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Treatment guidelines provided by PRODIGE-7 recommend perioperative systemic chemotherapy before cytoreductive surgery (CRS) for colorectal cancer peritoneal metastases (CRPM). Toxicity with multimodal treatment needs to be better defined. Chemotherapy response and impact on survival have not been reported. We assessed CRPM patients who received systemic oxaliplatin/irinotecan before CRS (preoperative) with Mitomycin C (35 mg/m2, 90 min) or Oxaliplatin (368 mg/m2, 30 min) heated intraperitoneal chemotherapy (HIPEC). Secondary analysis was performed from a prospective database. Overall survival (OS) in chemotherapy responders (R) and nonresponders (NR) was compared. Toxicity was assessed by rate of adverse events (AEs). From April 2005 to April 2021, 436 patients underwent CRS + HIPEC; 125 (29%) received preoperative chemotherapy. The 112 (90%) received oxaliplatin (64, 57%) or irinotecan (48, 43%). R, defined as complete (CR) or partial response on preoperative imaging and/or postoperative histology, was seen in 71, 63% (53.8-72.3); 16, 14% (8.4-22.2) had CR. Median OS in R versus NR was 43.7 months (37.9-49.4) versus 23.9 (16.3-31.4) p = 0.007, HR 0.51 (0.31-0.84). OS multivariable analysis showed HR 0.48 (0.25-0.95), p = 0.03 for chemotherapy response corrected by peritoneal cancer index, completeness of cytoreduction score. CRS led to 21% grade 3-4 AEs versus 4% for preoperative chemotherapy. HIPEC grade 3-4 AEs were 0.5%. Preoperative chemotherapy response is an independent predictor for OS in CRPM.
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We report herein an enantioselective palladium-catalyzed Heck-Matsuda reaction for the desymmetrization of N-protected 2,5-dihydro-1H-pyrroles with aryldiazonium salts, using the chiral N,N-ligand (S)-PyraBox. This strategy has allowed straightforward access to a diversity of 4-aryl-γ-lactams via Heck arylation followed by a sequential Jones oxidation. The overall method displays a broad scope and good enantioselectivity, favoring the (R) enantiomer. The applicability of the protocol is highlighted by the efficient enantioselective syntheses of the selective phosphodiesterase-4-inhibitor rolipram and the commercial drug baclofen as hydrochloride.
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The purpose of this qualitative study was to elicit client perspectives on the Los Angeles County Full Service Partnership (FSP) program - an adaptation of Assertive Community Treatment (ACT). Semi-structured interviews were conducted with 20 FSP clients. Qualitative data were analyzed using thematic analysis. Two major themes were identified from the interview data: (1) Clients' acknowledgement of the material benefits of the FSP program; and (2) FSP's impact on restoring and stabilizing clients' social and treatment relationships. Interviewees greatly valued the material (i.e., basic needs, housing assistance) and relational (i.e., relationships with providers, restored personal relationships) aspects of the program, but did not ascribe the same degree of value to mental health treatment. Interviewees' emphases on material and relational aspects reflect the status of assertive mental health treatment as an intervention on intermediary determinants of health in the lives of persons diagnosed with serious mental illness.
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Serviços Comunitários de Saúde Mental , Transtornos Mentais , Humanos , Transtornos Mentais/terapia , Los Angeles , HabitaçãoRESUMO
For high-power heavy ion accelerators, the development of a suitable charge stripper, which can handle intense beams, is essential. This Letter describes the first experimental demonstration of a heavy ion liquid lithium charge stripper. A 10-20 µm thick liquid lithium jet flowing at >50 m/s was formed and confirmed stable when bombarded by various heavy ion beams, while increasing the charge state of the incoming beams to the desired charge state range. This demonstration proved the existing power limitation with the conventional strippers can be overcome by the liquid-metal stripper, opening completely new possibilities in high-power accelerator development.
