bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1 open-label trial of intravenous administration of MVA-BN-brachyury-TRICOM vaccine in patients with advanced cancer
Authors: DeMaria Peter J , Lee-Wisdom Katherine , Donahue Renee N , Madan Ravi A , Karzai Fatima , Schwab Angie , Palena Claudia , Jochems Caroline , Floudas Charalampos , Strauss Julius , Marté Jennifer L , Redman Jason Mark , Dombi Eva , Widemann Brigitte , Korchin Borys , Adams Tatiana , Pico-Navarro Cesar , Heery Christopher , Schlom Jeffrey , Gulley James L , Bilusic Marijo 
Published: September 2021

BackgroundMVA-BN-brachyury-TRICOM is a recombinant vector-based therapeutic cancer vaccine designed to induce an immune response against brachyury. Brachyury, a transcription factor overexpressed in advanced cancers, has been associated with treatment resistance, epithelial-to-mesenchymal transition, and metastatic potential. MVA-BN-brachyury-TRICOM has demonstrated immunogenicity and safety in previous clinical trials of subcutaneously administered vaccine. Preclinical studies have suggested that intravenous administration of therapeutic vaccines can induce superior CD8+T cell responses, higher levels of systemic cytokine release, and stronger natural killer cell activation and proliferation. This is the first-in-human study of the intravenous administration of MVA-BN-brachyury-TRICOM.MethodsBetween January 2020 and March 2021, 13 patients were treated on a phase 1, open-label, 3+3 design, dose-escalation study at the National Institutes of Health Clinical Center. The study population was adults with advanced solid tumors and was enriched for chordoma, a rare sarcoma of the notochord that overexpresses brachyury. Vaccine was administered intravenously at three DLs on days 1, 22, and 43. Blood samples were taken to assess drug pharmacokinetics and immune activation. Imaging was conducted at baseline, 1 month, and 3 months post-treatment. The primary endpoint was safety and tolerability as determined by the frequency of dose-limiting toxicities; a secondary endpoint was determination of the recommended phase 2 dose.ResultsNo dose-limiting toxicities were observed and no serious adverse events were attributed to the vaccine. Vaccine-related toxicities were consistent with class profile (ie, influenza-like symptoms). Cytokine release syndrome up to grade 2 was observed with no adverse outcomes. Dose-effect trend was observed for fever, chills/rigor, and hypotension. Efficacy analysis of objective response rate per RECIST 1.1 at the end of study showed one patient with a partial response, four with stable disease, and eight with progressive disease. Three patients with stable disease experienced clinical benefit in the form of improvement in pain. Immune correlatives showed T cell activation against brachyury and other tumor-associated cascade antigens.ConclusionsIntravenous administration of MVA-BN-brachyury-TRICOM vaccine was safe and tolerable. Maximum tolerated dose was not reached. The maximum administered dose was 109infectious units every 3 weeks for three doses. This dose was selected as the recommended phase 2 dose.Trial registration numberNCT04134312.
Complications of transradial versus transfemoral access for neuroendovascular procedures: a meta-analysis
Authors: Schartz Derrek , Akkipeddi Sajal Medha K , Ellens Nathaniel , Rahmani Redi , Kohli Gurkirat Singh , Bruckel Jeffrey , Caplan Justin M , Mattingly Thomas K , Bhalla Tarun , Bender Matthew T 
Published: September 2021

BackgroundTransradial access (TRA) has gained increased usage among neurointerventionalists. However, the overall safety profile of access site complications (ASCs) and non-access site complications (NASCs) of TRA versus transfemoral access (TFA) for neuroendovascular procedures remains unclear.MethodsA systematic literature review and meta-analysis using a random effects model was conducted to investigate the pooled odds ratios (OR) of ASCs and NASCs. Randomized, case–control, and cohort studies comparing access-related complications were analyzed. An assessment of study heterogeneity and publication bias was also completed.ResultsSeventeen comparative studies met the inclusion criteria for final analysis. Overall, there was a composite ASC rate of 1.8% (49/2767) versus 3.2% (168/5222) for TRA and TFA, respectively (P<0.001). TRA was associated with a lower odds of ASC compared with TFA (OR 0.42; 95% CI 0.25 to 0.68, P<0.001, I2=31%). There was significantly lower odds of complications within the intervention and diagnostic subgroups. For NASC, TRA had a lower composite incidence of complications than TFA at 1.2% (31/2586) versus 4.2% (207/4909), P<0.001). However, on meta-analysis, we found no significant difference overall between TRA and TFA for NASCs (OR 0.79; 95% CI 0.51 to 1.22, P=0.28, I2=0%), which was also the case on subgroup analysis.ConclusionOn meta-analysis, the current literature indicates that TRA is associated with a lower incidence of ASCs compared with TFA, but is not associated with a lower rate of NASCs.
Oxidized Low-Density Lipoprotein Links Hypercholesterolemia and Bladder Cancer Aggressiveness by Promoting Cancer Stemness
Authors: Yang Lin , Sun Jingya , Li Meiqian , Long Yiming , Zhang Dianzheng , Guo Hongqian , Huang Ruimin , Yan Jun 
Published: September 2021

