-Hispanic Black Americans with Colorectal Cancer
Authors: Lawler Thomas P. , Khankari Nikhil K. , Shu Xiao-Ou , Steinwandel Mark , Cai Qiuyin , Jurutka Peter W. , Zheng Wei , Warren Andersen Shaneda
Published: August 2023

AbstractBackground:
Observational studies show high prediagnosis 25-hydroxyvitamin D is associated with lower mortality after colorectal cancer diagnosis. Results from clinical trials suggest vitamin D supplementation may improve outcomes among patients with colorectal cancer. Most studies included few Black Americans, who typically have lower 25-hydroxyvitamin D. We evaluated associations between serum 25-hydroxyvitamin D and mortality after colorectal cancer diagnosis among Black American cases.
Methods:
Data arose from 218 Black Americans from the Southern Community Cohort Study diagnosed with colorectal cancer during follow-up (age 40–79 at enrollment). Prediagnostic 25-hydroxyvitamin D was measured at enrollment and categorized as deficient (<12 ng/mL), insufficient (12–19.9 ng/mL), or sufficient (≥20 ng/mL). Mortality was determined from the National Death Index. Cox proportional hazards were used to estimate HRs and 95% confidence intervals (CI) for associations between 25-hydroxyvitamin D and mortality.
Results:
As a continuous exposure, higher 25-hydroxyvitamin D was associated with overall mortality [HR = 0.79 (0.65–0.96) per-SD increase, Ptrend = 0.02] and colorectal cancer–specific mortality [HR = 0.83 (0.64–1.08), Ptrend = 0.16]. For overall mortality, associations were strongest among females [HR = 0.65 (0.42–0.92)], current smokers [HR = 0.61 (0.38–0.98)], and obese participants [HR = 0.47 (0.29–0.77)]. Compared with those with deficiency, participants with sufficient 25-hydroxyvitamin D had lower overall mortality after multivariable adjustment [HR: 0.61 (0.37–1.01)].
Conclusions:
Prediagnosis 25-hydroxyvitamin D is inversely associated with overall and colorectal cancer–specific mortality among Black Americans with colorectal cancer. Correcting vitamin D deficiency may improve survival of these patients, particularly for obese individuals and smokers.
Impact:
Our results support including more Black Americans in trials of vitamin D supplementations to improve colorectal cancer outcomes.
Data from Early On-treatment Changes in Circulating Tumor DNA Fraction and Response to Enzalutamide or Abiraterone in Metastatic Castration-Resistant Prostate Cancer
Authors: Tolmeijer Sofie H. , Boerrigter Emmy , Sumiyoshi Takayuki , Kwan Edmond M. , Ng Sarah W.S. , Annala Matti , Donnellan Gráinne , Herberts Cameron , Benoist Guillemette E. , Hamberg Paul , Somford Diederik M. , van Oort Inge M. , Schalken Jack A. , Mehra Niven , van Erp Nielka P. , Wyatt Alexander W.
Published: August 2023

AbstractPurpose:
Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes.
Experimental Design:
Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months.
Results:
ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62–8.77 and univariate HR, 5.49; 95% CI, 2.76–10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses.
Conclusions:
Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification.

See related commentary by Sartor, p. 2745
Data from Alternating 17β-Estradiol and Aromatase Inhibitor Therapies Is Efficacious in Postmenopausal Women with Advanced Endocrine-Resistant ER+ Breast Cancer
Authors: Schwartz Gary N. , Kaufman Peter A. , Giridhar Karthik V. , Marotti Jonathan D. , Chamberlin Mary D. , Arrick Bradley A. , Makari-Judson Grace , Goetz Matthew P. , Soucy Shannon M. , Kolling Fred , Demidenko Eugene , Miller Todd W.
Published: August 2023

