bluuebunny/crossref_metadata_2025 huggingface dataset:
One generalist or several specialists? Comparative analysis of the polyphagous butterfly Adelpha serpa celerio and its serpa‐group relatives
Authors: Rush Cassidi E. , Freitas André V. L. , Magaldi Luiza , Willmott Keith R. , Hill Ryan I.
Published: June 2023

Patterns of larval food plant use and immature stage morphology help clarify Neotropical butterfly species diversity, and, in many cases, lineages identified with molecular data are corroborated by morphology and ecology of immature stages. Here, we investigate cryptic species in Adelpha butterflies (Nymphalidae), a group known for challenging adult wing similarity coupled with mimicry, and for its remarkably wide larval food plant breadth. We focus on the Adelpha serpa‐group and in particular Adelpha serpa celerio, whose immatures have been documented feeding on 11 plant families. Our analyses of A. serpa, and among serpa‐group species across the Neotropics, revealed evidence of cryptic species, but the pattern within A. serpa celerio showed relatively weak mtDNA and morphological differences, and no differentiation in food plant use. We conclude that A. serpa should be revised and recognize A. serpa to include the nominate subspecies and recognize A. celerio (revised status) as a geographically widespread species and a larval food plant generalist that contains A. c. celerio (revised status), A. c. duiliae (revised status) and A. c. diadochus (revised status). Four additional species within the serpa‐group show strong evidence of harbouring allopatric cryptic species, and further research should be done to clarify their species limits.
Synergistic Effects and Kinetics in Co-Pyrolysis of Waste Tire With Five Agricultural Residues Using Thermogravimetric Analysis
Authors: Wang Zhiwei , Guo Shuaihua , Chen Gaofeng , Zhang Mengju , Sun Tanglei , Chen Yan , Wu Mengge , Xin Xiaofei , Yang Shuhua , Lei Tingzhou , Burra Kiran G. , Gupta Ashwani K.
Published: June 2023

Continued social and mobility development has caused a sharp increase in the number of waste tires, increased environmental pollution, and waste of limited resources. Agricultural residues as a bioresource, which has drawn increased attention in recent years. The thermochemical conversion of waste tires and agricultural residues and their mixtures offers important prospects for scientific development, which can provide energy security and a much reduced environmental footprint. In this paper, pyrolysis of waste tires and its co-pyrolysis with maize stalk, wheat straw, cotton stalk, rape straw, or peanut shell agricultural residues, in mass ratios of 1:1 were investigated at different heating rate using thermogravimetric analysis. The kinetic parameters were calculated using Flynn–Wall–Ozawa (FWO) and Kissinger–Akahira–Sunose (KAS) kinetic models at heating rates of 20, 30, and 50 °C/min. The synergistic effect between waste tires and agricultural residues was explored by calculating the deviation between the experimental and calculated values. The results showed the presence of a synergistic effect between the co-pyrolysis of waste tires and the residual agricultural residues. In the kinetic analysis, activation energies of waste tires, agricultural residues, and their mixtures were calculated using the two models. The reaction followed a multistage reaction mechanism. The differential thermogravimetry behavior of the mixture was similar to the weighted aggregate results of the waste tire and agricultural waste samples, pyrolyzed separately. These results provide some insights into the combined treatment of waste tires and agricultural waste residues.
Understanding the Impact of an Online Level 1 Coach Education Award on Dodgeball Coaches’ Learning and Practice
Authors: Leeder Thomas M. , Beaumont Lee C. , Maloney Ciaran M.C.
Published: June 2023

Improved internet access and technological advancements have significantly influenced coaches’ learning opportunities, with numerous online coach education courses now available. Despite this, we know little about coaches’ experiences of such provision and how it shapes coach learning. Consequently, the aim of this research is to understand the impact of an online Level 1 coach education award on dodgeball coaches’ learning and practice. Data were collected via an online qualitative survey involving 57 dodgeball coaches who had completed the award, alongside follow-up virtual semistructured interviews with eight coaches. Following a reflexive thematic analysis process drawing upon the theoretical framework of Jennifer Moon, three themes were generated: (a) a surface or deep approach? Understanding dodgeball coaches’ experiences of the Level 1 award, (b) coaches’ preferences and learning styles: a barrier for online coach education, and (c) enhancing the impact of online coach education: assessment and postaward support. Findings indicate that the award’s impact on learning and practice varied depending upon coaches’ cognitive structures, which influenced their perceptions toward the value of online provision. Although coaches’ experiences were generally positive, authentic assessment(s) and mentoring opportunities were proposed to further enhance the award’s impact.
Diagnostic accuracy of endometrial sampling tests for detecting endometrial cancer: a systematic review and meta-analysis
Authors: Sakna Noha Abdelsattar , Elgendi Marwa , Salama Mohamed Hamed , Zeinhom Ahmed , Labib Somia , Nabhan Ashraf Fawzy
Published: June 2023

Objectives

To determine the diagnostic accuracy of different endometrial sampling tests for detecting endometrial carcinoma.

Design

Systematic review and meta-analysis of studies of diagnostic accuracy.

