bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal and fetal mitochondrial gene dysregulation in hypertensive disorders of pregnancy
Authors: Ricci Contessa A. , Reid Danielle M. , Sun Jie , Santillan Donna A. , Santillan Mark K. , Phillips Nicole R. , Goulopoulou Styliani
Published: May 2023

This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.
Quality Improvement of Dried Anchovies at Three Solar Drying Methods
Authors: Al-Saadi Aaisha , Pathare Pankaj B. , Al-Rizeiqi Mohammed , Al-Bulushi Ismail , Al-Ismaili Abdulrahim
Published: May 2023

Fish drying is one of the traditional methods where the fishermen land their catch on the beaches for drying traditionally under sun for several days. Dried fish provides valuable and economical sources of animal protein. The quality of dried fish is significantly influenced by the presence of microorganisms. Therefore, this study aims to determine the physical quality changes in anchovy under three different solar drying methods which are open sun drying (OSD), solar greenhouse tunnel dryer (GTD), and forced convective solar dryer (FCD) and to verify the chemical and microbial contamination in solar-dried anchovy. About (20 kg) of fresh anchovy were taken for experiments. Quality analyses were conducted in the samples before, during, and after drying. The parameters analyzed included three main analyses which are physical, chemical, and microbial analyses. The drying rate was higher in GTD compared to the two other methods. Moisture content, drying rate, and moisture ratio were significantly affected by drying methods. GTD required less time (6 hr) to dry anchovies compared to other drying methods (9 hr time). The highest reduction in lightness is in GTD dried anchovies followed by FCD and OSD. The drying methods and drying time statistically affect the lightness (L) of dried anchovies (

p
≤
0.05

). The water activity of solar-dried anchovies was 0.3. Experimentally dried anchovies were found to have lower microbial count compared to the dried fish quality standards. The total viable count (TVC) in fresh anchovy was 6.44 log CFU/g compared to the greenhouse tunnel dryer 2.90 log CFU/g, open sun dryer 4.16 log CFU/g, and forced convective dryer 4.19 log CFU/g anchovies. Water activity and moisture content did not affect total viable count (TVC) significantly, but it affects total fungal count (TFC) (

p
≤
0.05

). There was a significant difference on Krusal Wallis between the samples of three methods of drying and a fresh one on the water activity, ash content, and fat content (

p
≤
0.05

).
Effect of Early Nursing Intervention under Amplitude-Integrated Electroencephalography and Magnetic Resonance Images on Brain Injury in Premature Infants
Authors: Liu Aiyan , Zhang Huangai , Guo Wei
Published: May 2023

To investigate the effects of early nursing intervention on brain injury among premature infants, 100 premature infants diagnosed with brain injury were included in the research and randomly divided into the control group (50 cases) and the experimental group (50 cases). The patients in the two groups were performed with the same conventional comprehensive treatment. The patients in the control group received conventional nursing while those in the experimental group underwent early nursing intervention. During follow-up, neurodevelopment, motor behavior, the incidence rate of brain injury, and nursing satisfaction of the infants in the two groups were compared. It was demonstrated that the five neurodevelopment scores of the experimental group were all higher than those of the control group. The differences showed statistical significance (

P
<
0.05

). The total effective rate of motor development of the experimental group reached 94%, while that of the control group amounted to 80%. Obviously, the total effective rate of motor development of the experimental group was higher than that of the control group. The difference was statistically significant (

P
<
0.05

). The nursing satisfaction of the experimental group reached 98%, which was apparently higher than that of the control group (74%). The difference suggested statistical significance (

P
<
0.05

). The rates of brain injury at 1 and 2 years after the birth of the experimental group were 6% and 2%, respectively. The rates of brain injury at 1 and 2 years after the birth of the control group amounted to 18% and 14%, respectively. The rates of brain injury at 1 and 2 years after the birth of the experimental group were lower than those of the control group. The difference revealed statistical significance (

P
<
0.05

). Hence, the early nursing intervention of premature infants with brain injury could promote brain development, improve neurological function, reduce the incidence of brain injury, and achieve an ideal nursing effect.
Feeding Habits and Activity Patterns of Grivet Monkey (Chlorocebus aethiops L.) in Batiero Church Forest, Northern Ethiopia
Authors: Alelign Aschalew , Yonas Meheretu , Moges Eshetu
Published: May 2023

Grivet monkeys (Chlorocebus aethiops) are restricted to fragmented forests where food and space are limiting factors. The study investigated the feeding and activity patterns of grivet monkeys in Batiero Church Forest, northern Ethiopia, using focal and scan sampling techniques. Both focal and scan animal sessions lasted 15 min, with 5 min rest intervals between sessions. During the early dry season, grivet monkeys mainly fed on Acacia sieberiana (26.5%) and Juniperus procera (17.5%). Dry season food selection was significantly different, J. procera (20.5%), Acacia mearnsii (15.6%), A. sieberiana (14.2%), and Cyperus bulbosus (12.7%). The predominant plant parts eaten were seeds (42.6% and 33.3% in early dry and dry seasons, respectively) followed by leaves (34.5% and 22.5% in early dry and dry seasons, respectively). The activity patterns showed no significant seasonal variation, and the most frequent activity was feeding (33.3% and 32.6%, in early dry and dry seasons, respectively). The preferred food source tree species are threatened, and the survival of the grivet monkeys depends on the conservation of indigenous plants and trees.
Design of a Flexible Cylindrical Antenna with Rotatable Curved Frequency Selective Surface for Omnidirectional High-Gain Applications
Authors: Jing Hua , He Ge , Wang Shengyao
Published: May 2023