AbstractPurpose:
Strategies to implement estrogen therapy for advanced estrogen receptor–positive (ER+) breast cancer are underdeveloped. Preclinical data suggest that cycling treatment with 17β-estradiol followed by estrogen deprivation can control tumor growth long-term.
Patients and Methods:
Postmenopausal women with advanced ER+/HER2− breast cancer with recurrence or progression on ≥ 1 antiestrogen or aromatase inhibitor (AI)-based therapy were eligible. Patients received 17β-estradiol (2 mg orally, three times a day) for 8 weeks followed by AI (physician's choice) for 16 weeks, alternating treatments on an 8-week/16-week schedule until disease progression. Patients then optionally received continuous single-agent treatment until a second instance of disease progression. Endpoints included 24-week clinical benefit and objective response per RECIST, and tumor genetic alterations.
Results:
Of 19 evaluable patients, clinical benefit rate was 42.1% [95% confidence interval (CI), 23.1%–63.9%] and objective response rate (ORR) was 15.8% (95% CI, 5.7%–37.9%). One patient experienced a grade 3 adverse event related to 17β-estradiol. Among patients who received continuous single-agent treatment until a second instance of disease progression, clinical benefit was observed in 5 of 12 (41.7%) cases. Tumor ER (ESR1) mutations were found by whole-exome profiling in 4 of 7 (57.1%) versus 2 of 9 (22.2%) patients who did versus did not experience clinical benefit from alternating 17β-estradiol/AI therapy. The only two patients to experience objective responses to initial 17β-estradiol had tumor ESR1 mutations.
Conclusions:
Alternating 17β-estradiol/AI therapy may be a promising treatment for endocrine-refractory ER+ breast cancer, including following progression on CDK4/6 inhibitors or everolimus. Further study is warranted to determine whether the antitumor activity of 17β-estradiol differs according to ESR1 mutation status.
Data from Subsets of IFN Signaling Predict Response to Immune Checkpoint Blockade in Patients with Melanoma
Authors: Horowitch Brooke , Lee Daniel Y. , Ding Min , Martinez-Morilla Sandra , Aung Thazin Nwe , Ouerghi Feriel , Wang Xueting , Wei Wei , Damsky William , Sznol Mario , Kluger Harriet , Rimm David L. , Ishizuka Jeffrey J.
Published: August 2023

AbstractPurpose:
IFN signaling in the tumor microenvironment is a critical determinant of both response and resistance of cancer to immune checkpoint inhibitors (ICI). We hypothesized that distinct patterns of IFN signaling in melanoma are associated with clinical response or resistance to ICIs.
Experimental Design:
Two tissue microarrays containing samples from 97 patients with metastatic melanoma who received nivolumab, pembrolizumab, or a combination of ipilimumab and nivolumab at Yale New Haven Hospital between 2011 and 2017 were randomized into discovery and validation cohorts. Samples were stained and visualized using multiplexed immunofluorescence microscopy for STAT1, STAT1 phosphorylated at Y701 (pSTAT1Y701), and PD-L1, and signals were quantified using the automated quantitative analysis method of quantitative immunofluorescence. Treatment response was assessed using RECIST, and overall survival was analyzed. For in vitro studies, human melanoma cell lines were stimulated with IFNγ and IFNβ, and Western blotting was performed.
Results:
Pretreatment STAT1 levels were higher in responders to ICIs [complete response/partial response/stable disease (SD) for > 6 months] than in nonresponders (SD < 6 months/progressive disease). Higher pretreatment STAT1 levels were associated with improved survival after ICIs in both the discovery and validation cohorts. Western blot analysis of human melanoma cell lines stimulated with IFN demonstrated distinct patterns of upregulation of STAT1 compared with pSTAT1Y701 and PD-L1. When combining STAT1 and PD-L1 markers, patients with STAT1highPD-L1low tumors had improved survival compared with those with STAT1lowPD-L1high tumors.
Conclusions:
STAT1 may better predict melanoma response to ICIs than current strategies, and combined STAT1 and PD-L1 biomarkers may provide insight into IFN-responsive versus IFN-resistant states.
Data from Integrative Single-Cell and Bulk Transcriptomes Analyses Identify Intrinsic HNSCC Subtypes with Distinct Prognoses and Therapeutic Vulnerabilities
Authors: Dai Yibin , Wang Ziyu , Xia Yingchao , Li Jin , Wu Yaping , Wang Yanling , Jiang Hongbing , Cheng Jie
Published: August 2023

