tbuckley/cabot-search huggingface dataset:
Milk exosomes: Nature's abundant nanoplatform for theranostic applications
Authors: Benilde Adriano, Nycol M. Cotto, Neeraj Chauhan, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu
Journal: Bioactive Materials (2021)

Exosomes are a unique subpopulation of naturally occurring extracellular vesicles which are smaller intracellular membrane nanoparticle vesicles. Exosomes have proven to be excellent nanocarriers for carrying lipids, proteins, mRNAs, non-coding RNAs, and DNAs, and disseminating long-distance intercellular communications in various biological processes. Among various cell-line or biological fluid derived exosomes, milk exosomes are abundant in nature and exhibit many nanocarrier characteristics favorable for theranostic applications. To be an effective delivery carrier for their clinical translation, exosomes must inbuilt loading, release, targeting, and imaging/tracking characteristics. Considering the unmet gaps of milk exosomes in theranostic technology it is essential to focus the current review on drug delivery and imaging applications. This review delineates the efficiency of exosomes to load therapeutic or imaging agents and their successful delivery approaches. It is emphasized on possible modifications of exosomes towards increasing the stability and delivery of agents. This article also summarizes the specific applications and the process of developing milk exosomes as a future pharmaceutical drug delivery vehicle.
Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies
Authors: Sarah J. Nagle, Catherine Murphree, Philipp W. Raess, Levanto Schachter, Andy Chen, Brandon Hayes‐Lattin, Eneida Nemecek, Richard T. Maziarz
Journal: American Journal of Hematology (2021)

Abstract Chimeric antigen receptor T‐cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B‐cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single‐center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T‐cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T‐cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1‐year overall survival (OS) than patients without PHT (36% vs. 81%, P &lt; .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS ( P = .002), receipt of tocilizumab ( P = .002) or steroids ( P = .033), peak ferritin &gt;5000 ng/ml ( P = .048), peak C‐reactive protein (CRP) &gt; 100 mg/L ( P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T‐cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from &lt;5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T‐cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition.
Harold Bornstein: Donald Trump’s former personal physician
Authors: John Illman
Journal: BMJ (2021)

Credit: NBC News

In a medical letter in 2015 that was littered with unprecedented hyperbole, Harold Bornstein apparently wrote: “If elected, Mr Trump, I can state unequivocally, will be the healthiest individual ever elected to the presidency.” 

More than two years later Bornstein—a long haired, eccentric poet and Trump’s doctor for nearly 30 years—finally admitted what many had suspected. He told CNN that the overweight, junk food eating Republican candidate had dictated the letter himself.

The US TV anchor and political commentator Lawrence O’Donnell denounced the four paragraph report as “the single most absurd letter written by a doctor in the history of the practice of medicine.” (With hindsight maybe he should have said “attributed to a doctor.”)

The letter emerged after Trump …
Prediction of neo-epitope immunogenicity reveals TCR recognition determinants and provides insight into immunoediting
Authors: Julien Schmidt, Angela R. Smith, Morgane Magnin, Julien Racle, Jason R. Devlin, Sara Bobisse, Julien Cesbron, Victor Bonnet, Santiago J. Carmona, Florian Huber, Giovanni Ciriello, Daniel E. Speiser, Michal Bassani-Sternberg, George Coukos, Brian M. Baker, Alexandre Harari, David Gfeller
Journal: Cell Reports Medicine (2021)

