tbuckley/cabot-search huggingface dataset:
Challenges for the crosstalk between endoscopists and pathologists
Authors: Michael Vieth, Markus Neurath
Journal: Endoscopy (2019)

Diminutive colorectal polyps resected during endoscopy may sometimes by classified as normal tissue by pathologists, and this issue represents an important topic for the interdisciplinary crosstalk between endoscopists and pathologists. In this issue of Endoscopy, Ponugoti et al. [1] report on the disagreement between endoscopic and histological diagnoses of diminutive colon polyps. They compared 644 consecutive polyps ≤ 3 mm in size using endoscopic criteria and pathological assessment, and identified discrepancies in the classification and interpretation of such lesions. Clearly any discrepancy has quality assurance implications for both departments, but may also reflect the interaction and communication between the two specialities. The article ends with the clear statement that the findings provide evidence that pathology interpretation/assessment is not the gold standard for the management of lesions ≤ 3 mm in size.
A Feedback Loop between Hypoxia and Matrix Stress Relaxation Increases Oxygen-Axis Migration and Metastasis in Sarcoma
Authors: Daniel M. Lewis, Hawley Pruitt, Nupur Jain, Mark Ciccaglione, J. Michael McCaffery, Zhiyong Xia, Kristy Weber, T.S. Karin Eisinger-Mathason, Sharon Gerecht
Journal: Cancer Research (2019)

Upregulation of collagen matrix crosslinking directly increases its ability to relieve stress under the constant strain imposed by solid tumor, a matrix property termed stress relaxation. However, it is unknown how rapid stress relaxation in response to increased strain impacts disease progression in a hypoxic environment. Previously, it has been demonstrated that hypoxia-induced expression of the crosslinker procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2), in sarcomas has resulted in increased lung metastasis. Here, we show that short stress relaxation times led to increased cell migration along a hypoxic gradient in 3D collagen matrices, and rapid stress relaxation upregulated PLOD2 expression via TGFβ-SMAD2 signaling, forming a feedback loop between hypoxia and the matrix. Inhibition of this pathway led to a decrease in migration along the hypoxic gradients.
Targeting the Mitochondrial Metallochaperone Cox17 Reduces DNA Methylation and Promotes AML Differentiation through a Copper Dependent Mechanism
Authors: Rashim Pal Singh, Danny V. Jeyaraju, Veronique Voisin, Changjiang Xu, Samir H Barghout, Dilshad H. Khan, Rose Hurren, Marcela Gronda, Xiaoming Wang, Yulia Jitkova, David Sharon, Sanduni U. Liyanage, Joelle Soriano, Eric R. Lechman,, Neil MacLean, Mark D. Minden, Steven M Chan, John E. Dick, Gary D Bader, Aaron Schimmer
Journal: Blood (2018)
Abstract 2420: Loss of hCLCA4 promotes EMT in breast cancer
Authors: Yang Yu, Vijay Walia, Randolph C. Elble
Journal: Cancer Research (2012)

Abstract The epithelial to mesenchymal transition (EMT) is a developmental program in which epithelial cells downregulate their cell-cell junctions, acquire spindle cell morphology and exhibit cellular motility. In breast cancer, EMT facilitates invasion of surrounding tissues and correlates closely with cancer metastasis and relapse. Previous studies in our lab showed that the candidate tumor suppressor hCLCA2 is expressed in differentiated, growth-arrested mammary epithelial cells but is downregulated during tumor progression and EMT. We further showed that hCLCA2 is a p53-inducible growth inhibitor whose loss indicates an increased risk of metastasis. Subsequent studies have revealed that another member of the CLCA gene family, hCLCA4, is also expressed in mammary epithelial levels, albeit at lower levels than hCLCA2. We find that hCLCA4 is also induced by stress and is similarly downregulated in breast cancer cell lines. Like hCLCA2, hCLCA4 is downregulated when EMT is induced by TGF beta, ectopic expression of mesenchymal transcription factors, or dilution of immortalized cells. Furthermore, knockdown of hCLCA4 in HMLE by shRNAs caused EMT. RNA and protein profiling for EMT markers showed that knockdown cells have lower expression epithelial marker E-cadherin and higher expression level of mesenchymal markers vimentin and fibronectin. Moreover, we found that hCLCA4 is co-regulated with hCLCA2 in HMLE cells. Knockdown of hCLCA2 led to down-regulation of hCLCA4 and vice versa. These findings suggest that hCLCA4 is, like hCLCA2, a marker of epithelial differentiation whose loss contributes to EMT and possibly metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2420. doi:1538-7445.AM2012-2420
A 61 year old man with pancreatitis, pituitary dysfunction, and painful exophthalmos
Authors: Christopher Smith, Saira Hameed, Geoffrey E Rose, Florian Wernig
Journal: BMJ (2019)

A 61 year old man with a several years’ history of chronic pancreatitis and complex partial seizures was referred to endocrinology with low serum thyroid stimulating hormone (TSH).