AbstractPurpose:
Tumor heterogeneity in head and neck squamous cell carcinoma (HNSCC) profoundly compromises patient stratification, personalized treatment planning, and prognostic prediction, which underscores the urgent need for more effective molecular subtyping for this malignancy. Here, we sought to define the intrinsic epithelial subtypes for HNSCC by integrative analyses of single-cell and bulk RNA sequencing datasets from multiple cohorts and assess their molecular features and clinical significance.
Experimental Design:
Malignant epithelial cells were identified from single-cell RNA sequencing (scRNA-seq) datasets and subtyped on the basis of differentially expressed genes. Subtype-specific genomic/epigenetic abnormalities, molecular signaling, genetic regulatory network, immune landscape, and patient survival were characterized. Therapeutic vulnerabilities were further predicted on the basis of drug sensitivity datasets from cell lines, patient-derived xenograft models, and real-world clinical outcomes. Novel signatures for prognostication and therapeutic prediction were developed by machine learning and independently validated.
Results:
Three intrinsic consensus molecular subtypes (iCMS1–3) for HNSCC were proposed from scRNA-seq analyses and recapitulated in 1,325 patients from independent cohorts using bulk-sequencing datasets. iCMS1 was characterized by EGFR amplification/activation, stromal-enriched environment, epithelial-to-mesenchymal transition, worst survival, and sensitivities to EGFR inhibitor. iCMS2 was featured by human papillomavirus–positive oropharyngeal predilection, immune-hot, susceptibilities to anti–PD-1, and best prognosis. Moreover, iCMS3 displayed immune-desert and sensitivities to 5-FU and MEK, STAT3 inhibitors. Three novel, robust signatures derived from iCMS subtype-specific transcriptomics features were developed by machine learning for patient prognostication and cetuximab and anti–PD-1 response predictions.
Conclusions:
These findings reiterate molecular heterogeneity of HNSCC and advantages of scRNA-seq in pinpointing cellular diversities in complex cancer ecosystems. Our HNSCC iCMS regime might facilitate accurate patient stratification and individualized precise treatment.
Data from Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML
Authors: Letson Christopher T. , Balasis Maria E. , Newman Hannah , Binder Moritz , Vedder Alexis , Kinose Fumi , Ball Markus , Kruer Traci , Quintana Ariel , Lasho Terra L. , Finke Christy M. , Almada Luciana L. , Grants Jennifer M. , Zhang Guolin , Fernandez-Zapico Martin E. , Gaspar-Maia Alexandre , Lancet Jeffrey , Komrokji Rami , Haura Eric , Sallman David A. , Reuther Gary W. , Karsan Aly , Rix Uwe , Patnaik Mrinal M. , Padron Eric
Published: August 2023

AbstractPurpose:
Preclinical studies in myeloid neoplasms have demonstrated efficacy of bromodomain and extra-terminal protein inhibitors (BETi). However, BETi demonstrates poor single-agent activity in clinical trials. Several studies suggest that combination with other anticancer inhibitors may enhance the efficacy of BETi.
Experimental Design:
To nominate BETi combination therapies for myeloid neoplasms, we used a chemical screen with therapies currently in clinical cancer development and validated this screen using a panel of myeloid cell line, heterotopic cell line models, and patient-derived xenograft models of disease. We used standard protein and RNA assays to determine the mechanism responsible for synergy in our disease models.
Results:
We identified PIM inhibitors (PIMi) as therapeutically synergistic with BETi in myeloid leukemia models. Mechanistically, we show that PIM kinase is increased after BETi treatment, and that PIM kinase upregulation is sufficient to induce persistence to BETi and sensitize cells to PIMi. Furthermore, we demonstrate that miR-33a downregulation is the underlying mechanism driving PIM1 upregulation. We also show that GM-CSF hypersensitivity, a hallmark of chronic myelomonocytic leukemia (CMML), represents a molecular signature for sensitivity to combination therapy.
Conclusions:
Inhibition of PIM kinases is a potential novel strategy for overcoming BETi persistence in myeloid neoplasms. Our data support further clinical investigation of this combination.
Data from A Phase 1/2 Multicenter Randomized Trial of Local Ablation plus Toripalimab versus Toripalimab Alone for Previously Treated Unresectable Hepatocellular Carcinoma
Authors: Zhou Chunhui , Li Yan , Li Jiaping , Song Botian , Li Hanfeng , Liang Bin , Gu Shanzhi , Li Haiping , Chen Changyong , Li Sai , Peng Changli , Liu Fei , Xiao Juxiong , Long Xueying , Li Ping , Xiong Zhengping , Yi Xiaoping , Liao Weihua , Shi Liangrong
Published: August 2023