CD8+ T cell recognition of peptide epitopes plays a central role in immune responses against pathogens and tumors. However, the rules that govern which peptides are truly recognized by existing T cell receptors (TCRs) remain poorly understood, precluding accurate predictions of neo-epitopes for cancer immunotherapy. Here, we capitalize on recent (neo-)epitope data to train a predictor of immunogenic epitopes (PRIME), which captures molecular properties of both antigen presentation and TCR recognition. PRIME not only improves prioritization of neo-epitopes but also correlates with T cell potency and unravels biophysical determinants of TCR recognition that we experimentally validate. Analysis of cancer genomics data reveals that recurrent mutations tend to be less frequent in patients where they are predicted to be immunogenic, providing further evidence for immunoediting in human cancer. PRIME will facilitate identification of pathogen epitopes in infectious diseases and neo-epitopes in cancer immunotherapy.
Effects of Maternal Hyperglycemia Associated with Snack Intake on Male and Female Offspring High-Fat Diet Preference on Infancy
Authors: Gustavo Venâncio da Silva, Marina Galleazzo Martins, Giovana Pereira de Oliveira, Alessandra Gonçalves Cruz, Larissa Pereira Rodrigues, Barbara Christine Woodside, Ana Carolina Inhasz Kiss
Journal: Metabolism (2021)
Clinical efficacies, underlying mechanisms and molecular targets of Chinese medicines for diabetic nephropathy treatment and management
Authors: Guoyi Tang, Sha Li, Cheng Zhang, Haiyong Chen, Ning Wang, Yibin Feng
Journal: Acta Pharmaceutica Sinica B (2021)

Diabetic nephropathy (DN) has been recognized as a severe complication of diabetes mellitus and a dominant pathogeny of end-stage kidney disease, which causes serious health problems and great financial burden to human society worldwide. Conventional strategies, such as renin-angiotensin-aldosterone system blockade, blood glucose level control, and bodyweight reduction, may not achieve satisfactory outcomes in many clinical practices for DN management. Notably, due to the multi-target function, Chinese medicine possesses promising clinical benefits as primary or alternative therapies for DN treatment. Increasing studies have emphasized identifying bioactive compounds and molecular mechanisms of reno-protective effects of Chinese medicines. Signaling pathways involved in glucose/lipid metabolism regulation, antioxidation, anti-inflammation, anti-fibrosis, and podocyte protection have been identified as crucial mechanisms of action. Herein, we summarize the clinical efficacies of Chinese medicines and their bioactive components in treating and managing DN after reviewing the results demonstrated in clinical trials, systematic reviews, and meta-analyses, with a thorough discussion on the relative underlying mechanisms and molecular targets reported in animal and cellular experiments. We aim to provide comprehensive insights into the protective effects of Chinese medicines against DN.
Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity
Authors: Héloïse Flament, Matthieu Rouland, Lucie Beaudoin, Amine Toubal, Léo Bertrand, Samuel Lebourgeois, Camille Rousseau, Pauline Soulard, Zouriatou Gouda, Lucie Cagninacci, Antoine C. Monteiro, Margarita Hurtado-Nedelec, Sandrine Luce, Karine Bailly, Muriel Andrieu, Benjamin Saintpierre, Franck Letourneur, Youenn Jouan, Mustapha Si-Tahar, Thomas Baranek, Christophe Paget, Christian Boitard, Anaïs Vallet-Pichard, Jean-François Gautier, Nadine Ajzenberg, Benjamin Terrier, Frédéric Pène, Jade Ghosn, Xavier Lescure, Yazdan Yazdanpanah, Benoit Visseaux, Diane Descamps, Jean-François Timsit, Renato C. Monteiro, Agnès Lehuen
Journal: Nature Immunology (2021)

