bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA-007: The KPC model has helped advance pancreatic cancer therapy: Agree
Authors: Olive Kenneth P.
Published: November 2021

The KPC genetically engineered mouse has been widely utilized within the pancreatic cancer field as a preclinical model system that recapitulates many aspects of human pancreatic ductal adenocarcinoma. The model has proven particularly accurate in replicating many of the etiological, histopathological, and physiological features of the human disease. KPC mouse pancreatic tumors also exhibit the broad chemoresistance phenotype that characterizes human pancreatic cancer, proving to be uniquely resistant to a wide range of cytotoxic, targeted, and immuno-oncology drugs. Nevertheless, the lack of efficacy in several clinical trials that derived from studies initially performed in the KPC model has provoked questions about the clinical predictiveness of the model, and by extension, its preclinical utility. This presentation will summarize the history and lessons learned from using the KPC mouse model and highlight impacts the model has had on pancreatic cancer therapy. We will focus in particular on the appropriate interpretation of preclinical results and understanding the similarities and differences between corresponding trials performed in KPC mice and humans. To date, the model has proven successful both in advancing promising biology-based regimens to the clinic and of dissuading the further clinical development of ineffective regimens. Moreover, by providing a vehicle for the conduct of “post-clinical” trials, the KPC model has enabled the study and understanding of why pancreatic cancer trials can fail, leading to critical lessons that are informing the design of future clinical trials (and the prioritization of candidate therapeutic agents). Innovative and promising therapeutics approaches developed from studies in the KPC model continue to advance through clinical trials and are bolstered by ongoing co-clinical efforts that iteratively pass from human to mouse and back again.

Citation Format: Kenneth P. Olive. The KPC model has helped advance pancreatic cancer therapy: Agree [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-007.
Abstract PO-031: Lysosome inhibition overcomes resistance to CDK4/6 inhibition in PDA
Authors: Silva Dilru , Kinsey Conan , McMahon Martin
Published: November 2021

The current FDA-approved chemotherapies for patients with Pancreatic Ductal Adenocarcinoma (PDA) demonstrate substantial toxicities with only a modest survival benefit highlighting the urgent need to better understand the molecular mechanisms driving PDA and how they interact in order to develop more precise and less toxic pathway-targeted therapies. PDA often harbors oncogenic mutations in KRAS and CDKN2A that drive a dysregulated cell cycle through activation of CDK4/6 (Cyclin-Dependent Kinases 4 and 6), which mono-phosphorylate RB1 to govern progression through G0◊G1◊S phases. Currently, there are three FDA-approved CDK4/6 inhibitors, palbo-, abema-, and ribociclib (X-ciclibs), that are predicted to have anti-cancer activity in PDA cells. However, the benefits of X-ciclib treatment in PDA patients are largely underwhelming. We found that inherent resistance to X-ciclib treatment in vitro is due to compensatory activation of protective autophagy, a critical lysosomal degradation process that generates a source of nutrients during periods of cellular stress. We observed that X-ciclib treatment induces autophagic flux in PDA cell lines. This pro-cancer process can be targeted with the lysosomal inhibitors, chloroquine and hydroxychloroquine. The addition of chloroquine sensitizes PDA cells to X-ciclib treatment, resulting in diminished proliferative ability. Additionally, a late-stage PDA patient was treated with the combination of an X-ciclib and hydroxychloroquine and displayed a dramatic decrease in the bloodborne PDA biomarker, Cancer Antigen 19-9. These data may suggest a novel combination treatment strategy for late-stage PDA patients, but the molecular mechanisms underlying are yet to be studied in PDA. Future work will explore the role RB1 plays in CDK4/6 regulated autophagy by investigating how phosphorylation at distinct RB1 sites modulates autophagy-related gene expression and the extent to which mTORC1 deactivation is necessary for CDK4/6 regulated autophagy.

Citation Format: Dilru Silva, Conan Kinsey, Martin McMahon. Lysosome inhibition overcomes resistance to CDK4/6 inhibition in PDA [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-031.
Abstract PO-040: Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing
Authors: Grahovac Jelena , Pavlovic Marijana , Ostojic Marija , Zivic Kristina , Galun Daniel , Srdic-Rajic Tatjana
Published: November 2021

