tbuckley/cabot-search huggingface dataset:
Immunogenic Cell Death in Cancer Therapy
Authors: Guido Kroemer, Lorenzo Galluzzi, Oliver Kepp, Laurence Zitvogel
Journal: Annual Review of Immunology (2012)

Depending on the initiating stimulus, cancer cell death can be immunogenic or nonimmunogenic. Immunogenic cell death (ICD) involves changes in the composition of the cell surface as well as the release of soluble mediators, occurring in a defined temporal sequence. Such signals operate on a series of receptors expressed by dendritic cells to stimulate the presentation of tumor antigens to T cells. We postulate that ICD constitutes a prominent pathway for the activation of the immune system against cancer, which in turn determines the long-term success of anticancer therapies. Hence, suboptimal regimens (failing to induce ICD), selective alterations in cancer cells (preventing the emission of immunogenic signals during ICD), or defects in immune effectors (abolishing the perception of ICD by the immune system) can all contribute to therapeutic failure. We surmise that ICD and its subversion by pathogens also play major roles in antiviral immune responses.
Liver in haemoglobin H disease
Authors: C. B. Keng, T. K. Khoo
Journal: Gut (1970)

There have been no published reports on the liver of patients with haemoglobin H disease. In 11 Chinese patients studied (six male and five female) with haemoglobin H disease hepatic function and histology were studied. Liver function was normal in all cases; however, the gamma globulin level was raised in four cases, the increase being mainly in IgG in all cases and IgA in six cases. Liver histology showed that one case had portal cirrhosis, six cases mild fibrosis, and four cases no fibrosis. Haemosiderosis, mainly in the parenchymal cells of the peripheral lobules, was mild in one case, moderate in four, and severe in the remainder of the cases.
Arne Ljungqvist: the great fighter against doping
Authors: Per Renström
Journal: British Journal of Sports Medicine (2013)

Professor emeritus Arne Ljungqvist from Karolinska Institutet, Stockholm, who has served in various high positions in the IOC, International Association of Athletics Federations (IAAF), Swedish Sports Confederation, to mention some of them, has dedicated a great deal of his life to service in sports and sports medicine. Arne Ljungqvist has especially dedicated his career to the fight against doping and to the protection of the health of the athletes.

It is a great privilege for me to write this editorial as I have known and worked with Arne since the beginning of the 1970s. During the 1980s, I was a member of the Swedish Council of Sports Research under Arne’s leadership and later his successor as President. Above all, I have had the privilege to work in the IOC Medical Commission since 1989, and from 2003–2012 under the Chairmanship of Arne. During these years we have worked closely together, and it has been a great journey to learn from Arne how to manage the many difficult and intriguing problems that follows the Olympic Games. Now, Arne is stepping down from the Chairmanship and leaving the IOC Medical Commission this year after years of distinguished service.

It all started over 60 years ago when Arne became a Swedish senior champion in high jump in 1951, jumping as high as 201 cm. Arne was multi-talented and won …
miR-124 Inhibits STAT3 Signaling to Enhance T Cell–Mediated Immune Clearance of Glioma
Authors: Jun Wei, Fei Wang, Ling-Yuan Kong, Shuo Xu, Tiffany Doucette, Sherise D. Ferguson, Yuhui Yang, Kayla McEnery, Krishan Jethwa, Olsi Gjyshi, Wei Qiao, Nicholas B. Levine, Frederick F. Lang, Ganesh Rao, Gregory N. Fuller, George A. Calin, Amy B. Heimberger
Journal: Cancer Research (2013)

