bluuebunny/crossref_metadata_2025_split huggingface dataset:
89Zr-panitumumab Combined With 18F-FDG PET Improves Detection and Staging of Head and Neck Squamous Cell Carcinoma
Authors: Lee Yu-Jin , van den Berg Nynke S. , Duan Heying , Azevedo E. Carmen , Ferri Valentina , Hom Marisa , Raymundo Roan C. , Valencia Alex , Castillo Jessa , Shen Bin , Zhou Quan , Freeman Laura , Koran Mary Ellen , Kaplan Michael J. , Colevas A. Dimitrios , Baik Fred M. , Chin Frederick T. , Martin Brock A. , Iagaru Andrei , Rosenthal Eben L. 
Published: August 2022

Abstract

Purpose:
Determine the safety and specificity of a tumor-targeted radiotracer (89Zr-pan) in combination with 18F-FDG PET/CT to improve diagnostic accuracy in head and neck squamous cell carcinoma (HNSCC).

Experimental Design:
Adult patients with biopsy-proven HNSCC scheduled for standard-of-care surgery were enrolled in a clinical trial and underwent systemic administration of 89Zirconium-panitumumab and panitumumab-IRDye800 followed by preoperative 89Zr-pan PET/CT and intraoperative fluorescence imaging. The sensitivity, specificity, and AUC were evaluated.

Results:
A total of fourteen patients were enrolled and completed the study. Four patients (28.5%) had areas of high 18F-FDG uptake outside the head and neck region with maximum standardized uptake values (SUVmax) greater than 2.0 that were not detected on 89Zr-pan PET/CT. These four patients with incidental findings underwent further workup and had no evidence of cancer on biopsy or clinical follow-up. Forty-eight lesions (primary tumor, LNs, incidental findings) with SUVmax ranging 2.0–23.6 were visualized on 18F-FDG PET/CT; 34 lesions on 89Zr-pan PET/CT with SUVmax ranging 0.9–10.5. The combined ability of 18F-FDG PET/CT and 89Zr-pan PET/CT to detect HNSCC in the whole body was improved with higher specificity of 96.3% [confidence interval (CI), 89.2%–100%] compared to 18F-FDG PET/CT alone with specificity of 74.1% (CI, 74.1%–90.6%). One possibly related grade 1 adverse event of prolonged QTc (460 ms) was reported but resolved in follow-up.

Conclusions:
89Zr-pan PET/CT imaging is safe and may be valuable in discriminating incidental findings identified on 18F-FDG PET/CT from true positive lesions and in localizing metastatic LNs.
Preclinical Characterization of AZD5305, A Next-Generation, Highly Selective PARP1 Inhibitor and Trapper
Authors: Illuzzi Giuditta , Staniszewska Anna D. , Gill Sonja J. , Pike Andy , McWilliams Lisa , Critchlow Susan E. , Cronin Anna , Fawell Stephen , Hawthorne Glen , Jamal Kunzah , Johannes Jeffrey , Leonard Emilyanne , Macdonald Ruth , Maglennon Gareth , Nikkilä Jenni , O'Connor Mark J. , Smith Aaron , Southgate Harriet , Wilson Joanne , Yates James , Cosulich Sabina , Leo Elisabetta 
Published: August 2022

Abstract

Purpose:
We hypothesized that inhibition and trapping of PARP1 alone would be sufficient to achieve antitumor activity. In particular, we aimed to achieve selectivity over PARP2, which has been shown to play a role in the survival of hematopoietic/stem progenitor cells in animal models. We developed AZD5305 with the aim of achieving improved clinical efficacy and wider therapeutic window. This next-generation PARP inhibitor (PARPi) could provide a paradigm shift in clinical outcomes achieved by first-generation PARPi, particularly in combination.

Experimental Design:
AZD5305 was tested in vitro for PARylation inhibition, PARP-DNA trapping, and antiproliferative abilities. In vivo efficacy was determined in mouse xenograft and PDX models. The potential for hematologic toxicity was evaluated in rat models, as monotherapy and combination.

