Purpose: OptiSafe is an test method that identifies potential eye irritants based on macromolecular damage following test chemical exposure. The OptiSafe protocol includes a prescreen assessment that identifies test chemicals that are outside the applicability domain of the test method and thus determines the optimal procedure. We assessed the usefulness and limitations of the OptiSafe test method for identifying chemicals not requiring classification for ocular irritation (i.
View Article and Find Full Text PDFBackground: Gene-modified autologous T cells expressing NY-ESO-1, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells.
View Article and Find Full Text PDFThis study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor (TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 10 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells.
View Article and Find Full Text PDFPurpose: Eye and skin irritation test data are required or considered by chemical regulation authorities in the United States to develop product hazard labelling and/or to assess risks for exposure to skin- and eye-irritating chemicals. The combination of animal welfare concerns and interest in implementing methods with greater human relevance has led to the development of non-animal skin- and eye-irritation test methods. To identify opportunities for regulatory uses of non-animal replacements for skin and eye irritation tests, the needs and uses for these types of test data at U.
View Article and Find Full Text PDFWe evaluated the safety and activity of autologous T cells expressing NY-ESO-1, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1T cells were present postinfusion in all patients and persisted for at least 6 months in all responders.
View Article and Find Full Text PDFImmune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) have been highly successful in the treatment of cancer. While PD-1 expression has been widely investigated, its role in CD4+ effector T cells in the setting of health and cancer remains unclear, particularly in the setting of glioblastoma multiforme (GBM), the most aggressive and common form of brain cancer. We examined the functional and molecular features of PD-1+CD4+CD25-CD127+Foxp3-effector cells in healthy subjects and in patients with GBM.
View Article and Find Full Text PDFImmunotherapies targeting the immune checkpoint receptor programmed cell death protein 1 (PD-1) have shown remarkable efficacy in treating cancer. CD4CD25FoxP3 Tregs are critical regulators of immune responses in autoimmunity and malignancies, but the functional status of human Tregs expressing PD-1 remains unclear. We examined functional and molecular features of PD-1 Tregs in healthy subjects and patients with glioblastoma multiforme (GBM), combining functional assays, RNA sequencing, and cytometry by time of flight (CyTOF).
View Article and Find Full Text PDFE-learning has been widely used in the infection control field and has been recommended for use in hand hygiene (HH) programs by the World Health Organization. Such strategies are effective and efficient for infection control, but factors such as learner readiness for this method should be determined to assure feasibility and suitability in low- to middle-income countries. We developed a tailored, e-learning, Spanish-language HH course based on the WHO guidelines for HH in healthcare settings for the pediatric cancer center in Guatemala City.
View Article and Find Full Text PDFFOXP3+ Tregs are central for the maintenance of self-tolerance and can be defective in autoimmunity. In multiple sclerosis and type-1 diabetes, dysfunctional self-tolerance is partially mediated by a population of IFNγ-secreting Tregs. It was previously reported that increased NaCl concentrations promote the induction of proinflammatory Th17 cells and that high-salt diets exacerbate experimental models of autoimmunity.
View Article and Find Full Text PDFBackground: Meningiomas often harbor an immune cell infiltrate that can include substantial numbers of T and B cells. However, their phenotype and characteristics remain undefined. To gain a deeper understanding of the T and B cell repertoire in this tumor, we characterized the immune infiltrate of 28 resected meningiomas representing all grades.
View Article and Find Full Text PDFRegulatory T cells (Tregs) are critical to the human immune system, providing appropriately scaled immune responses and mediating peripheral tolerance. A central role for forkhead box protein 3 (FoxP3)(+) Tregs has been shown in the pathogenesis of mechanistically diverse central nervous system (CNS) diseases from autoimmune diseases such as multiple sclerosis to glioblastomas. Understanding how tumors induce Treg function to escape immune surveillance in marked contrast to autoimmune diseases, where there is loss of Treg function, will provide valuable lessons regarding Treg biology and potential therapeutic targets for CNS diseases.
View Article and Find Full Text PDFStreptococcus pyogenes is the causative agent of numerous diseases ranging from benign infections (pharyngitis and impetigo) to severe infections associated with high mortality (necrotizing fasciitis and bacterial sepsis). As with other bacterial infections, there is considerable interest in characterizing the contribution of interleukin-17A (IL-17A) responses to protective immunity. We here show significant il17a up-regulation by quantitative real-time PCR in secondary lymphoid organs, correlating with increased protein levels in the serum within a short time of S.
