bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B043: Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme
Authors: Dang Tuyen T. , Morales Julio C.
Published: January 2023

Glioblastoma multiforme (GBM) is a deadly brain cancer with a 4-10% five-year survival rate. Even with the advent of temozolomide and tumor treating fields, at best GBM patients can hope for a median survival of approximately 25 months. The major cause of poor survivorship is the recurrence of inoperable therapy resistant secondary tumors. With the poor survivorship, there is an urgent need for novel therapy regimens. We propose a novel therapy and metastatic target for GBM treatment. Tissue Factor Pathway Inhibitor (TFPI) is a serine proteinase inhibitor. Classically, TFPI inhibits FXa and/or TF-VIIa to reduce blood coagulation. Recently, TFPI expression have been correlated with solid tumors such as breast, pancreatic, colorectal and brain tumors. However, it is unknown how TFPI contributes to cancer disease. We observed that TFPI increased expression correlated with GBM tumor samples. Additionally, GBM patients with high expression of TFPI had a poorer survivorship than those with low expression of TFPI. Using live cell imaging, we found that TFPI is required for cell motility, an initial and required step in cancer cell invasion. Additionally, we found that loss of TFPI increased 53bp1 foci formation. Increased 53bp1 foci formation is an indication of defunct DNA double stranded break repair. We found that loss of TFPI sensitizes cells to ionizing radiation another indication of a dysfunctional DNA double stranded break repair program. We found that loss of TFPI sensitizes cells to Parp-1 inhibition, a hallmark of a defunct homologous recombination repair program. Homologous recombination and non-homologous end-joining are the two major repair pathways for DNA double stranded breaks. Based on these preliminary data, we hypothesize that TFPI plays role in motility/invasion and DNA repair, which leads to therapy resistance and metastasis in GBM. TFPI is an attractive radio-sensitizer for GBM treatment since radiation is a first-line therapy modality. Additionally, Parp-1 inhibition is currently in clinical trials for GBM treatments. Lastly, there is an FDA approved inhibitor for TFPI, ANDEXXA and several TFPI antibodies in clinical trials. Our future endeavors are to elucidate the mechanisms by which TFPI regulates DNA repair and cancer cell invasion. These findings will lay down the foundation for using TFPI inhibitors as a concurrent treatment plan to standard of care.

Citation Format: Tuyen T. Dang, Julio C. Morales. Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B043.
Abstract IA008: Biology of metastasis-competent circulating tumor cells
Authors: Alix-Panabières Catherine
Published: January 2023

The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity.

Citation Format: Catherine Alix-Panabières. Biology of metastasis-competent circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA008.
Abstract IA010: Hypomethylation of immune-related loci contribute to prostate tumorigenesis
Authors: Haber Daniel A. , Guo Hongshan , Wittner Ben S. , Vuille Joanna A , Lawrence Michael S. , Wu Chin-Lee , Toner Mehmet , Miyamoto David T. , Maheswaran Shyamala
Published: January 2023

Cancer-associated alterations in DNA methylation include hypermethylation of focal CpG islands within promoters, as well as hypomethylation of large stretches of gene-poor chromosomal domains, so called Partially Methylated Domains (PMDs). While CpG island hypermethylation is associated with silencing of tumor suppressor genes, the functional consequences of hypomethylation are uncertain. PMDs may be cause or consequence of cancer cell proliferation, and they have been associated with transcriptional de-repression of repetitive sequences, as well as histone modification-triggered silencing of rare protein encoding genes within these domains. In studying Circulating Tumor Cells (CTCs) isolated from blood specimens of patients with prostate cancer, we mapped PMDs at the single cell level, identifying a set of 40 “core PMDs” that are shared across cancer cells, within and across different individuals, as well as in prostate cancer cell lines. By analyzing single nuclei from micro-dissected early-stage prostate tumors, we find that hypomethylation of these core PMDs occurs early during prostate tumorigenesis. Core PMDs are highly enriched for immune-related genes, many of which are co-located within a single chromosomal locus targeted for hypomethylation-associated silencing. Nested between adjacent PMDs, we also identify domains that have retained DNA methylation (Preserved Methylation Islands; PMIs), which have sharply demarcated borders, spanning one or a small number of genes. In contrast to PMDs, PMIs are enriched for cell proliferation-associated genes. Together, these observations suggest that hypomethylation-associated silencing of immune-related genes, with sparing of adjacent proliferation-associated genes, is an early event in prostate cancer development. These large-scale chromosomal modifications are detectable within CTCs and may present diagnostic opportunities.