miRNAs (miR) have been shown to modulate critical gene transcripts involved in tumorigenesis, but their role in tumor-mediated immunosuppression is largely unknown. On the basis of miRNA gene expression in gliomas using tissue microarrays, in situ hybridization, and molecular modeling, miR-124 was identified as a lead candidate for modulating STAT3 signaling, a key pathway mediating immunosuppression in the tumor microenvironment. miR-124 is absent in all grades and pathologic types of gliomas. Upon upregulating miR-124 in glioma cancer stem cells (gCSC), the STAT3 pathway was inhibited, and miR-124 reversed gCSC-mediated immunosuppression of T-cell proliferation and induction of forkhead box P3 (Foxp3)(+) regulatory T cells (Treg). Treatment of T cells from immunosuppressed glioblastoma patients with miR-124 induced marked effector response including upregulation of interleukin (IL)-2, IFN-γ, and TNF-α. Both systemic administration of miR-124 or adoptive miR-124-transfected T-cell transfers exerted potent anti-glioma therapeutic effects in clonotypic and genetically engineered murine models of glioblastoma and enhanced effector responses in the local tumor microenvironment. These therapeutic effects were ablated in both CD4(+)- and CD8(+)-depleted mice and nude mouse systems, indicating that the therapeutic effect of miR-124 depends on the presence of a T-cell-mediated antitumor immune response. Our findings highlight the potential application of miR-124 as a novel immunotherapeutic agent for neoplasms and serve as a model for identifying miRNAs that can be exploited as immunotherapeutics.
Molecular Detection of Cytokeratin-19–Positive Cells in the Peripheral Blood of Patients With Operable Breast Cancer: Evaluation of Their Prognostic Significance
Authors: A. Stathopoulou, I. Vlachonikolis, D. Mavroudis, M. Perraki, Ch. Kouroussis, S. Apostolaki, N. Malamos, S. Kakolyris, A. Kotsakis, N. Xenidis, D. Reppa, V. Georgoulias
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To evaluate the prognostic significance of molecular detection of cytokeratin 19 (CK-19) mRNA-positive cells by nested reverse transcriptase polymerase chain reaction (RT-PCR) in the peripheral blood of women with stages I and II breast cancer before adjuvant chemotherapy. PATIENTS AND METHODS: The sensitivity and specificity of CK-19 mRNA detection by nested RT-PCR were investigated using MCF-7 and ARH-77 cells and blood from healthy women and patients with hematologic malignancies, metastatic colorectal cancer, and early and metastatic breast cancer. Peripheral blood from 148 patients with operable breast cancer, obtained before initiation of any adjuvant therapy, was tested for the presence of CK-19 mRNA-positive cells. RESULTS: The nested RT-PCR assay for CK-19 mRNA detected one MCF-7 tumor cell in 10 6 normal peripheral blood mononuclear cells in four of five experiments; no signal was detected with the CK-19–negative ARH-77 cells. CK-19 mRNA was detected in the peripheral blood of 3.7% of healthy blood donors, 14.3% of patients with hematologic malignancies, and 3.2% of patients with metastatic colorectal cancer. Detection rates for CK-19 mRNA-positive cells in the bone marrow/blood of patients with early or metastatic breast cancer were 63%/30% and 74%/52%, respectively. For stages I and II breast cancer, detection of CK-19–positive cells in the peripheral blood before adjuvant therapy was associated with reduced disease-free interval (P = .0007) and overall survival (P = .01). In multivariate analysis, detection of peripheral-blood CK-19–positive cells was an independent prognostic factor for disease relapse and death. CONCLUSION: Molecular detection of CK-19 mRNA-positive cells by RT-PCR in the peripheral blood of patients with stages I and II breast cancer before initiation of adjuvant therapy has independent prognostic value as a marker of poor clinical outcome.
Metastatic Model for Human Prostate Cancer Using Orthotopic Implantation in Nude Mice
Authors: R. A. Stephenson, C. P. N. Dinney, K. Gohji, N. G. Ordonez, J. J. Killion, I. J. Fidler
Journal: JNCI Journal of the National Cancer Institute (1992)

