bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB238: Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors
Authors: Tanabe Kenji
Published: April 2023

The gene encoding epidermal growth factor receptor (EGFR) is a major driver gene in cancer. Many drugs targeting EGFR-associated molecules have been developed, yet many have failed in clinical trials due to a lack of efficacy and/or unexpected side effects. In this study, I used image-based phenotypic profiling to screen a pharmacologically active compound library with the aim of identifying new druggable targets in the EGFR pathway. As anticipated, the phenotypic screen identified compounds that produce phenotypes resulting from targeting a known specific molecule or pathway. The assay also showed that compounds with diverse known mechanisms of action produced similar, EGFR-related cellular phenotypes. Biochemical assays revealed that those compounds share a previously unappreciated common target/pathway, showing that the image-based assay can identify new target molecules that are independent of the compound’s known target.

Citation Format: Kenji Tanabe. Image-based phenotypic profiling of a chemogenomic screening library identifies nobel targets of known inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB238.
Abstract LB255: Benchmarking NGS integration site analysis methods in support of long-term safety monitoring of gene therapy products
Authors: Otto Jeffrey M. , Fan Yongjun , Bao Guanhui , Corney David , Niu Ben , Yu Qiu , Khan Baursha , Turner Laure , Mozdzierz Chris , Latif Haythem , Zhou Ginger
Published: April 2023

The FDA Guidance to Industry on Long Term Follow-Up (LTFU) After Administration of Human Gene Therapy Products states the importance of longitudinal testing of gene products introduced into human subjects. Depending on the delivery mechanism, the therapeutic gene product may or may not integrate into the genome. Of particular interest are gene-product integrations near proto-oncogenes which might lead to malignancies. The FDA LTFU guidance states that recipients of an integrating gene therapy modality should be tracked for 15 years, while those receiving a non-integrating therapy modality should be tracked for 5 years. Therefore, advanced analytical methods are needed to identify, quantify, and track integration events across the genome. Here, we provide a comprehensive evaluation of methods leveraging next-generation sequencing approaches for genome-wide analysis of lentiviral integration events. Our analysis employed well-characterized standards consisting of varying copy number and known integration sites. ​

The approaches we characterized can be bucketed into two major groups: PCR amplification approaches and target capture-based approaches. All methods detected true positives with strong correlation to theoretical integration site dosage levels down to 1% allele frequency. Comparatively, PCR amplification-based approaches have lower data requirement per sample suggesting higher sensitivity, greater molecular capture, and lower limit of detection compared with target enrichment-based approaches. Target enrichment-based approaches can afford the flexibility to capture the integrated vector, which is of interest for characterizing partial integration events. While all methodologies performed well in our study, the choice of assay (or assays) for testing will depend on numerous factors including but not limited to the viral vector system and construct and starting material availability.

Citation Format: Jeffrey M. Otto, Yongjun Fan, Guanhui Bao, David Corney, Ben Niu, Qiu Yu, Baursha Khan, Laure Turner, Chris Mozdzierz, Haythem Latif, Ginger Zhou. Benchmarking NGS integration site analysis methods in support of long-term safety monitoring of gene therapy products [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB255.
Abstract LB274: Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance
Authors: Dou Xuefeng , Campisi Judith , Sun Yu
Published: April 2023

Cellular senescence is a permanent state of cell cycle arrest and occurs in proliferating cells subjected to various stresses. Although senescent cells remain metabolically active, little is known about their metabolic landscape and in vivo pathophysiological implications. Here we show that expression of the pyruvate dehydrogenase (PDH) inhibitory enzyme, pyruvate dehydrogenase kinase 4 (PDK4), is significantly upregulated in human senescent stromal cells. Preferentially expressed upon genotoxicity-induced senescence, PDK4 is negatively correlated with posttreatment survival of cancer patients. Upon cellular senescence, PDK4 shifts glucose metabolic flux from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, causing enhanced lactate production and forming an acidic microenvironment. However, distinct from the cancer cell-featured ‘Warburg effect’, senescent cells maintain an intensive use of pyruvate through the tricarboxylic acid cycle (TCA), displaying increased respiration and redox activity, indicative of a special form of metabolic reprogramming. Conditioned media from PDK4+ stromal cells change global expression and promote malignancy of recipient cancer cells in vitro and accelerate tumor progression in vivo. Nevertheless, specific targeting PDK4 curtails the adverse effects of senescent cells in cell-based assays, while promoting tumor regression and extending posttreatment survival in preclinical trials. Of note, increased levels of lactate in circulating blood after chemotherapy predicts lower survival in cancer clinics. PDK4 upregulation and ensuing lactate production are thus among key features of senescence, in addition to the established cell-autonomous and non-cell-autonomous hallmarks of senescent cells, providing a novel therapeutic target for future clinical oncology. Together, our study substantiates the hypercatabolic capacity of senescent cells, and reveals a metabolic link between senescence-associated acidic microenvironment and age-related pathologies, including but not limited to cancer.