Citation Format: Daniel A. Haber, Hongshan Guo, Ben S. Wittner, Joanna A Vuille, Michael S. Lawrence, Chin-Lee Wu, Mehmet Toner, David T. Miyamoto, Shyamala Maheswaran. Hypomethylation of immune-related loci contribute to prostate tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA010.
Abstract IA014: Effects of fluid shear stress on circulating tumor cells
Authors: Henry Michael
Published: January 2023

To colonize distant organ sites, cancer cells originating in solid tissues must traverse the circulatory system. How circulating tumor cells (CTCs) survive various biological and mechanical insults during this journey remains unclear. Mechanical challenges to CTCs include exposure to fluid shear stress (FSS) which ranges over several orders of magnitude throughout the circulatory system. To assess the effects of FSS on cancer cells, we developed a simple model to apply brief pulses of fluid shear stress to cancer cells in suspension. Surprisingly, we found that cancer cell lines, originating from many different tissues are more resistant to destruction by FSS than normal epithelial counterparts. FSS resistance is conferred on normal epithelial cells by transforming oncogenes and is evident in cancer cells acutely isolated from primary tumor tissues from mice and humans. Thus, FSS resistance is a conserved phenotype of viable transformed cells. FSS resistance is an active biological mechanism in viable cancer cells, dead and dying cancer cells are readily destroyed by FSS. In cancer cells, initial exposure to FSS results in rapid cell stiffening unlike non-transformed cells. This change in contractility of cancer cells exposed to FSS is associated with activation of RhoA/C GTPases. Correspondingly, in cancer cells exposed to FSS, there is a rapid increase in cortical F-actin that depends on formin activity, and myosin II activity is elevated. Both F-actin remodeling and myosin II activity are required for FSS resistance in vitro. Myosin II activity is also required for required for FSS resistance of experimental CTCs in vivo. Treatment of PC-3 cells with blebbistatin, a myosin II inhibitor, reduced the number of intact CTCs lodged in the lung and increased the number of CTCs destroyed immediately following tail vein injection. Moreover, treatment of mice bearing orthotopic prostate tumors with a non-toxic dose of blebbistatin reduced the levels of CTCs over 20-fold within 3h of treatment. As FSS exposure activates Rho GTPases, which are known to influence invasive and proliferative capacity of metastatic cells, more recently we have been investigating how FSS exposure may prime CTCs for metastasis. Exposure of both PC-3 and MDA-MB-231 cancer cell lines to FSS enhances metastatic colonization, invasive behavior in vitro and anchorage-independent proliferation. Ongoing efforts are to define the mechanisms that underly these emergent behaviors in response to FSS. In summary, we have found that viable CTCs actively resist destruction by FSS via a RhoA-dependent mechano-adaptive mechanism and that surviving cancer cells exposed to FSS exhibit enhanced metastatic potential.

Citation Format: Michael Henry. Effects of fluid shear stress on circulating tumor cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA014.
Abstract IA023: Tailored investigation and treatment of the brain metastasis micronich
Authors: Gephart Melanie Hayden
Published: January 2023

Brain metastases are highly aggressive, treatment-resistant malignancies with debilitating neurological sequelae and a grave prognosis. Common intrinsic features of the tumor and extrinsic features of the brain microenvironment, are relevant for cancer brain tropism and response to therapies. Efforts to understand, modulate, and target the metastatic brain tumor microenvironment have tremendous therapeutic potential.

Citation Format: Melanie Hayden Gephart. Tailored investigation and treatment of the brain metastasis micronich [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA023.
Abstract IA024: Cellular plasticity during metastatic colony formation in patients
Authors: Werner-Klein Melanie
Published: January 2023

Systemic cancer spread is a process whose complexity is only poorly understood. We have learned over the past years that metastatic dissemination starts very early in the evolution of a malignant clone of most cancers and that disseminated cancer cells (DCC) continue to acquire genomic alterations at the distant site. Consequently, it seems plausible that cellular phenotypes change during metastatic colony formation as well, although the impact of genotype changes on the cellular phenotypes is not clear at all. We studied this process in malignant melanoma, exploiting the unique chance that routine sentinel lymph node (SLN) biopsies provide for a cancer that is diagnosed much earlier and at smaller size than most other cancers. Moreover, mouse models suggest that lymph nodes serve as exit routes for systemic dissemination of cancer cells and that their colonization indues tumor-immune tolerance promoting distal metastasis. Melanoma DCC enter SLNs and may or may not give rise to a metastatic colony. We therefore first assessed in a large patient cohort comprising more than 500 early-stage melanoma patients, which melanoma marker is best suited to identify candidate metastasis founder cells and then progressed to provide their detailed molecular characterization. We found that melanoma cellular phenotypes indeed change over metastatic colony formation, indicating that differential molecular stage-specific targeting may be required to prevent metastasis formation. Of note, we observed mechanisms of very early immune suppression via DCC-derived EVs suggesting early DCC must find immune-escape strategies at the metastatic site.