Understanding the mechanism of prostate cancer metastasis is essential to the design of a more effective therapy. An effective therapy for this disease will depend on the development of a clinically relevant in vivo model.We describe the development of such a model by using orthotopic implantation of human prostate cells in BALB/c nude mice.We compared the tumorigenicity of and the incidence of metastasis of human prostate cancer PC-3M and LNCaP-FGC (LNCaP) cell lines subsequent to prostatic (orthotopic) or subcutaneous (ectopic) implantations in male nude mice.LNCaP cells produced tumors only in the prostate. Enhanced tumorigenicity at the orthotopic site was found for PC-3M cells. Lymph node metastases were observed in practically all mice given an injection of PC-3M cells in the prostate, but they were uncommon with subcutaneous injection of these cells. Bilateral orchiectomy did not alter the tumorigenicity of either PC-3M or LNCaP cells or the incidence of lymph node metastasis by PC-3M cells. LNCaP tumors in the mouse prostate (but not PC-3M tumors) elaborated detectable levels of human prostate-specific antigen (PSA) in the serum, even when tumors were small (1.5 mm in diameter). Immunohistochemistry analysis revealed the presence of the PSA marker in tissue sections of LNCaP but not of PC-3M tumors.The implantation of human prostate cancer cells in an ectopic environment does not permit expression of metastatic potential. In contrast, intraprostatic implantation does.These data suggest that the orthotopic injection of human prostate cancer cells into the nude mouse may provide a valuable model to study the biology and therapy of human prostate cancer.
QUANTITATIVE STUDIES OF NATURALLY OCCURRING MURINE LEUKEMIA VIRUS INFECTION OF AKR MICE
Authors: Wallace P. Rowe, Theodore Pincus
Journal: The Journal of Experimental Medicine (1972)

Quantitative studies were made of the organ distribution of murine leukemia virus in AKR mice of various ages. Infectious virus first appeared shortly before or after birth and was continuously present in all mice thereafter. Highest infectivity titers were found in uterus and bone, with spleen slightly lower. Virus titers in normal thymus were relatively low, but increased significantly with the development of thymic lymphoma. The level of viremia decreased after the 1st month of life, but increased sharply in lymphomatous mice.
On a regulatory gene controlling the expression of the murine lambda1 light chain.
Authors: W Geckeler, J Faversham, M Cohn
Journal: The Journal of Experimental Medicine (1978)

We describe here two alleles, an allele of the lambda1 locus present in the SJL strain (rlambda1lo) and an allele of the lambda1 locus present in the BALB/c strain (rlambda1 +), of a regulatory gene locus which specifically influences the expression of the mouse lambda1 light chain structural gene. The rlambda1 regulatory gene is not linked to either the major histocompatibility complex or to the heavy-chain allogroup but appears to be linked to the lambda1 structural gene locus. In the homozygous state, the present of the rlambda1lo allele results in a 50-fold reduction in the number of lambda1 antigen-sensitive, bone-marrow derived lymphocytes (ASCs) compared to the presence of the rlambda1 + allele. However, those few lambda1ASCs present in rlambda1lo homozygotes can be induced normally to produce lambda1 light chains indistinguishable from those found in rlambda1 + homozygotes. The reduction in lambda1ASC's due to the rlambda1lo allele results both in a reduction in the amount of lambda1 Ig in the serum and also in a large variation in the magnitude of the lambda1 antibody response to alpha(1,3) dextran by individual animals. This variation permits the estimate that, on the average, 50 B cells of anti-alpha(1,3) specificity must be present per animal to permit a measurable response. Surprisingly, the expression of a gene locus regulating lambda1 light chain expression (rlambda1 locus) shows a clear gene dosage effect with rlambda1lo/rlambda1 + heterozygotes having 1/2 the number of lambda1ASCs and 1/2 the amount of serum lambda1 Ig as rlambda1 +/rlambda1 + homozygotes. This fact permits an analysis of the relationship between germ-line v-genes and their individual expression in serum Ig. The rlambda1 locus controls specifically a DNA-level event which occurs in stem cells as they become committed to lambda1 light chain expression. We postulate that the rlambda1 locus represents one of the DNA level recognition sites involved in the translocation event which places the vlambda1 and clambda1 structural genes in a transcriptional unit.
Atrioventricular Nodal Reentrant Tachycardia in Patients Referred for Atrial Fibrillation Ablation
Authors: William H. Sauer, Concepcion Alonso, Erica Zado, Joshua M. Cooper, David Lin, Sanjay Dixit, Andrea Russo, Ralph Verdino, Sen Ji, Edward P. Gerstenfeld, David J. Callans, Francis E. Marchlinski
Journal: Circulation (2006)