At the time, examination was normal, and pituitary function tests revealed secondary hypothyroidism and secondary hypogonadism with normal prolactin and normal 9am cortisol.

Magnetic resonance imaging (MRI) of the pituitary gland showed an 8 mm infundibular mass with elevation, but not compression of the optic chiasm. Thyroxine and testosterone replacement were commenced.

His condition was stable for three years, after which he presented with an acute flare of pancreatitis, associated with painful, bilateral exophthalmos (fig 1). He was clinically and biochemically euthyroid on thyroxine replacement. Repeat MRI showed an increase in the size of the infundibular mass, and bilateral extra-ocular muscle expansion with lacrimal gland swelling.



Fig 1 
Bilateral inflammation of orbital tissue with yellow exudate.



1.  What is the most likely unifying diagnosis?

2.  What is the definitive investigation to diagnose this condition?

3.  How would you manage this condition?

### 1. What is the most likely unifying diagnosis?

This patient’s multiple pathologies (pituitary gland mass, exophthalmos, dacryoadenitis, chronic pancreatitis, and …
Eravacycline: A Review in Complicated Intra-Abdominal Infections
Authors: Lesley J. Scott
Journal: Drugs (2019)

Eravacycline (Xerava™), a novel fully synthetic fluorocycline, consists of the tetracyclic core scaffold with unique modifications in the tetracyclic D ring; consequently, it exhibits potent in vitro activity against Gram-positive and -negative bacterial strains expressing certain common tetracycline-specific acquired resistance mechanisms. In vitro, eravacycline exhibits potent activity against a broad spectrum of clinically relevant Gram-positive and -negative aerobic and anaerobic bacteria. Intravenous eravacycline is approved in several countries for the treatment of complicated intra-abdominal infections (cIAIs) in adult patients. In two pivotal double-blind, multinational trials in this patient population, eravacycline (infusion ≈ 1 h) was noninferior to intravenous ertapenem or meropenem at the test-of-cure visit in terms of clinical response rates in all prespecified populations. Eravacycline had an acceptable tolerability profile, with infusion site reactions, nausea, vomiting and diarrhoea the most commonly reported adverse reactions, most of which were of mild to moderate severity. Given its broad spectrum of activity against common clinically relevant pathogens (including those expressing certain tetracycline- and other antibacterial-specific acquired resistance mechanisms) and its more potent in vitro activity and better tolerability profile than tigecycline, eravacycline provides a novel emerging option for the treatment of adult patients with cIAIs, especially as empirical therapy when coverage of resistant pathogens is required.
Influenza Virus Vaccination Elicits Poorly Adapted B Cell Responses in Elderly Individuals
Authors: Carole Henry, Nai-Ying Zheng, Min Huang, Alexandra Cabanov, Karla Thatcher Rojas, Kaval Kaur, Sarah F. Andrews, Anna-Karin E. Palm, Yao-Qing Chen, Yang Li, Katerina Hoskova, Henry A. Utset, Marcos C. Vieira, Jens Wrammert, Rafi Ahmed, Jeanne Holden-Wiltse, David J. Topham, John J. Treanor, Hildegund C. Ertl, Kenneth E. Schmader, Sarah Cobey, Florian Krammer, Scott E. Hensley, Harry Greenberg, Xiao-Song He, Patrick C. Wilson
Journal: Cell Host & Microbe (2019)
170. Ex Vivo Gene Therapy of Metabolic Liver Disorders Using Uncultured and Lentivirally Transduced Hepatocytes
Journal: Molecular Therapy (2004)

