tbuckley/cabot-search huggingface dataset:
Pathophysiologic Changes in Extracellular pH Modulate Parathyroid Calcium-Sensing Receptor Activity and Secretion via a Histidine-Independent Mechanism
Authors: Katherine L. Campion, Wanda D. McCormick, Jim Warwicker, Mohd Ezuan Bin Khayat, Rebecca Atkinson-Dell, Martin C. Steward, Leigh W. Delbridge, Hee-Chang Mun, Arthur D. Conigrave, Donald T. Ward
Journal: Journal of the American Society of Nephrology (2015)

The calcium-sensing receptor (CaR) modulates renal calcium reabsorption and parathyroid hormone (PTH) secretion and is involved in the etiology of secondary hyperparathyroidism in CKD. Supraphysiologic changes in extracellular pH (pHo) modulate CaR responsiveness in HEK-293 (CaR-HEK) cells. Therefore, because acidosis and alkalosis are associated with altered PTH secretion in vivo, we examined whether pathophysiologic changes in pHo can significantly alter CaR responsiveness in both heterologous and endogenous expression systems and whether this affects PTH secretion. In both CaR-HEK and isolated bovine parathyroid cells, decreasing pHo from 7.4 to 7.2 rapidly inhibited CaR-induced intracellular calcium (Ca2+i) mobilization, whereas raising pHo to 7.6 potentiated responsiveness to extracellular calcium (Ca2+o). Similar pHo effects were observed for Ca2+o-induced extracellular signal-regulated kinase phosphorylation and actin polymerization and for L-Phe-induced Ca2+i mobilization. Intracellular pH was unaffected by acute 0.4-unit pHo changes, and the presence of physiologic albumin concentrations failed to attenuate the pHo-mediated effects. None of the individual point mutations created at histidine or cysteine residues in the extracellular domain of CaR attenuated pHo sensitivity. Finally, pathophysiologic pHo elevation reversibly suppressed PTH secretion from perifused human parathyroid cells, and acidosis transiently increased PTH secretion. Therefore, pathophysiologic pHo changes can modulate CaR responsiveness in HEK-293 and parathyroid cells independently of extracellular histidine residues. Specifically, pathophysiologic acidification inhibits CaR activity, thus permitting PTH secretion, whereas alkalinization potentiates CaR activity to suppress PTH secretion. These findings suggest that acid-base disturbances may affect the CaR-mediated control of parathyroid function and calcium metabolism in vivo.
Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group.
Authors: U Keilholz, S H Goey, C J Punt, T M Proebstle, R Salzmann, C Scheibenbogen, D Schadendorf, D Liénard, A Enk, R Dummer, B Hantich, A M Geueke, A M Eggermont
Journal: Journal of Clinical Oncology (1997)

The combination of interferon alfa-2a (IFN alpha) and high-dose interleukin-2 (IL-2) is active in metastatic melanoma. The addition of cisplatin (CDDP) has resulted in response rates greater than 50%. This study was performed to determine whether the addition of CDDP to a cytokine treatment regimen with IFN alpha and high-dose IL-2 influences survival of patients with metastatic melanoma.Patients with advanced metastatic melanoma were randomly assigned to receive treatment with IFN alpha 10 x 10(6) U/m2 subcutaneously on days 1 through 5 and a high-dose intravenous decrescendo regimen of IL-2 on days 3 through 8 (18 mIU/ m2/6 hours, 18 mIU/m2/12 hours, 18 mIU/m2/24 hours, and 4.5 mIU/m2/24 hours x 3) without (arm A) or with (arm B) CDDP 100 mg/m2 on day 1. Treatment cycles were repeated every 28 days to a maximum of four cycles.One hundred thirty-eight patients with advanced metastatic melanoma, of whom 87% had visceral metastases, were accrued for the trial. Both regimens were feasible in a multicenter setting. The objective response rate was 18% without and 33% with CDDP (P = .04). The progression-free survival was 53 days without and 92 days with CDDP (P = .02, Wilcoxon; P = .09, log-rank). There was no statistically significant difference in survival between treatment arms, with a median overall survival duration for all patients of 9 months.The addition of CDDP to cytokine treatment with IFN alpha and IL-2 does not influence survival of patients with advanced metastatic melanoma, despite a significant increase in response rate and progression-free survival.
Prohibitin and Cofilin Are Intracellular Effectors of Transforming Growth Factor β Signaling in Human Prostate Cancer Cells
Authors: Beibei Zhu, Kei Fukada, Haining Zhu, Natasha Kyprianou
Journal: Cancer Research (2006)