The objective of this study was to examine the expression of Nischarin (NISCH) in pancreatic ductal adenocarcinoma (PDAC), and its potential as a target for drug repurposing. NISCH has been described as a tumor suppressor in breast and ovarian cancers, and there are several clinically approved agonists for this receptor. NISCH has also been reported as a scaffolding protein with a role in cell adhesion, invasion and metabolism – aspects of the PDAC biology that are of interest for therapeutical intervention. We examined mRNA and protein expression of NISCH in publicly available datasets, patient tumor samples, representative PDAC cell lines and patient-derived stellate cells. We found that NISCH is a prognostic marker in PDAC patients and that it is expressed in both cancer cells and cancer-associated stroma. Gene set enrichment analysis showed that NISCH expression was associated with the regulation of cell motility, cell cycle and energy metabolism. Indeed, NISCH knockdown in cancer cells induced reorganization of the actin cytoskeleton. Next, we tested the effects of three clinically approved NISCH agonists (rilmenidine, clonidine and moxonidine) on cancer cells and cancer-associated fibroblasts (CAFs). We found that rilmenidine, agonist with the highest affinity for the NISCH receptor, had the most potent effect. Rilmenidine impaired cancer cell adhesion, limited migration and decreased production of pro-metastatic cytokines and extracellular matrix deposition in cancer cell-CAF co-cultures. Our study lays a ground for more extensive examination of the role of NISCH in PDAC and implies that NISCH agonists may be good candidates for drug repurposing in this type of cancer.

Citation Format: Jelena Grahovac, Marijana Pavlovic, Marija Ostojic, Kristina Zivic, Daniel Galun, Tatjana Srdic-Rajic. Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-040.
Abstract PO-044: Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics
Authors: Massey Andrew
Published: November 2021

Pancreatic cancer is one of the most lethal malignancies with a 5-year survival rate currently below 10%. Unfortunately, current diagnostic methods are unable to readily recognize early disease progression, and symptoms are commonly misdiagnosed. Therefore, determining novel biomarkers related to disease progression remains an important area of research. Transmembrane mucins, a major component of the cellular glycocalyx, normally play a protective role in epithelial tissues; they are also known to be overexpressed in various cancers, including pancreatic. In addition, mucins are known to increase aggressiveness, enhance drug resistance, and reduce survivability in cancers where they are upregulated. Although the biochemical effects of mucins are well understood, there is minimal research into how they affect cancer cells at a biophysical level. Recently, there has been great interest in examining the biophysical properties of cancer cells. The current consensus is that cancerous cells are softer than their normal counterparts, and that more metastatic cells become softer compared to more benign tumor cells. Measuring these physical properties could potentially give clinicians a more rapid way to diagnose tumors, determine the course of disease progression, physically determine the effect of a biomolecule when its expression is altered, or determine the efficacy of various chemotherapeutics. In this study, we will first use atomic force microscopy-based nanomechanical mapping to measure the biophysical differences between normal cells, cancerous cells, and the extracellular matrix extracted from human patient tumor tissues and track the measured changes, both before and after chemo treatments. Our preliminary in vitro results suggest that 2D-adherent human cancerous pancreatic cells are indeed softer than their normal counterparts, in agreement with the literature. In addition, modulation of the glycocalyx architecture via hyaluronidase treatment leads to considerable changes in cellular stiffness in both normal and cancerous cells, implying a link between the glycocalyx and the underlying actomyosin skeleton. Future studies will examine the in vitro effects of specific transmembrane mucins. Using overexpression and knockdown transfection models, the impact on cellular mechanics, as well as structural changes in the glycocalyx and actomyosin cortex, will be analyzed in pancreatic cancer cells to determine how these mucins effect cellular mechanics and by extension regulate tumorigenesis and metastasis.

Citation Format: Andrew Massey. Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-044.
Abstract PO-069: Modeling the tumor microenvironment using tissue engineering technologies
Authors: Curvello Rodrigo , Kast Verena , Loessner Daniela
Published: November 2021

Tissue engineering technologies provide controllable and reproducible approaches to reconstruct the extracellular and cellular elements of pancreatic cancer. In a reductionist approach they allow the modelling of the complex tumor microenvironment (TME) and the study of disease biology and anti-cancer treatments. Our objective is that an engineered TME model, that mimics the tissue and matrix composition, architecture and cell types, will behave like a real tumor and is suitable for preclinical drug testing. Using biomimetic materials, we recreated the desmoplastic tissue characteristics of the pancreatic TME. Our natural and synthetic biomaterials were tailored to achieve the mechanical properties that resembled the stiffness and viscoelasticity of patient-derived tissues, providing a supportive cell-matrix interface for 3D cell culture conditions. Pancreatic cancer cells grown embedded in the matrix scaffolds formed tumor spheroids. Cell-based assays and microscopic analysis indicated a high cell viability and proliferation of the tumor spheroids as well as the expression of cancer-associated markers. Incorporation of cancer-associated fibroblasts and myeloid cells led to a multicellular 3D systems and matrix stiffening due to the secretion of extracellular matrix proteins. Transcriptomic analysis of the 3D cell cultures identified differentially regulated pathways related to cell proliferation, mechano-transduction and the secretion of pro-inflammatory cytokines, indicative of a malignant behavior. Treatment with mechano-modulating inhibitors and anti-cancer compounds increased the efficacy of chemotherapeutics, thereby reducing matrix stiffness and the release of cytokines. Our engineered TME model provides an easily translatable technology to ease the burden of pancreatic cancer, allowing us to characterize combination treatments that slow down or reduce tumor growth.