Although the most common sites of atrial ectopy that trigger atrial fibrillation (AF) are in or around the pulmonary veins (PVs), atrioventricular nodal reentrant tachycardia (AVNRT) can also cause or coexist with AF. We sought to characterize patients with AF and AVNRT and assess clinical outcomes after ablation.To determine the prevalence of concomitant AVNRT and AF, 629 consecutive patients referred for catheter ablation between November 1998 and March 2005 were studied. Electrophysiological studies with programmed stimulation during isoproterenol infusion identified atrial ectopy that initiated AF and the presence of inducible AVNRT. AF ablation consisted of proximal isolation of PVs and elimination of any non-PV trigger of AF, including AVNRT. There were 27 patients (4.3%) who had inducible AVNRT at the time of AF ablation. Of these, 13 underwent AVNRT ablation without PV isolation. Compared with the rest of the cohort, patients with AVNRT and AF were younger at the time of symptom onset (age 36.8+/-13.8 versus 48.2+/-11.7 years; P<0.01). Freedom from AF with or without previously ineffective antiarrhythmic medication was similar in both groups (96.3% versus 90.7%; mean follow-up 21.4+/-9.4 months); however, patients with AVNRT targeted for ablation were more likely to be AF free while not taking any antiarrhythmic medication after a single procedure during the follow-up period (87.5% versus 54.7%; P<0.01) and had fewer complications (0% versus 2.5%; P=0.30). Twelve of the 13 patients who underwent slow-pathway ablation without left atrial ablation remained AF free without the need for antiarrhythmic medication after a single procedure.AVNRT is an uncommon AF trigger seen more frequently in younger patients. Ablation of AVNRT in patients with AF was associated with improved outcomes compared with those with other triggers of AF.
Modification and validation of the Birmingham Vasculitis Activity Score (version 3)
Authors: C Mukhtyar, R Lee, D Brown, D Carruthers, B Dasgupta, S Dubey, O Flossmann, C Hall, J Hollywood, D Jayne, R Jones, P Lanyon, A Muir, D Scott, L Young, R A Luqmani
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Abstract</h3> Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), novel highly multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimised and validated image segmentation strategies and automated the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. Incorporating user-specific plugins, imcyto can be flexibly tailored to a wide range of segmentation needs. With these methods we interrogated the dramatic remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, showcasing their potential as key discovery tools to enhance understanding of the interplay between tumour, stroma, and immune cells in the spatial context of the tissue.
Pulmonary function in chronic renal failure: effects of dialysis and transplantation.
Authors: A Bush, R Gabriel
Journal: Thorax (1991)

Many possible pulmonary complications of renal disease have been described, but little is known of their physiological importance or the effects on them of different forms of renal replacement therapy. Four groups were recruited, each containing 20 patients. The groups consisted of patients with chronic renal failure before dialysis (group 1); patients receiving continuous ambulatory peritoneal dialysis, never having received a transplant (group 2); patients receiving haemodialysis, never having received a transplant (group 3); and patients after their first successful cadaveric renal transplant (group 4). All were attending the same regional dialysis and transplant unit. None was known to have clinically important lung or chest wall disease. Flow-volume loops were recorded before and after 400 micrograms of salbutamol, and plethysmographic lung volumes and airway conductance and single breath carbon monoxide transfer factor were measured. Only nine of 80 patients had normal lung function. The reductions in spirometric values were minor. Whole lung carbon monoxide transfer factor was reduced in all groups (mean % predicted with 95% confidence intervals: group 1 81.7% (74-89%); group 2 69.7% (62-77%); group 3 87.5% (80-96%); group 4 82.5% (78-87%]. The values were significantly lower in those having continuous ambulatory peritoneal dialysis (group 2). Residual volume was reduced significantly in the group who had undergone renal transplantation (85.7%, 77-94%). There was no correlation between these changes and smoking habit, age, duration or severity of renal failure, duration of treatment, or biochemical derangement. It is concluded that abnormal lung function is common in renal disease. The main change is a reduction in carbon monoxide transfer that persists after transplantation. The likeliest explanation is that subclinical pulmonary oedema progresses to fibrosis before transplantation. The fibrosis may worsen further to cause the reduced residual volume in the recipients of grafts.
Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease.
Authors: F P Nestel, K S Price, T A Seemayer, W S Lapp
Journal: The Journal of Experimental Medicine (1992)

