tbuckley/cabot-search huggingface dataset:
CD27 cooperates with the pre-T cell receptor in the regulation of murine T cell development.
Authors: L A Gravestein, W van Ewijk, F Ossendorp, J Borst
Journal: The Journal of Experimental Medicine (1996)

CD27 is a lymphocyte-specific member of the TNF receptor family and has a TNF-related transmembrane ligand, CD70. The CD27/CD70 receptor-ligand pair cooperates with the TCR in the regulation of the peripheral T cell response. The study presented here reveals that CD27 may play a similar role in thymic pre-T cell development. We have previously cloned the cDNA encoding murine CD27, prepared specific mAbs and observed that murine CD27 is expressed on virtually all thymocytes, with the exception of a subpopulation of CD4-8- precursor T cells. It is shown here that induction of murine CD27 expression occurs at the transition from the CD4-8-25+ to the CD4-8-25- precursor T cell stage and is regulated by the pre-TCR. Therefore, we investigated whether CD27 contributes to pre-TCR-mediated thymocyte development. Pre-TCR function was mimicked by the induction of CD3 signaling in thymocytes of recombination activating gene (RAG)-deficient mice. This in vivo anti-CD3 epsilon mAb treatment induces an about fifty fold numerical expansion of CD4-8-25+ thymocytes and their differentiation to the CD4+8+25- stage. Co-injection of anti-CD27 mAb inhibited the CD3-mediated expansion and differentiation of the CD4-8-25+ precursor population. Also, injection of anti-CD27 mAb in TCR alpha-/- mutant mice led to a reduction in the absolute number of CD4+8+25- thymocytes. We present evidence that in these in vivo systems, anti-CD27 mAb inhibits CD27-ligand interaction. Therefore, we conclude that CD27 may contribute to normal murine T cell development by synergizing with the pre-TCR-mediated signal.
Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor
Authors: Huei San Leong, Kelan Chen, Yifang Hu, Stanley Lee, Jason Corbin, Miha Pakusch, James M. Murphy, Ian J. Majewski, Gordon K. Smyth, Warren S. Alexander, Douglas J. Hilton, Marnie E. Blewitt
Journal: Cancer Research (2012)

Abstract SMCHD1 is an epigenetic modifier of gene expression that is critical to maintain X chromosome inactivation. Here, we show in mouse that genetic inactivation of Smchd1 accelerates tumorigenesis in male mice. Loss of Smchd1 in transformed mouse embryonic fibroblasts increased tumor growth upon transplantation into immunodeficient nude mice. In addition, loss of Smchd1 in Eμ-Myc transgenic mice that undergo lymphomagenesis reduced disease latency by 50% relative to control animals. In premalignant Eμ-Myc transgenic mice deficient in Smchd1, there was an increase in the number of pre-B cells in the periphery, likely accounting for the accelerated disease in these animals. Global gene expression profiling suggested that Smchd1 normally represses genes activated by MLL chimeric fusion proteins in leukemia, implying that Smchd1 loss may work through the same pathways as overexpressed MLL fusion proteins do in leukemia and lymphoma. Notably, we found that SMCHD1 is underexpressed in many types of human hematopoietic malignancy. Together, our observations collectively highlight a hitherto uncharacterized role for SMCHD1 as a candidate tumor suppressor gene in hematopoietic cancers. Cancer Res; 73(5); 1591–9. ©2012 AACR.
A basal gradient of Wnt and stem-cell number influences regional tumour distribution in human and mouse intestinal tracts
Authors: Simon J Leedham, Pedro Rodenas-Cuadrado, Kimberley Howarth, Annabelle Lewis, Sreelakshmi Mallappa, Stefania Segditsas, Hayley Davis, Rosemary Jeffery, Manuel Rodriguez-Justo, Satish Keshav, Simon P L Travis, Trevor A Graham, James East, Susan Clark, Ian P M Tomlinson
Journal: Gut (2012)

