18 results on '"Rebecca B. Hasley"'
Search Results
2. Accuracy of resident self-assessment in objective structured clinical examination
- Author
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Spencer B. Wilson, Rebecca B. Hasley, Luise I. Pernar, David McAneny, and Brian Carmine
- Published
- 2022
3. Perioperative Outcomes for Centers Routinely Admitting Postoperative Endovascular Aortic Aneurysm Repair to the ICU
- Author
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Virendra I. Patel, Rebecca B. Hasley, Denis Rybin, Alik Farber, Karan Garg, Scott R. Levin, Thomas W. Cheng, Mahmoud B. Malas, Ahmed Kayssi, and Jeffrey J. Siracuse
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Male ,medicine.medical_specialty ,medicine.medical_treatment ,030230 surgery ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,medicine ,Humans ,Stroke ,Aged ,Aortic aneurysm repair ,business.industry ,Endovascular Procedures ,Percutaneous coronary intervention ,Perioperative ,Length of Stay ,medicine.disease ,Intensive care unit ,Limb ischemia ,Abdominal aortic aneurysm ,Aortic Aneurysm ,Intensive Care Units ,030220 oncology & carcinogenesis ,Conventional PCI ,Emergency medicine ,Female ,Surgery ,business ,Boston - Abstract
Intensive care unit (ICU) admission after endovascular aortic aneurysm repair (EVAR) varies across medical centers. We evaluated the association of postoperative ICU use with perioperative and long-term outcomes after EVAR.The Vascular Quality Initiative (2003-2019) was queried for index elective EVARs. Included centers were categorized by percentage of patients with EVARs postoperatively admitted to the ICU; routine ICU (rICU) centers as ≥80% ICU admissions and nonroutine ICU (nrICU) centers as ≤20% ICU admissions. Patients admitted preoperatively or with same day discharge were excluded. Perioperative outcomes and survival were compared between rICU and nrICU centers.Of 45,310 EVARs in the database, 35,617 were performed at rICU or nrICU centers - 5,443 (15.3%) at 71 rICU centers and 30,174 (84.7%) at 200 nrICU centers. Overall, mean age was 73.4 years and 81.6% were male. Postoperative myocardial infarction, pulmonary complications, stroke, leg ischemia, and in-hospital mortality were similar between rICU and nrICU centers (all p0.05). Postoperative length of stay (LOS) was prolonged at rICU centers (mean) (2.2 ± 3.6 vs 2 ± 4.2 days, p0.001). One-year survival was similar between rICU and nrICU centers, respectively, (94.9% vs 95.4%, p = 0.085). When compared with nrICU centers, rICU centers had similar 1-year mortality risk (hazard ratio [HR] 1.15, 95% CI 0.99-1.34, p = 0.076), but were associated with longer postoperative LOS (means ratio 1.1, 95% CI 1.08-1.13, p0.001).Routine ICU use after EVAR was associated with prolonged postoperative LOS, without improved perioperative/long-term morbidity or mortality. Updated care pathways to include postoperative admission to lower acuity care units may reduce costs without compromising care.
