bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C015: EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype and promotes immune surveillance in PDAC
Authors: Chibaya Loretah , Murphy Katherine C. , Diaz Yvette Lopez , DeMarco Kelly D. , Liu Haibo , Gopalan Sneha , Faulkner Melissa , Li Junhui , IV John P. Morris , Ho Yu-jui , Simon Janelle , Luan Wei , Kulick Amanda , de Stanchina Elisa , Simin Karl , Zhu Lihua J. , Fazzio Thomas G. , Lowe Scott W. , Ruscetti Marcus
Published: November 2022

T-cell based immunotherapies that produce durable and sometimes curative responses in other malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to poor T cell infiltration and tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be a powerful way to enhance T cell infiltration into tumors and reactivate a different type of innate Natural Killer (NK) cell anti-tumor immunity that can mediate tumor control. Here, we found that the pancreas tumor microenvironment (TME) suppresses NK cell surveillance following therapy-induced senescence (TIS) with MEK and CDK4/6 inhibitor treatment through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity enhanced the production of pro-inflammatory SASP factors and led to NK and T cell infiltration and immune-mediated tumor control in transplanted and genetically engineered PDAC mouse models. Mechanistically, EZH2 suppression induced expression of SASP factors CCL2 and CXCL9/10 necessary for lymophocyte chemotaxis into the pancreas TME. EZH2 levels were also associated with reduced NK cell numbers, SASP expression, and overall survival in a PDAC patient cohort. Taken together these results demonstrate that EZH2 mediates repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to reactivate absent NK and T cell surveillance in PDAC to achieve immune-mediated tumor responses.

Citation Format: Loretah Chibaya, Katherine C. Murphy, Yvette Lopez Diaz, Kelly D. DeMarco, Haibo Liu, Sneha Gopalan, Melissa Faulkner, Junhui Li, John P. Morris IV, Yu-jui Ho, Janelle Simon, Wei Luan, Amanda Kulick, Elisa de Stanchina, Karl Simin, Lihua J. Zhu, Thomas G. Fazzio, Scott W. Lowe, Marcus Ruscetti. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype and promotes immune surveillance in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C015.
Abstract C068: Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC)
Authors: Ganbold Munkhzul , Louphrasitthiphol Pakavarin , Miyazaki Yoshihiro , Oda Tatsuya , Tominaga Kenichi , Isoda Hiroko
Published: November 2022

Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer due lack of early diagnosis and inherent refractory to traditional chemo- and even novel immune-therapies. PDAC is marked by its extensive desmoplastic stroma containing extracellular matrix (ECM), vasculature and most importantly cancer-associated fibroblasts (CAFs). CAFs that exist in heterogenous subtypes are responsible for shaping PDAC tumor microenvironment being the main source of: ECM deposition leading up to desmoplasia that hampers the efficacy of various therapeutics, as well as diverse cytokines and growth factors that promote the growth of cancer cells and the shift towards dedifferentiated and invasive phenotype and contribute towards immune suppressive microenvironment. Thus, modulating CAFs phenotype is an attractive mean to increase the efficacy of therapies targeting PDAC cells. Here we assessed the potential therapeutic benefits of Isorhamnetin, a flavonoid previously shown to exert anti-proliferative, anti-fibrotic and anti-inflammatory effect in various cancer types, to modulates PDAC microenvironment by characterizing Isorhamnetin effect on human PDAC-derived CAFs. Isorhamnetin inhibited CAFs proliferation, induced apoptosis, and cell cycle arrest by impairing mitochondrial health. Importantly, isorhamnetin attenuates the expression of inflammatory CAFs (iCAFs) signature including IL1A, IL6, LIF, CXCL1 and promotes phenotype shift towards myofibroblasts (myCAFs)-as evident in higher level of αSMA positive CAFs. Our results demonstrate antiproliferative effect of isorhamnetin on human PDAC-derived CAFs and a phenotype switch from iCAFs to myCAFs and warrant further investigation for its use in combinatorial therapy that target both the cancer and the tumor microenvironment as a whole.

Citation Format: Munkhzul Ganbold, Pakavarin Louphrasitthiphol, Yoshihiro Miyazaki, Tatsuya Oda, Kenichi Tominaga, Hiroko Isoda. Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C068.
Abstract C080: Longitudinal profiling of patient pancreatic tumor samples reveals evolution of immune cellular compartments
Authors: Carpenter Eileen S. , Kadiyala Padma , Elhossiny Ahmed , Freeman Julia , Dai Henry , Gunchick Valerie , Bednar Filip , di Magliano Marina Pasca , Sahai Vaibhav
Published: November 2022

