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PURPOSE: Language sampling is a critical component of language assessments. However, there are many ways to elicit language samples that likely impact the results. The purpose of this study was to examine how different discourse types and elicitation tasks affect various language sampling outcomes. METHOD: A diverse group of K-3 students (N = 1,037) contributed eight spoken language samples in four elicitation conditions: (a) expository generation, (b) expository retell, (c) narrative generation, and (d) narrative retell. Samples were audio-recorded, transcribed, and coded for number of total words, number of different words, mean length of utterance in words (MLUW), and number of clauses per communication unit (i.e., Subordination Index [SI]). RESULTS: Narrative retell and expository generation conditions yielded the largest samples with the greatest lexical diversity when compared to narrative generation and expository retell. MLUW was higher in expository conditions, but mean SI was higher in narrative conditions. For both measures of syntax, narrative retell and expository generation yielded the highest mean scores. For each outcome, there were expected increases corresponding to grades; however, the differences faded between second and third grade. CONCLUSION: As a component of language assessments, clinicians' selection of language sampling procedures will impact the sample length, lexical diversity, utterance length, and syntactical complexity of the samples. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.24185649.
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Lenguaje , Estudiantes , Humanos , Narración , Pruebas del LenguajeRESUMEN
BACKGROUND: Male breast cancer (MBC) management is extrapolated from female BC. Mastectomy remains the most frequently used surgical procedure for male breast cancer (MBC). We performed a literature review to assess the use of breast-conservation (BCS) in MBC as well as outcomes following BCS. METHODS: A systematic literature was performed, and articles screened to identify studies that measured overall survival (OS), disease-free survival (DFS), or local recurrence (LR) in patients undergoing BCS. Weighted averages based on study size were performed for LR, DFS, and 5-year OS. RESULTS: Eight studies met the inclusion criteria with male breast surgery cases, and 859 (14.7%) underwent BCS. The mean follow-up time was 53 months, and mean age was 62.6 years, with stage II as the most common presentation. Two studies reported that 50-71.4% of patients underwent sentinel lymph node biopsy, and four studies reported axillary lymph node dissection in 14.3-100%. Five studies reported on adjuvant radiation therapy in 12.0-100% of total patients undergoing BCS. Four studies reported use of hormonal therapy in 73.8-100% of patients. Four studies reported use of chemotherapy in 25-66.7% of patients. Seven studies reported LR among 116 patients, with a weighted average of 9.9%. Three studies reported on DFS in 14 patients, with a weighted average 85.6%. Two studies report OS in 143 patients with a weighted average of 84.4%. CONCLUSIONS: Breast conservation may be considered a safe alternative in the surgical treatment of MBC. Future research should focus on better standardization of local therapy for MBC and improved reporting of outcomes.
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Neoplasias de la Mama Masculina/cirugía , Mastectomía Segmentaria/métodos , Humanos , Masculino , PronósticoRESUMEN
Ballast water management systems (BWMS) must be tested to assess their compliance with standards for the discharge of organisms, for example in the ≥ 10- and < 50-µm size category, which is dominated by phytoplankton. Assessment of BWMS performance with the vital stains fluorescein diacetate + 5-chlorofluorescein diacetate, required by regulations in the USA, is problematic in the case of ultraviolet-C (UVC) radiation. This is because UVC targets nucleotides-and thus reproduction, hence viability-rather than membrane integrity, which is assayed by the stains. The Serial Dilution Culture-Most Probable Number (SDC-MPN) method, long used to enumerate fragile phytoplankton from natural communities, is appropriate for counting viable phytoplankton. We developed QA/QC "best practice" criteria for its application as a robust and repeatable assay of viable cells in cultures of phytoplankton before and after experimental treatment, then constructed dose-response curves for UVC-induced loss of viable cells in 12 species of phytoplankton from seven divisions. Sensitivity to UVC, expressed as the dose required to reduce viability by 99%-the criterion for type approval of treatment systems-varied more than 10-fold and was not correlated with cell size. The form of the dose-response curves varied between taxa, with most having a threshold dose below which there was no reduction in viability. Analysis of the patterns of growth indicates that if recovery from treatment occurred, it was complete in 1 or 2 days in > 80% of cases, long before the assays were terminated. We conclude that the SDC-MPN assay as described is robust and adaptable for use on natural phytoplankton.