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α–IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α–IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation. Severe COVID-19 is characterized by hyperinflammation, and there is a need for accurate predictive biomarkers of progression. Lehuen et al. demonstrate that patients with severe COVID-19 show a dramatic loss of MAIT cells, and those that do remain are in a highly activated state.
Prognosis of Incidental Brain Metastases in Patients With Advanced Renal Cell Carcinoma
Authors: Ritesh R. Kotecha, Ronan Flippot, Taylor Nortman, Annalisa Guida, Sujata Patil, Bernard Escudier, Robert J. Motzer, Laurence Albiges, Martin H. Voss
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Metastatic renal cell carcinoma (mRCC) management guidelines recommend brain imaging if clinically indicated and the rate of occult central nervous system (CNS) metastasis is not well-defined. Early detection could have major therapeutic implications, because timely interventions may limit morbidity and mortality. Patients and Methods: A retrospective review was performed to characterize patients with mRCC incidentally diagnosed with asymptomatic brain metastases during screening for clinical trial participation at Gustave Roussy and Memorial Sloan Kettering Cancer Center. Descriptive statistics and time-to-event methods were used to evaluate the cohort. Results: Across 68 clinical trials conducted between 2001 and 2019 with a median 14.1-month follow-up, 72 of 1,689 patients (4.3%) with mRCC harbored occult brain metastases. The International Metastatic RCC Database Consortium (IMDC) risk status was favorable (26%), intermediate (61%), and poor (13%), and 86% of patients had ≥2 extracranial sites of disease, including lung metastases in 92% of patients. CNS involvement was multifocal in 38.5% of patients, and the largest brain metastasis was &gt;1 cm in diameter in 40% of the cohort. Localized brain-directed therapy was pursued in 93% of patients, predominantly radiotherapy. Median overall survival was 10.3 months (range, 7.0–17.9 months), and the 1-year overall survival probability was 48% (95% CI, 37%–62%). IMDC risk and number or size of lesions did not correlate with survival (log-rank, P =.3, P =.25, and P =.067, respectively). Conclusions: This large multi-institutional mRCC cohort study identified occult brain metastasis in a notable proportion of patients (4.3%) and highlights that the risk of asymptomatic CNS involvement extends to those with favorable risk features per IMDC risk assessment. These data provide rationale for brain screening in patients with advanced RCC.
Challenges and advances in clinical applications of mesenchymal stromal cells
Authors: Tian Zhou, Zenan Yuan, Jianyu Weng, Duanqing Pei, Xin Du, Chang He, Peilong Lai
Journal: Journal of Hematology & Oncology (2021)

Mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated for clinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapy for diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in varied animal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvements in bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Here in this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting the diversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, and finally the usage of MSCs for COVID-19 pandemic disease.
Abstract 11614: ASC Methylation and Outcomes in Heart Failure
Authors: Brittany Butts, Sandra B Dunbar, Rebecca A Gary, Javed Butler
Journal: Circulation (2015)

Background: Heart failure (HF) is associated with inflammation characterized by the formation of a protein complex, the inflammasome that triggers maturation of inflammatory cytokines. Inflammation in HF is associated with lower quality of life (QOL), depression, and poor outcomes. ASC, a vital component of the inflammasome, is controlled through epigenetic modification via methylation of CpG islands surrounding exon 1, and this methylation is a candidate pathway of worsening HF. The purpose of this study is to examine the relationships between ASC methylation and clinical, psychological, and QOL outcomes in HF. Methods: Stored samples from 155 HF outpatients (age 56.9±12.0 years, 64% male, 47% black, and mean LVEF 29.9±14.9) were analyzed for % methylation of seven CpG sites in the intron region preceding exon 1 of the ASC gene using pyrosequencing of bisulfite treated genomic DNA. Clinical, QOL (Kansas City Cardiomyopathy Questionnaire), and psychological (Patient Health Questionnaire [PHQ-9]) outcomes were assessed. Two-year combined clinical endpoint (death, heart transplantation, ventricular assist device implantation, or all-cause hospitalization) was analyzed. Results: Mean total ASC methylation was 5.96±0.55%. ASC methylation was inversely related to ASC mRNA (r=-.33, p&lt;0.001) and protein (r=-.464, p&lt;.001). ASC methylation had a positive linear relationship with ejection fraction (r=.81, p&lt;.001) and six-minute walk distance (r=.63, p=.005). ASC methylation had a negative linear relationship with PHQ-9 scores (r=-.65, p&lt;.001) and a positive linear relationship with QOL (r=.83, p&lt;.001). Combined clinical endpoint occurred in 71% (N=110) of participants. Higher levels of ASC methylation were associated with lower odds of clinical endpoint (odd ratio=0.43, 95% CI .187, .997, p=.049), while higher levels of ASC protein expression were associated with higher odds (OR=1.27, 95% CI 1.04,1.54, p=.016). Conclusion: Increased methylation of CpG sites in the intron region of ASC is associated with improved clinical, psychological and QOL outcomes in HF. The associated decrease in ASC expression implicates this inflammatory mediator as a possible driver of HF outcomes, and may represent a therapeutic target.
Dynamin-related protein 1 inhibition reduces hepatic PCSK9 secretion
Authors: Maximillian A Rogers, Joshua D Hutcheson, Takehito Okui, Claudia Goettsch, Sasha A Singh, Arda Halu, Florian Schlotter, Hideyuki Higashi, Lixiang Wang, Mary C Whelan, Andrew K Mlynarchik, Alan Daugherty, Masatoshi Nomura, Masanori Aikawa, Elena Aikawa
Journal: Cardiovascular Research (2021)