Citation Format: Rodrigo Curvello, Verena Kast, Daniela Loessner. Modeling the tumor microenvironment using tissue engineering technologies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-069.
Abstract PO-079: Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer
Authors: Xu Yi , East Michael , Morrison Ashley , Herrera Gabriela , Peng Laura , Johnson Gary , Yeh Jen Jen
Published: November 2021

Pancreatic adenocarcinoma (PDAC) remains an extremely lethal disease with few effective therapeutic options. Targeted therapy development has remained largely unsuccessful due to complex tumor heterogeneity and better molecular indicators of response are urgently needed. We have previously identified two distinct molecular tumor subtypes in PDAC, basal-like and classical, which are prognostic and dictate response to chemotherapy. We have also developed a patient derived xenograft (PDX) mouse model that maintains the integrity of patient tumor biology and recapitulates primary tumor subtypes in vivo. Here, we aim to utilize multiplexed kinase inhibitor beads and quantitative mass spectrometry (MIB-MS) to determine baseline kinase expression and adaptive kinome responses to therapy in PDAC PDX tumors. A total of 381 kinases were identified across all samples and tumor specific kinases were isolated by alignment to human peptides. Distinct kinase expression profiles were observed for basal-like and classical tumors. Basal-like tumors showed high expression of kinases involved in receptor tyrosine kinase activity, MAP kinase activity, and clathrin-dependent endocytosis. Classical subtype tumors showed increased expression of kinases involved in metabolism and cytoskeletal regulatory kinases. Differential protein expression was further validated by differential gene expression using RNAseq. MIB profiling of kinome response to EGFR inhibition by erlotinib indicated kinome reprogramming with upregulation of microtubule associated kinases and MAP kinase family members. Overall, these results suggest that basal-like and classical subtype tumors exhibit distinct kinome profiles that present possible subtype specific vulnerabilities to kinase inhibition. Stratifying kinase inhibitor therapies based on tumor subtype could improve response to targeted therapies in PDAC.

Citation Format: Yi Xu, Michael East, Ashley Morrison, Gabriela Herrera, Laura Peng, Gary Johnson, Jen Jen Yeh. Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-079.
Abstract PO-088: Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer
Authors: Shin Sauyeun , Nicolle Remy , Liauzun Mehdi , Solorzano Jacobo , Brunel Alexia , Jean Christine , Samain Remi , Raffenne Jerôme , Neuzillet Cindy , Joffre Carine , Rocci Stephane , Iovanna Juan , Dusetti Nelson , Larsson Ola , Pyronnet Stephane , Bousquet Corinne , Martineau Yvan
Published: November 2021

Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly dysregulated in both PDA cancer cells and their microenvironment. We aim at assessing whether quantification of mRNA translation could provide a distinct perspective on PDA and identify novel tumor subtypes. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed transcriptome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis allowed PDA tumors classification according to mRNA translation rate. PDX-derived cancer cells as well as common PDA cell lines were used to functionally characterize newly identified subtype. Independent component analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Therefore, the drug-resistant cancer cell phenotype showing auxotrophy to both serine and cysteine may be amenable to targeted therapy. Overall, our study highlights profiling of mRNA translation in cancer as an underexplored avenue for identification of previously unrecognized subtypes together with potential treatments.

Citation Format: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau. Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-088.
Abstract PR-014: Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1
Authors: Hasselluhn Marie C. , Decker Amanda R. , Garcia Alvaro Curiel , Maurer Carlo , Thomas Dafydd , Olive Kenneth P.
Published: November 2021

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an extremely heterogeneous tumor microenvironment (TME) paired with a sparse and compromised vascular network. These features of the TME shape drug responses and contributes to PDAC’s distinctive chemotherapeutic resistance. Prior work demonstrated that inhibition of the Hedgehog (Hh) signaling using Smoothened (Smo) inhibitors relieved some of the local angiogenic suppression. However, the precise mechanisms through which the Hh pathway regulates angiogenesis has remained elusive. Subsequent studies evaluating different timepoints yielded conflicting data on the role of Hedgehog signaling in angiogenesis. In order to replicate the heterogeneity and spatial patterning of cells in pancreatic tumors, we developed a novel tumor explant system for short-term cultures of both murine and human PDAC. Briefly, we cultured intact 300 μm slices of PDAC tissues in a modified gelatin platform system with a novel culture medium informed by the metabolic composition of PDAC tumor interstitial fluid. This system replicates some of the nutrient/waste gradient of PDAC and enables tumors to be culture up to one week with good representation of multiple cell types. Studies in explants were complemented by work in the KPC genetically engineered model of PDAC. Comparison of short versus long-term Smo inhibition in KPC mouse pancreatic tumors revealed a robust increase in vessel density in short-term treatment, which is lost at later timepoints. Studies in murine and human PDAC explants employing different Smo inhibitors demonstrated increased endothelial tip cell formation upon two days of treatment, resulting in increased vessel density after four days. Computational analyses of human PDAC single cell RNAseq data identified candidate cellular subsets potentially involved in the signaling cascade. RNAseq of pre- and on-treatment tumor samples from KPC mice identified Wif1 as a candidate Hh target gene that effected these programs. Mechanistic studies in tumor explants reveal a complex, multi-step mechanism involving multiple cell types that led to suppression of angiogenesis in PDAC. These studies demonstrate how the tumor explant platform can elucidate complex intercellular signaling cascades and provide a candidate mechanism for the Hh-mediated suppression of angiogenesis in PDAC.

