bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Identifying Good Candidates for Active Surveillance of Ductal Carcinoma In Situ: Insights from a Large Neoadjuvant Endocrine Therapy Cohort
Authors: Glencer Alexa C. , Miller Phoebe N. , Greenwood Heather , Maldonado Rodas Cristian K. , Freimanis Rita , Basu Amrita , Mukhtar Rita A. , Brabham Case , Kim Paul , Hwang E. Shelley , Rosenbluth Jennifer M. , Hirst Gillian L. , Campbell Michael J. , Borowsky Alexander D. , Esserman Laura J.
Published: April 2023

Ductal carcinoma in situ (DCIS) is a biologically heterogenous entity with uncertain risk for invasive ductal carcinoma (IDC) development. Standard treatment is surgical resection often followed by radiation. New approaches are needed to reduce overtreatment. This was an observational study that enrolled patients with DCIS who chose not to pursue surgical resection from 2002 to 2019 at a single academic medical center. All patients underwent breast MRI exams at 3- to 6-month intervals. Patients with hormone receptor–positive disease received endocrine therapy. Surgical resection was strongly recommended if clinical or radiographic evidence of disease progression developed. A recursive partitioning (R-PART) algorithm incorporating breast MRI features and endocrine responsiveness was used retrospectively to stratify risk of IDC. A total of 71 patients were enrolled, 2 with bilateral DCIS (73 lesions). A total of 34 (46.6%) were premenopausal, 68 (93.2%) were hormone-receptor positive, and 60 (82.1%) were intermediate- or high-grade lesions. Mean follow-up time was 8.5 years. Over half (52.1%) remained on active surveillance without evidence of IDC with mean duration of 7.4 years. Twenty patients developed IDC, of which 6 were HER2 positive. DCIS and subsequent IDC had highly concordant tumor biology. Risk of IDC was characterized by MRI features after 6 months of endocrine therapy exposure; low-, intermediate-, and high-risk groups were identified with respective IDC rates of 8.7%, 20.0%, and 68.2%. Thus, active surveillance consisting of neoadjuvant endocrine therapy and serial breast MRI may be an effective tool to risk-stratify patients with DCIS and optimally select medical or surgical management.
Significance:
A retrospective analysis of 71 patients with DCIS who did not undergo upfront surgery demonstrated that breast MRI features after short-term exposure to endocrine therapy identify those at high (68.2%), intermediate (20.0%), and low risk (8.7%) of IDC. With 7.4 years mean follow-up, 52.1% of patients remain on active surveillance. A period of active surveillance offers the opportunity to risk-stratify DCIS lesions and guide decisions for operative management.
Data from Antibody Binding and Neutralization of Live SARS-CoV-2 Variants Including BA.4/5 Following Booster Vaccination of Patients with B-cell Malignancies
Authors: Chang Andres , Akhtar Akil , Lai Lilin , Orellana-Noia Victor M. , Linderman Susanne L. , McCook-Veal Ashley A. , Switchenko Jeffrey M. , Saini Manpreet , Valanparambil Rajesh M. , Blum Kristie A. , Allen Pamela B. , Lechowicz Mary Jo , Romancik Jason T. , Ayers Amy , Leal Alyssa , O'Leary Colin B. , Churnetski Michael C. , Baird Katelin , Kives Melissa , Wrammert Jens , Nooka Ajay K. , Koff Jean L. , Dhodapkar Madhav V. , Suthar Mehul S. , Cohen Jonathon B. , Ahmed Rafi
Published: April 2023

Patients with non–Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B-cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared with those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. Patients with NHL/CLL demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential.
Significance:
Limited data exist on antibody responses against current SARS-CoV-2 variants after booster vaccination in patients with NHL/CLL. We showed inferior antibody responses against Omicron variants after booster vaccination in these patients but some generated anti-Omicron titers. This stresses the importance of vaccinating patients with updated formulations.
Data from Grain, Gluten, and Dietary Fiber Intake Influence Gut Microbial Diversity: Data from the Food and Microbiome Longitudinal Investigation
Authors: Um Caroline Y. , Peters Brandilyn A. , Choi Hee Sun , Oberstein Paul , Beggs Dia B. , Usyk Mykhaylo , Wu Feng , Hayes Richard B. , Gapstur Susan M. , McCullough Marjorie L. , Ahn Jiyoung
Published: April 2023