- Published
- 2021
4. The role of protease-activated receptor 1 signaling in CD8 T cell effector functions
- Author
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Pablo M. Irusta, Rebecca B. Hasley, Mindy Smith, Hui Chen, Dorian B. McGavern, Cecile Le Saout, Jie Cheng, Jose A. Martina, Tatiana S. Karpova, Ziang Zhu, Marta Catalfamo, Jasmin Herz, Andres Gronda, and Tong Li
- Subjects
Multidisciplinary ,Effector ,Chemistry ,Molecular biology ,Science ,Immunology ,Microtubule organizing center ,Lymphocytic choriomeningitis ,medicine.disease ,Acquired immune system ,Article ,Immunological synapse ,Cell biology ,Protease-Activated Receptor 1 ,medicine ,cardiovascular system ,Cytotoxic T cell ,Immune response ,CD8 - Abstract
Summary CD8 T cells are essential for adaptive immunity against viral infections. Protease activated receptor 1 (PAR1) is expressed by CD8 T cells; however, its role in T cell effector function is not well defined. Here we show that in human CD8 T cells, PAR1 stimulation accelerates calcium mobilization. Furthermore, PAR1 is involved in cytotoxic T cell function by facilitating granule trafficking via actin polymerization and repositioning of the microtubule organizing center (MTOC) toward the immunological synapse. In vivo, PAR1−/− mice have reduced cytokine-producing T cells in response to a lymphocytic choriomeningitis virus (LCMV) infection and fail to efficiently control the virus. Specific deletion of PAR1 in LCMV GP33-specific CD8 T cells results in reduced expansion and diminished effector function. These data demonstrate that PAR1 plays a role in T cell activation and function, and this pathway could represent a new therapeutic strategy to modulate CD8 T cell effector function., Graphical abstract, Highlights • PAR1 signaling in human CD8 T cells accelerates TCR-induced calcium mobilization • PAR1 participates in the repositioning of the MTOC at the immunological synapse • PAR1 facilitates polarized secretion of cytotoxic granules at the immunological synapse • PAR1−/− Gp33-specific CD8 T cells show reduced expansion and effector function, Molecular biology; Immunology; Immune response
- Published
- 2021
5. Application of the Caprini Risk Assessment Model to Select Patients for Extended Thromboembolism Prophylaxis After Sleeve Gastrectomy
- Author
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Rebecca B, Hasley, Sherif, Aly, Cullen O, Carter, Brian, Carmine, Donald T, Hess, David, McAneny, and Luise I, Pernar
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Postoperative Complications ,Gastrectomy ,Risk Factors ,Anticoagulants ,Humans ,Female ,Venous Thromboembolism ,Risk Assessment ,Retrospective Studies - Abstract
The Caprini risk assessment model is a well-validated tool that identifies patients who would benefit from extended venous thromboembolism (VTE) prophylaxis beyond hospital discharge. VTE, particularly portal mesenteric vein thrombosis (PMVT), is a potentially devastating complication of laparoscopic sleeve gastrectomy (LSG); therefore, we sought to examine whether the model can be safely applied to LSG patients. We hypothesized that its use can minimize the incidence of postoperative VTE, including PMVT, without increasing the likelihood of bleeding complications.We conducted a retrospective chart review of those patients who underwent LSG at our institution from 2010 and 2018, at which time the Caprini risk assessment model was already our institutional standard. We determined the patients' Caprini scores at the time of discharge and whether patients at high risk of VTE were discharged from hospital on extended courses of VTE prophylaxis. We also recorded if bleeding complications or VTE events occurred in the first 180 days after LSG.Six hundred thirty-eight patients underwent LSG, including 521 (81.7%) women, with an average preoperative body mass index (BMI) of 44.4 kg/mThe Caprini risk assessment model can effectively identify patients after LSG who might benefit from extended courses of VTE prophylaxis. Extended VTE prophylaxis does not seem to confer increased bleeding risk in this patient population.
- Published
- 2021
6. Chronic exposure to type-I IFN under lymphopenic conditions alters CD4 T cell homeostasis.
- Author
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Cecile Le Saout, Rebecca B Hasley, Hiromi Imamichi, Lueng Tcheung, Zonghui Hu, Megan A Luckey, Jung-Hyun Park, Scott K Durum, Mindy Smith, Adam W Rupert, Michael C Sneller, H Clifford Lane, and Marta Catalfamo
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
HIV infection and the associated chronic immune activation alter T cell homeostasis leading to CD4 T cell depletion and CD8 T cell expansion. The mechanisms behind these outcomes are not totally defined and only partially explained by the direct cytopathic effect of the virus. In this manuscript, we addressed the impact of lymphopenia and chronic exposure to IFN-α on T cell homeostasis. In a lymphopenic murine model, this interaction led to decreased CD4 counts and CD8 T cell expansion in association with an increase in the Signal Transducer and Activator of Transcription 1 (STAT1) levels resulting in enhanced CD4 T cell responsiveness to IFN-α. Thus, in the setting of HIV infection, chronic stimulation of this pathway could be detrimental for CD4 T cell homeostasis.