Data sources

Cochrane Library, MEDLINE/PubMed, CINAHL, Web of Science and Scopus, from the date of inception of the databases to 18 January 2023. Additionally, the reference lists of included studies and other systematic reviews were thoroughly searched.

Eligibility criteria

We included published cross‐sectional studies that evaluated any endometrial sampling test (index tests) in women (participants) with clinical suspicion of endometrial carcinoma (target condition) in comparison with histopathology of hysterectomy specimens (reference standard). We excluded case–control and case series studies. No restrictions on language or date of publication were applied.

Data extraction and synthesis

Two independent reviewers extracted study data and assessed study quality using the revised quality assessment tool for diagnostic accuracy studies (QUADAS-2). We used bivariate diagnostic random-effects meta-analysis and presented the results in a summary receiver operating characteristic curve. We assessed the certainty of evidence as recommended by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach.

Results

Twelve studies (1607 participants), published between 1986 and 2022, contributed data to the meta-analysis results. Seven studies were judged to be at a low risk of bias in all domains and all studies had low applicability concerns. The most studied index tests were Pipelle and conventional dilation and curettage (D&C). The sensitivity, specificity, positive likelihood ratio and negative likelihood ratio (95% CIs) for Pipelle were 0.774 (0.565 to 0.900), 0.985 (0.927 to 0.997), 97.000 (14.000 to 349.000) and 0.241 (0.101 to 0.442) and for conventional D&C were 0.880 (0.281 to 0.993), 0.984 (0.956 to 0.995), 59.300 (14.200 to 153.000) and 0.194 (0.007 to 0.732), respectively.

Conclusion

High certainty evidence indicates that endometrial sampling using Pipelle or conventional D&C is accurate in diagnosing endometrial cancer. Studies assessing other endometrial sampling tests were sparse.

Trial registration number

https://osf.io/h8e9z.
Causes of death in children with congenital anomalies up to age 10 in eight European countries
Authors: Rissmann Anke , Tan Joachim , Glinianaia Svetlana V , Rankin Judith , Pierini Anna , Santoro Michele , Coi Alessio , Garne Ester , Loane Maria , Given Joanne , Reid Abigail , Aizpurua Amaia , Akhmedzhanova Diana , Ballardini Elisa , Barisic Ingeborg , Cavero-Carbonell Clara , de Walle Hermien E K , Gatt Miriam , Gissler Mika , Heino Anna , Jordan Sue , Urhoj Stine Kjaer , Klungsøyr Kari , Lutke Renee , Mokoroa Olatz , Neville Amanda Julie , Thayer Daniel S , Wellesley Diana G , Yevtushok Lyubov , Zurriaga Oscar , Morris Joan
Published: June 2023

Background

Congenital anomalies (CAs) increase the risk of death during infancy and childhood. This study aimed to evaluate the accuracy of using death certificates to estimate the burden of CAs on mortality for children under 10 years old.

Methods

Children born alive with a major CA between 1 January 1995 and 31 December 2014, from 13 population-based European CA registries were linked to mortality records up to their 10th birthday or 31 December 2015, whichever was earlier.

Results

In total 4199 neonatal, 2100 postneonatal and 1087 deaths in children aged 1–9 years were reported. The underlying cause of death was a CA in 71% (95% CI 64% to 78%) of neonatal and 68% (95% CI 61% to 74%) of postneonatal infant deaths. For neonatal deaths the proportions varied by registry from 45% to 89% and by anomaly from 53% for Down syndrome to 94% for tetralogy of Fallot. In children aged 1–9, 49% (95% CI 42% to 57%) were attributed to a CA. Comparing mortality in children with anomalies to population mortality predicts that over 90% of all deaths at all ages are attributable to the anomalies. The specific CA was often not reported on the death certificate, even for lethal anomalies such as trisomy 13 (only 80% included the code for trisomy 13).

Conclusions

Data on the underlying cause of death from death certificates alone are not sufficient to evaluate the burden of CAs on infant and childhood mortality across countries and over time. Linked data from CA registries and death certificates are necessary for obtaining accurate estimates.
Regional variations in heart failure: a global perspective
Authors: Yogeswaran Vidhushei , Hidano Danelle , Diaz Andrea E , Van Spall Harriette G C , Mamas Mamas A , Roth Gregory A , Cheng Richard K
Published: June 2023

Heart failure (HF) is a global public health concern that affects millions of people worldwide. While there have been significant therapeutic advancements in HF over the last few decades, there remain major disparities in risk factors, treatment patterns and outcomes across race, ethnicity, socioeconomic status, country and region. Recent research has provided insight into many of these disparities, but there remain large gaps in our understanding of worldwide variations in HF care. Although the majority of the global population resides across Asia, Africa and South America, these regions remain poorly represented in epidemiological studies and HF trials. Recent efforts and registries have provided insight into the clinical profiles and outcomes across HF patterns globally. The prevalence of HF and associated risk factors has been reported and varies by country and region ranges, with minimal data on regional variations in treatment patterns and long-term outcomes. It is critical to improve our understanding of the different factors that contribute to global disparities in HF care so we can build interventions that improve our general cardiovascular health and mitigate the social and economic cost of HF. In this narrative review, we hope to provide an overview of the global and regional variations in HF care and outcomes.
Update on advanced interventional neuromodulatory approaches to lower blood pressure
Authors: Kiuchi Marcio Galindo , Carnagarin Revathy , Schultz Carl , Shetty Sharad , Ward Natalie C , Santos Carlos Eduardo , Schlaich Markus P
Published: June 2023