Abstract A proteomic analysis was pursued to identify new signaling effectors of transforming growth factor β1 (TGF-β1) that serve as potential intracellular effectors of its apoptotic action in human prostate cancer cells. The androgen-sensitive and TGF-β-responsive human prostate cancer cells, LNCaP TβRII, were used as in vitro model. In response to TGF-β, significant posttranslational changes in two proteins temporally preceded apoptotic cell death. TGF-β mediated the nuclear export of prohibitin, a protein involved in androgen-regulated prostate growth, to the cytosol in the LNCaP TβRII cells. Cofilin, a protein involved in actin depolymerization, cell motility, and apoptosis, was found to undergo mitochondrial translocation in response to TGF-β before cytochrome c release. Loss-of-function approaches (small interfering RNA) to silence prohibitin expression revealed a modest decrease in the apoptotic response to TGF-β and a significant suppression in TGF-β-induced cell migration. Silencing Smad4 showed that the cellular localization changes associated with prohibitin and cofilin action in response to TGF-β are independent of Smad4 intracellular signaling. (Cancer Res 2006; 66(17): 8640-7)
Mechanism of apnea lengthening across the night in obstructive sleep apnea.
Authors: J M Montserrat, E N Kosmas, M G Cosio, R J Kimoff
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

We have previously shown in patients with obstructive sleep apnea (OSA) that the length of apneas increases from the beginning to the end of the night (Chest 1994;106:1695-1701). To investigate this, in light of recent evidence that neural feedback related to inspiratory effort during apneas plays an important role in apnea termination (Am. J. Respir. Crit. Care Med. 1994;149:707-714), we measured transdiaphragmatic pressure (Pdi) and the diaphragm tension-time index (TTdi = Pdi/Pdi(max)) Ti/Ttot) during overnight polysomnography in seven male subjects with severe OSA (mean apnea-hypopnea index [AHI] = 64.1 +/- 8.8 [SD] events/h). We assessed apnea duration, SaO2, and inspiratory effort during apneas at the start and end of the night in Stage 2 sleep. Mean apnea duration increased from 26.6 +/- 2.0 s (SEM) to 32.6 =/- 2.5 s (p < 0.05). The rate of fall in SaO2 during apneas decreased, and end-apneic SaO2 remained unchanged across the night, suggesting a possible role for metabolic factors in mediating the increase in apnea duration. Both Pdi and TTdi at end-apnea just prior to arousal increased significantly from the beginning to the end of the night (e.g., Pdi from 41.0 +/- 4.9 to 49.9 +/- 7.9 cm H20; p < 0.05). These findings, together with those in previous studies, suggest that there is a blunting over the night of the arousal response to neural stimuli produced during obstructed inspiratory effort, which plays a major role in mediating apnea lengthening across the night in OSA.
One-Stage, en Bloc Resection for Colonic-Uterine Fistula Caused by Diverticulitis
Authors: Richard C. Clay
Journal: JAMA (1969)