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While many standardized assessment measures exist to track child mental health treatment outcomes, the degree to which such tools have been adequately tested for reliability and validity across race, ethnicity, and class is uneven. This paper examines the corpus of published tests of psychometric properties for the ten standardized measures used in U.S. child outpatient care, with focus on breadth of testing across these domains. Our goal is to assist care providers, researchers, and legislators in understanding how cultural mismatch impacts measurement accuracy and how to select tools appropriate to the characteristics of their client populations. We also highlight avenues of needed research for measures that are in common use. The list of measures was compiled from (1) U.S. state Department of Mental Health websites; (2) a survey of California county behavioral health agency directors; and (3) exploratory literature scans of published research. Ten measures met inclusion criteria; for each one a systematic review of psychometrics literature was conducted. Diversity of participant research samples was examined as well as differences in reliability and validity by gender, race or ethnicity, and socio-economic class. All measures showed adequate reliability and validity, however half lacked diverse testing across all three domains and all lacked testing with Asian American/Pacific Islander and Native American children. ASEBA, PSC, and SDQ had the broadest testing.
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Saúde Mental , Criança , Humanos , Psicometria , Reprodutibilidade dos Testes , Inquéritos e Questionários , Resultado do TratamentoRESUMO
BACKGROUND: Obesity rates are higher in children with intellectual and developmental disabilities (DD) compared to typically developing (TD) children. In TD children, family-based (FB) interventions for obesity are the most effective interventions. Research addressing obesity interventions for children with IDD is limited. METHOD: We adapted a community-based obesity intervention created for TD children for children with IDD and added a parent education component. The current study examined the feasibility of Enhanced-Operation Fit, a camp-based intervention created in order to reduce weight, and improve health behavior outcomes. Participants were 16 children (68.8% male; Mage = 13.15, SDage = 1.62) and their parents. RESULTS: Results indicated that incorporating a daily parent education group limited recruitment potential, but showed promising preliminary improvements in parent feeding and child eating behaviors. CONCLUSIONS: Health interventions for children with IDD are greatly needed and the current study may be a cost and time-efficient intervention to help address this public health crisis.
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Deficiências do Desenvolvimento , Deficiência Intelectual , Criança , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pais , Projetos PilotoRESUMO
Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone. This current is abolished by additional co-expression of a dominant-negative GluD1 dead pore mutant. We then characterized mGlu1-dependent currents in dopamine neurons from midbrain slices. Both the agonist-evoked and the slow postsynaptic currents are abolished by expression of the dominant-negative GluD1 mutant, pointing to the involvement of native GluD1 channels in these currents. Likewise, both mGlu1-dependent currents are suppressed in GRID1 knockout mice, which reportedly display endophenotypes relevant for schizophrenia. It is known that mGlu1 activation triggers the transition from tonic to burst firing of dopamine neurons, which signals salient stimuli and encodes reward prediction. In vivo recordings of dopamine neurons showed that their spontaneous burst firing is abolished in GRID1 knockout mice or upon targeted expression of the dominant-negative GluD1 mutant in wild-type mice. Our results de-orphanize GluD1, unravel its key role in slow glutamatergic transmission and provide insights into how GRID1 gene alterations can lead to dopaminergic dysfunctions in schizophrenia.
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Neurônios Dopaminérgicos/metabolismo , Glutamato Desidrogenase/genética , Receptores de Glutamato/genética , Animais , Cerebelo/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Glutamato Desidrogenase/fisiologia , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Glutamato/fisiologia , Receptores de Glutamato Metabotrópico/genética , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/genética , Análise de Célula ÚnicaRESUMO
Epidemiological studies report strong association between mood disorders and tobacco addiction. This high comorbidity requires adequate treatment but the underlying mechanisms are unknown. We demonstrate that nicotine exposure, independent of drug withdrawal effects, increases stress sensitivity, a major risk factor in mood disorders. Nicotine and stress concur to induce long-lasting cellular adaptations within the dopamine (DA) system. This interplay is underpinned by marked remodeling of nicotinic systems, causing increased ventral tegmental area (VTA) DA neurons' activity and stress-related behaviors, such as social aversion. Blocking ß2 or α7 nicotinic acetylcholine receptors (nAChRs) prevents, respectively, the development and the expression of social stress-induced neuroadaptations; conversely, facilitating α7 nAChRs activation specifically in the VTA promotes stress-induced cellular and behavioral maladaptations. Our work unravels a complex nicotine-stress bidirectional interplay and identifies α7 nAChRs as a promising therapeutic target for stress-related psychiatric disorders.