Results:
AZD5305 is a highly potent and selective inhibitor of PARP1 with 500-fold selectivity for PARP1 over PARP2. AZD5305 inhibits growth in cells with deficiencies in DNA repair, with minimal/no effects in other cells. Unlike first-generation PARPi, AZD5305 has minimal effects on hematologic parameters in a rat pre-clinical model at predicted clinically efficacious exposures. Animal models treated with AZD5305 at doses ≥0.1 mg/kg once daily achieved greater depth of tumor regression compared to olaparib 100 mg/kg once daily, and longer duration of response.

Conclusions:
AZD5305 potently and selectively inhibits PARP1 resulting in excellent antiproliferative activity and unprecedented selectivity for DNA repair deficient versus proficient cells. These data confirm the hypothesis that targeting only PARP1 can retain the therapeutic benefit of nonselective PARPi, while reducing potential for hematotoxicity. AZD5305 is currently in phase I trials (NCT04644068).
Transient Inhibition of Trastuzumab–Tumor Binding to Overcome the “Binding-Site Barrier” and Improve the Efficacy of a Trastuzumab–Gelonin Immunotoxin
Authors: Chen Ping , Bordeau Brandon M. , Zhang Yu , Balthasar Joseph P. 
Published: August 2022

Abstract
We have recently shown that coadministration of mAbs with anti-idiotypic distribution enhancers (AIDE) that inhibit mAb binding to tumor antigens enabled increased intratumoral mAb distribution and increased efficacy of an antibody–drug conjugate (trastuzumab emtansine, T-DM1). In this article, a pharmacokinetic/pharmacodynamic (PK/PD) model was applied to predict the impact of this optimization strategy on the within-tumor distribution and antitumor efficacy of trastuzumab–gelonin, where the released payload (gelonin) is expected to exhibit negligible bystander activity. Immunofluorescence histology was used to investigate trastuzumab–gelonin distribution in solid tumors following dosing with or without coadministration of anti-trastuzumab AIDEs. Antitumor efficacy of trastuzumab–gelonin, with or without coadministration of AIDEs, was also evaluated in tumor-bearing mice. Trastuzumab–gelonin efficiently induced cytotoxicity when applied to NCI-N87 cells in culture (IC50: 0.224 ± 0.079 nmol/L). PK/PD simulations predicted that anti-idiotypic single-domain antibodies AIDEs with dissociation rate constants between 0.03 and 0.2 per hour would provide optimal enhancement of trastuzumab–gelonin efficacy. LE8 and 1HE, anti-trastuzumab AIDEs, were selected for evaluation in vivo. Coadministration of trastuzumab–gelonin with the inhibitors increased the portion of tumor area that stained positive for trastuzumab–gelonin by 58% (P = 0.0059). In addition, LE8 or 1HE coadministration improved trastuzumab–gelonin efficacy in NCI-N87 xenograft-bearing mice by increasing the percent increase in life span (%ILS) from 27.8% (for trastuzumab–gelonin administered alone) to 62.5% when administered with LE8 (P = 0.0007) or 83.3% (P = 0.0007) when administered with 1HE. These findings support the hypothesis that transient, competitive inhibition of mAb-tumor binding can improve the intratumoral distribution and efficacy of immunotoxins when applied for treatment of solid tumors.
Bioengineered BERA-Wnt5a siRNA Targeting Wnt5a/FZD2 Signaling Suppresses Advanced Prostate Cancer Tumor Growth and Enhances Enzalutamide Treatment
Authors: Ning Shu , Liu Chengfei , Lou Wei , Yang Joy C. , Lombard Alan P. , D'Abronzo Leandro S. , Batra Neelu , Yu Ai-Ming , Leslie Amy R. , Sharifi Masuda , Evans Christopher P. , Gao Allen C. 
Published: August 2022