A sigmoidouterine fistula due to diverticulitis of the colon developed in one patient. This was treated by one-stage, en bloc resection of the uterus and sigmoid segment. Because of the difficulty of determining that a sigmoidouterine fistula is not due to cancer, which could be implanted in the operative field if the involved organs were separated during removal, en bloc resection when it is technically feasible seems to offer an improved chance of total recovery.
MOLECULAR APPROACHES TO AMYOTROPHIC LATERAL SCLEROSIS
Authors: R. Glenn Smith, M.D., Ph.D, Stanley H. Appel, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract New discoveries are expanding our knowledge of mechanisms involved in amyotrophic lateral sclerosis (ALS) pathogenesis. Some recent advances in our understanding of motoneuron death in familial ALS (fALS) and sporadic ALS (sALS) are reviewed, with emphasis on molecular similarities that may further unite these phenotypically linked diseases.
HERV-K–specific T cells eliminate diverse HIV-1/2 and SIV primary isolates
Authors: R. Brad Jones, Keith E. Garrison, Shariq Mujib, Vesna Mihajlovic, Nasra Aidarus, Diana V. Hunter, Eric Martin, Vivek M. John, Wei Zhan, Nabil F. Faruk, Gabor Gyenes, Neil C. Sheppard, Ingrid M. Priumboom-Brees, David A. Goodwin, Lianchun Chen, Melanie Rieger, Sophie Muscat-King, Peter T. Loudon, Cole Stanley, Sara J. Holditch, Jessica C. Wong, Kiera Clayton, Erick Duan, Haihan Song, Yang Xu, Devi SenGupta, Ravi Tandon, Jonah B. Sacha, Mark A. Brockman, Erika Benko, Colin Kovacs, Douglas F. Nixon, Mario A. Ostrowski
Journal: Journal of Clinical Investigation (2012)

The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1–infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)–specific CD8+ T cells obtained from HIV-1–infected human subjects responded to HIV-1–infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)–specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)–specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)–targeted HIV-1 vaccines and immunotherapeutics.
Impairment of Cognitive Function in Women Receiving Adjuvant Treatment for High-Risk Breast Cancer: High-Dose Versus Standard-Dose Chemotherapy
Authors: Frits S. A. M. van Dam, Willem Boogerd, Sanne B. Schagen, Martin J. Muller, Maria E. Droogleever Fortuyn, Elsken v.d. Wall, Sjoerd Rodenhuis
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: Although high-dose chemotherapy is rapidly gaining acceptance as a treatment option for a number of cancers, the long-term toxic effects of such therapy are a concern. Cognitive deficits (e.g., problems with memory and concentration) are not uncommon after chemotherapy, but they have not been documented systematically. In this study, we assessed the prevalence of cognitive deficits in a group of patients with high-risk breast cancer who were randomly assigned to receive either high-dose or standard-dose adjuvant chemotherapy plus tamoxifen, and we investigated whether high-dose chemotherapy impaired cognitive functioning more than standard-dose chemotherapy. Methods: Cognitive functioning was evaluated by use of a battery of neuropsychologic tests. In addition, patients were interviewed with regard to cognitive problems, health-related quality of life, anxiety, and depression. Results from patients who received adjuvant systemic therapy were compared with results from patients who had early stage breast cancer not treated with such therapy (control patients). Results: The study population consisted of 34 patients treated with highdose chemotherapy plus tamoxifen, 36 patients treated with standard-dose chemotherapy plus tamoxifen, and 34 control patients. For all patients, the average time since the completion of last nonhormonal therapy was 2 years. Cognitive impairment was found in 32% of the patients treated with high-dose chemotherapy, in 17% of the patients treated with standard-dose chemotherapy, and in 9% of the control patients. In comparison with the control patients, patients treated with high-dose chemotherapy appeared to have an 8.2-times higher risk of cognitive impairment (odds ratio; 95% confidence interval [CI] = 1.8–37.7); in comparison with the patients who received standard-dose chemotherapy, this risk of impairment was 3.5-times higher (95% CI = 1.0–12.8). Conclusion: High-dose chemotherapy appears to impair cognitive functioning more than standard-dose chemotherapy. Central nervous system toxicity may be a doselimiting factor in high-dose chemotherapy regimens.
Enrichment of specific suppressor T cells and characterization of their surface markers.
Authors: M Taniguchi, J F Miller
Journal: The Journal of Experimental Medicine (1977)

A simple method is described which allows antigen-specific suppressor T cells to be enriched by greater than 100-fold. The enriched cells have the following characteristic markers: Ig-, Thy-1+, Ly-1-, Ly-2,3+, and I-J+. More than 30% of this population could be killed directly by an antiserum specific for the I-J subregion gene product in the presence of complement.
Interleukin-11: a new cytokine critical for osteoclast development.
Authors: G Girasole, G Passeri, R L Jilka, S C Manolagas
Journal: Journal of Clinical Investigation (1994)