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Since starch is a significant part of human diet, its oral detection would be highly beneficial. This study was designed to determine whether starch or its degradation products can be tasted and what factors influence its perception. Subjects were asked 1) to taste 8% raw and cooked starch samples for 5, 15, and 35 s and rate perceived intensities of sweetness and "other" taste (i.e., other than sweet), 2) to donate saliva to obtain salivary flow rate (mg/s) and salivary α-amylase activity (per mg saliva), and 3) to fill out a carbohydrate consumption survey. Subsequently, in vitro hydrolysis of starch was performed; saliva was collected from 5 subjects with low and high amylase activities and reacted with 8% raw and cooked starch at 2, 15, and 30 s. Hydrolysis products were then quantified using a High performance liquid chromatography. The results showed cooking increased the digestibility of starch such that the amount of hydrolysis products increased with reaction time. However, cooking did not influence taste ratings, nor were they influenced by tasting time. Subjects' salivary amylase activities were associated with the efficacy of their saliva to degrade starch, in particular cooked starch, and thus the amount of maltooligosaccharide products generated. Effective α-amylase activity [i.e. α-amylase activity (per mg saliva) × salivary flow rate (mg/s)] and carbohydrate consumption score (i.e. consumption frequency × number of servings) were also independently associated with sensory taste ratings. Human perception of starch is undoubtedly complex as shown in this study; the data herein point to the potential roles of salivary α-amylase activity and carbohydrate consumption in the perception of cooked starch.
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Culinaria , Digestión/fisiología , alfa-Amilasas Salivales/metabolismo , Almidón/metabolismo , Percepción del Gusto/fisiología , Gusto/fisiología , Adolescente , Adulto , Femenino , Humanos , Masculino , Factores de Tiempo , Adulto JovenRESUMEN
Evaluating the behavioral effects of enrichment on animals housed in biomedical facilities is necessary to effectively support their care and wellbeing. We tested the cumulative effects of an enhanced enrichment program on sooty mangabey behavior: locomotion, feeding and foraging, manipulating items in the enclosure, social affiliation, aggression, and abnormal behavior. The enhanced enrichment program included the addition of a substrate (timothy hay), widely distributing small pieces of produce and a forage mixture in the hay, adding structures and perching, and increasing the variety of food items, foraging devices, and other manipulable items. We tested 10 groups living in runs (n = 54) by using an ABA experimental design (phase A, standard enrichment; phase B, enhanced enrichment) and Wilcoxon signed-rank tests to compare behavior across phases. During phase B, subjects significantly increased feeding, foraging, and manipulation of items, and they decreased self-grooming, social affiliation, and aggression. Combined enrichment use increased from approximately 10% to 21% of the mangabeys' time. Enhanced enrichment did not affect locomotion or abnormal behavior. The increases in feeding, foraging, and manipulation during enhanced enrichment were driven primarily by the subjects' preference for foraging in the hay: it was the most effective component of the program in promoting feeding and foraging behavior, which comprises the majority of wild sooty mangabeys' daily activity. Developing an effective, species-appropriate, and comprehensive enrichment program is essential to successfully promote the health and wellbeing of captive NHP.
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Crianza de Animales Domésticos , Animales de Laboratorio , Cercocebus atys , Agresión , Animales , Conducta Animal , Ambiente Controlado , Femenino , Vivienda para Animales , MasculinoRESUMEN
It is widely accepted that humans can taste mono- and disaccharides as sweet substances, but they cannot taste longer chain oligo- and polysaccharides. From the evolutionary standpoint, the ability to taste starch or its oligomeric hydrolysis products would be highly adaptive, given their nutritional value. Here, we report that humans can taste glucose oligomer preparations (average degree of polymerization 7 and 14) without any other sensorial cues. The same human subjects could not taste the corresponding glucose polymer preparation (average degree of polymerization 44). When the sweet taste receptor was blocked by lactisole, a known sweet inhibitor, subjects could not detect sweet substances (glucose, maltose, and sucralose), but they could still detect the glucose oligomers. This suggests that glucose oligomer detection is independent of the hT1R2/hT1R3 sweet taste receptor. Human subjects described the taste of glucose oligomers as "starchy," while they describe sugars as "sweet." The dose-response function of glucose oligomer was also found to be indistinguishable from that of glucose on a molar basis.