Citation Format: Xuefeng Dou, Judith Campisi, Yu Sun. Senescent cells develop PDK4-dependent hypercatabolism and form an acidic microenvironment to drive cancer resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB274.
Abstract LB303: Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer
Authors: Zaheer Javeria , Shanmugiah Joycie , Kim Hyeongi , Kim Jin Su
Published: April 2023

The deposition of the extracellular matrix (ECM) is associated with poor prognosis and therapy response in gastric cancer. An elevated extracellular matrix (ECM) and interstitial fluid pressure in gastric cancer limits the targeting of HER2-expressing gastric cancer cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here we used Losartan (LOS), which is an antihypertensive drug, to downregulate ECM and interstitial fluid pressure in gastric cancer mice model. After 40 mg/kg of LOS treatment, a 2-fold higher Alexa-647-TRZ uptake significantly enhanced 64Cu-TRZ uptake by positron emission tomography (PET) imaging, LOS treatment decreased the tumor volume, and enhanced the survival rate. LOS-treated samples showed reduced SERPINE1 mRNA expression compared with the controls, as determined by qRT-PCR. Downregulated mRNA expression of TGFβ-1, and upregulated mRNA expression of MMP-2 in LOS-treated samples were observed. The corresponding protein expression of SERPINE1 was confirmed using western blotting. We also confirmed that silencing of SERPINE1 increased MMP2 activity. We revealed that the enhanced therapeutic effect of 64Cu-TRZ via LOS was due to the downregulation of SERPINE1, which degrades the ECM through MMP2. Our novel combinational therapy of using 64Cu-TRZ with LOS is highly effective for treatment of gastric cancer.

Citation Format: Javeria Zaheer, Joycie Shanmugiah, Hyeongi Kim, Jin Su Kim. Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB303.
Abstract LB340: Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer
Authors: Qu Shuang , Wang Jiafan , Jia Meng , Liang Hongwei , Liu Yuan , Zen Ke
Published: April 2023

Red blood cells (RBCs) have been widely used in delivering various drugs including cancer antigens. However, due to their inherent biocompatibility and low immunogenicity, RBC-based tumor antigen delivery often fails to initiate anti-tumor immunity and results in lower clinical efficacy of cancer vaccines. Here we report that tumor antigen-encapsulated RBCs can be rapidly transformed to spur cells which have much higher immunogenicity. Compared to normal RBCs, spur cells display a defused surface CD47 pattern with a lower affinity to SIRPα, and thus can be rapidly engulfed by activated macrophages and dendritic cells. The tumor antigen-loaded spur cells elicit high antigen responses both in vitro and in vivo. In combination with the SHP-1 inhibitor, spur cell-delivered KRASG12D antigenic peptides markedly suppress tumor growth in KRASG12D spontaneous mouse lung cancer model. In addition, a specific T cell population targeting the KRASG12D mutated peptide antigen is detected in cancer-survival mice. Our study thus has developed spur cell-delivered cancer neoantigen as an effective cancer vaccine.

Citation Format: Shuang Qu, Jiafan Wang, Meng Jia, Hongwei Liang, Yuan Liu, Ke Zen. Spur cell-delivered peptide antigen generates T cell immunity to eradicate mouse KRASG12D spontaneous lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB340.
Abstract LB351: A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer
Authors: Jaeger Alex M. , Weeden Andrew , Ali Anika
Published: April 2023

Antigen presentation is a fundamental component of cancer immunity. Cytotoxic CD8+ T cells, the primary mediators of cell killing, recognize peptide antigens presented in the context of Major Histocompatibility Complex Class I (MHC-I). MHC-I presents an astoundingly diverse array of peptides, collectively known as the immunopeptidome. The biosynthesis of the immunopeptidome, which integrates gene expression, protein synthesis, and proteolytic processing, is not well understood. Additionally, most studies interrogating the immunopeptidome use cultured cells in vitro, which lack physiologically relevant stimuli. In contrast, in vivo studies utilize bulk tumor or tissue lysates, in which heterogeneous cell mixtures obscure the ability to understand cell type or disease specific patterns of antigen presentation. The technical limitations have hampered our understanding of the cancer immunopeptidome in physiologically relevant tumor microenvironments in vivo. Here we present a novel genetically engineered mouse model (GEMM) of cancer, that includes KrasLox-Stop-Lox-G12D; p53fl/fl; a Cre conditionally tagged MHC-I (KbStrep), and a Cre conditionally tagged ribosome (Rpl22HA/HA), termed the “KP/RiboMHC” mouse model. The KP/RiboMHC model enables simultaneous purification of ribosomes and peptide MHC complexes to functionally interrogate translational dynamics and antigen presentation in vivo. We developed optimized workflows to perform simultaneous ribosome profiling and immunopeptidomics from lung and pancreas cancer cell lines in vitro and specifically from malignant cells in vivo. Thus, the KP/RiboMHC model provides an unprecedented opportunity to ask fundamental questions regarding the influence of physiological stimuli in the tumor microenvironment on the biosynthesis of the immunopeptidome. Insights gained using this mouse will pave the way forward for the development of context specific, peptide-centric cancer immunotherapies.