Background: Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a 5-year survival rate of 11%. This poor prognosis is due in part to a lack of early disease detection methods and resistance to standard chemotherapeutic agents. Consequently, there is an unmet need for the development of efficacious therapies for treating PDAC patients. The mechanisms driving therapeutic resistance are not well understood. To characterize the cellular and molecular heterogeneity across PDAC patients and map out the heterogeneity of immune and tumor compartments at single cell resolution we developed a novel specimen collection pipeline. We obtain specimens during endoscopic diagnostic biopsy (treatment-naïve) and matched surgical resection (post-treatment) from pancreatic cancer patients for single cell RNA sequencing analysis. Results: We currently have 7 patients enrolled in our longitudinal study and thus far have collected matched pre- and post-treatment tumor tissue from 2 patients. Preliminary transcriptomics analysis show notable changes in PDAC tumor microenvironment imparted by FOLFIRINOX chemotherapy, including dampening of effector immune responses in cytotoxic T cells. In addition, we observed an increase in exhausted CD8 T cells and T regulatory cells in PDAC post chemotherapy. Additionally, we have successfully cultured organoids from matched tumor samples and have isolated peripheral autologous immune cells and plan to validate these findings with complimentary functional in vitro studies. Conclusion: Our preliminary results support utilization of transcriptomic analysis of matched longitudinal pre- and post-treatment tumor tissue in PDAC patients for a comprehensive study of how the tumor microenvironment changes over time in response to chemotherapy, with the ultimate goal of understanding mechanisms of chemoresistance in this deadly disease.

Citation Format: Eileen S. Carpenter, Padma Kadiyala, Ahmed Elhossiny, Julia Freeman, Henry Dai, Valerie Gunchick, Filip Bednar, Marina Pasca di Magliano, Vaibhav Sahai. Longitudinal profiling of patient pancreatic tumor samples reveals evolution of immune cellular compartments [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C080.
Abstract C083: Deconvoluting the metastatic PDA tumor microenvironment
Authors: Singh Rima , Halbrook Christopher , Steele Nina
Published: November 2022

Pancreatic Ductal Adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US with a 5-year survival of 11%. Most patients die from disseminated disease, with liver being the most frequently colonized metastatic site. In primary PDA tumors, the tumor microenvironment has been extensively linked to therapy resistance and immune suppression. However, the extent that the microenvironment in the liver metastatic niche promotes immune evasion compared to primary PDA lesions remains unclear. Importantly, strategies to effectively target metastatic disease will provide the most immediate benefit for clinical treatment of PDA. The heterogeneous tumor microenvironment has been recognized as a primary barrier to PDA treatment. Here, the immune and stromal cells are not functioning in a manner beneficial for the host. Numerous cell types have been shown to have a pro-tumor function including regulatory T cells, tumor associated macrophages (TAMs), myeloid derived suppressor cells, and cancer associated fibroblasts (CAFs). Recently, we and others have shown that there are metabolic crosstalk interactions between cancer cells, TAMs, and CAFs. These interactions function to support primary tumor growth, immune suppression, and resistance to chemotherapy. However, the degree that the cancer cell heterogeneity, immune infiltration, and stromal populations present in metastatic lesions mirror primary tumors remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. Using this system, we have identified differential programming among the different cell populations between pancreas and liver PDA lesions using single cell RNA sequencing. Further, we directly compared immune infiltration between primary and metastatic tumors using mass cytometry. Our data indicate alternative mechanisms of immune suppression in liver PDA lesions, which can be directly targeted in combination with checkpoint inhibition strategies. Overall, these data have the potential to lead to new avenues to activate or target the immune system to treat metastatic PDA, an urgent clinical need for pancreatic cancer patients.

Citation Format: Rima Singh, Christopher Halbrook, Nina Steele. Deconvoluting the metastatic PDA tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C083.
Abstract IA002: Contextual determinants of pancreatic tumorigenesis
Authors: Bar-Sagi Dafna
Published: November 2022

Pancreatic cancer, in its most common form - pancreatic ductal (PDAC) - is one of the most lethal cancers with overall 5-year survival of 11%. Approximately 61,000 new cases of PDAC were diagnosed in the US in the past year, and the incidence is rising at a rate of 0.5% to 1.0% per year. On this trajectory, PDAC is projected to become the second most common cause of cancer-related deaths in the US. The evolution of PDAC is driven by a network of complex molecular and cellular alterations that affect the tumor cells themselves and the environment that surrounds them. The focus of our efforts has been to define the context-dependent contribution of these alterations to the pathophysiological characteristics of PDAC with the goal of leveraging this information to identify actionable vulnerabilities in this disease.

Citation Format: Dafna Bar-Sagi. Contextual determinants of pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA002.
Abstract PR013: High sensitive mutation detection in liquid biopsy with duodenal fluid captures genetic mutations associated with pancreatic carcinogenesis
Authors: Ono Yusuke , Takahashi Kenji , Karasaki Hidenori , Mizukami Yusuke
Published: November 2022

