tbuckley/cabot-search huggingface dataset:
Circulating Tumor DNA as a Prognostic Marker in Stage III Colon Cancer—Reply
Authors: Jeanne Tie, Bert Vogelstein, Peter Gibbs
Journal: JAMA Oncology (2020)

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Tubular STAT3 Limits Renal Inflammation in Autosomal Dominant Polycystic Kidney Disease
Authors: Amandine Viau, Maroua Baaziz, Amandine Aka, Manal Mazloum, Clément Nguyen, E. Wolfgang Kuehn, Fabiola Terzi, Frank Bienaimé
Journal: Journal of the American Society of Nephrology (2020)

Significance Statement Recent research into the pathophysiology of autosomal dominant polycystic kidney disease indicates that both signaling of primary cilia of tubular cells and immune cell infiltration play key roles. However, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, an important modulator of inflammatory response and a cilia component, is activated in polycystin 1 (PKD1)–deficient tubular cells and is suspected to promote cyst growth. In this work, the authors used murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia to assess STAT3’s role in the disease. They found that, contrary to previous assumptions, STAT3 does not appear to be a critical mediator of cyst growth, but instead acts in a feedback loop that restricts cilia-dependent renal inflammation by repressing proinflammatory cytokines. Background The inactivation of the ciliary proteins polycystin 1 or polycystin 2 leads to autosomal dominant polycystic kidney disease (ADPKD). Although signaling by primary cilia and interstitial inflammation both play a critical role in the disease, the reciprocal interactions between immune and tubular cells are not well characterized. The transcription factor STAT3, a component of the cilia proteome that is involved in crosstalk between immune and nonimmune cells in various tissues, has been suggested as a factor fueling ADPKD progression. Method To explore how STAT3 intersects with cilia signaling, renal inflammation, and cyst growth, we used conditional murine models involving postdevelopmental ablation of Pkd1 , Stat3 , and cilia, as well as cultures of cilia-deficient or STAT3-deficient tubular cell lines. Results Our findings indicate that, although primary cilia directly modulate STAT3 activation in vitro , the bulk of STAT3 activation in polycystic kidneys occurs through an indirect mechanism in which primary cilia trigger macrophage recruitment to the kidney, which in turn promotes Stat3 activation. Surprisingly, although inactivating Stat3 in Pkd1 -deficient tubules slightly reduced cyst burden, it resulted in a massive infiltration of the cystic kidneys by macrophages and T cells, precluding any improvement of kidney function. We also found that Stat3 inactivation led to increased expression of the inflammatory chemokines CCL5 and CXCL10 in polycystic kidneys and cultured tubular cells. Conclusions STAT3 appears to repress the expression of proinflammatory cytokines and restrict immune cell infiltration in ADPKD. Our findings suggest that STAT3 is not a critical driver of cyst growth in ADPKD but rather plays a major role in the crosstalk between immune and tubular cells that shapes disease expression.
Interaction between Epithelial Sodium Channel γ-Subunit and Claudin-8 Modulates Paracellular Sodium Permeability in Renal Collecting Duct
Authors: Ali Sassi, Yubao Wang, Alexandra Chassot, Olga Komarynets, Isabelle Roth, Valérie Olivier, Gilles Crambert, Eva Dizin, Emilie Boscardin, Edith Hummler, Eric Feraille
Journal: Journal of the American Society of Nephrology (2020)

Water and solute transport across epithelia can occur via the transcellular or paracellular pathways. Tight junctions play a key role in mediating paracellular ion reabsorption in the kidney. In the renal collecting duct, which is a typical absorptive tight epithelium, coordination between transcellular sodium reabsorption and paracellular permeability may prevent the backflow of reabsorbed sodium to the tubular lumen along a steep electrochemical gradient.To investigate whether transcellular sodium transport controls tight-junction composition and paracellular permeability via modulating expression of the transmembrane protein claudin-8, we used cultured mouse cortical collecting duct cells to see how overexpression or silencing of epithelial sodium channel (ENaC) subunits and claudin-8 affect paracellular permeability. We also used conditional kidney tubule-specific knockout mice lacking ENaC subunits to assess the ENaC's effect on claudin-8 expression.Overexpression or silencing of the ENaC γ-subunit was associated with parallel and specific changes in claudin-8 abundance. Increased claudin-8 abundance was associated with a reduction in paracellular permeability to sodium, whereas decreased claudin-8 abundance was associated with the opposite effect. Claudin-8 overexpression and silencing reproduced these functional effects on paracellular ion permeability. Conditional kidney tubule-specific ENaC γ-subunit knockout mice displayed decreased claudin-8 expression, confirming the cell culture experiments' findings. Importantly, ENaC β-subunit or α-subunit silencing or kidney tubule-specific β-ENaC or α-ENaC knockout mice did not alter claudin-8 abundance.Our data reveal the specific coupling between ENaC γ-subunit and claudin-8 expression. This coupling may play an important role in preventing the backflow of reabsorbed solutes and water to the tubular lumen, as well as in coupling paracellular and transcellular sodium permeability.
T follicular regulatory cells and IL-10 promote food antigen–specific IgE
Authors: Markus M. Xie, Qiang Chen, Hong Liu, Kai Yang, Byunghee Koh, Hao Wu, Soheila J. Maleki, Barry K. Hurlburt, Joan Cook-Mills, Mark H. Kaplan, Alexander L. Dent
Journal: Journal of Clinical Investigation (2020)

