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In JoVE (1)
- Экс естественных Расширение опухоли-реактивных Т-клеток посредством систем бриостатин 1/Ionomycin и общие гамма Сеть Цитокины Разработка
Other Publications (37)
- Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society
- General and Comparative Endocrinology
- The Journal of Thoracic and Cardiovascular Surgery
- Biology of Reproduction
- Cancer Immunology, Immunotherapy : CII
- International Immunology
- The New Phytologist
- Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract
- American Journal of Surgery
- Archives of Surgery (Chicago, Ill. : 1960)
- Cancer Immunology, Immunotherapy : CII
- Cancer Immunology, Immunotherapy : CII
- International Immunopharmacology
- Lancet Neurology
- Interactive Cardiovascular and Thoracic Surgery
- Breast Cancer Research and Treatment
- Journal of Translational Medicine
- American Journal of Surgery
- Breast Cancer Research and Treatment
- Journal of the American College of Surgeons
- BMC Immunology
- BMC Public Health
- Breast Cancer Research and Treatment
- Stroke; a Journal of Cerebral Circulation
- Journal of Translational Medicine
- Journal of the American College of Surgeons
- British Journal of Neurosurgery
- Molecular Cancer Research : MCR
- American Journal of Surgery
- Annals of Surgery
- Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research
- Annals of Surgery
- The American Surgeon
- Journal of Surgical Education
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Articles by Laura Graham in JoVE
Экс естественных Расширение опухоли-реактивных Т-клеток посредством систем бриостатин 1/Ionomycin и общие гамма Сеть Цитокины Разработка
Maciej Kmieciak1, Amir Toor2, Laura Graham3, Harry D. Bear3, Masoud H. Manjili1
1Department of Microbiology & Immunology, Virginia Commonwealth University- Massey Cancer Center, 2Department of Internal Medicine, Virginia Commonwealth University- Massey Cancer Center, 3Department of Surgery, Virginia Commonwealth University- Massey Cancer Center
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Other articles by Laura Graham on PubMed
Clinical Autonomic Research : Official Journal of the Clinical Autonomic Research Society. Apr, 2002 | Pubmed ID: 12102456
To describe the clinical characteristics of patients presenting to a tertiary referral centre undergoing tilt table testing (HUT), comparing those who have vasovagal syncope (VVS) confirmed as a cause of symptoms and those with unexplained syncope after HUT.
Endocrine Patterns Associated with Reproduction in the Nile Hippopotamus (Hippopotamus Amphibius) As Assessed by Fecal Progestagen Analysis
General and Comparative Endocrinology. Aug, 2002 | Pubmed ID: 12270790
The hippopotamus (Hippopotamus amphibius) is a popular zoo animal and an integral part of wetland ecosystems in its native continent of Africa. However, information about the reproductive physiology of the hippopotamus is limited compared to the other megaherbivores of Africa such as the elephant and the rhinoceros. This study is the first to report on the endocrine patterns associated with ovulation and pregnancy in the Nile hippopotamus. Fecal samples were collected 3 times per week from female hippopotami (N = 9) housed in captivity in Florida. Progesterone metabolites were extracted from the feces with 80% MeOH and quantified using a progestagen EIA. Fecal progestagen analysis indicated hippopotami had a cycle length of 35.3 +/- 1.3 days and ovulated throughout the year. Fecal progestagen concentrations during pregnancy (N = 11 pregnancies) were higher on average (833.5 +/- 115.2 ng/g; P < 0.05) than those observed during non-pregnant luteal phases (309.5 +/- 20.9 ng/g) and remained elevated throughout gestation. Fecal progestagen analysis revealed the onset of puberty in three females between 3 and 4 years of age and all conceived by their fourth cycle. Lactational suppression of ovulation during nursing was usually, but not always, observed and lasted for 33.9 +/- 1.8 weeks. The observed calving interval in females with lactational anovulation was 17 months. The majority of births (63.6%) occurring during the summer rainy season and the inconsistency of lactational anovulation suggested the possibility of environmental influences on reproduction.