In this paper, a high-gain flexible cylindrical antenna with rotatable curved frequency selective surface (FSS) is presented, which is designed for the 2.4 GHz industrial scientific medical (ISM) band. The array of 3 × 3 optimized FSS unit cells (102 × 102 mm2) is applied to improve the gain of the antenna (50.4 × 28 × 0.1 mm3). Through the rotation of the FSS, omnidirectional gain enhancement is realized. The simulation and measurement results demonstrate the feasibility of this work. The measured antenna with the FSS has omnidirectional high-gain in the operational band of 2.18–2.90 GHz, and the gain can be increased by 5.31 dBi at most. The antenna can be used in cylindrical conformal devices, and the proposed design method provides a new solution for gain enhancement of cylindrical omnidirectional antennas.
Effect of Nonthermal Plasma on Shear Bond Strength of Translucent Zirconia in Layering Ceramic
Authors: Seyedi Dorsa , Valizadeh Sara , Ghodsi Safoura , Salimi Kimia , Atri Faezeh
Published: May 2023

Background. Today, various methods are used to increase the bond strength of zirconia in layering ceramics. This study evaluated the effects of nonthermal argon plasma on zirconia shear bond strength to layering porcelain. Materials and Method. In this experimental study, 42 square blocks of zirconia were prepared and randomly divided into three groups (n = 14) according to the applying surface treatment: (1) the control group (without any surface treatment), (2) the plasma-treated group with argon nonthermal plasma, and (3) the air abrasion group with 50 µm Al2O3 particles. All samples were layered with porcelain. One sample from each group was evaluated by electron microscopy (SEM) to examine the cross-sectional area of the zirconia–ceramic bond. The rest of the specimens were subjected to thermocycling with 5,000 baths to imitate the aging process in the mouth and then were tested for shear bond strength. The failure pattern of the samples was examined by stereomicroscope. Bond strength data were analyzed by one-way ANOVA test in three groups and Tamhane post hoc test in pairs. The significance level of p-value was considered 0.05. Results. The shear bond strength of the plasma-treated group was significantly higher than the control group (

p
=
0.032

) but the shear bond strength between the sandblast and the plasma-treated group was not significantly different (

p
=
0.656

). The shear bond strength between the sandblast and the control group was also not significant (

p
=
0.202

). Regarding the mode of failure, failures were mostly adhesive and then mixed. Examination of the samples under SEM showed that the bond area is the thickest in the sandblast group and also the surface roughness is the highest in the sandblast group and the lowest in the control group. Conclusion. This study demonstrated that the use of nonthermal argon plasma treatment is an effective way to enhance the quality and quantity of shear bond strength between layering porcelain and zirconia.
Cardioprotective Effects of Insect Apis melifera‐Based Complementary Foods Using an In Vivo Mouse Model
Authors: Mekuria Shewangzaw Addisu , Mokua Beatrice Kiage , Tenagashaw Mesfin Wogayehu , Kinyuru John N.
Published: May 2023

Background. Cardiovascular disease is the cause of one‐third of deaths worldwide because of increased risk factors, such as intake of cholesterol and saturated fat. Atherosclerosis begins in childhood; therefore, nutritional prevention should begin at an early stage. This study assessed the lipid profile, atherogenic, and castill’s risk index intake of Apis melifera‐based complementary foods using an in vivo mouse model. Methods. The experiment was conducted for 28 days. A total of 75 male white albino mice were randomly assigned to five diets in triplicate. The diets were Diet 1 = casein diet; Diet 2 = (57% maize, 29% teff, 14% soybean); Diet 3 = (58% maize, 29% teff, 13% bee larvae); Diet 4 = commercial wean mix; Diet 5 = basal diet alone. Mouse blood samples were collected by cardiac puncture. The lipid profiles of TC, TG, HDL‐C, and LDL‐C were analysed using an automated pentra C400 made in France. Results. Biochemical (mg/dl) parameters showed that mice fed Diet 3 had high (P ≤ 0.001), TG (167.79), HDL‐C (67.18), and low LDL‐C (71.73) levels. The atherogenic indices CRI‐I (1.84), CRI‐II (1.07), and AC (0.84) were low in Diet 3. The atherogenicity indices showed a significant positive correlation (P ≤ 0.001) with one another as follows: CRI‐I vs. CRI‐II (r = 0.919), CRI‐I vs. AC (r = 1), and CRI‐II vs. AC (r = 0.919). Conclusion. The results of the present investigation confirm that intake of an Apis mellifera‐based diet could prevent children from atherosclerotic cardiovascular disease in a mouse model.
Image Dehazing Based on Improved Color Channel Transfer and Multiexposure Fusion
Authors: Ma Shaojin , Pan Weiguo , Liu Hongzhe , Dai Songyin , Xu Bingxin , Xu Cheng , Li Xuewei , Guan Huaiguang
Published: May 2023