Background: Blood-based liquid biopsy for comprehensive genomic profiling is available for cancer patients; however, given the limited amount of tumor-derived DNA in plasma, it remained challenging to detect pancreatic ductal adenocarcinoma (PDA) at earlier stages. Here, we evaluated the mutation detection in DNA from the duodenal fluid as an alternative biospecimen obtained by a less-invasive approach relative to endoscopic biopsy. Methods: In 300 patients of PDA, IPMN, or other pancreatic diseases in seven institutions, we collected duodenal fluid containing pancreatic juice from the duodenal lumen through the endoscopic channel. Plasma was also collected, and DNA was extracted from both samples, and molecular barcode sequencing, which enabled the highly sensitive detection of low- frequent mutation, targeting five pancreatic cancer-associated genes, namely, KRAS, GNAS, TP53, CDKN2A, and SMAD4, were performed. Detected mutations were evaluated for concordance with surgically resected tissue or needle biopsy. Results: DNA extracted from the duodenal fluids (DFDNA) had a much higher yield (avg. 25.4 ng/ml) than plasma cell-free DNA (avg. 1.3 ng/ml). While plasma cfDNA had a typical fragmentation pattern with a peak at 160 bp, DFDNA has a variety of fragmentation patterns. Hotspot mutations detected in the duodenal fluids showed as much as 51.4% concordance with a 0.2 % the limit of detection (LOD) for its variant allele frequency in PDA-associated mutations in the DFDNA (n=109) with the mutations in PDA lesion, whereas only 25% concordance with 0.4% LOD in the plasma cfDNA (n=104). In contrast to plasma cfDNA, where liquid-tissue matches were limited to advanced stages of cancer, DFDNA assay enabled the higher concordance through a wide range of PDA stages, even Stage 0 (83.3%) or I (45.5%) UICC 8th, or IPMN cases, and allowed to detect of additional mutations that were originated from multicentric/concomitant lesions in the pancreas. Conclusions: Duodenal fluid-derived DNA can be a potent biospecimen to detect mutations with higher yield and sensitivity than plasma cfDNA. Although validation of the duodenal fluid collection and methods up to more sensitive analysis is required to meet the standards of practical testing, it has the potential to detect fast-stage pancreatic disease and the detection of lesions that were not visible on pathological images and is expected to lead to the implementation of highly sensitive liquid biopsy.

Citation Format: Yusuke Ono, Kenji Takahashi, Hidenori Karasaki, Yusuke Mizukami. High sensitive mutation detection in liquid biopsy with duodenal fluid captures genetic mutations associated with pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR013.
What Went Wrong with VEGF-A in Peripheral Arterial Disease? A Systematic Review and Biological Insights on Future Therapeutics
Authors: Kastora Stavroula L. , Eley Jonathan , Gannon Martin , Melvin Ross , Munro Euan , Makris Sotirios A.
Published: November 2022

Background: Of the 200 million patients worldwide affected by peripheral arterial disease (PAD), 4% will inevitably require major limb amputation. Previous systematic reviews presented a conflicting body of evidence in terms of vascular endothelial growth factor (VEGF) family member effects upon PAD natural progression. Despite that, modulation of intrinsic angiogenesis mechanisms targeting the VEGF family members still confers an attractive therapeutic target. The aim of the present study was to evaluate current evidence of VEGF modulation in the context of PAD. Methods: This is a systematic literature review conducted according to the PRISMA guidelines and registered under PROSPERO database [CRD42021285988]. Independent literature search was performed up to April 1, 2022, on six databases. A total of 22 eligible studies were identified [N: 3, interventional patient studies; N: 19, animal studies]. Animal studies were appraised by the SYRCLE risk of bias tool, while human participant studies were assessed by the Newcastle Ottawa scale. Overall, quality of evidence was deemed fair for both animal and human studies. Main study outcomes were percentage change of injured vessel lumen stenosis and neointimal area formation upon VEGF modulation (inhibition or activation) in comparison with control group. Findings: Nineteen animal models and three human participant studies were included in the systematic review and assessed separately. Positive modulation of VEGF-A in animal models resulted in a median decrease of 65.58% [95% CI 45.2; 71.87] in lumen stenosis [14 studies]. Furthermore, positive modulation of VEGF-A was found to reduce neointimal area proliferation by a median decrease of 63.41% [95% CI 41.6; 79.59] [14 studies]. Median end of study duration was 28 days [range: 14–84 days]. Data were insufficient to assess these outcomes with respect to VEGF-B or VEGF-C modulation. The limited number of available human studies presented inadequate outcome assessment despite their overall fair NOS grading. Interpretation: VEGF-A-positive modulation decreases lumen stenosis and neointimal hyperplasia in PAD simulation animal models. Previously identified variability among outcomes was found to strongly stem from the variability of experimental designs. Clinical applicability and safety profile of VEGF-A in the context of PAD remain to be defined by a robust and uniformly designed body of further animal model-based experiments.
Predicting Inadequate Bowel Preparation When Using Sodium Picosulfate plus Magnesium Citrate for Colonoscopy: Development and Validation of a Prediction Score
Authors: Okamoto Norihiro , Tanaka Shinwa , Abe Hirohumi , Miyazaki Haruka , Nakai Tastuya , Tsuda Kazunori , Sakaguchi Hiroya , Yoshizaki Tetsuya , Ikezawa Nobuaki , Inoue Jun , Ooi Makoto , Kodama Yuzo
Published: November 2022