Citation Format: Melanie Werner-Klein. Cellular plasticity during metastatic colony formation in patients [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA024.
Abstract PR004: Mechanistic basis for TGF-β-induced fibrogenic EMTs in metastasis
Authors: Lee Jun Ho , Basnet Harihar , Sánchez-Rivera Francisco , Wang Zhenghan , Li Liangji , Massagué Joan
Published: January 2023

The cytokine TGF-β is a central regulator of tissue homeostasis and regeneration through multiple coordinated effects on epithelial, immune, and mesenchymal stromal systems. Malfunctions of TGF-β signaling cause fibrosis, immune dysfunction, and cancer. As part of its multifunctional program, TGF-β induces epithelial-mesenchymal transitions (EMTs). Carcinoma cells use TGF-β to undergo EMT and adopt a highly plastic phenotype that facilitates tumor growth and metastasis. Notably, TGF-β-induced EMTs in epithelial progenitor cells are accompanied by the expression of fibrogenic factors that activate fibroblasts to produce and remodel the extracellular matrix. This not only occurs during wound healing but also in lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PDAC) cells, suggesting that EMT and fibrogenesis are parts of an orchestrated program. We recently showed that the transcription factor RAS-Responsive Element-Binding Protein 1 (RREB1) activated by RAS-MAPK signaling synergizes with SMADs to coordinately activate the expression of EMT transcription factor Snai1 and fibrogenic genes in carcinoma progenitors (Su et al Nature 2020). Using metastasis transplantation models, we have now found that both arms of the RREB1-dependent TGF-β responses are important for metastasis. Knockout of individual fibrogenic genes in cancer cells inhibited metastasis without altering the induction of EMT by TGF-β. To address why these TGF-β target genes specifically require KRAS-activated RREB1 for transcriptional induction, we employed proteomics approaches coupled with a CRISPR-based genetic screen. With this approach we identified DXH9 and INO80 as RREB1-interacting factors essential for TGF-β activation of fibrogenic EMT programs in PDAC and LUAD cells. DXH9 and INO80 are helicases that interact and SMAD3 and RREB1 in response to TGF-β. Knockout of Dhx9 or Ino80 abolished the induction of Snai1 and fibrogenic genes by TGF-β, inhibited the LUAD metastasis, and decreased intratumoral fibrosis, thus phenocopying the knockout of Rreb1. The helicase domain of DHX9 is required for TGF-β gene responses and metastasis. Our evidence indicates that RREB1, DXH9, and INO80 function to remodel the chromatin at specific loci that constitute a TGF-β-dependent fibrogenic EMT program. This work illuminates a previously unknown cooperation between TGF-β and RAS-MAPK pathways during epithelial tissue regeneration and its cooption in carcinoma metastasis.

Citation Format: Jun Ho Lee, Harihar Basnet, Francisco Sánchez-Rivera, Zhenghan Wang, Liangji Li, Joan Massagué. Mechanistic basis for TGF-β-induced fibrogenic EMTs in metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR004.
Abstract PR008: Timing complex copy number gains in whole genome duplicated tumors
Authors: Baker Toby M. , Lai Siqi , Dentro Stefan , Tarabichi Maxime , Loo Peter Van
Published: January 2023

The accumulation of genetic copy number aberrations is a process common to the development of many cancers. Tumors that have undergone a whole genome duplication (WGD) are known to have high degrees of genomic instability and often contain genomic regions that have undergone a series of copy number gains resulting in multiple copies of both alleles. Metastases are known to have an even greater rate of WGDs and general genomic instability. WGDs provide a powerful handle to time genetic events, such as single nucleotide variants or copy-number aberrations, in tumor evolution. However, the relative timing of copy number gains in whole genome duplicated tumors is complicated by the fact that there are multiple plausible route histories that could give rise to them. Typically, the most parsimonious event history is assumed to take place but this has never been validated. Here we describe a method, GRITIC, that overcomes this problem by evaluating all possible histories that could result in a given copy number state and determining the timing of the most likely series of gains. GRITIC allows the gains leading to any copy number state to be inferred. On a representative simulated cohort, it accurately measures the timing of complex copy number gains. By applying GRITIC to 6,010 primary and metastatic tumor samples from the Pan-Cancer Analysis of Whole Genomes and Hartwig Medical Foundation datasets, we find that the principle of maximum parsimony is violated in at least 25% of all copy number gains in whole genome duplicated tumors, with gains occurring both much earlier and later than thought under this assumption. We also find evidence for punctuated bursts of gains in WGD tumors, independent of the duplication itself. Finally, GRITIC allows us to look at the influence of WGD on copy-number events by comparing pre- and post-WGD copy number aberration landscapes. We find that the frequency with which different chromosome arms are gained before a WGD is highly correlated with the frequency that they are gained post-WGD. In contrast, the correlation between pre- and post-WGD losses is much smaller. We suggest that this indicates that a genome duplication changes the evolutionary trajectories of copy number losses but not gains. As an exception to this trend, chromosome 8 was disproportionately likely to be gained pre-WGD in metastatic prostate cancer as well as 1q in both breast and liver cancers. Altogether, GRITIC allows for a more accurate inference of evolutionary histories in different cancer types and better insights into the early genomic events that occur in tumors that underwent a WGD.