Food allergies are a major clinical problem and are driven by IgE antibodies (Abs) specific for food antigens (Ags). T follicular regulatory (Tfr) cells are a specialized subset of FOXP3+ T cells that modulate Ab responses. Here, we analyzed the role of Tfr cells in regulating Ag-specific IgE using a peanut-based food allergy model in mice. Peanut-specific IgE titers and anaphylaxis responses were significantly blunted in Tfr cell–deficient Foxp3-Cre Bcl6fl/fl mice. Loss of Tfr cells led to greatly increased nonspecific IgE levels, showing that Tfr cells have both helper and suppressor functions in IgE production in the germinal center (GC) that work together to facilitate the production of Ag-specific IgE. Foxp3-Cre Ptenfl/fl mice with augmented Tfr cell responses had markedly higher levels of peanut-specific IgE, revealing an active helper function by Tfr cells on Ag-specific IgE. The helper function of Tfr cells for IgE production involves IL-10, and the loss of IL-10 signaling by B cells led to a severely curtailed peanut-specific IgE response, decreased GCB cell survival, and loss of GC dark zone B cells after peanut sensitization. We thus reveal that Tfr cells have an unexpected helper role in promoting food allergy and may represent a target for drug development.
A phase II study of gefitinib in patients with metastatic melanoma
Authors: S. Patel, A. Bedikian, K. Kim, N. Papadopoulos, P. Hwu, A. Vardeleon, V. Prieto, M. Bar Eli, Y. Bronstein, R. Bassett
Journal: Journal of Clinical Oncology (2009)

9057 Background: Gefitinib is an inhibitor of epidermal growth factor receptor (EGFR), which is frequently expressed on both choroidal and non-choroidal melanoma cells. We evaluated the clinical efficacy of gefitinib in patients (pts) with metastatic melanoma. Methods: Pts with stage IV or unresectable or recurrent stage III melanoma and Zubrod performance status of 0 to 2 were eligible. For non-choroidal melanoma, pts must have received systemic cytotoxic therapy, but no more than 2 regimens; for choroidal melanoma, pts could be either chemo-naïve or have received up to 2 systemic cytotoxic therapies. The dose of oral gefitinib was 250 mg daily, and tumor response was evaluated every 6 weeks per RECIST. Ten patients with cutaneous disease were also consented for paired biopsies and blood collection for correlative studies at baseline and after 3 weeks of treatment. Results: Fifty-two pts (46 non-choroidal; 6 choroidal primay) were treated and evaluated for toxicity, and 50 pts were evaluable for response. Median age of pts was 62.5 years, with median Zubrod PS Score of 1. The median number of prior systemic treatments was 1. Forty-one pts (79%) had stage M1c disease. There were no drug-related grade 4 or 5 adverse events (AEs), and fatigue was the only grade 3 AEs in &gt;5% of the patients. There were 2 (4%) partial responses, including a pt with metastatic choroidal melanoma, and 13 pts (26%) had disease stabilization. A median duration of response was 9.5 months among the responders. Median time to progression was 6 weeks, and median overall survival was 4.6 months. Among 7 pts with sufficient tissue on paired biopsies, there were no notable trends in the changes of the expression of pERK1/2, pAKT, or pPAK1 with treatment. Additionally, no trends were identified in serum VEGF or IL-8 levels after treatment. Conclusions: Gefitinib was well tolerated, but had minimal clinical efficacy as a single-agent therapy for metastatic melanoma of cutaneous origin. There were no consistent changes in the expressions of downstream kinase proteins with gefitinib treatment. No significant financial relationships to disclose.
Urgent dental care for patients during the COVID-19 pandemic
Authors: Manas Dave, Noha Seoudi, Paul Coulthard
Journal: The Lancet (2020)