<h3>Objective</h3> Wnt signalling is critical for normal intestinal development and homeostasis. Wnt dysregulation occurs in almost all human and murine intestinal tumours and an optimal but not excessive level of Wnt activation is considered favourable for tumourigenesis. The authors assessed effects of pan-intestinal Wnt activation on tissue homeostasis, taking into account underlying physiological Wnt activity and stem-cell number in each region of the bowel. <h3>Design</h3> The authors generated mice that expressed temporally controlled, stabilised β-catenin along the crypt–villus axis throughout the intestines. Physiological Wnt target gene activity was assessed in different regions of normal mouse and human tissue. Human intestinal tumour mutation spectra were analysed. <h3>Results</h3> In the mouse, β-catenin stabilisation resulted in a graduated neoplastic response, ranging from dysplastic transformation of the entire epithelium in the proximal small bowel to slightly enlarged crypts of non-dysplastic morphology in the colorectum. In contrast, stem and proliferating cell numbers were increased in all intestinal regions. In the normal mouse and human intestines, stem-cell and Wnt gradients were non-identical, but higher in the small bowel than large bowel in both species. There was also variation in the expression of some Wnt modulators. Human tumour analysis confirmed that different <i>APC</i> mutation spectra are selected in different regions of the bowel. <h3>Conclusions</h3> There are variable gradients in stem-cell number, physiological Wnt activity and response to pathologically increased Wnt signalling along the crypt-villus axis and throughout the length of the intestinal tract. The authors propose that this variation influences regional mutation spectra, tumour susceptibility and lesion distribution in mice and humans.
<i>Toxoplasma</i>Infection and Later Development of Schizophrenia in Mothers
Authors: Marianne Giørtz Pedersen, Hanne Stevens, Carsten Bøcker Pedersen, Bent Nørgaard-Pedersen, Preben Bo Mortensen
Journal: American Journal of Psychiatry (2011)

Several studies based on clinical samples have found an association between Toxoplasma gondii infection and schizophrenia, and a case-control study among U.S. military personnel with specimens available from both before and after diagnosis found a positive association between T. gondii immunoglobulin G (IgG) antibody level and schizophrenia. These findings have never been replicated in a prospective cohort study. The purpose of this study was to determine whether mothers infected with T. gondii have an elevated risk of schizophrenia or related disorders and whether the risk depends on IgG antibody level.In a register-based prospective cohort study of 45,609 women born in Denmark, the level of T. gondii-specific IgG antibodies was measured in connection with childbirth between 1992 and 1995. Women were followed up from the date of delivery until 2008.A significant positive association between T. gondii IgG antibody level and schizophrenia spectrum disorders was found. Mothers with the highest IgG level had a relative risk of 1.73 (95% confidence interval [CI]=1.12-2.62) compared with mothers with the lowest IgG level. For schizophrenia, the relative risk was 1.68 (95% CI=0.77-3.46). When the mothers were classified according to IgG level, only those with the highest IgG levels had a significantly higher risk of schizophrenia spectrum disorders.Women with high levels of T. gondii-specific IgG antibodies have a significantly elevated risk of developing schizophrenia spectrum disorders.
TACI and BAFF-R mediate isotype switching in B cells
Authors: Emanuela Castigli, Stephen A. Wilson, Sumi Scott, Fatma Dedeoglu, Shengli Xu, Kong-Peng Lam, Richard J. Bram, Haifa Jabara, Raif S. Geha
Journal: The Journal of Experimental Medicine (2005)

The tumor necrosis factor family members BAFF and APRIL induce Ig isotype switching in human B cells. We analyzed the ability of BAFF and APRIL to induce isotype switching in murine B cells to IgG1, IgA, and IgE. APRIL and BAFF each engage two receptors, transmembrane activator and calcium-modulator and cytophilin ligand interactor (TACI) and B cell maturation antigen (BCMA), on B cells. In addition, BAFF engages a third receptor on B cells, BAFF-R. To determine the role of these receptors in isotype switching, we examined B cells from mice deficient in TACI, BCMA, and BAFF-R. The results obtained indicate that both TACI and BAFF-R are able to transduce signals that result in isotype switching.
Steroid receptors and heat-shock proteins in patients with primary biliary cirrhosis
Authors: Arturo D. Jorge, Arturo O. Stati, Laura Vargas Roig, Guillermo Ponce, Oliver A. Jorge, Daniel R. Ciocca
Journal: Hepatology (1993)

