tbuckley/cabot-search huggingface dataset:
Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab
Authors: Andrew Hantel, Brooke Gabster, Jason X. Cheng, Harvey Golomb, Thomas F. Gajewski
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Treatment of metastatic melanoma patients with immune checkpoint inhibitors is an important standard of care. Side effects are due to immune activation, can affect virtually all organ systems, and are occasionally severe. Although hematologic toxicity has been reported, we present a case of hemophagocytic lymphohistiocytosis (HLH) due to immune checkpoint inhibitor therapy. <h3>Case presentation</h3> A patient with metastatic melanoma was treated with one course of ipilimumab + nivolumab and presented 3 weeks later with severe anemia and hyperferritinemia. A bone marrow biopsy revealed necrotic tumor cells, infiltrating T cells, and hemophagocytosis. The patient was treated with high-dose steroids; 12&nbsp;months later, the patient remains off all therapy and in complete remission of both HLH and metastatic melanoma. <h3>Conclusions</h3> The hemophagocytic syndromes are attributable to dysregulated immune activation and share pathophysiologic mechanisms with immune activation from checkpoint inhibitors. Increasing use of regimens that include immune checkpoint inhibition require vigilant monitoring for immune-activating side effects as they can occasionally be life threatening, as in this case of HLH.
Identification of Metastatic Lymph Nodes in MR Imaging with Faster Region-Based Convolutional Neural Networks
Authors: Yun Lu, Qiyue Yu, Yuanxiang Gao, Yunpeng Zhou, Guangwei Liu, Qian Dong, Jinlong Ma, Lei Ding, Hongwei Yao, Zhongtao Zhang, Gang Xiao, Qi An, Guiying Wang, Jinchuan Xi, Weitang Yuan, Yugui Lian, Dianliang Zhang, Chunbo Zhao, Qin Yao, Wei Liu, Xiaoming Zhou, Shuhao Liu, Qingyao Wu, Wenjian Xu, Jianli Zhang, Dongshen Wang, Zhenqing Sun, Yuan Gao, Xianxiang Zhang, Jilin Hu, Maoshen Zhang, Guanrong Wang, Xuefeng Zheng, Lei Wang, Jie Zhao, Shujian Yang
Journal: Cancer Research (2018)

MRI is the gold standard for confirming a pelvic lymph node metastasis diagnosis. Traditionally, medical radiologists have analyzed MRI image features of regional lymph nodes to make diagnostic decisions based on their subjective experience; this diagnosis lacks objectivity and accuracy. This study trained a faster region-based convolutional neural network (Faster R-CNN) with 28,080 MRI images of lymph node metastasis, allowing the Faster R-CNN to read those images and to make diagnoses. For clinical verification, 414 cases of rectal cancer at various medical centers were collected, and Faster R-CNN-based diagnoses were compared with radiologist diagnoses using receiver operating characteristic curves (ROC). The area under the Faster R-CNN ROC was 0.912, indicating a more effective and objective diagnosis. The Faster R-CNN diagnosis time was 20 s/case, which was much shorter than the average time (600 s/case) of the radiologist diagnoses.Significance: Faster R-CNN enables accurate and efficient diagnosis of lymph node metastases. Cancer Res; 78(17); 5135-43. ©2018 AACR.
Stent-Based Local Delivery of Nuclear Factor-κB Decoy Attenuates In-Stent Restenosis in Hypercholesterolemic Rabbits
Authors: KishoOhtani, KensukeEgashira, KakuNakano, GangZhao, KoutaFunakoshi, YoshikoIhara, SatoshiKimura, RyujiTominaga, RyuichiMorishita, KenjiSunagawa
Journal: Circulation (2006)

Background— Nuclear factor-κB (NF-κB) plays a critical role in the vascular response to injury. However, the role of NF-κB in the mechanism of in-stent restenosis remains unclear. We therefore tested the hypothesis that blockade of NF-κB by stent-based delivery of a cis-element “decoy” of NF-κB reduces in-stent neointimal formation. Methods and Results— Stents were coated with a polymer containing or not containing NF-κB decoy, which represented a fast-release formulation (<7 days). Bare, polymer-coated, and NF-κB decoy–eluting stents were implanted in iliac arteries of hypercholesterolemic rabbits. Increased NF-κB activity was noted at early stages after stenting, which was suppressed by stent-based delivery of NF-κB decoy. NF-κB decoy–eluting stents also reduced monocyte infiltration and monocyte chemoattractant protein-1 expression and suppressed CD14 activation on circulating leukocytes. Importantly, NF-κB decoy–eluting stents attenuated neointimal formation on day 28. There was no evidence of an inco...
Post-injury Nose-to-Brain Delivery of Activin A and SerpinB2 Reduces Brain Damage in a Mouse Stroke Model
Authors: Bettina Buchthal, Ursula Weiss, Hilmar Bading
Journal: Molecular Therapy (2018)

Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice. The observed reduction of the infarct volume was comparable to the protection obtained by intracerebroventricular injection of recombinant Activin A or SerpinB2 or by stereotactic delivery 3 weeks prior to the injury of a recombinant adeno-associated virus containing an expression cassette for the potent neuroprotective transcription factor Npas4. These results establish post-injury, nose-to-brain delivery of Activin A and SerpinB2 as effective and possibly clinically applicable treatments of acute and chronic neurodegenerative conditions. Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice. The observed reduction of the infarct volume was comparable to the protection obtained by intracerebroventricular injection of recombinant Activin A or SerpinB2 or by stereotactic delivery 3 weeks prior to the injury of a recombinant adeno-associated virus containing an expression cassette for the potent neuroprotective transcription factor Npas4. These results establish post-injury, nose-to-brain delivery of Activin A and SerpinB2 as effective and possibly clinically applicable treatments of acute and chronic neurodegenerative conditions.
Noise reduction in diffusion MRI using non-local self-similar information in joint<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.gif" overflow="scroll"><mml:mrow><mml:mi>x</mml:mi><mml:mo>−</mml:mo><mml:mi>q</mml:mi></mml:mrow></mml:math>space
Authors: Geng Chen, Yafeng Wu, Dinggang Shen, Pew-Thian Yap
Journal: Medical Image Analysis (2019)
Evaluation of the Oncotype Dx recurrence score (RS) in hormone-positive ipsilateral breast tumor recurrences.
Authors: Irene Wapnir, Marilyn Florero
Journal: Journal of Clinical Oncology (2012)

e11032 Background: IBTR (ipsilateral breast tumor recurrence) is considered a marker of risk for metastasis. Most IBTRs occur in the vicinity of the index tumor while elsewhere recurrences may represent new primaries. Oncotype DX®, 21-gene expression assay, quantifies a recurrence score (RS) in node negative, ER+ breast cancer. This modality can guide treatment decisions and has been extended to select node positive patients. Concordance of RS between the primary and IBTR is presented here. Methods: Archival blocks corresponding of 11 patients were obtained but only 8 were evaluable. The blocks were submitted using a blinded identification scheme to link the primary and recurrent tumor blocks. All were ER positive breast cancers. Six were N0, one N1, and one NX. Some assay results were preexisting. RS and single gene expression profiles for ER, PR and HER2 were compared. Scatterplots and descriptive statistics were produced for this exploratory hypothesis-generating (but not hypothesis-testing) study. Results: The time interval between primary and recurrence ranged from 12 to 216 months (mean 73.5 months). Among the 8 paired samples, RS’s were similar in 5 and different in 3. In the latter, RS shifted from 2 to 29, 15 to 23 and 25 to 14. These IBTRs occurred in a different quadrant, were simultaneous with axillary recurrence, or appeared after trastuzumab therapy. Overall, the Pearson correlation coefficient was 0.68 (95% CI -0.09, 0.93). Only one case shifted from ER+ to ER-; two cases from PR+ to PR- and one from PR- to PR+. No change in HER2 status was noted. The paired differences for ER were -0.01 (95% CI -1.09, 1.07), PR -0.74 ( 95% CI -2.43, 0.96) and HER2 -0.51 (95% CI -1.20, 0.17). The Pearson correlation coefficients and 95% CI were ER 0.72 (-0.02, 0.94); PR 0.61 (-0.22, 0.91); and HER2 0.89 (0.45, 0.98) respectively. Conclusions: The RS of the IBTR was similar to primary breast cancer in 5 of 8 cases in this exploratory pilot study. Hormone receptor status changed in only one of 8 cases. The clinical significance of these observations and the utility of these results in guiding therapeutic strategies is unknown.
C1q/TNF-α–Related Protein 1 (CTRP1) Maintains Blood Pressure Under Dehydration Conditions
Authors: Sora Han, Ae Lee Jeong, Sunyi Lee, Jeong Su Park, Sumiyasuren Buyanravjikh, Wonku Kang, Seungmok Choi, Changmin Park, Jin Han, Woo-Chan Son, Kyung Hyun Yoo, Jae Hoon Cheong, Goo Taeg Oh, Won-Young Lee, Jongwan Kim, Suk Hyo Suh, Sang-Hak Lee, Jong-Seok Lim, Myeong-Sok Lee, Young Yang
Journal: Circulation Research (2018)