Central Sympathetic Blockade Ameliorates Brain Death-induced Cardiotoxicity and Associated Changes in Myocardial Gene Expression
The Journal of Thoracic and Cardiovascular Surgery. Dec, 2002 | Pubmed ID: 12447173
Brain death results in cardiac injury and hemodynamic instability. After brain death, catecholamine levels surge in concert with increased expression of select myocardial gene products. Sympathetic blockade was used to investigate the effects of the adrenergic nervous system on myocardial gene expression in a rabbit model of brain death.
Efficacy of Porcine Gonadotropins for Repeated Stimulation of Ovarian Activity for Oocyte Retrieval and in Vitro Embryo Production and Cryopreservation in Siberian Tigers (Panthera Tigris Altaica)
Biology of Reproduction. Jan, 2003 | Pubmed ID: 12493701
A comparison of the amino acid sequences demonstrated that Siberian tiger gonadotropins are more homologous with those of porcine than any other commercially available preparation. The present study measured the efficacy of repeated ovarian stimulation with purified porcine gonadotropins on the follicular, hormonal, and immunogenic responses in Siberian tigers as well as on the ability of oocytes retrieved by laparoscopic follicular aspiration to fertilize and cleave in vitro. Controlled rate and vitrification cryopreservation methods were also compared for their ability to support ongoing cleavage following thawing of presumptive 2- to 4-cell tiger embryos generated in vitro. Vitrification supported continued embryonic cleavage in vitro while controlled rate freezing did not. Stereological microscopy indicated an excellent ovarian response with the recovery of quality cumulus-oocyte complexes that apparently fertilized and cleaved in vitro. However, ultrastructural and physiological examination revealed abnormal and unnatural responses such as the failure of some cumulus-oocyte complexes to reach maturity and progestagen levels to approach normalcy. At the same time, analyses of blood for antibodies failed to detect an immune reaction to these foreign gonadotropins in an assay that tested positive for the chorionic gonadotropin-stimulated domestic cat. Together, these observations suggest that porcine gonadotropins may be effective for the ovarian stimulation of tigers but that some modifications to administration protocols are needed to produce a more natural response.
Successful Adoptive Immunotherapy with Vaccine-sensitized T Cells, Despite No Effect with Vaccination Alone in a Weakly Immunogenic Tumor Model
Cancer Immunology, Immunotherapy : CII. Dec, 2003 | Pubmed ID: 12827306
Tumor cell vaccines have been successful at inducing immunity in naïve mice, but only in a few reports has vaccination alone induced regression of established tumors and, generally, only when they are very small. Clinically, vaccinations alone may not be able to cause regression of established human cancers, which tend to be weakly immunogenic. We hypothesized that pharmacologic ex vivo amplification of a vaccination-induced immune response with subsequent adoptive immunotherapy (AIT) to tumor-bearing animals would be more effective in treatment of these animals than vaccination alone. The 4T1 and 4T07 mammary carcinomas are derived from the same parental cell line, but 4T1 is much less immunogenic and more aggressive than 4T07. Vaccination with either 4T1, 4T1-IL-2, or 4T07-IL-2 was not effective as treatment for established 4T1 tumors. However, 4T1 or 4T07-IL-2-vaccine-sensitized draining lymph node (DLN) cells, activated ex vivo with bryostatin 1 and ionomycin and expanded in culture, induced complete tumor regressions when adoptively transferred to 4T1 tumor-bearing animals. This was effective against small tumors as well as more advanced tumors, 10 days after tumor cell inoculation. Furthermore, as would be required for this approach to be used clinically, vaccine-DLN cells obtained from mice with established progressive 4T1 tumors (inoculated 10 days before vaccination) also induced regression of 4T1 tumors in an adoptive host. In none of these experiments was exogenous IL-2 required to induce tumor regression. The response to tumor cell vaccine can be amplified by ex vivo pharmacologic activation of sensitized T cells, which can then cure an established, weakly immunogenic and highly aggressive tumor that was resistant to vaccination alone.