Abstract
The next-generation antiandrogen drugs such as enzalutamide and abiraterone extend survival times and improve quality of life in patients with advanced prostate cancer. However, resistance to both drugs occurs frequently through mechanisms that are incompletely understood. Wnt signaling, particularly through Wnt5a, plays vital roles in promoting prostate cancer progression and induction of resistance to enzalutamide and abiraterone. Development of novel strategies targeting Wnt5a to overcome resistance is an urgent need. In this study, we demonstrated that Wnt5a/FZD2-mediated noncanonical Wnt pathway is overexpressed in enzalutamide-resistant prostate cancer. In patient databases, both the levels of Wnt5a and FZD2 expression are upregulated upon the development of enzalutamide resistance and correlate with higher Gleason score, biochemical recurrence, and metastatic status, and with shortened disease-free survival duration. Blocking Wnt5a/FZD2 signal transduction not only diminished the activation of noncanonical Wnt signaling pathway, but also suppressed the constitutively activated androgen receptor (AR) and AR variants. Furthermore, we developed a novel bioengineered BERA-Wnt5a siRNA construct and demonstrated that inhibition of Wnt5a expression by the BERA-Wnt5a siRNA significantly suppressed tumor growth and enhanced enzalutamide treatment in vivo. These results indicate that Wnt5a/FZD2 signal pathway plays a critical role in promoting enzalutamide resistance, and targeting this pathway by BERA-Wnt5a siRNA can be developed as a potential therapy to treat advanced prostate cancer.
AZD4625 is a Potent and Selective Inhibitor of KRASG12C
Authors: Chakraborty Atanu , Hanson Lyndsey , Robinson David , Lewis Hilary , Bickerton Sue , Davies Michael , Polanski Radoslaw , Whiteley Rebecca , Koers Alex , Atkinson James , Baker Tamara , del Barco Barrantes Ivan , Ciotta Giovanni , Kettle Jason G. , Magiera Lukasz , Martins Carla P. , Peter Alison , Wigmore Eleanor , Underwood Zoe , Cosulich Sabina , Niedbala Michael , Ross Sarah 
Published: August 2022

Abstract
AZD4625 is a potent, selective, and orally bioavailable inhibitor of oncogenic KRASG12C as demonstrated in cellular assays and in vivo in preclinical cell line–derived and patient-derived xenograft models. In vitro and cellular assays have shown selective binding and inhibition of the KRASG12C mutant isoform, which carries a glycine to cysteine mutation at residue 12, with no binding and inhibition of wild-type RAS or isoforms carrying non-KRASG12C mutations. The pharmacology of AZD4625 shows that it has the potential to provide therapeutic benefit to patients with KRASG12C mutant cancer as either a monotherapy treatment or in combination with other targeted drug agents.
Hiding in Plain Sight: A Novel Microbial Driver for Colorectal Cancer?
Authors: Jain Tejeshwar , Dudeja Vikas 
Published: August 2022

Summary:
In this issue of Cancer Discovery, Drewes and colleagues demonstrate a surprising role for the common gut pathogen Clostridioides difficile in driving colorectal cancer in preclinical models through the bacterial toxin–dependent reprogramming of the epithelial and immune compartments.
See related article by Drewes et al., p. 1873 (3).
A new species of pincer wasps of Deinodryinus Perkins (Hymenoptera, Dryinidae) from oceanic archipelago of Fernando de Noronha, Brazil
Authors: Martins André Luis 
Published: August 2022

The first record of the genus Deinodryinus Perkins and the description of a new species Deinodryinus noronhensis sp. nov. from oceanic archipelago of Fernando de Noronha (Brazil) are performed. Additionally, an illustration of the new species and a modified key are presented together with a discussion on the Deinodryinus records for the northeastern region of Brazil.
Adherence and Exercise Capacity Improvements of Patients With Adult Congenital Heart Disease Participating in Cardiac Rehabilitation
Authors: Sheng S. Peter , Feinberg Jodi L. , Bostrom John A. , Tang Ying , Sweeney Greg , Pierre Alicia , Katz Edward S. , Whiteson Jonathan H. , Haas François , Dodson John A. , Halpern Dan G. 
Published: August 2022

Background
As the number of adults with congenital heart disease increases because of therapeutic advances, cardiac rehabilitation (CR) is increasingly being used in this population after cardiac procedures or for reduced exercise tolerance. We aim to describe the adherence and exercise capacity improvements of patients with adult congenital heart disease (ACHD) in CR.