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- 2014
- Full Text
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7. Reasons for long-term tunneled dialysis catheter use and associated morbidity
- Author
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Victor Castro, Scott R. Levin, Logan Mendez, Jeffrey J. Siracuse, Rebecca B. Hasley, Yixin Zhang, Thomas W. Cheng, Quinten G. Dicken, and Alik Farber
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Male ,medicine.medical_specialty ,Catheterization, Central Venous ,Time Factors ,medicine.medical_treatment ,Clinical Decision-Making ,030204 cardiovascular system & hematology ,Risk Assessment ,Limited access ,03 medical and health sciences ,0302 clinical medicine ,Arteriovenous Shunt, Surgical ,Catheters, Indwelling ,Renal Dialysis ,Risk Factors ,medicine ,Central Venous Catheters ,Humans ,030212 general & internal medicine ,Dialysis ,Device Removal ,Retrospective Studies ,business.industry ,Patient Preference ,Dialysis catheter ,Middle Aged ,medicine.disease ,Thrombosis ,Surgery ,Catheter ,Treatment Outcome ,Heart failure ,Cohort ,Female ,Hemodialysis ,Cardiology and Cardiovascular Medicine ,business - Abstract
Objective Tunneled dialysis catheters (TDCs) are generally used as a temporary means to provide hemodialysis until permanent arteriovenous (AV) access is established. However, some patients may have long-term catheter-based hemodialysis because of the lack of alternatives for other dialysis access. Our objective was to evaluate characteristics of patients with, reasons for, and mortality associated with long-term TDC use. Methods A retrospective single-institution analysis was performed. Long-term TDC use was defined as >180 days without more than a 7-day temporary removal time. Reasons for long-term TDC use and complications were recorded. Summary statistics were performed. Kaplan-Meier analysis compared mortality between patients with long-term TDC use and a comparison cohort who underwent AV access creation with subsequent TDC removal. Results We identified 50 patients with long-term TDC use from 2013 to 2018. The average age was 63 years, 44% were male, and 76% were African American. Previous TDC use was found in 42% of patients with subsequent removal after alternative access was established. Median TDC duration was 333 days (range, 185-2029 days). The primary reasons for long-term TDC use were failed (occluded) AV access (34%), nonmaturing AV (nonoccluded) access (32%), delayed AV access placement (14%), no AV access options (10%), patient refusal for AV access placement (6%), and medically high risk for AV access placement (4%). In 46% of patients, TDC complications including central venous stenosis (33.4%), TDC-related infections (29.6%), TDC displacement (27.8%), and thrombosis (7.9%) occurred. Overall, 47.6% required a catheter exchange during the prolonged TDC period. The majority (76.4%) had the catheter removed because of established alternative access during follow-up. The long-term TDC group, in relation to the comparator group (n = 201), had fewer male patients (44% vs 61.2%; P = .028) and higher proportion of congestive heart failure (66% vs 40.3%; P = .001). Kaplan-Meier analysis showed no significant difference in survival at 24 months for the long-term TDC group compared with the comparator group (93.6% vs 92.7%; P = .28). Conclusions Patients with long-term TDCs experienced significant TDC-related morbidity. Whereas permanent access is preferable, some patients may require long-term TDC use because of difficulty in establishing a permanent access, limited access options, and patient preference. There was no difference in survival between the groups.