AbstractPurpose:
To assess the safety and efficacy of local ablation plus PD-1 inhibitor toripalimab in previously treated unresectable hepatocellular carcinoma (HCC).
Patients and Methods:
In the multicenter, two-stage, and randomized phase 1/2 trial, patients were randomly assigned to receive toripalimab alone (240 mg, every 3 weeks), subtotal local ablation followed by toripalimab starting on post-ablation day 3 (Schedule D3), or on post-ablation day 14 (Schedule D14). The first endpoint of stage 1 was to determine which combination schedule could continue and progression-free survival (PFS) as the primary endpoint for stage 1/2.
Results:
A total of 146 patients were recruited. During stage 1, Schedule D3 achieved numerically higher objective response rate (ORR) than Schedule D14 for non-ablation lesions (37.5% vs. 31.3%), and was chosen for stage 2 evaluation. For the entire cohort of both stages, patients with Schedule D3 had a significantly higher ORR than with toripalimab alone (33.8% vs. 16.9%; P = 0.027). Moreover, patients with Schedule D3 had improved median PFS (7.1 vs. 3.8 months; P < 0.001) and median overall survival (18.4 vs. 13.2 months; P = 0.005), as compared with toripalimab alone. In addition, six (9%) patients with toripalimab, eight (12%) with Schedule D3, and 4 (25%) with Schedule D14 developed grade 3 or 4 adverse events, and one patient (2%) with Schedule D3 manifested grade 5 treatment-related pneumonitis.
Conclusions:
In patients with previously treated unresectable HCC, subtotal ablation plus toripalimab improved the clinical efficacy as compared with toripalimab alone, with an acceptable safety profile.
Data from An Open-label Phase I Study of GDC-0927 in Postmenopausal Women with Locally Advanced or Metastatic Estrogen Receptor–Positive Breast Cancer
Authors: Chandarlapaty Sarat , Dickler Maura N. , Perez Fidalgo Jose Alejandro , Villanueva-Vázquez Rafael , Giltnane Jennifer , Gates Mary , Chang Ching-Wei , Cheeti Sravanthi , Fredrickson Jill , Wang Xiaojing , Collier Ann , Moore Heather M. , Metcalfe Ciara , Lauchle Jennifer , Humke Eric W. , Bardia Aditya
Published: August 2023