During the initial phase of a pandemic, when a vaccine is not available, personal protective equipment (PPE)1Coulthard P The oral surgery response to coronavirus disease (COVID-19). Keep calm and carry on?.Oral Surg. 2020; (published online March 20.)DOI:10.1111/ors.12489Crossref Scopus (20) Google Scholar plays a major part in disease control. Dental and oral surgery procedures using drills or ultrasonic devices cause aerosol release, and routine dentistry has therefore been suspended in several countries, including the UK, to reduce virus transmission. There is an urgent need for organised emergency dental care delivered by teams provided with appropriate PPE.2Meng L Hua F Coronavirus disease 2019 (COVID-19): emerging and future challenges for dental and oral medicine.J Dent Res. 2020; 1222034520914246Google Scholar This also allows for redistribution of PPE to urgent care when there is inevitably an initial shortage and distribution challenge. Timely and major reorganisation of dental care services is challenging. Early management of acute dental emergencies is important to avert patients from Accident and Emergency services and to avoid hospital admissions. One concern is that with the suspension of routine dental care, more patients than usual could need admission for the management of acute dental infections that threaten the airway and require intensive care. Patients with substantial swellings can progress to life-threatening emergencies, which can increase risks in the setting of reduced health-care availability. For such patients, extractions of the causative pathogenic teeth should be prioritised over restorative rescue, and input from dedicated oral surgery and oral and maxillofacial services and close follow-up should be instigated as locally appropriate. This approach has many benefits, including stewardship of antimicrobials, but is a deviation away from routine dentistry that should be thoroughly discussed with patients. Decisions on undertaking treatment should therefore be made with appropriate patient consent. Clinicians might wish to follow up patients digitally (eg, through video calls), if appropriate, to ensure patient safety, but also to minimise repeated patient contact. Testing for coronavirus disease 2019 (COVID-19) in dental professionals should be undertaken with the same high priority as that of medical health-care workers in hospitals. The risk of a dental practitioner being positive for COVID-19 and potentially infecting patients attending emergency dental services should not be underestimated. Proactive and preventive measures need to be established as mainstay protocol to contain the spread of the virus. We declare no competing interests.
Efficacy of venetoclax in high risk relapsed mantle cell lymphoma ( <scp>MCL</scp> ) ‐ outcomes and mutation profile from venetoclax resistant <scp>MCL</scp> patients
Authors: Shuangtao Zhao, Rashmi Kanagal‐Shamanna, Lucy Navsaria, Chi Young Ok, Shaojun Zhang, Krystle Nomie, Guangchun Han, Dapeng Hao, Holly A. Hill, Changying Jiang, Yixin Yao, Loretta Nastoupil, Jason Westin, Luis Fayad, Ranjit Nair, Raphel Steiner, Sairah Ahmed, Felipe Samaniego, Swaminathan P. Iyer, Onyeka Oriabure, Wendy Chen, Xingzhi Song, Jianhua Zhang, Maria Badillo, Omar Moghrabi, Jorge Aranda, Guilin Tang, C. Cameron Yin, Keyur Patel, Leonard Jeffrey Medeiros, Shaoying Li, Francisco Vega, Selvi Thirumurthi, Guofan Xu, Sattva Neelapu, Christopher R. Flowers, Jorge Romaguera, Nathan Fowler, Linghua Wang, Michael L. Wang, Preetesh Jain
Journal: American Journal of Hematology (2020)

Venetoclax is effective in relapsed patients with mantle cell lymphoma (MCL). Mechanisms of resistance to venetoclax in MCL are poorly understood. We describe the clinical outcomes and genomic characteristics of 24 multiply relapsed patients (median of five prior lines of therapy) who received venetoclax-based therapies; 67% had progressed on BTK inhibitors (BTKi) and 54% had blastoid or pleomorphic histology. Median follow up after venetoclax treatment was 17 months. The overall response rate was 50% and complete response (CR) rate was 21%, 16 patients had progressed and 15 died. The median progression free, overall and post venetoclax survival were 8, 13.5 and 7.3 months respectively. Whole-exome sequencing (WES) was performed on samples collected from seven patients (including five pairs; before starting venetoclax and after progression on venetoclax). The SMARCA4 and BCL2 alterations were noted only after progression, while TP53, CDKN2A, KMT2D, CELSR3, CCND1, NOTCH2 and ATM were altered 2-4-fold more frequently after progression. In two patients with serial samples, we demonstrated clonal evolution of novel SMARCA4 and KMT2C/D mutations at progression. Mutation dynamics in venetoclax resistant MCL is demonstrated. Our data indicates that venetoclax resistance in MCL is predominantly associated with non-BCL2 gene mutations. Further studies are ongoing in MCL patients to evaluate the efficacy of venetoclax in combination with other agents and understand the biology of venetoclax resistance in MCL.
Rapalog-Mediated Repression of Tribbles Pseudokinase 3 Regulates Pre-mRNA Splicing
Authors: Bojana Stefanovska, Cecile Edith Vicier, Thibault Dayris, Vasily Ogryzko, Veronique Scott, Ibrahim Bouakka, Suzette Delaloge, Anna Rocca, Olivia Le Saux, Olivier Trédan, Thomas Bachelot, Fabrice André, Olivia Fromigué
Journal: Cancer Research (2020)