Primary biliary cirrhosis has a definite female preponderance. Increased estrogen levels have been found in patients with this disease; however no studies indicate the status of sex hormone steroid receptors in primary biliary cirrhosis patients. In this study the occurrence and distribution of estrogen receptors, progesterone receptors and androgen receptors in liver biopsy specimens from patients with primary biliary cirrhosis were examined and compared with these receptors in the normal liver. In addition, three heat-shock proteins associated with steroid receptors (90 kD, 70 kD and 27 kD) were examined. All of the receptor proteins were detected on immunocytochemical study using specific receptor antibodies; monoclonal and polyclonal antibodies were also used to detect the heat-shock proteins. Normal bile duct epithelial cells displayed low-to-moderate amount of estrogen receptors and abundant 90- kD, 70- kD and 27-kD heat-shock protein expression, whereas normal hepatocytes showed moderate estrogen receptor and 90-kD heat-shock protein and high 70-kD heat-shock protein expression. Expression of 70-kD heat-shock protein was due mainly to the constitutive form of this protein (hsc72). In patients with primary biliary cirrhosis, significant increases in estrogen receptor and 90-kD heat-shock protein content were seen in bile duct cells and in hepatocytes. Levels of 27-kD heat-shock protein were also increased in some of the primary biliary cirrhosis biopsy specimens. The expression of progesterone receptor and androgen receptor was very low in normal and primary biliary cirrhosis bile duct cells and hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
Inhaled Prostacyclin and Iloprost in Severe Pulmonary Hypertension Secondary to Lung Fibrosis
Authors: HORST OLSCHEWSKI, H. ARDESCHIR GHOFRANI, DIETER WALMRATH, RALPH SCHERMULY, BETTINA TEMMESFELD-WOLLBRÜCK, FRIEDRICH GRIMMINGER, WERNER SEEGER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Pulmonary hypertension is a life-threatening complication of lung fibrosis. Vasodilator therapy is difficult owing to systemic side effects and pulmonary ventilation–perfusion mismatch. We compared the effects of intravenous prostacyclin and inhaled NO and aerosolized prostacyclin in randomized order and, in addition, tested for effects of oxygen and systemic calcium antagonists (CAAs) in eight patients with lung fibrosis and pulmonary hypertension. Aerosolized prostaglandin (PG)I2 caused preferential pulmonary vasodilatation with a decrease in mean pulmonary arterial pressure from 44.1 ± 4.2 to 31.6 ± 3.1 mm Hg, and pulmonary vascular resistance (Rl) from 810 ± 226 to 386 ± 69 dyn · s · cm− 5 (p < 0.05, respectively). Systemic arterial pressure, arterial oxygen saturation, and pulmonary right-to-left shunt flow, measured by multiple inert gas analysis, were not significantly changed. Inhaled NO similarly resulted in selective pulmonary vasodilatation, with Rl decreasing from 726 ± 217 to 458 ± 81 dyn · s · cm− 5. In contrast, both intravenous PGI2 and CAAs were not pulmonary selective, resulting in a significant drop in arterial pressure. In addition, PGI2 infusion caused a marked increase in shunt flow. Long-term therapy with aerosolized iloprost (long-acting PGI2 analog) resulted in unequivocal clinical improvement from a state of immobilization and severe resting dyspnea in a patient with decompensated right heart failure. We concluded that, in pulmonary hypertension secondary to lung fibrosis, aerosolization of PGI2 or iloprost causes marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure. Long-term therapy with inhaled iloprost may be life saving in decompensated right heart failure from pulmonary hypertension secondary to lung fibrosis.
Protection against Respiratory Syncytial Virus Infection by DNA Immunization
Authors: Xiaomao Li, Suryaprakash Sambhara, Cindy Xin Li, Mary Ewasyshyn, Mark Parrington, Judy Caterini, Olive James, George Cates, Run-Pan Du, Michel Klein
Journal: The Journal of Experimental Medicine (1998)

Respiratory syncytial virus (RSV) remains a major cause of morbidity and mortality in infants and the elderly and is a continuing challenge for vaccine development. A murine T helper cell (Th) type 2 response associates with enhanced lung pathology, which has been observed in past infant trials using formalin-inactivated RSV vaccine. In this study, we have engineered an optimized plasmid DNA vector expressing the RSV fusion (F) protein (DNA-F). DNA-F was as effective as live RSV in mice at inducing neutralizing antibody and cytotoxic T lymphocyte responses, protection against infection, and high mRNA expression of lung interferon γ after viral challenge. Furthermore, a DNA-F boost could switch a preestablished anti-RSV Th2 response towards a Th1 response. Critical elements for the optimization of the plasmid constructs included expression of a secretory form of the F protein and the presence of the rabbit β-globin intron II sequence upstream of the F-encoding sequence. In addition, anti-F systemic immune response profile could be modulated by the route of DNA-F delivery: intramuscular immunization resulted in balanced responses, whereas intradermal immunization resulted in a Th2 type of response. Thus, DNA-F immunization may provide a novel and promising RSV vaccination strategy.
FACTORS RELATING TO THE VIRULENCE OF STAPHYLOCOCCI
Authors: M. Glenn Koenig, Marian Ann Melly, David E. Rogers
Journal: The Journal of Experimental Medicine (1962)