- Published
- 2020
8. Long-term Tunneled Dialysis Catheter Use Is Not Associated With Mortality but Is Associated With Increased Morbidity
- Author
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Jeffrey J. Siracuse, Alik Farber, Victor Castro, Thomas W. Cheng, Logan Mendez, Rebecca B. Hasley, Yixin Zhang, Quinten G. Dicken, and Scott R. Levin
- Subjects
medicine.medical_specialty ,business.industry ,Medicine ,Surgery ,Dialysis catheter ,Cardiology and Cardiovascular Medicine ,business ,Term (time) - Published
- 2020
9. Activated platelet–T-cell conjugates in peripheral blood of patients with HIV infection
- Author
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Rebecca B. Hasley, Jing Qin, Kunio Nagashima, Tomozumi Imamichi, H. Clifford Lane, Adam Harned, Adam Rupert, David A. Stephany, Alex G Ober, Marta Catalfamo, Stefania Pittaluga, Shahed Abdullah, Mindy Smith, and Samantha A. Green
- Subjects
Blood Platelets ,T cell ,Immunology ,HIV Infections ,Inflammation ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Fibrin Fibrinogen Degradation Products ,platelet–T-cell conjugates ,Basic Science ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,Platelet ,Viremia ,Platelet activation ,Blood Coagulation ,Innate immune system ,Viral Load ,HIV infection ,Acquired immune system ,CD4 Lymphocyte Count ,Infectious Diseases ,medicine.anatomical_structure ,Coagulation ,Case-Control Studies ,coagulation/inflammation and T cells ,medicine.symptom ,Biomarkers ,CD8 - Abstract
Background: Despite successfully suppressed viremia by treatment, patients with high levels of biomarkers of coagulation/inflammation are at an increased risk of developing non-AIDS defining serious illnesses such as cardiovascular diseases. Thus, there is a relationship between persistent immune activation and coagulation/inflammation, although the mechanisms are poorly understood. Platelets play an important role in this process. Although interactions between platelets and elements of the innate immune system, such as monocytes, are well described, little is known about the interaction between platelets and the adaptive immune system. Design: We investigated the interaction of a component of the coagulation system, platelets, and the adaptive immune system T cells. Methods: Healthy controls and combination antiretroviral therapy (cART)-treated HIV-infected patients with viral loads of less than 40 copies/ml for more than 15 months were analysed for platelet–T-cell conjugate formation. Results: Platelets can form conjugates with T cells and were preferentially seen in CD4+ and CD8+ T-cell subsets with more differentiated phenotypes [memory, memory/effector and terminal effector memory (TEM)]. Compared with healthy controls, these conjugates in patients with HIV infection were more frequent, more often composed of activated platelets (CD42b+CD62P+), and were significantly associated with the D-dimer serum levels. Conclusion: These data support a model in which platelet–T-cell conjugates may play a critical role in the fast recruitment of antigen-experienced T cells to the place of injury. This mechanism can contribute in maintaining a state of coagulation/inflammation observed in these patients contributing to the pathology of the disease.
- Published
- 2015
10. Quantitative sensory testing measures individual pain responses in emergency department patients
- Author
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Jumana Al-Baghli, Rebecca B. Hasley, Jessica M Rupp, Melissa J. Repine, Katharyn L Flickinger, Saad Feroz, Jeffrey Kristan, Maria L. Pacella, Alexandro Gianforcaro, Brian Suffoletto, Clifton W. Callaway, and Kevin J Duffy
- Subjects
medicine.medical_specialty ,emergency department ,quantitative sensory testing ,Placebo ,03 medical and health sciences ,0302 clinical medicine ,Physical medicine and rehabilitation ,medicine ,Journal of Pain Research ,Depression (differential diagnoses) ,Original Research ,hyperalgesia ,business.industry ,030208 emergency & critical care medicine ,Emergency department ,anxiety ,Anesthesiology and Pain Medicine ,Nociception ,Opioid ,Hyperalgesia ,depression ,Physical therapy ,opioid ,Anxiety ,medicine.symptom ,business ,Oxycodone ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Kevin J Duffy,Katharyn L Flickinger,Jeffrey T Kristan,Melissa J Repine,Alexandro Gianforcaro, Rebecca B Hasley,Saad Feroz,Jessica M Rupp,Jumana Al-Baghli,Maria L Pacella,Brian P Suffoletto,Clifton W Callaway Department of Emergency Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA Background: Refining and individualizing treatment of acute pain in the emergency department (ED) is a high priority, given that painful complaints are the most common reasons for ED visits. Few tools exist to objectively measure pain perception in the ED setting. We speculated that variation in perception of fixed painful stimuli would explain individual variation in reported pain and response to treatment among ED patients. Materials and methods: In three studies, we 1) describe performance characteristics of brief quantitative sensory testing (QST) in 50 healthy volunteers, 2) test effects of 10 mg oxycodone versus placebo on QST measures in 18 healthy volunteers, and 3) measure interindividual differences in nociception and treatment responses in 198 ED patients with a painful complaint during ED treatment. QST measures adapted for use in the ED included