Citation Format: Marie C. Hasselluhn, Amanda R. Decker, Alvaro Curiel Garcia, Carlo Maurer, Dafydd Thomas, Kenneth P. Olive. Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-014.
Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies
Authors: Zheng Sisi , Gillespie Elisabeth , Naqvi Ammar S. , Hayer Katharina E. , Ang Zhiwei , Torres-Diz Manuel , Quesnel-Vallières Mathieu , Hottman David A. , Bagashev Asen , Chukinas John , Schmidt Carolin , Asnani Mukta , Shraim Rawan , Taylor Deanne M. , Rheingold Susan R. , O'Brien Maureen M. , Singh Nathan , Lynch Kristen W. , Ruella Marco , Barash Yoseph , Tasian Sarah K. , Thomas-Tikhonenko Andrei
Published: November 2021

Downregulation of surface epitopes causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma membrane–bound CD22 Δex5–6 splice isoform, which is resistant to chimeric antigen receptor (CAR) T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein, thereby defining an event that is rate limiting for epitope presentation. Indeed, forcing exon 2 skipping with morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody–drug conjugate inotuzumab ozogamicin in vitro. Furthermore, among inotuzumab-treated pediatric patients with B-ALL, we identified one nonresponder in whose leukemic blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy.

Significance:

The mechanism(s) underlying downregulation of surface CD22 following CD22-directed immunotherapy remains underexplored. Our biochemical and correlative studies demonstrate that in B-ALL, CD22 expression levels are controlled by inclusion/skipping of CD22 exon 2. Thus, aberrant splicing of CD22 is an important driver/biomarker of de novo and acquired resistance to CD22-directed immunotherapies.

See the interview with Sarah K. Tasian, MD, and Andrei Thomas-Tikhonenko, PhD, corecipients of the 2024 Blood Cancer Discovery Award for Outstanding Journal Article: https://vimeo.com/992990779

See related commentary by Bourcier and Abdel-Wahab, p. 87.

This article is highlighted in the In This Issue feature, p. 85.
Clinical Characteristics and Outcomes Among Patients Undergoing High‐Risk Percutaneous Coronary Interventions by Single or Multiple Operators: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program
Authors: Kovach Christopher P. , Hebbe Annika , Barón Anna E. , Strobel Aaron , Plomondon Mary E. , Valle Javier A. , Waldo Stephen W.
Published: November 2021

Background

High‐risk percutaneous coronary intervention (HR‐PCI) is increasingly common among contemporary patients with coronary artery disease. Experts have advocated for a collaborative 2‐operator approach to support intraprocedural decision‐making for these complex interventions. The impact of a second operator on patient and procedural outcomes is unknown.

Methods and Results

Patients who underwent HR‐PCI from 2015 to 2018 within the Veterans Affairs Healthcare System were identified. Propensity‐matched cohorts were generated to compare the outcomes following HR‐PCI performed by a single or multiple (≥2) operators. The primary end point was the 12‐month rate of major adverse cardiovascular events. We identified 6672 patients who underwent HR‐PCI during the study period; 6211 (93%) were treated by a single operator, and 461 (7%) were treated by multiple operators, with a nonsignificant trend toward increased multioperator procedures over time. A higher proportion of patients treated by multiple operators underwent left main (10% versus 7%,
P
=0.045) or chronic total occlusion intervention (11% versus 5%,
P
<0.001). Lead interventionalists participating in multioperator procedures practiced at centers with higher annual HR‐PCI volumes (124±71.3 versus 111±69.2; standardized mean difference, 0.197;
P
<0.001) but otherwise performed a similar number of HR‐PCI procedures per year (34.4±35.3 versus 34.7±30.7; standardized mean difference, 0.388;
P
=0.841) compared with their peers performing single‐operator interventions. In a propensity‐matched cohort, there was no significant difference in major adverse cardiovascular events (32% versus 30%,
P
=0.444) between patients who underwent single‐operator versus multioperator HR‐PCI. Adjusted analyses accounting for site‐level variance showed no significant differences in outcomes.