Four clumping factor-negative strains of Staphylococcus aureus were found to closely resemble the diffuse colonial variant of the Smith strain. All produced fatal intraperitoneal infections in mice, all grew in diffuse, streaming colonies in plasma or serum soft agar, and all behaved like encapsulated microorganisms in in vitro opsonic systems. These staphylococci were resistant to phagocytosis in the peritoneal cavities of normal mice. When mice were immunized with heat-killed vaccines prepared from the Smith diffuse variant these strains were rapidly ingested by peritoneal leukocytes and the animals survived. This observation suggests that these strains share the same or a similar phagocytosis-retarding antigen. While most pathogenic staphylococci isolated from human material do not behave like these unusual mouse-virulent strains, indirect evidence is cited to support the suggestion that other staphylococci may acquire similar phagocytosis-resisting characteristics during in vivo multiplication. Studies to support or refute this thesis are in progress.
SNS-032 inhibits mTORC1/mTORC2 activity in acute myeloid leukemia cells and has synergistic activity with perifosine against Akt
Authors: Haitao Meng, Yingming Jin, Hui Liu, Liangshun You, Chunmei Yang, Xue Yang, Wenbin Qian
Journal: Journal of Hematology & Oncology (2013)

Acute myeloid leukemia (AML) is a heterogeneous disorder with aberrant regulation of a variety of signal pathways. Therefore, simultaneous targeting of two or even more deregulated signal transduction pathways is needed to overcome drug resistance. Previously, it was reported that SNS-032, a selective cyclin-dependent kinase inhibitor, is an effective agent for treatment of AML; however, the molecular mechanisms of SNS-032-induced cell death of AML cells are not yet fully understood. The aim of the study was to characterize the effects in vitro of SNS-032, used alone and in combination with an Akt inhibitor perifosine, against AML cells and to identify the mechanism involved.SNS-032 significantly induced cytotoxicity in human AML cell lines and blasts from patients with newly diagnosed or relapsed AML. However, Kasumi-1 cells and some of leukemic samples (14.9%) from AML patients were resistant to SNS-032-mediated cell death. Western blot analysis showed that SNS-032 strongly inhibited the phosphorylation of mammalian target of rapamycin (mTOR) on Ser 2448 and Ser2481, and that removal of SNS-032 resulted in partial recovery of cell death and reactivation of phosphorylation of mTOR. Moreover, exogenous insulin-like growth factor-1 (IGF-1) did not reverse SNS-032-induced cell growth inhibition and downregualtion of phosphor-mTOR at Ser2448 and Ser2481 although slight suppression of IGF-1R expression was triggered by the agent. Furthermore, SNS-032 at a lower concentration (60-80 nM) enhanced AML cell cytotoxicity induced by perifosine, an Akt inhibitor. Importantly, SNS-032 treatment reduced colony formation ability of AML cells, which was significantly increased when two agents were combined. This combination therapy led to almost complete inhibition of Akt activity.We conclude that SNS-032 might directly target mammalian target of rapamycin complex 1 (mTORC1)/mTORC2. Our results further provide a rationale for combining SNS-032 with perifosine for the treatment of AML.
Management of ankle sprains: a randomised controlled trial of the treatment of inversion injuries using an elastic support bandage or an Aircast ankle brace
Authors: S H Boyce, M A Quigley, S Campbell
Journal: British Journal of Sports Medicine (2005)