Introduction: Sodium picosulfate plus magnesium citrate is a bowel preparation agent with high patient acceptability. However, it is unclear which patients are more likely to have inadequate bowel preparation when using this agent. This study aimed to identify the risk factors for inadequate bowel preparation when using sodium picosulfate plus magnesium citrate for colonoscopy and to develop a scoring model to predict which patients will have inadequate bowel preparation. Methods: A total of 350 Japanese patients were enrolled from June 2021 to April 2022. Data on patient background, details of colonoscopy, and satisfaction assessment questionnaire results were prospectively collected. The scoring model for inadequate bowel preparation was developed based on multiple logistic regression analyses, and its performance was internally validated using bootstrapping. Results: Adequate bowel preparation was obtained in 295 patients (84.3%); 335 (95.7%) were able to ingest the drug without difficulty. The scoring model consisted of five independent risk factors and points of risk scores were assigned to each one as follows: American Society of Anesthesiologists physical status III (1 point), diabetes comorbidities (5 points), use of laxatives (4 points), no defecation once in a day (2 points), and drug use for mental disorder (6 points). The C-statistics of the scoring system for inadequate bowel preparation was 0.75. Discussion: We identified five risk factors for inadequate bowel preparation when using sodium picosulfate plus magnesium citrate regimen and developed a scoring model for inadequate bowel preparation with satisfactory discrimination and calibration.
Disparities in Hospital Length of Stay Across Race and Ethnicity Among Patients With Heart Failure
Authors: Zheng Jimmy , Tisdale Rebecca L. , Heidenreich Paul A. , Sandhu Alexander T.
Published: November 2022

Background:

Reducing hospital length of stay (LOS) has been identified as an important lever for minimizing the burden of heart failure hospitalization, yet the impact of social and structural determinants of health on LOS has received little attention. We investigated disparities in LOS across race/ethnicity and their possible drivers.

Methods:

We analyzed patients hospitalized for heart failure from 2017 to 2020 using the Get With The Guidelines-Heart Failure registry. We characterized LOS differences across race/ethnicity by insurance and disposition, adjusting for demographics, comorbidities, and clinical severity. Effects of hospital-level clustering on LOS across race/ethnicity were assessed using hierarchical mixed-effects models. We evaluated the association between LOS and discharge rates of guideline-directed medical therapy.

Results:

Three thousand three seven hundred thirty patients hospitalized for heart failure were identified. After excluding inpatient deaths, the adjusted LOS for Black (5.72 days [95% CI, 5.62–5.82]), Hispanic (5.94 days [95% CI, 5.79–6.08]), and Indigenous American/Pacific Islander (6.06 days [95% CI, 5.85–6.27]) patients remained significantly longer compared with non-Hispanic White patients (5.32 days [95% CI, 5.25–5.39]). This pattern was driven by LOS differences among patients discharged to hospice or nursing facilities. After accounting for variability between hospitals, associations of race/ethnicity with LOS either were attenuated or reversed in direction. Guideline-directed medical therapy rates on discharge did not differ significantly across race/ethnicity despite longer LOS for Black, Hispanic, and Indigenous American/Pacific Islander patients.

Conclusions:

Differences between hospitals drive LOS disparities across race/ethnicity. Longer LOS among Black, Hispanic, and Indigenous American/Pacific Islander patients was not associated with improved quality of care.
Culprit Lesion Morphology of Rapidly Progressive and Extensive Anterior-Wall ST-Segment Elevation Myocardial Infarction
Authors: Okada Kozo , Hibi Kiyoshi , Kikuchi Shinnosuke , Kirigaya Hidekuni , Hanajima Yohei , Sato Ryosuke , Nakahashi Hidefumi , Minamimoto Yugo , Matsuzawa Yasushi , Maejima Nobuhiko , Iwahashi Noriaki , Kosuge Masami , Ebina Toshiaki , Tamura Kouichi , Kimura Kazuo
Published: November 2022

Background:

Rapidly progressive, extensive myocardial injury/infarction (RPEMI) beyond the concept of wave-front phenomenon can be observed even when achieving timely reperfusion; however, the pathogenesis of RPEMI remains unknown. This retrospective study investigated clinical and lesion characteristics of RPEMI, focusing on culprit-lesion morphology (CLM).

Methods:

Among patients with extensive anterior-wall ST-segment elevation myocardial infarction due to proximal left anterior descending artery lesions who had reperfusion within 3 hours of symptom onset, 60 patients undergoing both intravascular ultrasound and cardiac magnetic resonance imaging were enrolled. Myocardial injury/infarction before reperfusion therapy was assessed by QRS scores at hospitalization electrocardiogram, and the extent of myocardial injury/infarction was evaluated by cardiac magnetic resonance imaging, which measured area at risk, infarct size, myocardial salvage index, microvascular obstruction, and left ventricular ejection fraction. RPEMI was defined as lower left ventricular ejection fraction (less median value) with microvascular obstruction.

Results:

Despite comparable onset-to-door and onset-to-reperfusion times and area at risk, patients with RPEMI showed higher QRS scores at hospitalization (5 [4.3–6] versus 3 [2–4],
P
<0.001) and infarct size (26.5±9.1 versus 20.4±10.5%,
P
=0.04), and a tendency toward lower myocardial salvage index (0.27±0.14 versus 0.36±0.20,
P
=0.10) compared with those without. Patients with versus without RPEMI more frequently observed specific CLM on intravascular ultrasound, characterized by the combination of vulnerable plaques, plaque ruptures, and/or large thrombi. When stratified by CLM-score composed of these 3 criteria, higher CLM-scores were or tended to be associated with higher QRS scores and incidence of RPEMI. In multivariate analyses including no-reflow phenomenon and final coronary-flow deterioration, increased CLM-score (≥2) was independently associated with high QRS scores and RPEMI (odd ratio 11.25 [95% CI, 2.43–52.00];
P
=0.002).