Citation Format: Toby M. Baker, Siqi Lai, Stefan Dentro, Maxime Tarabichi, Peter Van Loo. Timing complex copy number gains in whole genome duplicated tumors [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR008.
Abstract PR009: Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer
Authors: Pradat Yoann , Viot Julien , Gunbin Konstantin , Iurchenko Andrei , Deloger Marc , Cerbone Luigi , Grisay Guillaume , Verlingue Loic , Scott Veronique , Michiels Stefan , Hollebecque Antoine , Jules-Clement Gerome , Laine Antoine , Friboulet Luc , Mezquita Laura , Loriot Yohann , Besse Benjamin , Andre Fabrice , Cournede Paul-Henry , Gautheret Daniel , Nikolaev Sergey
Published: January 2023

Metastatic relapse after treatment is the primary cause of cancer morbidity and mortality. While genetic mechanisms of primary tumors and, to a lesser extent, metastatic cancers have been studied in large cohorts, refractory metastatic tumors are not yet sufficiently characterized. Markers of aggressiveness and resistance that molecular profiling can extract from these tumors have yet to be identified and incorporated into clinical care. In this study, we present a pan-cancer cohort of 1,031 metastatic tumors (which we refer to as META-PRISM) that are resistant to at least one systemic therapy or with no approved treatment options. We retrieved the complete clinical history of patients and performed whole-exome (n=571) and transcriptome sequencing (n=947) for this cohort. The prevalence of detected cancer biomarkers was assessed and compared to an external cohort of primary tumors. In the META-PRISM cohort, we observed an increase in (i) whole-genome duplication frequency, (ii) tumor mutational burden, (iii) germline cancer-predisposing variants, and (iv) somatic alterations in cancer genes, including KRAS, EGFR, CCND1, MYC, and TP53, as compared to the tumor type-matched primary tumors. The most extensive increase in genomic variation at metastatic stage was observed in prostate cancer. We also identified enrichment of standard-of-care resistance biomarkers in most cancer types. However, only 7.6% of tumors harbored at least one such biomarker, indicating that the current understanding of resistance mechanisms remains insufficient. Our cohort demonstrated a significantly improved 6-month survival prediction from models incorporating molecular markers over models with only clinical markers for breast cancer patients and to a lesser extent for other studied tumor types. Overall, our data establish a unique resource for investigating treatment resistance mechanisms and performing predictive analyses in cancer.

Citation Format: Yoann Pradat, Julien Viot, Konstantin Gunbin, Andrei Iurchenko, Marc Deloger, Luigi Cerbone, Guillaume Grisay, Loic Verlingue, Veronique Scott, Stefan Michiels, Antoine Hollebecque, Gerome Jules-Clement, Antoine Laine, Luc Friboulet, Laura Mezquita, Yohann Loriot, Benjamin Besse, Fabrice Andre, Paul-Henry Cournede, Daniel Gautheret, Sergey Nikolaev. Integrative pan-cancer genomic and transcriptomic analyses of refractory metastatic cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR009.
Abstract PR011: The glutathione S-transferase, Gstt1 is a robust driver of survival and dissemination in metastases
Authors: Ferrer Christina M.
Published: January 2023

Identifying adaptive mechanisms of metastatic cancer cells remains an elusive question in the treatment of metastatic disease, particularly in pancreatic cancer (PDA), where the majority of patients present with metastatic lesions at the time of diagnosis. A loss-of-function shRNA targeted screen in metastatic-derived cells identified Gstt1, a member of the glutathione S-transferase superfamily, as uniquely required for metastasis and dissemination however dispensable for primary tumor growth. Gstt1 is expressed in early disseminated tumor cells (DTCs), is retained within a subpopulation of slow-cycling cells within established metastases and its inhibition completely abolished macrometastatic lesions. This distinct Gstt1high population is highly metastatic and retains slow-cycling phenotypes, EMT features, and DTC characteristics compared to the Gstt1low population. Mechanistic studies indicate that in this subset of cells, Gstt1 maintains metastases by binding to and modifying intracellular fibronectin, regulating fibronectin secretion from cancer cells and deposition into the metastatic microenvironment. We identified Gstt1 as a novel mediator of metastasis, highlighting the importance of metastatic heterogeneity and its influence on the metastatic tumor microenvironment.

Citation Format: Christina M. Ferrer. The glutathione S-transferase, Gstt1 is a robust driver of survival and dissemination in metastases [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr PR011.
Metformin’s Role in Hyperlactatemia and Lactic Acidosis in ICU Patients: A Systematic Review
Authors: Mueller Livia , Moser Michel , Prazak Josef , Fuster Daniel G. , Schefold Joerg C. , Zuercher Patrick
Published: January 2023