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Neurônios Dopaminérgicos/efeitos dos fármacos , Receptores Nicotínicos/fisiologia , Animais , Dopamina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Estresse Psicológico/metabolismo , Fumar Tabaco/efeitos adversos , Fumar Tabaco/psicologia , Área Tegmentar Ventral/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/efeitos dos fármacosRESUMO
Tonically active cholinergic interneurons (TANs) from the nucleus accumbens (NAc) are centrally involved in reward behavior. TANs express a vesicular glutamate transporter referred to as VGLUT3 and thus use both acetylcholine and glutamate as neurotransmitters. The respective roles of each transmitter in the regulation of reward and addiction are still unknown. In this study, we showed that disruption of the gene that encodes VGLUT3 (Slc17a8) markedly increased cocaine self-administration in mice. Concomitantly, the amount of dopamine (DA) release was strongly augmented in the NAc of VGLUT3(-/-) mice because of a lack of signaling by metabotropic glutamate receptors. Furthermore, dendritic spines and glutamatergic synaptic transmission on medium spiny neurons were increased in the NAc of VGLUT3(-/-) mice. Increased DA and glutamate signaling in the NAc are hallmarks of addiction. Our study shows that TANs use glutamate to reduce DA release and decrease reinforcing properties of cocaine in mice. Interestingly, we also observed an increased frequency of rare variations in SLC17A8 in a cohort of severe drug abusers compared with controls. Our findings identify VGLUT3 as an unexpected regulator of drug abuse.
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Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/patologia , Dopamina/metabolismo , Predisposição Genética para Doença/genética , Ácido Glutâmico/metabolismo , Núcleo Accumbens/metabolismo , Transdução de Sinais/fisiologia , Proteínas Vesiculares de Transporte de Glutamato/genética , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Adulto , Animais , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Humanos , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/patologia , Autoadministração , Potenciais Sinápticos/efeitos dos fármacos , Potenciais Sinápticos/genética , Proteínas Vesiculares de Transporte de Glutamato/deficiênciaRESUMO
Smoking is the most important preventable cause of morbidity and mortality worldwide. Recent genome-wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer. Several polymorphisms in the CHRNA3-CHRNA5-CHRNB4 cluster coding for the nicotinic acetylcholine receptor (nAChR) α3, α5 and ß4 subunits were implicated. In mouse models, we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic (DAergic) neurons of the ventral tegmental area (VTA). We first investigated the reinforcing effects of nicotine in drug-naive α5(-/-) mice using an acute intravenous nicotine self-administration task and ex vivo and in vivo electrophysiological recordings of nicotine-elicited DA cell activation. We designed lentiviral re-expression vectors to achieve targeted re-expression of wild-type or mutant α5 in the VTA, in general, or in DA neurons exclusively. Our results establish a crucial role for α5*-nAChRs in DAergic neurons. These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement. Finally, we demonstrate that a single-nucleotide polymorphism, the non-synonymous α5 variant rs16969968, frequent in many human populations, exhibits a partial loss of function of the protein in vivo. This leads to increased nicotine consumption in the self-administration paradigm. We thus define a critical link between a human predisposition marker, its expression in DA neurons and nicotine intake.