Although short-term feeding studies demonstrated effects of grains, fiber, and gluten on gut microbiome composition, the impact of habitual intake of these dietary factors is poorly understood. We examined whether habitual intakes of whole and refined grains, fiber, and gluten are associated with gut microbiota in a cross-sectional study. This study included 779 participants from the multi-ethnic Food and Microbiome Longitudinal Investigation study. Bacterial 16SV4 rRNA gene from baseline stool was amplified and sequenced using Illumina MiSeq. Read clustering and taxonomic assignment was performed using QIIME2. Usual dietary intake was assessed by a 137-item food frequency questionnaire. Association of diet with gut microbiota was assessed with respect to overall composition and specific taxon abundances. Whole grain intake was associated with overall composition, as measured by the Jensen–Shannon divergence (multivariable-adjusted Ptrend for quartiles = 0.03). The highest intake quartile was associated with higher abundance of Bacteroides plebeius, Faecalibacterium prausnitzii, Blautia producta, and Erysipelotrichaceae and lower abundance of Bacteroides uniformis. These bacteria also varied by dietary fiber intake. Higher refined grain and gluten intake was associated with lower Shannon diversity (Ptrend < 0.05). These findings suggest that whole grain and dietary fiber are associated with overall gut microbiome structure, largely fiber-fermenting microbiota. Higher refined grain and gluten intakes may be associated with lower microbial diversity.
Significance:
Regular consumption of whole grains and dietary fiber was associated with greater abundance of gut bacteria that may lower risk of colorectal cancer. Further research on the association of refined grains and gluten with gut microbial composition is needed to understand their roles in health and disease.
Data from Reprogramming the Canine Glioma Microenvironment with Tumor Vaccination plus Oral Losartan and Propranolol Induces Objective Responses
Authors: Ammons Dylan T. , Guth Amanda , Rozental Aaron J. , Kurihara Jade , Marolf Angela J. , Chow Lyndah , Griffin John F. , Makii Rebecca , MacQuiddy Brittany , Boss Mary-Keara , Regan Daniel P. , Frank Chad , McGrath Stephanie , Packer Rebecca A. , Dow Steven
Published: April 2023

Purpose:
Malignant gliomas have a highly immune-suppressive tumor microenvironment (TME) which renders them largely unresponsive to conventional therapeutics. Therefore, the current study evaluated a therapeutic protocol designed to overcome the immune barrier by combining myeloid cell–targeted immunotherapy with tumor vaccination.
Experimental Design:
We utilized a spontaneously occurring canine glioma model to investigate an oral TME modifying immunotherapy in conjunction with cancer stem cell (CSC) vaccination. Dogs were treated daily with losartan (monocyte migration inhibitor) and propranolol (myeloid-derived suppressor cell depleting agent) plus anti-CSC vaccination on a biweekly then monthly schedule. Tumor volume was monitored by MRI and correlated with patient immune responses.
Results:
Ten dogs with histologically confirmed gliomas were enrolled into a prospective, open-label clinical trial to evaluate the immunotherapy protocol. Partial tumor regression was observed in 2 dogs, while 6 dogs experienced stable disease, for an overall clinical benefit rate of 80%. Overall survival times (median = 351 days) and progression-free intervals (median = 163 days) were comparable with prior studies evaluating surgical debulking followed by immunotherapy. Dogs with detectable anti-CSC antibody responses had an increased overall survival time relative to dogs that did not generate antibody responses (vaccine responder MST = 500 days; vaccine nonresponder MST = 218 days; P = 0.02).
Conclusions:
These findings suggest that combining myeloid cell–targeted oral immunotherapy with tumor vaccination can generate objective tumor responses, even in the absence of conventional therapy. Overall, this approach has promise as a readily implemented therapeutic strategy for use in patients with brain cancer.
Significance:
In a pilot study of 10 dogs with glioma, we found that orally administered losartan and propranolol plus vaccination induced durable tumor responses in 8 of 10 treated dogs. The immunotherapy protocol was well tolerated, without systemic or local toxicities. These findings indicate that continuous oral immunotherapy plus tumor vaccination is a promising new strategy for glioma management that can be readily applied in clinical trials.
Data from Integrated, Longitudinal Analysis of Cell-free DNA in Uveal Melanoma
Authors: Wong Derek , Luo Ping , Znassi Nadia , Arteaga Diana P. , Gray Diana , Danesh Arnavaz , Han Ming , Zhao Eric Y. , Pedersen Stephanie , Prokopec Stephenie , Sundaravadanam Yogi , Torti Dax , Marsh Kayla , Keshavarzi Sareh , Xu Wei , Krema Hatem , Joshua Anthony M. , Butler Marcus O. , Pugh Trevor J.
Published: April 2023

Uveal melanomas are rare tumors arising from melanocytes that reside in the eye. Despite surgical or radiation treatment, approximately 50% of patients with uveal melanoma will progress to metastatic disease, most often to the liver. Cell-free DNA (cfDNA) sequencing is a promising technology due to the minimally invasive sample collection and ability to infer multiple aspects of tumor response. We analyzed 46 serial cfDNA samples from 11 patients with uveal melanoma over a 1-year period following enucleation or brachytherapy (n = ∼4/patient) using targeted panel, shallow whole genome, and cell-free methylated DNA immunoprecipitation sequencing. We found detection of relapse was highly variable using independent analyses (P = 0.06–0.46), whereas a logistic regression model integrating all cfDNA profiles significantly improved relapse detection (P = 0.02), with greatest power derived from fragmentomic profiles. This work provides support for the use of integrated analyses to improve the sensitivity of circulating tumor DNA detection using multi-modal cfDNA sequencing.
Significance:
Here, we demonstrate integrated, longitudinal cfDNA sequencing using multi-omic approaches is more effective than unimodal analysis. This approach supports the use of frequent blood testing using comprehensive genomic, fragmentomic, and epigenomic techniques.
Data from A Miniaturized Screening Platform to Identify Novel Regulators of Extracellular Matrix Alignment
Authors: Jones Caitlin E. , Sharick Joe T. , Sizemore Steven T. , Cukierman Edna , Strohecker Anne Marie , Leight Jennifer L.
Published: April 2023

