bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diminished Immune Surveillance during Histologic Progression of Intraductal Papillary Mucinous Neoplasms Offers a Therapeutic Opportunity for Cancer Interception
Authors: Hernandez Sharia , Parra Edwin Roger , Uraoka Naohiro , Tang Ximing , Shen Yu , Qiao Wei , Jiang Mei , Zhang Shanyu , Mino Barbara , Lu Wei , Pandurengan Renganayaki , Haymaker Cara , Affolter Kajsa , Scaife Courtney L. , Yip-Schneider Michele , Schmidt C. Max , Firpo Matthew A. , Mulvihill Sean J. , Koay Eugene J. , Wang Huamin , Wistuba Ignacio I. , Maitra Anirban , Solis Luisa M. , Sen Subrata 
Published: May 2022

Abstract

Purpose:
Intraductal papillary mucinous neoplasms (IPMN) are bona fide precursors to pancreatic ductal adenocarcinoma (PDAC). While genomic alterations during multistep IPMN progression have been well cataloged, the accompanying changes within the tumor immune microenvironment (TIME) have not been comprehensively studied. Herein, we investigated TIME-related alterations during IPMN progression, using multiplex immunofluorescence (mIF) coupled with high-resolution image analyses.

Experimental Design:
Two sets of formalin-fixed, paraffin-embedded tissue samples from surgically resected IPMNs were analyzed. The training set of 30 samples consisted of 11 low-grade IPMN (LG-IPMN), 17 high-grade IPMN (HG-IPMN), and 2 IPMN with PDAC, while a validation set of 93 samples comprised of 55 LG-IPMN and 38 HG-IPMN. The training set was analyzed with two panels of immuno-oncology–related biomarkers, while the validation set was analyzed with a subset of markers found significantly altered in the training set.

Results:
Cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells, and antigen-experienced T cells and B cells, were all found at higher densities within isolated LG-IPMNs compared with HG-IPMNs. Notably, the TIME of LG-IPMNs that had progressed at the time of surgical resection (progressor LGD) resembled that of the synchronous HG-IPMNs, underscoring that attenuated immune surveillance occurs even in LG-IPMNs destined for progression.

Conclusions:
Our findings provide a basis for interception of cystic neoplasia to PDAC, through maintenance of sustained immune surveillance using vaccines and other prevention approaches.
Ultrasmall Nanoparticle Delivery of Doxorubicin Improves Therapeutic Index for High-Grade Glioma
Authors: Aragon-Sanabria Virginia , Aditya Anusha , Zhang Li , Chen Feng , Yoo Barney , Cao Tianye , Madajewski Brian , Lee Rachel , Turker Melik Z. , Ma Kai , Monette Sebastien , Chen Peiming , Wu Jing , Ruan Shutian , Overholtzer Michael , Zanzonico Pat , Rudin Charles M. , Brennan Cameron , Wiesner Ulrich , Bradbury Michelle S. 
Published: May 2022

Abstract

Purpose:
Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (&lt;8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C′ dots), for the efficacious treatment of high-grade gliomas.

Experimental Design:
This work presents first-in-kind renally clearable ultrasmall (&lt;8 nm) multimodal C′ dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models.

Results:
Optimal drug-per-particle ratios of as-developed nanoparticle–drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor–driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model.

Conclusions:
Ultrasmall C′ dot–drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
Trabectedin and Durvalumab Combination Is Feasible and Active in Relapsing Ovarian Cancer
Authors: Digklia Antonia , Coukos George , Homicsko Krisztian 
Published: May 2022

Summary
The combination of chemotherapy and immune therapies still promises to synergize for prolonged tumor control. However, the quest for optimal combinations tailored for tumor histology remains ongoing. A recent study provides evidence on the feasibility of the trabectedin/durvalumab combination and reports on interesting preliminary efficacy.
See related article by Toulmonde et al., p. 1765
Niraparib Shows Superior Tissue Distribution and Efficacy in a Prostate Cancer Bone Metastasis Model Compared with Other PARP Inhibitors
Authors: Snyder Linda A. , Damle Rajendra , Patel Shefali , Bohrer Jared , Fiorella Anna , Driscoll Jenny , Hawkins Rebecca , Stratton Christopher F. , Manning Carol D. , Tatikola Kanaka , Tryputsen Volha , Packman Kathryn , Mamidi Rao N.V.S. 
Published: May 2022