Conclusions:

Vulnerable CLM was a consistent determinant of advanced myocardial injury/infarction both before and after reperfusion therapy and may play a pivotal role in the development of RPEMI.
Optimal Echocardiographic Parameters to Improve the Diagnostic Yield of Tc-99m-Bone Avid Tracer Cardiac Scintigraphy for Transthyretin Cardiac Amyloidosis
Authors: Cuddy Sarah AM , Datar Yesh , Ovsak Gavin , Saith Sunil , Murphy Sean P. , Bay Camden P. , Haddad Mia , Lilleness Brian , Muralidhar Varsha , Pipilas Alexandra , Vuong Jacqueline , Guardino Eric , Maurer Mathew S. , Ruberg Frederick L. , Falk Rodney H. , Dorbala Sharmila
Published: November 2022

Background:

Echocardiographic deformation-based ratios and novel multi-parametric scores have been suggested to discriminate transthyretin cardiac amyloidosis (ATTR-CM) from other causes of increased left ventricular wall thickness among patients referred for ATTR-CM evaluation. Their relative predictive accuracy has not been well studied. We sought to (1) identify echocardiographic parameters predictive of ATTR-CM and (2) compare the diagnostic accuracy of these parameters in patients with suspected ATTR-CM referred for technetium-99m-pyrophosphate scintigraphy.

Methods:

Echocardiograms from 598 patients referred to 3 major amyloidosis centers for technetium-99m-pyrophosphate to detect ATTR-CM were analyzed, including longitudinal strain (LS) analysis. Deformation ratios (septal apex to base ratio, relative apical sparing, ejection fraction to global LS), a multi-center European increased wall thickness score, and Mayo Clinic derived ATTR score (transthyretin cardiac amyloidosis score) were calculated. A logistic regression model was used to identify the parameters that best associated with a diagnosis of ATTR-CM. Comparison of the diagnostic capacity of the parameters was performed by receiver operating characteristic curves and the area under the curve (AUC).

Results:

Over half of the subjects (54.2%) were diagnosed with ATTR-CM (78% were men, median age of 76 years). Age, inferolateral wall thickness, and basal LS were the strongest predictors of ATTR-CM, AUC of 0.87 (95% CI: 0.83, 0.90), superior to the increased wall thickness score AUC of 0.78 (95% CI: 0.73, 0.83;
P
=0.004). An inferolateral wall thickness of ≥14 mm (AUC: 0.73) was as accurate as the published cut-offs for transthyretin cardiac amyloidosis score and septal apex to base (AUC: 0.72 and 0.69,
P
=0.8 and
P
=0.1, respectively), and was superior to ejection fraction to global LS and relative apical sparing (AUC: 0.64 and 0.53,
P
<0.001, respectively). A cut-off of ≥−8% for average basal LS (AUC: 0.76, CI: 0.72–0.79) had a similar area under the curve to transthyretin cardiac amyloidosis score (TCAS) (
P
=0.2); outperforming the other indices (
P
<0.01).

Conclusion:

Inferolateral wall thickness and average basal LS performed as well as or better than more complex echo ratios and multiparametric scores to predict ATTR-CM.
Impact of Intravascular Ultrasound–Derived Lesion-Specific Virtual Fractional Flow Reserve Predicts 3-Year Outcomes of Untreated Nonculprit Lesions: The PROSPECT Study
Authors: Seike Fumiyasu , Mintz Gary S. , Matsumura Mitsuaki , Ali Ziad A. , Liu Mengdan , Jeremias Allen , Ben-Yehuda Ori , De Bruyne Bernard , Serruys Patrick W. , Yasuda Kazunori , Stone Gregg W. , Maehara Akiko
Published: November 2022

Background:

Hemodynamic assessment of untreated nonculprit lesions was not studied in the PROSPECT study (Providing Regional Observations to Study Predictors of Events in the Coronary Tree). We developed a virtual intravascular ultrasound–derived lesion-specific fractional flow reserve (lesion-specific IVUS-FFR) algorithm to assess individual lesion-level FFR. We sought to investigate the relation between lesion-specific IVUS-FFR and major adverse cardiovascular events (MACE) arising from untreated nonculprit lesions in the PROSPECT study.

Methods:

In PROSPECT, 697 patients with acute coronary syndromes underwent 3-vessel grayscale and virtual histology–IVUS to correlate untreated nonculprit plaque morphology with 3-year nonculprit related MACE (composite of cardiac death, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina). Lesion-specific IVUS-FFR was calculated from volumetric IVUS lumen area measurements at 0.4 mm intervals by applying a mathematical circulation model using basic fluid dynamics equations.

Results:

Lesion-specific IVUS-FFR was analyzable in 3227 nonculprit lesions in 660 patients among whom 54 nonculprit MACE events (3 myocardial infarctions) occurred at median 3.4-year follow-up. By receiver-operating characteristic analysis, the best cutoff value of lesion-specific IVUS-FFR to predict nonculprit MACE was ≤0.95. After adjusting for patient and lesion characteristics, lesion-specific IVUS-FFR (hazard ratio, 4.83 [95% CI, 2.20–10.61];
P
<0.001) was an independent predictor of 3-year nonculprit MACE, in addition to minimum lumen area≤4.0 mm
2
, plaque burden ≥70%, and virtual histology thin-cap fibroatheroma.