Image dehazing is one of the problems that need to be solved urgently in the field of computer vision. In recent years, more and more algorithms have been applied to image dehazing and achieved good results. However, the image after dehazing still has color distortion, contrast and saturation disorder, and other challenges; in order to solve these problems, in this paper, an effective image dehazing method is proposed, which is based on improved color channel transfer and multiexposure image fusion to achieve image dehazing. First, the image is preprocessed using a color channel transfer method based on k-means. Second, gamma correction is introduced on the basis of guided filtering to obtain a series of multiexposure images, and the obtained multiexposure images are fused into a dehazed image through a Laplacian pyramid fusion scheme based on local similarity of adaptive weights. Finally, contrast and saturation corrections are performed on the dehazed image. Experimental verification is carried out on synthetic dehazed images and natural dehazed images, and it is verified that the method proposed is superior to existing dehazed algorithms from both subjective and objective aspects.
FigureS1-S11 from ASS1-Mediated Reductive Carboxylation of Cytosolic Glutamine Confers Ferroptosis Resistance in Cancer Cells
Authors: Hu Qiangsheng , Dai Jie , Zhang Zheng , Yu Huansha , Zhang Jing , Zhu Xinsheng , Qin Yi , Zhang Lele , Zhang Peng
Published: May 2023

Supplementary Figures and Figure Legends
Supplementary Figure 4 from Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines
Authors: Schwörer Simon , Cimino Francesco V. , Ros Manon , Tsanov Kaloyan M. , Ng Charles , Lowe Scott W. , Carmona-Fontaine Carlos , Thompson Craig B.
Published: May 2023

Supplementary Figure 4, related to Figures 4 and 6
Supplementary Figure 2 from Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell–Derived Cytokines
Authors: Schwörer Simon , Cimino Francesco V. , Ros Manon , Tsanov Kaloyan M. , Ng Charles , Lowe Scott W. , Carmona-Fontaine Carlos , Thompson Craig B.
Published: May 2023

Supplementary Figure 2, related to Figure 2
Supplementary Fig. S3 from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: May 2023

Quality control analysis of scRNA-seq.
Supplementary Data from Single-Cell Spatial Analysis Identifies Regulators of Brain Tumor–Initiating Cells
Authors: Mirzaei Reza , D'Mello Charlotte , Liu Marina , Nikolic Ana , Kumar Mehul , Visser Frank , Bose Pinaki , Gallo Marco , Yong V. Wee
Published: May 2023

Legends of Supplementary figures and tables.
Turning Down Oxygen to Turn Up Inflammation in CAFs
Authors: Fuentes Natividad R. , Taniguchi Cullen M.
Published: May 2023

Pancreatic ductal adenocarcinoma (PDAC) contains a desmoplastic stroma that limits blood perfusion and thus the delivery of nutrients, oxygen, and even therapeutics, creating a hypoxic microenvironment that resists nearly all forms of treatment, including immunomodulating therapy. Cancer-associated fibroblasts (CAF) are the main cellular components and producers of stroma in PDAC. Interestingly, CAFs exist as functionally diverse subpopulations derived from distinct lineages, some of which can be either inflammatory (iCAF) or myofibroblastic (myCAF). While previous work has suggested a link between hypoxia and the iCAF phenotype, direct experimental evidence is lacking. In this issue of Cancer Research, Schwörer and colleagues investigate the role of hypoxia and hypoxia-inducible factor-1α (HIF1α) in maintaining fibroblast heterogeneity and promoting tumor progression in PDAC. The authors use a combination of in vitro and orthotopic techniques to identify a strong role for hypoxia in combination with tumor-derived cytokines in maintaining an iCAF phenotype highlighted by IL6 expression. The authors use an innovative in vitro system to simulate oxygen gradients and use these methods to support their assertions regarding hypoxia as a proinflammatory state. These findings suggest that HIF1α promotes the generation of iCAFs, providing novel insight into CAF heterogeneity.

See related article by Schwörer et al., p. 1596
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: May 2023

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.
Supplementary Data 1 from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

Supplementary Data: Methods and tables.
Supplementary Figure S4 from Duvelisib Eliminates CLL B Cells, Impairs CLL-Supporting Cells, and Overcomes Ibrutinib Resistance in a Xenograft Model
Authors: Chen Shih-Shih , Barrientos Jacqueline C. , Ferrer Gerardo , King-Richards Morgan , Chen Yu-Ju , Ravichandran Priyadarshini , Ibrahim Michael , Kieso Yasmine , Waters Sheila , Kutok Jeffery L. , Peluso Marisa , Sharma Sujata , Weaver David T. , Pachter Jonathan A. , Rai Kanti R. , Chiorazzi Nicholas
Published: May 2023

Distinct actions of PI3K-δ and PI3K-γ on human cytokines in PDX model of U-CLL and M-CLL patients.
Figure S2 from Immunologic Predictors for Clinical Responses during Immune Checkpoint Blockade in Patients with Myelodysplastic Syndromes
Authors: Lee Sung-Eun , Wang Feng , Grefe Maison , Trujillo-Ocampo Abel , Ruiz-Vasquez Wilfredo , Takahashi Koichi , Abbas Hussein A. , Borges Pamella , Antunes Dinler Amaral , Al-Atrash Gheath , Daver Naval , Molldrem Jeffrey J. , Futreal Andrew , Garcia-Manero Guillermo , Im Jin S.
Published: May 2023

