tbuckley/cabot-search huggingface dataset:
An evidence-based framework for determining the optimal amount of intervention for autistic children
Authors: David Trembath, Hannah Waddington, Rhylee Sulek, Kandice Varcin, Catherine Bent, Jill Ashburner, Valsamma Eapen, Emma Goodall, Kristelle Hudry, Natalie Silove, Andrew Whitehouse
Journal: The Lancet Child & Adolescent Health (2021)
Prevalence of hypoxaemia in children with pneumonia in low-income and middle-income countries: a systematic review and meta-analysis
Authors: Ahmed Ehsanur Rahman, Aniqa Tasnim Hossain, Harish Nair, Mohammod Jobayer Chisti, David Dockrell, Shams El Arifeen, Harry Campbell
Journal: The Lancet Global Health (2022)

Pneumonia accounts for around 15% of all deaths of children younger than 5 years globally. Most happen in resource-constrained settings and are potentially preventable. Hypoxaemia is one of the strongest predictors of these deaths. We present an updated estimate of hypoxaemia prevalence among children with pneumonia in low-income and middle-income countries.
Abstract 10260: Risk Factors for Developmental Delay in Congenital Heart Disease Patients Following Surgery
Authors: Kate Taylor, Andrew Well, Amelia Mercado, Shannon Reilly, Hannah Whipple, Carlie Spence, Brittany Barnhill, Kimberly Krauklis, Heather Van Diest, Carlos M Mery, Alexandra Lamari-fisher
Journal: Circulation (2021)

Introduction: Children with congenital heart disease (CHD) receiving cardiac surgical intervention are at greater risk for developmental delays (DD). Identification of DD and early interventions may improve long term outcomes. The Ages and Stages Questionnaire (version 3) (ASQ3) is a DD screening tool. We hypothesized that clinical and perioperative risk factors are associated with DD in the early post-operative period. Methods: Patients who received an ASQ3 from 2019-2021 post CHD surgery were included. The ASQ3 was administered at outpatient surgical consultation or inpatient, if specific DD risk criteria were met. Those with incomplete operative data were excluded. DD was defined by an ASQ3 score for any domain below the at-risk cutoff. Associations between DD, patient characteristics, clinical factors, and perioperative factors were analyzed utilizing descriptive, univariate, and multivariable statistics. Results: A total of 57 patients were identified: median age at screening was 4 [IQR: 2-9] months, 22(39%) had a non-cardiac congenital abnormality (NCAA) and 17 (30%) a chromosomal abnormality (CA) (Table). Median cardiopulmonary bypass (CPB) time was 194 [IQR: 89-239] minutes. Forty-six (81%) patients had a DD. The median time between surgery and screening was 2 [IQR: 1-5] months. Patients with a NCAA (p = 0.037) and CA (p = 0.024) were more likely to have a DD. No other significant differences were found. In models adjusted for NCAA and CA, CPB times were not significant. Conclusions: The ASQ3 detected a high prevalence of DD among patients screened post CHD surgery. Despite known associations between CHD surgery and DD, few clinical factors, including CPB times, in our sample were associated with ASQ3 determined DD. More studies are needed to assess if the ASQ3 is sensitive and specific enough to serve as a screening tool in this population.
E-Cadherin: Context-Dependent Functions of a Quintessential Epithelial Marker in Metastasis
Authors: Cao Fang, Yibin Kang
Journal: Cancer Research (2021)

Abstract Loss of E-cadherin expression has been well known as a hallmark of epithelial–mesenchymal transition (EMT), which is linked to increased risk of cancer metastasis. However, it was less clear whether E-cadherin and its downstream signaling pathways are functionally involved in driving EMT and the prometastatic phenotype. A study by Onder and colleagues in 2008 discovered that E-cadherin loss not only helps tumor cells detach from each other by breaking down cell–cell junctions but also elicits intracellular signaling events to confer a mesenchymal cell state and metastatic phenotype. This study established E-cadherin as an important global regulator, rather than just a marker, of EMT. The discovery inspired further investigation in the following decade that significantly deepened our understanding of E-cadherin and its diverse functions and more broadly of cellular plasticity in different stages and contexts of cancer metastasis. See related article by Onder and colleagues, Cancer Res 2008;68:3645–3654.
Lung Transplantation for Covid-19–Related Respiratory Failure in the United States
Authors: Amy Roach, Joanna Chikwe, Pedro Catarino, Reinaldo Rampolla, Paul W Noble, Dominick Megna, Qiudong Chen, Dominic Emerson, Natalia Egorova, Shaf Keshavjee, James K Kirklin
Journal: New England Journal of Medicine (2022)
Abstract EP22: Sex And Socioeconomic Difference In 30-day Readmission After Hypertensive Crisis
Authors: Kyeeun Park, Mohammed Ebrahim, Pyi Phyo Aung, Navya Konindala
Journal: Circulation (2022)