Introduction: Metformin-treated patients may experience severe hyperlactatemia or lactic acidosis (LA). LA often requires intensive-care-unit (ICU) treatment, and mortality rates are high. Here, we investigate the impact of renal dysfunction and renal replacement therapy (RRT) on the outcomes of critically ill patients with metformin-associated LA (MALA). Furthermore, we assessed associations between mortality and metformin dose, metformin plasma/serum concentrations, lactate level, and arterial pH. Finally, we investigated whether the recommended classification in MALA, metformin-unrelated LA, metformin-induced LA, and LA in metformin therapy appears useful in this regard. Methods: We performed a retrospective analysis based on a systematic PubMed search for publications on hyperlactatemia/LA in metformin-treated ICU patients from January 1995 to February 2020. Case-level data including demographics and clinical conditions were extracted, and logistic regression analyses were performed. Results: A total of 92 ICU patients were reported. Two of these patients had no comorbidities interfering with lactate metabolism. In the overall group, arterial pH, lactate levels, and metformin plasma/serum concentrations were similar in survivors versus non-survivors. Ingested daily metformin doses and plasma/serum creatinine levels were significantly higher in survivors versus non-survivors (p = 0.007 vs. p = 0.024, respectively). Higher plasma/serum creatinine levels, higher lactate levels, and lower arterial pH were all associated with patients receiving RRT (all p < 0.05). Overall mortality was 22% (20 out of 92 patients) and did not differ between the RRT and non-RRT groups. Conclusion: Mortality is high in ICU patients with metformin-associated hyperlactatemia/LA. Unexpectedly, higher ingested metformin dose and plasma/serum creatinine were associated with a better outcome. Survival was similar in patients with or without need for RRT.
Serum Immunoglobulin G Testing against Pigeon Egg in Stable Fibrotic Hypersensitivity Pneumonitis
Authors: Okuda Ryo , Takemura Tamiko , Baba Tomohisa , Hagiwara Eri , Okudela Koji , Ogura Takashi
Published: January 2023

Introduction: The accuracy of serum immunoglobulin (Ig) G testing for diagnosis of stable bird-related fibrotic hypersensitivity pneumonitis (HP) is controversial. Furthermore, avian serum, extracts, or feathers were employed as antigens in bird-related HP; however, the usage of egg whites has not been reported. We investigated the utility of IgG testing against pigeon egg whites in patients with stable bird-related fibrotic HP. Methods: Patients having a positive inhalation test for pigeon antigen and a histological investigation with diagnostic confidence of fibrotic HP greater than moderate confidence were included. The control group consisted of patients with interstitial lung diseases (ILDs) other than HP. To select patients in the stable phase, patients with fibrotic HP were excluded if they were clinically considered to be in the acute exacerbation or acute phase. The IgG testing against pigeon egg whites by enzyme-linked immunosorbent assay and the commercialized anti-pigeon IgG testing by fluorescence enzyme immunoassay were investigated. Results: In this study, 37 patients with stable bird-related fibrotic HP and 32 patients with ILDs other than HP participated. Serum IgG testing for pigeon egg whites revealed that the control group’s optical density was 0.147 and the group with bird-related fibrotic HP had a mean value of 0.207 (p = 0.011). IgG testing in bronchial alveolar lavage fluid was not significantly higher in the bird-related fibrotic HP group than in controls (p = 0.42). No significant difference in area under the curve between an IgG testing against pigeon egg whites and a commercialized anti-pigeon IgG testing was observed (p = 0.24). Test accuracy for stable bird-related fibrotic HP ranged from 62% to 76% sensitivity and 59–66% specificity. Conclusion: IgG testing to identify the inciting antigen in patients with stable bird-related fibrotic HP had relatively low accuracy.
Challenges for Plasma-Derived Medicinal Products
Authors: Strengers Paul F.W.
Published: January 2023

Background: Plasma-derived medicinal products (PDMPs) are medicinal products derived from human plasma, and a number of PDMPs are listed on the WHO Model List of Essential Medicines. These and other PDMPs are crucial for the prophylaxis and treatment of patients with immune deficiencies, autoimmune and inflammatory diseases, bleeding disorders, and a variety of congenital deficiency disorders. The majority of plasma supplies for manufacturing of PDMPs is coming from the USA. Summary: The future of treatments with PDMPs for PDMP-dependent patients depends on the supply of plasma. An imbalance in the global collection of plasma has resulted in regional and global shortages of essential PDMPs. The challenges at different level are mainly related on a balanced and sufficient supply in order to help the patients in need and should be addressed in order to safeguard the treatment with these essential lifesaving and disease mitigating medicines. Key Messages: It is advocated to consider plasma as a strategic resource comparable to energy and other rare resources and to investigate whether for the treatment of patients with rare diseases, a free market of PDMPs has its limitations and special protection measures should be developed. At the same time, plasma collections should be increased outside the USA, including in low- and middle-income countries.
Patient and Parent Perspectives on Testicular Adrenal Rest Tumors in Congenital Adrenal Hyperplasia
Authors: Nebesio Todd D. , Kim Mimi S. , Szymanski Konrad M. , Kokorowski Paul J. , Geffner Mitchell E. , Eugster Erica A. ,   on behalf of the Life with Congenital Adrenal Hyperplasia Study Group
Published: January 2023