Abstract

Hypercholesterolemia is a prevalent metabolic disorder that has been implicated in the development of steroid-targeted cancers. However, the link between hypercholesterolemia and urinary bladder cancer (UBC), a non–steroid-targeted cancer, remains unresolved. Here we show that diet-induced and Ldlr deficiency–induced hypercholesterolemia enhances both UBC stemness and progression. Inhibition of intestinal cholesterol absorption by ezetimibe reversed diet-induced hypercholesterolemia and cancer stemness. As a key component in hypercholesterolemic sera, oxidized low-density lipoprotein (ox-LDL), but not native low-density lipoprotein-cholesterol or metabolite 27-hydroxycholesterol, increased cancer stemness through its receptor CD36. Depletion of CD36, ectopic expression of an ox-LDL binding–disabled mutant form of CD36(K164A), and the neutralization of ox-LDL and CD36 via neutralizing antibodies all reversed ox-LDL–induced cancer stemness. Mechanistically, ox-LDL enhanced the interaction of CD36 and JAK2, inducing phosphorylation of JAK2 and subsequently activating STAT3 signaling, which was not mediated by JAK1 or Src in UBC cells. Finally, ox-LDL levels in serum predicted poor prognosis, and the ox-LDLhigh signature predicted worse survival in patients with UBC. These findings indicate that ox-LDL links hypercholesterolemia with UBC progression by enhancing cancer stemness. Lowering serum ox-LDL or targeting the CD36/JAK2/STAT3 axis might serve as a potential therapeutic strategy for UBCs with hypercholesterolemia. Moreover, elevated ox-LDL may serve as a biomarker for UBC.

Significance:
This study demonstrates how hypercholesterolemia-induced oxidized LDL promotes urinary bladder cancer stemness via a CD36/STAT3 signaling axis, highlighting these factors as biomarkers and potential therapeutic targets of aggressive disease.
Hemochromatosis, Iron Overload–Related Diseases, and Pancreatic Cancer Risk in the Surveillance, Epidemiology, and End Results (SEER)-Medicare
Authors: Julián-Serrano Sachelly , Yuan Fangcheng , Barrett Michael J. , Pfeiffer Ruth M. , Stolzenberg-Solomon Rachael Z. 
Published: September 2021

Abstract

Background:
Experimental studies suggest that iron overload might increase pancreatic cancer risk. We evaluated whether prediagnostic hemochromatosis and iron-overload diseases, including sideroblastic and congenital dyserythropoietic anemias, and non–alcoholic-related chronic liver disease (NACLD) were associated with pancreatic cancer risk in older adults.

Methods:
We conducted a population-based, case–control study within the U.S. Surveillance, Epidemiology, and End Results Program (SEER)-Medicare linked data. Incident primary pancreatic cancer cases were adults &gt; 66 years. Controls were alive at the time cases were diagnosed and matched to cases (4:1 ratio) by age, sex, and calendar year. Hemochromatosis, iron-overload anemias, and NACLD were reported 12 or more months before pancreatic cancer diagnosis or control selection using Medicare claims data. Adjusted unconditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI) between hemochromatosis, sideroblastic and congenital dyserythropoietic anemias, NACLD, and pancreatic cancer.

Results:
Between 1992 and 2015, 80,074 pancreatic cancer cases and 320,296 controls were identified. Overall, we did not observe statistically significant associations between hemochromatosis, sideroblastic anemia, or congenital dyserythropoietic anemia and pancreatic cancer; however, sideroblastic anemia was associated with later primary pancreatic cancer (OR, 1.30; 95% CI, 1.03–1.64). NACLD was associated with first (OR, 1.10; 95% CI, 1.01–1.19), later (OR, 1.17; 95% CI, 1.02–1.35), and all (OR, 1.12; 95% CI, 1.04–1.20) pancreatic cancer.

Conclusions:
Overall hemochromatosis and iron-overload anemias were not associated with pancreatic cancer, whereas NACLD was associated with increased risk in this large study of older adults.