Citation Format: Alex M. Jaeger, Andrew Weeden, Anika Ali. A novel mouse model to interrogate the functional relationship between protein synthesis and antigen presentation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB351.
Abstract LB361: Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death
Authors: Choe Joshua H. , Kawase Tatsuya , Xu An , Guzman Asja , Tong David R. , Obradovic Aleksandar Z. , Low-Calle Ana M. , Alaghebandan Bita , Raghavan Ananya , Long Kaitlin , Hwang Paul M. , Schiffman Joshua D. , Zhu Yan , Zhao Ruiying , Lee Dung-Fang , Katz Chen , Prives Carol L.
Published: April 2023

Mutations that occur within the oligomerization domain (OD) of the tumor suppressor p53 generally abolish p53 tetramerization and are associated with increased cancer susceptibility in Li-Fraumeni syndrome (LFS). Despite their prevalence, the impact of OD-mutant p53 proteins in cancer, especially beyond a loss of canonical p53 activity, has not been well elucidated. We sought to delineate the gain-of-function (GOF) vs. loss-of-function (LOF) activities of OD-mutant p53, specifically focusing on the LFS tumor-derived p53(A347D) variant. We obtained LFS patient-derived dermal fibroblasts heterozygous for the mutation and generated an allelic series of U2OS cancer cell lines expressing wild-type p53, heterozygous (p53+/AD) or homozygous (p53AD/AD) mutant p53 or no p53 (p53 KO). In contrast to wild-type p53, mutant p53(A347D) exclusively forms dimers in both fibroblasts and cancer cells and has lost the ability to bind and transactivate the majority of canonical p53 target genes, which yields comparable tumorigenic properties between mutant p53 and p53 KO cells. Mutant p53(A347D), however, displays neomorphic activities. Glycolysis and oxidative phosphorylation pathways are enriched in cells bearing p53(A347D) relative to both wild-type p53 and p53 KO cells. Furthermore, dimeric mutant p53 induces striking mitochondrial network aberration and preferentially associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Ultimately, we describe dimeric mutant p53 as wielding a double-edged sword: driving tumorigenesis through LOF while gaining enhanced apoptogenic activity, thereby providing a potential basis for select therapeutic approaches.

Citation Format: Joshua H. Choe, Tatsuya Kawase, An Xu, Asja Guzman, David R. Tong, Aleksandar Z. Obradovic, Ana M. Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M. Hwang, Joshua D. Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol L. Prives. Li-Fraumeni syndrome-associated dimer-forming mutant p53 promotes transactivation-independent mitochondrial cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB361.
Supplementary Data from Hedgehog Signaling Regulates Treg to Th17 Conversion Through Metabolic Rewiring in Breast Cancer
Authors: Hinshaw Dominique C. , Benavides Gloria A. , Metge Brandon J. , Swain Courtney A. , Kammerud Sarah C. , Alsheikh Heba A. , Elhamamsy Amr , Chen Dongquan , Darley-Usmar Victor , Rathmell Jeffrey C. , Welner Robert S. , Samant Rajeev S. , Shevde Lalita A.
Published: April 2023

Supplementary Figures and Table
Table S2 from IOA-244 is a Non–ATP-competitive, Highly Selective, Tolerable PI3K 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

Table showing values of microsomal stability of IOA-244
Figure S4 from IOA-244 is a Non–ATP-competitive, Highly Selective, Tolerable PI3K 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

Tumor experiments showing monotherapy testing of IOA-244
Data from IOA-244 is a Non–ATP-competitive, Highly Selective, Tolerable PI3K 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

PI3K delta (PI3Kδ) inhibitors are used to treat lymphomas but safety concerns and limited target selectivity curbed their clinical usefulness. PI3Kδ inhibition in solid tumors has recently emerged as a potential novel anticancer therapy through the modulation of T-cell responses and direct antitumor activity. Here we report the exploration of IOA-244/MSC2360844, a first-in-class non–ATP-competitive PI3Kδ 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 regulatory T cell proliferation while having limited antiproliferative 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 Lewis lung carcinoma 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 natural killer 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 hematologic tumors.
Significance:
IOA-244 is a first-in-class non–ATP-competitive, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.
Kann man die IgA-Nephritis im Darm behandeln?
Authors: von Vietinghoff Sibylle
Published: April 2023