Extracellular matrix (ECM) alignment contributes to metastasis in a number of cancers and is a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Cancer-associated fibroblasts (CAF) play a critical role in this process, particularly via matrix production and modulation of key signaling pathways controlling cell adhesion and contractility. Stroma normalization, as opposed to elimination, is a highly sought strategy, and screening for drugs that effectively alter ECM alignment is a practical way to identify novel CAF-normalizing targets that modulate ECM organization. To meet this need, we developed a novel high-throughput screening platform in which fibroblast-derived matrices were produced in 384-well plates, imaged with automated confocal microscopy, and analyzed using a customized MATLAB script. This platform is a technical advance because it miniaturizes the assay, eliminates costly and time-consuming experimental steps, and streamlines data acquisition and analysis to enable high-throughput screening applications. As a proof of concept, this platform was used to screen a kinase inhibitor library to identify modulators of matrix alignment. A number of novel potential regulators were identified, including several receptor tyrosine kinases [c-MET, tropomyosin receptor kinase 1 (NTRK1), HER2/ERBB2] and the serine/threonine kinases protein kinase A, C, and G. The expression of these regulators was analyzed in publicly available patient datasets to examine the association between stromal gene expression and patient outcomes.
Significance:
ECM fiber organization and alignment contribute to metastasis in a number of cancers and are a known prognostic stromal factor; however, the mechanisms controlling matrix organization remain unclear. Here, a high-throughput assay was developed to enable discovery-based screening for an in vitro ECM fiber alignment assay. As proof of concept, this platform was used to screen a kinase inhibitor library and identified several novel modulators of matrix alignment.
Data from Elevated Dietary Carbohydrate and Glycemic Intake Associate with an Altered Oral Microbial Ecosystem in Two Large U.S. Cohorts
Authors: Monson Kelsey R. , Peters Brandilyn A. , Usyk Mykhaylo , Um Caroline Y. , Oberstein Paul E. , McCullough Marjorie L. , Purdue Mark P. , Freedman Neal D. , Hayes Richard B. , Ahn Jiyoung
Published: April 2023

The human oral microbiome is associated with chronic diseases including cancer. However, our understanding of its relationship with diet is limited. We assessed the associations between carbohydrate and glycemic index (GI) with oral microbiome composition in 834 nondiabetic subjects from the NCI Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the American Cancer Society Cancer Prevention Study II cohorts. The oral microbiome was characterized using 16Sv3-4 rRNA sequencing from oral mouthwash samples. Daily carbohydrate and GI were assessed from food frequency questionnaires. We used linear regression, permutational multivariate ANOVA, and negative binomial Generalized Linear Models (GLM) to test associations of diet with α- and β-diversity and taxon abundance (adjusting for age, sex, cohort, body mass index, smoking, caloric intake, and alcohol). A q-value (FDR-adjusted P value) of <0.05 was considered significant. Oral bacterial α-diversity trended higher in participants in the highest quintiles of carbohydrate intake, with marginally increased richness and Shannon diversity (Ptrend = 0.06 and 0.07). Greater carbohydrate intake was associated with greater abundance of class Fusobacteriia (q = 0.02) and genus Leptotrichia (q = 0.01) and with lesser abundance of an Actinomyces operational taxonomic unit (q = 4.7E-04). Higher GI was significantly related to greater abundance of genus Gemella (q = 0.001). This large, nationwide study provides evidence that diets high in carbohydrates and GI may influence the oral microbiome.
Significance:
Taxonomic differences at the highest intake quintiles may reflect diet-induced increases in carcinogenic bacteria and decreases in protective bacteria. Genus Leptotrichia has been implicated in cancer and inflammatory disease, while immunostimulatory genus Gemella may increase inflammatory disease risk. These differences further our understanding of possible mechanisms leading to oral and systemic disease.
Data from Targeting NEDDylation is a Novel Strategy to Attenuate Cisplatin-induced Nephrotoxicity
Authors: Jones Trace M. , Espitia Claudia M. , Chipollini Juan , Lee Benjamin R. , Wertheim Jason A. , Carew Jennifer S. , Nawrocki Steffan T.
Published: April 2023

Although cisplatin remains a backbone of standard-of-care chemotherapy regimens for a variety of malignancies, its use is often associated with severe dose-limiting toxicities (DLT). Notably, 30%–40% of patients treated with cisplatin-based regimens are forced to discontinue treatment after experiencing nephrotoxicity as a DLT. New approaches that simultaneously prevent renal toxicity while improving therapeutic response have the potential to make a major clinical impact for patients with multiple forms of cancer. Here, we report that pevonedistat (MLN4924), a first-in-class NEDDylation inhibitor, alleviates nephrotoxicity and synergistically enhances the efficacy of cisplatin in head and neck squamous cell carcinoma (HNSCC) models. We demonstrate that pevonedistat protects normal kidney cells from injury while enhancing the anticancer activity of cisplatin through a thioredoxin-interacting protein (TXNIP)-mediated mechanism. Cotreatment with pevonedistat and cisplatin yielded dramatic HNSCC tumor regression and long-term animal survival in 100% of treated mice. Importantly, the combination decreased nephrotoxicity induced by cisplatin monotherapy as evidenced by the blockade of kidney injury molecule-1 (KIM-1) and TXNIP expression, a reduction in collapsed glomeruli and necrotic cast formation, and inhibition of cisplatin-mediated animal weight loss. Inhibition of NEDDylation represents a novel strategy to prevent cisplatin-induced nephrotoxicity while simultaneously enhancing its anticancer activity through a redox-mediated mechanism.
Significance:
Cisplatin therapy is associated with significant nephrotoxicity, which limits its clinical use. Here we demonstrate that NEDDylation inhibition with pevonedistat is a novel approach to selectively prevent cisplatin-induced oxidative damage to the kidneys while simultaneously enhancing its anticancer efficacy. Clinical evaluation of the combination of pevonedistat and cisplatin is warranted.
Data from The Splicing Factor PTBP1 Represses TP63 γ Isoform Production in Squamous Cell Carcinoma
Authors: Taylor William , Deschamps Stéphane , Reboutier David , Paillard Luc , Méreau Agnès , Audic Yann
Published: April 2023

