tbuckley/cabot-search huggingface dataset:
Abstract P010: Relationship Of Pulse Pressure And Cognitive Performance In Individuals With Advanced Carotid Atherosclerosis
Authors: Cedric Williams, Gloria Morel Valdés, Carol Mitchell, Robert J Dempsey, Stephanie Wilbrand, Thomas Cook
Journal: Circulation (2022)

Introduction: Elevation in pulse pressure (PP), the difference between systolic and diastolic blood pressure, is associated with vascular remodeling, arterial stiffness, and carotid plaque instability (i.e. strain indices and ulceration), which is a risk factor for vascular cognitive decline. We have previously demonstrated that increased carotid plaque strain indices are associated with poorer cognitive performance in individuals with advanced carotid atherosclerosis. We examined the relationship between pre-operative pulse-pressure and cognition in individuals undergoing clinically indicated carotid endarterectomy. We hypothesized that higher PP will be associated with poorer cognitive performance. Methods: Patients with advanced carotid atherosclerosis (&gt;60 % stenosis NASCET, ACAS criteria) underwent neurocognitive testing, blood pressure measurements, and PP calculation (n=128). Cognition was measured using a 60-minute neuropsychological battery recommended by the National Institute of Neurological Disorders and Canadian Stroke Network (NINDS-CSN). Kendell Tau correlations were used to examine the relationship between cognitive tests, ulceration and PP. Results: Participants were a median age of 72 (IQR 13) years of age, 50 females (40%), 78 males (60%), median 70% stenosis (IQR 10.8), median systolic blood pressure of 132 (IQR 26) mmHg, median diastolic blood pressure of 71.5 (IQR 15) mmHg, and median PP of 58.5 mmHg (IQR 23.75). PP ranged from 36 mmHg to 163 mmHg. Results did demonstrate evidence of an association between PP and WAIS-IV Block Design in asymptomatic patients (τ=-0.23, p=0.02). It did not show a significant relationship between PP and other subtests (all p-values&gt;0.05). There was no significant association between PP and operative plaque ulceration scores (p=0.542). Conclusions: PP was not associated with cognitive performance in individuals with advanced carotid atherosclerosis except for the relationship between PP and WAIS-IV Block Design in asymptomatic patients. This finding is consistent with prior work that suggests visuospatial processing presenting as one of the earliest declines in patients with cerebrovascular disease. Though asymptomatic patients did not show classic signs of stroke, they likely had silent strokes due to plaque instability.
Longitudinal Atopic Dermatitis Endotypes: An Atopic March Paradigm That Includes Black Children
Authors: Jocelyn Biagini, John Kroner, Hua He, Brittany Grashel, Daniel Spagna, Michael Sherenian, Lisa Martin, Gurjit Khurana Hershey
Journal: Journal of Allergy and Clinical Immunology (2022)

The atopic march has been studied mostly in White populations, biasing our current paradigms. We defined the atopic march in Black and White children and explore mechanisms for racial differences. Utilizing the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH) cohort (N=601), we assessed longitudinal sensitization, SCORAD, transepidermal water loss (TEWL), skin filaggrin (FLG) expression, exposures and genetic heritability to define AD progression endotypes in Black and White children. White MPAACH children were more likely to be sensitized to aero/food allergens (p=0.0001) and over 3-times more likely to develop food allergy (FA) and/or allergic rhinitis (AR) without asthma risk (p<0.0001). In contrast, Black children were over 6-times more likely to proceed to high asthma risk without FA, sensitization, or AR (p<0.0001). White children had higher lesional and non-lesional TEWL (both p<0.001) and decreased non-lesional keratinocyte FLG expression (p=0.02). Black children had increased genetic heritability for asthma risk and higher rates of exposures to secondhand smoke and traffic-related air pollution. Black and White children with AD have distinct allergic trajectories defined by different longitudinal endotypes. Black children exhibit higher asthma risk despite a more intact skin barrier, and less sensitization, FA and AR. White children have less asthma risk, despite a more dysfunctional skin barrier, and more FA, AR and sensitization. The observed racial differences are likely due, in part, to increased genetic heritability for asthma risk and harmful environmental exposures in Black children. Our findings provide a new atopic march paradigm that is inclusive of Black children.
Preoperative and Postoperative Systemic Therapy for Operable Non–Small-Cell Lung Cancer
Authors: Jamie E. Chaft, Yu Shyr, Boris Sepesi, Patrick M. Forde
Journal: Journal of Clinical Oncology (2022)