Herein, we review interventional peripheral neuromodulatory approaches to reduce blood pressure (BP), specifically focusing on catheter-based renal denervation (RDN), as well as the latest data from recent clinical trials underpinning its clinical use. Given the apparent failure of established lifestyle measures and pharmacologic BP-lowering approaches to improve hypertension (HTN) control rates, the past decade has seen remarkable scientific efforts to explore the utility of interventional strategies for BP management. Experimental studies and human clinical trials have demonstrated the crucial role of the sympathetic nervous system in the development and mainenance of HTN - consequently, most recent interventional technologies aimed primarily at modulating neural pathways. Advanced approaches that were rigorously tested in human studies include RDN, endovascular baroreflex amplification, baroreflex activation therapy and cardiac neuromodulation stimulation.

Amongst these, RDN is by far the most established technology. With recent robust evidence from clinical trials and real-world data showing the safety and efficacy of both ultrasound and radiofrequency-based approaches, a recent clinical consensus statement of the European Society of Cardiology Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions concludes that RDN represents an ancillary therapeutic option in patients with uncontrolled resistant HTN confirmed by ambulatory blood pressure measurement and in spite of attention to lifestyle changes and optimised pharmacological treatment. Furthermore, RDN could alos be considered for patienst unlikley to adhere to or tolerate long-term antihypertensive drug treatment. Very recent data indicate long-term safety and efficacy up to 10 years. Appropriate implementation of RDN into clinical practice is now warranted.

For all other interventions additional data from adequately designed human studies are required to establish their safety and clinical utility for potential future use in routine practice.
Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke: results of the prospective HEBRAS study
Authors: Hellwig Simon , Krause Thomas , Scheitz Jan F , Herm Juliane , Grittner Ulrike , Jauert Nadja , Fiebach Jochen B , Kasner Mario , Doehner Wolfram , Endres Matthias , Wachter Rolf , Elgeti Thomas , Nolte Christian H , Haeusler Karl Georg
Published: June 2023

Background

Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke (AIS). We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital.

Methods

Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke (HEBRAS) study at the Charité, Berlin, Germany. Patients with AIS without known atrial fibrillation (AF) underwent cardiovascular MR imaging (CMR), MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.

Results

Among 356 patients with AIS (mean age 66 years, 37.6% female), enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care (17.7% vs 5.3%; p<0.001). Consequently, fewer patients were classified as cryptogenic after enhanced diagnostic workup (38.5% vs 45.5%, p<0.001). Routine care included echocardiography in 228 (64.0%) patients. CMR was successfully performed in 292 (82.0%) patients and revealed more often a prespecified pathological finding compared with routine echocardiography (16.1% vs 5.3%). Furthermore, study-related ECG monitoring (median duration 162 hours (IQR 98–210)) detected AF in 16 (4.5%) patients, while routine monitoring (median duration 51 hours (IQR 34–74)) detected AF in seven (2.0%) patients.

Conclusions

Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke.

Trial registration number

NCT02142413.
ECS News-What’s on ECS News?
Authors: Ortiz Jennifer
Published: June 2023

What’s on ECS News - Summer 2023
ECS Mourns Gordon E. Moore, Longtime Society Member and Honoree
Authors: Chaves Frances N.
Published: June 2023

Gordon E. Moore, author of Moore’s Law and co-founder of Intel Corporation, passed away on March 24, 2023. Many at ECS knew him during his 66 years as a Society member. We tracked the extraordinary progress of his research through our meetings and publications. He actively mentored a generation of scientists who followed his lead in the semiconductor revolution. “His seminal work defines the technological world of the 21st Century,” said ECS Past President Turgut Gür.
Tech Highlights - Summer 2023
Authors: Pile Donald , Gallaway Joshua , Karuppaiah Chock , Liu Chao , Liu Zenghe , McNulty David
Published: June 2023

A collection of technology highlights pulled from recent papers published in ECS journals.
Existence Results of Langevin Equations with Caputo–Hadamard Fractional Operator
Authors: Dhaniya Sombir , Kumar Anoop , Khan Aziz , Abdeljawad Thabet , Alqudah Manar A.
Published: June 2023

In this manuscript, we deal with a nonlinear Langevin fractional differential equation that involves the Caputo–Hadamard and Caputo fractional operators, with nonperiodic and nonlocal integral boundary conditions. The results presented in this study establish the existence, uniqueness, and Hyers–Ulam (HU) stability of the solution to the proposed equation. We achieved our main result by using the Banach contraction mapping principle and Krasonoselskii’s fixed point theorem. Furthermore, we introduce an application to demonstrate the validity of the results of our findings.
Unsupervised Domain Adaptation Damage Identification Approach of High Arch Dams after Earthquakes
Authors: Xiangyu Cao , Liang Chen , Jianyun Chen , Jing Li , Wenyan Lu , Haixiang Liu , Liu Pengfei , Minyong Ke , Yunqing Tang
Published: June 2023