Conclusions:

Minor reductions in lesion-specific IVUS-FFR were independently associated with future nonculprit MACE arising from untreated angiographically mild stenoses along with previously established high-risk lesion morphological characteristics.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00180466.
Lifetime Management of Aortic Stenosis: Transcatheter Versus Surgical Treatment for Young and Low-Risk Patients
Authors: Russo Giulio , Tang Gilbert H.L. , Sangiorgi Giuseppe , Pedicino Daniela , Enriquez-Sarano Maurice , Maisano Francesco , Taramasso Maurizio
Published: November 2022

Transcatheter aortic valve replacement is now indicated across all risk categories of patients with symptomatic severe aortic stenosis and has been proposed as first line option for the majority of patients >74 years old. However, median age of patients enrolled in the transcatheter aortic valve replacement low-risk trials is 74 years and transcatheter aortic valve replacement has never been systematically investigated in young low risk patients. Although the long-term data in surgical aortic valve replacement in young patients (age <75) are well known, such data remain lacking in transcatheter aortic valve replacement. In the absence of clear guideline recommendations in patients with challenging anatomies (eg, hostile calcium, bicuspid), it is important to know the potential advantages and disadvantages of each treatment and to consider how they might integrate with each other in the lifetime management of such patients. In this review, we discuss current outstanding issues on the management of severe aortic stenosis from a lifetime management perspective, particularly in terms of initial intervention and future reinterventions.
Hemispheric Asymmetries of Individual Differences in Functional Connectivity
Authors: Perez Diana C. , Dworetsky Ally , Braga Rodrigo M. , Beeman Mark , Gratton Caterina
Published: November 2022

Resting-state fMRI studies have revealed that individuals exhibit stable, functionally meaningful divergences in large-scale network organization. The locations with strongest deviations (called network “variants”) have a characteristic spatial distribution, with qualitative evidence from prior reports suggesting that this distribution differs across hemispheres. Hemispheric asymmetries can inform us on constraints guiding the development of these idiosyncratic regions. Here, we used data from the Human Connectome Project to systematically investigate hemispheric differences in network variants. Variants were significantly larger in the right hemisphere, particularly along the frontal operculum and medial frontal cortex. Variants in the left hemisphere appeared most commonly around the TPJ. We investigated how variant asymmetries vary by functional network and how they compare with typical network distributions. For some networks, variants seemingly increase group-average network asymmetries (e.g., the group-average language network is slightly bigger in the left hemisphere and variants also appeared more frequently in that hemisphere). For other networks, variants counter the group-average network asymmetries (e.g., the default mode network is slightly bigger in the left hemisphere, but variants were more frequent in the right hemisphere). Intriguingly, left- and right-handers differed in their network variant asymmetries for the cingulo-opercular and frontoparietal networks, suggesting that variant asymmetries are connected to lateralized traits. These findings demonstrate that idiosyncratic aspects of brain organization differ systematically across the hemispheres. We discuss how these asymmetries in brain organization may inform us on developmental constraints of network variants and how they may relate to functions differentially linked to the two hemispheres.
The Qumran Opisthograph 4Q509/4Q496/4Q506 as an Intentional Collection of Prayers
Authors: Aksu Ayhan
Published: November 2022

4Q509/4Q496/4Q506 is the only opisthograph from Qumran with extant evidence for three different compositions: the recto preserves a copy of Festival Prayers (4Q509), and the verso contains copies of the War Scroll (4Q496) and Words of the Luminaries (4Q506). This article investigates the circumstances under which these texts were written down together, and explores a potential performative setting for this manuscript. Palaeographic and codicological examination indicates that the manuscript preserves extracts of these three compositions and shares similar scribal features on both the recto and verso. Literary and form-critical analysis suggests a performative context for Festival Prayers, Words of the Luminaries, and the War Scroll. Based on these considerations, I argue that different scribes wrote 4Q509, 4Q496, and 4Q506 intentionally together in order to create a liturgical collection on a single manuscript—highlighting the scribe as a collectionneur that purposely selected passages from different texts that were of importance.
Performance in Ancient and Medieval Judaism
Authors: Khan Geoffrey , Najman Hindy
Published: November 2022

This article explores the performance of Jewish sacred textual traditions. Performance, as we define it, is both textual and oral and works dynamically between the two. In the Second Temple period, we show the variety of performance which embodies the vitality of the texts. Performance is a feature of scribal practice and liturgy (e.g., Hodayot). It draws on existing text to create something new (e.g., Apostrophe to Zion). From the Second Temple period into the Middle Ages, we see continued pluriformity in the oral performance of the written text of the Hebrew Bible. Creativity is evident across oral and material representation. The texts discussed throughout this article remained dynamic and diverse. The focus and scope of this article also prepares for many of the ideas picked up by the essays which follow in this volume.
Dots, Versification and Grammar
Authors: Lundberg Johan M.V.
Published: November 2022

The Syriac gospel of Matthew is divided into sentences by means of pausal accent dots, both single clause sentences and complex sentences. This article explores the relationship between these pausal accent dots and verse division, comparing the Syriac dotting system with Greek punctuation marks and Hebrew accents. All three traditions divide the text into larger and smaller sections. In the Hebrew Bible the smaller sections are often classified as verses that are further subdivided through cantillation marks, typically called accents. This article explains why the Syriac dots, also called accents, have a fundamentally different function than the Hebrew accents. It also explores the similarities between the Syriac dots and the Greek punctuation marks. The conclusion is that the “verse” is not a concept that can easily be applied to Syriac Bible manuscripts. Instead, the Syriac dots indicate different types of boundary tones, pauses associated with a specific pitch contour.
Variations on a Theme by Muḥammad
Authors: Nasser Shady Hekmat
Published: November 2022