In this report we have investigated macrophage (M phi) activity and tumor necrosis factor alpha (TNF-alpha) production during graft-vs.-host disease (GVHD). TNF-alpha production by M phi requires two signals: priming of M phi by interferon followed by triggering of TNF-alpha production and release by lipopolysaccharide (LPS). The state of M phi activation was examined in nonirradiated B6AF1 recipient mice injected with either 60 x 10(6) (acute GVHD) or 30 x 10(6) (nonlethal GVHD) parental B6 lymphoid cells. During the early phase of acute GVHD, administration of normally sublethal amounts of LPS-triggered release of significant amounts of TNF-alpha into the serum resulting in death of the animals within 36 h. Normal animals treated with the same dose of LPS neither died nor produced detectable amounts of serum TNF-alpha. In vitro studies demonstrated that M phi were primed during GVHD. The level of M phi priming was greater during acute GVHD than nonlethal GVHD since 100-fold less LPS was required to trigger killing of a TNF-alpha-sensitive cell line by M phi from acute GVHD animals. The amount of TNF-alpha released into the serum after LPS injection increased during the course of the GVHD and was significantly greater in acute GVH-reactive mice. Endogenous LPS was detected in the serum of acute GVH-reactive animals coincident with the onset of mortality. The data provide evidence that during GVHD M phi are primed as a result of the allogeneic reaction and that endogenous LPS therefore triggers M phi production of TNF-alpha resulting in the symptoms characteristic of acute GVHD.
Respiratory response to CO2 in patients with chronic obstructive pulmonary disease in acute respiratory failure
Authors: C Tardif, G Bonmarchand, JF Gibon, MF Hellot, J Leroy, P Pasquis, J Milic-Emili, JP Derenne
Journal: European Respiratory Journal (1993)

The aim of our study was to determine the importance of chemoreceptor stimulation by carbon dioxide in setting the level of ventilation in patients with chronic obstructive pulmonary disease (COPD) in acute respiratory failure. We studied the ventilatory and mouth occlusion pressure (P0.1) responses to CO2 in 25 COPD patients under treatment for episodes of acute respiratory failure, and in 24 normal subjects. Carbon dioxide rebreathing tests were performed in the spontaneously breathing, intubated patients, after arterial blood gases had been quasi-normalized by mechanical ventilation, which allowed us to compare both groups at similar resting arterial carbon dioxide tension (PaCO2) and acid-base status. The slopes of the ventilatory responses were markedly lower in the patients (mean +/- SEM, 1.28 +/- 0.23 versus 12.53 +/- 1.13 l.min-1.kPa-1). The slopes of the P0.1 responses were lower in the patients (0.27 +/- 0.05 versus 0.45 +/- 0.05 kPa.kPa-1), but the absolute P0.1 values were not significantly different from the normals. Increasing PaCO2 from 5.3 to 8 kPa (40 to 60 mmHg) resulted in a mean increase of 34% in ventilation. These results show that CO2 drive is a major determinant of respiratory stimulation in many COPD patients with acute respiratory failure.
Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome
Authors: Charlotte Summers, Nanak R Singh, Jessica F White, Iain M Mackenzie, Andrew Johnston, Chandra Solanki, K K Balan, A Michael Peters, Edwin R Chilvers
Journal: Thorax (2014)

<h3>Rationale</h3> Acute respiratory distress syndrome (ARDS) affects over 200 000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. <h3>Methods</h3> Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. <h3>Main results</h3> Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with &lt;5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. <h3>Conclusions</h3> We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then ‘deprime’ and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.