The TP63 gene encodes the p63 transcription factor. It is frequently amplified or overexpressed in squamous cell carcinomas. Owing to alternative splicing, p63 has multiple isoforms called α, β, γ, and δ. The regulatory functions of p63 are isoform specific. The α isoform inhibits the epithelial-to-mesenchymal transition (EMT) and controls apoptosis, while the γ isoform promotes EMT. Using The Cancer Genome Atlas data, we observed that a higher proportion of the TP63γ isoform is a detrimental factor for the survival of patients with head and neck squamous cell carcinoma (HNSCC) and is accompanied by the downregulation of desmosomal genes. By a correlation-based approach, we investigated the regulation of the production of the TP63γ isoform. According to our analysis of GTEx data, the expression of the RNA-binding protein PTBP1 (polypyrimidine tract binding protein 1) is negatively correlated with the abundance of TP63γ in several tissues. Accordingly, we demonstrated that PTBP1 depletion in HNSCC cell lines, keratinocyte or Xenopus embryos leads to an increase in TP63γ isoform abundance. By RNA immunoprecipitation and in vitro interaction assays, we showed that PTBP1 directly binds to TP63 pre-mRNA in close proximity to the TP63γ-specific exon. Intronic regions around the TP63γ-specific exon were sufficient to elicit a PTBP1-dependent regulation of alternative splicing in a splice reporter minigene assay.

Together, these results identify TP63γ as an unfavorable prognostic marker in HNSCC, and identify PTBP1 as the first direct splicing regulator of TP63γ production and a potential route toward TP63 isoform control.
Significance:
Quantifying TP63γ isoforms in patients’ tumors could allow for the early detection of patients with HNSCC with an early loss in desmosomal gene expression and poor prognostic. The identification of PTBP1 as a transacting factor controlling TP63γ production may allow to control TP63γ expression.
Data from Incorporating RNA-based Risk Scores for Genomic Instability to Predict Breast Cancer Recurrence and Immunogenicity in a Diverse Population
Authors: Hamilton Alina M. , Van Alsten Sarah C. , Gao Xiaohua , Nsonwu-Farley Joseph , Calhoun Benjamin C. , Love Michael I. , Troester Melissa A. , Hoadley Katherine A.
Published: April 2023

Markers of genomic instability, including TP53 status and homologous recombination deficiency (HRD), are candidate biomarkers of immunogenicity and immune-mediated survival, but little is known about the distribution of these markers in large, population-based cohorts of racially diverse patients with breast cancer. In prior clinical trials, DNA-based approaches have been emphasized, but recent data suggest that RNA-based assessment can capture pathway differences conveniently and may be streamlined with other RNA-based genomic risk scores. Thus, we used RNA expression to study genomic instability (HRD and TP53 pathways) in context of the breast cancer immune microenvironment in three datasets (total n = 4,892), including 1,942 samples from the Carolina Breast Cancer Study, a population-based study that oversampled Black (n = 1,026) and younger women (n = 1,032). Across all studies, 36.9% of estrogen receptor (ER)-positive and 92.6% of ER-negative breast cancer had presence of at least one genomic instability signature. TP53 and HRD status were significantly associated with immune expression in both ER-positive and ER-negative breast cancer. RNA-based genomic instability signatures were associated with higher PD-L1, CD8 T-cell marker, and global and multimarker immune cell expression. Among tumors with genomic instability signatures, adaptive immune response was associated with improved recurrence-free survival regardless of ER status, highlighting genomic instability as a candidate marker for predicting immunotherapy response. Leveraging a convenient, integrated RNA-based approach, this analysis shows that genomic instability interacts with immune response, an important target in breast cancer overall and in Black women who experience higher frequency of TP53 and HR deficiency.
Significance:
Despite promising advances in breast cancer immunotherapy, predictive biomarkers that are valid across diverse populations and breast cancer subtypes are needed. Genomic instability signatures can be coordinated with other RNA-based scores to define immunogenic breast cancers and may have value in stratifying immunotherapy trial participants.
Data from Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy
Authors: Groeneveldt Christianne , van Ginkel Jurriaan Q. , Kinderman Priscilla , Sluijter Marjolein , Griffioen Lisa , Labrie Camilla , van den Wollenberg Diana J.M. , Hoeben Rob C. , van der Burg Sjoerd H. , ten Dijke Peter , Hawinkels Lukas J.A.C. , van Hall Thorbald , van Montfoort Nadine
Published: April 2023