pressure sensation threshold, pressure pain threshold (PPT), pressure pain response (PPR), and cold pain tolerance (CPT) tests. Results: First, all QST measures had high inter-rater reliability and test–retest reproducibility. Second, 10 mg oxycodone reduced PPR, increased PPT, and prolonged CPT. Third, baseline PPT and PPR revealed hyperalgesia in 31 (16%) ED subjects relative to healthy volunteers. In 173 (88%) ED subjects who completed repeat testing 30 minutes after pain treatment, PPT increased and PPR decreased (Cohen’s dz 0.10–0.19). Verbal pain scores (0–10) for the ED complaint decreased by 2.2 (95% confidence intervals [CI]: 1.9, 2.6) (Cohen’s dz 0.97) but did not covary with the changes in PPT and PPR (r=0.05–0.13). Treatment effects were greatest in ED subjects with a history of treatment for anxiety or depression (Cohen’s dz 0.26–0.43) or with baseline hyperalgesia (Cohen’s dz 0.40–0.88). Conclusion: QST reveals individual differences in perception of fixed painful stimuli in ED patients, including hyperalgesia. Subgroups of ED patients with hyperalgesia and psychiatric history report larger treatment effects on ED pain and QST measures. Keywords: emergency department, quantitative sensory testing, hyperalgesia, opioid, anxiety, depression
- Published
- 2017
11. PAR1 signaling is involved in TCR-mediated CD8 T cell granule exocytosis
- Author
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Mindy Marie Smith, Hui Chen, Rebecca B. Hasley, Tatiana Karpova, and Marta Catalfamo
- Subjects
Immunology ,Immunology and Allergy - Abstract
The Protease Activated Receptor (PAR1) is the receptor of thrombin, the main serine protease of the coagulation cascade. PAR1 is expressed by platelets, endothelial cells and cells of the innate immune system and mediates platelet aggregation and secretion of pro-inflammatory cytokines. PAR1 is expressed by T lymphocytes, however its role in T cell function is not well defined. We have previously shown that human CD4 and CD8 T cells express PAR1. PAR1 expression was higher in CD8 than CD4 T cells and is associated with T cell differentiation. CD8 T cell Effector Memory and Terminal Effector Memory phenotypes have higher PAR1 expression than Naïve T cells. PAR1 activation by thrombin enhanced CD8 T cell function including chemokinesis and cytokine secretion. In the present study, we address the role of PAR1 signaling in CD8 T cell mediated cytotoxicity by the granule exocytosis pathway. We found that expression of PAR1 on CD8 T cells is associated with expression of the transcription factors T-bet and Eomes and effector molecules, granzyme A, granzyme B and perforin. PAR1 activation by thrombin enhanced TcR-induced degranulation in CD8 T cells. In addition, in a redirected killing assay, we show that granule exocytosis and cytotoxicity of target cells was efficiently blocked by PAR1 antagonist (SCH79797). Confocal microscopy of the CD8 T-APC conjugates revealed that PAR1 blockade inhibit actin polymerization and decreased the docking of the Microtubule Organizing Center (MTOC) at the immunological synapse. These findings suggest that PAR1 signaling is involved in several effector functions of CD8 T cells including the cytotoxicity by the granule exocytosis pathway. These data have implications in CD8 T cell function and disease.
- Published
- 2019
12. Enhanced Effector Function of CD8+ T Cells From Healthy Controls and HIV-Infected Patients Occurs Through Thrombin Activation of Protease-Activated Receptor 1
- Author
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Tatiana S. Karpova, Erin Nickel, James G. McNally, Rebecca B. Hasley, Dean Follmann, Stephen Shaw, Jeanette Higgins, Amanda Hurley, Beverly Packard, Nariman Balenga, H. Clifford Lane, Zonghui Hu, Mindy Smith, Kirk M. Druey, Marta Catalfamo, Michael C. Sneller, Natalya V. Belkina, and Hiromi Imamichi
- Subjects
Male ,Chemokinesis ,HIV Infections ,CD8-Positive T-Lymphocytes ,Biology ,Lymphocyte Activation ,Thrombomodulin ,Proinflammatory cytokine ,Major Articles and Brief Reports ,Thrombin ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Receptor, PAR-1 ,Blood Coagulation ,Inflammation ,Middle Aged ,Acquired immune system ,Molecular biology ,Infectious Diseases ,Immunology ,HIV-1 ,Cytokines ,Female ,Cytokine secretion ,Immunologic Memory ,CD8 ,medicine.drug - Abstract
Disruption of vascular integrity by trauma and other tissue insults leads to inflammation and activation of the coagulation cascade. The serine protease thrombin links these 2 processes. The proinflammatory function of thrombin is mediated by activation of protease-activated receptor 1 (PAR-1). We found that peripheral blood effector memory CD4(+) and CD8(+) T lymphocytes expressed PAR-1 and that expression was increased in CD8(+) T cells from human immunodeficiency virus (HIV)-infected patients. Thrombin enhanced cytokine secretion in CD8(+) T cells from healthy controls and HIV-infected patients. In addition, thrombin induced chemokinesis, but not chemotaxis, of CD8(+) T cells, which led to structural changes, including cell polarization and formation of a structure rich in F-actin and phosphorylated ezrin-radexin-moesin proteins. These findings suggest that thrombin mediates cross-talk between the coagulation system and the adaptive immune system at sites of vascular injury through increased T-cell motility and production of proinflammatory cytokines.