In actual concrete arch dam engineering scenarios, the dynamic data obtained by the health monitoring system of an arch dam are incomplete. The data acquired typically depend on the state of the dam structure, that is, whether it is intact or incomplete. Besides, the future environmental loads of the structure are unpredictable. Thus, environmental noise is also uncertain. In practical engineering, the use of a damage identification model constructed based on incomplete information is problematic in scenarios with variable loads. Consequently, detecting the water level in actual arch dam projects after an earthquake and determining the impact of environmental uncertainty are necessary. Accordingly, this paper proposes a denoising contractive sparse deep autoencoder (DCS-DAE) model based on domain adaptation. The core idea of the proposed method is to constrain the data probability distribution of feature spaces in the source and target domains using maximum mean discrepancy. This fusion enables the DCS-DAE model to be capable of feature extraction. Moreover, it resolves the problem in which the objective function cannot be applied to other similar scenarios because of the lack of consistency constraints of feature spaces in the source and target domains. Four working conditions are designed to reproduce the uncertainty of structural modeling and the variability of water levels. The conditions are based on the postseismic water level detection requisites of dams in practical engineering. The results show that the proposed anomaly detection model enhances the generalization performance of the DCS-DAE in terms of feature design. Hence, the constructed model can “infer other things from one fact.” The results of this study are meaningful for the real-time cross-domain monitoring of structures under variable load conditions, providing a driving force to apply similar methods to practical arch dam projects.
Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex
Authors: Nyquist Michael D. , Coleman Ilsa M. , Lucas Jared M. , Li Dapei , Hanratty Brian , Meade Hannah , Mostaghel Elahe A. , Plymate Stephen R. , Corey Eva , Haffner Michael C. , Nelson Peter S.
Published: June 2023

The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.

Significance:

Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.
Wnt Signaling Stimulates Cooperation between GREB1 and HNF4α to Promote Proliferation in Hepatocellular Carcinoma
Authors: Matsumoto Shinji , Harada Akikazu , Seta Minami , Akita Masayuki , Gon Hidetoshi , Fukumoto Takumi , Kikuchi Akira
Published: June 2023

Wnt signaling is known to maintain two cell states, hepatocyte differentiation and proliferation, in hepatocellular carcinoma (HCC). On the other hand, activation of Wnt signaling in colon cancer promotes uncontrollable stereotypic proliferation, whereas cells remain undifferentiated. To elucidate the unique mode of Wnt signaling in HCC, we comprehensively investigated HCC-specific Wnt pathway target genes and identified GREB1. Wnt signaling induced expression of GREB1 coupled with HNF4α and FOXA2, master transcription factors that maintain hepatic differentiation. Moreover, GREB1 was enriched at the regulatory region of atypical HNF4α target genes, including progrowth genes, thereby stimulating HCC proliferation. Therefore, GREB1 acts as a unique mediator of versatile Wnt signaling in HCC progression, bridging the roles of the Wnt pathway in differentiation and proliferation.

Significance:

GREB1 is a liver cancer–specific Wnt signaling target gene that induces an oncogenic shift of HNF4α, a putative tumor suppressor, and may represent a therapeutic target in Wnt-activated hepatocellular carcinoma.
Urine pH and Risk of Bladder Cancer in Northern New England
Authors: Fischer Alexander H. , Wong Jason Y.Y. , Baris Dalsu , Koutros Stella , Karagas Margaret R. , Schwenn Molly , Johnson Alison , Alguacil Juan , Silverman Debra T. , Rothman Nathaniel
Published: June 2023

Background:

Acidic urine pH is associated with rapid hydrolysis of N-glucuronide conjugates of aromatic amines into metabolites that may undergo metabolism in the bladder lumen to form mutagenic DNA adducts. We previously reported that consistently acidic urine was associated with increased bladder cancer risk in a hospital-based case–control study in Spain. Here, we conducted a separate study in northern New England to replicate these findings.

Methods:

In a large, population-based case–control study conducted in Maine, New Hampshire, and Vermont, we examined bladder cancer risk in relation to consistent urine pH, measured twice daily by participants over 4 consecutive days using dipsticks. In parallel, we collected spot urine samples and conducted laboratory measurements of urinary acidity using a pH meter. Unconditional logistic regression was used to estimate associations, adjusting for age, gender, race, Hispanic status, and state. Analyses were further stratified by smoking status.

Results:

Among 616 urothelial carcinoma cases and 897 controls, urine pH consistently ≤ 6.0 was associated with increased bladder cancer risk (OR = 1.27; 95% confidence interval, 1.02–1.57), with the effect limited to ever-smokers. These findings were supported by analyses of a spot urine, with statistically significant exposure–response relationships for bladder cancer risk overall (Ptrend = 5.1×10−3) and among ever-smokers (Ptrend = 1.2×10−3).