The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8+ T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics. Here, we investigated the effect of TGF-β blockade on the antitumor efficacy of Reo&CD3-bsAb therapy in the preclinical pancreatic KPC3 and colon MC38 tumor models, where TGF-β signaling is active. TGF-β blockade impaired tumor growth in both KPC3 and MC38 tumors. Furthermore, TGF-β blockade did not affect reovirus replication in both models and significantly enhanced the Reo-induced T-cell influx in MC38 colon tumors. Reo administration decreased TGF-β signaling in MC38 tumors but instead increased TGF-β activity in KPC3 tumors, resulting in the accumulation of α-smooth muscle actin (αSMA+) fibroblasts. In KPC3 tumors, TGF-β blockade antagonized the antitumor effect of Reo&CD3-bsAb therapy, even though T-cell influx and activity were not impaired. Moreover, genetic loss of TGF-β signaling in CD8+ T cells had no effect on therapeutic responses. In contrast, TGF-β blockade significantly improved therapeutic efficacy of Reo&CD3-bsAb in mice bearing MC38 colon tumors, resulting in a 100% complete response. Further understanding of the factors that determine this intertumor dichotomy is required before TGF-β inhibition can be exploited as part of viroimmunotherapeutic combination strategies to improve their clinical benefit.
Significance:
Blockade of the pleiotropic molecule TGF-β can both improve and impair the efficacy of viro-immunotherapy, depending on the tumor model. While TGF-β blockade antagonized Reo&CD3-bsAb combination therapy in the KPC3 model for pancreatic cancer, it resulted in 100% complete responses in the MC38 colon model. Understanding factors underlying this contrast is required to guide therapeutic application.
Data from Mouse IgG2a Isotype Therapeutic Antibodies Elicit Superior Tumor Growth Control Compared with mIgG1 or mIgE
Authors: Vukovic Natasa , Segués Aina , Huang Shuyu , Waterfall Martin , Sijts Alice J.A.M. , Zaiss Dietmar M.
Published: April 2023

In the last decades, antibody-based tumor therapy has fundamentally improved the efficacy of treatment for patients with cancer. Currently, almost all tumor antigen–targeting antibodies approved for clinical application are of IgG1 Fc isotype. Similarly, the mouse homolog mIgG2a is the most commonly used in tumor mouse models. However, in mice, the efficacy of antibody-based tumor therapy is largely restricted to a prophylactic application. Direct isotype comparison studies in mice in a therapeutic setting are scarce. In this study, we assessed the efficacy of mouse tumor-targeting antibodies of different isotypes in a therapeutic setting using a highly systematic approach. To this end, we engineered and expressed antibodies of the same specificity but different isotypes, targeting the artificial tumor antigen CD90.1/Thy1.1 expressed by B16 melanoma cells. Our experiments revealed that in a therapeutic setting mIgG2a was superior to both mIgE and mIgG1 in controlling tumor growth. Furthermore, the observed mIgG2a antitumor effect was entirely Fc mediated as the protection was lost when an Fc-silenced mIgG2a isotype (LALA-PG mutations) was used. These data confirm mIgG2a superiority in a therapeutic tumor model.
Significance:
Direct comparisons of different antibody isotypes of the same specificity in cancer settings are still scarce. Here, it is shown that mIgG2a has a greater effect compared with mIgG1 and mIgE in controlling tumor growth in a therapeutic setting.
Data from Evaluating Pneumonitis Incidence in Patients with Non–small Cell Lung Cancer Treated with Immunotherapy and/or Chemotherapy Using Real-world and Clinical Trial Data
Authors: Liu Qi , Zhang Chenan , Huang Yue , Huang Ruihao , Huang Shiew-Mei , Larkins Erin , Stapleford Liza , Rivera Donna R. , Kluetz Paul G. , Wang Shenggang , Zhu Hao , Weese James , Cromartie Elizabeth , Teka Mahder , Walters Sheetal , Wolf Frank , Brown Thomas D.
Published: April 2023