- Published
- 2012
13. The CD8+HLA-DR+T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls
- Author
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Alice Rosenberg, Rebecca B. Hasley, Amy Nelson, Michael Baseler, Gregg Roby, Hiromi Imamichi, Sonya Krishnan, H. Clifford Lane, Catherine Rehm, Richard A. Lempicki, Christian Woods, Mark Pavlick, and Joseph W. Adelsberger
- Subjects
Interleukin 21 ,Immune system ,Clonal anergy ,Antigen ,Immunology ,T-cell receptor ,HLA-DR ,Immunology and Allergy ,Cell cycle ,Biology ,CD8 - Abstract
HIV-induced immune activation leads to expansion of a subset of human CD8 + T cells expressing HLA-DR antigens. Expansion of CD8 + HLA-DR + T cells can be also observed in non-HIV settings including several autoimmune diseases and aging. Although these cells are felt to represent “immune exhaustion” and/or to be anergic, their precise role in host defense has remained unclear. Here, we report that this subset of cells exhibits a restricted repertoire, shows evidence of multiple rounds of division, but lacks markers of recent TCR engagement. Detailed cell cycle analysis revealed that compared with their CD8 + HLA-DR − counterpart, the CD8 + HLA-DR + T-cell pool contained an increased fraction of cells in S-phase with elevated levels of the G2/M regulators: cyclin A2, CDC25C, Cdc2 (CDK1), indicating that these cells are not truly anergic but rather experiencing proliferation in vivo. Together, these data support a hypothesis that antigen stimulation leads to the initial expansion of a CD8 + pool of cells in vivo that undergo further expansion independent of ongoing TCR engagement. No qualitative differences were noted between CD8 + HLA-DR + cells from HIV + and HIV − donors, indicating that the generation of CD8 + HLA-DR + T cells is a part of normal immune regulation that is exaggerated in the setting of HIV-1 infection.
- Published
- 2012
14. IL-7-dependent STAT1 activation limits homeostatic CD4 T cell expansion
- Author
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Megan A. Luckey, Rebecca B. Hasley, Jung-Hyun Park, Alejandro V. Villarino, John J. O'Shea, H. Clifford Lane, Marta Catalfamo, Hiromi Imamichi, Cecile Le Saout, Mindy Smith, and Timothy G. Myers
- Subjects
CD4-Positive T-Lymphocytes ,0301 basic medicine ,T cell ,Immunology ,HIV Infections ,Lymphocyte Activation ,Transcriptome ,Mice ,03 medical and health sciences ,Downregulation and upregulation ,Transcription (biology) ,Lymphopenia ,STAT5 Transcription Factor ,medicine ,Animals ,Homeostasis ,Humans ,Immunology and Allergy ,STAT1 ,Phosphorylation ,Gene ,STAT5 ,Cell Proliferation ,Cell Size ,Mice, Knockout ,biology ,Chemistry ,Interleukin-7 ,General Medicine ,Cell biology ,STAT1 Transcription Factor ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,biology.protein ,Research Article ,Signal Transduction - Abstract
IL-7 regulates homeostatic mechanisms that maintain the overall size of the T cell pool throughout life. We show that under steady state conditions, IL-7 signaling is principally mediated by activation of Signal Transducers and Activators of Transcription 5 (STAT5). In contrast, under lymphopenic conditions there is a modulation of STAT1 expression resulting in an IL-7-dependent STAT1 and STAT5 activation. Consequently, the IL-7-induced transcriptome is altered with enrichment of interferon (IFN) stimulated genes (ISGs). Moreover, STAT1 overexpression was associated with reduced survival in CD4 T cells undergoing Lymphopenia-Induced Proliferation (LIP). We propose a model in which T cells undergoing LIP upregulate STAT1 protein, “switching on” an alternate IL-7-dependent program. This mechanism could be a physiological process to “sense space” regulating the size of the CD4 T cell pool. During HIV infection the virus could exploit this pathway leading to the homeostatic dysregulation of the T cell pools observed in these patients.