Bryostatin 1/ionomycin (B/I) Ex Vivo Stimulation Preferentially Activates L-selectinlow Tumor-sensitized Lymphocytes
International Immunology. Sep, 2004 | Pubmed ID: 15262898
We have shown that tumor vaccine-sensitized draining lymph node (vDLN) cells activated ex vivo with bryostatin and ionomycin (B/I) were capable of inducing antigen-specific regression of a murine mammary tumor, 4T07. vDLN cells not activated with B/I were ineffective. We hypothesized that B/I selectively activates tumor-sensitized (CD62Llow) lymphocytes, to account for the highly potent and tumor-specific activity. We hypothesized that CD8+ CD62Llow cells may be preferentially activated by B/I treatment, infiltrate the tumors and mediate tumor regression in mice. 4T07-IL2 tumor cells were injected into one hind footpad of BALB/c mice. Ten days later, vDLN were harvested and separated based on CD62L expression. After separation, cells were activated with B/I, expanded with IL2 (40 IU/ml) for 10 days, and adoptively transferred to 4T07 tumor bearing mice. Naive mice were also treated with different subsets of T cells and later were challenged with 4T07 tumor cells. To test in vitro responses to antigen, expanded lymphocytes were cultured either alone or with irradiated 4T07 tumor cells. Supernatants were harvested after 24 h and tested by ELISA for IFN-gamma. The importance of the host immune response was tested by AIT into 4T07-bearing nude athymic mice. Host mice were depleted in vivo of CD4 or CD8 T cells after vDLN AIT to ascertain the mediators of tumor regression. In order to track B/I activated vDLN cells, they were prestained with CFSE prior to adoptive transfer into tumor-bearing hosts. At various time points, tumors, spleens and lymph nodes of host mice were harvested, dual stained for activation marker expression and analyzed by flow cytometry. CD62Llow cells expanded 12-fold more than CD62Lhigh lymphocytes during the 10 day culture period. Supernatant from CD62Llow cells + 4T07 cultures contained 33-fold more IFN-gamma than supernatant from CD62Lhigh cells + 4T07 cultures (843.9 pg/ml +/- 135.8 vs 25.89 pg/ml +/- 0.01). Adoptive transfer of CD62Llow lymphocytes induced complete tumor regressions in all mice, while tumors regressed in only 17% of mice treated with CD62Lhigh lymphocytes. Naive mice that received B/I-activated CD62Llow cells were protected from future tumor challenges, while mice given CD62Lhigh cells did not exhibit the same resistance to tumor growth. Tumors in nude host mice regressed after AIT treatment. In vivo depletion of CD4 T cells after AIT did not inhibit tumor regression, but CD8 T cell depletion abrogated tumor regression. vDLN cells tracked preferentially to tumor draining lymph nodes and proliferated in vivo, persisting for at least 21 days, and were 95% CD44+ and 39% CD69+. Bryostatin 1 and ionomycin, by increasing PKC activity and intracellular calcium, respectively, mimic intracellular signals that result in T cell activation. CD62Llow cells are preferentially activated by B/I, leading to a highly effective anti-tumor T cell population.
The New Phytologist. Jul, 2005 | Pubmed ID: 15948837
The consequences of increasing atmospheric carbon dioxide for long-term adaptation of forest ecosystems remain uncertain, with virtually no studies undertaken at the genetic level. A global analysis using cDNA microarrays was conducted following 6 yr exposure of Populus x euramericana (clone I-214) to elevated [CO(2)] in a FACE (free-air CO(2) enrichment) experiment. Gene expression was sensitive to elevated [CO(2)] but the response depended on the developmental age of the leaves, and < 50 transcripts differed significantly between different CO(2) environments. For young leaves most differentially expressed genes were upregulated in elevated [CO(2)], while in semimature leaves most were downregulated in elevated [CO(2)]. For transcripts related only to the small subunit of Rubisco, upregulation in LPI 3 and downregulation in LPI 6 leaves in elevated CO(2) was confirmed by anova. Similar patterns of gene expression for young leaves were also confirmed independently across year 3 and year 6 microarray data, and using real-time RT-PCR. This study provides the first clues to the long-term genetic expression changes that may occur during long-term plant response to elevated CO(2).