Figure S2. Schema for study design
Supplementary Table S1 from Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis
Authors: Liam Chong Kin , Ahmad Azura Rozila , Hsia Te-Chun , Zhou Jianying , Kim Dong-Wan , Soo Ross Andrew , Cheng Ying , Lu Shun , Shin Sang Won , Yang James Chih-Hsin , Zhang Yiping , Zhao Jun , Berghoff Karin , Bruns Rolf , Johne Andreas , Wu Yi-Long
Published: May 2023

Demographic data of all individuals enrolled
Figure S1 from Immunologic Predictors for Clinical Responses during Immune Checkpoint Blockade in Patients with Myelodysplastic Syndromes
Authors: Lee Sung-Eun , Wang Feng , Grefe Maison , Trujillo-Ocampo Abel , Ruiz-Vasquez Wilfredo , Takahashi Koichi , Abbas Hussein A. , Borges Pamella , Antunes Dinler Amaral , Al-Atrash Gheath , Daver Naval , Molldrem Jeffrey J. , Futreal Andrew , Garcia-Manero Guillermo , Im Jin S.
Published: May 2023

Figure S1. Information on treatment and available testing results for analysis
Supplementary Data1 from Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma
Authors: Chavez Julio C. , Foss Francine M. , William Basem M. , Brammer Jonathan E. , Smith Sonali M. , Prica Anca , Zain Jasmine M. , Tuscano Joseph M. , Shah Harsh , Mehta-Shah Neha , Geethakumari Praveen Ramakrishnan , Wang Ben X. , Zantinge Stephanie , Wang Lisa , Zhang Ling , Boutrin Anmarie , Zhao Weiguang , Cheng Lily , Standifer Nathan , Hewitt Lisa , Enowtambong Enowmpey , Shao Weiping , Sharma Shringi , Carlesso Gianluca , Moscow Jeffrey A. , Siu Lillian L.
Published: May 2023

Supplemental Tables and Protocol Description
Supplementary Figure S2 from Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis
Authors: Liam Chong Kin , Ahmad Azura Rozila , Hsia Te-Chun , Zhou Jianying , Kim Dong-Wan , Soo Ross Andrew , Cheng Ying , Lu Shun , Shin Sang Won , Yang James Chih-Hsin , Zhang Yiping , Zhao Jun , Berghoff Karin , Bruns Rolf , Johne Andreas , Wu Yi-Long
Published: May 2023

Duration of PFS in the patient subgroup with MET amplification
Supplementary Figure S1 from Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis
Authors: Liam Chong Kin , Ahmad Azura Rozila , Hsia Te-Chun , Zhou Jianying , Kim Dong-Wan , Soo Ross Andrew , Cheng Ying , Lu Shun , Shin Sang Won , Yang James Chih-Hsin , Zhang Yiping , Zhao Jun , Berghoff Karin , Bruns Rolf , Johne Andreas , Wu Yi-Long
Published: May 2023

Outcomes of treatment for all individuals enrolled
Figure S4 from Quiescent Ovarian Cancer Cells Secrete Follistatin to Induce Chemotherapy Resistance in Surrounding Cells in Response to Chemotherapy
Authors: Cole Alexander J. , Panesso-Gómez Santiago , Shah Jaynish S. , Ebai Tonge , Jiang Qi , Gumusoglu-Acar Ece , Bello Maya G. , Vlad Anda , Modugno Francesmary , Edwards Robert P. , Buckanovich Ronald J.
Published: May 2023

Supplementary Figure 4. The effect of ATF2 siRNA on gene expression and PT340 FST induced chemoresistance. A. Schematic detailing the transwell experiments. CellTrace Violet cells were sorted for rapidly dividing (Dim) or quiescent cells (Bright) which were then plated in transwell chambers either as Dim:Dim or Bright:Dim. Cells were untreated or treated with taxol alone or in combination with IgG or anti-FST antibody. Cell counts were performed on the dim cells and data was expressed as fold chnage. B. Relative ATF2 gene expression of PT412 and PT340 treated with scrambled siRNA or two independent ATF2 siRNAs (ATF2 siRNA #1 and #2). C. Viable cell number of PT340 cells treated with control scrambled siRNA or knocked down with ATF2 siRNA and treated with cisplatin +/- FST. *P<0.05, ns = not significant.
Figure S1 from PSMA-positive Circulating Tumor Cell Detection and Outcomes with Abiraterone or Enzalutamide Treatment in Men with Metastatic Castrate-resistant Prostate Cancer
Authors: Gupta Santosh , Halabi Susan , Yang Qian , Roy Akash , Tubbs Alisa , Gore Yamini , George Daniel J. , Nanus David M. , Antonarakis Emmanuel S. , Danila Daniel C. , Szmulewitz Russell Z. , Wenstrup Richard , Armstrong Andrew J.
Published: May 2023

PSMA protein expression distribution from men with mCRPC at a single cell CTC level before (baseline, N= 97) and after (progression, N= 57) abiraterone or enzalutamide therapy.
Supplementary Table S2 from Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial
Authors: Gulati Shuchi , Crist McKenzie , Riaz Muhammed Kashif , Takiar Vinita , Lehn Maria , Monroe Ilaina , Palackdharry Sarah , Kurtzweil Nicky , Jandarov Roman , Harun Nusrat , Wise-Draper Trisha M.
Published: May 2023