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Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Nicotina/farmacologia , Receptores Nicotínicos/genética , Potenciais de Ação/efeitos dos fármacos , Animais , Masculino , Camundongos , Camundongos Knockout , Nicotina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Reforço Psicológico , Autoadministração , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Cardiac fibrosis is a major hallmark of cardiac diseases. For evaluation of cardiac fibrosis, the development of highly specific and preferably noninvasive methods is desired. Our aim was to evaluate CNA35, a protein known to specifically bind to collagen, as a specific marker of cardiac fibrosis. Fluorescently labeled CNA35 was applied ex vivo on tissue sections of fibrotic rat, mouse, and canine myocardium. After quantification of CNA35, sections were examined with picrosirius red (PSR) and compared to CNA35. Furthermore, fluorescently labeled CNA35 was administered in vivo in mice. Hearts were isolated, and CNA35 labeling was examined in tissue sections. Serial sections were histologically examined with PSR. Ex vivo application of CNA35 showed specific binding to collagen and a high correlation with PSR (Pearson r â=â .86 for mice/rats and r â=â .98 for canine; both p < .001). After in vivo administration, CNA35 labeling was observed around individual cardiomyocytes, indicating its ability to penetrate cardiac endothelium. High correlation was observed between CNA35 and PSR (r â=â .91, p < .001). CNA35 specifically binds to cardiac collagen and can cross the endothelial barrier. Therefore, labeled CNA35 is useful to specifically detect collagen both ex vivo and in vivo and potentially can be converted to a noninvasive method to detect cardiac fibrosis.
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Moléculas de Adesão Celular/análise , Moléculas de Adesão Celular/metabolismo , Miócitos Cardíacos/metabolismo , Animais , Biomarcadores/análise , Biomarcadores/química , Moléculas de Adesão Celular/química , Cães , Fibrose Endomiocárdica/diagnóstico , Fibrose Endomiocárdica/patologia , Fluoresceína-5-Isotiocianato , Camundongos , RatosRESUMO
Smoking is the most important preventable cause of mortality and morbidity worldwide. This nicotine addiction is mediated through the nicotinic acetylcholine receptor (nAChR), expressed on most neurons, and also many other organs in the body. Even within the ventral tegmental area (VTA), the key brain area responsible for the reinforcing properties of all drugs of abuse, nicotine acts on several different cell types and afferents. Identifying the precise action of nicotine on this microcircuit, in vivo, is important to understand reinforcement, and finally to develop efficient smoking cessation treatments. We used a novel lentiviral system to re-express exclusively high-affinity nAChRs on either dopaminergic (DAergic) or γ-aminobutyric acid-releasing (GABAergic) neurons, or both, in the VTA. Using in vivo electrophysiology, we show that, contrary to widely accepted models, the activation of GABA neurons in the VTA plays a crucial role in the control of nicotine-elicited DAergic activity. Our results demonstrate that both positive and negative motivational values are transmitted through the dopamine (DA) neuron, but that the concerted activity of DA and GABA systems is necessary for the reinforcing actions of nicotine through burst firing of DA neurons. This work identifies the GABAergic interneuron as a potential target for smoking cessation drug development.