Impact:
These results partly support the hypothesis that iron-overload diseases increase pancreatic cancer risk.
Tissue-Agnostic Drug Development: A New Path to Drug Approval
Authors: Thein Kyaw Z. , Lemery Steven J. , Kummar Shivaani 
Published: September 2021

Abstract

Summary:
In recent years, there has been remarkable progress in our understanding of cancer biology, host responses, and the concept of precision oncology. These advances have focused attention on biomarker-driven, tissue-agnostic drug development strategies. The recent approvals by the FDA of pembrolizumab for the treatment of unresectable or metastatic, microsatellite instability–high or deficient mismatch repair solid tumors, and more recently for the treatment of tumor mutational burden–high tumors; and of larotrectinib and entrectinib for the treatment of neurotrophic tyrosine kinase (NTRK) fusion–positive solid tumors, have further heightened interest in target-driven as opposed to histology-driven drug development. Herein, we focus on tissue-agnostic clinical drug development with an understanding of target modulation in the context of histology. The use of molecular genetics and biomarker-driven strategies rather than traditional histology based on organ of origin has reinforced the concept of tissue-agnostic drug development. Recent approvals in the United States, Europe, Japan, Australia, and other regions have further heightened interest in target-driven as opposed to histology-driven drug development.
Dissecting Response and Resistance to Anti–PD-1 Therapy in Microsatellite-Unstable Gastric Cancer
Authors: Fontana Elisa , Smyth Elizabeth C. 
Published: September 2021

Abstract

Summary:
Most, but not all, patients with microsatellite-unstable gastric cancer respond to anti–PD-1 therapy. In this issue, Kwon and colleagues show, first, that differences in tumor mutation burden (TMB) may drive this variation in outcomes and, second, that treatment with immune checkpoint inhibitors leads to further immunoediting and a reduction in TMB in responding patients.
See related article by Kwon et al., p. 2168.
mRNA Export as a Novel Cancer-Specific Dependency
Authors: Wang Eric , Abdel-Wahab Omar 
Published: September 2021

Abstract

Summary:
In this issue, Malone and colleagues identified the nuclear mRNA export factor NXT1 as a novel genetic dependency in neuroblastoma as well as several additional pediatric cancers. These data highlight potential cell type–specific differences in the nuclear export machinery that may be exploited as cancer therapeutics.
See related article by Malone et al., p. 2282.
Bacterial Genotoxin Accelerates Transient Infection–Driven Murine Colon Tumorigenesis
Authors: Liu Yue , Fu Kai , Wier Eric M. , Lei Yifan , Hodgson Andrea , Xu Dongqing , Xia Xue , Zheng Dandan , Ding Hua , Sears Cynthia L. , Yang Jian , Wan Fengyi 
Published: September 2021

Abstract

Chronic and low-grade inflammation associated with persistent bacterial infections has been linked to colon tumor development; however, the impact of transient and self-limited infections in bacterially driven colon tumorigenesis has remained enigmatic. Here we report that UshA is a novel genotoxin in attaching/effacing (A/E) pathogens, which include the human pathogens enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and their murine equivalent Citrobacter rodentium (CR). UshA harbors direct DNA digestion activity with a catalytic histidine–aspartic acid dyad. Injected via the type III secretion system (T3SS) into host cells, UshA triggers DNA damage and initiates tumorigenic transformation during infections in vitro and in vivo. Moreover, UshA plays an indispensable role in CR infection–accelerated colon tumorigenesis in genetically susceptible ApcMinΔ716/+ mice. Collectively, our results reveal that UshA, functioning as a bacterial T3SS-dependent genotoxin, plays a critical role in prompting transient and noninvasive bacterial infection–accelerated colon tumorigenesis in mice.

Significance:
We identified UshA, a novel T3SS-dependent genotoxin in A/E pathogens that possesses direct DNA digestion activity and confers bacterially accelerated colon tumorigenesis in mice. Our results demonstrate that acute and noninvasive infection with A/E pathogens harbors a far-reaching impact on the development of colon cancer.
This article is highlighted in the In This Issue feature, p. 1
Мікробіота пародонтальних кишень у пацієнтів з ішемічною хворобою серця та хронічним генералізованим пародонтитом
Authors: Скибчик О. В. 
Published: September 2021