Pneumonitis is a potentially life-threatening complication of anticancer therapy, and future treatment decisions may be informed by characterizing patients receiving therapies in the real-world setting. In this study, the incidence of treatment-associated pneumonitis (TAP) was compared among patients with advanced non–small cell lung cancer receiving immune checkpoint inhibitors (ICI) or chemotherapies in either of two settings: randomized clinical trials (RCT) or real world data (RWD)-based clinical practice. Pneumonitis cases were identified using International Classification of Diseases codes (for RWD), or the Medical Dictionary for Regulatory Activities preferred terms (for RCTs). TAP was defined as pneumonitis diagnosed during treatment or within 30 days of the last treatment administration. Overall TAP rates in the RWD cohort were lower [ICI: 1.9%; 95% confidence interval (CI), 1.2–3.2; chemotherapy: 0.8%; 95% CI, 0.4–1.6] than overall rates in the RCT cohort (ICI: 5.6%; 95% CI, 5.0–6.2; chemotherapy: 1.2%; 95% CI, 0.9–1.5). Overall RWD TAP rates were similar to grade 3+ RCT TAP rates (ICI: 2.0%; 95% CI, 1.6–2.3; chemotherapy: 0.6%; 95% CI, 0.4–0.9). In both cohorts, higher TAP incidence was observed among patients with a past medical history of pneumonitis than those without, regardless of treatment group. On the basis of this sizable study leveraging RWD, TAP incidence was low in the RWD cohort, likely in part due to methodology used for RWD focusing on clinically significant cases. Past medical history of pneumonitis was associated with TAP in both cohorts.
Significance:
Pneumonitis is a potentially life-threatening complication of anticancer treatment. As treatment options expand, management decisions become increasingly complex, and there is a greater need to understand the safety profiles of the treatment options in the real-world setting. Real-world data serve as an additional source of valuable information to complement clinical trial data and inform understanding of toxicity in patients with non–small cell lung cancer receiving ICIs or chemotherapies.
Data from Digital spatial profiling links beta-2-microglobulin expression with immune checkpoint blockade outcomes in head and neck squamous cell carcinoma
Authors: Gavrielatou Niki , Vathiotis Ioannis A. , Aung Thazin Nwe , Shafi Saba , Burela Sneha , Fernandez Aileen I. , Moutafi Myrto , Burtness Barbara A. , Economopoulou Panagiota , Anastasiou Maria , Foukas Periklis , Psyrri Amanda , Rimm David L.
Published: April 2023

Abstract
Programmed cell death protein‐1 (PD-1) targeted immunotherapy is approved for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treatment. Although its efficacy correlates with PD-L1 expression, response is limited even among positive cases. We employed digital spatial profiling (DSP) to discover potential biomarkers of immunotherapy outcomes in HNSCC. Fifty prospectively collected, pre-treatment biopsy samples from anti-PD-1-treated R/M HNSCC patients, were assessed using DSP, for 71 proteins in 4 molecularly defined compartments (tumor, leukocyte, macrophage and stroma). Markers were evaluated for associations with progression free (PFS) and overall survival (OS). High beta-2 microglobulin (B2M), LAG-3, CD25 and 4-1BB in tumor; high B2M, CD45, CD4 in stroma, and low fibronectin in the macrophage compartment, correlated with prolonged PFS. Improved PFS and OS were observed for cases with high B2M by quantitative and mRNA. Findings were validated in an independent cohort for PFS [HR, 0.41; 95% CI, 0.19-0.93; p = 0.034]. B2M-high tumors showed enrichment with immune-cell and immune-checkpoint markers. Our study illustrates B2M expression is associated with improved survival for ICI-treated HNSCC.
Data from IOA-244 is a non-ATP-competitive, highly selective, tolerable phosphoinositide 3-kinase delta inhibitor that targets solid tumors and breaks immune tolerance
Authors: Johnson Zoë , Tarantelli Chiara , Civanelli Elisa , Cascione Luciano , Spriano Filippo , Fraser Amy , Shah Pritom , Nomanbhoy Tyzoon , Napoli Sara , Rinaldi Andrea , Niewola-Staszkowska Karolina , Lahn Michael , Perrin Dominique , Wenes Mathias , Migliorini Denis , Bertoni Francesco , van der Veen Lars , Di Conza Giusy
Published: April 2023

Abstract
Phosphoinositide 3-kinase delta (PI3Kd) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kd inhibition in solid tumors has recently emerged as a potential novel anti-cancer therapy through the modulation of T cell responses and direct anti-tumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non-ATP-competitive PI3Kd inhibitor, for the treatment of solid tumors. We confirm IOA-244’s selectivity as tested against a large set of kinases, enzymes, and receptors. IOA-244 inhibits the in vitro growth of lymphoma cells and its activity correlates with the expression levels of PIK3CD, suggesting cancer cell-intrinsic effects of IOA-244. Importantly, IOA-244 inhibits Treg proliferation while having limited anti-proliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells. Instead, treatment of CD8 T cells with IOA-244 during activation, favors the differentiation of memory-like, long-lived CD8, known to have increased antitumor capacity. These data highlight immune-modulatory properties that can be exploited in solid tumors. In CT26 colorectal and LLC lung cancer models, IOA-244 sensitized the tumors to anti-PD-1 (Programmed cell death protein 1) treatment, with similar activity in the Pan-02 pancreatic and A20 lymphoma syngeneic mouse models. IOA-244 reshaped the balance of tumor-infiltrating cells, favoring infiltration of CD8 and NK cells, while decreasing suppressive immune cells. IOA-244 presented no detectable safety concerns in animal studies and is currently in clinical Phase Ib/II investigation in solid and hematological tumors.
Data from Induction of PARP7 Creates a Vulnerability for Growth
Inhibition by RBN2397 in Prostate Cancer Cells
Authors: Yang Chunsong , Wierbilowicz Krzysztof , Dworak Natalia M , Bae Song Yi , Tengse Sachi B , Abianeh Nicki , Drake Justin M , Abbas Tarek , Ratan Aakrosh , Wotton David , Paschal Bryce M
Published: April 2023