The therapeutic potential of a novel, targeted-release formulation of oral budesonide (Nefecon) for the treatment of IgA nephropathy (IgAN) was first demonstrated by the phase 2b NEFIGAN trial. To verify these findings, the phase 3 NefigArd trial tested the efficacy and safety of nine months of treatment with Nefecon (16 mg/d) versus placebo in adult patients with primary IgAN at risk of progressing to kidney failure (ClinicalTrials.gov: NCT03643965). NefIgArd was a multicenter, randomized, double-blind, placebo-controlled two-part trial. In Part A, 199 patients with IgAN were treated with Nefecon or placebo for nine months and observed for an additional three months. The primary endpoint for Part A was 24-hour urine protein-to-creatinine ratio (UPCR) after nine months. Secondary efficacy outcomes evaluated included estimated glomerular filtration rate (eGFR) at nine and 12 months and the UPCR at 12 months. At nine months, UPCR was 27% lower in the Nefecon group compared with placebo, along with a benefit in eGFR preservation corresponding to a 3.87 ml/min/1.73 m2 difference versus placebo (both significant). Nefecon was well-tolerated, and treatment-emergent adverse events were mostly mild to moderate in severity and reversible. Part B is ongoing and will be reported on later. Thus, NefIgArd is the first phase 3 IgA nephropathy trial to show clinically important improvements in UPCR and eGFR and confirms the findings from the phase 2b NEFIGAN study.
Krankheitsbewältigung bei Colitis ulcerosa: Die therapeutischen Ziele für die Zukunft bei der Behandlung von Colitis ulcerosa
Authors: Ramos Laura , Teo-Loy Jeny , Barreiro-de Acosta Manuel
Published: April 2023

Die Colitis ulcerosa, eine der phänotypischen Formen entzündlicher Darmerkrankungen, sollte als fortschreitende Erkrankung mit einem erhöhten Risiko für Komplikationen angesehen werden, wenn die Darmentzündung nicht ausreichend kontrolliert wird. Die Einführung neuer Behandlungsmethoden für diese Krankheit hat die therapeutischen Ziele verändert und erweitert, um den natürlichen Verlauf und die Entwicklung der Krankheit zu verändern. Das Konzept der «Krankheitsbewältigung» (Disease Clearance) bei Colitis ulcerosa zielt darauf ab, bei diesen Patienten eine klinische und biologische Remission sowie eine Mukosaheilung (endoskopisch, histologisch und in Zukunft auch molekular) zu erreichen. Der vorliegende Übersichtsartikel enthält die verfügbaren Daten zu den einzelnen Zielen der Krankheitsbewältigung bei Colitis ulcerosa, die in den kommenden Jahren in der klinischen Praxis Anwendung finden sollen.
Enhanced Mitochondria-SR Tethering Triggers Adaptive Cardiac Muscle Remodeling
Authors: Nichtová Zuzana , Fernandez-Sanz Celia , De La Fuente Sergio , Yuan Yuexing , Hurst Stephen , Lanvermann Sebastian , Tsai Hui-Ying , Weaver David , Baggett Ariele , Thompson Christopher , Bouchet-Marquis Cedric , Várnai Péter , Seifert Erin L. , Dorn Gerald W. , Sheu Shey-Shing , Csordás György
Published: April 2023

Background:

Cardiac contractile function requires high energy from mitochondria, and Ca
2+
from the sarcoplasmic reticulum (SR). Via local Ca
2+
transfer at close mitochondria-SR contacts, cardiac excitation feedforward regulates mitochondrial ATP production to match surges in demand (excitation-bioenergetics coupling). However, pathological stresses may cause mitochondrial Ca
2+
overload, excessive reactive oxygen species production and permeability transition, risking homeostatic collapse and myocyte loss. Excitation-bioenergetics coupling involves mitochondria-SR tethers but the role of tethering in cardiac physiology/pathology is debated. Endogenous tether proteins are multifunctional; therefore, nonselective targets to scrutinize interorganelle linkage. Here, we assessed the physiological/pathological relevance of selective chronic enhancement of cardiac mitochondria-SR tethering.

Methods:

We introduced to mice a cardiac muscle-specific engineered tether (linker) transgene with a fluorescent protein core and deployed 2D/3D electron microscopy, biochemical approaches, fluorescence imaging, in vivo and ex vivo cardiac performance monitoring and stress challenges to characterize the linker phenotype.

Results:

Expressed in the mature cardiomyocytes, the linker expanded and tightened individual mitochondria-junctional SR contacts; but also evoked a marked remodeling with large dense mitochondrial clusters that excluded dyads. Yet, excitation-bioenergetics coupling remained well-preserved, likely due to more longitudinal mitochondria-dyad contacts and nanotunnelling between mitochondria exposed to junctional SR and those sealed away from junctional SR. Remarkably, the linker decreased female vulnerability to acute massive β-adrenergic stress. It also reduced myocyte death and mitochondrial calcium-overload-associated myocardial impairment in ex vivo ischemia/reperfusion injury.