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Considerable research is focused on understanding the functionality of starch hydrolysis products (SHP) consisting of glucose, maltose, maltooligosaccharides (MOS), and maltopolysaccharides (MPS). A confounding factor in this research is the high molecular dispersity of commercially available SHP. The study presented herein characterizes a flexible fractionation approach for lowering the dispersity of such products. This was accomplished by fractionating a corn syrup solids (CSS) preparation based on the differential solubility of its component saccharides in aqueous-ethanol solutions. Products obtained from selected fractionations were characterized with respect to degree of polymerization (DP; liquid chromatography), dextrose equivalency (reducing sugar assays), and prevalence of branching (NMR). Glucose and maltose were preferentially removed from CSS using high (⩾90%) ethanol extractants. Preparations with relatively narrow ranges of MOS, lower DP MPS, and higher DP MPS were obtained through repetitive 70%-ethanol extractions. Linear, as opposed to branched, MOS and MPS were preferentially extracted under all conditions tested.
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Etanol/química , Glucosa/análisis , Maltosa/análisis , Oligosacáridos/análisis , Almidón/química , Fraccionamiento Químico , Hidrólisis , Solubilidad , SolucionesRESUMEN
The sense of taste is essential for identifying potential nutrients and poisons. Accordingly, specialized taste receptor cells are activated by food-derived chemicals. Because of its importance in the human diet, oral detection of starch, or its degradation products, would presumably be highly beneficial. Yet, it has long been assumed that simple sugars are the only class of carbohydrates that humans can taste. There is, however, considerable evidence that rodents can taste starch degradation products (i.e., glucose polymers composed of maltooligosaccharides with 3-10 glucose units and maltopolysaccharides with >10 glucose units) and that their detection is independent of the sweet taste receptor, T1R2/T1R3. The present study was designed 1) to measure individual differences in human taste perception of glucose polymers, 2) to understand individual differences in the activity of salivary α-amylase, and 3) to investigate the role that salivary α-amylase may play in the taste perception of glucose polymers. In the first experiment, subjects rated taste intensity of glucose, sucrose, NaCl, and glucose polymers of various chain lengths, while their noses were clamped. Saliva samples from the subjects were also collected and their salivary α-amylase activity was assayed. Results showed that the perceived intensities of glucose, sucrose, and NaCl were significantly correlated (r = 0.75-0.85, P < 0.001), but not with the longer chain glucose polymers, whereas intensity ratings of all glucose polymers were highly correlated with one another (r = 0.69-0.82, P < 0.001). Importantly, despite large individual differences in α-amylase activity among subjects, responsiveness to glucose polymers did not significantly differ between individuals with high and low α-amylase activity. A follow up experiment was conducted to quantify the concentrations of glucose and maltose that were inherently present in the glucose polymer stimuli and to determine whether the amounts were within a perceptually detectable range. Results revealed that the amounts of simple sugars present in the test stimuli were trivial and were mostly at an undetectable level. These data together provide strong evidence that humans can taste glucose polymers and that the responsiveness to glucose polymers is independent of that to simple sugars.