Top of pageAbstract
At the present time, orthotopic liver transplantation is the only effective therapy for several congenital and acquired hepatic disorders. Because of a chronic organ shortage, and of the necessity of heavy and lifelong immunosuppression after transplantation, gene therapy represents a promising alternative. Ex vivo liver gene therapy approach carries several advantages: (i) it allows for an elective targeting of the hepatocytes thereby avoiding, without the need for highly tissue-specific expression systems, that the transgene be expressed in professional antigen-presenting cells, (ii) it avoids most of the potential biohazards linked to the in vivo approach such as vector dissemination and integration in inappropriate target cells. We have previously described a new liver-directed ex vivo gene therapy protocol that allows very high rates of transduction of human hepatocytes (up to 98%), in which freshly isolated hepatocytes are transduced while kept in suspension and immediately transplanted. This protocol is easily performed, rapid (<5 hours) and preserves full cell engraftment potential and in vivo cell functionality. Two prototypic metabolic liver diseases were used as models to evaluate our approach: Hemophilia B, a defect in blood coagulation Factor IX and Crigler-Najjar syndrome type I (CNI), a defect in bilirubin UDPglucuronyltransferase (BGT1). Stable and persistent expression of human Factor IX (hFIX), up to 200 days and 10% of physiologic levels, was observed in C57BL/6 receiving hepatocytes that have been transduced with vectors coding for hFIX under control of the liver-specific transthyretin promoter. Therefore, these results prompt further studies in mice and dog model of hemophilia B. To correct BGT1 deficiency in Gunn rat, which is the model for CNI, we constructed vectors coding for human BGT1 under control of the E1-alpha ubiquitous promoter. In rats receiving 6 millions transduced hepatocytes, serum bilirubin levels decreased by 20–30%, a decline equivalent to that found in previously reported studies using normal hepatocytes, and was sustained for up to 150 days. In contrast, in rats receiving untransduced hepatocytes, serum didn't decline but rather increased. Noteworthy, these results also suggested an absence of immune response against the transduced hepatocytes, as expected by selective targeting of the hepatocytes using an ex vivo approach, even though transgene expression was driven by a ubiquitous promoter. Recent clinical trials have shown that freshly isolated and uncultured allogeneic hepatocyte transplantation has resulted in therapeutic benefits in patients with metabolic liver disorders. Altogether, these data open new perspectives for the treatment of metabolic liver disorders using an ex vivo approach.
Co-Transplantation of Mesenchymal Stem Cells Can Ameliorates Acute Gvhd and Viremia after Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia: A Multi-Center Retrospective Study of 119 Patients
Authors: Minmin Chen, Zhizhong Zheng, Guangsheng He, Shengyun Lin, Donghua Zhang, Huijing Hu, Jia Liu, Zhizhe Chen, Jianda Hu, Ting Yang
Journal: Blood (2018)
Case 29-2018: A 31-Year-Old Woman with Infertility
Authors: Christos Coutifaris, Aoife Kilcoyne, Adam S. Feldman, Mary E. Sabatini, Esther Oliva
Journal: New England Journal of Medicine (2018)

A 31-year-old woman with a history of primary amenorrhea and infertility was seen in the fertility center to discuss family-planning options. She had minimal body hair and a normal vagina; the cervix and uterus were absent. Management decisions were made.
Alternative Splicing in Tumors — A Path to Immunogenicity?
Authors: Jill E. Slansky, Paul T. Spellman
Journal: New England Journal of Medicine (2019)

The ability of cancer cells to elicit an immune response depends on several factors, including their expression of neoantigens. How many antigens do tumor cells express? Do different types of tumors express the same neoantigens? A recent analysis provides some clues.
Citius, altius, fortius . . . . faster, higher, stronger
Authors: Pierre Ronco, Brad Rovin, P. Toby Coates, Olivier Devuyst, Tilman B. Drueke, Jürgen Floege, Agnes B. Fogo, T. Alp Ikizler, Masaomi Nangaku, Jai Radhakrishnan, Germaine Wong, Christina Wyatt
Journal: Kidney International (2019)
Automated insulin dosing guidance to optimise insulin management in patients with type 2 diabetes: a multicentre, randomised controlled trial
Authors: Richard M Bergenstal, Mary Johnson, Rebecca Passi, Anuj Bhargava, Natalie Young, Davida F Kruger, Eran Bashan, Stanley G Bisgaier, Deanna J Marriott Isaman, Israel Hodish
Journal: The Lancet (2019)
Much to HAPO FUS About: Increasing Maternal Glycemia in Pregnancy Is Associated With Worsening Childhood Glucose Metabolism
Authors: Florence M. Brown, Elvira Isganaitis, Tamarra James-Todd
Journal: Diabetes Care (2019)

The initial purpose of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was to examine the associations of increasing degrees of untreated maternal glycemia, less severe than overt diabetes, with adverse pregnancy and neonatal outcomes and bring a unified approach to the diagnosis of gestational diabetes mellitus (GDM).