Introduction: Hypertensive crisis (HC) is associated with serious health implication such as hypertensive heart disease, kidney disease and strokes and frequent healthcare utilization, especially unplanned 30-day readmission. ACC/AHA published new guideline for hypertensive crisis in 2017, but its impact on unplanned readmission has not been fully appreciated. Reporting readmission trends by sex and socioeconomic difference is crucial for public health surveillance and improved healthcare equity. Methods and Results: We conducted a retrospective analysis of the 2018 to 2019 Nationwide Readmission Database (NRD). Study populations were selected using ICD-10 diagnosis code. Discharge-level weight analysis was used to produce a national estimate. Social economic status (SES) was evaluated using median household income of patient’s ZIP code and dived into quarter. We conducted univariate and multivariable hierarchical regression analysis to calculate odds ratio (OR) with STATA 17. During the study period, there were 1,495,230 hospitalizations with hypertensive crisis of which 53.68% were female. According to SES study, 39.29% of patients were from the lowest quartile followed by 27.00%, 20.80% and 12.90% respectively. The overall incidence of unplanned readmission was 15.85 %( 237,052 of 1,495,230). Readmission rate was higher in female (15.93% v 15.77%; p = 0.006) and lower income quartiles (17.17% v 15.55% v 14.78% v 14.32%; p &lt;0.0001). The most common indication for readmission was repeated hypertensive crisis with higher proportion being female (18.39% v 17.42%) and the lowest income quartile (18.59%). After adjusting for age and comorbidities, female sex (OR 1.05; 95% CI, 1.04 - 1.07; p&lt; 0.0001) and the lowest income quartile (OR 1.12; 95% CI, 1.11 - 1.14; p&lt; 0.0001) were found to be significant predictors for 30-day readmission. Discussion: According to prior study, the 30-day readmission rate after HC has been improved with implementation of the ACC/AHA 2017 guideline (15.85% v 17.8%). However, disparities in HC burden and hospital utilization by sex and socioeconomic status persists. Public health interventions are needed to reduce HC hospitalization burden in female and low socioeconomic patients.
Modern Lung Magnetic Resonance Imaging to Screen for Pulmonary Complications in Patients with Dyskeratosis Congenita
Authors: Laura L. Walkup, Kasiani C. Myers, Matthew M. Willmering, Parinda A. Mehta, Adam S. Nelson, Robert J. Fleck, Jason C. Woods, Stella M. Davies, Christopher T. Towe
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

"Modern Lung Magnetic Resonance Imaging to Screen for Pulmonary Complications in Patients with Dyskeratosis Congenita." American Journal of Respiratory and Critical Care Medicine, 204(11), pp. 1340–1343
Abstract 044: Moderate Alcohol Drinking With Meals Is Related To Lower Incidence Of Type 2 Diabetes
Authors: Hao Ma, Xuan Wang, Xiang Li, Yoriko Heianza, Lu Qi
Journal: Circulation (2022)