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Glucanos/metabolismo , Percepción del Gusto , Adolescente , Adulto , Femenino , Humanos , Masculino , Saliva/enzimología , Saliva/metabolismo , Gusto , Adulto Joven , alfa-Amilasas/metabolismoRESUMEN
Radiotherapy is a successful treatment modality for localized cancer. Our group has been exploring radiotherapy in combination with immunotherapy (radioimmunotherapy) to enhance systemic antitumor responses. Previously, we have shown that when local radiotherapy was combined with monoclonal antibodies (mAbs) (that enable T-cell responses by engaging costimulation [anti (α)-CD137] and blocking coinhibition [α-PD-1] [corrected], up to 100% of mice bearing established syngeneic AT-3 mammary tumors were cured, but single modality treatments were not curative. Here, we investigated the molecular mechanisms underlying responses to this radioimmunotherapy approach. We observed that inhibition of signaling through the mammalian target of rapamycin (mTOR) pathway during the first 10 days of treatment severely impaired the curative effect of radioimmunotherapy, at least in part by reducing MHC class I expression on tumor cells, reducing dendritic cell (DC) activation status and CD8+ T-cell function. This data indicates that the efficacy of this type of radioimmunotherapy approach involves mTOR signaling and therefore, mTOR inhibitory drugs may impede the efficacy of similar radioimmunotherapy approaches in humans.
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Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/radioterapia , Radioinmunoterapia/métodos , Transducción de Señal/inmunología , Transducción de Señal/efectos de la radiación , Serina-Treonina Quinasas TOR/metabolismo , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de la radiación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Neoplasias Mamarias Experimentales/inmunología , Ratones , Ratones Endogámicos C57BL , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
The tumor microenvironment can promote tumor growth and reduce treatment efficacy. Tumors can occur in many sites in the body, but how surrounding normal tissues at different anatomical sites affect tumor microenvironments and their subsequent response to therapy is not known.We demonstrated that tumors from renal, colon, or prostate cell lines in orthotopic locations responded to immunotherapy consisting of three agonist antibodies, termed Tri-mAb, to a much lesser extent than the same tumor type located subcutaneously. A tissue-specific response to Tri-mAb was confirmed by ex vivo separation of subcutaneous (SC) or orthotopic tumor cells from stromal cells, followed by reinjection of tumor cells into the opposite site. Compared with SC tumors, orthotopic tumors had a microenvironment associated with a type 2 immune response, related to immunosuppression, and an involvement of alternatively activated macrophages in the kidney model. Orthotopic kidney tumors were more highly vascularized than SC tumors. Neutralizing the macrophage- and Th2-associated molecules chemokine (C-C motif) ligand 2 or interleukin-13 led to a significantly improved therapeutic effect. This study highlights the importance of the tissue of implantation in sculpting the tumor microenvironment. These are important fundamental issues in tumor biology and crucial factors to consider in the design of experimental models and treatment strategies.
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Inmunoterapia , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Antígenos CD40/antagonistas & inhibidores , Antígenos CD40/inmunología , Línea Celular Tumoral , Quimiocina CCL2/inmunología , Neoplasias del Colon/inmunología , Modelos Animales de Enfermedad , Expresión Génica , Interleucina-13/inmunología , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones , Neoplasias/mortalidad , Neoplasias/terapia , Neovascularización Patológica/inmunología , Especificidad de Órganos/inmunología , Próstata/inmunología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/antagonistas & inhibidores , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/inmunología , Resultado del Tratamiento , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/antagonistas & inhibidores , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunologíaRESUMEN
The chemokine CCL2, which is best known for its chemotactic functions, is expressed not only by immune cells, but also by several types of malignant and stromal cells. CCL2 has been shown to exert both pro- and anti-tumor effects. However, recent results demonstrate a main role for CCL2 in tumor progression and metastasis, suggesting that this chemokine may constitute a therapeutic target for anticancer drugs. Mammary carcinoma models, including models of implantable, transgenic, and chemically-induced tumors, were employed in the setting of Ccl2 or Ccr2 knockout mice or CCL2 neutralization with a monoclonal antibody to further investigate the role of the CCL2/CCR2 signaling axis in tumor progression and metastatic spread. In our implantable tumor models, an anti-CCL2 monoclonal antibody inhibited the growth of primary malignant lesions in a biphasic manner and reduced the number of metastases. However, in Ccl2-/- or Ccr2-/- mice developing implanted or transgenic tumors, the number of pulmonary metastases was increased despite a reduction in the growth rate of primary neoplasms. Transgenic Mtag.Ccl2-/- or Mtag.Ccr2-/- mice also exhibited a significantly earlier of disease onset. In a chemical carcinogenesis model, anti-CCL2 monoclonal antibody inhibited the growth of established lesions but was ineffective in the tumor induction phase. In contrast to previous studies indicating a role for CCL2 in the establishment of metastases, we have demonstrated that the absence of CCL2/CCR2-signaling results in increased metastatic disease. Thus, the CCL2/CCR2 signaling axis appears to play a dual role in mediating early tumor immunosurveillance and sustaining the growth and progression of established neoplasms. Our findings support the use of anti-CCL2 therapies for the treatment of established breast carcinoma, although the complete abrogation of the CCL2 signaling cascade may also limit immunosurveillance and support metastatic spread.