Conclusions

Patients who underwent multioperator HR‐PCI had similar outcomes compared with single‐operator procedures. Further studies are needed to determine if the addition of a second operator offers clinical benefits to a subset of HR‐PCI patients undergoing left main or chronic total occlusion intervention.
Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice
Authors: Ott Christiane , Pappritz Kathleen , Hegemann Niklas , John Cathleen , Jeuthe Sarah , McAlpine Cameron S. , Iwamoto Yoshiko , Lauryn Jonathan H. , Klages Jan , Klopfleisch Robert , Van Linthout Sophie , Swirski Fil , Nahrendorf Matthias , Kintscher Ulrich , Grune Tilman , Kuebler Wolfgang M. , Grune Jana
Published: November 2021

Background

Degenerative aortic valve (AoV) disease and resulting aortic stenosis are major clinical health problems. Murine models of valve disease are rare, resulting in a translational knowledge gap on underlying mechanisms, functional consequences, and potential therapies. Naïve New Zealand obese (NZO) mice were recently found to have a dramatic decline of left ventricular (LV) function at early age. Therefore, we aimed to identify the underlying cause of reduced LV function in NZO mice.

Methods and Results

Cardiac function and pulmonary hemodynamics of NZO and age‐matched C57BL/6J mice were monitored by serial echocardiographic examinations. AoVs in NZO mice demonstrated extensive thickening, asymmetric aortic leaflet formation, and cartilaginous transformation of the valvular stroma. Doppler echocardiography of the aorta revealed increased peak velocity profiles, holodiastolic flow reversal, and dilatation of the ascending aorta, consistent with aortic stenosis and regurgitation. Compensated LV hypertrophy deteriorated to decompensated LV failure and remodeling, as indicated by increased LV mass, interstitial fibrosis, and inflammatory cell infiltration. Elevated LV pressures in NZO mice were associated with lung congestion and
cor pulmonale
, evident as right ventricular dilatation, decreased right ventricular function, and increased mean right ventricular systolic pressure, indicative for the development of pulmonary hypertension and ultimately right ventricular failure.

Conclusions

NZO mice demonstrate as a novel murine model to spontaneously develop degenerative AoV disease, aortic stenosis, and the associated end organ damages of both ventricles and the lung. Closely mimicking the clinical scenario of degenerative AoV disease, the model may facilitate a better mechanistic understanding and testing of novel treatment strategies in degenerative AoV disease.
Obligations of Conscience
Authors: Glackin Shane N.
Published: November 2021

In this paper, I outline and defend a commonly-held moral view which has received surprisingly little sustained philosophical attention. This view, which I call the ‘authority of conscience,’ states that believing ourselves to have moral obligations to act in a certain way does in fact create an obligation to act in that way. Although I do not provide a positive case for the principle of authoritative conscience, beyond its popularity and intuitive force, I defend it against several prima facie objections. I then go on to demonstrate that the principle does not entail any anti-realist metaethical commitments, and is therefore compatible in particular, and contrary to appearances, with plausible formulations of moral realism.
Carex maolanensis (Cyperaceae), a new species from Guizhou, China
Authors: ZHANG XIXI , YAO ZHENGMING , MENG HUILI , DENG YUNFEI
Published: November 2021

Carex maolanensis, a new species of Cyperaceae is described and illustrated from Guizhou, China. The new species belongs to sect. Decorae, and it is similar to C. jizhuangensis, but differs in having short rhizome, 3–7 spikes per node, terminal spikes androgynous, female glumes awned. The morphology of perigynium and achene of C. maolanensis and C. jizhuangensis is compared. According to the IUCN Red List criteria, it may be turned out to Endangered (EN) or Vulnerable (VU), however, for the present, it is better to be classified as Data Deficient (DD) because the field survey for the species is necessary. A revised identification key to the species of sect. Decorae from China is provided.
Rediscovery of Oocephalus foliosus (Hyptidinae—Lamiaceae): notes on taxonomy and conservation of a species endemic to the campo rupestre of Central Brazil
Authors: SOARES ARTHUR DE SOUZA , NEGRÃO RAQUEL , HARLEY RAYMOND MERVYN , PASTORE JOSÉ FLORIANO BARÊA , JARDIM JOMAR GOMES
Published: November 2021

Oocephalus foliosus was described in the first half of 19th century, based on a collection from central Goiás state, Brazil, being collected again only three times in surrounding areas. Although this species seems to be rare and endemic to a narrow area, it has never been listed on any threatened list or had its conservation status assessed. Recently, we recorded a small population of O. foliosus in the Pireneus peak, an area of campo rupestre located in the municipality of Pirenópolis, Goiás, allowing us to improve the species description, assess its extinction risk and comment on its taxonomy. Also, a second step lectotypification was needed to the species and is here proposed.
Murdannia triquetra var. ahuchawlense, a new variety of Murdannia triquetra from North Lakhimpur, Assam
Authors: PAGAG KANGKAN , BORTHAKUR SASHIN KUMAR
Published: November 2021