Conclusions:

We propose that mitochondria-SR/endoplasmic reticulum contacts operate at a structural optimum. Although acute changes in tethering may cause dysfunction, upon chronic enhancement of contacts from early life, adaptive remodeling of the organelles shifts the system to a new, stable structural optimum. This remodeling balances the individually enhanced mitochondrion-junctional SR crosstalk and excitation-bioenergetics coupling, by increasing the connected mitochondrial pool and, presumably, Ca
2+
/reactive oxygen species capacity, which then improves the resilience to stresses associated with dysregulated hyperactive Ca
2+
signaling.
Is Democracy the Answer to Intractable Climate Change?
Authors: Chesler Angela , Javeline Debra , Peh Kimberly , Scogin Shana
Published: April 2023

Climate change is the greatest governance challenge humanity has ever faced. Understanding why some governments successfully reduce greenhouse gas emissions and others fail is thus imperative. While regime type is often hypothesized to be a source of variation in greenhouse gas emissions, empirical findings about the effects of democracy and autocracy on climate action are contradictory. This research note reconciles these inconsistencies and adopts a quasi-experimental approach to investigate the relationship between democratization and greenhouse gas emissions. A fixed effects model with a synthetic control estimator is used to construct appropriate counterfactuals and evaluate the effect of regime type on emissions with data from the World Bank and Varieties of Democracy Project. The analysis shows that movement toward democracy does not have a significant effect on emissions, suggesting that research on the politics of emissions reduction should focus on factors other than regime type.
Beyond Legal Pluralism: Chinese Customs and Customary Laws in Colonial Hong Kong (1841–1997)
Authors: Chiang Cho Kiu
Published: April 2023

This article challenges the label of legal pluralism used in overseas Chinese studies. While legal pluralism has been the long-standing academic tradition of characterizing the law in overseas Chinese societies, the case of colonial Hong Kong, with its experience in rejecting, distorting, and manipulating Chinese customs and customary laws, illustrates that legal pluralism is an untenable position regarding the “plurality” of laws under a colonial regime and the “plurality” of social fields or legal orders with a “plurality” of sources of law. It is further argued that “legal pluralism” as academic jargon, a theory, and a framework, is intertwined with colonialism and therefore not useful as a descriptive category or as a normative ideal. We must go beyond legal pluralism to understand law in overseas Chinese studies.
New records of Neopetrosia carbonaria (Lamarck, 1814) from the Brazilian coast reveal new morphological features and spicule types
Authors: SANDES JOANA , ROCHA LÍVIA , PINHEIRO ULISSES , SANTOS GEORGE GARCIA
Published: April 2023

Sponges of the family Petrosiidae have usually a stony and brittle texture due the high silica content of the mineral skeleton that is formed by a more-or-less regular isotropic reticulation of undefined primary and secondary tracts. Neopetrosia species are distributed worldwide and twelve species are found in the Tropical Western Atlantic Ocean, of which four are recorded from the Brazilian coast. Here, we describe new Neopetrosia carbonaria specimens from several localities along the NE Brazilian coast, analyze the Neopetrosia carbonaria holotype and review the previous record of N. carbonaria from the Brazilian coast. Our study reveals new morphological features and spicule types in the Brazilian populations of N. carbonaria. Now, Neopetrosia carbonaria is defined by a thick encrusting to repent or ramose sponge, with reddish brown to brown color or dark green to black color in vivo, two categories of oxeas as megascleres and raphidiform toxas as microscleres. These toxas are quite rare and occur in both black and brown sponges. Due the absence and rarity of raphidiform toxas in some specimens, unrelated to its color, we assume that these differences are intraspecific. However, we suggest that all records of Neopetrosia carbonaria should be reevaluated, since toxas can be easily overlooked, added to the use of molecular methods to investigate the relationship between the Caribbean and Brazilian populations.
The millipede family Striariidae Bollman, 1893. VIII. Three new genera and four new species of minute millipedes from Oregon and Washington, USA(Diplopoda, Chordeumatida, Striarioidea)
Authors: SHEAR WILLIAM A. , MAREK PAUL E.
Published: April 2023

We describe three new genera and four new species of small, litter-dwelling millipedes from the states of Oregon and Washington, USA: Miniaria ramifera, n. gen., n. sp., Miniaria richarti, n. gen., n. sp., Tigraria oregonensis, n. gen., n. sp., and Kingaria prattensis, n. gen., n. sp. Some of the unusual characters of these species are discussed, including a new type of sensory array on the third tarsus of males and a newly observed mandibular gland.
Rediscovery and phylogenetic position of the glassfrog “Centrolene”acanthidiocephalum (Ruiz-Carranza and Lynch, 1989) (Anura: Centrolenidae)with the description of its advertisement call and comments on clutches and tadpoles
Authors: CARVAJAL-COGOLLO JUAN E. , QUIROGA-HUERTAS KAROL A. , MUÑOZ-CASTRO JOHANA A. , HERNÁNDEZ-AVENDAÑO PAOLA , GONZÁLEZ-DURÁN GUSTAVO A. , MEZA-JOYA FABIO LEONARDO
Published: April 2023

The lack of basic natural history and distributional data represents a challenge for the conservation of rare and endemic amphibian species. This is the case of “Centrolene” acanthidiocephalum, a poorly known glassfrog endemic to the Cordillera Oriental of the Colombian Andes. This species was formally described in the late 1980s and no records have been reported over the last quarter century. Therefore, little is known about its distributional boundaries, morphological variation, natural history, and evolutionary relationships. Here we report the finding of a population of “Centrolene” acanthidiocephalum from a locality around its historical range and provide additional information on its geographic distribution, clutch size, and adult morphology. We also present for the first time data on tadpole morphology, as well as a description of its advertisement call and a phylogenetic tree based on mitochondrial genetic data corroborating its generic position within Centrolene.
A new genus and species of the scale insect family Qinococcidae (Hemiptera: Coccomorpha) from China
Authors: ZHENG XINYI , WU SAN’AN
Published: April 2023