Abstract
Patients with prostate cancer whose tumors bear deleterious mutations in DNA-repair pathways often respond to PARP inhibitors. Studies were conducted to compare the activity of several PARP inhibitors in vitro and their tissue exposure and in vivo efficacy in mice bearing PC-3M-luc-C6 prostate tumors grown subcutaneously or in bone. Niraparib, olaparib, rucaparib, and talazoparib were compared in proliferation assays, using several prostate tumor cell lines and in a cell-free PARP-trapping assay. PC-3M-luc-C6 cells were approximately 12- to 20-fold more sensitive to PARP inhibition than other prostate tumor lines, suggesting that these cells bear a DNA damage repair defect. The tissue exposure and efficacy of these PARP inhibitors were evaluated in vivo in PC-3M-luc-C6 subcutaneous and bone metastasis tumor models. A steady-state pharmacokinetic study in PC-3M-luc-C6 tumor-bearing mice showed that all of the PARP inhibitors had favorable subcutaneous tumor exposure, but niraparib was differentiated by superior bone marrow exposure compared with the other drugs. In a PC-3M-luc-C6 subcutaneous tumor efficacy study, niraparib, olaparib, and talazoparib inhibited tumor growth and increased survival to a similar degree. In contrast, in the PC-3M-luc-C6 bone metastasis model, niraparib showed the most potent inhibition of bone tumor growth compared with the other therapies (67% vs. 40%–45% on day 17), and the best survival improvement over vehicle control [hazard ratio (HR), 0.28 vs. HR, 0.46–0.59] and over other therapies (HR, 1.68–2.16). These results show that niraparib has superior bone marrow exposure and greater inhibition of tumor growth in bone, compared with olaparib, rucaparib, and talazoparib.
Olfactory Receptor OR2H1 Is an Effective Target for CAR T Cells in Human Epithelial Tumors
Authors: Martin Alexandra L. , Anadon Carmen M. , Biswas Subir , Mine Jessica A. , Handley Katelyn F. , Payne Kyle K. , Mandal Gunjan , Chaurio Ricardo A. , Powers John J. , Sprenger Kimberly B. , Rigolizzo Kristen E. , Innamarato Patrick , Harro Carly M. , Mehta Sumit , Perez Bradford A. , Wenham Robert M. , Conejo-Garcia Jose R. 
Published: May 2022

Abstract
Although chimeric antigen receptor (CAR)-expressing T cells have proven success in hematologic malignancies, their effectiveness in solid tumors has been largely unsuccessful thus far. We found that some olfactory receptors are expressed in a variety of solid tumors of different histologic subtypes, with a limited pattern of expression in normal tissues. Quantification of OR2H1 expression by qRT-PCR and Western blot analysis of 17 normal tissues, 82 ovarian cancers of various histologies, eight non–small cell lung cancers (NSCLCs), and 17 breast cancers demonstrated widespread OR2H1 expression in solid epithelial tumors with expression in normal human tissues limited to the testis. CAR T cells recognizing the extracellular domain of the olfactory receptor OR2H1 were generated with a targeting motif identified through the screening of a phage display library and demonstrated OR2H1-specific cytotoxic killing in vitro and in vivo, using tumor cells with spontaneous expression of variable OR2H1 levels. Importantly, recombinant OR2H1 IgG generated with the VH/VL sequences of the CAR construct specifically detected OR2H1 protein signal in 60 human lung cancers, 40 ovarian carcinomas, and 73 cholangiocarcinomas, at positivity rates comparable with mRNA expression and without OR2H1 staining in 58 normal tissues. CRISPR/Cas9-mediated ablation of OR2H1 confirmed targeting specificity of the CAR and the tumor-promoting role of OR2H1 in glucose metabolism. Therefore, T cells redirected against OR2H1-expressing tumor cells represent a promising therapy against a broad range of epithelial cancers, likely with an admissible toxicity profile.
Colchicine-Binding Site Agent CH-2-77 as a Potent Tubulin Inhibitor Suppressing Triple-Negative Breast Cancer
Authors: Deng Shanshan , Krutilina Raisa I. , Hartman Kelli L. , Chen Hao , Parke Deanna N. , Wang Rui , Mahmud Foyez , Ma Dejian , Lukka Pradeep B. , Meibohm Bernd , Seagroves Tiffany N. , Miller Duane D. , Li Wei 
Published: May 2022

Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive type of breast cancer. Unlike other subtypes of breast cancer, TNBC lacks hormone and growth factor receptor targets. Colchicine-binding site inhibitors (CBSI) targeting tubulin have been recognized as attractive agents for cancer therapy, but there are no CBSI drugs currently FDA approved. CH-2-77 has been reported to have potent antiproliferative activity against a panel of cancer cells in vitro and efficacious antitumor effects on melanoma xenografts, yet, its anticancer activity specifically against TNBC is unknown. Herein, we demonstrate that CH-2-77 inhibits the proliferation of both paclitaxel-sensitive and paclitaxel-resistant TNBC cells with an average IC50 of 3 nmol/L. CH-2-77 also efficiently disrupts the microtubule assembly, inhibits the migration and invasion of TNBC cells, and induces G2–M cell-cycle arrest. The increased number of apoptotic cells and the pattern of expression of apoptosis-related proteins in treated MDA-MB-231 cells suggest that CH-2-77 induces cell apoptosis through the intrinsic apoptotic pathway. In vivo, CH-2-77 shows acceptable overall pharmacokinetics and strongly suppresses the growth of orthotopic MDA-MB-231 xenografts without gross cumulative toxicities when administered 5 times a week. The in vivo efficacy of CH-2-77 (20 mg/kg) is comparable with that of CA4P (28 mg/kg), a CBSI that went through clinical trials. Importantly, CH-2-77 prevents lung metastasis originating from the mammary fat pad in a dose-dependent manner. Our data demonstrate that CH-2-77 is a promising new generation of tubulin inhibitors that inhibit the growth and metastasis of TNBC, and it is worthy of further development as an anticancer agent.
Converting Tumoral PD-L1 into a 4-1BB Agonist for Safer and More Effective Cancer Immunotherapy
Authors: Li Zihai , Azar Joseph H. , Rubinstein Mark P. 
Published: May 2022

Summary:
Dose-limiting toxicities are thought to temper the efficacy of single-agent 4-1BB agonists. To overcome this hurdle, in this issue of Cancer Discovery, Muik and colleagues report preclinical and clinical studies describing a first-in-class bispecific fusion protein targeting 4-1BB and PD-L1.
See related article by Muik et al., p. 1248 (9).
An internet of things-based medication validity monitoring system
Authors: Makki Mohialden Yasmin , Mahmood Hussien Nadia , Jabbar Qabas Abdal Zahraa , Mohammed Mostafa Abduhgafoor , Sutikno Tole 
Published: May 2022

Medicine is <span>critical to our everyday lives and to the well-being of individuals of all ages and backgrounds. With the beginning of the Corona pandemic and a rise in Corona virus infection cases, the use of medications to prevent and recover from infection has increased, as well as to treat illness consequences, has grown. The effectiveness of medicines is greatly influenced by the expiration date. In this paper, a system for pharmacy or medical store's information storage system was developed and enhanced by automatically monitoring the validity of medications on a periodic basis and sending expiry reports to medicine authorities through e-mail to warn them that a medicine is approaching expiration. The system was also enhanced with </span><span lang="EN-ID">internet of thing </span><span>(IoT) for fast and secure delivery of the medicine validity report.</span>
Abstract 116: Platelet-Induced Neutrophil Extracellular Traps Drive Ischemic Stroke Brain Injury
Authors: Denorme Frederik , Portier Irina , Cody Mark J , Neal Matthew D , Rondina Matthew T , Majersik Jennifer J , Yost Christian C , Campbell Robert A 
Published: May 2022