Journal of Gastrointestinal Surgery : Official Journal of the Society for Surgery of the Alimentary Tract. Apr, 2008 | Pubmed ID: 18270782
This study was undertaken to examine the effect of cirrhosis on elective and emergent umbilical herniorrhapy outcomes.
American Journal of Surgery. Aug, 2008 | Pubmed ID: 18513688
Incisional hernia repair (IHR) with mesh has been associated with decreased hernia recurrence. We analyzed variation in mesh use for IHR.
Archives of Surgery (Chicago, Ill. : 1960). Jun, 2008 | Pubmed ID: 18559752
Enterotomy or unplanned bowel resection (EBR) may occur during elective incisional hernia repair (IHR) and significantly affects surgical outcomes and hospital resource use.
Study Design and Methods of the BoTULS Trial: a Randomised Controlled Trial to Evaluate the Clinical Effect and Cost Effectiveness of Treating Upper Limb Spasticity Due to Stroke with Botulinum Toxin Type A
Trials. 2008 | Pubmed ID: 18947418
BACKGROUND: Following a stroke, 55-75% of patients experience upper limb problems in the longer term. Upper limb spasticity may cause pain, deformity and reduced function, affecting mood and independence. Botulinum toxin is used increasingly to treat focal spasticity, but its impact on upper limb function after stroke is unclear.The aim of this study is to evaluate the clinical and cost effectiveness of botulinum toxin type A plus an upper limb therapy programme in the treatment of post stroke upper limb spasticity. METHODS: Trial design: A multi-centre open label parallel group randomised controlled trial and economic evaluation. Participants: Adults with upper limb spasticity at the shoulder, elbow, wrist or hand and reduced upper limb function due to stroke more than 1 month previously. Interventions: Botulinum toxin type A plus upper limb therapy (intervention group) or upper limb therapy alone (control group).Outcomes: Outcome assessments are undertaken at 1, 3 and 12 months. The primary outcome is upper limb function one month after study entry measured by the Action Research Arm Test (ARAT). Secondary outcomes include: spasticity (Modified Ashworth Scale); grip strength; dexterity (Nine Hole Peg Test); disability (Barthel Activities of Daily Living Index); quality of life (Stroke Impact Scale, Euroqol EQ-5D) and attainment of patient-selected goals (Canadian Occupational Performance Measure). Health and social services resource use, adverse events, use of other antispasticity treatments and patient views on the treatment will be compared. Participants are clinically reassessed at 3, 6 and 9 months to determine the need for repeat botulinum toxin type A and/or therapy.Randomisation : A web based central independent randomisation service. Blinding: Outcome assessments are undertaken by an assessor who is blinded to the randomisation group. Sample size: 332 participants provide 80% power to detect a 15% difference in treatment successes between intervention and control groups. Treatment success is defined as improvement of 3 points for those with a baseline ARAT of 0-3 and 6 points for those with ARAT of 4-56. TRIAL REGISTRATION: ISRCTN78533119 Eudra CT 2004-002427-40 CTA 17136/0230/001 FUNDING: National Institute for Health Research, Health Technology Assessment Programme. Ipsen Ltd provide botulinum toxin type A (Dysport(R)).
Adoptive Transfer of HER2/neu-specific T Cells Expanded with Alternating Gamma Chain Cytokines Mediate Tumor Regression when Combined with the Depletion of Myeloid-derived Suppressor Cells
Cancer Immunology, Immunotherapy : CII. Jun, 2009 | Pubmed ID: 18979098
Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.