Stromal cells of the bone marrow control the development of osteoclasts through the production of cytokines capable of promoting the proliferation and differentiation of hematopoietic progenitors. Moreover, the deregulated production of the cytokine IL-6 in the bone marrow mediates an increase in osteoclastogenesis after estrogen loss. IL-6, however, does not influence osteoclastogenesis in the estrogen-replete state, suggesting that other cytokines might be responsible for osteoclast development under physiologic circumstances. We report here that IL-11, a newly discovered cytokine that is produced by marrow stromal cells, induced the formation of osteoclasts exhibiting an unusually high degree of ploidy in cocultures of murine bone marrow and calvarial cells. Osteoclasts formed in the presence of IL-11 were capable of bone resorption, as evidenced by the formation of resorption pits, as well as the release of 45Ca from prelabeled murine calvaria. Further, an antibody neutralizing IL-11 suppressed osteoclast development induced by either 1,25-dihydroxyvitamin D3, parathyroid hormone, interleukin-1, or tumor necrosis factor; whereas inhibitors of IL-1 or TNF had no effect on IL-11-stimulated osteoclast formation. The effects of IL-11 on osteoclast development were blocked by indomethacin; more important, however, they were independent of the estrogen status of the marrow donors.
RelB Enhances Prostate Cancer Growth: Implications for the Role of the Nuclear Factor-κB Alternative Pathway in Tumorigenicity
Authors: Yong Xu, Sajni Josson, Fang Fang, Terry D. Oberley, Daret K. St. Clair, X. Steven Wan, Yulan Sun, Vasudevan Bakthavatchalu, Anantharaman Muthuswamy, William H. St. Clair
Journal: Cancer Research (2009)

Abstract The nuclear factor-κB (NF-κB) classic pathway is thought to be critical for tumorigenesis, but little is known about the role of the NF-κB alternative pathway in cancer development. Recently, high constitutive nuclear levels of RelB have been observed in human prostate cancer specimens with high Gleason scores. Here, we used four complementary approaches to test whether RelB contributes to tumorigenicity of prostate cancer. Inhibiting RelB in aggressive androgen-independent PC-3 cells by stable or conditional expression of a dominant-negative p100 mutant significantly reduced the incidence and growth rate of tumors. The decrease in tumorigenicity coincided with a reduction in the NF-κB target interleukin-8 (IL-8). Consistently, down-regulation of RelB by small interfering RNA targeting also reduced tumor growth and decreased levels of IL-8. Conversely, stable expression of RelB in androgen-responsive LNCaP tumors increased the circulating IL-8 levels. Taken together, these results reveal a tumor-supportive role of RelB, implicate the NF-κB alternative pathway as a potential target for preventing prostate cancer, and suggest the use of IL-8 as a marker for prostate cancer prognosis. [Cancer Res 2009;69(8):3267–71]
Cerebral Microvascular Disease Predicts Renal Failure in Type 2 Diabetes
Authors: Takashi Uzu, Yasuo Kida, Nobuo Shirahashi, Tamaki Harada, Atsushi Yamauchi, Makoto Nomura, Keiji Isshiki, Shin-ichi Araki, Toshiro Sugimoto, Daisuke Koya, Masakazu Haneda, Atsunori Kashiwagi, Ryuichi Kikkawa
Journal: Journal of the American Society of Nephrology (2010)

Abnormalities in small renal vessels may increase the risk of developing impaired renal function, but methods to assess these vessels are extremely limited. We hypothesized that the presence of small vessel disease in the brain, which manifests as silent cerebral infarction (SCI), may predict the progression of kidney disease in patients with type 2 diabetes. We recruited 608 patients with type 2 diabetes without apparent cerebrovascular or cardiovascular disease or overt nephropathy and followed them for a mean of 7.5 years. At baseline, 177 of 608 patients had SCI, diagnosed by cerebral magnetic resonance imaging. The risk for the primary outcome of ESRD or death was significantly higher for patients with SCI than for patients without SCI [hazard ratio, 2.44; 95% confidence interval (CI) 1.36 to 4.38]. The risk for the secondary renal end point of any dialysis or doubling of the serum creatinine concentration was also significantly higher for patients with SCI (hazard ratio, 4.79; 95% CI 2.72 to 8.46). The estimated GFR declined more in patients with SCI than in those without SCI; however, the presence of SCI did not increase the risk for progression of albuminuria. In conclusion, independent of microalbuminuria, cerebral microvascular disease predicted renal morbidity among patients with type 2 diabetes.
Trance, a Tumor Necrosis Factor Family Member, Enhances the Longevity and Adjuvant Properties of Dendritic Cells in Vivo
Authors: Régis Josien, Hong-Li Li, Elizabeth Ingulli, Supria Sarma, Brian R.Wong, Maria Vologodskaia, Ralph M. Steinman, Yongwon Choi
Journal: The Journal of Experimental Medicine (2000)

Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.
Trans-Splicing and Operons in Metazoans: Translational Control in Maternally Regulated Development and Recovery from Growth Arrest
Authors: Gemma B. Danks, Martina Raasholm, Coen Campsteijn, Abby M. Long, J. Robert Manak, Boris Lenhard, Eric M. Thompson
Journal: Molecular Biology and Evolution (2014)

Polycistronic mRNAs transcribed from operons are resolved via the trans-splicing of a spliced-leader (SL) RNA. Trans-splicing also occurs at monocistronic transcripts. The phlyogenetically sporadic appearance of trans-splicing and operons has made the driving force(s) for their evolution in metazoans unclear. Previous work has proposed that germline expression drives operon organization in Caenorhabditis elegans, and a recent hypothesis proposes that operons provide an evolutionary advantage via the conservation of transcriptional machinery during recovery from growth arrested states. Using a modified cap analysis of gene expression protocol we mapped sites of SL trans-splicing genome-wide in the marine chordate Oikopleura dioica. Tiled microarrays revealed the expression dynamics of trans-spliced genes across development and during recovery from growth arrest. Operons did not facilitate recovery from growth arrest in O. dioica. Instead, we found that trans-spliced transcripts were predominantly maternal. We then analyzed data from C. elegans and Ciona intestinalis and found that an enrichment of trans-splicing and operon gene expression in maternal mRNA is shared between all three species, suggesting that this may be a driving force for operon evolution in metazoans. Furthermore, we found that the majority of known terminal oligopyrimidine (TOP) mRNAs are trans-spliced in O. dioica and that the SL contains a TOP-like motif. This suggests that the SL in O. dioica confers nutrient-dependent translational control to trans-spliced mRNAs via the TOR-signaling pathway. We hypothesize that SL-trans-splicing provides an evolutionary advantage in species that depend on translational control for regulating early embryogenesis, growth and oocyte production in response to nutrient levels.
Protein Carbonylation as a Novel Mechanism in Redox Signaling
Authors: Chi Ming Wong, Amrita K. Cheema, Lihua Zhang, Yuichiro J. Suzuki
Journal: Circulation Research (2007)

Reactive oxygen species serve as second messengers for signal transduction; however, molecular targets of oxidant signaling have not been defined. Here, we show that ligand-receptor-mediated signaling promotes reactive oxygen species-dependent protein carbonylation. Treatment of pulmonary artery smooth muscle cells with endothelin-1 increased protein carbonyls. Carbonylation of the majority of proteins occurred transiently, suggesting that there is also a mechanism for decarbonylation induced by endothelin-1. Decarbonylation was suppressed by inhibition of thioredoxin reductase, and cellular thioredoxin was upregulated during the decarbonylation phase. These results indicate that endothelin-1 promotes oxidant signaling as well as thioredoxin-mediated reductive signaling to regulate carbonylation and decarbonylation mechanisms. In cells treated with endothelin receptor antagonists, hydrogen peroxide scavengers, or an iron chelator, we identified, via mass spectrometry, proteins that are carbonylated in a receptor- and Fenton reaction-dependent manner, including annexin A1, which promotes apoptosis and suppresses cell growth. Carbonylation of annexin A1 by endothelin-1 was followed by proteasome-dependent degradation of this protein. We propose that carbonylation and subsequent degradation of annexin A1 may play a role in endothelin-mediated cell growth and survival, important events in pulmonary vascular remodeling. Protein carbonylation in response to ligand-receptor interactions represents a novel mechanism in redox signaling.