Ischemic stroke prompts a strong inflammatory response which is associated with exacerbated stroke outcomes. However, classic anti-inflammatory strategies have been unsuccessful in stroke patients implying other unknown mechanisms contribute to injurious inflammation in stroke. Increasing evidence suggests immunothrombosis, a process involving coagulation, neutrophil and platelet activation, and neutrophil extracellular trap (NET) formation, is an important contributor to cardiovascular diseases. However, mechanistic regulators of immunothrombosis and their role in ischemic stroke remain unclear.
We examined markers of immunothrombosis in ischemic stroke patients and matched healthy donors. Stroke patients had significantly increased levels of D-Dimers, platelet factor 4, neutrophil calprotectin, citrullinated histone H3 (H3cit) and MPO-DNA complexes, markers of NET formation. In particular, H3cit and MPO-DNA complexes positively correlated with long-term stroke outcomes. Mechanistically, we observed increased plasma and platelet HMGB1 in stroke patients, which significantly correlated with plasma NETs, indicating a role for platelet HMGB1 in NET formation. To directly examine the role of platelet HMGB1, we employed a transient ischemic stroke mouse model. Depleting platelets significantly reduced plasma HMGB1 levels, inhibited NET formation and improved stroke outcomes. Correspondingly, administrating a HMGB1 inhibitor reduced NET formation and improved stroke outcomes, implying a causative role for platelet HMGB1 in mediating NET formation after stroke. As NETs appeared detrimental in ischemic stroke, we investigated the therapeutic potential of an endogenous NET inhibitory factor (NIF), recently discovered in neonates. Mice pretreated with NIF had reduced brain injury, improved neurological and motor function and enhanced survival after stroke. Importantly, NIF specifically blocked NET formation after stroke without affecting brain neutrophil recruitment. Critically, NIF still improved stroke outcomes when administered after stroke onset.
These results support a pathological role for NETs in stroke brain injury and indicate the use of NIF as a therapeutic strategy to target immunothrombosis in stroke.
Combined Associations of Physical Activity and Particulate Matter With Subsequent Cardiovascular Disease Risk Among 5‐Year Cancer Survivors
Authors: Choi Daein , Choi Seulggie , Kim Kyae Hyung , Kim Kyuwoong , Chang Jooyoung , Kim Sung Min , Kim Seong Rae , Cho Yoosun , Lee Gyeongsil , Son Joung Sik , Park Sang Min 
Published: May 2022

Background
The combined associations of physical activity and particulate matter (PM) with subsequent cardiovascular disease (CVD) risk is yet unclear.

Methods and Results

The study population consisted of 18 846 cancer survivors who survived for at least 5 years after initial cancer diagnosis from the Korean National Health Insurance Service database. Average PM levels for 4 years were determined in administrative district areas, and moderate‐to‐vigorous physical activity (MVPA) information was acquired from health examination questionnaires. A multivariable Cox proportional hazards model was used to evaluate the risk for CVD. Among patients with low PM with particles ≤2.5 µm (PM2.5; (19.8–25.6 μg/m
3
) exposure, ≥5 times per week of MVPA was associated with lower CVD risk (adjusted hazard ratio [aHR], 0.77; 95% CI, 0.60–0.99) compared with 0 times per week of MVPA. Also, a higher level of MVPA frequency was associated with lower CVD risk (
P
for trend=0.028) among cancer survivors who were exposed to low PM2.5 levels. In contrast, ≥5 times per week of MVPA among patients with high PM2.5 (25.8–33.8 μg/m
3
) exposure was not associated with lower CVD risk (aHR, 0.98; 95% CI, 0.79–1.21). Compared with patients with low PM2.5 and MVPA ≥3 times per week, low PM2.5 and MVPA ≤2 times per week (aHR, 1.26; 95% CI, 1.03–1.55), high PM2.5 and MVPA ≥3 times per week (aHR, 1.34; 95% CI, 1.07–1.67), and high PM2.5 and MVPA ≤2 times per week (aHR, 1.38; 95% CI, 1.12–1.70) was associated with higher CVD risk.

Conclusions
Cancer survivors who engaged in MVPA ≥5 times per week benefited from lower CVD risk upon low PM2.5 exposure. High levels of PM2.5 exposure may attenuate the risk‐reducing effects of MVPA on the risk of CVD.
Obesity, Galectin‐3, and Incident Heart Failure: The ARIC Study
Authors: Florido Roberta , Kwak Lucia , Echouffo‐Tcheugui Justin B. , Zhang Sui , Michos Erin D. , Nambi Vijay , Goldberg Ronald B. , Hoogeveen Ron C. , Lazo Mariana , Gerstenblith Gary , Post Wendy S. , Blumenthal Roger S. , Coresh Josef , Folsom Aaron R. , Selvin Elizabeth , Ballantyne Christie , Ndumele Chiadi E. 
Published: May 2022

Background
Laboratory data suggest obesity is linked to myocardial inflammation and fibrosis, but clinical data are limited. We aimed to examine the association of obesity with galectin‐3, a biomarker of cardiac inflammation and fibrosis, and the related implications for heart failure (HF) risk.