Incubation of Antigen-sensitized T Lymphocytes Activated with Bryostatin 1 + Ionomycin in IL-7 + IL-15 Increases Yield of Cells Capable of Inducing Regression of Melanoma Metastases Compared to Culture in IL-2
Cancer Immunology, Immunotherapy : CII. Oct, 2009 | Pubmed ID: 19198835
Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). We hypothesized that B/I-activated T cells cultured in IL-7 + IL-15 might proliferate and survive in culture better than cells cultured in IL-2, and that these cells would have equal or greater anti-tumor activity in vivo. Tumor antigen-sensitized DLN lymphocytes from either wild-type or T cell receptor transgenic mice were harvested, activated with B/I, and expanded in culture with either IL-2, IL-7 + IL-15 or a regimen of alternating cytokines. Cell yields, proliferation, apoptosis, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for anti-tumor activity against melanoma lung metastases established by prior i.v. injection of B16 melanoma cells. IL-7 + IL-15 or alternating cytokines resulted in much faster and prolonged proliferation and much less apoptosis of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately tenfold greater yields of viable cells. Culture in IL-7 + IL-15 yielded higher proportions of CD8+ T cells and a higher proportion of cells with a central memory phenotype. Despite this, T cells grown in IL-7 + IL-15 had higher IFN-gamma release responses to tumor antigen than cells grown in IL-2. Adoptive transfer of B/I-activated T cells grown in IL-7 + IL-15 or the alternating regimen had equal or greater efficacy on a "per-cell" basis against melanoma metastases. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in adoptive immunotherapy of cancer.
Gemcitabine Directly Inhibits Myeloid Derived Suppressor Cells in BALB/c Mice Bearing 4T1 Mammary Carcinoma and Augments Expansion of T Cells from Tumor-bearing Mice
International Immunopharmacology. Jul, 2009 | Pubmed ID: 19336265
Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.
Primary Sternal Plating to Prevent Sternal Wound Complications After Cardiac Surgery: Early Experience and Patterns of Failure
Interactive Cardiovascular and Thoracic Surgery. Nov, 2009 | Pubmed ID: 19710069
Sternal closure with rigid titanium plates (primary sternal plating) may reduce sternal wound complications in high-risk patients. We began performing primary sternal plating for the following indications: obesity, manual laborer, osteoporotic sternum, or intraoperative transverse sternal fracture. Patients receiving plate closure were compared to a risk-matched control group receiving wire closure. Outcomes of interest were postoperative length of stay and sternal wound complications [sterile dehiscence or deep sternal wound infection (DSWI)]. Wound complications were classified by time of occurrence as early (
Radiofrequency Thermal Ablation of Breast Tumors Combined with Intralesional Administration of IL-7 and IL-15 Augments Anti-tumor Immune Responses and Inhibits Tumor Development and Metastasis
Breast Cancer Research and Treatment. Apr, 2009 | Pubmed ID: 18425677
Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC.
Human T Cells Express CD25 and Foxp3 Upon Activation and Exhibit Effector/memory Phenotypes Without Any Regulatory/suppressor Function
Journal of Translational Medicine. 2009 | Pubmed ID: 19849846
Foxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation.
Elective Surgical Case Cancellation in the Veterans Health Administration System: Identifying Areas for Improvement
American Journal of Surgery. Nov, 2009 | Pubmed ID: 19887185
This study evaluated elective surgical case cancellation (CC) rates, reasons for these cancellations, and identified areas for improvement within the Veterans Health Administration (VA) system.
Influence of the Phosphodiesterase-5 Inhibitor, Sildenafil, on Sensitivity to Chemotherapy in Breast Tumor Cells
Breast Cancer Research and Treatment. Nov, 2010 | Pubmed ID: 20155316
Studies were performed to determine the influence of the phosphodiesterase-5 inhibitor, sildenafil, on sensitivity to adriamycin (doxorubicin) in four human breast tumor cell lines and one murine breast tumor line. Sildenafil did not interfere with the effectiveness of adriamycin in any of the cell lines tested. Sildenafil also failed to protect MDA-MB231 cells against the cytotoxicity of cisplatin, taxol or camptothecin. Sildenafil enhanced sensitivity to adriamycin markedly in the p53 mutant MDA-MB231 and p53 null MCF-7/E6 cells and moderately in the MCF-7/caspase 3 and 4T1 cell lines. In the MDA-MB231 cells, sildenafil increased the extent of DNA damage induced by adriamycin as well as the extent of apoptotic cell death. Sildenafil did not influence sensitivity to adriamycin in bone marrow cells or macrophages. In an immunocompetent model of breast cancer (4T1 mammary carcinoma in Balb/c mice), sildenafil did not attenuate the antitumor effects of adriamycin; furthermore, the combination of sildenafil with adriamycin was no more toxic to the animals than adriamycin alone. Given that sildenafil has been shown to have the potential to protect the heart against the toxicity of adriamycin, these studies suggest that the inclusion of sildenafil with conventional chemotherapeutic protocols involving adriamycin (and possibly cisplatin, camptothecin and/or paclitaxel) should not compromise the antitumor effectiveness of these drugs nor enhance their toxicity to the patient.