View Article and Find Full Text PDFThe cellular prion protein (PrP(C)) is widely expressed in neural and non-neural tissues, but its function is unknown. Elucidation of the part played by PrP(C) in adaptive immunity has been a particular conundrum: increased expression of cell surface PrP(C) has been documented during T-cell activation, yet the functional significance of this activation remains unclear, with conflicting data on the effects of Prnp gene knockout on various parameters of T-cell immunity. We show here that Prnp mRNA is highly inducible within 8-24 h of T-cell activation, with surface protein levels rising from 24 h.
View Article and Find Full Text PDFHepatitis C virus (HCV) particles found in vivo are heterogeneous in density and size, but their detailed characterization has been restricted by the low titre of HCV in human serum. Previously, our group has found that HCV circulates in blood in association with very-low-density lipoprotein (VLDL). Our aim in this study was to characterize HCV RNA-containing membranes and particles in human liver by both density and size and to identify the subcellular compartment(s) where the association with VLDL occurs.
View Article and Find Full Text PDFPhilos Trans A Math Phys Eng Sci
May 2008
Faraday's work inspired the development of electrical motors and generators. Until Maxwell pointed out the significance of Ampere's Law, there was no rigorous design method for magnetic devices. His interpretation strongly influenced the creation, by others, of the 'magnetic circuit' approach, which became the seminal design technique.
View Article and Find Full Text PDFInt J Radiat Oncol Biol Phys
November 2003
To evaluate the use of the ultrasound-based BAT system for daily prostate alignment. Prostate alignments using the BAT system were compared with alignments using radiographic images of implanted radiopaque markers. The latter alignments were used as a reference.
View Article and Find Full Text PDFWe have previously compared both generalized eigensystem (GES) and Tikhonov regularization methods for estimating epicardial potentials from measured body surface potentials. Both of these methods require the choice of a regularization parameter. In this study we compare two methods for choosing this parameter: the Composite Residual Error and Smoothing Operator (CRESO) method, and a new Zero Crossing (ZC) method.
View Article and Find Full Text PDFIn order to assess the utility of margin width in relation to other histopathologic features as a determinant of local control in ductal carcinoma in situ (DCIS) of the breast, we retrospectively examined the treatment of 109 breasts treated with (n = 54) or without adjuvant radiotherapy (n = 55). Median follow-up was 49 and 54 months for patients treated with excision alone (E) or excision plus adjuvant radiotherapy (E+XRT), respectively. Cases treated with E+XRT were significantly larger and had a trend towards closer surgical margins than those treated with E alone.
View Article and Find Full Text PDFInt J Radiat Oncol Biol Phys
May 2001
Purpose: To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma.
Methods And Materials: From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (< or = 3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram.
Although a curable malignancy, testis cancer and its treatment have unique associated morbidities that largely affect reproductive dysfunction. In this focused review, the factors that contribute to infertility in men with testis cancer are outlined. The treatment-specific risks to fertility that accompany cancer management are also discussed.
View Article and Find Full Text PDFRabbit peritoneal polymorphonuclear neutrophils (PMN), incubated in medium containing [35S]sulphate, incorporated 35S into proteoglycan and protein fractions. Approximately 46% of the 35S-labelled macromolecules associated with the PMN cells after 1 h of incubation were recovered in a cytoplasmic granule extract, the majority being present in azurophil granules. Analysis of the azurophil granule fraction showed that approximately 90% of the 35S-labelled macromolecules were proteoglycans.
View Article and Find Full Text PDFThe Draize rabbit eye test was developed to provide a method for assessing the irritation potential of materials that might come in contact with human eyes. The method involves the instillation of 0.1 ml of a test liquid (100 mg solid) into the conjunctival sac of an animal's eye.
View Article and Find Full Text PDFScreens aid in identifying some severe irritants or corrosives and eliminating them from consideration for in vivo eye irritation testing. Products may be evaluated for ocular irritation potential in a stepwise progression as follows: (1) products at pH extremes of 2 or below or of 11.5 or above may be considered to be ocular irritants; (2) based on chemical structure-activity considerations, some products may be judged to have ocular irritation potential; (3) validated and accepted in vitro systems may possibly be used as a screen in the future; (4) when a test material demonstrates severe acute dermal toxicity (lethality at < or = 200 mg/kg body weight), further testing for either dermal or ocular irritation may not need to be undertaken; (5) if a substance shows a primary dermal irritation index of 5 or above, it may be considered to be an ocular irritant; (6) materials that are not removed from consideration based on these proposed screens may then be considered for testing for ocular irritation in rabbits under accepted procedures.
View Article and Find Full Text PDFA proposal encompassing considerations and criteria for the development of in vitro alternatives to the eye irritation test has been developed and is presented here. Two factors need to be considered initially in developing an alternative test. The first is to determine whether the alternative assay is to be used as a screen or as a replacement for the eye irritation test.
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