N/A
An assessment of the taxonomic validity of three species of marsupial frogs (Anura: Hemiphractidae: Gastrotheca) from the Yungas of Bolivia based on external morphology and cranial osteology
Authors: LANSAC CLAUDIA , AGUAYO RODRIGO , DE LA RIVA IGNACIO
Published: November 2021

The genus Gastrotheca (Anura: Hemiphractidae) is a group of marsupial frogs particularly diverse in Andean regions. Several taxonomic studies of this genus have been conducted in the humid cloud forests—or Yungas—of the Andean eastern slopes of central Bolivia (departments of Cochabamba and Santa Cruz). Yet, the distinction among three species that occur sympatrically in these forests, G. lauzuricae (proposed as a junior synonym of G. coeruleomaculatus in 2015), G. piperata, and G. splendens, remains unclear since the morphological characters that purportedly support their differentiation are variable and partly shared among them. We have carried out external morphological studies, including multivariate morphometric analyses, to assess how they support the taxonomic status of these three species. We also evaluated characters of the cranial osteology of a sample of six individuals using micro CT-scanning. Principal component and linear discriminant analyses resulted in a great overlap among the putative species. Cranial osteological comparisons did not reveal highly significant differences among them, but suggested that different degrees of hyperossification could be related to the developmental state of individuals. Our results indicate that most morphological and osteological reported differences between the three species likely represent intraspecific variation. Thus, we propose that the three nominal species belong to a single biological entity, for which the name Gastrotheca splendens (Schmidt, 1857) has priority. We also restrict the name Gastrotheca coeruleomaculatus (Werner, 1899) to externally similar congeneric populations from the Yungas forests of department of La Paz, but highlighting the need of a detailed evaluation of their taxonomic identity.
A new genus and species of sand-hopper, Mauritiorchestia fayetta gen. nov., sp. nov. (Amphipoda, Talitridae) from Mauritius
Authors: GREEN M.A.A. , APPADOO C. , LOWRY J.K. , MYERS A.A.
Published: November 2021

A new genus and species, Mauritiorchestia fayetta gen. nov., sp. nov., of talitrid amphipod is described from beaches in Mauritius. Mauritiorchestia differs significantly from the closely related genus Platorchestia in the maxilla 1 palp (absent in Mauritiorchestia, vestigial in Platorchestia) and in the dactylus of gnathopod 1 (simplidactylate in Mauritiorchestia, cuspidactylate in Platorchestia).
Effects of Parathyroidectomy on Normocalcemic Primary Hyperparathyroidism and the Role of Intraoperative PTH Measurement
Authors: Alameer Ehab , Omar Mahmoud , Hoof Marcus , Shalaby Hosam , Abdelgawad Mohamed , Zora Ghassan , Shama Mohamed , Kandil Emad
Published: November 2021

Background

Normocalcemic primary hyperparathyroidism (NCpHPT) and normohormonal primary hyperparathyroidism (NHpHPT) are recently recognized variants of primary hyperparathyroidism. Current guidelines for the management hyperparathyroidism recognize NCpHPT as one of the areas that are recommended for more research due to limited available data.

Methods

A retrospective review of patients who had parathyroidectomy between 2014 and 2019. We excluded patients with multiple endocrine neoplasia syndromes and secondary and tertiary hyperparathyroidism. Included patients were classified based on the biochemical profile into classic or normocalcemic hyperparathyroidism group. Collected data included demographics, preoperative localizing imaging, intraoperative parathyroid hormone levels, and postoperative cure rates.

Results

261 patients were included: 160 patients in the classic and 101 patients in the normocalcemic group. Patients in the normocalcemic group had significantly more negative sestamibi scans (n = 58 [8.2%] vs 78 [51.3%], P = <.01), smaller parathyroid glands (mean weight 436.0 ± 593.0 vs 742.4 ± 1109.0 mg, P = .02), higher parathyroid hyperplasia rates (n = 51 [50.5%] vs 69 [43.1%]), and significantly higher intraoperative parathyroid hormone at 10 minutes (78.1 ± 194.6 vs 43.9 ± 62.4 1, P = .04). Positive predictive value of both intraoperative parathyroid hormone and cure rate was lower in the normocalcemic group (84.2% vs 95.7%) and (80.5% vs 95%), respectively.