Conclusions:

Consistent with a previous study in Spain, our findings suggest that acidic urine pH is associated with increased bladder cancer risk.

Impact:

Our findings align with experimental results showing that acidic urine pH, which is partly modifiable by lifestyle factors, is linked to hydrolysis of acid-labile conjugates of carcinogenic aromatic amines.
Ethnic Disparities in Early-Onset Gastric Cancer Persist across Rural–Urban Geographies
Authors: Narasimman Manasa , Pruitt Sandi L. , Murphy Caitlin C. , Singal Amit G. , Tavakkoli Anna
Published: June 2023

Background:

The incidence of noncardia gastric cancer is increasing in adults ages less than 50 years old. Early-onset gastric cancer (EOGC) is characterized by ethnic disparities occurring more in Hispanic persons than non-Hispanic persons. It is unknown whether rural–urban disparities exist in EOGC and if this intersects with ethnic disparities.

Methods:

We utilized the Surveillance Epidemiology and End Results 17 Census Tract-level Socioeconomic Status and Rurality Database from 2006 to 2018 to calculate incidence rates and incidence rate ratios of EOGC among Hispanic and non-Hispanic persons by census tract rural–urban location, age, gender, persistent poverty, and stage of disease. We used the Tiwari Method to estimate incidence rate ratios with 95% confidence intervals (CI).

Results:

Hispanic persons had higher incidence rates of EOGC compared with non-Hispanic persons in both rural [incident rate ratios (IRR), 2.12; 95% confidence interval (CI), 1.64–2.73] and urban census tracts (IRR, 2.03; 95% CI, 1.91–2.16). Similar findings were seen when comparing Hispanic to non-Hispanic persons in rural and urban census tracts by age, stage of disease, and persistent poverty.

Conclusions:

Higher incidence rates of EOGC among Hispanic persons persist across rural–urban locations. Further research is needed to understand the etiology of this elevated risk in young Hispanics and interventions that may help to modify their outcome.

Impact:

While other cancers have ethnic disparities which may differ by rural–urban location, the ethnic disparity in EOGC among Hispanic and non-Hispanic persons does not differ by rural–urban residence.
A Carbonic Anhydrase IX/SLC1A5 Axis Regulates Glutamine Metabolism Dependent Ferroptosis in Hypoxic Tumor Cells
Authors: Venkateswaran Geetha , McDonald Paul C. , Chafe Shawn C. , Brown Wells S. , Gerbec Zachary J. , Awrey Shannon J. , Parker Seth J. , Dedhar Shoukat
Published: June 2023

The ability of tumor cells to alter their metabolism to support survival and growth presents a challenge to effectively treat cancers. Carbonic anhydrase IX (CAIX) is a hypoxia-induced, metabolic enzyme that plays a crucial role in pH regulation in tumor cells. Recently, through a synthetic lethal screen, we identified CAIX to play an important role in redox homeostasis. In this study, we show that CAIX interacts with the glutamine (Gln) transporter, solute carrier family 1 member 5 (SLC1A5), and coordinately functions to maintain redox homeostasis through the glutathione/glutathione peroxidase 4 (GSH/GPX4) axis. Inhibition of CAIX increases Gln uptake by SLC1A5 and concomitantly increases GSH levels. The combined inhibition of CAIX activity and Gln metabolism or the GSH/GPX4 axis results in an increase in lipid peroxidation and induces ferroptosis, both in vitro and in vivo. Thus, this study demonstrates cotargeting of CAIX and Gln metabolism as a potential strategy to induce ferroptosis in tumor cells.
MTX-13, a Novel PTK7-Directed Antibody–Drug Conjugate with Widened Therapeutic Index Shows Sustained Tumor Regressions for a Broader Spectrum of PTK7-Positive Tumors
Authors: Kong Chao , Pu Junyi , Zhao Qianqian , Weng Weining , Ma Linjie , Qian Yu , Hu Wenhao , Meng Xun , Meng Tao
Published: June 2023

Protein tyrosine kinase 7 (PTK7) is a Wnt signaling pathway protein implicated in cancer development and metastasis. When using a potent microtubule inhibitor (Aur0101), PTK7-targeting antibody–drug conjugate (ADC), h6M24-vc0101 (PF-06647020/cofetuzumab pelidotin) is efficacious only in limited tumor types with low response rates in a phase I trial. To improve patient response and to expand responding tumor types, we designed MTX-13, a PTK7-targeting ADC consisting of a novel antibody (Ab13) conjugated to eight molecules of topoisomerase I inhibitor exatecan through T1000, a novel self-immolative moiety. MTX-13 exhibited PTK7-specific cell binding, efficient internalization, and exatecan release to cause cytotoxic activity through DNA damage and apoptosis induction, and a strong bystander killing. MTX-13 displayed potent antitumor activities on cell line–derived xenograft and patient-derived xenograft models from a wide range of solid tumors, significantly outperforming h6M24-vc0101. PTK7 was shown to be an actionable target in small cell lung cancer for which MTX-13 showed complete and durable responses. With a consistent overexpression of PTK7 in squamous cell carcinomas derived from diverse anatomic sites, strong potency of MTX-13 in this group of heterogenous tumors suggested a common treatment strategy. Finally, MTX-13 inhibited tumor growth and metastasis in an orthotopic colon cancer xenograft model. MTX-13 displayed a favorable pharmacokinetic and safety profile in monkeys with the highest non-severely toxic dose (HNSTD) of ≥30 mg/kg, significantly higher than 3–5 mg/kg of HNSTD for h6M24-vc0101. The higher therapeutic index of MTX-13 bodes well for its clinical translation with the potential to expand the responding patient population beyond that of current PTK7-targeting ADCs.
Enhancing CAR T-cell Therapy Using Fab-Based Constitutively Heterodimeric Cytokine Receptors
Authors: Righi Matteo , Gannon Isaac , Robson Matthew , Srivastava Saket , Kokalaki Evangelia , Grothier Thomas , Nannini Francesco , Allen Christopher , Bai Yuchen V. , Sillibourne James , Cordoba Shaun , Thomas Simon , Pule Martin
Published: June 2023