Introduction: Alcohol drinking has both adverse and beneficial effects on health. The benefits of moderate drinking on glucose metabolism have been documented in several well-designed clinical trials. However, it is still unclear whether such benefits on glucose metabolism will translate into a reduction in type 2 diabetes (T2D). Inconsistent results on the relationship between moderate drinking and T2D were observed in previous studies. Intriguingly, we noted that, the alcoholic beverages were usually served with meals in those clinical trials that have detected the beneficial effects of moderate alcohol intake on glucose metabolism. Hypothesis: We hypothesized that the association between alcohol intake and risk of T2D might differ by the timing of alcohol intake with respect to meals. Methods: A total of 312,388 healthy current drinkers from UK biobank without T2D at baseline were included. Cox proportional hazards models were used to examine the association between the timing of alcohol intake with respect to meals and risk of T2D. Results: During a median of 10.9 years of follow-up, 8,598 incident cases of T2D were documented. After adjustment for covariates and the amount of alcohol consumed, consuming alcohol with meals was significantly associated with a 14% lower risk of T2D (HR, 95 % CI, 0.86, 0.81-0.91), as compared with consuming alcohol outside of meals. In addition, we found that the timing of alcohol intake with respect to meals significantly modified the relations between the amount of alcohol consumed and risk of T2D ( P -interaction=0.010), the beneficial association of moderate drinking with T2D risk was only observed in participants who consumed alcohol with meals, but not in others. Further analyses on various types of alcoholic beverages indicated that the beneficial associations between alcohol drinking with meals and T2D were mainly driven by the wine consumption. Conclusions: In the current drinkers, moderate drinking of alcohol, especially wine, with meals is associated a lower risk of T2D.
Activating P2Y1 receptors improves function in arteries with repressed autophagy
Authors: Jae Min Cho, Seul-Ki Park, Oh Sung Kwon, David Taylor La Salle, James Cerbie, Caitlin C Fermoyle, David Morgan, Ashley Nelson, Amber Bledsoe, Leena P Bharath, Megan Tandar, Satya P Kunapuli, Russell S Richardson, Pon Velayutham Anandh Babu, Sohom Mookherjee, Bellamkonda K Kishore, Fei Wang, Tianxin Yang, Sihem Boudina, Joel D Trinity, John David Symons
Journal: Cardiovascular Research (2022)

Abstract Aim The importance of endothelial cell (EC) autophagy to vascular homeostasis in the context of health and disease is evolving. Earlier, we reported that intact EC autophagy is requisite to maintain shear-stress-induced nitric oxide (NO) generation via glycolysis-dependent purinergic signalling to endothelial NO synthase (eNOS). Here, we illustrate the translational and functional significance of these findings. Methods and results First, we assessed translational relevance using older male humans and mice that exhibit blunted EC autophagy and impaired arterial function vs. adult controls. Active hyperaemia evoked by rhythmic handgrip exercise-elevated radial artery shear-rate similarly from baseline in adult and older subjects for 60 min. Compared with baseline, indexes of autophagy initiation, p-eNOSS1177 activation, and NO generation, occurred in radial artery ECs obtained from adult but not older volunteers. Regarding mice, indexes of autophagy and p-eNOSS1177 activation were robust in ECs from adult but not older animals that completed 60-min treadmill-running. Furthermore, 20 dyne • cm2 laminar shear stress × 45-min increased autophagic flux, glycolysis, ATP production, and p-eNOSS1177 in primary arterial ECs obtained from adult but not older mice. Concerning functional relevance, we next questioned whether the inability to initiate EC autophagy, glycolysis, and p-eNOSS1177 in vitro precipitates arterial dysfunction ex vivo. Compromised intraluminal flow-mediated vasodilation displayed by arteries from older vs. adult mice was recapitulated in vessels from adult mice by (i) NO synthase inhibition; (ii) acute autophagy impairment using 3-methyladenine (3-MA); (iii) EC Atg3 depletion (iecAtg3KO mice); (iv) purinergic 2Y1-receptor (P2Y1-R) blockade; and (v) germline depletion of P2Y1-Rs. Importantly, P2Y1-R activation using 2-methylthio-ADP (2-Me-ADP) improved vasodilatory capacity in arteries from (i) adult mice treated with 3-MA; (ii) adult iecAtg3KO mice; and (iii) older animals with repressed EC autophagy. Conclusions Arterial dysfunction concurrent with pharmacological, genetic, and age-associated EC autophagy compromise is improved by activating P2Y1-Rs.
CAR T cells expressing a bacterial virulence factor trigger potent bystander antitumour responses in solid cancers
Authors: Chuan Jin, Jing Ma, Mohanraj Ramachandran, Di Yu, Magnus Essand
Journal: Nature Biomedical Engineering (2022)