This essay explores the tense relationship between the oral and written transmissions in the history of the Qurʾān. While Muslim scholars consider “orality” to be the cornerstone in the process of transmitting their holy text, I argue that writing, in its various forms, was a crucial element in transmitting and validating the Qurʾān. Orality was also an important component in this process of transmission but it also played a theological role in establishing the superiority of the Qurʾān over the Bible. Indeed, the written transmission of the Qurʾān might have been more authoritative than its oral counterpart, which was/is mainly used as an argumentative device to establish the integrity of the text rather than to establish the text itself.
Morphological and molecular data reveal Retiboletus cyanescens sp. nov. and the new subgenus Nigroretiboletorum (Boletaceae)
Authors: LI JIN , WANG ZHEN , LIU EN-DE , YANG ZHU L. , LI YAN-CHUN
Published: November 2022

Relationships between species of Retiboletus were inferred from morphology and nucleotide sequences of the translation elongation factor 1-α gene (tef1-α), the second largest subunit of RNA polymerase II (rpb2), the nuclear ribosomal large subunit (nrLSU), and the nuclear ribosomal internal transcribed spacer (ITS), based on Maximum Likelihood and Bayesian analyses. Our analyses indicated that the genus Retiboletus is divided into two major clades, with at least 10 species-level lineages in China. Accordingly, we describe a new subgenus, i.e. R. subg. Nigroretiboletorum, and a new species R. cyanescens of this subgenus. The newly proposed subgenus accommodates R. griseus and its allied taxa characterized by grayish white, white, or grayish pink hymenophores and white to gray context in pileus. Color pictures of fresh basidiomata and line drawings of the new species are provided, with a discussion concerning its taxonomic and phylogenetic relationships within the genus. In addition, a key to the species of Retiboletus in China is provided.
Taxonomic studies on the genus Delphinium (Ranunculaceae) from China (XXII): Clarifying morphological distinction between D. drepanocentrum and D. umbrosum and synonymizing D. umbrosoides with D. drepanocentrum
Authors: YUAN QIONG , YANG QIN-ER
Published: November 2022

Based on critical observations on herbarium specimens (including type material), we demonstrate that Delphinium drepanocentrum (Ranunculaceae), an eastern Himalayan species distributed in Bhutan and China (southern Xizang), is most readily distinguishable from D. umbrosum, a species endemic to northwestern Yunnan, China, by an array of morphological characters, particularly by the indumentum on plant body. Our results support the treatment of D. drepanocentrum as an independent species. Moreover, some collections from Cona in southern Xizang previously cited as D. umbrosum var. drepanocentrum or misidentified as D. umbrosum subsp. drepanocentrum on the determination slips are determined not to belong to D. drepanocentrum, but represent a hitherto undescribed species. Furthermore, D. umbrosoides, described recently from Xizang, is determined to be conspecific with D. drepanocentrum and thus is synonymized herein. Finally, we pointed out that D. umbrosum var. hispidum is identical with D. omeiense, a species distributed in southwestern Sichuan and northeastern Yunnan, China.
Novelties in Austroblechnum (Blechnaceae) from Colombia
Authors: MURILLO-A. JOSÉ , TRIANA-MORENO LUZ A.
Published: November 2022

Austroblechnum bullatum, a new species from Colombia, is described and illustrated. This fern is characterized by having pendulous laminae, rachis abundantly covered with hairs up to 2.5 mm long, and pinnae bullate on both surfaces. In addition, the distribution range is extended for A. aequatoriense, a species previously known from northern Ecuador, and now also recorded for Colombia. Lastly, an identification key for the nine Colombian species of Austroblechnum is presented.
A new Octomeria (Orchidaceae: Pleurothallidinae) and nomenclatural notes for related Southern Brazilian species
Authors: FARIA DOS SANTOS THIAGO , BRITO ANTONIO LUIZ VIEIRA TOSCANO DE , SMIDT ERIC DE CAMARGO
Published: November 2022

Octomeria imigiae is proposed as a new species from the Atlantic Rainforest of South Brazil. It is described, illustrated, and compared with sympatric and similar species. An identification key is provided. The new species is recognised by its reptant growth habit and tiny yellow flowers. It is similar to Octomeria chamaeleptotes and several other terete-leaved species from which it can be easily distinguished by its vegetative and floral morphology. Octomeria riograndensis and Octomeria sancti-angeli are proposed as new synonyms of Octomeria chamaeleptotes, and typification designations for this complex are made.
A new species of planthopper in the genus Tico (Hemiptera: Auchenorrhyncha: Derbidae) on palms in Costa Rica
Authors: ECHAVARRIA MARCO A. ZUMBADO , BARRANTES BARRANTES EDWIN A. , HELMICK ERICKA E. , BARTLETT CHARLES R. , BAHDER BRIAN W.
Published: November 2022