Резюме. Хронічний генералізований пародонтит (ХГП) визнаний одним із незалежних факторів ризику у виникненні ішемічної хвороби серця (ІХС). Існують припущення про те, що одним із основних пускових факторів розвитку атеросклеротичного ушкодження судин унаслідок ХГП виступає саме патогенна мікробіота пародонтальних кишень, яка спричиняє вивільнення прозапальних медіаторів, С-реактивного білка і, як наслідок, призводить до виникнення системного запалення та дисфункції ендотелію.
Мета дослідження – визначити склад мікробіоти пародонтальних кишень у пацієнтів з ішемічною хворобою серця та хронічним генералізованим пародонтитом.
Матеріали і методи. Проведено мікробіологічне дослідження вмісту пародонтальних кишень 84 хворих із ХГП початкового-І, ІІ та ІІІ ступенів тяжкості: 64 хворих із ХГП та ІХС основної групи (середній вік – (56,9±7,9) року) та 20 осіб із ХГП, не обтяжених ІХС, що склали групу порівняння (середній вік – (45,2±11,8) року).
Результати досліджень та їх обговорення. У результаті мікробіологічного дослідження вмісту пародонтальних кишень у всіх обстежених хворих на ІХС та ХГП було виявлено наявність патогенної мікробіоти, яка характеризувалася видовою різноманітністю та високим рівнем загального обсіменіння. У хворих основної групи простежувалося переважання стрептококів (Str. Mitis, Str. Salivarius, Str. Pyogenes) та коринебактерій (Corynebacterium spp.). За показниками частоти виявлення представників анаеробної ланки в основній групі зареєстровано переважання висівання A. actinomycetemcomitans, P. intermedia, B. melaninogenicus, Fusobacterium spp., Veillonella spp. та E. Corrodens., частота виявлення яких зростала із ступенем тяжкості патологічного процесу в тканинах пародонта.
Висновки. Результати аналізу проведених мікробіологічних досліджень показали зміни мікробіоти вмісту пародонтальних кишень, у тому числі аеробних та анаеробних мікроорганізмів у хворих із ХГП на тлі ІХС. Встановлено високий рівень колонізації патогенною пародонтальною мікробіотою, порівняно з групою осіб із ХГП, не обтяжених ІХС. Простежується перерозподіл між грамнегативною та грампозитивною мікробіотою: при ХГП ІІ ступеня та ХГП ІІІ ступеня частка грамнегативних анаеробів зростає та активності набирає більша кількість їх видів.
Оцінка чинників ризику розвитку раннього дитячого карієсу в дітей за даними анкетування батьків
Authors: Гринкевич Л. Г. 
Published: September 2021

Резюме. Ранній дитячий карієс є першим захворюванням, яке дає виклик стоматологічному здоров’ю дитини та майбутньої дорослої людини. На сьогодні добре відомо його етіопатогенез, але разом з тим чимало чинників впливає на процес розвитку патологічного процесу в твердих тканинах дитини.
Мета дослідження – проаналізувати чинники ризику розвитку раннього дитячого карієсу в дітей за даними анкетування батьків.
Матеріали і методи. Для аналізу чинників, що впливають на розвиток карієсу зубів у дітей, ми провели анкетування батьків із використанням Google-форми. В опитуванні взяли участь 113 батьків дітей віком до 3 років, які народилися та проживають у м. Чернівці.
Результати досліджень та їх обговорення. Аналіз відповідей респондентів дає підстави стверджувати проте, що у дітей віком до 3 років, які проживають у м. Чернівці, наявні такі чинники ризику розвитку карієсу тимчасових зубів, як неналежний режим вигодовування протягом першого року життя дитини, шкідливі харчові звички та уподобання дітей, споживання води з неконтрольованих за рівнем фтору джерел, неналежний догляд за ротовою порожниною, відсутність вчасної кваліфікованої консультації щодо індивідуальної гігієни ротової порожнини та недостатня обізнаність батьків відносно причин розвитку карієсу зубів у дітей та методів їх усунення.
Висновки. Одержана інформація є важливою з точки зору розуміння напрямку організації санітарно-просвітницької роботи з батьками дітей задля усунення тих чи інших чинників ризику розвитку раннього дитячого карієсу.
Utility of Intracardiac Echocardiography in the Early Experience of Transcatheter Edge to Edge Tricuspid Valve Repair
Authors: Eleid Mackram F. , Alkhouli Mohamad , Thaden Jeremy J. , Zahr Firas , Chadderdon Scott , Guerrero Mayra , Reeder Guy S. , Rihal Charanjit S. 
Published: September 2021

Background:
Tricuspid edge to edge repair (TEER) is a novel treatment for severe tricuspid regurgitation and is highly dependent on intraprocedural image quality. To date, transesophageal echocardiography (TEE) has been the primary imaging modality used to guide TEER. The role of intracardiac echocardiography (ICE) has not been assessed. The objective of this study was to describe the use and role of 2-dimensional ICE in the early experience of TEER.