Lateral ligament ankle sprains are the single most common sports injury.To determine the functional outcome of the ankle joint after a moderate or severe inversion injury, comparing standard treatment with an elastic support bandage against an Aircast ankle brace.Prospective, randomised controlled trial.Two accident and emergency departments.Fifty patients presenting consecutively were randomised into two equal groups: one group was treated with an elastic support bandage and the other with an Aircast ankle brace. All patients were given a standardised advice sheet referring to rest, ice, compression, and elevation. Patients were reviewed after 48-72 hours, 10 days, and one month.Ankle joint function assessed at 10 days and one month using the modified Karlsson scoring method (maximum score 90).The difference in ankle girth (swelling) and pain score at 10 days.Seventeen patients in the elastic support bandage group (six defaulted, two excluded) and 18 patients in the Aircast ankle brace group (six defaulted, one excluded) completed the study. There were no significant differences between the two groups at presentation in terms of age (mean 35.3 and 32.6 years respectively), sex, dominant leg, left or right ankle injured, previous injury, time to presentation (median three and four hours respectively), difference in ankle girth (mean 14.5 and 14.3 mm respectively), and pain scores (mean 6.2 and 5.8 respectively). The Karlsson score was significantly higher in the Aircast ankle cast group than in the elastic bandage group at 10 days (mean 50 v 35, p = 0.028, 95% confidence interval (CI) 1.7 to 27.7) and one month (mean 68 v 55, p = 0.029, 95% CI 1.4 to 24.8) (Student's t test). There was no difference between the groups in the secondary outcome measures (swelling, p = 0.09; pain, p = 0.07). When hierarchical multiple regression analysis was used to correct for possible baseline confounding factors, the Aircast ankle brace group was significantly associated with higher Karlsson scores at 10 days (p = 0.009) and one month (p = 0.024).The use of an Aircast ankle brace for the treatment of lateral ligament ankle sprains produces a significant improvement in ankle joint function at both 10 days and one month compared with standard management with an elastic support bandage.
Macrolide Treatment for <i>Mycobacterium abscessus</i> and <i>Mycobacterium massiliense</i> Infection and Inducible Resistance
Authors: Go-Eun Choi, Sung Jae Shin, Choul-Jae Won, Ki-Nam Min, Taegwon Oh, Mi-Young Hahn, Keehoon Lee, Soo Hyun Lee, Charles L. Daley, Seonwoo Kim, Byeong-Ho Jeong, Kyeongman Jeon, Won-Jung Koh
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Macrolides, such as clarithromycin (CLR) and azithromycin (AZM), are frequently the only oral antibiotics that are active against Mycobacterium abscessus and M. massiliense infections.Objectives: To compare the activity of CLR and AZM in experimental models.Methods: We compared the treatment efficacies of CLR and AZM and determined the correlation between efficacy and induced erythromycin ribosome methyltransferase gene (erm)(41) expression in experimental models of M. abscessus and M. massiliense infections.Measurements and Main Results: In all tested M. abscessus isolates, a high level of inducible CLR resistance developed (minimal inhibitory concentration [MIC] on Day 3 versus Day 14; P < 0.001). Whereas the AZM MIC increased on Day 14 (P < 0.01 versus Day 3), the level was significantly lower than the CLR MIC on Day 14 (P < 0.001). However, the MICs of CLR and AZM for the M. massiliense isolates did not change. Compared with CLR, AZM presented greater antibiotic activity against M. abscessus in vitro, ex vivo, and in vivo (P < 0.05), whereas both macrolides were comparably effective against M. massiliense. In M. abscessus infection, the level of erm(41) expression was higher after exposure to CLR than after exposure to AZM (P < 0.001). Experiments using an erm(41)-knockout M. abscessus mutant and an M. massiliense transformant expressing M. abscessus erm(41) confirmed that erm(41) was responsible for inducible CLR resistance.Conclusions: CLR induces greater erm(41) expression and thus higher macrolide resistance than AZM in M. abscessus infection. AZM may be more effective against M. abscessus, whereas both macrolides appear to be equally effective against M. massiliense.
Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis
Authors: Shinji Shimoda, Kenichi Harada, Hiroaki Niiro, Ken Shirabe, Akinobu Taketomi, Yoshihiko Maehara, Koichi Tsuneyama, Yasuni Nakanuma, Patrick Leung, Aftab A. Ansari, M. Eric Gershwin, Koichi Akashi
Journal: Hepatology (2011)

Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. Although there have been significant advances in the dissection of the adaptive immune response against the mitochondrial autoantigens, there are increasing data that suggest a contribution of innate immune mechanisms in inducing chronic biliary pathology. We have taken advantage of our ability to isolate subpopulations of liver mononuclear cells (LMC) and examined herein the role of Toll-like receptors (TLRs), their ligands, and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). In particular, we demonstrate that Toll-like receptor 4 ligand (TLR4-L)-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand (TLR3-L)-stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. There were also marked increases in the cytotoxic activity of hepatic NK cells from PBC patients compared to NK cells from controls but only when the NK cells were prepared following ligation of both TLR3-L- and TLR4-L-stimulated LMC. These functional data are supported by the immunohistochemical observation of an increased presence of CD56-positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls. Conclusion: These data highlight critical differences in the varied roles of Mo and NK cells following TLR3-L and TLR4-L stimulation. (HEPATOLOGY 2011.)