Adoptive T-cell therapy aims to achieve lasting tumor clearance, requiring enhanced engraftment and survival of the immune cells. Cytokines are paramount modulators of T-cell survival and proliferation. Cytokine receptors signal via ligand-induced dimerization, and this principle has been hijacked utilizing nonnative dimerization domains. A major limitation of current technologies resides in the absence of a module that recapitulates the natural cytokine receptor heterodimeric pairing. To circumvent this, we created a new engineered cytokine receptor able to constitutively recreate receptor-heterodimer utilizing the heterodimerization domain derived from the IgG1 antibody (dFab_CCR). We found that the signal delivered by the dFab_CCR-IL2 proficiently mimicked the cytokine receptor heterodimerization, with transcriptomic signatures like those obtained by activation of the native IL2 receptor. Moreover, we found that this dimerization structure was agnostic, efficiently activating signaling through four cytokine receptor families. Using a combination of in vivo and in vitro screening approaches, we characterized a library of 18 dFab_CCRs coexpressed with a clinically relevant solid tumor–specific GD2-specific chimeric antigen receptor (CAR). Based on this characterization, we suggest that the coexpression of either the common β-chain GMCSF or the IL18 dFab_CCRs is optimal to improve CAR T-cell expansion, engraftment, and efficacy. Our results demonstrate how Fab dimerization is efficient and versatile in recapitulating a cytokine receptor heterodimerization signal. This module could be applied for the enhancement of adoptive T-cell therapies, as well as therapies based on other immune cell types. Furthermore, these results provide a choice of cytokine signal to incorporate with adoptive T-cell therapies.
Supplemental Figure 4 from Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L , Fonseca Jairo A , Zhou Chengjing , Evans Alysa N , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M , Rafiq Sarwish , Langermann Solomon , Liu Linda N , Henry Curtis J , Porter Christopher C
Published: June 2023

Sig15 is required for immune evasion by murine B-ALL.
Supplemental Figure 1 from Siglec-15 promotes evasion of adaptive immunity in B-cell acute lymphoblastic leukemia
Authors: Pillsbury Claire E. , Dougan Jodi , Rabe Jennifer L , Fonseca Jairo A , Zhou Chengjing , Evans Alysa N , Abukharma Hasan , Ichoku Ona , Gonzalez-Flamenco Gloria , Park Sunita I. , Aljudi Ahmed , DeRyckere Deborah , Castellino Sharon M , Rafiq Sarwish , Langermann Solomon , Liu Linda N , Henry Curtis J , Porter Christopher C
Published: June 2023

Pathological overexpression of Sig15 in leukemia.
Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer
Authors: Mehra Siddharth , Garrido Vanessa T. , Dosch Austin R. , Lamichhane Purushottam , Srinivasan Supriya , Singh Samara P. , Zhou Zhiqun , De Castro Silva Iago , Joshi Chandrashekar , Ban Yuguang , Datta Jashodeep , Gilboa Eli , Merchant Nipun B. , Nagathihalli Nagaraj S.
Published: June 2023

Pancreatic ductal adenocarcinoma (PDAC) is a significant contributor to cancer-related morbidity and mortality, and it is known for its resistance to conventional treatment regimens, including chemotherapy and immune checkpoint blockade (ICB)-based therapies. We have previously shown that Urolithin A (Uro A), a gut microbial metabolite derived from pomegranates, can target and inhibit KRAS-dependent PI3K/AKT/mTOR signaling pathways to overcome therapeutic resistance and improve survival in PDAC. However, the effect of Uro A on the tumor immune microenvironment and its ability to enhance ICB efficacy has not been explored. This study demonstrates that Uro A treatment reduces stromal fibrosis and reinvigorates the adaptive T-cell immune response to overcome resistance to PD-1 blockade in a genetically engineered mouse model (GEMM) of PDAC. Flow cytometric–based analysis of Uro A-treated mouse tumors revealed a significant attenuation of immunosuppressive tumor-associated M2-like macrophages with a concurrent increase in the infiltration of CD4+ and CD8+ T cells with memory-like phenotype along with reduced expression of the exhaustion-associated protein, PD-1. Importantly, the combination of Uro A treatment with anti-PD-1 immunotherapy promoted enhancement of the antitumor response with increased infiltration of CD4+ Th1 cells, ultimately resulting in a remarkable improvement in overall survival in GEMM of PDAC. Overall, our findings provide preclinical evidence for the potential of Uro A as a novel therapeutic agent to increase sensitivity to immunotherapy in PDAC and warrant further mechanistic exploration in preclinical and clinical studies.