Background: Testicular adrenal rest tumors (TARTs) increase the risk of infertility in males with classic congenital adrenal hyperplasia (CAH). There is no consensus regarding at what age screening testicular ultrasounds should begin and how often they should be repeated. Furthermore, it is unknown whether patients and parents are aware of the significance of TARTs. Objective: The objective of the study was to investigate awareness, concern, and screening rates for TARTs in males with classic CAH. Methods: Males with CAH and parents completed an online questionnaire from 2019 to 2020. Responses to questions about TARTs were analyzed. Fisher’s exact test was used to determine statistical significance. Results: Of 123 responders, 14 were males with CAH (range 16–54 years) and 109 were parents of males with CAH (son’s age range infancy to 37 years). Of all responders, 74% were concerned about the possibility of TARTs, 48% had discussions about TARTs with their endocrinologist, and 42% were aware of possible infertility in males with CAH. There was no difference between responses provided by affected males and parents for these topics (p ≥ 0.08). Among male responders with CAH, 93% had at least one testicular ultrasound, and 77% had undergone more than one. Among parent responders, 30% of their sons had at least one testicular ultrasound, and 61% had more than one. The frequency, total number, and age when the first testicular ultrasound was obtained were inconsistent in both groups. Fifty percent of male responders with CAH and 11% of sons were referred to a urologist for evaluation. Conclusions: Although most responders were concerned about TARTs, less than half recalled discussing this issue with their endocrinologist, and less than half were aware of the possibility of infertility. Although TARTs are most often treated medically, several responders were referred to a urologist. Standardized patient education and consensus guidelines are needed for the surveillance and management of TARTs in males with classic CAH.
A (Des)construção do feminino em Uma aprendizagem ou O livro dos prazeres
Authors: Ianof de la Fuente Jenifer
Published: January 2023

O presente artigo visa à análise do processo de ressignificação do conceito de feminino e da constituição da protagonista como sujeito do livro Uma aprendizagem ou O livro dos prazeres, de Clarice Lispector.
Para esse fim, far-se-á um breve estudo da linguagem usada pela autora à luz da hermenêutica, da psicanálise lacaniana e de teorias feministas de autoras como Simone de Beauvoir e Virginia Woolf. Assim, expõem-se os questionamentos dos padrões históricos, sociais e culturais de gênero e as quebras de paradigmas, tanto conceituais como estilísticos de que lançam mão a autora.
Será analisada uma passagem do romance para exemplificar a complexidade da obra em relação ao tema em questão e mostrar como ocorre uma desmontagem de estereótipos e o valor estético do livro.
50 anos do Programa de Pós-Graduação em Literatura Brasileira da FFLCH-USP: anos de formação
Authors: Angelozzi Amanda , Enabe Cláudia Ayumi , Dos Santos Fernando Borsato
Published: January 2023

Esta seção reúne depoimentos de docentes e egressos do Programa de Pós-Graduação em Literatura Brasileira, dando continuidade às celebrações do aniversário de 50 anos. Os relatos acompanham as trajetórias formativas junto ao PPGLB, de modo a atingir uma perspectiva afetiva da história do Programa. Os autores das rememorações a serem lidas nas próximas páginas são: Acauam Oliveira, egresso e professor da Universidade de Pernambuco; Caio Cesar Esteves de Souza, egresso e doutorando na Universidade de Harvard; Ligia Rivello Baranda Kimori, egressa e do IEB e pesquisadora independente; João Roberto Gomes de Faria, professor titular do PPGLB; Noemi Jaffe, egressa, escritora e professora; e Yudith Rosenbaum, professora do PPGLB.
A new species of Aulacospermum (Umbelliferae) from Uzbekistan
Authors: PIMENOV MICHAEL G. , TOJIBAEV KOMILJON SH. , DEGTJAREVA GALINA V. , OSTROUMOVA TATIANA A. , ZAKHAROVA EKATERINA A. , KARIMOV FARKHOD I. , SAMIGULLIN TAHIR H.
Published: January 2023

A new species, Aulacospermum multicaule from the southwestern Tian-Shan (eastern part of the Kurama Range in Uzbekistan), is described and illustrated. The new species is related to A. roseum and differs in the features of stem (9–11 vs. solitary or 2–4), stem base (mostly black membranous vs. brown fibrous remains of petioles and sheaths of leaves of the preceding year at rootstock), and petals (yellowish vs. white). Molecular analysis of nrITS sequence data provides further evidence to recognize A. multicaule as a member of the genus Aulacospermum.
Phylogenetic placement of Tretospeira cheirospora in Phaeosphaeriaceae
Authors: LIU NING-GUO , LIU JIAN-KUI , SUN YA-RU , JUMPATHONG JUANGJUN
Published: January 2023

A new hyphomycetous species, Tretospeira cheirospora, collected on decaying wood in a terrestrial habitat in northern Thailand is described and illustrated. It has macronematous, mononematous, erect, short, simple, brown to dark brown conidiophores, monotretic conidiogenous cells, and cheiroid, olivaceous brown to brown, distoseptate conidia composed of 4 columns and with an apical, hyaline, gelatinous sheath. Molecular data of Tretospeira are provided for the first time. The phylogenetic analysis of combined LSU and ITS sequence data shows that Tretospeira cheirospora belongs to Phaeosphaeriaceae and presents a distinct lineage which is sister to Banksiophoma australiensis. Hyphomycetous asexual morphs in Phaeosphaeriaceae and morphologically similar genera are compared and discussed.
Aletheia, a new replacement name for Aenigma (Luer) Szlach. & Kolan. (Orchidaceae, Pleurothallidinae) with new combinations
Authors: FENG ZHENHAO
Published: January 2023