AbstractPurpose:
GDC-0927 is a novel, potent, nonsteroidal, orally bioavailable, selective estrogen receptor (ER) degrader that induces tumor regression in ER+ breast cancer xenograft models.
Patients and Methods:
This phase I dose-escalation multicenter study enrolled postmenopausal women with ER+/HER2− metastatic breast cancer to determine the safety, pharmacokinetics, and recommended phase II dose of GDC-0927. Pharmacodynamics was assessed with [18F]-fluoroestradiol (FES) PET scans.
Results:
Forty-two patients received GDC-0927 once daily. The MTD was not reached. The most common adverse events (AE) regardless of causality were nausea, constipation, diarrhea, arthralgia, fatigue, hot flush, back pain, and vomiting. There were no deaths, grade 4/5 AEs, or treatment-related serious AEs. Two patients experienced grade 2 AEs of special interest of deep vein thrombosis and jugular vein thrombosis, both considered unrelated to GDC-0927. Following dosing, approximately 1.6-fold accumulation was observed, consistent with the observed half-life and dosing frequency. There were no complete or partial responses. Pharmacodynamics was supported by >90% reduction in FES uptake and an approximately 40% reduction in ER expression, suggesting ER degradation is not the mechanistic driver of ER antagonism. Twelve patients (29%) achieved clinical benefit; 17 patients (41%) showed a confirmed best overall response of stable disease. Baseline levels of ER and progesterone receptor protein and mutant ESR1 circulating tumor DNA did not correlate with clinical benefit.
Conclusions:
GDC-0927 appeared to be well tolerated with pharmacokinetics supporting once-daily dosing. There was evidence of target engagement and preliminary evidence of antitumor activity in heavily pretreated patients with advanced/metastatic ER+/HER2− breast cancer with and without ESR1 mutations.
Data from Determinants of survival in HER2+ metastatic esophagogastric cancer
Authors: Maron Steven B. , Chatila Walid , Walch Henry , Chou Joanne F. , Ceglia Nicholas , Ptashkin Ryan , Do Richard Kinh Gian. , Paroder Viktoriya , Pandit-Taskar Neeta , Lewis Jason S. , Biachi De Castria TIago , Sabwa Shalom , Socolow Fiona , Feder Lara , Thomas Jasmine , Schulze Isabell , Kim Kwanghee , Elzein Arijh , Bojilova Viktoria , Zatzman Matthew , Bhanot Umesh , Nagy Rebecca J. , Lee Jeeyun , Simmons Marc , Segal Michal , Ku Geoffrey Y. , Ilson David H. , Capanu Marinela , Hechtman Jaclyn F. , Merghoub Taha , Shah Sohrab , Schultz Nikolaus , Solit David B. , Janjigian Yelena Y.
Published: August 2023

Abstract
Purpose: We report updated clinical outcomes from a phase II study of pembrolizumab, trastuzumab, and chemotherapy (PTC) in metastatic esophagogastric (EG) cancer in conjunction with outcomes from an independent MSK cohort. Experimental Design: The significance of pre-treatment 89Zr-trastuzumab PET, plasma circulating tumor DNA (ctDNA) dynamics, and tumor HER2 expression and whole exome sequencing was evaluated to identify prognostic biomarkers and mechanisms of resistance in patients treated on-protocol with PTC. Additional prognostic features were evaluated using a multivariable Cox regression model of trastuzumab-treated MSK patients (n=226). Single cell RNA sequencing data from MSK and Samsung were evaluated for mechanisms of therapy resistance. Results: 89Zr-trastuzumab PET, single cell RNA-seq (scRNAseq), and serial ctDNA with CT imaging identified how pre-treatment intrapatient genomic heterogeneity contributes to inferior progression-free survival (PFS). We demonstrated that presence of intensely-avid lesions by 89Zr-trastuzumab PET, decline in tumor-matched ctDNA by 3 weeks, and clearance of tumor-matched ctDNA by 9 weeks were minimally invasive biomarkers of durable PFS. Paired pre- and on-treatment scRNAseq identified rapid clearance of HER2-expressing tumor clones with expansion of clones expressing a transcriptional resistance program, which was associated with MT1H, MT1E, MT2A, and MSMB expression. Amongst trastuzumab-treated patients at MSK, ERBB2 amplification was associated with improved PFS, while alterations in MYC and CDKN2A/B were associated with inferior PFS. Conclusions: These findings highlight the clinical relevance of identifying baseline intrapatient heterogeneity and serial ctDNA monitoring of HER2-positive EG cancer patients to identify early evidence of treatment resistance, which could guide proactive therapy escalation or de-escalation.
Data from Schlafen 11 (SLFN11) Kills Cancer Cells Undergoing Unscheduled Re-replication
Authors: Murai Junko , Ceribelli Michele , Fu Haiqing , Redon Christophe E. , Jo Ukhyun , Murai Yasuhisa , Aladjem Mirit I. , Thomas Craig J. , Pommier Yves
Published: August 2023