Conclusion

Normocalcemic hyperparathyroidism is a challenging disease. Surgeons should be aware of the lower cure rate in this group, interpret intraoperative parathyroid hormone with caution, and have a lower threshold for bilateral neck exploration and 4 glands visualization.
Book review: Rakesh Ankit, India in the Interregnum: Interim Government, September 1946–August 1947
Authors: Gupta Saumya
Published: November 2021

Rakesh Ankit, India in the Interregnum: Interim Government, September 1946–August 1947, New Delhi: Oxford University Press, 2019, 376 pp.
Investigation of anisotropy effects in glass fibre reinforced polymer composites on tensile and shear properties using full field strain measurement and finite element multi-scale techniques
Authors: Gonabadi Hassan , Oila Adrian , Yadav Arti , Bull Steve
Published: November 2021

Designing highly stressed offshore renewable energy composite structures (e.g. wind and tidal turbine blades) necessitates characterisation of woven fabric composite under off axial loading. In this work a combined method of finite element analysis, digital image correlation and microscopy is used to assess the effect of ply orientation on the tensile/shear properties and failure modes of woven glass fibre reinforced polymer composites. Full field strain maps obtained by the digital image correlation method were used to evaluate the damage development and the inhomogeneity of strain localisation. The development of finite element models of mechanical test specimens is based on the analysis of micro-mechanical models of representative volume elements using a homogenisation technique in order to calculate the effective orthotropic properties. The agreement between numerically and experimentally calculated strains obtained in the elastic regimes indicates that stress analysis conducted by numerical methods is useful when characterising the effect of ply orientation on mechanical behaviour. Strain measurement conducted by the digital image correlation method indicated that there is a strong relationship between the strain distribution and the microstructure/ply orientation. In addition, it was found that the levels of localised tensile strain are higher than the global strain indicating the structural heterogeneity of the composite material. Finally, microstructural analysis of tension and shear test specimens showed that the main failure modes are de-bonded fibres, fibre pull out, in-plane/inter-laminar shear cracks and delamination.
Citizenship as Politics and Performance of Religious Identity: Hindu Refugees from Sindh
Authors: Bhatia Mohita
Published: November 2021

Drawing from the ethnographic insights and experiences of Pakistani Hindu refugees in Rajasthan, India, this article examines their agency, politics and dilemmas. It illustrates how they actively participate in the process of their ‘becoming citizens’ by making use of the majoritarian political space and nationalist ‘Hindu India’ imagery. Their expressions of a cohesive Hindu identity, however, remain illusionary and incomplete as they do not correspond with the lived realities of fractures, antagonisms and heterogeneities within various Hindu communities. These differentiations also lay open the hierarchies within Hindu refugees and enable an analysis of citizenship as a continued, contested and differentiated process based on caste and class locations of the refugees. For the lower-caste/-class refugees, their citizenship assertions go beyond the point of acquiring legal citizenship and merges with the struggles of native Dalits. Through these variegated expressions and claims of citizenship of Hindu refugees, this article foregrounds the idea of citizenship as performative and processual, and not necessarily contingent on legal status or state’s sovereignty logic of citizen/non-citizen binary.
Effect of waist ease distribution on aesthetic fit
Authors: Bi Huijuan , Sun Yue , Zou Fengyuan , Liu Zheng
Published: November 2021

When a garment is given a certain amount of ease, the body shape characteristics and matching degree of air gap distribution determine the aesthetic fit of garment sculpt. The purpose of this study is to investigate the relationship between the aesthetic fit and air gap distribution of the bust and waist sections. Three factors, the ratio of the horizontal radius vector to the bust and waist sections ( HrvB, HrvW) and the location and proportion of darts ( DL, DP), have been considered in this analysis. Ten female participants with different Hrv (including HrvB and HrvW) were recruited and asked to wear 10 sample blouses with different DL and DP. Samples worn by participants are observed at different angles, and evaluated with scores by 30 experts. The air gap thickness (THA) between the garment and skin are measured by a TC2 scanner and Qualisys three-dimensional motion capture system. The results show that Hrv is the most important factor affecting the aesthetic fit, while DL and DP have significant influence on the formation of garment wrinkles. A round body shape has higher scores when wearing sample garments whose waist dart is close to the front and middle (samples L2, L3) and smaller back middle dart and front waist dart (samples P1, P2), while a flat body shape has higher scores in the opposite condition (sample L5, P5). In terms of air gap distribution, there is a significant positive correlation between HrvB and THA in the front area (132–180°). Here, HrvW was negatively correlated with THA in the back side area. The correlation coefficients are all above 0.6. The DL has a great influence on THA in the side area of the bust section and front side area of the waist section, while DP has a great influence on THA in the front and back areas of the bust section and the back side area of the waist section. In a comparative analysis, this paper proved that the smaller fluctuation of THA and the uniform ease distribution are more likely to present an aesthetic and fit dressing appearance. Although the relationship between THA and the three factors was not significant, the regularity of its distribution is accompanied by a significant change of dressing score.
Classroom Management Coaching for First-Year Urban Teachers: Purpose, Design, and Implementation
Authors: Kwok Andrew , Svajda-Hardy Megan
Published: November 2021