A new genus of Qinococcidae, Abrococcus Zheng & Wu gen. n. is established for a new species Abrococcus cunninghamia Zheng & Wu sp. n., which was collected on Cunninghamia lanceolata (Cupressaceae) from Guizhou Province, P. R. China. Descriptions and illustrations are provided for the adult female and first-, second- and third-instar female nymphs. Keys to the adult females and first-instar nymphs of the genera of Qinococcidae and known developmental stages of A. cunninghamia are provided.
Microlia cayaponia, a new pollen-feeder species from Brazil (Staphylinidae: Aleocharinae: Hoplandriini) and its potential competitionin pollinator activity in Cayaponia plants (Cucurbitaceae)
Authors: ZILBERMAN BRUNO , CARDOSO RENAN KOBAL DE OLIVEIRA ALVES , PIRES-SILVA CARLOS M. , SANTOS ISABEL ALVES DOS
Published: April 2023

Microlia Casey is a genus of small rove beetles from the New World and Australasia. Many species are recorded to be associated with the flowers of Cucurbitaceae, Solanaceae, Asteraceae, and Monimiaceae. In this work, a new species from Brazil associated with flowers of Cayaponia (Cucurbitaceae), Microlia cayaponia Zilberman & Pires-Silva sp. nov., is described and illustrated. Aspects of its natural history are also investigated, with insights on foraging, reproduction, and the supposed impact on the plant and pollinator’s fitness.
Public Health and Political Corporate Social Responsibility: Pharmaceutical Company Engagement in COVAX
Authors: Scholz Markus , Smith N. Craig , Riegler Maria , Burton Anna
Published: April 2023

Pharmaceutical companies developed Covid-19 vaccines in record time. However, it soon became apparent that global access to the vaccines was inequitable. Through a qualitative inquiry as the pandemic unfolded (to mid-2021), we provide an in-depth analysis of why companies engaged with the Covid-19 Vaccines Global Access Facility (COVAX), identifying the internal (to the company) and external factors that facilitated or impeded engagement. While all producers of the World Health Organization (WHO)-approved vaccines engaged with COVAX, our analysis highlights the differential levels of COVAX engagement and identifies contractual obligations, opportunities and company strategy, and reputational pressures as key explanatory factors. We discuss our empirical findings relative to the literature on political corporate social responsibility (PCSR). Accordingly, we question whether pharmaceutical companies lived up to their responsibilities as corporate citizens and conclude that they failed to fulfill the implied responsibility of combating inequitable vaccine distribution. We conclude with implications of our research for practice, in relation to the challenges of global access to Covid-19 vaccines and for access to medicines more generally.
Expanding Pharmacy Services to the Hemophilia Treatment Center
Authors: Charafi Lena , Campanella Lauren , Shay Blake , Rabatin Abigail , Hughes Adriana , Kennerly-Shah Julie
Published: April 2023

Background: Hemophilia treatment centers (HTC) are multidisciplinary clinics that serve as medical homes for patients with hemophilia and other bleeding or clotting disorders. Traditionally, hemophilia treatment center teams have included hematologists, social workers, nurse coordinators, physical therapists, and in some instances, other healthcare professionals. Objective: This report describes the role of clinical pharmacy services added at 2 HTCs. Method: Retrospective review of services provided by pharmacists integrated into the care team conducted at 2 HTCs. Conclusions: Pharmacists have the knowledge and training to positively contribute to the care of hemophilia treatment center patients. Specifically, with expertise in therapeutic drug monitoring, pharmacokinetics and patient counseling, pharmacists have the ability to manage the cost of care by promoting adherence, minimizing emergency department visits, and assisting providers in formulating optimal treatment plans to improve care for this patient population.
Tracking the Effects: Examining the Opportunity Stratification Hypothesis in Action
Authors: Edosomwan Kristian , Young Jemimah L. , Butler Bettie Ray , Young Jamaal R. , Williams John A.
Published: April 2023

The relationship between academic tracking and exclusionary discipline actions has only been studied in a limited number of empirical studies. By placing students at the lower strata, schools deprive them of the educational opportunities, widening the educational opportunity gap in a process we define as “opportunity stratification.” Using a quantitative analysis of data from the Educational Longitudinal Study, we found students in low-track, non-college preparatory courses had higher odds of experiencing both in-school and out-of-school suspensions when compared to students in the high-track, college preparatory courses. Our findings support the intersecting role of exclusionary discipline and tracking in opportunity stratification.
Determinants of Patient Satisfaction in Indigenous Cancer Palliative Care Services
Authors: Cheboi Solomon K. , Nyawira Daisy N. , Ngolo Peter M. , Ng’ang’a Wanjiru S.
Published: April 2023