Methods:
Consecutive patients undergoing TEER (with or without concomitant mitral repair) with off-label use of MitraClip (Abbott, Santa Clara, CA) were included in the study. Utilization of 2-dimensional ICE in comparison with TEE imaging were collected in each procedure through retrospective review of the procedural reports and images.

Results:

Of 42 TEER cases, ICE was used in 15 (36%) and concomitant mitral repair was performed in 37 (86%). ICE was increasingly used over time for TEER. ICE was able to visualize the tricuspid leaflets with high resolution and provided superior leaflet visualization to TEE in 40% of cases where it was used. Patients treated with ICE guidance tended to have a greater baseline severity of tricuspid regurgitation compared with patients treated with TEE guidance alone (8/15 [53%] massive or greater tricuspid regurgitation versus 6/27 [22%];
P
=0.09). Degree of tricuspid regurgitation reduction was similar with TEE alone versus ICE plus TEE guidance (1.9±1.0 versus 2.1±1.1 grade reduction,
P
=0.28).

Conclusions:
ICE was increasingly used in the early experience of TEER over time. ICE facilitates leaflet visualization for grasping and is a useful adjunct to TEE during TEER.
Serine 26 in Early Growth Response‐1 Is Critical for Endothelial Proliferation, Migration, and Network Formation
Authors: Santiago Fernando S. , Li Yue , Khachigian Levon M. 
Published: September 2021

Background
Vascular endothelial cell proliferation, migration, and network formation are key proangiogenic processes involving the prototypic immediate early gene product, Egr‐1 (early growth response‐1). Egr‐1 undergoes phosphorylation at a conserved Ser26 but its function is completely unknown in endothelial cells or any other cell type.

Methods and Results

A CRISPR/Cas9 strategy was used to introduce a homozygous Ser26>Ala mutation into endogenous Egr‐1 in human microvascular endothelial cells. In the course of generating mutant cells, we produced cells with homozygous deletion in
Egr
‐1
caused by frameshift and premature termination. We found that Ser26 mutation in Egr‐1, or Egr‐1 deletion, perturbed endothelial cell proliferation in models of cell counting or real‐time growth using the xCELLigence System. We found that Ser26 mutation or Egr‐1 deletion ameliorated endothelial cell migration toward VEGF‐A
165
(vascular endothelial growth factor‐A) in a dual‐chamber model. On solubilized basement membrane preparations, Ser26 mutation or Egr‐1 deletion prevented endothelial network (or tubule) formation, an in vitro model of angiogenesis. Flow cytometry further revealed that Ser26 mutation or Egr‐1 deletion elevated early and late apoptosis. Finally, we demonstrated that Ser26 mutation or Egr‐1 deletion increased VE‐cadherin (vascular endothelial cadherin) expression, a regulator of endothelial adhesion and signaling, permeability, and angiogenesis.

Conclusions
These findings not only indicate that Egr‐1 is essential for endothelial cell proliferation, migration, and network formation, but also show that point mutation in Ser26 is sufficient to impair each of these processes and trigger apoptosis as effectively as the absence of Egr‐1. This highlights the importance of Ser26 in Egr‐1 for a range of proangiogenic processes.
Validation of the 2016 ASE/EACVI Guideline for Diastolic Dysfunction in Patients With Unexplained Dyspnea and a Preserved Left Ventricular Ejection Fraction
Authors: van de Bovenkamp Arno A. , Enait Vidya , de Man Frances S. , Oosterveer Frank T. P. , Bogaard Harm Jan , Vonk Noordegraaf Anton , van Rossum Albert C. , Handoko M. Louis 
Published: September 2021

Background
Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo‐algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited.

Methods and Results

The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H
2
FPEF score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e′ (septal and average) or early mitral inflow (E), and PCWP (
r
=0.25–0.30,
P
values all <0.01). No correlation was found in our cohort between e′ (septal or lateral) or tricuspid valve regurgitation and PCWP. The correlation between diastolic function grades of the ASE/EACVI algorithm and PCWP was poor (
r
=0.17,
P
<0.05). The ASE/EACVI algorithm had a sensitivity and specificity of 35% and 87%, respectively; an accuracy of 67% and an area under the curve of 0.56. Moreover, in 30% of cases the algorithm was not applicable or indeterminate. H
2
FPEF score had a modest correlation with PCWP (
r
=0.44,
P
<0.0001), and accuracy was 73%; NT‐proBNP correlated weakly with PCWP (
r
=0.24,
P
<0.001), and accuracy was 57%.

Conclusions
The 2016 ASE/EACVI algorithm for the assessment of diastolic function has a limited diagnostic accuracy in patients evaluated for unexplained dyspnea and/or pulmonary hypertension, and especially sensitivity to detect diastolic dysfunction was low.