All treatment-related adverse events on trial
Supplementary Figure S6 from Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial
Authors: Gulati Shuchi , Crist McKenzie , Riaz Muhammed Kashif , Takiar Vinita , Lehn Maria , Monroe Ilaina , Palackdharry Sarah , Kurtzweil Nicky , Jandarov Roman , Harun Nusrat , Wise-Draper Trisha M.
Published: May 2023

Supplementary Figure 6. Comparison of outcomes between patients that were p16 positive vs. negative A) Progression-free survival and B) Overall survival comparison
Supplementary Figure S2 from Safety and Efficacy of Axicabtagene Ciloleucel versus Standard of Care in Patients 65 Years of Age or Older with Relapsed/Refractory Large B-Cell Lymphoma
Authors: Westin Jason R. , Locke Frederick L. , Dickinson Michael , Ghobadi Armin , Elsawy Mahmoud , van Meerten Tom , Miklos David B. , Ulrickson Matthew L. , Perales Miguel-Angel , Farooq Umar , Wannesson Luciano , Leslie Lori , Kersten Marie José , Jacobson Caron A. , Pagel John M. , Wulf Gerald , Johnston Patrick , Rapoport Aaron P. , Du Linqiu , Vardhanabhuti Saran , Filosto Simone , Shah Jina , Snider Julia T. , Cheng Paul , To Christina , Oluwole Olalekan O. , Sureda Anna
Published: May 2023

Overall survival (interim) and progression-free survival in patients ≥70 years
Figure S1 from The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma
Authors: Schober Sebastian Johannes , Schoening Caroline , Eck Jennifer , Middendorf Charlotte , Lutsch Julia , Knoch Pia , von Ofen Anna Josefine , Gassmann Hendrik , Thiede Melanie , Hauer Julia , Kolk Andreas , Mantwill Klaus , Gschwend Jürgen E. , Burdach Stefan E.G. , Nawroth Roman , Thiel Uwe , Holm Per Sonne
Published: May 2023

Supplemental Figure 1: Combination of XVir-N-31 and CDK4/6 inhibition increases oncolysis, viral particle formation associated by RB downregulation.
Data from Durvalumab plus Cetuximab in Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: An Open-label, Nonrandomized, Phase II Clinical Trial
Authors: Gulati Shuchi , Crist McKenzie , Riaz Muhammed Kashif , Takiar Vinita , Lehn Maria , Monroe Ilaina , Palackdharry Sarah , Kurtzweil Nicky , Jandarov Roman , Harun Nusrat , Wise-Draper Trisha M.
Published: May 2023

AbstractPurpose:
The efficacy of cetuximab is poor in metastatic head and neck squamous cell carcinoma (HNSCC). Cetuximab initiates natural killer (NK) cell–mediated antibody-dependent cellular cytotoxicity, with resultant recruitment of immune cells and suppression of antitumor immunity. We hypothesized that adding an immune-checkpoint inhibitor (ICI) could overcome this and lead to an enhanced antitumor response.
Patients and Methods:
A phase II study of cetuximab and durvalumab in metastatic HNSCC was conducted. Eligible patients had measurable disease. Patients who had received both cetuximab and an ICI were excluded. The primary endpoint was objective response rate (ORR) by RECIST 1.1 at 6 months.
Results:
As of April 2022, 35 patients enrolled, of whom 33 received at least 1 dose of durvalumab and were included in the response analysis. Eleven patients (33%) had received prior platinum-based chemotherapy, 10 an ICI (30%), and 1 patient (3%) cetuximab. ORR was 39% (13/33) with a median duration of response of 8.6 months [95% confidence interval (CI): 6.5–16.8]. Median progression-free and overall survivals were 5.8 months (95% CI: 3.7–14.1) and 9.6 months (95% CI: 4.8–16.3), respectively. There were 16 grade 3 treatment-related adverse events (TRAE) and one grade 4 TRAE, with no treatment-related deaths. Overall and progression-free survival did not correlate with PD-L1 status. NK cell cytotoxic activity was increased by cetuximab and further increased with the addition of durvalumab in responders.
Conclusions:
The combination of cetuximab and durvalumab demonstrated durable activity with a tolerable safety profile in metastatic HNSCC and warrants further investigation.
Data from The Oncolytic Adenovirus XVir-N-31 Joins Forces with CDK4/6 Inhibition Augmenting Innate and Adaptive Antitumor Immunity in Ewing Sarcoma
Authors: Schober Sebastian Johannes , Schoening Caroline , Eck Jennifer , Middendorf Charlotte , Lutsch Julia , Knoch Pia , von Ofen Anna Josefine , Gassmann Hendrik , Thiede Melanie , Hauer Julia , Kolk Andreas , Mantwill Klaus , Gschwend Jürgen E. , Burdach Stefan E.G. , Nawroth Roman , Thiel Uwe , Holm Per Sonne
Published: May 2023