Optimal quality of care remains an integral formal service along the continuum of care pathway. Patient satisfaction is an important health system responsiveness goal which has been shown to influence quality of care except in the indigenous settings. This study identified the determinants of patient satisfaction in the context of indigenous palliative care in Kenya. A descriptive cross-sectional study was conducted among cancer patients exiting indigenous care outlets located in 12 towns across Kenya using a structured modular questionnaire. Exit interviews were undertaken with 433 respondents leaving 193 mapped indigenous outlets. Overall services satisfaction was assessed as the dependent variable using a computed single-item satisfaction mean score. The data was analyzed using IBM Statistical Package for Social Sciences version 22. 0. Bivariate and multivariate analyses were conducted to identify the potential determinants. Against the 433 study respondents, 248 (57.3%) expressed overall satisfaction with indigenous palliative care services: Satisfaction was positively associated with waiting time (AOR = 2.663, 95% CI = 1.235-5.743), provider attention (AOR = 3.698, 95% CI = 1.657-8.254), provider politeness (AOR = 6.774, 95% CI = 3.697-12.413) and provider social communication skills (AOR = 6.520, 95% CI = 3.642-11.673). Good patient-provider interaction, provider social skills and service waiting time influence patient satisfaction with indigenous palliative care. The finding contributes to the understanding of indigenous palliative cancer care and provides scientific evidence for providers and policy makers to redesign and improve their service and outlet setting to provide patient centered holistic palliative care.
Components of Behavioral Parent Training for Children With Attention-Deficit/Hyperactivity Disorder: A Series of Replicated Single-Case Experiments
Authors: Hornstra Rianne , Onghena Patrick , van den Hoofdakker Barbara J. , van der Veen-Mulders Lianne , Luman Marjolein , Staff Anouck I. , van der Oord Saskia
Published: April 2023

Behavioral parent training (BPT) is an evidence-based treatment for children with attention-deficit/hyperactivity disorder (ADHD). Stimulus control techniques (antecedent-based techniques, e.g., clear rules, instructions) and contingency management techniques (consequent-based techniques, e.g., praise, ignore) are the most common ones that are being taught to parents in BPT. However, research into the additive effects of these techniques is scarce. In this replicated single-case experimental ABC phase design, including six children on stable medication for ADHD (8–11 years) and their parents, the added efficacy of consequent-based techniques on top of antecedent-based techniques was evaluated. After a baseline period (phase A), we randomized the commencement time of two sessions parent training in antecedent-based techniques and two sessions parent training in consequent-based techniques for each child. Children’s behaviors were assessed by daily parent ratings of selected problem behaviors and an overall behavior rating. Although visual inspection showed that behavior improved for most children in both phases, randomization tests did not demonstrate the added efficacy of the consequent-based techniques on top of the antecedent-based techniques. Limitations of the study and recommendations for future single-case experiments in this population are discussed.
How Values Are Discussed, Reflected Upon, and Acted On by Patients and Family Caregivers in the Context of Heart Failure: A Scoping Review
Authors: Bechthold Avery C. , Knoepke Christopher E. , Ejem Deborah B. , McIlvennan Colleen K. , Wells Rachel D. , Matlock Daniel D. , Bakitas Marie A. , Dionne-Odom J. Nicholas
Published: April 2023

Purpose

Values are critical to how individuals make decisions and cope, yet the values of heart failure (HF) patients and their family caregivers (FCGs) remain understudied. We sought to report the state of the science on how values are discussed, reflected upon, and acted on by patients with HF, their FCGs, or both related to health-related decision making and coping.

Method

A scoping review was conducted of empirical studies using the following keywords: “heart failure,” “values,” “decision-making,” and “coping.” PubMed, PsycINFO, and Scopus were searched from inception to June 2022 in English. Included articles reported values as a key finding (outcome/theme) in their abstract.

Results

Of 448 articles screened for eligibility, 16 met the inclusion criteria. Twelve articles reported findings addressing patient values, 3 addressed patient and FCG values, and 1 addressed FCG values. Values were reported to influence patient self-care behaviors and left ventricular assist device (LVAD) implantation decisions, although their prioritization varied across time and contexts. When prioritized values conflicted with recommended self-care activities, some patients modified their approach to achieving the value. Others modified or abandoned tasks in favor of the value and accompanying goals. Low motivation and alignment between unhealthy behaviors and values often led to nonadherent decisions. Five of 8 articles focusing on cardiac devices reported patient survival as the most prioritized value during implantation decisions. FCG values were rarely reported or evaluated separately from patient values. Patients leveraged several coping strategies, although the processes through which values affected coping was not described.

Conclusions

Prioritized values influenced HF-related decisions, including self-care and LVAD implantation. While several articles reported on coping and values, none described processes through which values affect coping, which highlights a research gap.