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Establishing n-3 polyunsaturated fatty acid contents in canned wild Alaska pink salmon products is challenging due to ample natural variation found in lipid content of pink salmon muscle. This study investigated the effect of adding salmon oil (SO) to canned pink salmon produced from fish exhibiting two opposite degrees of skin watermarking, bright (B) and dark (D). Specific goals of the study were to evaluate the benefits of adding SO to canned pink salmon with regard to nutritional value of the product, sensory characteristics, and the oxidative and hydrolytic stability of the lipids over thermal processing. Six groups of canned pink salmon were produced with variable levels of SO, either using bright (with 0, 1, or 2% SO) or dark (with 0, 2, or 4% SO) pink salmon. Compositional analysis revealed highest (P < 0.05) lipid content in sample B2 (8.7%) and lowest (P < 0.05) lipid content in sample D0 (3.5%). Lipid content of samples B0, B1, D2, and D4 was not significantly different (P > 0.05) ranging from 5.7% to 6.8%. Consequently, addition of SO to canned pink salmon allowed for consistent lipid content between bright and dark fish. Addition of 1% or 2% SO to canned bright pink salmon was not detrimental to the sensory properties of the product. It is recommended that canned bright pink salmon be supplemented with at least 1% SO, while supplementation with 2% SO would guarantee a minimum quantity of 1.9 g of n-3 fatty acids per 100 g of product. Addition of 4% SO to canned dark pink salmon was detrimental to product texture and taste, while supplementation with 2% SO did not negatively affect sensorial properties of the product. Accordingly, canned dark pink salmon should be supplemented with 2% SO so that a minimum n-3 fatty acids content of 1.5 g per 100 g of product.
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Portopulmonary hypertension (PoPH) refers to pulmonary arterial hypertension associated with portal hypertension with or without evidence of an underlying liver disease. Despite the potential for curing PoPH with liver transplantation, the presence of moderate or severe PoPH is associated with increased morbidity and mortality and is, therefore, a contraindication to transplantation. Previous studies have predominantly used intravenous epoprostenol for treatment in order to qualify patients for liver transplantation. In this retrospective case series, we describe the clinical course of 11 patients whom we successfully treated (predominantly with oral sildenafil and subcutaneous treprostinil) in order to qualify them for liver transplantation. The mean pulmonary artery pressure significantly improved from 44 to 32.9 mm Hg, and the pulmonary vascular resistance decreased from 431 to 173 dyn second cm(-5) . There were significant improvements in the cardiac output and the transpulmonary gradient with these therapies as well. All 11 patients subsequently received liver transplants with a 0% mortality rate to date; the duration of follow-up ranged from 7 to 60 months. After transplantation, 7 of the 11 patients (64%) were off all pulmonary vasodilators, and only 2 patients required transiently increased doses of prostacyclins. In conclusion, an aggressive approach to the treatment of PoPH with sildenafil and/or treprostinil and subsequent liver transplantation may be curative for PoPH in some patients.