AbstractPurpose:
Ewing sarcoma (EwS) is a highly malignant pediatric tumor characterized by a non-T-cell-inflamed immune-evasive phenotype. When relapsed or metastasized, survival is poor, emphasizing the need for novel treatment strategies. Here, we analyze the novel combination approach using the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition to augment EwS immunogenicity.
Experimental Design:
In vitro, viral toxicity, replication, and immunogenicity were studied in several EwS cell lines. In vivo tumor xenograft models with transient humanization were applied to evaluate tumor control, viral replication, immunogenicity, and dynamics of innate as well as human T cells after treatment with XVir-N-31 combined with CDK4/6 inhibition. Furthermore, immunologic features of dendritic cell maturation and T-cell-stimulating capacities were assessed.
Results:
The combination approach significantly increased viral replication and oncolysis in vitro, induced HLA-I upregulation, and IFNγ-induced protein 10 expression and enhanced maturation of monocytic dendritic cells with superior capacities to stimulate tumor antigen-specific T cells. These findings were confirmed in vivo showing tumor infiltration by (i) monocytes with antigen-presenting capacities and M1 macrophage marker genes, (ii) TReg suppression in spite of adenovirus infection, (iii) superior engraftment, and (iv) tumor infiltration by human T cells. Consequently, survival was improved over controls with signs of an abscopal effect after combination treatment.
Conclusions:
The joint forces of the YB-1-driven oncolytic adenovirus XVir-N-31 and CDK4/6 inhibition induce therapeutically relevant local and systemic antitumor effects. Innate as well as adaptive immunity against EwS is boosted in this preclinical setting, pointing toward high therapeutic potential in the clinic.
Data from Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy
Authors: Bidkar Anil P. , Wang Sinan , Bobba Kondapa Naidu , Chan Emily , Bidlingmaier Scott , Egusa Emily A. , Peter Robin , Ali Umama , Meher Niranjan , Wadhwa Anju , Dhrona Suchi , Dasari Chandrashekhar , Beckford-Vera Denis , Su Yang , Tang Ryan , Zhang Li , He Jiang , Wilson David M. , Aggarwal Rahul , VanBrocklin Henry F. , Seo Youngho , Chou Jonathan , Liu Bin , Flavell Robert R.
Published: May 2023

AbstractPurpose:
Radiopharmaceutical therapy is changing the standard of care in prostate cancer and other malignancies. We previously reported high CD46 expression in prostate cancer and developed an antibody–drug conjugate and immunoPET agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. Here, we present the preparation, preclinical efficacy, and toxicity evaluation of [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody.
Experimental Design:
[225Ac]DOTA-YS5 was developed, and its therapeutic efficiency was tested on cell-derived (22Rv1, DU145), and patient-derived (LTL-545, LTL484) prostate cancer xenograft models. Biodistribution studies were carried out on 22Rv1 tumor xenograft models to confirm the targeting efficacy. Toxicity analysis of the [225Ac]DOTA-YS5 was carried out on nu/nu mice to study short-term (acute) and long-term (chronic) toxicity.
Results:
Biodistribution study shows that [225Ac]DOTA-YS5 agent delivers high levels of radiation to the tumor tissue (11.64% ± 1.37%ID/g, 28.58% ± 10.88%ID/g, 29.35% ± 7.76%ID/g, and 31.78% ± 5.89%ID/g at 24, 96, 168, and 408 hours, respectively), compared with the healthy organs. [225Ac]DOTA-YS5 suppressed tumor size and prolonged survival in cell line–derived and patient-derived xenograft models. Toxicity analysis revealed that the 0.5 μCi activity levels showed toxicity to the kidneys, likely due to redistribution of daughter isotope 213Bi.
Conclusions:
[225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including prostate-specific membrane antigen–positive and prostate-specific membrane antigen–deficient models. Overall, this preclinical study confirms that [225Ac]DOTA-YS5 is a highly effective treatment and suggests feasibility for clinical translation of CD46-targeted radioligand therapy in prostate cancer.
Data from Randomized Trial of Tepotinib Plus Gefitinib versus Chemotherapy in EGFR-Mutant NSCLC with EGFR Inhibitor Resistance Due to MET Amplification: INSIGHT Final Analysis
Authors: Liam Chong Kin , Ahmad Azura Rozila , Hsia Te-Chun , Zhou Jianying , Kim Dong-Wan , Soo Ross Andrew , Cheng Ying , Lu Shun , Shin Sang Won , Yang James Chih-Hsin , Zhang Yiping , Zhao Jun , Berghoff Karin , Bruns Rolf , Johne Andreas , Wu Yi-Long
Published: May 2023