Tico is a small genus of planthopper comprised of four species primarily known from Costa Rica, with one species known from Trinidad and Venezuela. Recent survey work has documented multiple new species from palms and other broadleaf monocots in Costa Rica. Herein, a new species, Tico villablanca sp. n., is described from palms in the Los Angeles cloud forest, Costa Rica. Novel molecular data for the 18S rRNA gene and cytochrome c oxidase subunit I (COI) gene is provided for the new species and supplements morphological support for placement in the genus Tico. An updated key is provided for the species of Tico.
A new species of planthopper in the genus Haplaxius from Osa Peninsula in Costa Rica (Hemiptera: Fulgoroidea: Cixiidae)
Authors: ECHAVARRIA MARCO A. ZUMBADO , BARRANTES BARRANTES EDWIN A. , BARTLETT CHARLES R. , HELMICK ERICKA E. , KUNZ GERNOT , BAHDER BRIAN W.
Published: November 2022

Haplaxius is a large genus of New World cixiid planthoppers. The genus is of particular interest because Haplaxius crudus can transmit palm infecting phytoplasmas and the recent discovery of additional Haplaxius on palms during survey work highlights the need to fully understand the diversity of this genus on palms. Herein, a new species, Haplaxius cotinga sp. n., is described from the Osa Peninsula in Costa Rica. This species is most similar to H. deleter from southern Panama, from which it differs mostly by features of the male terminalia. Molecular data for the cytochrome c oxidase subunit I (COI), 18S rRNA, and histone 3 (H3) gene is provided and demonstrates supplemental support for placing the novel taxon in Haplaxius.
The Physical Processes Dominating the Impact of the Summer North Atlantic Oscillation on the Eastern Tibetan Plateau Summer Rainfall
Authors: Hu Shuai , Zhou Tianjun , Wu Bo
Published: November 2022

The summer North Atlantic Oscillation (SNAO), an important climate signal in regulating the interannual variability of Tibetan Plateau (TP) summer rainfall, is closely related to a meridional precipitation dipole pattern between the southeastern and northeastern TP. In this study, based on diagnoses of observations and multiple realizations of the CESM2 historical simulation, we find that there are fundamental differences between the formation processes dominating the SNAO-related summer rainfall anomaly in the southeastern and northeastern TP. An atmospheric moisture budget analysis reveals that the anomalous vertical (horizontal) moisture advection makes the largest contribution to the southeastern (northeastern) TP summer rainfall anomaly. During the negative phase of SNAO, the increased precipitation in the southeastern TP is related to the anomalous ascending flows, which are driven by two processes according to the moist static energy budget. The first is the southward shift of the subtropical westerly jet stream, which produces positive anomalous zonal advection of the climatological moist enthalpy in the upper-middle troposphere over the southeastern TP. The second is related to the enhanced transport of anomalous warm moist air to the south of TP, which produces positive anomalous meridional advection of anomalous moist enthalpy into the lower troposphere over the southeastern TP under the control of climatological monsoonal meridional circulations. This positive moist enthalpy advection enhances the atmospheric moist static energy and facilitate enhanced local convection. For the northeastern TP, the decreased precipitation is dominated by negative anomalous horizontal moisture advections due to the SNAO-induced equivalent-barotropic anomalous cyclone near the eastern edge of the TP.
SNOT-22 Quality of Life Scores Improve After Endoscopic Endonasal Repair of Spontaneous Cerebrospinal Fluid Rhinorrhea
Authors: Liu Matthew Y. , Woodworth Bradford A. , Kanaan Alissa , Jang David W. , Yao William C. , Radabaugh Jeffrey Paul , Gardner James Reed , Goros Martin , Grayson Jessica W. , Wang Zhu , Chen Philip G.
Published: November 2022

Objectives:

Patients with spontaneous cerebrospinal fluid (CSF) rhinorrhea can experience significant sinonasal symptom burden, leading to poor quality of life (QOL). The objective of this study was to investigate sinonasal outcome test-22 (SNOT-22) scores in patients undergoing endoscopic endonasal surgery for spontaneous CSF rhinorrhea and compare them to patients undergoing endoscopic sinus surgery (ESS) for chronic rhinosinusitis without nasal polyps (CRSsNP).

Methods:

A multi-institutional retrospective review of patients with spontaneous CSF rhinorrhea and CRSsNP was performed. Pre-surgery and post-surgery SNOT-22 scores and domains were compared within each group. Improvements in SNOT-22 scores after surgery were compared between the groups.

Results:

Ninety-one patients were in the CSF rhinorrhea group and 105 patients were in the CRSsNP group. Within each group, surgery significantly improved total SNOT-22 scores, domain scores, and most of the individual symptoms. Comparing the 2 groups revealed similar improvements in total SNOT-22 scores ( P = .244). The CSF rhinorrhea group improved more in runny nose ( P < .001), postnasal discharge ( P < .001), wake up at night ( P = .024), and embarrassed ( P = .002). The CRSsNP group improved more in sneezing ( P = .027), nasal blockage ( P < .001), decreased sense of smell/taste ( P = .011), thick nasal discharge ( P < .001), facial pain/pressure ( P = .008), and the ear/facial domain ( P = .010).

Conclusions:

Patients with spontaneous CSF rhinorrhea experience significant symptom burden. Those who undergo CSF leak repair should experience significant improvement in QOL similar to patients who undergo ESS for CRSsNP as measured by SNOT-22.