Journal of the American College of Surgeons. May, 2010 | Pubmed ID: 20421023
Incisional hernia repair (IHR) is plagued by high recurrence rates and lack of long-term outcomes data to guide repair technique. Mesh repair reduces recurrence rates but lacks standardization of technique. We investigated long-term outcomes of elective IHR, focusing on technical predictors of recurrence.
Phenotype, Functions and Fate of Adoptively Transferred Tumor Draining Lymphocytes Activated Ex Vivo in Mice with an Aggressive Weakly Immunogenic Mammary Carcinoma
BMC Immunology. 2010 | Pubmed ID: 21050466
Regression of established tumors can be induced by adoptive immunotherapy with tumor draining lymph node lymphocytes activated with bryostatin and ionomycin. We hypothesized that tumor regression is mediated by a subset of the transferred T lymphocytes, which selectively infiltrate the tumor draining lymph nodes and proliferate in vivo.
HIV and Hepatitis B and C Incidence Rates in US Correctional Populations and High Risk Groups: a Systematic Review and Meta-analysis
BMC Public Health. 2010 | Pubmed ID: 21176146
High Human Immunodeficiency Virus (HIV) prevalence and high risk behaviors have been well documented within United States (US) correctional systems. However, uncertainty remains regarding the extent to which placing people in prison or jail increases their risk of HIV infection, and regarding which inmate populations experience an increased incidence of HIV. Describing these dynamics more clearly is essential to understanding how inmates and former detainees may be a source for further spread of HIV to the general US population.
IL-7 + IL-15 Are Superior to IL-2 for the Ex Vivo Expansion of 4T1 Mammary Carcinoma-specific T Cells with Greater Efficacy Against Tumors in Vivo
Breast Cancer Research and Treatment. Jul, 2010 | Pubmed ID: 19826947
Regression of established tumors can be induced by adoptive immunotherapy (AIT) with tumor draining lymph node (DLN) lymphocytes activated with bryostatin and ionomycin (B/I). Tumor antigen-sensitized DLN lymphocytes from BALB/c mice with 10-day 4T1 mammary carcinomas were harvested, activated with B/I, and expanded in culture with either interleukin-2 (IL-2) or IL-7 + IL-15. Cell yields, proliferation, phenotypes, and in vitro responses to tumor antigen were compared for cells grown in different cytokines. These T cells were also tested for antitumor activity against established 4T1 mammary carcinomas after inoculation of tumor cells subcutaneously (s.c.). IL-7/15 resulted in much faster and more prolonged proliferation of B/I-activated T cells than culturing the same cells in IL-2. This resulted in approximately 5-10-fold greater yields of viable cells. Culture in IL-7/15 yielded higher proportions of CD8(+) T cells and a higher proportion of cells with a central memory phenotype. T cells grown in IL-2 had higher interferon-gamma (IFN-gamma) release responses to tumor antigen than cells grown in IL-7/15. Adoptive transfer of B/I-activated T cells grown in IL-7/15 demonstrated much greater efficacy against 4T1 tumors in vivo. Activation of tumor antigen-sensitized T cells with B/I and culture in IL-7 + IL-15 is a promising modification of standard regimens for production of T cells for use in AIT of cancer.