This qualitative study explores one urban district's purpose, design, and implementation of a unique classroom management coaching program for first-year teachers (FYTs). Through interviews of coaches, assistant principals, and district administrators, we identify why and how this program supported FYTs’ struggles with classroom management. Results highlight difficulties related to culturally responsive classroom management, which was mitigated by district coaches who provided individualized support. Data also indicates specific misconceptions held by FYTs, strategic district decisions in designing the coaching program, and challenges encountered throughout implementation. Findings have implications for the preparation and support of culturally responsive classroom management for FYTs.
Trade-offs in Substitution Treatment: A Qualitative Study of an Opioid Substitution Therapy Clinic as an Enabling and a Risk-Environment
Authors: Jakobsen Josefine Skou , Kloster Malene Lindgaard , Christensen Louise , Johansen Katrine Schepelern , Kappel Nanna , Kronbæk Mette , Fahnøe Kristian Relsted , Houborg Esben
Published: November 2021

This article presents results from a study of clients’ experiences of attending an opioid substitution treatment clinic in Copenhagen, Denmark. The study is part of a research project about the everyday lives of marginalized people who use drugs in Copenhagen, their risk environments, and their access to formal and informal resources. Thirty-eight clients participated in structured interviews, covering topics concerning drug use, income, housing, social relations, violence, and use of health and social services. A risk environment/enabling environment framework was developed to analyze the data. The study highlights the importance of including the drug scene that surrounds the clinic to understand the clinic as both an enabling, constraining, and risky environment affecting the clients’ everyday lives, their safety, health, and well-being. The study shows that the clinic gives the clients access to different material, social and affective resources, but that access to resources often involves different trade-offs. For the clients, such trade-offs include balancing enabling and risky aspects of interaction with other clients or accepting constraints to get access to substitution medicine. Some clients accept such trade-offs, others do not and choose to find other ways to get resources, exposing themselves to potential harm. By paying particular attention to these trade-offs, this study provides a nuanced picture of the clinic’s dual role in both being a source of stability and a place that many clients associate with feeling worried and insecure.
Outcomes, Union Rate, and Complications After Operative and Nonoperative Treatments of Neer Type II Distal Clavicle Fractures: A Systematic Review and Meta-analysis of 2284 Patients
Authors: Uittenbogaard Sophie J. , van Es Laurian J.M. , den Haan Chantal , van Deurzen Derek F.P. , van den Bekerom Michel P.J.
Published: November 2021

Background:

As nonoperative treatment of Neer type II distal clavicle fractures is associated with nonunion rates up to 33%, operative treatment is frequently advocated. However, evidence is lacking regarding which operative treatment to perform and whether this is superior to nonoperative treatment in terms of functional outcome and complication rate.

Purpose:

(1) To evaluate which surgical technique in the treatment of Neer type II distal clavicle fractures is optimal with regard to patient-reported outcomes and union and complication rates. (2) To review nonoperatively treated patients.

Study Design:

Systematic review; Level of evidence, 4.

Methods:

A systematic review of the literature and meta-analysis were performed on January 27, 2021, in PubMed, Embase, CENTRAL, CINAHL/EBSCO, Web of Science/Clarivate Analytics, and SPORTDiscus/EBSCO. The search included all studies regarding nonoperative and operative treatment of Neer type II distal clavicle fractures with a minimum of 20 patients and follow-up of 12 months. The primary and secondary outcomes were patient-reported outcome measures at 12 months and union, complication, and revision rates.

Results:

A total of 59 articles were included involving 2284 patients. Coracoclavicular fixation, hook plate, transacromial pins, alternative plate, tension band wire/K-wire, a combination of surgical techniques, and a nonoperative group were described. Hook plates showed lower Constant-Murley scores as compared with coracoclavicular fixation (standard mean difference, –0.77; 95% CI, –1.26 to –0.28; P = .002). However, no significant difference was seen when the hook plate was compared with the locking plate and tension band wire/K-wire groups, and no significant difference in union rate was seen among all operative treatment groups. Operatively treated patients had significantly higher union rates than patients treated nonoperatively (standard mean difference: 0.05; 95% CI, 0.01 to 0.37; P = .004).

Conclusion:

Patients treated with hook plates showed significantly lower Constant-Murley scores and higher complication and revision rates as compared with those treated with coracoclavicular fixation, without differences in union rate. Higher Constant-Murley scores were seen in those patients with supplemental coracoclavicular fixation when using locking. Nonoperatively treated patients showed good functional outcome despite the 31% nonunion rate, although future studies are necessary to substantiate this conclusion. When using a locking plate, additional craniocaudal fixation showed significant better functional outcome.