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Epoprostenol/análogos & derivados , Hipertensión Portal/tratamiento farmacológico , Fallo Hepático/cirugía , Trasplante de Hígado , Piperazinas/administración & dosificación , Circulación Pulmonar/efectos de los fármacos , Sulfonas/administración & dosificación , Adulto , Antihipertensivos/administración & dosificación , Epoprostenol/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Hipertensión Portal/complicaciones , Tiempo de Internación , Fallo Hepático/complicaciones , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 5/administración & dosificación , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , Purinas/administración & dosificación , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Citrato de SildenafilRESUMEN
Oncolytic virotherapy using vaccinia virus (Vv) has shown some encouraging antitumor responses in mouse models and patients, but the breadth of efficacy in clinical trials has been somewhat limited. Given that antitumor effects have correlated with increased host immune responses, we hypothesized that improved therapeutic outcomes may be achieved by using oncolytic virus (OV) in combination with a potent immune agonist reagent. In this study, we carried out a preclinical evaluation of a genetically engineered strain of oncolytic vaccinia virus (Vvdd) for its capacity to induce antitumor responses when combined with an agonist antibody (Ab) specific for the costimulatory molecule 4-1BB (CD137). In immune-competent syngeneic mouse models of cancer, this combination therapy significantly reduced the growth of established subcutaneous tumors relative to either treatment alone. Importantly, the development of pulmonary metastatic lesions was also reduced. Tumor growth inhibition was associated with increased numbers of CD11b(+) and CD11c(+) myeloid cells in the tumor draining lymph nodes, greater infiltration of CD8(+) effector T and natural killer (NK) cells, and a more sustained presence of neutrophils at the tumor site. Depletion of T or NK cells or neutrophils reduced efficacy, confirming their contribution to an effective therapeutic response. We further extended this conclusion through results from IFNγ-deficient mice. In summary, our findings offered a proof-of-concept for a combinatorial approach to enhance the antitumor efficacy of an OV, suggesting a strategy to improve their use as an immunotherapeutic treatment for cancer.
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Anticuerpos Monoclonales/uso terapéutico , Neoplasias Experimentales/terapia , Viroterapia Oncolítica , Miembro 9 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/inmunología , Inmunidad Adaptativa , Animales , Línea Celular Tumoral , Terapia Combinada , Inmunidad Innata , Interferón gamma/fisiología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/patología , Virus VacciniaRESUMEN
Cancer stem cells (CSC) are resistant to radiation and chemotherapy and play a significant role in cancer recurrence and metastatic disease. It is therefore important to identify alternative strategies, such as immunotherapies that can be used to control this refractory population. A CD44(+)CD24(-/low) subpopulation of cells within the B6 PyMT-MMTV transgenic mouse-derived AT-3 mammary carcinoma cell line was identified, which had CSC-like characteristics, including pluripotency and a resistance to chemo- and radiotherapy. Therefore, unlike xenograph models that require immunocompromised settings, this novel system may provide a means to study immune-mediated responses against CSC-like cells. The immunobiology of the AT-3 CSC-like cell population was studied by their surface molecule expression profile and their sensitivity to specified cell death pathways. Comparable levels of Rae-1, CD155, CD54 and higher levels of Fas and DR5 were expressed on the AT-3 CSC-like cells compared to non-CSC-like tumor cells. Expression correlated with an in vitro sensitivity to cell death by NK cells or through the ligation of the death receptors (Fas or DR5), by their ligands or anti-Fas and anti-DR5 mAbs. Indeed, compared to the rest of the AT-3 tumor cells, the CD44(+)CD24(-/low) subpopulation of cells were more sensitive to both Fas- and TRAIL-mediated cell death pathways. Therefore, despite the refractory nature of CSC to other conventional therapies, these CSC-like cells were not inherently resistant to specified forms of immune-mediated cell death. These results encourage the continued investigation into immunotherapeutic strategies as a means of controlling breast CSC, particularly through their cell death pathways.