Cisplatin-based adjuvant chemotherapy remains the standard of care for patients with resected stage II or III non-small-cell lung cancer. However, biomarker-informed clinical trials are starting to push the management of early-stage lung cancer beyond cytotoxic chemotherapy. This review explores recent and ongoing studies focused on improving cytotoxic chemotherapy and incorporating targeted and immunotherapies in the management of early-stage, resectable lung cancer. Adjuvant osimertinib for patients with
Occludin stalls HCV particle dynamics apart from hepatocyte tight junctions, promoting virion internalization
Authors: Maika S. Deffieu, Camille M. H Clément, Cristina M. Dorobantu, Emma Partiot, Yonis Bare, Orestis Faklaris, Benjamin Rivière, Nilda Vanesa Ayala‐Nunez, Thomas F. Baumert, Philippe Rondé, Yves Mély, Vincent Lucansky, Raphael Gaudin
Journal: Hepatology (2022)

Abstract Background and Aims Numerous HCV entry factors have been identified, and yet information regarding their spatiotemporal dynamics is still limited. Specifically, one of the main entry factors of HCV is occludin (OCLN), a protein clustered at tight junctions (TJs), away from the HCV landing site. Thus, whether HCV particles slide toward TJs or, conversely, OCLN is recruited away from TJs remain debated. Approach and Results Here, we generated CRISPR/CRISPR‐associated protein 9 edited Huh7.5.1 cells expressing endogenous levels of enhanced green fluorescent protein/OCLN and showed that incoming HCV particles recruit OCLN outside TJs, independently of claudin 1 (CLDN1) expression, another important HCV entry factor located at TJs. Using ex vivo organotypic culture of hepatic slices obtained from human liver explants, a physiologically relevant model that preserves the overall tissue architecture, we confirmed that HCV associates with OCLN away from TJs. Furthermore, we showed, by live cell imaging, that increased OCLN recruitment beneath HCV particles correlated with lower HCV motility. To decipher the mechanism underlying virus slow‐down upon OCLN recruitment, we performed CRISPR knockout (KO) of CLDN1, an HCV entry factor proposed to act upstream of OCLN. Although CLDN1 KO potently inhibits HCV infection, OCLN kept accumulating underneath the particle, indicating that OCLN recruitment is CLDN1 independent. Moreover, inhibition of the phosphorylation of Ezrin, a protein involved in HCV entry that links receptors to the actin cytoskeleton, increased OCLN accumulation and correlated with more efficient HCV internalization. Conclusions Together, our data provide robust evidence that HCV particles interact with OCLN away from TJs and shed mechanistic insights regarding the manipulation of transmembrane receptor localization by extracellular virus particles.
Abstract 078: Mid- To Long- Term Follow-up Care Insufficiencies From A Cross-sectional School- Based Cholesterol Screening Program
Authors: Rachel A Kohler, Paige Poffenberger, Christa lilly, Lee A Pyles
Journal: Circulation (2022)

Introduction: The CARDIAC project surveyed cardiometabolic risk and risk for familial hypercholesterolemia (FH) through a school-based program, demonstrating the importance of universal blood cholesterol screening in children. At most, 10% of FH is diagnosed in the United States. Hypothesis: We hypothesize a disconnect between identification of risk factors and the follow-up care received by those children and young adults. Methods: Between 1998 and 2016, 60,404 5th grade children had their LDL-C levels assessed through venipuncture lipid panels. Of the 638 children who had an LDL-C ≥ 160mg/dl, indicative of probable FH, 395 were identified through EPIC EHR, phone calls, and mail surveys. WVU IRB approved verbal consent by participants. Information on their current status was obtained including medical care for their cholesterol, lipid-lowering medications (LLM), other medications, and family history of cardiac-related events. Results: Out of the 395 children identified, 174 were male and 221 were female. We had follow-up lipid panels for 58. Eight participants on a LLM had a follow-up LDL-C that was 57.5 +/- 50.1 mg/dl lower than the 5th grade level. Fifty subjects not on a LLM had an LDL-C that was 27.2 +//- 48.0 mg/dl lower than baseline. No follow-up LDL-C data was available on 33 participants who received a LLM. While only 41 children had ever taken a LLM, 56 participants were taking oral contraceptive, and 63 a psychotropic medicine. Only 1 participant was enrolled in the FH Registry. No subject was found with major adverse coronary event. Conclusion: Follow-up after screening demonstrated improved lipid levels in several subjects without known medication. Many subjects were receiving oral contraceptive agents and psychotropic medicines associated with dyslipidemia, usually without follow-up lipid panels. Roughly one-third of participants had unknown mid-term course. Epic EHR for WVU Health System found 393 subjects. The inability to document ongoing medical care in addition to demonstrated lack of care received by those who had an LDL greater than 160mg/dl shows that there is insufficient follow-up care for young people with probable FH. In conclusion, the data points to areas to improve, including better education for patients with this cardiometabolic risk factor. Education of health care professionals, telemedicine, patient-driven advocacy groups, EHRs that cover large catchments, and patient communication portals promise to better focus ongoing care for persons with abnormal lipid profiles.
Randomized phase III study of etoposide plus cisplatin versus irinotecan plus cisplatin in advanced neuroendocrine carcinoma of the digestive system: A Japan Clinical Oncology Group study (JCOG1213).
Authors: Chigusa Morizane, Nozomu Machida, Yoshitaka Honma, Takuji Okusaka, Narikazu Boku, Ken Kato, Shogo Nomura, Nobuyoshi Hiraoka, Shigeki Sekine, Hirokazu Taniguchi, Naohiro Okano, Kensei Yamaguchi, Takuji Sato, Masafumi Ikeda, Nobumasa Mizuno, Masato Ozaka, Tomoko Kataoka, Yuko Kitagawa, Masanori Terashima, Junji Furuse
Journal: Journal of Clinical Oncology (2022)