Proteostasis maintains protein homeostasis and participates in regulating critical cardiometabolic disease risk factors including proprotein convertase subtilisin/kexin type 9 (PCSK9). Endoplasmic reticulum (ER) remodeling through release and incorporation of trafficking vesicles mediates protein secretion and degradation. We hypothesized that ER remodeling that drives mitochondrial fission participates in cardiometabolic proteostasis.
Elevated gut microbiome abundance of <i>Christensenellaceae, Porphyromonadaceae and Rikenellaceae</i> is associated with reduced visceral adipose tissue and healthier metabolic profile in Italian elderly
Authors: Teresa Tavella, Simone Rampelli, Giulia Guidarelli, Alberto Bazzocchi, Chiara Gasperini, Estelle Pujos-Guillot, Blandine Comte, Monica Barone, Elena Biagi, Marco Candela, Claudio Nicoletti, Fawzi Kadi, Giuseppe Battista, Stefano Salvioli, Paul W. O’Toole, Claudio Franceschi, Patrizia Brigidi, Silvia Turroni, Aurelia Santoro
Journal: Gut Microbes (2021)

Aging is accompanied by physiological changes affecting body composition and functionality, including accumulation of fat mass at the expense of muscle mass, with effects upon morbidity and quality of life. The gut microbiome has recently emerged as a key environmental modifier of human health that can modulate healthy aging and possibly longevity. However, its associations with adiposity in old age are still poorly understood. Here we profiled the gut microbiota in a well-characterized cohort of 201 Italian elderly subjects from the NU-AGE study, by 16S rRNA amplicon sequencing. We then tested for association with body composition from dual-energy X-ray absorptiometry (DXA), with a focus on visceral and subcutaneous adipose tissue. Dietary patterns, serum metabolome and other health-related parameters were also assessed. This study identified distinct compositional structures of the elderly gut microbiota associated with DXA parameters, diet, metabolic profiles and cardio-metabolic risk factors.
Ligation of CD24 on T cells and B cells modulates the cytokine production profile of activated tumor-draining lymph node cells
Authors: Qiao Li, Mu Li, Alfred Chang
Journal: Cancer Research (2008)

4627  CD24 is a heat-stable antigen (HSA) expressed on the surface of a variety of cell types. AlthoughCD24 expression onT cells is required for optimal homeostatic T cell proliferation, the role of CD24 on tumor-primed T cells and B cellsis largely unknown. In this study, we evaluated the regulation of CD24 expression on activated tumor-draining lymph node (TDLN) cells and examined the cytokine production by these activated TDLN cells after CD24 ligation using an anti-CD24 mAb. Freshly harvested TDLNs from MCA205 tumor-bearing mice are comprised of 50-60% T cells and 20-30% B cells. By FACS analysis, approximately 5% of the TDLN cells are T cells expressing CD24 (CD3+CD24+), whereas almost all of the B cells express CD24 (CD19+CD24+). TDLN cells activated in vitro with anti-CD24 alone did not result in proliferation. Activation of TDLN cells with anti-CD3 or anti-CD3/anti-CD28 increased the percentage of CD3+CD24+ cells to approximately 15% and 25% respectively, while all the B cells remained CD24 positive. Culture supernatants of antibody-activated TDLN cells, with or without CD24 engagement, were collected for cytokine production assay. While CD3/CD28 co-stimulation significantly increased IFNγ and GM-CSF production compared with CD3 activation alone, CD3/CD24 co-stimulation failed to do so. However, CD24 ligation in addition to CD3/CD28 co-stimulation resulted in significantly enhanced IFNγ and GM-CSF production compared with CD3/CD28 activation. In these experiments, the IL-10 levels were not drastically changed. Furthermore, CD24 engagement with simultaneous T cell activation with anti-CD3/anti-CD28 and B cell activation with LPS plus anti-CD40 further significantly enhanced IFNγ and GM-CSF production. However, under these culture conditions, IL-10 secretion was also markedly up-regulated. These results indicated that CD24 expression on TDLN T cells can be up-regulated by CD3 or CD3/CD28 activation. While CD24 was unable to provide a co-stimulation signal to T cells activated via the primary TCR pathway, ligation of CD24 was found to act as a third signal to boost CD3/CD28-activated T cells. In addition, simultaneous ligation of CD24 on anti-CD3/anti-CD28-activated T cells and LPS/anti-CD40-activated B cells could further modulate the cytokine profile of these TDLN cells. Our results suggest that the in vitro ligation of CD24 on tumor-primed T and B cells may have utility in generating tumor reactive effector cells for cancer immunotherapy.
Effects of a 2-Year Primary Care Lifestyle Intervention on Cardiometabolic Risk Factors
Authors: Christoph Höchsmann, James L. Dorling, Corby K. Martin, Robert L. Newton, John W. Apolzan, Candice A. Myers, Kara D. Denstel, Emily F. Mire, William D. Johnson, Dachuan Zhang, Connie L. Arnold, Terry C. Davis, Vivian Fonseca, Carl J. Lavie, Eboni G. Price-Haywood, Peter T. Katzmarzyk
Journal: Circulation (2021)