The HAPO study (1) demonstrated linear increases in the risk of the primary outcomes of neonatal birth weight, cord C-peptide >90th percentile, neonatal hypoglycemia, and primary cesarean delivery with increasing maternal glycemia on a one-step 75-g 2-h oral glucose tolerance test (OGTT). The secondary outcomes including neonatal skinfold thicknesses >90th percentile, preterm delivery, preeclampsia, and shoulder dystocia had similar associations. In two long-term offspring follow-up studies published in this issue of Diabetes Care (2,3), risks of adverse outcomes related to this continuum of maternal glycemia in pregnancy are now demonstrated to persist into early adolescence.

The long-term risk of maternal hyperglycemia to the offspring exposed in utero has been an ongoing concern for decades. In 1954, Pedersen (4) proposed that excessive glucose in mothers with diabetes is available for trans-placental passage, resulting in fetal hyperinsulinemia and excess fat accretion. In his Banting lecture, Norbert Freinkel (5) proposed the concept that fetal exposures to altered levels of maternal fuels, after organogenesis, may result in long-range adverse anatomical and metabolic changes in the offspring, which he called “fuel-mediated teratogenesis.” A related “fetal programming” hypothesis proposed by Barker and Osmond (6) holds that nutritional (and other environmental) exposures during critical developmental windows may induce changes in tissue development and function that contribute to long-term chronic disease risk. Based on studies in animal models and in …
RIPK3-Induced Inflammation by I-MDSCs Promotes Intestinal Tumors
Authors: Asha Jayakumar, Alfred L.M. Bothwell
Journal: Cancer Research (2019)

Myeloid-derived suppressor cells (MDSC) promote colorectal cancer by several mechanisms, including suppression of antitumor T cells and production of tumorigenic factors. We previously showed that an intermediate MDSC subset (I-MDSC) is expanded in an intestinal tumor model (ApcMin/+ mice), but the importance of this subset in promoting tumors is unclear. Here, we show that I-MDSCs are a distinct heterogeneous subset due to differential and reduced expression of the monocytic marker, Ly6C, and granulocytic marker, Ly6G. Besides causing necroptotic cell death, receptor-interacting protein kinase 3 (RIPK3) has an alternate function as a signaling component inducing cytokine synthesis. We evaluated whether RIPK3 regulates inflammatory cytokines in I-MDSCs to assess the nonimmunosuppressive function of I-MDSCs in promoting tumors. Inhibition of RIPK3 with the commercially available small-molecule inhibitor GSK 872 showed that RIPK3-mediated inflammation promoted intestinal tumors in two intestinal tumor models, ApcMin/+ mice and an MC38 transplantable tumor model. Mechanistically, RIPK3 signaling in I-MDSC increased tumor size by expanding IL17-producing T cells in MC38 tumors. Collectively, these data suggest RIPK3 signaling as a potential therapeutic target in colorectal cancer. SIGNIFICANCE: The specific role of RIPK3 in intestinal tumors and MDSC function sheds light on a key inflammatory mechanism driving tumorigenesis and allows for possible therapeutic intervention.
Human Memory B Cells Harbor Diverse Cross-Neutralizing Antibodies against BK and JC Polyomaviruses
Authors: John M. Lindner, Vanessa Cornacchione, Atul Sathe, Celine Be, Honnappa Srinivas, Elodie Riquet, Xavier-Charles Leber, Andreas Hein, Matthias B. Wrobel, Meike Scharenberg, Thomas Pietzonka, Christian Wiesmann, Johanna Abend, Elisabetta Traggiai
Journal: Immunity (2019)
Brief Ex Vivo Incubation with Fas Ligand Selectively Depletes Alloreactive T Cells and Antigen Presenting Cells from Stem Cell Grafts
Authors: Hilit Levy-Barazany, Liat Pinkas, Galina Rodionov, Nitzan Marelly, Michal Tzadok, Hila Wildbaum, Tamar Katz, Ronit Bakimer, Shai Yarkoni, Amnon Peled, Jerry Stein, Tsila Zuckerman
Journal: Blood (2018)
Choline transporter-like protein 1 (CTL1/SLC44A1) is a therapeutic target molecule for prostate cancer therapy
Authors: M. Inazu, I. Saiki, H. Uchino, T. Yamanaka
Journal: Annals of Oncology (2019)