Circulating CTRP1 (C1q/TNF-α [tumor necrosis factor-α]-related protein 1) levels are increased in hypertensive patients compared with those in healthy subjects. Nonetheless, little is known about the molecular and physiological function of CTRP1 in blood pressure (BP) regulation.To investigate the physiological/pathophysiological role of CTRP1 in BP regulation.CTRP1 production was increased to maintain normotension under dehydration conditions, and this function was impaired in inducible CTRP1 KO (knockout) mice (CTRP1 ΔCAG). The increase in CTRP1 under dehydration conditions was mediated by glucocorticoids, and the antagonist mifepristone prevented the increase in CTRP1 and attenuated BP recovery. Treatment with a synthetic glucocorticoid increased the transcription, translation, and secretion of CTRP1 from skeletal muscle cells. Functionally, CTRP1 increases BP through the stimulation of the AT1R (Ang II [angiotensin II] receptor 1)-Rho (Ras homolog gene family)/ROCK (Rho kinase)-signaling pathway to induce vasoconstriction. CTRP1 promoted AT1R plasma membrane trafficking through phosphorylation of AKT and AKT substrate of 160 kDa (AS160). In addition, the administration of an AT1R blocker, losartan, recovered the hypertensive phenotype of CTRP1 TG (transgenic) mice.For the first time, we provide evidence that CTRP1 contributes to the regulation of BP homeostasis by preventing dehydration-induced hypotension.
miRNA-30 Family Members Inhibit Breast Cancer Invasion, Osteomimicry, and Bone Destruction by Directly Targeting Multiple Bone Metastasis–Associated Genes
Authors: Martine Croset, Francesco Pantano, Casina W.S. Kan, Edith Bonnelye, Françoise Descotes, Catherine Alix-Panabières, Charles-Henri Lecellier, Richard Bachelier, Nathalie Allioli, Saw-See Hong, Kai Bartkowiak, Klaus Pantel, Philippe Clézardin
Journal: Cancer Research (2018)

miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivoIn vitro, miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell-conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation (IL8, IL11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11), and invasiveness (CTGF, ITGA5, ITGB3) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention.Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer. Cancer Res; 78(18); 5259-73. ©2018 AACR.
Left Ventricular Ejection Fraction Cut Point of 50% for Heart Failure With Preserved Ejection Fraction
Authors: Thong Huy Cao
Journal: JAMA Cardiology (2018)

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Increased interleukin 6 levels at 24 hours after ST-elevation myocardial infarction are associated with decreased cardiac function at 4 months
Authors: H. E. Hilde Groot, L. Al Ali, I. C. C. Van der Horst, E. Lipsic, D. J. Van Veldhuisen, J. C. Karper, P. Van der Harst
Journal: European Journal of Heart Failure (2018)
Network Analysis to Risk Stratify Patients With Exercise Intolerance
Authors: William M. Oldham, Rudolf K.F. Oliveira, Rui-Sheng Wang, Alexander R. Opotowsky, David M. Rubins, Jon Hainer, Bradley M. Wertheim, George A. Alba, Gaurav Choudhary, Adrienn Tornyos, Calum A. MacRae, Joseph Loscalzo, Jane A. Leopold, Aaron B. Waxman, Horst Olschewski, Gabor Kovacs, David M. Systrom, Bradley A. Maron
Journal: Circulation Research (2018)

Rationale: Current methods assessing clinical risk because of exercise intolerance in patients with cardiopulmonary disease rely on a small subset of traditional variables. Alternative strategies incorporating the spectrum of factors underlying prognosis in at-risk patients may be useful clinically, but are lacking. Objective: Use unbiased analyses to identify variables that correspond to clinical risk in patients with exercise intolerance. Methods and Results: Data from 738 consecutive patients referred for invasive cardiopulmonary exercise testing at a single center (2011–2015) were analyzed retrospectively (derivation cohort). A correlation network of invasive cardiopulmonary exercise testing parameters was assembled using |r|&gt;0.5. From an exercise network of 39 variables (ie, nodes) and 98 correlations (ie, edges) corresponding to P &lt;9.5e −46 for each correlation, we focused on a subnetwork containing peak volume of oxygen consumption (pV o 2 ) and 9 linked nodes. K-mean clustering based on these 10 variables identified 4 novel patient clusters characterized by significant differences in 44 of 45 exercise measurements ( P &lt;0.01). Compared with a probabilistic model, including 23 independent predictors of pV o 2 and pV o 2 itself, the network model was less redundant and identified clusters that were more distinct. Cluster assignment from the network model was predictive of subsequent clinical events. For example, a 4.3-fold ( P &lt;0.0001; 95% CI, 2.2–8.1) and 2.8-fold ( P =0.0018; 95% CI, 1.5–5.2) increase in hazard for age- and pV o 2 -adjusted all-cause 3-year hospitalization, respectively, were observed between the highest versus lowest risk clusters. Using these data, we developed the first risk-stratification calculator for patients with exercise intolerance. When applying the risk calculator to patients in 2 independent invasive cardiopulmonary exercise testing cohorts (Boston and Graz, Austria), we observed a clinical risk profile that paralleled the derivation cohort. Conclusions: Network analyses were used to identify novel exercise groups and develop a point-of-care risk calculator. These data expand the range of useful clinical variables beyond pV o 2 that predict hospitalization in patients with exercise intolerance.
Cardiomyopathy and Preeclampsia
Authors: Hilary S. Gammill, Rakesh Chettier, Alina Brewer, James M. Roberts, Raj Shree, Eleni Tsigas, Kenneth Ward
Journal: Circulation (2018)