501 Background: Neuroendocrine carcinoma (NEC) arising in the digestive system is a rare and high-grade malignant tumor. Treatment guidelines for advanced NEC recommend platinum-based chemotherapy regimens. Etoposide plus cisplatin (EP) and irinotecan plus cisplatin (IP) are commonly used as community standard regimens for NEC. However, it is unknown which is more effective. This phase III study aimed to identify more effective regimen between EP and IP in terms of overall survival (OS) for patients with advanced NEC. Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable, histologically confirmed NEC (WHO2010) arising from the gastrointestinal tract (GI), hepatobiliary and pancreas (HBP), ECOG PS of 0-1, age of 20–75 years. In the EP arm, etoposide (100 mg/m 2 on days 1, 2 and 3) and cisplatin (80 mg/m 2 on day 1) were administered every 3 weeks. In the IP arm, irinotecan (60 mg/m 2 on days 1, 8 and 15) and cisplatin (60 mg/m 2 on day 1) were repeated every 4 weeks. The primary endpoint was OS. Total of 140 patients (114 events) were required to detect a hazard ratio (HR) of 0.67 (median OS; 8/12 months in inferior/superior arms) with a two-sided alpha of 10% and power of 70%. Due to a rapid accrual, the sample size was increased to 170 (power of 80%). Pathology was centrally reviewed after the start of treatment. Results: Of all enrolled 170 patients (GI: 100, HBP: 70) from Aug 2014 to March 2020, median OS was 12.5 months in EP and 10.9 months in IP (HR 1.043 [a ratio of EP to IP], 90% CI, 0.794-1.370, p= 0.797). Median progression-free survival (PFS) was 5.6 months in EP and 5.1 months in IP (HR 1.060, 95% CI, 0.777-1.445). Response rate (RR) was 54.5% (42/77) in EP and 52.5% (42/80) in IP among patients with target lesions. No interactions with OS, PFS, or RR were seen in pre-planned subgroup analyses including primary organs or pathological findings. The common Grade 3-4 AEs (EP/IP) was neutropenia (91.5%/53.7%), leukocytopenia (61.0%/30.5%), and febrile neutropenia (26.8%/12.2%). Conclusions: A superiority was not demonstrated, which indicates that both EP and IP remain standard first-line chemotherapy. Clinical trial information: UMIN000014795.
BDTX-1535 Goes after Osimertinib Resistance
Journal: Cancer Discovery (2021)

According to a preclinical report, the investigational tyrosine kinase inhibitor BDTX-1535 may mitigate resistance to osimertinib, the standard of care for EGFR-mutant non-small cell lung cancer. It could also potentially treat central nervous system metastases, having shown preclinical efficacy in glioblastoma.
Abstract P217: Cardiovascular Events Among Adults Who Qualify For Statin Therapy Based On Age Alone Alone: A Reasons For Geographical And Racial Differences In Stroke (REGARDS) Study
Authors: Nathan Kong, Swati Sakhuja, Lisandro Colantonio, Emily B Levitan, Donald Lloyd-Jones, Mary Cushman, Paul Muntner, Tamar S Polonsky
Journal: Circulation (2022)