Abstract Chimeric antigen receptor T cells (CAR T cells) are effective against haematologic malignancies. However, in solid tumours, their potency is hampered by local immunosuppression and by the heterogeneous expression of the antigen that the CAR targets. Here we show that CAR T cells expressing a pluripotent pro-inflammatory neutrophil-activating protein (NAP) from Helicobacter pylori trigger endogenous bystander T-cell responses against solid cancers. In mice with subcutaneous murine pancreatic ductal adenocarcinomas, neuroblastomas or colon carcinomas, CAR(NAP) T cells led to slower tumour growth and higher survival rates than conventional mouse CAR T cells, regardless of target antigen, tumour type and host haplotype. In tumours with heterogeneous antigen expression, NAP secretion induced the formation of an immunologically ‘hot’ microenvironment that supported dendritic cell maturation and bystander responses, as indicated by epitope spreading and infiltration of cytotoxic CD8 + T cells targeting tumour-associated antigens other than the CAR-targeted antigen. CAR T cells armed with NAP neither increased off-tumour toxicity nor hampered the efficacy of CAR T cells, and hence may have advantageous translational potential.
Carbonic anhydrase XII mediates the survival and prometastatic functions of macrophages in human hepatocellular carcinoma
Authors: Wan-Ru Ning, Da Jiang, Xing-Chen Liu, Yu-Fan Huang, Zhi-Peng Peng, Ze-Zhou Jiang, Tiebang Kang, Shi-Mei Zhuang, Yan Wu, Limin Zheng
Journal: Journal of Clinical Investigation (2022)

Macrophages constitute a major immune component in tumor tissues, but how these cells adapt to and survive in the nutrient-depleted and lactic acid–induced acidic tumor microenvironments is not yet fully understood. Here, we found that levels of carbonic anhydrase XII (CA12) expression were significantly and selectively upregulated on macrophages in human hepatocellular carcinoma (HCC). Transient glycolytic activation of peritumoral monocytes induced sustained expression of CA12 on tumor-infiltrating macrophages via autocrine cytokines and HIF1α pathways. On the one hand, CA12 mediated the survival of macrophages in relatively acidic tumor microenvironments, while on the other hand, it induced macrophage production of large amounts of C-C motif chemokine ligand 8 (CCL8), which enhanced cancer cell epithelial-mesenchymal transition (EMT) and facilitated tumor metastasis. Consistently, the accumulation of CA12+ macrophages in tumor tissues was associated with increased tumor metastatic potential and reduced survival of patients with HCC. Selective targeting of tumor-infiltrating macrophages with a CA12 inhibitor reduced tumor growth in mice and was sufficient to synergistically enhance the therapeutic efficacy of immune-checkpoint blockade. We suggest that CA12 activity is a previously unappreciated mechanism regulating the accumulation and functions of macrophages in tumor microenvironments and therefore represents a selective vulnerability that could be exploited in future designs for antitumor immunotherapeutic strategies.
First Metatarsal Bone Metastasis From Clear Cell Renal Cell Carcinoma on SPECT/CT
Authors: Olgierd Chrabański, Tomasz Gołąb
Journal: Clinical Nuclear Medicine (2021)

Abstract We report metatarsal metastasis in SPECT/CT in a 65-year-old man, 5 years after radical right nephrectomy. Tumor from first metatarsal was histopathologically proven from clear cell renal cell carcinoma. Metatarsal metastasis is very rare. Less than 0.01% of patients have metastases in the foot bone. Tumor histotype is mainly lung cancer. Metastases from renal carcinoma are often lytic with a poor osteoblastic response, there may be limited uptake of the 99m Tc-MDP tracer, and all uncertain regions should be diagnosed with SPECT/CT, if it is possible.
Heterogeneity of CAFfeinated Tumors: Sweet Targeting Perspectives
Authors: Olivier De Wever
Journal: Cancer Research (2022)