Abstract
The ADP-ribosyltransferase PARP7 modulates protein function by conjugating ADP-ribose to the side chains of acceptor amino acids. PARP7 has been shown to affect gene expression in prostate cancer cells and certain other cell types by mechanisms that include transcription factor ADP-ribosylation. Here, we use a recently developed catalytic inhibitor to PARP7, RBN2397, to study the effects of PARP7 inhibition in androgen receptor-positive and androgen receptor-negative prostate cancer cells. We find that RBN2397 has nanomolar potency for inhibiting androgen-induced ADP-ribosylation of the androgen receptor. RBN2397 inhibits the growth of prostate cancer cells in culture when cells are treated with ligands that activate the androgen receptor, or the aryl hydrocarbon receptor, and induce PARP7 expression. We show that the growth inhibitory effects of RBN2397 are distinct from its enhancement of interferon signaling recently shown to promote tumor immunogenicity. RBN2397 treatment also induces trapping of PARP7 in a detergent-resistant fraction within the nucleus, which is reminiscent of how inhibitors such as Talazoparib affect PARP1 fractionation. Because PARP7 is expressed in AR negative metastatic tumors and RBN2397 can affect cancer cells through multiple mechanisms, PARP7 may be an actionable target in advanced prostate cancer.
Data from Plexin-B1 Mutation Drives Metastasis in Prostate Cancer Mouse Models
Authors: Shorning Boris , Trent Neil , Griffiths David F. , Worzfeld Thomas , Offermanns Stefan , Smalley Matthew J. , Williamson Magali
Published: April 2023

Metastatic prostate cancer is essentially incurable and is a leading cause of cancer-related morbidity and mortality in men, yet the underlying molecular mechanisms are poorly understood. Plexins are transmembrane receptors for semaphorins with divergent roles in many forms of cancer.

We show here that prostate epithelial cell–specific expression of a mutant form of Plexin-B1 (P1597L) which was identified in metastatic deposits in patients with prostate cancer, significantly increases metastasis, in particular metastasis to distant sites, in two transgenic mouse models of prostate cancer (PbCre+Ptenfl/flKrasG12Vand PbCre+Ptenfl/flp53fl/fl). In contrast, prostate epithelial cell–specific expression of wild-type (WT) Plexin-B1 in PbCre+Ptenfl/flKrasG12V mice significantly decreases metastasis, showing that a single clinically relevant Pro1597Leu amino-acid change converts Plexin-B1 from a metastasis-suppressor to a metastasis-promoter. Furthermore, PLXNB1P1597L significantly increased invasion of tumor cells into the prostate stroma, while PLXNB1WTreduced invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Deletion of RhoA/C or PDZRhoGEF in Ptenfl/flKrasG12VPLXNB1P1597L mice suppressed metastasis, implicating the Rho/ROCK pathway in this phenotypic switch. Germline deletion of Plexin-B1, to model anti-Plexin-B1 therapy, significantly decreased invasion and metastasis in both models.

Our results demonstrate that Plexin-B1 plays a complex yet significant role in metastasis in mouse models of prostate cancer and is a potential therapeutic target to block the lethal spread of the disease.
Significance:
Few therapeutic targets have been identified specifically for preventing locally invasive/oligometastatic prostate cancer from becoming more widely disseminated. Our findings suggest Plexin-B1 signaling, particularly from the clinically relevant P1597L mutant, is such a target.
Searching for a Semantic Parallel to the Concept of Depression
Authors: Cerroni Enrico
Published: April 2023

This paper examines whether a semantic parallel to the modern use of the word depression can be identified in ancient Greek. To that end, it retraces the development of the lexical family of the verb θλίβω, ‘to press’, and the abstract noun θλῖψις to gain the emotional and psychological meaning of ‘pressure’ or ‘affliction’. An analysis of the collected data suggests that a similar valence may be found in Hellenistic and Imperial Greek. However, this development is disregarded by authors with greater stylistic ambitions. Even physicians such as Galen continue to use θλῖψις solely in a physical, concrete sense. Conversely, the conceptualization in the singular of the word de-pression is lacking in ancient Greek. An antecedent may be identified in the formation of the prefixed verb καταθλίβω and the derived noun κατάθλιψις, found only from Late Antiquity onward, but this retains a concrete valence.
Study on Algorithms for α/β Pulse-Shape Discrimination of Liquid Scintillation Detection
Authors: Qi Ye-lin , Lai Yong-fang , Zhang Xuan , Zhao Ying-ying , Tang Huang
Published: April 2023

In this paper, the basic characteristics of the output pulse waveforms of α and β particles from liquid scintillation detection are analyzed, and the basic principles, advantages and disadvantages of the typical waveform discrimination algorithms are also analyzed
comparatively. Meanwhile by using of Matlab, the output pulses of α and β particles from liquid scintillation detection are simulated, the α/β waveform discrimination effect of charge comparison method, pulse gradient analysis method, frequency
gradient analysis method and discrete Fourier method are studied. From the simulation results in this paper, frequency gradient analysis method has acquired the best discrimination effect and far exceeds the existing discrimination methods, which can provide an important reference for discriminating
α and β particles in liquid scintillation detection.
Estimation Method of State of Charge of Power Battery of New Energy Vehicle Based on K Nearest Neighbor Regression
Authors: Su Qinglie
Published: April 2023