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Muerte Celular/fisiología , Neoplasias Mamarias Experimentales/inmunología , Células Madre Neoplásicas/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antígeno CD24/biosíntesis , Muerte Celular/efectos de los fármacos , Muerte Celular/efectos de la radiación , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos/fisiología , Femenino , Citometría de Flujo , Receptores de Hialuranos/biosíntesis , Inmunofenotipificación , Neoplasias Mamarias Experimentales/metabolismo , Neoplasias Mamarias Experimentales/patología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Tolerancia a Radiación/fisiología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Receptor fas/metabolismoRESUMEN
Microvascular complications of diabetes can result in peripheral neuropathy and impaired sensation in the feet. These issues can significantly affect morbidity and quality of life. Regular foot exams play a major role in early detection of foot problems and may help prevent amputations. An initial review found that a comprehensive diabetic foot exam (CDFE) was documented 13.5% of the time. A quality improvement effort combined provider and staff education, a standardized documentation form, an electronic reminder, and a well-defined process to improve the frequency and completeness of diabetic foot exams. After the intervention, 44.5% of CDFEs found in dictated notes lacked at least 1 component of the exam, whereas less than 4% of charts using a standardized form lacked documentation of any part of the foot exam. These efforts demonstrate the benefit of engaging providers and staff in a quality improvement initiative to increase consistency and frequency of documentation of annual CDFEs.
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Pie Diabético/diagnóstico , Examen Físico/normas , Benchmarking , Humanos , Auditoría Médica , Medio Oeste de Estados Unidos , Garantía de la Calidad de Atención de Salud/métodosRESUMEN
The status of a host's immune response influences both the development and progression of a malignancy such that immune responses can have both pro- and anti-tumorigenic effects. Cancer immunotherapy is a form of treatment that aims to improve the ability of a cancer-bearing individual to reject the tumor immunologically. However, antitumor immunity elicited by the host or by immunotherapeutic strategies, can be actively attenuated by mechanisms that limit the strength and/or duration of immune responses, including the presence of immunoregulatory cell types or the production of immunosuppressive factors. As our knowledge of tumor-induced immune suppression increases, it has become obvious that these mechanisms are probably a major barrier to effective therapy. The identification of multiple mechanisms of tumor-induced immune suppression also provides a range of novel targets for new cancer therapies. Given the vital role that a host's immune response is known to play in cancer progression, therapies that target immune suppressive mechanisms have the potential to enhance anticancer immune responses thus leading to better immune surveillance and the limitation of tumor escape. In this review, mechanisms of tumor-associated immune suppression have been divided into four forms that we have designated as (1) regulatory cells; (2) cytokines/chemokines; (3) T cell tolerance/exhaustion and (4) metabolic. We discuss select mechanisms representing each of these forms of immunosuppression that have been shown to aid tumors in evading host immune surveillance and overview therapeutic strategies that have been recently devised to "suppress these suppressors."
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Tolerancia Inmunológica , Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Animales , Citocinas/inmunología , Citocinas/uso terapéutico , Humanos , Inmunidad Celular , Linfocitos T/inmunología , Escape del Tumor/inmunologíaRESUMEN
BACKGROUND: Bone morphogenetic proteins (BMPs) contribute to many different aspects of development including mesoderm formation, heart development, neurogenesis, skeletal development, and axis formation. They have previously been recognized only as secreted growth factors, but the present study detected Bmp2, Bmp4, and Gdf5/CDMP1 in the nuclei of cultured cells using immunocytochemistry and immunoblotting of nuclear extracts. RESULTS: In all three proteins, a bipartite nuclear localization signal (NLS) was found to overlap the site at which the proproteins are cleaved to release the mature growth factors from the propeptides. Mutational analyses indicated that the nuclear variants of these three proteins are produced by initiating translation from downstream alternative start codons. The resulting proteins lack N-terminal signal peptides and are therefore translated in the cytoplasm rather than the endoplasmic reticulum, thus avoiding proteolytic processing in the secretory pathway. Instead, the uncleaved proteins (designated nBmp2, nBmp4, and nGdf5) containing the intact NLSs are translocated to the nucleus. Immunostaining of endogenous nBmp2 in cultured cells demonstrated that the amount of nBmp2 as well as its nuclear/cytoplasmic distribution differs between cells that are in M-phase versus other phases of the cell cycle. CONCLUSIONS: The observation that nBmp2 localization varies throughout the cell cycle, as well as the conservation of a nuclear localization mechanism among three different BMP family members, suggests that these novel nuclear variants of BMP family proteins play an important functional role in the cell.