Abstract The tumor microenvironment (TME) shows heterogeneity within a tumor. An important element of the TME is cancer-associated fibroblasts (CAF). In this issue of Cancer Research, Bouchard and colleagues investigate the heterogeneity of CAFs from spatially different zones of lung adenocarcinoma resection specimens. Multiomics analysis revealed changes in the O-glycoproteome, unique to CAFs from the tumor edge, an effect reinforced by contact with cancer cells. This O-glycoprotein signature offers unique targeting perspectives that reciprocally affect cancer cell epithelial-to-mesenchymal plasticity, a key mechanism of cancer progression. Deeper understanding of the cancer-stimulating and cancer-inhibiting role of CAF subtypes will facilitate the development of CAF-directed therapeutic approaches. See related article by Bouchard et al., p. 648
Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL
Authors: Regina M. Myers, Agne Taraseviciute, Seth M. Steinberg, Adam J. Lamble, Jennifer Sheppard, Bonnie Yates, Alexandra E. Kovach, Brent Wood, Michael J. Borowitz, Maryalice Stetler-Stevenson, Constance M. Yuan, Vinodh Pillai, Toni Foley, Perry Chung, Lee Chen, Daniel W. Lee, Colleen Annesley, Amanda DiNofia, Stephan A. Grupp, Samuel John, Deepa Bhojwani, Patrick A. Brown, Theodore W. Laetsch, Lia Gore, Rebecca A. Gardner, Susan R. Rheingold, Michael A. Pulsipher, Nirali N. Shah
Journal: Journal of Clinical Oncology (2021)

PURPOSE CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.
18F-FDG PET/CT Imaging of G-CSF–Producing Dedifferentiated Liposarcoma
Authors: Yukari Eizuru, Masatoyo Nakajo, Masanori Nakajo, Naohiro Shinohara, Takashi Yoshiura
Journal: Clinical Nuclear Medicine (2021)

Abstract Granulocyte colony-stimulating factor (G-CSF)–producing tumors are malignant tumors associated with a poor prognosis, and G-CSF–producing liposarcoma is particularly rare. We report a case of G-CSF–producing dedifferentiated liposarcoma. 18 F-FDG PET/CT showed abnormal 18 F-FDG uptake throughout the bone marrow and in the primary site. When a diffuse bone marrow 18 F-FDG uptake was observed on 18 F-FDG PET/CT, G-CSF–producing dedifferentiated liposarcoma should be included in the differential diagnosis.
Single-cell Characterization of the Cellular Landscape of Acral Melanoma Identifies Novel Targets for Immunotherapy
Authors: Jiannong Li, Inna Smalley, Zhihua Chen, Jheng-Yu Wu, Manali S. Phadke, Jamie K. Teer, Thanh Nguyen, Florian A. Karreth, John M. Koomen, Amod A. Sarnaik, Jonathan S. Zager, Nikhil I. Khushalani, Ahmad A. Tarhini, Vernon K. Sondak, Paulo C. Rodriguez, Jane L. Messina, Y. Ann Chen, Keiran S.M. Smalley
Journal: Clinical Cancer Research (2022)

Acral melanoma is a rare subtype of melanoma that arises on the non-hair-bearing skin of the palms, soles, and nail beds. In this study, we used single-cell RNA sequencing (scRNA-seq) to map the transcriptional landscape of acral melanoma and identify novel immunotherapeutic targets.We performed scRNA-seq on nine clinical specimens (five primary, four metastases) of acral melanoma. Detailed cell type curation was performed, the immune landscapes were mapped, and key results were validated by analysis of The Cancer Genome Atlas (TCGA) and single-cell datasets. Cell-cell interactions were inferred and compared with those in nonacral cutaneous melanoma.Multiple phenotypic subsets of T cells, natural killer (NK) cells, B cells, macrophages, and dendritic cells with varying levels of activation/exhaustion were identified. A comparison between primary and metastatic acral melanoma identified gene signatures associated with changes in immune responses and metabolism. Acral melanoma was characterized by a lower overall immune infiltrate, fewer effector CD8 T cells and NK cells, and a near-complete absence of γδ T cells compared with nonacral cutaneous melanomas. Immune cells associated with acral melanoma exhibited expression of multiple checkpoints including PD-1, LAG-3, CTLA-4, V-domain immunoglobin suppressor of T cell activation (VISTA), TIGIT, and the Adenosine A2A receptor (ADORA2). VISTA was expressed in 58.3% of myeloid cells and TIGIT was expressed in 22.3% of T/NK cells.Acral melanoma has a suppressed immune environment compared with that of cutaneous melanoma from nonacral skin. Expression of multiple, therapeutically tractable immune checkpoints were observed, offering new options for clinical translation.