Abstract
Schlafen 11 (SLFN11) is an increasingly prominent predictive biomarker and a molecular sensor for a wide range of clinical drugs: topoisomerases, PARP and replication inhibitors, and platinum derivatives. To expand the spectrum of drugs and pathways targeting SLFN11, we ran a high-throughput screen with 1,978 mechanistically annotated, oncology-focused compounds in two isogenic pairs of SLFN11-proficient and -deficient cells (CCRF-CEM and K562). We identified 29 hit compounds that selectively kill SLFN11-proficient cells, including not only previously known DNA-targeting agents, but also the neddylation inhibitor pevonedistat (MLN-4924) and the DNA polymerase α inhibitor AHPN/CD437, which both induced SLFN11 chromatin recruitment. By inactivating cullin-ring E3 ligases, pevonedistat acts as an anticancer agent partly by inducing unscheduled re-replication through supraphysiologic accumulation of CDT1, an essential factor for replication initiation. Unlike the known DNA-targeting agents and AHPN/CD437 that recruit SLFN11 onto chromatin in 4 hours, pevonedistat recruited SLFN11 at late time points (24 hours). While pevonedistat induced unscheduled re-replication in SLFN11-deficient cells after 24 hours, the re-replication was largely blocked in SLFN11-proficient cells. The positive correlation between sensitivity to pevonedistat and SLFN11 expression was also observed in non-isogenic cancer cells in three independent cancer cell databases (NCI-60, CTRP: Cancer Therapeutics Response Portal and GDSC: Genomic of Drug Sensitivity in Cancer). The present study reveals that SLFN11 not only detects stressed replication but also inhibits unscheduled re-replication induced by pevonedistat, thereby enhancing its anticancer efficacy. It also suggests SLFN11 as a potential predictive biomarker for pevonedistat in ongoing and future clinical trials.
Data from Polymorphisms in the Nonhomologous End-joining DNA Repair Pathway are Associated with HPV Integration in Cervical Dysplasia
Authors: Geris Jennifer M. , Amirian E. Susan , Marquez-Do Deborah A. , Guillaud Martial , Dillon Laura M. , Follen Michele , Scheurer Michael E.
Published: August 2023

Abstract
Previous evidence indicates that human papillomavirus (HPV) integration status may be associated with cervical cancer development and progression. However, host genetic variation within genes that may play important roles in the viral integration process is understudied. The aim of this study was to examine the association between HPV16 and HPV18 viral integration status and SNPs in nonhomologous-end-joining (NHEJ) DNA repair pathway genes on cervical dysplasia. Women enrolled in two large trials of optical technologies for cervical cancer detection and positive for HPV16 or HPV18 were selected for HPV integration analysis and genotyping. Associations between SNPs and cytology (normal, low-grade, or high-grade lesions) were evaluated. Among women with cervical dysplasia, polytomous logistic regression models were used to evaluate the effect of each SNP on viral integration status. Of the 710 women evaluated [149 high-grade squamous intraepithelial lesion (HSIL), 251; low-grade squamous intraepithelial lesion (LSIL, 310 normal)], 395 (55.6%) were positive for HPV16 and 192 (27%) were positive for HPV18. Tag-SNPs in 13 DNA repair genes, including RAD50, WRN, and XRCC4, were significantly associated with cervical dysplasia. HPV16 integration status was differential across cervical cytology, but overall, most participants had a mix of both episomal and integrated HPV16. Four tag-SNPs in the XRCC4 gene were found to be significantly associated with HPV16 integration status. Our findings indicate that host genetic variation in NHEJ DNA repair pathway genes, specifically XRCC4, are significantly associated with HPV integration, and that these genes may play an important role in determining cervical cancer development and progression.
Prevention Relevance:
HPV integration in premalignant lesions and is thought to be an important driver of carcinogenesis. However, it is unclear what factors promote integration. The use of targeted genotyping among women presenting with cervical dysplasia has the potential to be an effective tool in assessing the likelihood of progression to cancer.
Gemcitabine, Docetaxel, Capecitabine, Cisplatin, Irinotecan as First-line Treatment for Metastatic Pancreatic Cancer
Authors: Wilbur H. Catherine , Durham Jennifer N. , Lim Su Jin , Purtell Katrina , Bever Katherine M. , Laheru Daniel A. , De Jesus-Acosta Ana , Azad Nilofer S. , Wilt Bradley , Diaz Luis A. , Le Dung T. , Wang Hao
Published: August 2023