Methods and Results

We evaluated 8687 participants (mean age 63 years; 21% Black) at ARIC (Atherosclerosis Risk in Communities) Visit 4 (1996–1998) who were free of heart disease. We used adjusted logistic regression to estimate the association of body mass index (BMI) categories with elevated galectin‐3 (≥75th sex‐specific percentile) overall and across demographic subgroups, with tests for interaction. We used Cox proportional hazards models to assess the combined associations of galectin‐3 and BMI with incident HF (through December 31, 2019). Higher BMI was associated with higher odds of elevated galectin‐3 (odds ratio [OR], 2.32; 95% CI, 1.88–2.86) for severe obesity ([BMI ≥35 kg/m
2
] versus normal weight [BMI 18.5‐<25 kg/m
2
]). There were stronger associations of BMI with elevated galectin‐3 among women versus men and White versus Black participants (both
P
‐for‐interaction <0.05). Elevated galectin‐3 was similarly associated with incident HF among people with and without obesity (HR, 1.49; 95% CI, 1.18–1.88; and HR, 1.71; 95% CI, 1.38–2.11, respectively). People with severe obesity and elevated galectin‐3 had >4‐fold higher risk of HF (HR, 4.19; 95% CI, 2.98–5.88) than those with normal weight and galectin‐3 <25th percentile.

Conclusions
Obesity is strongly associated with elevated galectin‐3. Additionally, the combination of obesity and elevated galectin‐3 is associated with marked HF risk, underscoring the importance of elucidating pathways linking obesity with cardiac inflammation and fibrosis.
IV Sotalol Use in Pediatric and Congenital Heart Patients: A Multicenter Registry Study
Authors: Malloy‐Walton Lindsey E. , Von Bergen Nicholas H. , Balaji Seshadri , Fischbach Peter S. , Garnreiter Jason M. , Asaki S. Yukiko , Moak Jeffrey P. , Ochoa Luis A. , Chang Philip M. , Nguyen Hoang H. , Patel Akash R. , Kirk Christa , Sherman Ashley K. , Avari Silva Jennifer N. , Saul J. Philip 
Published: May 2022

Background
There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol.

Methods and Results
A total of 85 patients (age 1 day–36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. Severely decreased cardiac function by echocardiography was seen before IV sotalol in 7 (9%). The average dose was 1 mg/kg (range 0.5–1.8 mg/kg/dose) over a median of 60 minutes (range 30–300 minutes). Successful arrhythmia termination occurred in 31 patients (49%, 95% CI [37%–62%]) with improvement in rhythm control defined as rate reduction permitting overdrive pacing in an additional 18 patients (30%, 95% CI [19%–41%]). Eleven patients (16%) had significant QTc prolongation to >465 milliseconds after the infusion, with 3 (4%) to >500 milliseconds. There were 2 patients (2%) for whom the infusion was terminated early.

Conclusions
IV sotalol was safe and effective for termination or improvement of tachyarrhythmias in 79% of pediatric patients and patients with congenital heart disease, including those with severely depressed cardiac function. The most common dose, for both acute and maintenance dosing, was 1 mg/kg over ~60 minutes with rare serious complications.
Age‐Related Associations of Low‐Density Lipoprotein Cholesterol and Atherosclerotic Cardiovascular Disease: A Nationwide Population‐Based Cohort Study
Authors: Jung Han Na , Kim Min‐Ju , Kim Hwi Seung , Lee Woo Je , Min Se Hee , Kim Ye‐Jee , Jung Chang Hee 
Published: May 2022

Background
The relationship between low‐density lipoprotein cholesterol (LDL‐C) and atherosclerotic cardiovascular disease (ASCVD) according to age remains undetermined. Thus, this study aimed to investigate the age‐related association of LDL‐C and ASCVD.

Methods and Results

Data from the Korean NHIS‐HEALS (National Health Insurance Service‐National Health Screening Cohort) were analyzed. Individuals previously diagnosed with cardiovascular disease or taking lipid‐lowering drugs were excluded. Age‐specific association between LDL‐C and ASCVD was calculated using adjusted Cox proportional hazards models. During a median follow‐up of 6.44 years for 285 119 adults, ASCVD developed in 8996 (3.2%). All age groups showed positive associations between LDL‐C and ASCVD risk, mostly with statistical significance from LDL‐C of 160 mg/dL onward. ASCVD risk did not differ significantly between the age groups (
P
for interaction=0.489). Correspondingly, subgroup analysis in type 2 diabetes exhibited no difference in the age‐specific association of LDL‐C and ASCVD (
P
for interaction=0.784).

Conclusions
The study demonstrated that people aged ≥75 years with higher LDL‐C at baseline still presented increased ASCVD risk, which was not significantly different from the younger groups. These findings support the importance of managing LDL‐C for the prevention of primary ASCVD in the growing elderly population.