Background: Intensive lifestyle interventions (ILIs) are the first-line approach to effectively treat obesity and manage associated cardiometabolic risk factors. Because few people have access to ILIs in academic health centers, primary care must implement similar approaches for a meaningful effect on obesity and cardiometabolic disease prevalence. To date, however, effective lifestyle-based obesity treatment in primary care is limited. We examined the effectiveness of a pragmatic ILI for weight loss delivered in primary care among a racially diverse, low-income population with obesity for improving cardiometabolic risk factors over 24 months. Methods: The PROPEL trial (Promoting Successful Weight Loss in Primary Care in Louisiana) randomly allocated 18 clinics equally to usual care or an ILI and subsequently enrolled 803 (351 usual care, 452 ILI) adults (67% Black, 84% female) with obesity from participating clinics. The usual care group continued to receive their normal primary care. The ILI group received a 24-month high-intensity lifestyle-based obesity treatment program, embedded in the clinic setting and delivered by health coaches in weekly sessions initially and monthly sessions in months 7 through 24. Results: As recently demonstrated, participants receiving the PROPEL ILI lost significantly more weight over 24 months than those receiving usual care (mean difference, −4.51% [95% CI, −5.93 to −3.10]; P &lt;0.01). Fasting glucose decreased more in the ILI group compared with the usual care group at 12 months (mean difference, −7.1 mg/dL [95% CI, −12.0 to −2.1]; P &lt;0.01) but not 24 months (mean difference, −0.8 mg/dL [95% CI, −6.2 to 4.6]; P =0.76). Increases in high-density lipoprotein cholesterol were greater in the ILI than in the usual care group at both time points (mean difference at 24 months, 4.6 mg/dL [95% CI, 2.9–6.3]; P &lt;0.01). Total:high-density lipoprotein cholesterol ratio and metabolic syndrome severity ( z score) decreased more in the ILI group than in the usual care group at both time points, with significant mean differences of the change of −0.31 (95% CI, −0.47 to −0.14; P &lt;0.01) and −0.21 (95% CI, −0.36 to −0.06; P =0.01) at 24 months, respectively. Changes in total cholesterol, low-density lipoprotein cholesterol, triglycerides, and blood pressure did not differ significantly between groups at any time point. Conclusions: A pragmatic ILI consistent with national guidelines and delivered by trained health coaches in primary care produced clinically relevant improvements in cardiometabolic health in an underserved population over 24 months. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02561221.
Factor VIIa induces extracellular vesicles from the endothelium: a potential mechanism for its hemostatic effect
Authors: Kaushik Das, Shiva Keshava, Shabbir A. Ansari, Vijay Kondreddy, Charles T. Esmon, John H. Griffin, Usha R. Pendurthi, L. Vijaya Mohan Rao
Journal: Blood (2021)