Preeclampsia is associated with diastolic dysfunction, peripartum cardiomyopathy, and both pre-existing and subsequent maternal cardiovascular disease. Gene mutations causing idiopathic cardiomyopathy were recently implicated in peripartum cardiomyopathy. We sought to determine whether cardiomyopathy gene mutations are also a contributory factor in preeclampsia.Subjects were participants in The Preeclampsia Registry and Biobank. After providing informed consent, subjects with a history of preeclampsia completed a detailed questionnaire and provided medical records for diagnostic confirmation. Saliva samples were collected for DNA isolation. Whole exome sequencing was performed to detect rare variants (minor allele frequency of <0.1%) in 43 genes associated with cardiomyopathy. Missense variants were deemed damaging missense if so classified by any of 7 standard function prediction algorithms. Variants were defined as loss-of-function if they caused a stop-gain, splicing, or frame-shift insertion or deletion. Results were compared with data from 2 control groups: unrelated women with a gynecologic disorder sequenced using the same methods and instruments (n=530) as well as published variant data from 33 000 subjects in the Exome Aggregation Consortium. Preeclampsia was not excluded in control groups.Of 181 subjects with confirmed preeclampsia, 96% were white. Seventy-two percent had ≥1 preterm preeclampsia delivery <37 weeks. Among preeclampsia subjects, whole exome sequencing demonstrated 10 rare loss-of-function variants and 228 rare damaging missense variants in the 43 cardiomyopathy genes considered. The prevalence of these loss-of-function variants was significantly higher in preeclampsia subjects (5.5%) compared with the local control (2.5%) population ( P=0.014). Sixty-eight percent of women with preeclampsia carried ≥1 loss-of-function or damaging missense variant (mean of 1.94 mutations). As seen with peripartum cardiomyopathy, most mutations (55%) were found in the TTN gene. Seventy-three percent of preeclampsia subjects had TTN mutations in the preeclampsia cohort versus 48% in local controls ( P=1.36E-11).Women who develop preeclampsia are more likely to carry protein-altering mutations in genes associated with cardiomyopathy, particularly in TTN. Mutations promoting cardiomyopathy are prevalent in preeclampsia, idiopathic cardiomyopathy, and peripartum cardiomyopathy, and they are important risk factors for a widening spectrum of cardiovascular disorders. Detecting these variants should allow more specific diagnosis, classification, counseling, and management of women at risk.
Subendocardial and Intramural Temperature Response During Radiofrequency Catheter Ablation in Chronic Myocardial Infarction and Normal Myocardium
Authors: HansKottkamp, GerhardHindricks, EckehardHorst, ThomasBaal, ChristianFechtrup, GünterBreithardt, MartinBorggrefe
Journal: Circulation (1997)

Background The ability of radiofrequency energy to extend across scar tissue is unknown. We investigated the effects of radiofrequency catheter ablation on intramural temperature in experimental chronic myocardial infarction. Methods and Results Myocardial infarction was induced in eight dogs by a transcatheter coronary artery occlusion-reperfusion technique. The dogs were reanesthetized after 15 to 24 days. Four additional dogs served as controls. The freshly excised preparations were cut and placed in a saline bath at 37°C. Temperature-guided energy applications with a preselected catheter tip temperature of 80°C were performed for 60 seconds with a 7F ablation catheter. Thermoelements were inserted into the ventricular muscle at depths of 2.5 to 3.0 mm (“subendocardial”) and 5.5 to 6.0 mm (“intramural”). Surviving muscle fibers were interspersed among the transmural scar tissue. The maximal temperatures did not differ significantly between normal hearts and chronic infarctions at the subendocardial (64...