Methods and Results
This retrospective study included patients with ACHD in CR at New York University Langone Rusk Rehabilitation from 2013 to 2020. We collected data on patient characteristics, number of sessions attended, and functional testing results. Pre‐CR and post‐CR metabolic equivalent task, exercise time, and maximal oxygen uptake were assessed. In total, 89 patients with ACHD (mean age, 39.0 years; 54.0% women) participated in CR. Referral indications were reduced exercise tolerance for 42.7% and post–cardiac procedure (transcatheter or surgical) for the remainder. Mean number of sessions attended was 24.2, and 42 participants (47.2%) completed all 36 CR sessions. Among participants who completed the program as well as pre‐CR and post‐CR functional testing, metabolic equivalent task increased by 1.3 (95% CI, 0.7–1.9; baseline mean, 8.1), exercise time increased by 66.4 seconds (95% CI, 21.4–111.4 seconds; baseline mean, 536.1 seconds), and maximal oxygen uptake increased by 2.5 mL/kg per minute (95% CI, 0.7–4.2 mL/kg per minute; baseline mean, 20.2 mL/kg per minute).

Conclusions
On average, patients with ACHD who completed CR experienced improvements in exercise capacity. Efforts to increase adherence would allow more patients with ACHD to benefit.
Functional Echocardiographic and Serum Biomarker Changes Following Surgical and Percutaneous Atrial Septal Defect Closure in Children
Authors: van der Ven Jelle P. G. , van den Bosch Eva , Kamphuis Vivian P. , Terol Covadonga , Gnanam Devi , Bogers Ad J. J. C. , Breur Johannes M. P. J. , Berger Rolf M. F. , Blom Nico A. , Koopman Laurens , ten Harkel Arend D. J. , Helbing Willem A. 
Published: August 2022

Background
Ventricular performance is temporarily reduced following surgical atrial septal defect closure. Cardiopulmonary bypass and changes in loading conditions are considered important factors, but this phenomenon is incompletely understood. We aim to characterize biventricular performance following surgical and percutaneous atrial septal defect closure and to relate biomarkers to ventricular performance following intervention.

Methods and Results

In this multicenter prospective study, children scheduled for surgical or percutaneous atrial septal defect closure were included. Subjects were assessed preoperatively, in the second week postintervention (at 2‐weeks follow‐up), and 1‐year postintervention (1‐year follow‐up). At each time point, an echocardiographic study and a panel of biomarkers were obtained. Sixty‐three patients (median age, 4.1 [interquartile range, 3.1–6.1] years) were included. Forty‐three patients underwent surgery. At 2‐weeks follow‐up, right ventricular global longitudinal strain was decreased for the surgical, but not the percutaneous, group (−17.6±4.1 versus −27.1±3.4;
P
<0.001). A smaller decrease was noted for left ventricular global longitudinal strain at 2‐weeks follow‐up for the surgical group (surgical versus percutaneous, −18.6±3.2 versus −20.2±2.4;
P
=0.040). At 1‐year follow‐up, left ventricular performance returned to baseline, whereas right ventricular performance improved, but did not reach preintervention levels. Eight biomarkers relating to cardiovascular and immunological processes differed across study time points. Of these biomarkers, only NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) correlated with less favorable left ventricular global longitudinal strain at 2‐weeks follow‐up.