Rapalogs have become standard-of-care in patients with metastatic breast, kidney, and neuroendocrine cancers. Nevertheless, tumor escape occurs after several months in most patients, highlighting the need to understand mechanisms of resistance. Using a panel of cancer cell lines, we show that rapalogs downregulate the putative protein kinase TRIB3 (tribbles pseudokinase 3). Blood samples of a small cohort of patients with cancer treated with rapalogs confirmed downregulation of TRIB3. Downregulation of TRIB3 was mediated by LRRFIP1 independently of mTOR and disrupted its interaction with the spliceosome, where it participated in rapalog-induced deregulation of RNA splicing. Conversely, overexpression of TRIB3 in a panel of cancer cell lines abolished the cytotoxic effects of rapalogs. These findings identify TRIB3 as a key component of the spliceosome, whose repression contributes significantly to the mechanism of resistance to rapalog therapy. SIGNIFICANCE: Independent of mTOR signaling, rapalogs induce cytoxicity by dysregulating spliceosome function via repression of TRIB3, the loss of which may, in the long term, contribute to therapeutic resistance.
Differences in Age at Onset of Symptoms, and Effects of Genetic Variants, in Patients With Early vs Late-Onset Idiopathic Chronic Pancreatitis in a North American Cohort
Authors: Michele D. Lewis, Jyothsna Talluri, C. Mel Wilcox, Judah N. Abberbock, Gong Tang, Darwin L. Conwell, Peter A. Banks, Gregory A. Cote, Stuart Sherman, Samer Alkaade, Timothy B. Gardner, Michelle A. Anderson, Bimaljit S. Sandhu, Thiruvengadam Muniraj, Chris E. Forsmark, Nalini Guda, Andres Gelrud, Joseph Romagnuolo, Randall Brand, Jessica LaRusch, Stephen T. Amann, Adam Slivka, David C. Whitcomb, Dhiraj Yadav
Journal: Clinical Gastroenterology and Hepatology (2020)
Consequences of Abrupt Cessation of Alpha<sub>1</sub>-Antitrypsin Replacement Therapy
Authors: Oliver J. McElvaney, Tomás P. Carroll, Alessandro N. Franciosi, James Sweeney, Brian D. Hobbs, Vikita Kowlessar, Cedric Gunaratnam, Emer P. Reeves, Noel G. McElvaney
Journal: New England Journal of Medicine (2020)

Stopping Therapy for Alpha1-Antitrypsin Deficiency In Ireland, augmentation treatment of patients with genetic alpha1-antitrypsin deficiency was abruptly discontinued when government–industry price...
Bridging the Gap Among Clinical Practice Guidelines for Pain Management in Cancer and Sickle Cell Disease
Authors: Alyssa A. Schatz, Thomas K. Oliver, Robert A. Swarm, Judith A. Paice, Deepika S. Darbari, Deborah Dowell, Salimah H. Meghani, Katy Winckworth-Prejsnar, Eduardo Bruera, Robert M. Plovnick, Lisa Richardson, Neha Vapiwala, Dana Wollins, Clifford A. Hudis, Robert W. Carlson
Journal: Journal of the National Comprehensive Cancer Network (2020)