Surgery. Feb, 2011 | Pubmed ID: 21238712
Mesh placement during ventral incisional hernia repair has been shown to result in superior outcomes; however, significant variation persists in the adoption of this technique. We performed a multi-institutional study to understand how variation in surgical technique influences outcomes.
Botulinum Toxin for the Upper Limb After Stroke (BoTULS) Trial: Effect on Impairment, Activity Limitation, and Pain
Stroke; a Journal of Cerebral Circulation. May, 2011 | Pubmed ID: 21415398
Botulinum toxin is increasingly used to treat upper limb spasticity due to stroke, but its impact on arm function is unclear. We evaluated botulinum toxin for upper limb spasticity and function poststroke.
Journal of Translational Medicine. 2011 | Pubmed ID: 21453513
Emerging data from pre-clinical and clinical studies suggest that HER-2/neu-specific T cell responses could induce HER-2/neu antigen loss in the tumor cells. These data suggest that patients with HER-2/neu negative breast cancer might have had HER-2/neu positive premalignant lesions in the past that progressed to HER-2/neu negative breast cancer under HER-2/neu-specific immune pressure.
Journal of the American College of Surgeons. Apr, 2011 | Pubmed ID: 21463777
The frequency of subsequent abdominal operations (SAO) and complications attributable to earlier ventral incisional hernia repair (VIHR) are unknown. We examined the effect of repair type and technique on the difficulty and complications of subsequent surgery.
British Journal of Neurosurgery. Jun, 2011 | Pubmed ID: 21501062
Cranioplasty (CP) following decompressive craniectomy (DC) is traditionally viewed as a cosmetic procedure having no effect on neurological function in most cases after severe brain injury. However, anecdotal cases of improvement in conscious level after CP have been observed in clinical practice.
Molecular Cancer Research : MCR. Aug, 2011 | Pubmed ID: 21693597
Methyl cytosine binding domain protein 2 (MBD2) has been shown to bind to and mediate repression of methylated tumor suppressor genes in cancer cells, where repatterning of CpG methylation and associated gene silencing is common. We have investigated the role of MBD2 in breast cancer cell growth and tumor suppressor gene expression. We show that stable short hairpin RNA (shRNA)-mediated knockdown of MBD2 leads to growth suppression of cultured human mammary epithelial cancer lines, SK-BR-3, MDA-MB-231, and MDA-MB-435. The peak antiproliferative occurs only after sustained, stable MBD2 knockdown. Once established, the growth inhibition persists over time and leads to a markedly decreased propensity for aggressive breast cancer cell lines to form in vivo xenograft tumors in Bagg Albino (BALB)/C nu/nu mice. The growth effects of MBD2 knockdown are accompanied by derepression of tumor suppressor genes, including DAPK1 and KLK10. Chromatin immunoprecipitation assays and bisulfite sequencing show MBD2 binding directly to the hyper methylated and CpG-rich promoters of both DAPK1 and KLK10. Remarkably, the promoter CpG island-associated methylation of these genes remained stable despite robust transcriptional activation in MBD2 knockdown cells. Expression of a shRNA-resistant MBD2 protein resulted in restoration of growth and resilencing of the MBD2-dependent tumor suppressor genes. Our data suggest that uncoupling CpG methylation from repressive chromatin remodeling and histone modifications by removing MBD2 is sufficient to initiate and maintain tumor suppressor gene transcription and suppress neoplastic cell growth. These results show a role for MBD2 in cancer progression and provide support for the prospect of targeting MBD2 therapeutically in aggressive breast cancers.
American Journal of Surgery. Jul, 2011 | Pubmed ID: 21741517
Prosthetic mesh used for incisional hernia repair (IHR) reduces hernia recurrence. Mesh infection results in significant morbidity and challenges for subsequent abdominal wall reconstruction. The risk factors that lead to mesh explantation are not well known.
Agreement Between Patient Survey and Medical Chart: Pitfalls in Measurement Strategies for Hernia Recurrence
Surgery. Sep, 2011 | Pubmed ID: 21783217
Little information is available on agreement between patient-reported outcomes and data collected from medical chart abstraction (MCA) for recurring events. Recurring conditions pose a risk of misclassification, especially when events occur relatively close together in time. We examined agreement, predictors of agreement, and relative accuracy of patient survey and MCA for assessment of outcomes of incisional hernia repair (IHR).