Purpose:

Treatment of advanced pancreatic cancer with a single therapeutic at a maximal dose has been largely ineffective at increasing survival. Combination therapies are commonly studied but often limited by toxicity. We previously showed that low-dose multiagent therapy with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), and cisplatin (GTX-C) was safe, well tolerated, and effective (NCT01459614). Here, we hypothesize that adding irinotecan to GTX-C may improve survival with minimal toxicity.

Experimental Design:

Patients with treatment-naïve metastatic pancreatic adenocarcinoma were treated with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), cisplatin, and irinotecan (GTX-CI). Treatment consisted of capecitabine 500 mg twice daily on days 1–14 and gemcitabine 300 to 500 mg/m2, docetaxel 20 mg/m2, cisplatin 15 to 20 mg/m2, and irinotecan 20 to 60 mg/m2 on days 4 and 11 of a 21-day cycle. The primary objective was 9-month overall survival (OS). Secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and OS.

Results:

The regimen was well tolerated. The recommended phase II dose was gemcitabine 500 mg/m2, docetaxel 20 mg/m2, capecitabine 500 mg po bid, cisplatin 20 mg/m2, and irinotecan 20 mg/m2. Median follow-up in phase II was 11.02 months (2.37–45.17). Nine-month OS rate was 57% [95% confidence interval (CI): (41–77)]. RR was 57% [95% CI: (37–75) 50% PR and 7% CR]. DCR was 87% [95% CI: (69–96)]. Median OS and PFS were 11.02 [95% CI: (8.54–21.09)] and 8.34 [95% CI: (6.34–NA)] months, respectively.

Conclusions:

The addition of irinotecan to GTX-C was safe and well tolerated. While the study did not meet its primary objective, the responses were clinically meaningful using a well-tolerated regimen.

Significance:

We aimed to optimize the previously reported efficacious regimen of low-dose multiagent therapy with GTX-C for the treatment of metastatic pancreatic ductal adenocarcinoma by adding irinotecan. The primary objective was not met, but GTX-CI was well tolerated. The RR of 57%, median PFS of 8.3 months, median OS of 11 months, and 36-month OS rate of 19% suggest clinical benefit. Further optimization of this regimen is warranted.
As condições para o surgimento do Movimento Armado Socialista do México e a contrainsurgência entre as décadas de 1960 e 1980
Authors: Riberti Larissa Jacheta
Published: August 2023

Fenômeno social que se manifestou na zona rural e urbana do país, o Movimento Armado Socialista (MAS) foi um conjunto de guerrilhas surgidas entre as décadas de 1960 e 1980 no México. Apesar de terem diferentes orientações ideológicas, esses grupos contestaram o progressivo fechamento das vias institucionais de diálogo e um sistema político autoritário e violento, controlado, há várias décadas, pelo Partido Revolucionário Institucional (PRI). Tal experiência também está marcada pelo contexto da Guerra Fria, pela ampliação e sistematização da violência e da perseguição aos movimentos sociais. Durante as décadas em que o MAS atuou, o governo mexicano colocou em prática uma estratégia de contrainsurgência, mobilizando grupos militares e paramilitares para a perseguição e aniquilação dos lutadores sociais, bem como para a desarticulação de possíveis redes de apoio. Esse artigo analisa o contexto de surgimento do MAS, a atuação de diferentes guerrilhas nas zonas rurais e urbanas, bem como as estratégias de repressão praticadas pelos agentes do Estado mexicano. Para tanto, recorre-se à produção historiográfica sobre o assunto e ao Informe Histórico da Fiscalía Especial para Movimientos Sociales y Políticos del Pasado (FEMOSPP), publicado em 2006.
O pluralismo jurídico como alternativa para a América Latina em âmbito supranacional de proteção multinível de direitos humanos
Authors: Mendes Guilherme Marinho de Araújo , Silva Claudyvan José dos Santos Nascimento
Published: August 2023