In order to improve the power battery state of charge detection ability of new energy vehicles and reduce harmonic interference, a measurement method of power battery state of new energy vehicles based on K-nearest neighbor regression analysis is proposed. Build a charging state parameter
collection model of new energy vehicle power battery, consider the unbalanced power of uncertain factors, realize the oscillation and fusion processing of charging state of new energy vehicle power battery through the dynamic matching method of mobile energy storage resources of electric vehicle,
extract the microgrid load fluctuation characteristic value of charging state signal of new energy vehicle power battery, and analyze the percentage of remaining electricity to rated capacity. The initial charge and capacity characteristics of the battery of the new energy vehicle power battery
are matched. The K-nearest neighbor regression analysis method is used to realize the regression analysis and dynamic estimation of the battery state of charge parameters. According to the state of charge of the new energy vehicle power battery, the steady-state characteristic quantity is
output, and the demand response load model parameter reconstruction and load balance matching method are used to realize the state of charge estimation and parameter adaptive evaluation of the new energy vehicle power battery. The simulation results show that the accuracy of measuring the
state of charge of the power battery of new energy vehicles is high, and the harmonic suppression ability is strong, which improves the balanced configuration and load balancing scheduling ability of the power system of the power battery of new energy vehicles.
Removal of Salt and Pepper Noise Using Hybrid Adaptive Switching Median Filter with Ant Colony Optimization Technique in Nano Electronic Applications
Authors: Vairaprakash S. , Karuppaiah Jayakumar , Buvaneswari B. , Alghamdi Abdullah
Published: April 2023

Background: Restoration of noisy images from the salt and pepper noise is an interesting area in the field of image processing. The restoration process can be done using various filtering algorithms. The restoration process should not affect the pixels of the original image. The problem
of the existing work persists as the increase in the error rate while the dimensions as well as the image format changes. The proposed work consists of Hybrid Adaptive Switching median filtering (HASMF). The hybrid technique corrupted images’ high-density salt and pepper noise removal
using Ant colony Optimization technique. This hybrid technique would remove the high-density salt and pepper noise from the corrupted images. The noisy pixel value from the corrupted images is identified and selected using the Ant Colony Optimization technique (ACO). The identified corrupted
value can be replaced using the Adaptive Switching Median Filter. The switching process is carried out using the pixel by pixel with the normalized median values. The noisy pixels are identified and selected using Ant colony Optimization. The optimized values are subjected to the filtering
process. The proposed method decreases the salt and pepper noise within the original image. The hybrid design approach was used in the proposed study, which used 45 nm technology combined with a Verilog-A model-based circuit that was implemented using Spintronic. It was discovered that the
suggested changed task had less latency, used less space, and dissipated less power than the original. Furthermore, it was discovered that designed memory arrays were both energy and space-efficient. It does not affect the normal pixels within the original image. The comparison process has
been made with the various existing algorithms such as Median Filter (MF), Modified Decision Based Unsymmetrical Trimmed Median Filter (MDBUTMF). The proposed method has overcome the various performance metrics such as Peak Signal Noise Ratio (PSNR), Mean Square Error (MSE), and Structural
Similarity Index (SSIM). The results obtained have shown the significant results in terms of object measures as well as visual perception of the denoised image.
Computational Treatment of Magnetohydrodynamic Micropolar Fluid Flow Through Porous Medium Over an Exponentially Stretching Sheet with Heat Sink and Chemical Reaction Effects
Authors: Salah Faisal , Alqahtani Hessah
Published: April 2023

The purpose of this research is to look into the magnetohydrodynamic boundary layer flow of Maxwell fluid across an exponentially stretching sheet with chemical reaction, and radiation impacts, that involves a heat sink. The PDE governing equation is converted to an ODE governing system.
A Successive Linearization Method is then used to solve the system numerically. Graphically, the numerical outputs of, temperature, concentration profiles, and velocity are displayed. The results of several parameters are explored and examined. The numerical outcomes for the skin friction
coefficient, local Nusselt number, Deborah number, local Sherwood number, and porosity are reported and analyzed. Based on the results, many characteristics have a considerable effect on fluid flow profiles. The reaction rate parameter had a significant impact on the concentration profile
and the thickness of the boundary layer dropped as the reaction rate parameter was increased. The analyses’ findings were compared to those of previous studies and found to be in great agreement.
Sliding Mode Control of Digital Directional Valve Drive System Based on New Approach Rate
Authors: Zhang Yang , Li Jian-Ying , Zhang Qi-Zheng , Peng Chen
Published: April 2023

As an important development direction of hydraulic control components, static and dynamic properties of the spool drive mechanism determine the dynamic and static performance of the digital valve. For the study, permanent magnet synchronous motor and screw nut unit are used as the core
drive mechanism for digital directional valve. To solve the practical problems that permanent magnet synchronous motor can not meet the performance requirements of digital directional valve in terms of spool position control accuracy and response speed, a sliding mode variable structure control
algorithm with improved approach rate is registered, then the controller is devised and applied to position high-performance control of spool drive mechanism of digital directional valve. The simulation platform of digital directional valve drive system is built by MATLAB/Simulink software
and compared with the control effect of traditional PI control algorithm. The emulation results show that can improved approach rate sliding-mode controller can be good for raise the speed of response and reinforce the trueness of the dynamic tracking accuracy of the system, has good dynamic
response characteristics, and satisfies the performance requirements of digital directional valve.