Highlights

Family caregiver values were rarely reported or evaluated separately from patient values, highlighting a gap in the literature.
The Nose and Paranasal Sinuses
Authors: Varricchio A. , Avvisati F. , Varricchio A.M. , Tortoriello G. , Ciprandi G.
Published: April 2023

The airways should be considered as a functional unit. Indeed, disorders involving the upper respiratory tract (URT) spread to the lower respiratory tract (LRT). Modern functional anatomy divides URT in three, mutually dependent, “junction boxes”: i) the ostio-meatal complex (OMC), ii) the spheno-ethmoidal recess (SER), and iii) the rhinopharynx (RP). The first is the most interesting as it joins the anterior paranasal sinuses with the nose. The correct ventilation and the effective mucociliary clearance of these “three pathophysiologic junction boxes” condition the healthy physiology of the entire respiratory system. The OMC, SER and RP obstruction is the first pathogenic step in the inflammatory cascade of the rhino-sinusal-pharyngeal disorders. The inflammation of the respiratory mucosa is the main pathogenic factor for “airway obstruction” that may be generically defined as a heterogeneous group of pathologies. Moreover, the bacterial biofilms are an important local cause of recurrent diseases: they are a strategic modality of survival set up by bacteria and the main cause of their resistance to systemic antibiotic therapy.
The Infections of the Upper Respiratory Tract in Children
Authors: Bonsignori F. , Chiappini E. , De Martino M.
Published: April 2023

Upper respiratory tract infections in children are common and usually self-limiting conditions, which include acute otitis media (AOM), acute rhinosinusitis (ARS), and acute pharyngitis (AP). Management of pediatric AOM considers observation strategy for selected and uncomplicated cases, older than 2 years of age, only when adequate follow-up can be ensured. Otherwise, an antibiotic treatment should be prescribed. Amoxicillin should be preferred as the first-choice therapy. Switch therapy to ceftriaxone is suggested if amoxicillin regimen failure occurs within 48–72 hours. The diagnosis of ARS is established by the persistence of purulent nasal of post-nasal draining lasting at least 10 days especially if accompanied by supporting symptoms and signs. Amoxicillin is the first choice drug for mild ARS in children. When symptoms persist or worsen, amoxicillin/clavulanate or cefpodoxime proxetil, or ceftriaxone are recommended. Clinical criteria alone are not sufficiently accurate in children with AP to distinguish bacterial and viral etiology. Thus microbiological evaluation is needed and positive throat colture or rapid antigen detection test are required to establish the diagnosis of streptococcal pharyngitis and consequently to prescribe antibiotic treatment. The first choice treatment in European countries still remains amoxicillin or amoxicillin/clavulanate.
Insights into Infectious Otitis Media
Authors: Marchisio P. , Bianchini S. , Capaccio P. , Esposito S. , Fusi M. , Nazzari E. , Torretta S. , Principi N.
Published: April 2023

Otitis media is a multifactorial disease. It represents a major public health burden, as it is the most common diagnosis in children and is characterized by both immediate and long-term morbidity. For years the knowledge about risk factors and microbiology of otitis media has been relatively stable. In recent years new data have been gathered regarding different microbiological aspects of otitis media. This new knowledge may contribute toward the development and implementation of therapeutic and preventive strategies.
Role of Nasal Cytology
Authors: Gelardi M. , Fiorella M.L. , Russo C. , Fiorella R. , Ciprandi G.
Published: April 2023

Nasal cytology represents a valid method in the differential diagnosis of allergic and non-allergic nasal diseases, as it is simple, safe, non-invasive, cost-effective, and easy to perform both in the medical and paediatric office. In particular, through cytological investigation it is possible to diagnose a group of “non-allergic infective rhinitis” that still today constitutes a vague aspect of the clinical-diagnostic-therapeutic approach to eosinophilic non-allergic rhinitis (NARES), non-allergic rhinitis mast cell (NARMA), neutrophilic non-allergic rhinitis (NARNA), and eosinophil-mast cell non-allergic rhinitis (NARESMA). Preventive treatment of nasal diseases, when guided by rhinocytograms, leads to a favorable clinical and time-dependent outcome. These advantages are reflected in a better quality of life and in a reduction in National Health Service costs, without chronic evolution of the disease to complications.
Upper Airways Disease: Role of Corticosteroids
Authors: Mori F. , Barni S. , Pucci N. , Rossi M.E. , Battaglini C. Orsi , Novembre E.
Published: April 2023

Nasal topical steroids (INCSs) are well established effective therapy in allergic rhinitis both in children and adults. There is clear benefit in using INCSs over antihistamines in allergic rhinitis while short courses of oral corticosteroids (CSs) may be indicated in severe cases. The addition of INCSs to oral antibiotics has been proven to be more effective than antibiotics alone for achieving symptomatic improvement in patients with acute rhino sinusitis. INCSs as monotherapy are also effective in the treatment of allergic rhinosinusitis (ARS). Several randomized controlled trials have evaluated the role of INCSs in chronic RS with the majority demonstrating a beneficial effect. In adults, the clinical efficacy of oral corticosteroids in the management of chronic RS with nasal polyposis is well established. There are no randomized controlled trials evaluating the efficacy of systemic CSs in chronic RS without nasal polyposis.