Background: Predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk in the Pooled Cohort equation increases substantially with age. Some older adults have estimated ASCVD risk ≥7.5% without elevated risk factors; it is unclear whether the observed ASCVD risk is high in this group. We compared the incidence of ASCVD between adults with an estimated 10-year ASCVD risk ≥7.5% based on age alone vs those with elevated risk factors. Methods: Adults ages 45-79 enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study without a history of ASCVD, diabetes mellitus, or statin use were included (i.e, a primary prevention subset). Ten-year ASCVD risk was estimated using the Pooled Cohort Risk Equation. Participants were categorized into 3 groups according to the predicted ASCVD risk: &lt;7.5%, “age-only” ≥7.5%, and “elevated factors” ≥7.5%. Participants with “age-only” risk ≥7.5% were nonsmokers with untreated SBP &lt;130 mmHg, total cholesterol &lt;200 mg/dL, and HDL-C ≥50 mg/dL for women or ≥40 mg/dL for men. All other participants with predicted ASCVD ≥7.5% were considered “elevated factors” ≥7.5%. Incident ASCVD was defined as ischemic or hemorrhagic stroke, nonfatal MI, or CHD death. Results: Among 10,742 participants, 891 ASCVD events occurred over a median follow-up of 11.1 (7.1 - 13.0) years. The “age-only” risk ≥7.5% group included 352 (3.3%) participants with mean age 69.9 ± 5.0. The risk &lt;7.5%, and “elevated factors” risk ≥7.5% had a mean age of 56.3 ± 5.9, and 66.3 ± 7.1 years, respectively. Compared to the risk &lt;7.5% group, the “age-only” and “elevated factors” risk ≥7.5% group experienced 2.6-fold and 3.6-fold higher event rates, respectively (Table). Conclusions: Few adults in this primary prevention population had predicted risk ≥7.5% based on age alone. Even without elevated risk factors, adults with predicted ASCVD risk ≥7.5% based on age alone experienced substantial event rates consistent with their predicted risk.
Regrow or Repair: An Update on Potential Regenerative Therapies for the Kidney
Authors: Melissa H. Little, Benjamin D. Humphreys
Journal: Journal of the American Society of Nephrology (2021)

Fifteen years ago, this journal published a review outlining future options for regenerating the kidney. At that time, stem cell populations were being identified in multiple tissues, the concept of stem cell recruitment to a site of injury was of great interest, and the possibility of postnatal renal stem cells was growing in momentum. Since that time, we have seen the advent of human induced pluripotent stem cells, substantial advances in our capacity to both sequence and edit the genome, global and spatial transcriptional analysis down to the single-cell level, and a pandemic that has challenged our delivery of health care to all. This article will look back over this period of time to see how our view of kidney development, disease, repair, and regeneration has changed and envision a future for kidney regeneration and repair over the next 15 years.
DRUGGABLE MM THERAPEUTICS: PATHOGENETIC PATHWAYS
Authors: Enrique M Ocio
Journal: HemaSphere (2022)

In the current treatment scenario, after 1, 2 or at most 3 lines of therapy, most MM patients have exposed (or are refractory), to PIs, IMiDs and anti-CD38 MoAb. Novel alternatives are currently being developed, mostly using BCMA as a target, and some of them such as CAR-Ts or ADCs have already been approved although they are still not widely available, at least in Europe. But there is still an active search for novel therapeutic options based on the MM pathogenetic vulnerabilites. One such mechanism, although not novel, is DNA damage, and Melflufen, a Peptide-Drug conjugate (PDC) showed activity in heavily pretreated patients, what led to its initial FDA approval, although, significant concerns about long term toxicity have been raised in the phase III study. Selinexor inhibits XPO-1, a protein that exports different proteins from the nucleus of the tumor cell. In combination with dexamethasone, it has demonstrated activity in penta-refractory or triple-class refractory patients, with an ORR of 26% and a DOR of 4 months, that lead to its FDA and EMA approval. Another important target is the E3 ubiquitin ligase CRBN, and in fact, two CELMoDs (CRBN modulators), Iberdomide (CC-220) and CC-92480, have demonstrated activity (ORR 30-50%) and a favorable safety profile in heavily pretreated patients. MM cells are also largely dependent on the antiapoptotic molecule Bcl2, and venetoclax, an inhibitor of this protein, has demonstrated to be active particularly in patients carrying t(11;14). More recently, several Mcl-1 inhibitors are also being evaluated both preclinically and clinically. Another interesting target could be the RAS pathway as it is mutated in around 50% of MM patients and RAS/RAF/MEK inhibitors have demonstrated activity in selected patients populations. Other approaches are also attractive such as myc inhibition or additional ways of activating the immune system. In this last field, two novel mechanisms hold significant promise: inhibition of the do not eat me signal with anti-CD47 MoAb such as Magrolimab, or the use of Modakafusp a CD38 MoAb with two IFN attenuated molecules that induces a anti-tumoral One important field of investigation is the search for biomarkers predicting sensitivity or resistance to a given agents, such as venetoclax in t(11;14) patients, Mcl-1 inhibitors in patients with 1q+, or RAS/RAF/MEK inhibitors for patients with activation of this pathway.
Highlights From the <i>Circulation</i> Family of Journals
Authors: Amin Al-Ahmad, Vivek Reddy, Audrius Aidietis, Matthew Daly, Iain Melton, Yan Hu, Matthew Sulkin, Gediminas Rackauskas, Adrian Ebner, Darren Hooks, Aamir Sofi, Petr Neužil, Ian Crozier, Shaan Khurshid, Nina Mars, Christopher Haggerty, Qiuxi Huang, Lu-Chen Weng, Dustin Hartzel, Regeneron Genetics Center, Kathryn Lunetta, Jeffrey Ashburner, Christopher Anderson, Emelia Benjamin, Veikko Salomaa, Patrick Ellinor, Brandon Fornwalt, Samuli Ripatti, Ludovic Trinquart, Steven Lubitz, Théo Pezel, Thierry Unterseeh, Philippe Garot, Thomas Hovasse, Francesca Sanguineti, Solenn Toupin, Stéphane Morisset, Stéphane Champagne, Jérôme Garot, Do-Yoon Kang, Jung-Min Ahn, Sung-Cheol Yun, Hanbit Park, Sang-Cheol Cho, Tae Kim, Sangwoo Park, ; Pil, Hyung Lee, Seung-Whan Lee, Seong-Wook Park, Duk-Woo Park, Seung-Jung Park
Journal: Circulation (2021)