The generic name Aenigma Keller (2017a: 59) was established by the author with two twining species Aenigma patens Keller (2017a: 60) and A. micrantha Keller (2017a: 64) both from Misiones Province, Argentina, belonging to Apocynaceae. In the same year, Keller & Liede-Schumann (2017b) noticed that Bosse (1932: 27) has published a red algae genus, Enigma. To avoid phonetic homonym, the two authors published a replacement name Topea and established a new subtribe Topeinae Keller & Liede (2017b: 134) based on phylogenetic results. Szlachetko et al. (2022: 23) presented new phylogenetic research of Andinia-complex and they decided to elevate the former Andinia subgen. Aenigma (Luer) Karremans & Mark Wilson (2017: 121) to generic rank, namely Aenigma (Luer) Szlachetko & Kolanowska. A new later homonym is made because of unawareness.
Preliminary inventory of terrestrial Heteroptera from Lebanon (Hemiptera: Leptopodomorpha, Cimicomorpha and Pentatomomorpha)
Authors: MATOCQ ARMAND , AZAR DANY
Published: January 2023

This paper gives, for the first time, a faunistic list of terrestrial Heteroptera (Leptopodomorpha, Cimicomorpha and Pentatomomorpha) known to occur in Lebanon. The list is based on examination and identification by the first author of specimens preserved in various collections and on reliable published records. A total of 231 species and subspecies belonging to 161 genera and 26 families are recorded for the country. Among these species, 71 belonging to 60 genera and 11 families are not cited in the Catalogue of the Heteroptera of the Palaearctic Region (Aukema & Rieger, 1995–2006; Aukema et al., 2013; Aukema 2018–2022), as being present in Lebanon, and thus may be considered as new for the country. A list of 18 species of terrestrial Heteroptera housed at the Lebanese University Collection is also given but these identifications need to be verified.
Inuit-defined determinants of food security in academic research focusing on Inuit Nunangat and Alaska: A scoping review protocol
Authors: Naylor Angus , Kenny Tiff-Annie , Harper Sherilee , Beale Dorothy , Premji Zahra , Furgal Chris , Ford James , Little Matthew
Published: January 2023

Background

Academic research on food security in Inuit Nunangat and Alaska frequently adopts the Food and Agriculture Organization of the United Nations' working definition of food security and Western conceptualisations of what it means to be ‘food secure’. However, in 2014, the Alaskan branch of the Inuit Circumpolar Council (ICC) stated that academic and intergovernmental definitions and understandings ‘are important, but not what we are talking about when we say food security’. The organisation subsequently developed its own conceptualisation and definition: the Alaskan Inuit Food Security Conceptual Framework (AIFSCF), which in 2020 received informal assent by ICC-Canada.

Aim

This protocol establishes a review strategy to examine how well academic research reflects Inuit conceptualisations and understandings of food security, as outlined in the AIFSCF.

Methods

Review structure and reporting will be completed according to adapted RepOrting standards for Systematic Evidence Syntheses (ROSES) guidelines. A comprehensive search strategy will be used to locate peer-reviewed research from Medline, Scopus, Web of Science and the Arctic and Antarctic Regions (EBSCO) databases. Dual reviewer screening will take place at the abstract, title, and full-text stages. Different study methodologies (qualitative, quantitative, and mixed methods) will be included for review, on the proviso that articles identify drivers of food security. An a priori coding framework will be applied by a single reviewer to extract data on publication characteristics, methods and article aims. Deductive thematic content analysis will then identify the frequency and precedence afforded within literature to the drivers and dimensions of food security identified by the AIFSCF.
Effectiveness and safety of transcatheter aortic valve replacement in elderly people with severe aortic stenosis with different types of heart failure
Authors: Dong Mei , Wang Lizhen , Tse Gary , Dai Tao , Wang Lihong , Xiao Zhicheng , Liu Tong , Ren Faxin
Published: January 2023

Background

Impaired left ventricular function is an independent predictor of adverse clinical outcomes in patients with aortic stenosis. The aim of this study is to evaluate the short-term changes of echocardiographic parameters, New York Heart Association (NYHA) class and B-type natriuretic peptide (BNP) level and adverse events amongst patients with heart failure (HF) after transcatheter aortic valve replacement (TAVR) procedure.

Methods

This was a retrospective cohort study conducted at affiliated Yantai Yuhuangding Hospital of Qingdao University between September 2017 and September 2022. TAVR cases were stratified into three groups [heart failure with reduced ejection fraction (HFrEF), heart failure with mildly reduced ejection fraction (HFmrEF), heart failure with preserved ejection fraction (HFpEF)] by left ventricular ejection fraction (LVEF). Baseline characteristics, changes in echocardiographic parameters (1 week and 1 month), BNP (1 month), and NYHA class (6 months) post-TAVR were compared across the three groups. Meanwhile, we observed the adverse events of the patients after TAVR.