- Published
- 2017
15. HIV immune activation drives increased Eomes expression in memory CD8 T cells in association with transcriptional downregulation of CD127
- Author
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Jung-Hyun Park, Tomozumi Imamichi, Rebecca B. Hasley, Grace Kim, Julie A. Hixon, Scott K. Durum, Travis Friesen, Wenqing Li, H. Clifford Lane, Marta Catalfamo, Changwan Hong, Yoriko M. Nakamura, Zonghui Hu, Michael C. Sneller, and Raphael M. Oguariri
- Subjects
Period (gene) ,Immunology ,Eomesodermin ,Gene Expression ,chemical and pharmacologic phenomena ,HIV Infections ,CD8-Positive T-Lymphocytes ,Real-Time Polymerase Chain Reaction ,Article ,Flow cytometry ,Cohort Studies ,Interleukin-7 Receptor alpha Subunit ,Downregulation and upregulation ,medicine ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Interleukin-7 receptor ,biology ,medicine.diagnostic_test ,Gene Expression Profiling ,virus diseases ,hemic and immune systems ,Flow Cytometry ,Cell biology ,Infectious Diseases ,Cross-Sectional Studies ,Polyclonal antibodies ,biology.protein ,T-Box Domain Proteins ,CD8 - Abstract
BACKGROUND: During HIV infection distinct mechanisms drive immune activation of the CD4 and CD8 T cells leading to CD4 T-cell depletion and expansion of the CD8 T-cell pool. This immune activation is polyclonal and extends beyond HIV-specific T cells. One consequence of this immune activation is a profound decrease in IL-7Rα (CD127) expression on memory CD8 T cells. The mechanisms leading to this are unknown and because of the potential impact of reduced IL-7 signaling in memory T cells specific to HIV and other pathogens, in the present study we examined the molecular mechanisms implicated in this downregulation of CD127. METHODS: Membrane bound (mIL7RA) and soluble (sIL7RA) mRNA expression was determined by qRT-PCR. CD127, Eomesodermin (Eomes) and T-bet expression in healthy controls and HIV-infected patients were studied by flow cytometry. RESULTS: CD127 downregulation occurs at the transcriptional level for both mIL7RA and sIL7RA alternative spliced forms in the CD127(low) memory CD8 T cells. CD127(low) memory CD8 T cells exhibited increased Eomes expression and an ‘effector-like’ gene profile. These changes were associated with higher HIV-RNA levels. Following combination antiretroviral therapy (cART), there was an increase in CD127 expression over an extended period of time (>5 months) which was associated with decreased Eomes expression. CONCLUSION: CD127 is downregulated at a transcriptional level in memory CD8 T cells in association with upregulation of Eomes expression.