O fortalecimento da proteção multinível de direitos humanos, que englobe os âmbitos internacional, supranacional, nacional e local de maneira integrada, é um constante esforço dos mais variados segmentos sociais para consolidar a efetividade e expansão do conceito de dignidade da pessoa humana. A proteção multinível de direitos humanos é um sistema jurídico estruturado que busca o diálogo entre as ordens jurídicas internas e externas. Nesse contexto, o objetivo do presente ensaio é refletir acerca da possibilidade de construção de um sistema multinível de proteção de direitos humanos no contexto da América Latina. O que se percebe é que na América Latina não se verifica a existência de um sistema multinível efetivo, de maneira que formas de integração e proteção de direitos humanos no bloco devem ser discutidas. Contribuir com o debate que visa formular instrumentos que tornem viável a efetivação de um modelo de proteção multinível dos direitos humanos na América Latina é o que se busca com o presente ensaio.
Children’s Human Right to Be Heard at the Ocean-climate Nexus
Authors: Shields Sophie , Longo Andrea , Strand Mia , Morgera Elisa
Published: August 2023

This article aims to clarify the obligations of States under the law of the sea to put children’s human rights at the heart of decision-making on the protection of the marine environment, particularly at the ocean-climate nexus. The relevance of the provisions of the United Nations Convention on the Rights of the Child and in particular, children’s human right to be heard in the context of existing provisions on deep-sea mining activities under the International Seabed Authority and the Agreement on the Conservation and Sustainable Use of Marine Biological Diversity of Areas Beyond National Jurisdiction are discussed. Reflections on more ambitious approaches to integrating intergenerational dialogue within international ocean fora, as ways to implement intergenerational equity and protect humankind at the ocean-climate nexus, on the basis of good practices in the area of children’s human rights are offered.
Ghana Beyond Aid: A Bargaining Chip for Draconian Economic Policies in Ghana
Authors: Ntim Emmanuel O. , Botchway Thomas P.
Published: August 2023

This article evaluates the austere economic policies implemented by the Akufo- Addo-Administration using the Ghana Beyond Aid vision as a guarantee. For a state that virtually depends on the benevolence of the external world for its economic growth and national development, the enactment of policies to wean its political economy from the generosity of industrialized nations and multinational institutions is not only politically expedient, but also socially gratifying. Nonetheless, instead of the government to concentrate on formulating pragmatic policies that form the niches of the Ghana Beyond Aid agenda with public support, it has rather taken a uniquely detested trajectory of dedicating little attention to the vision in pursuit of policies that have lost touch with the public, but which the vision is occasionally cited as the bargaining chip. This article examines these political nuances using the case study strategy. The paper argues that while it is prudent to implement policies towards the attainment of the Ghana Beyond Aid vision, the political leadership should be guided by public opinion and consensus building to reduce the degree of adversities posed by these policies. The study also makes a case for policy initiatives and strategies to make the beyond aid agenda feasible.
Vocative strategies and accent in Armenian: synchrony and diachrony
Authors: Martirosyan Hrach
Published: August 2023

The vocative, the case of direct address, is a form used for calling out and attracting or maintaining the addressee’s attention. It is not represented in Classical Armenian as an independent case category (§ 1b). At different stages of Armenian the vocative is often characterized by initial accentuation, which is comparable to other Indo-European traditions (§ 2). Accented vocative particles are used both in Classical Armenian and dialects (§ 3). Mostly in dialects, several words, particularly kinship terms and anthroponyms, take endings, one or a few of which may be regarded as relics of older vocative case endings (§ 4). In the Armenian dialects of Syria, one finds a few kinship terms the vocatives of which are compounds with ayr ‘man’ or tikin ‘mistress, lady’ (§ 5)