Significance:

Immunotherapeutic agents are ineffective against pancreatic cancer, mainly due to the immunosuppressive tumor microenvironment and stromal desmoplasia. Our current study demonstrates the therapeutic utility of a novel gut microbial metabolite, Uro A, to remodel the stromal-immune microenvironment and improve overall survival with anti-PD-1 therapy in pancreatic cancer.
Sequential Chromogenic IHC: Spatial Analysis of Lymph Nodes Identifies Contact Interactions between Plasmacytoid Dendritic Cells and Plasmablasts
Authors: Claudio Natalie , Nguyen My-Tien , Wanner Adrian , Pucci Ferdinando
Published: June 2023

Recent clinical observations have emphasized the critical role that the spatial organization of immune cells in lymphoid structures plays in the success of cancer immunotherapy and patient survival. However, implementing sequential chromogenic IHC (scIHC) to analyze multiple biomarkers on a single tissue section has been limited because of a lack of a standardized, rigorous guide to the development of customized biomarker panels and a need for user-friendly analysis pipelines that can extract meaningful data. In this context, we provide a comprehensive guide for the development of novel biomarker panels for scIHC, using practical examples and illustrations to highlight the most common complications that can arise during the setup of a new biomarker panel, and provide detailed instructions on how to prevent and detect cross-reactivity between secondary reagents and carryover between detection antibodies. We also developed a novel analysis pipeline based on non-rigid tissue deformation correction, Cellpose-inspired automated cell segmentation, and computational network masking of low-quality data. We applied this biomarker panel and pipeline to study regional lymph nodes from patients with head and neck cancer, identifying novel contact interactions between plasmablasts and plasmacytoid dendritic cells in vivo. Given that Toll-like receptors, which are highly expressed in plasmacytoid dendritic cells, play a key role in vaccine efficacy, the significance of this cell–cell interaction decisively warrants further studies. In summary, this work provides a streamlined approach to the development of customized biomarker panels for scIHC that will ultimately improve our understanding of immune responses in cancer.

Significance:

We present a comprehensive guide for developing customized biomarker panels to investigate cell–cell interactions in the context of immune responses in cancer. This approach revealed novel contact interactions between plasmablasts and plasmacytoid dendritic cells in lymph nodes from patients with head and neck cancer.
Causes and Mitigation Schemes of Project Delays among Selected Construction Companies in Cebu City
Authors: Dela Cruz Roselyn D. , Polinar Mark Anthony N.
Published: June 2023

A project's completion is crucial because it shows that goals and objectives have been met, guarantees client happiness, upholds a project's good reputation, and creates new prospects for those working in the construction business. However, in the field, construction projects need help with their timely execution and successful execution due to project delays, which can also affect costs, schedules, and stakeholder satisfaction. Hence, this phenomenological study explores the lived experiences of the project engineers who have existing projects on what are the perceived factors that cause project delays. On top of that, the study forms a series of recommendations to mitigate the identified causes of project delays. Eight (8) key informants were chosen using purposive sampling to be interviewed individually. In using Colaizzi's approach, eight themes materialized in the study: (1) Poor Management, (2) Limited Manpower, (3) Unskilled Workers, (4) Unforeseen Circumstances, (5) Poor Communication, (6) Financial Capabilities, (7) Insufficient Resources, and (8) External Factors. Ultimately, the authors concluded the need for solid project management practices, proactive risk reduction, and efficient communication to reduce delays and guarantee good project outcomes. Also, the authors concluded that if the entities appropriately and situationally consider these mechanisms recommended in the study, they will result in more precise and targeted responses to project delay issues, leading to service excellence and customer satisfaction.
Assessing Students’ Learning: Revisiting Challenges of Secondary Mathematics Teachers in Bicol Region, Philippines
Authors: Sionicio Joan Belen , Besmonte Al Banico
Published: June 2023

The COVID-19 pandemic led to a sudden paradigm shift in education worldwide.  To ensure that education would be undisrupted, many countries, including the Philippines, shifted from the usual face-to-face classes to distance learning modalities such as modular, online and blended.  With these rapid changes, mathematics teachers were confronted with a lot of uncertainties.  To investigate the challenges they encountered in assessing their students’ learning during the remote setting, this study used a descriptive research design.  Data were gathered through online questionnaires in Google form and informal interviews among 268 secondary mathematics teachers from the different divisions in Bicol Region, Philippines.  Thematic analysis was utilized in the analysis of qualitative data.  Results show challenges in terms of the quality of outputs, materials and resources, students’ performance and feedback mechanism. On a positive note, they regarded the pandemic as an opportunity for professional advancement and pedagogical flexibility.