AbstractPurpose:
The final analyses of the INSIGHT phase II study evaluating tepotinib (a selective MET inhibitor) plus gefitinib versus chemotherapy in patients with MET-altered EGFR-mutant NSCLC (data cut-off: September 3, 2021).
Patients and Methods:
Adults with advanced/metastatic EGFR-mutant NSCLC, acquired resistance to first-/second-generation EGFR inhibitors, and MET gene copy number (GCN) ≥5, MET:CEP7 ≥2, or MET IHC 2+/3+ were randomized to tepotinib 500 mg (450 mg active moiety) plus gefitinib 250 mg once daily, or chemotherapy. Primary endpoint was investigator-assessed progression-free survival (PFS). MET-amplified subgroup analysis was preplanned.
Results:
Overall (N = 55), median PFS was 4.9 months versus 4.4 months [stratified HR, 0.67; 90% CI, 0.35–1.28] with tepotinib plus gefitinib versus chemotherapy. In 19 patients with MET amplification (median age 60.4 years; 68.4% never-smokers; median GCN 8.8; median MET/CEP7 2.8; 89.5% with MET IHC 3+), tepotinib plus gefitinib improved PFS (HR, 0.13; 90% CI, 0.04–0.43) and overall survival (OS; HR, 0.10; 90% CI, 0.02–0.36) versus chemotherapy. Objective response rate was 66.7% with tepotinib plus gefitinib versus 42.9% with chemotherapy; median duration of response was 19.9 months versus 2.8 months. Median duration of tepotinib plus gefitinib was 11.3 months (range, 1.1–56.5), with treatment >1 year in six (50.0%) and >4 years in three patients (25.0%). Seven patients (58.3%) had treatment-related grade ≥3 adverse events with tepotinib plus gefitinib and five (71.4%) had chemotherapy.
Conclusions:
Final analysis of INSIGHT suggests improved PFS and OS with tepotinib plus gefitinib versus chemotherapy in a subgroup of patients with MET-amplified EGFR-mutant NSCLC, after progression on EGFR inhibitors.
Efficacy and Imaging-Enabled Pharmacodynamic Profiling of KRAS G12C Inhibitors in Xenograft and Genetically Engineered Mouse Models of Cancer
Authors: Lee Catherine , Jiang Ziyue Karen , Planken Simon , Manzuk Lisa K. , Ortiz Roberto , Hall Michael , Noorbehesht Kavon , Ram Sripad , Affolter Timothy , Troche Gabriel E. , Ihle Nathan T. , Johnson Theodore , Ahn Youngwook , Kraus Manfred , Giddabasappa Anand
Published: May 2023

KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non–small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.
Atrial Fibrillation Ablation in Young Adults: Measuring Quality of Life Using Patient-Reported Outcomes Over 5 Years
Authors: Johnson Brett M. , Wazni Oussama M. , Farwati Medhat , Saliba Walid I. , Santangeli Pasquale , Madden Ruth , Bouscher Patricia , Chung Mina , Kanj Mohamed , Dresing Thomas J. , Callahan Thomas D. , Bhargava Mandeep , Baranowski Bryan , Rickard John , Cantillon Daniel J. , Tchou Patrick J. , Sroubek Jakub , Nakagawa Hiroshi , Hussein Ayman A.
Published: May 2023

Background:

Ablation is used for both rhythm control and improved quality of life (QoL) in atrial fibrillation (AF). It has been suggested that young adults may experience high recurrence rates after ablation and data remain lacking regarding QoL benefits. We aimed to investigate AF ablation outcomes and QoL benefits in young adults undergoing AF ablation using a large prospectively maintained registry and automated patient-reported outcomes (PRO).

Methods:

All patients undergoing AF ablation (2013–2016) at our center were prospectively enrolled. Patients aged 50 years or younger were included. For PROs, QoL measures and symptoms were assessed at baseline, 3 months after ablation, and every 6 months thereafter. The AF severity score served as the main assessment of QoL.

Results:

A total of 241 young adults (age, 16–50 years) were included (17% female, 40.3% persistent AF). In all, 77.2% of patients remained arrhythmia-free during the first year of follow-up (80% in nonstructural AF and 66% in structural AF). Using PROs, 90% of patients reported improvement in QoL throughout all survey time points up to 5 years postablation (
P
<0.0001). The baseline median AF severity score was 14 and improved to between 2 and 4 on all follow-up after ablation (
P
<0.0001). Patients also reported fewer and shorter AF episodes, fewer emergency room visits secondary to AF, and fewer hospitalizations (
P
<0.0001).

Conclusions:

Ablation remains an effective rhythm-control strategy in young adults with AF. Young adults also experience significant improvement in QoL with reduction of the frequency and duration of AF episodes and AF-related healthcare utilization.
Progressive Cardiac Metabolic Defects Accompany Diastolic and Severe Systolic Dysfunction in Spontaneously Hypertensive Rat Hearts
Authors: Li Jie , Minczuk Krzysztof , Huang Qiao , Kemp Brandon A. , Howell Nancy L. , Chordia Mahendra D. , Roy R. Jack , Patrie James T. , Qureshi Zoraiz , Kramer Christopher M. , Epstein Frederick H. , Carey Robert M. , Kundu Bijoy K. , Keller Susanna R.
Published: May 2023

Background

Cardiac metabolic abnormalities are present in heart failure. Few studies have followed metabolic changes accompanying diastolic and systolic heart failure in the same model. We examined metabolic changes during the development of diastolic and severe systolic dysfunction in spontaneously hypertensive rats (SHR).

Methods and Results

We serially measured myocardial glucose uptake rates with dynamic 2‐[
18
F] fluoro‐2‐deoxy‐
d
‐glucose positron emission tomography in vivo in 9‐, 12‐, and 18‐month‐old SHR and Wistar Kyoto rats. Cardiac magnetic resonance imaging determined systolic function (ejection fraction) and diastolic function (isovolumetric relaxation time) and left ventricular mass in the same rats. Cardiac metabolomics was performed at 12 and 18 months in separate rats. At 12 months, SHR hearts, compared with Wistar Kyoto hearts, demonstrated increased isovolumetric relaxation time and slightly reduced ejection fraction indicating diastolic and mild systolic dysfunction, respectively, and higher (versus 9‐month‐old SHR decreasing) 2‐[
18
F] fluoro‐2‐deoxy‐
d
‐glucose uptake rates (Ki). At 18 months, only few SHR hearts maintained similar abnormalities as 12‐month‐old SHR, while most exhibited severe systolic dysfunction, worsening diastolic function, and markedly reduced 2‐[
18
F] fluoro‐2‐deoxy‐
d
‐glucose uptake rates. Left ventricular mass normalized to body weight was elevated in SHR, more pronounced with severe systolic dysfunction. Cardiac metabolite changes differed between SHR hearts at 12 and 18 months, indicating progressive defects in fatty acid, glucose, branched chain amino acid, and ketone body metabolism.