This month's highlights from the subspecialty journals over the past month span several important topics in cardiovascular medicine.The experience with a first-in-human radiofrequency ablation catheter with a camera is described in Circulation: Arrhythmia and Electrophysiology.In Circulation: Genomic and Precision Medicine, a clinical and genetic risk model for atrial fibrillation is described.A large observational registry suggests that revascularization of severe ischemia by stress cardiac magnetic resonance imaging is associated with greater survival in Circulation: Cardiovascular Imaging.Outcomes associated with intravascular ultrasound-guided left main revascularization are reported in Circulation: Cardiovascular Interventions.Performance metrics for machine-learning models are assessed in Circulation: Cardiovascular Quality and Outcomes.Last, the impact of remote visits on management of heart failure during the COVID pandemic is reported in Circulation: Heart Failure.
LIGHT CHAIN DEPOSITION DISEASE
Authors: Josephine M.I. Vos
Journal: HemaSphere (2022)

Light chain deposition disease (LCDD) is a very rare, non-amyloid variant of the deposition diseases seen in monoclonal gammopathies. LCDD is one of the non-amyloid Monoclonal immunoglobulin deposition diseases next to heavy chain (HCDD), or combined light and heavy chain deposition disease (LHCDD). The underlying clone in LCDD, most commonly plasmacell but can be lymphoid, is mostly small (median 10% BM infiltration) and therefore LCDD can be considered as one of the Monoclonal Gammopathies of Renal Significance (MGRS). Often there is only light chain as the circulating monoclonal component, most often kappa, followed by IgG heavy chain. The clinical presentation is markedly different from AL Amyloidosis: LCDD virtually always presents with kidney involvement while cardiac, liver and other organs are involved in a minority of patients only. Up to 30% of patients present with End Stage Renal Disease at diagnosis. LCDD is diagnosed by demonstrating monoclonal light chain (mostly kappa) deposits in a biopsy of an involved organ (most commonly the kidney). Of importance, renal prognosis among those diagnosed in 4 or 5 Chronic Kidney Disease is better among patients with LCDD than renal AL amyloidosis. In the latter, end stage kidney disease is rarely reversible, while in LCDD improvements can be seen even in patients that start treatment in stage 4 CKD. Achievement of a durable hematological CR or VGPR is associated with significant and ongoing improvements in renal function in most patients. However, LCDD patients that do not achieve a CR or VGPR will most likely to experience progressieve renal failure. Also, prognosis is better in patients with <4 CKD compared to stage 4 or 5 CK at diagnosis. Therefore, timely diagnosis and achievement of a rapid and durable deep hematological response are important goals in LCDD. There are no prospective data on optimal treatment for this rare disease. Based on retrospective data, clone direct therapy including proteasome inhibitor based induction followed by High Dose Melfalan + autologous stemcell rescue have yielded high and deep responses (both hematological and renal) in retrospective series. Some small reports have shown favourable results of daratumumab. Renal transplantation has been performed successfully in patients in a hematological remission, but is unsuccessful if patients with active hematological disease.