Asunto(s)
Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 4/metabolismo , Núcleo Celular/metabolismo , Secuencia de Aminoácidos , Animales , Proteína Morfogenética Ósea 2/análisis , Proteína Morfogenética Ósea 2/genética , Proteína Morfogenética Ósea 4/análisis , Proteína Morfogenética Ósea 4/genética , División Celular , Línea Celular , Codón Iniciador , Factor 5 de Diferenciación de Crecimiento/análisis , Factor 5 de Diferenciación de Crecimiento/metabolismo , Ratones , Datos de Secuencia Molecular , Transducción de SeñalRESUMEN
CD11b(+)Gr-1(+)-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. However, the intrinsic molecular events that drive their protumorigenic behavior remain to be elucidated. Although CD11b(+)Gr-1(+) cells exist at low frequencies in normal mice, it also remains unresolved whether they are biologically distinct from those of tumor-bearing hosts. These objectives were investigated using CD11b(+)Gr-1(+) cells from both implantable (4T1) and autochthonous (mouse mammary tumor virus-polyomavirus middle T Ag (MMTV-PyMT)) mouse models of mammary carcinoma. Limited variation was observed in the expression of markers associated with immunoregulation between CD11b(+)Gr-1(+) cells of both tumor models, as well as with their respective controls (Cnt). Despite limited differences in phenotype, tumor-induced CD11b(+)Gr-1(+) cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b(+)Gr-1(+) cells. Furthermore, when admixed with tumor cells, CD11b(+)Gr-1(+) cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cnt mice. However, the protumorigenic behavior of these tumor-induced CD11b(+)Gr-1(+) cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced. The loss of this protumorigenic effect occurred independently of the host immune system and correlated with a CD11b(+)Gr-1(+) cytokine/chemokine production pattern that resembled cells from nontumor-bearing Cnt mice. Overall, our data indicate that 1) tumor-induced CD11b(+)Gr-1(+) cells from both cancer models were phenotypically similar, but biologically distinct from their nontumor-bearing counterparts and 2) modulation of IFN regulatory factor 8 levels in tumor-induced CD11b(+)Gr-1(+) cells can significantly abrogate their protumorigenic behavior, which may have important implications for cancer therapy.
Asunto(s)
Antígeno CD11b/biosíntesis , Regulación Leucémica de la Expresión Génica/inmunología , Regulación Neoplásica de la Expresión Génica/inmunología , Factores Reguladores del Interferón/biosíntesis , Factores Reguladores del Interferón/genética , Células Mieloides/inmunología , Células Mieloides/patología , Receptores de Quimiocina/biosíntesis , Animales , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular/genética , Movimiento Celular/inmunología , Proliferación Celular , Femenino , Factores Reguladores del Interferón/fisiología , Masculino , Neoplasias Mamarias Experimentales/genética , Neoplasias Mamarias Experimentales/inmunología , Neoplasias Mamarias Experimentales/patología , Neoplasias Mamarias Experimentales/terapia , Virus del Tumor Mamario del Ratón/genética , Virus del Tumor Mamario del Ratón/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Células Mieloides/metabolismo , Poliomavirus/genética , Poliomavirus/inmunología , Regulación hacia Arriba/genética , Regulación hacia Arriba/inmunologíaRESUMEN
A surge in interest in the chemokine-chemokine receptor network is probably related to the expanding roles that chemokines have now been identified to play in human biology, particularly immunity. Specific tissue microenvironments express distinct chemokines and both hematopoietic and nonhematopoietic cells have receptor expression profiles that permit the coordinated trafficking and organization of cells within these specific tissues. Since the chemokine network plays critical roles in both the function of the immune system and the progression of cancer, it is an attractive target for therapeutic manipulation. This review will focus on chemokine and chemokine receptor network-related therapeutic interventions that utilize host-tumor interactions particularly involving the immune system.