Conclusions

Diastolic and severe systolic dysfunction in SHR are associated with decreasing cardiac glucose uptake, and progressive abnormalities in metabolite profiles. Whether and which metabolic changes trigger progressive heart failure needs to be established.
Sodium‐Glucose Cotransporter‐2 Inhibitor Prevents Stroke in Patients With Diabetes and Atrial Fibrillation
Authors: Chang Sheng‐Nan , Chen Jien‐Jiun , Huang Pang‐Shuo , Wu Cho‐Kai , Wang Yi‐Chih , Hwang Juey‐Jen , Tsai Chia‐Ti
Published: May 2023

Background

Atrial fibrillation (AF) is associated with increasing risk of thromboembolic or ischemic stroke. The CHA
2
DS
2
‐VASc score is a well‐established predictor of AF stroke. Patients with AF have an increased risk of stroke if they have diabetes. Use of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i) has been shown to be associated with favorable cardiovascular outcomes in patients with diabetes. It was unknown whether use of SGLT2i decreased stroke risk in patients with AF who have diabetes.

Methods and Results

A total of 9116 patients with AF and diabetes from the National Taiwan University historical cohort were longitudinally followed up for 5 years (January 2016–December 2020). The risk of stroke related to SGLT2i use was evaluated by Cox model, adjusting CHA
2
DS
2
‐VASc score in the propensity score–matched population with 474 SGLT2i users and 3235 nonusers. Adverse thromboembolic end points during follow‐up were defined as ischemic stroke. The mean age was 73.2±10.5 years, and 61% of patients were men. There were no significant differences of baseline characteristics between users and nonusers of SGLT2i, including CHA
2
DS
2
‐VASc score in the propensity score–matched population. The stroke rate was 3.4% (95% CI, 2.8–4.2) patient‐years in SGLT2i users and 4.3% (95% CI, 4.0–4.6) in nonusers (
P
=0.021). SGLT2i users had a 20% reduction of stroke (hazard ratio, 0.80 [95% CI, 0.64–0.99];
P
=0.043) after adjustment for the CHA
2
DS
2
‐VASc score.

Conclusions

Use of SGLT2i was associated with a lower stroke risk in patients with diabetes and AF, and it may be considered to escalate SGLT2i to the first‐line treatment in patients with diabetes and AF.
Hemodynamic Effects of Ketone Bodies in Patients With Pulmonary Hypertension
Authors: Nielsen Roni , Christensen Kristian Hylleberg , Gopalasingam Nigopan , Berg‐Hansen Kristoffer , Seefeldt Jacob , Homilius Casper , Boedtkjer Ebbe , Andersen Mads Jønsson , Wiggers Henrik , Møller Niels , Bøtker Hans Erik , Mellemkjær Søren
Published: May 2023

Background

Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3‐hydroxybutyrate (3‐OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3‐OHB in patients with PAH or CTEPH.

Methods and Results

We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3‐OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3‐OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague–Dawley rats. Ketone body infusion increased circulating 3‐OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (
P
<0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%,
P
<0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%,
P
=0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%,
P
<0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3‐OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%,
P
<0.001) and had no effect on right ventricular systolic pressures (
P
=0.63), whereas pressures rose at a slower pace (dP/dtmax,
P
=0.02).

Conclusions

In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long‐term studies are warranted to assess the clinical role of hyperketonemia.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04615754.
Feasibility of Lipid Screening During First Trimester of Pregnancy to Identify Women at Risk of Severe Dyslipidemia
Authors: Golwala Sohil , Dolin Cara D. , Nemiroff Richard , Soffer Daniel , Denduluri Srinivas , Jacoby Douglas , Lewey Jennifer
Published: May 2023

Background

Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease, especially when disease presents at a young age. Despite national screening guidelines to perform a lipid profile test in children and young adults, many reproductive‐age women have not undergone lipid screening. Our objective was to assess the feasibility of lipid screening during the first trimester of pregnancy as a strategy to increase lipid screening rates among women receiving prenatal care.

Methods and Results

A nonfasting lipid panel was incorporated into routine prenatal care among obstetricians at a single academic clinic. Educational materials and a clinical referral pathway were developed for patients with abnormal results. Over 6 months, 445 patients had a first prenatal care visit. Of the 358 patients who completed laboratory testing, 236 (66%) patients completed lipid testing. Overall, 59 (25%) patients had abnormal results. One patient with previously undiagnosed suspected familial hypercholesterolemia was identified. Barriers to ordering lipid tests included the burden of reviewing additional laboratory results and uncertainty about patient counseling.

Conclusions

Implementation of nonfasting lipid screening as part of routine prenatal care during the first trimester is feasible and may play a crucial role in timely diagnosis and management of lipid disorders in women of reproductive age. Future work should focus on optimizing health system workflow to minimize burden on clinical staff and facilitate follow‐up with appropriate specialists.