Conclusions
Right, and to a lesser degree left, ventricular performance was reduced early after surgical atrial septal defect closure. Right ventricular performance at 1‐year follow‐up remained below baseline levels. Several biomarkers showed a pattern over time similar to ventricular performance. These biomarkers may provide insight into the processes that affect ventricular function.

Registration

URL:
https://www.trialregister.nl/
; Unique identifier: NL5129
Short‐Term Outcomes Following Left Atrial Appendage Closure in the Very Elderly: A Population‐Based Analysis
Authors: Farwati Medhat , Amin Mustapha , Isogai Toshiaki , Saad Anas M. , Abushouk Abdelrahman I. , Krishnaswamy Amar , Wazni Oussama , Kapadia Samir R. 
Published: August 2022

Background
Data on percutaneous left atrial appendage closure (LAAC) outcomes in the very elderly with atrial fibrillation are limited. We aimed to investigate the clinical characteristics and short‐term outcomes of patients 80 years or older following percutaneous LAAC in a large nationwide database.

Methods and Results

Using the Nationwide Readmissions Database, we identified patients who underwent percutaneous LAAC between January 2016 and December 2018. Patients were categorized based on age (≥80 and <80 years old). The primary outcome was in‐hospital mortality. Secondary outcomes were in‐hospital end points including periprocedural complications, 30‐day outcomes, and all‐cause 30‐day readmissions. A propensity score–matched model (1:1) was used to adjust for baseline characteristics among the study groups. A total of 13 208 patients were included in this study (43% women, median age in years [interquartile range] 79.5 [73–84]) and matched one‐to‐one (6604 and 6604 patients were ≥80 and <80 years old, respectively). In‐hospital mortality was not statistically different between the study groups and occurred in 21 patients ≥80 years old (0.32%) and in 14 patients <80 years old (0.21%);
P
=0.236. Rates of in‐hospital stroke/transient ischemic attack were higher in patients ≥80 years old compared with those <80 years old (1.22% versus 0.77%;
P
=0.009). In‐hospital bleeding requiring transfusion, vascular complications, systemic embolization, and pericardial effusion/tamponade requiring pericardiocentesis or surgical intervention occurred more frequently in patients ≥80 years old. Furthermore, the elderly group was more likely to be readmitted within 30 days compared with those <80 years old (9.91% versus 8.4%;
P
=0.004); however, rates of 30‐day complications were not statistically different between the study groups.

Conclusions
In a large nationwide database, patients ≥80 years old undergoing percutaneous LAAC were found to have similar in‐hospital mortality but an increased risk of periprocedural complications and 30‐day readmission compared with younger patients. Our data suggest that LAAC should be considered on a case‐by‐case basis in the very elderly, taking into consideration the risks and benefits of this intervention. Further studies are needed to assess long‐term LAAC outcomes in this high‐risk population.
Effect of Canagliflozin on Total Cardiovascular Burden in Patients With Diabetes and Chronic Kidney Disease: A Post Hoc Analysis From the CREDENCE Trial
Authors: Li Jing‐Wei , Arnott Clare , Heerspink Hiddo J. L. , MBiostat Qiang Li , Cannon Christopher P. , Wheeler David C. , Charytan David M. , Barraclough Jennifer , Figtree Gemma A. , Agarwal Rajiv , Bakris George , de Zeeuw Dick , Greene Tom , Levin Adeera , Pollock Carol , Zhang Hong , Zinman Bernard , Mahaffey Kenneth W. , Perkovic Vlado , Neal Bruce , Jardine Meg J. 
Published: August 2022

Background
The sodium‐glucose cotransporter 2 inhibitor canagliflozin reduced the risk of first cardiovascular composite events in the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial. In this post hoc analysis, we evaluated the effect of canagliflozin on total (first and recurrent) cardiovascular events.