Results

A total of 96 patients were included, of whom 15 (15.6%) had HFrEF, 15 (15.6%) had HFmrEF, and 66 (68.8%) had HFpEF. Compared to the HFpEF subgroup, patients in the HFrEF subgroup were younger (p < 0.05), and with a higher BNP (p < 0.05). The left ventricular end-diastolic dimension (LVEDD) in HFrEF group decreased significantly after TAVR. HFmrEF and HFrEF patients showed significant improvements in LVEF after TAVR. The pulmonary artery systolic pressure (PASP), aortic valve peak gradient (AVPG) and aortic valve peak gradient (Vmax) decreased significantly 1 month after TAVR in all three groups compared to the baseline (all p < 0.05). BNP significantly reduced in HFrEF group compared to HFpEF patients after TAVR (p < 0.05). The majority of patients experienced an improvement at least one NYHA class in all three groups 6 months post-TAVR. There is no significant increase in the risk of adverse events in the HFrEF group.

Conclusions

Patients who underwent TAVR achieved significant improvements in BNP, NYHA class, LVEDD, LVEF, and PASP across the three HF classes, with a more rapid and pronounced improvement in the HFrEF and HFmrEF groups. Complication rates were low in the different HF groups. There is no significant increase in the risk of periprocedural complications in the HFrEF and HFmrEF groups.
Evaluation of acute flaccid paralysis surveillance system in the River Nile State - Northern Sudan, 2021
Authors: Ali Alhaj Saad Mohamed Ahmed , Allzain Haghamad , Ahmed Omran M. , Mahgoub Elsadig , Bashir Mazin Babekir Musa , Gorish Babbiker Mohammed Tahir
Published: January 2023

Background

One of the four main elements of the worldwide polio eradication strategy is acute flaccid paralysis surveillance (AFP). This system is based on (acute flaccid paralysis (AFP) cases reported and tested at World Health Organization (WHO) accredited laboratories. To measure and monitor performance, indicators were created. The current study aims to evaluate the system components, performance, and efficiency in River Nile State, Northern Sudan, and their compliance with World Health Organization (WHO) requirements for it to be adopted as a good system; its results can be used to certify whether a country is polio-free or not.

Material and methods

A facility-based retrospective descriptive study was conducted in the River Nile State, Northern Sudan, from Jan 2017 to Dec 2020. This study included all reporting sites/units, workers who reported acute flaccid paralysis (AFP) cases, and officers at the locality level. A total of 50 health institutions were visited for surveillance, and interviews with 59 health workers who were part of the AFP surveillance system were undertaken. The data were collected from participants using a pre-tested questionnaire designed and constructed by the World Health Organization (WHO) framework, and the data were analyzed using the SPSS version (22).

Results

The River Nile State’s AFP surveillance system was of high quality in terms of the infrastructure that had been put in place and the effectiveness of the system’s operations, as evidenced by the following statistics: from 2017 to 2020, the reported non-polio acute flaccid paralysis (AFP) cases were at a mean rate of 4.02 per 100,000 children under the age of 15; the majority of AFP reported cases were under 10 years; and males made up 73.3% of reported cases; The completeness of reports and surveillance documents exceeded 80%, and active surveillance was applied in 80% of reporting sites.

Conclusion

Despite the fact that the surveillance system is capable of detecting cases, Sudan continues to report cases of imported polio from other countries, highlighting the need to strengthen surveillance systems and eradication efforts in these countries.
A machine learning approach to determine the influence of specific health conditions on self-rated health across education groups
Authors: Gumà-Lao Jordi , Arpino Bruno
Published: January 2023

Background

Self-rated health, a subjective health outcome that summarizes an individual’s health conditions in one indicator, is widely used in population health studies. However, despite its demonstrated ability as a predictor of mortality, we still do not full understand the relative importance of the specific health conditions that lead respondents to answer the way they do when asked to rate their overall health. Here, education, because of its ability to identify different social strata, can be an important factor in this self-rating process.

The aim of this article is to explore possible differences in association pattern between self-rated health and functional health conditions (IADLs, ADLs), chronic diseases, and mental health (depression) among European women and men between the ages of 65 and 79 according to educational attainment (low, medium, and high).

Methods

Classification trees (J48 algorithm), an established machine learning technique that has only recently started to be used in social sciences, are used to predict self-rated health outcomes. The data about the aforementioned health conditions among European women and men aged between 65 and 79 comes from the sixth wave of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 27,230).

Results

It is confirmed the high ability to predict respondents’ self-rated health by their reports related to their chronic diseases, IADLs, ADLs, and depression. However, in the case of women, these patterns are much more heterogeneous when the level of educational attainment is considered, whereas among men the pattern remains largely the same.

Conclusions

The same response to the self-rated health question may, in the case of women, represent different health profiles in terms of the health conditions that define it. As such, gendered health inequalities defined by education appear to be evident even in the process of evaluating one’s own health status.