Opioids are a critical component of pain relief strategies for the management of patients with cancer and sickle cell disease. The escalation of opioid addiction and overdose in the United States has led to increased scrutiny of opioid prescribing practices. Multiple reports have revealed that regulatory and coverage policies, intended to curb inappropriate opioid use, have created significant barriers for many patients. The Centers for Disease Control and Prevention, National Comprehensive Cancer Network, and American Society of Clinical Oncology each publish clinical practice guidelines for the management of chronic pain. A recent JAMA Oncology article highlighted perceived variability in recommendations among these guidelines. In response, leadership from guideline organizations, government representatives, and authors of the original article met to discuss challenges and solutions. The meeting featured remarks by the Commissioner of Food and Drugs, presentations on each clinical practice guideline, an overview of the pain management needs of patients with sickle cell disease, an overview of perceived differences among guidelines, and a discussion of differences and commonalities among the guidelines. The meeting revealed that although each guideline varies in the intended patient population, target audience, and methodology, there is no disagreement among recommendations when applied to the appropriate patient and clinical situation. It was determined that clarification and education are needed regarding the intent, patient population, and scope of each clinical practice guideline, rather than harmonization of guideline recommendations. Clinical practice guidelines can serve as a resource for policymakers and payers to inform policy and coverage determinations.
Antibody avidity-based approach to estimate population-level incidence of hepatitis C
Authors: Denali Boon, Veronica Bruce, Eshan U. Patel, Jeffrey Quinn, Aylur K. Srikrishnan, Saravanan Shanmugam, Syed Iqbal, Pachamuthu Balakrishnan, Matthew Sievers, Gregory D. Kirk, David L. Thomas, Thomas C. Quinn, Andrea L. Cox, Kimberly A. Page, Sunil S. Solomon, Shruti H. Mehta, Oliver Laeyendecker
Journal: Journal of Hepatology (2020)
Interleukin‐17A Is Produced by CD4+ but Not CD8+ T Cells in Synovial Fluid Following T Cell Receptor Activation and Regulates Different Inflammatory Mediators Compared to Tumor Necrosis Factor in a Model of Psoriatic Arthritis Synovitis
Authors: Xiaofei Xu, Nadine Davelaar, Anne‐Marie Mus, Patrick S. Asmawidjaja, Johanna M. W. Hazes, Dominique L. P. Baeten, Marijn Vis, Radjesh J. Bisoendial, Errol P. Prens, Erik Lubberts
Journal: Arthritis & Rheumatology (2020)

Objective Interleukin‐17A ( IL ‐17A) and tumor necrosis factor ( TNF ) contribute to the pathogenesis of psoriatic arthritis (PsA). However, their functional relationship in PsA synovitis has not been fully elucidated. Additionally, although CD 8+ T cells in PsA have been recognized via flow cytometry as a source of IL ‐17A production, it is not clear whether CD 8+ T cells secrete IL ‐17A under more physiologically relevant conditions in the context from PsA synovitis. This study was undertaken to clarify the roles of IL ‐17A and TNF in the synovial fluid ( SF ) from patients with PsA and investigate the impact of CD 8+ T cells on IL ‐17A production. Methods IL ‐17A+ T cells were identified by flow cytometry in SF samples from 20 patients with active PsA, blood samples from 22 treatment‐naive patients with PsA, and blood samples from 22 healthy donors. IL ‐17A+ T cells were sorted from 12 PsA SF samples and stimulated using anti‐ CD 3/anti‐ CD 28 or phorbol myristate acetate ( PMA ) and ionomycin ex vivo, alone (n = 3) or together with autologous monocytes (n = 3) or PsA fibroblast‐like synoviocytes ( FLS ) (n = 5–6). To evaluate the differential allogeneic effects of neutralizing IL ‐17A and TNF , SF CD 4+ T cells and PsA FLS cocultures were also used (n = 5–6). Results Flow cytometry analyses of SF samples from patients with PsA showed IL‐17A positivity for CD 4+ and CD 8+ T cells ( IL ‐17A, median 0.71% [interquartile range 0.35–1.50%] in CD 4+ cells; median 0.44% [interquartile range 0.17–1.86%] in CD 8+ T cells). However, only CD 4+ T cells secreted IL ‐17A after anti‐ CD 3/anti‐ CD 28 activation, when cultured alone and in cocultures with PsA monocytes or PsA FLS (each P &lt; 0.05). Remarkably, CD 8+ T cells only secreted IL ‐17A after 4‐ or 72‐hour stimulation with PMA /ionomycin. Anti– IL ‐17A and anti‐ TNF treatments both inhibited PsA synovitis ex vivo. Neutralizing IL ‐17A strongly inhibited IL ‐6 ( P &lt; 0.05) and IL ‐1β ( P &lt; 0.01), while anti‐ TNF treatment was more potent in reducing matrix metalloproteinase 3 ( MMP ‐3) ( P &lt; 0.05) and MMP ‐13. Conclusion CD 8+ T cells, in contrast to CD 4+ T cells, in SF specimens obtained from PsA patients did not secrete IL ‐17A following T cell receptor activation. Overlapping, but distinct, effects at the level of inflammatory cytokines and MMP s were found after neutralizing IL ‐17A or TNF ex vivo in a human model of PsA synovitis.