Methods and Results

The CREDENCE trial compared canagliflozin or matching placebo in 4401 patients with type 2 diabetes, albuminuria, and estimated glomerular filtration rate of 30 to <90 mL/min per 1.73 m
2
, over a median of 2.6 years. The primary outcome was analyzed as a composite of any cardiovascular event including myocardial infarction, stroke, hospitalization for heart failure, hospitalization for unstable angina, and cardiovascular death. Negative binomial regression models were used to assess the effect of canagliflozin on the net burden of cardiovascular events. During the trial, 634 patients had 883 cardiovascular events, of whom 472 (74%) had just 1 cardiovascular event and 162 (26%) had multiple cardiovascular events. Canagliflozin reduced first cardiovascular events by 26% (hazard ratio, 0.74 [95% CI, 0.63–0.86];
P
<0.001) and total cardiovascular events by 29% (incidence rate ratio, 0.71 [95% CI, 0.59–0.86];
P
<0.001). The absolute risk difference per 1000 patients treated over 2.5 years was −44 (95% CI, −67 to −21) first cardiovascular events and −73 (95% CI, −114 to −33) total events.

Conclusions
Canagliflozin reduced cardiovascular events, with a larger absolute benefit for total cardiovascular than first cardiovascular events. These findings provide further support for the benefit of continuing canagliflozin therapy after an initial event to prevent recurrent cardiovascular events.

Registration Information

URL:
https://www.clinicaltrials.gov
; Unique Identifier: NCT02065791.
Impact of Insulin Receptor Substrate‐1 rs956115 and CYP2C19 rs4244285 Genotypes on Clinical Outcome of Patients Undergoing Percutaneous Coronary Intervention
Authors: Zong Jiaxin , Tang Yingdan , Wang Tong , Ullah Inam , Xu Ke , Wang Jing , Chen Pengsheng , Chen Zengguang , Zhu Tiantian , Chen Jun , Li Jimin , Wang Fei , Yang Lu , Fan Yuansheng , Shi Lu , Gong Xiaoxuan , Eikelboom John W. , Zhao Yang , Li Chunjian 
Published: August 2022

Background

Insulin receptor substrate‐1 (
IRS‐1
) rs956115 is associated with vascular risk in patients with coronary artery disease and concomitant diabetes.
CYP2C19*2
(rs4244285) modulates clopidogrel response and predicts the outcome of coronary artery disease. This study was designed to explore the association between
IRS‐1
,
CYP2C19*2
genotypes, platelet reactivity, and 1‐year outcome in patients with coronary artery disease undergoing percutaneous coronary intervention.

Methods and Results

Genotyping was performed using an improved multiplex ligation detection reaction technique. Platelet aggregation was assessed by light transmission aggregometry. Major adverse cardiovascular events were defined as a composite of cardiovascular death, myocardial infarction, and ischemic stroke. A total of 2213 consecutive patients were screened and 1614 were recruited. At 1 month, patients with
IRS‐1
CG genotype had significantly lower levels of ADP‐induced platelet aggregation compared with patients with CC homozygotes. Patients with
IRS‐1
CG or GG genotype had a 2.09‐fold higher risk of major adverse cardiovascular events compared with those with CC homozygotes (95% CI, 1.04–4.19;
P
=0.0376). By comparison, patients with
CYP2C19*2
GA or AA genotype had higher ADP‐induced platelet aggregation compared with patients with GG homozygotes. Although there was no significant difference in risk of major adverse cardiovascular events between patients with GA/AA and GG genotypes, patients with GA genotype had a 2.19‐fold higher risk than those with GG homozygotes (95% CI, 1.13–4.24;
P
=0.0200). No interaction between
IRS‐1
and
CYP2C19*2
genotypes was observed.

Conclusions

In patients following percutaneous coronary intervention,
IRS‐1
GG/CG and
CYP2C19*2
GA genotypes were associated with 2.09‐ and 2.19‐fold increased cardiovascular risk, respectively, at 1‐year follow‐up. The association between
IRS‐1
genotypes and major adverse cardiovascular events appeared to be independent of known clinical predictors.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01968499.