Annals of Surgery. Sep, 2011 | Pubmed ID: 21817889
The objective of this study was to evaluate whether the Surgical Care Improvement Project (SCIP) improved surgical site infection (SSI) rates using national data at the patient level for both SCIP adherence and SSI occurrence.
Journal of Interferon & Cytokine Research : the Official Journal of the International Society for Interferon and Cytokine Research. Sep, 2011 | Pubmed ID: 21864028
The antigrowth and immunomodulatory actions of interferons (IFNs) have enabled these cytokines to be used therapeutically for the treatment of a variety of hematologic and solid malignancies. IFNs exert their effects by activation of the Jak/Stat signaling pathway. IFNγ stimulates the tyrosine kinases Jak1 and Jak2, resulting in activation of the Stat1 transcription factor, whereas type 1 IFNs (IFNα/β) activate Jak1 and Tyk2, which mediate their effects through Stat1 and Stat2. Disruption in the expression of IFNγ, IFNα receptors, or Stat1 inhibits antitumor responses and blunt cancer immunosurveillance in mice. Mutations in Jak2 or constitutive activation of Jak1 or Jak2 also promote the development of a variety of malignancies. Although there are data indicating that Tyk2 plays a role in the pathogenesis of lymphomas, the effects of Tyk2 expression on tumorigenesis are unknown. We report here that Tyk2(-/-) mice inoculated with 4T1 breast cancer cells show enhanced tumor growth and metastasis compared to Tyk2(+/+) animals. Accelerated growth of 4T1 cells in Tyk2(-/-) animals does not appear to be due to decreased function of CD4(+), CD8(+) T cells, or NK cells. Rather, the tumor suppresive effects of Tyk2 are mediated at least in part by myeloid-derived suppressor cells, which appear to be more effective in inhibiting T cell responses in Tyk2(-/-) mice. Our results provide the first evidence for a role of Tyk2 in suppressing the growth and metastasis of breast cancer.
Annals of Surgery. Dec, 2011 | Pubmed ID: 21869677
This study aimed to assess the attributable risk and potential benefit of smoking cessation on surgical outcomes.
The American Surgeon. Aug, 2011 | Pubmed ID: 21944508
This study examines the effect of emergent repair on incisional hernia repair outcomes at 16 Veteran's Affairs Medical Centers between 1998 and 2002. Of the 1452 cases reviewed, 63 (4.3%) were repaired emergently. Patients undergoing emergent repair were older (P = 0.02), more likely to be black (P = 0.02), and have congestive heart failure (P = 0.001) or chronic obstructive pulmonary disease (P = 0.001). Of emergent repairs, 76.2 per cent involved intestinal incarceration versus 7.2 per cent of elective repairs (P < 0.0001), and 17.5 per cent had concomitant bowel resection compared with 3.9 per cent of elective cases (P < 0.0001). Patients undergoing emergent repair were also more likely to receive primary suture repair (49.2 vs 31.1%, P = 0.003), develop a postoperative complication (26.0 vs 11.3%, P = 0.002), and have increased postoperative length of stay (7 vs 4 days, P < 0.0001). There were nine (14.3%) deaths at 30 days for the emergent group compared with 10 (0.7%) in the elective group (P < 0.001). However, there was no significant difference between emergent and elective repairs in long-term complications. Emergent hernia repair is associated with increased mortality rates, early complications, and longer length of stay; however, long-term outcomes are equivalent to elective cases. These data suggest that technical outcomes for emergent repairs approach those of elective operations.
Journal of Surgical Education. Nov, 2011 | Pubmed ID: 22000530
Few tasks are more ingrained within the minds of practicing surgeons than the dictation of the narrative report of an operation. However, the construct of these reports varies widely among surgeons and is rarely formally taught and not tested formally during surgical training or board certification.