The COVID-19 pandemic led to a sudden paradigm shift in education worldwide.  To ensure that education would be undisrupted, many countries, including the Philippines, shifted from the usual face-to-face classes to distance learning modalities such as modular, online and blended.  With these rapid changes, mathematics teachers were confronted with a lot of uncertainties.  To investigate the challenges they encountered in assessing their students’ learning during the remote setting, this study used a descriptive research design.  Data were gathered through online questionnaires in Google form and informal interviews among 268 secondary mathematics teachers from the different divisions in Bicol Region, Philippines.  Thematic analysis was utilized in the analysis of qualitative data.  Results show challenges in terms of the quality of outputs, materials and resources, students’ performance and feedback mechanism. On a positive note, they regarded the pandemic as an opportunity for professional advancement and pedagogical flexibility.
The Transitioning Experiences from Traditional to Agile Project Management: A Case of an Information Technology Department of a Private-Owned Financial Institution in Cebu City
Authors: Gerona Abigail W. , Ocampo Alex P.
Published: June 2023

Incorporating the Agile Project Management (APM) approach was the institution’s initiative to accelerate project delivery and be more flexible in changing requirements and client demands while producing quality software. The research explores the lived experiences of the institution's project managers to uncover the challenges and demonstrated benefits during Agile Project Management (APM) implementation. This research utilized the qualitative approach through interviews with key informants who are project managers of the institution. The data gathered were from the responses of the five (5) private-owned financial institution project managers. The responses were thoroughly reviewed and tabulated to reveal the commonalities in the data gathered. The study showed that implementing APM significantly changed how the project management team handled and delivered the projects. The project management team moved the project with agility by simplifying the scope and adapting to changes in requirements to increase customer satisfaction and value; the teams were more collaborative, flexible, and able to cope with the risks. However, the study revealed that the main challenges that the project management team experienced were the uncontrollable growth of changes in project scope, under-estimated timelines, and inefficient allocation and delegation of workloads, which resulted in the delayed delivery of projects. Also, it revealed that the current coping strategies were deprioritizing other projects to accommodate new requirements, extending project deadlines, and rendering overtime, which could have been more sustainable when appropriately handled. Furthermore, the study provided recommendations and action plans to improve the implementation of Agile Project Management.
Understanding the Influence of Cyberbullying Among High School Students in Philippine Public Schools in the Post-Pandemic Era
Authors: Buguina Lydia A. , Buguina Emil Constantine
Published: June 2023

This research sought to explore the effects of cyberbullying on high school students attending public schools in the Philippines. Given the widespread use of digital communication platforms and social media, cyberbullying has emerged as a significant societal concern. The study aims to determine the perceptions of senior high school students in the concept of bullying in the post pandemic era. The participants in this study consisted of 41 Grade 12 students from a public high school in the Philippines. Simple random sampling technique was used to select students which formed the research population. The study reveals that a significant number of SHS students possess knowledge about cyberbullying and its consequences. Among the coping strategies employed by these students include confiding with friends, emerges as a vital source of support in combating cyberbullying. Moreover, the collaboration between parents, students, and the school, along with the involvement of mental health professionals, enables effective communication and provision of assistance to students affected by cyberbullying. It is crucial for schools, teachers, parents, and students to increase their internet posting awareness and understanding of cyberbullying, while students should prioritize treating others kindly online and reporting cyberbullying. Parents should engage in open conversations and monitor their children’s digital activities while teachers and principals must foster a safe environment through education, anti-cyberbullying policies, and victim support.
The Effectiveness of Curriculum Review in Improving Quality, Relevance, and Students’ Employability in University Education in Uganda
Authors: Tagulwa Elvaida Agnes , Owino Philip , Muwonge Francis , Kaahwa Maria Goretti
Published: June 2023

The study examined the relationship between curriculum review and students’ employability in the faculty of science at Kyambogo University, Uganda. The population comprised of lecturers in the faculty of science and the sample size consisted of 66 full time lecturers. The specific objective of the study was to assess the relationship between curriculum review and students’ employability. Curriculum review was assessed regarding its relevance in developing professional skills, personal skills, and interpersonal skills as important employability skills for students. Quantitative results revealed that there is a positive statistically significant correlation between curriculum review and students’ employability (Professional skills r= 0.766, p=.0.001; Personal skills r=0.596, p=0.356; interpersonal skills, r=0.349, p=0.497). Regression analysis indicated that curriculum review (β = 0.75, P = 0.00) < 0.05) had a strong positive significant effect on students’ employability. Qualitative results revealed that curriculum review is one of the strategies of quality assurance at the programme level; participation of key stakeholders in the curriculum review ensures the quality and relevance of the curriculum; and financial facilitation of curriculum review process motivates higher levels of output. It is therefore recommended that: the University financially facilitates curricula reviews so that key stakeholders get involved to improve the quality and relevance of curricula; Kyambogo University should collaborate and develop partnerships with industries to improve educational innovation, University technology, and promote knowledge transfer from university to industry and society, and consequently enhance students’ employability.