- Published
- 2013
16. The CD8+ HLA-DR+ T cells expanded in HIV-1 infection are qualitatively identical to those from healthy controls
- Author
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Hiromi, Imamichi, Richard A, Lempicki, Joseph W, Adelsberger, Rebecca B, Hasley, Alice, Rosenberg, Gregg, Roby, Catherine A, Rehm, Amy, Nelson, Sonya, Krishnan, Mark, Pavlick, Christian J, Woods, Michael W, Baseler, and H Clifford, Lane
- Subjects
Adult ,Clonal Anergy ,Cell Cycle ,Receptors, Antigen, T-Cell ,Cell Cycle Proteins ,HIV Infections ,HLA-DR Antigens ,CD8-Positive T-Lymphocytes ,Middle Aged ,Lymphocyte Activation ,Article ,Gene Expression Regulation ,T-Lymphocyte Subsets ,HIV-1 ,Humans ,Biomarkers ,Cells, Cultured ,Cell Proliferation - Abstract
HIV-induced immune activation leads to expansion of a subset of human CD8(+) T cells expressing HLA-DR antigens. Expansion of CD8(+) HLA-DR(+) T cells can be also observed in non-HIV settings including several autoimmune diseases and aging. Although these cells are felt to represent "immune exhaustion" and/or to be anergic, their precise role in host defense has remained unclear. Here, we report that this subset of cells exhibits a restricted repertoire, shows evidence of multiple rounds of division, but lacks markers of recent TCR engagement. Detailed cell cycle analysis revealed that compared with their CD8(+) HLA-DR(-) counterpart, the CD8(+) HLA-DR(+) T-cell pool contained an increased fraction of cells in S-phase with elevated levels of the G2/M regulators: cyclin A2, CDC25C, Cdc2 (CDK1), indicating that these cells are not truly anergic but rather experiencing proliferation in vivo. Together, these data support a hypothesis that antigen stimulation leads to the initial expansion of a CD8(+) pool of cells in vivo that undergo further expansion independent of ongoing TCR engagement. No qualitative differences were noted between CD8(+) HLA-DR(+) cells from HIV(+) and HIV(-) donors, indicating that the generation of CD8(+) HLA-DR(+) T cells is a part of normal immune regulation that is exaggerated in the setting of HIV-1 infection.
- Published
- 2011
17. [Untitled]
- Author
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Marta Catalfamo, Zonghui Hu, Rebecca B. Hasley, Cecile Le Saout, Hiromi Imamichi, Michael C. Sneller, H. Clifford Lane, Megan A. Luckey, Hyun Park, and Lueng Tcheung
- Subjects
Autoimmune disease ,Activator (genetics) ,Effector ,T cell ,Immunology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,medicine.anatomical_structure ,Immunity ,medicine ,Cancer research ,STAT protein ,Immunology and Allergy ,Cytotoxic T cell ,Molecular Biology ,Homeostasis - Abstract
To maintain the size of T cell pools throughout life, homeostatic mechanisms regulate both survival and proliferation, which is achieved by IL-7 and TCR signaling. IL-7 (through lymphopenia-induced proliferation/LIP) can also mediate expansion of autoreactive clones leading to the onset of autoimmune disease or enhance effector function against tumors and viruses. In the setting of chronic HIV infection, CD4 T cell depletion and the increased availability of IL-7 triggers LIP that occurs in an inflammatory environment rich in Type-I IFNs; we hypothesized that this pathway could contribute to the immune activation leading to CD4 T cell depletion and CD8 T cell pool expansion. Accordantly, we found that genes associated with γ c cytokines and Type-I IFN signaling were differentially expressed in CD4 and CD8 T cells from chronic HIV infected patients. Using a lymphopenic murine model, we present new evidence that, in vivo, IL-7 differentially regulated the expression of the total-Signal Transducer and Activator of Transcription 1 (t-STAT1) in CD4 and CD8 T cells undergoing LIP and in so doing enhanced CD4 T cell responsiveness to Type-I IFN. In this setting, chronic treatment with IFN- α led to decreased CD4 T cell counts and CD8 T cell expansion. This interplay between IL-7 and Type-I IFN might be advantageous in immunity against pathogens, however chronic stimulation of this pathway could be deleterious for CD4 T cell homeostasis and may contribute to the aberrant immune activation and eventual CD4 T cell depletion observed during HIV infection.
- Published
- 2013
18. CS02-3 In vivo IL-7 exposure of CD4 T cells during HIV induced lymphopenia leads to an enhanced Type-I IFN response
- Author
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Gregg Roby, Clifford Lane, Catherine Rehm, Jung-Hyun Park, Marta Catalfamo, Rebecca B. Hasley, Lueng Tcheung, Hiromi Imamichi, Cecile Le Saout, and Michael C. Sneller
- Subjects
Ifn response ,business.industry ,Immunology ,Human immunodeficiency virus (HIV) ,Hematology ,medicine.disease_cause ,Biochemistry ,Virology ,Interleukin 21 ,In vivo ,Immunology and Allergy ,Medicine ,Cytotoxic T cell ,business ,Molecular Biology - Published
- 2011
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