Background: Prostate cancer is one of the most common types of cancer in men. Choline is an essential component of cell membrane phospholipids and is metabolized and internalized into cells by choline kinase, an enzyme that is overexpressed in certain tumors, such as prostate cancer. Two choline tracers are available for clinical use, which are labeled either with 11C-choline or with 18F-choline. These choline PET tracers that target cell membrane metabolism have influenced prostate cancer imaging, particularly in biochemical relapse, and are therefore FDA approved for use in patients with recurrent disease. However, the uptake system for choline and the functional expression of choline transporters in prostate cancer are not totally understood. Methods: We examined [3H]choline uptake in the prostate cancer cell line LNCaP, which depends on androgen. Cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum and grown at 37 °C in 5% CO2. The CellTiter-Glo Luminescent Cell Viability Assay is a homogeneous method of determining the number of viable cells. The Caspase-Glo 3/7 assay reagent was used for caspase detection in treated cells. Results: [3H]Choline uptake is mediated by a single Na+-independent and intermediate-affinity transport system. Choline transporter-like protein 1 (CTL1) and CTL2 mRNA are highly expressed. CTL1 and CTL2 immunoreactivity were recognized in the plasma membrane and intracellular compartments, respectively. The anticancer drugs, flutamide, and bicalutamide inhibited cell viability and [3H]choline uptake in a concentration-dependent manner. The correlations between the effect of both anticancer drugs for cell viability and [3H]choline uptake were significant. The caspase-3/7 activity significantly increased by flutamide and bicalutamide. Furthermore, both flutamide and bicalutamide decreased the expression level of CTL1 in LNCaP cells. Conclusions: These results suggest that CTL1 are functionally expressed in prostate cancer cells and are also involved in abnormal proliferation. Identification of this CTL1-mediated choline transport system provides a potential new target for prostate cancer therapy. Legal entity responsible for the study: Tokyo Medical University. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Management of cardiovascular risk in patients with multiple myeloma
Authors: Chris Plummer, Christoph Driessen, Zsolt Szabo, María-Victoria Mateos
Journal: Blood Cancer Journal (2019)

Abstract Multiple myeloma (MM) is a plasma cell malignancy that accounts for 10% of hematological cancers. It predominantly affects elderly people; median age at diagnosis is 70 years. Consequently, many patients with MM have cardiovascular comorbidities or risk factors. MM can cause cardiac comorbidities such as cardiomyopathy and heart failure caused by cardiac amyloidosis and/or anemia. Some of the treatments used in MM can also affect cardiovascular health. Advances in pharmacotherapy for MM, such as the introduction of immunomodulators, proteasome inhibitors, histone deacetylase inhibitors, and monoclonal antibodies, have dramatically improved progression-free survival and life expectancy, but new agent classes are associated with adverse events that were not previously observed on a regular basis, including cardiovascular events. However, with careful risk assessment, monitoring, and prophylactic therapy, many of these cardiovascular complications can be managed or treated successfully. Most routine cardiovascular surveillance is undertaken by the treating hemato-oncologist, but a multidisciplinary approach involving cardiologists may help to optimize patient outcomes. In this review, we survey the cardiac complications commonly reported in patients with MM, discuss how they can be prevented and managed, and summarize the role cardiologists can play in delivering the best possible outcomes for patients with MM and cardiovascular comorbidities.
P10.26 Anaplastic oligodendroglioma and oligoastrocytoma without 1p-19q co-deletion: a mono-institutional retrospective study
Authors: P. Gaviani
Journal: Neuro-Oncology (2017)

Allelic losses of chromosomes 1p and 19q in patients with anaplastic oligodendroglioma(AOD) and oligoastrocytoma(AOA) represent a strong prognostic factor and a powerful predictor of survival. These subset of patients benefit from the addition of chemotherapy(CT) to radiotherapy(RT), with a significant improvement of overall survival (OS) and progression-free survival (PFS). In patients without 1p19q co-deletion, there are no standard-of-care and conflicting opinions impose to review the possible therapeutic approach. A total of 214 patients with histological proven of AOD and AOA treated in our Institution over the last 10 years were evaluated. Eighty patients were eligible for loss-of-heterozigosity (LOH) evaluation. The absence of 1p19q co-deletion was confirmed in 33 patients. Clinical and genetic data, treatments and survival assessment were described and discussed. In non co-deleted group, m-OS and m-PFS were respectively 38,4 months (95% CI 21,99-59,77) (P=0,018) and 16 months (95% CI 13,0-20,0). On the other hand, m-OS of the whole group was 59.7 months. Concerning treatments, therapeutic approach has been variable with a higher percentage in RT and concomitant temozolomide in the past two years. In 6% of patients CT was considered as first-line treatment after surgery. Data confirmed the prognostic role of LOH, with the most advantages for patients with co-deletion. Regarding therapeutic approaches, results show a quite aggressive attitude in our clinical practice. The choice between RT or CT as first line treatment after surgery do not seem to influence the prognosis.