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Neurônios Dopaminérgicos/fisiologia , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Nicotina/farmacologia , Reforço Psicológico , Área Tegmentar Ventral/fisiologia , Potenciais de Ação/fisiologia , Animais , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios GABAérgicos/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Camundongos , Agonistas Nicotínicos/farmacologia , Receptores Nicotínicos/fisiologia , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
Background: The United States lacks equitable surgical access, prompting us to investigate whether there is an inverse relationship between Social Vulnerability Indices and the number of surgeons in a census tract, using the Inland Empire as a model. Methods: The Centers for Disease Control's (CDC) SVI 2018 database, composed of 823 census tracts, was compared against demographics of 1008 surgeons, from the American Medical Association's (AMA) 2018 Physician Masterfile. Analysis was performed via Spearman's bivariate and multiple regression. Results: An inverse relationship exists between surgeon number and overall social vulnerability (ρ = -0.266 [95 % CI -0.330 to -0.199], p < .001), and between surgeon number and each category of social vulnerability: Socioeconomic (ρ = -0.345 [95 % CI -0.0405 to -0.281], p < .001), Household Composition and Disability (ρ = -0.121 [95 % CI -0.190 to -0.051], p < .001), Minority Status and Language (ρ = -0.0317 [95 % CI -0.379 to -0.252], p < .001), and Housing Type and Transportation (ρ = -0.093 [95 % CI -0.153 to -0.023], p = .005). Multiple regression analysis revealed that the following were associated with a higher number of surgeons: higher "Per Capita Income" (B = 0.000151 [95 % CI 0.000079 to 0.000223], t(820) = 4.104, p < .001), larger Daytime Population (B = 0.000143 [95 % CI 0.000072 to 0.000214]; t(820) = 3.956, p < .001), larger Total Population (B = -0.013 [95 % CI -0.022 to -0.003]; t(820) = -2.672, p = .008), and smaller number of Persons aged 17 and younger (B = -0.005 [95 % CI -0.008 to -0.001]; t(820) = -2.794, p = .005). Conclusions: This study concludes that social vulnerability is predictive of, and significantly linked to, differences in surgical access and continues to advocate for research into understanding the surgeon's role in both individual and population health. Key message: Our work demonstrates that the number of surgeons in a census tract is inversely proportional to the census tract's overall Social Vulnerability Indices. Thus, this research can serve to educate the public, physicians, and other healthcare providers about the importance of incorporating social determinants of health into the construction of healthcare policy and practice, as well as the importance of continued funding for local and national social service programs as a means to alleviate specific health inequities, such as language and transportation.
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Imaging and neuropathology studies have demonstrated significant abnormalities not only in subcortical, but also in cortical regions of patients with multiple system atrophy (MSA). This raises the possibility that cognitive dysfunction may contribute to the clinical spectrum of this disorder to a greater extent than it is currently not widely appreciated. In this cross-sectional multicenter study from the European multiple system atrophy study group ( http://www.emsa-sg.org ), we applied an extensive neuropsychological test battery in a series of 61 clinically diagnosed probable MSA patients. The results demonstrated that general cognitive decline as assessed by MMSE was uncommon (2 out of 61 patients <24). In contrast, frontal lobe-related functions (as measured by FAB) were impaired in 41 % of patients, with abstract reasoning and sustained attention less compromised. This pattern was similar to our control group of 20 patients with Parkinson's disease (matched for disease duration and age at onset). There was no difference in cognitive performance between MSA patients with the parkinsonian versus the cerebellar variant. Behaviourally, MSA patients had greater depression than PD and in the case of MSA of the cerebellar variant significantly lower anxiety. Our data show that cognitive abnormalities are relatively frequent in multiple system atrophy and this involves primarily frontal-executive functions. Their contribution to clinical disability and disease progression needs to be addressed in larger prospective studies.
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Atenção/fisiologia , Cerebelo/fisiopatologia , Cognição/fisiologia , Atrofia de Múltiplos Sistemas/psicologia , Transtornos Parkinsonianos/psicologia , Idoso , Ansiedade/psicologia , Estudos Transversais , Depressão/psicologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/fisiopatologia , Testes Neuropsicológicos , Transtornos Parkinsonianos/fisiopatologiaRESUMO
AIMS: The occurrence of connexin40 (Cx40) minor polymorphism (-44 G â A) was increased in patients with idiopathic atrial fibrillation (AF), although its effect on atrial Cx40 protein expression is unknown. We aimed to evaluate whether alterations in Cx40 are directly linked to the development of AF, we studied the effect of this polymorphism on Cx40 expression and distribution in patients without any history of AF and in patients who developed post-operative AF. METHODS AND RESULTS: Hundred and eight patients (mean age 67 ± 9 years), without a history of AF or conditions that predispose to AF, were included. During heart surgery, 10 cc blood was collected for DNA genotyping and the right atrial appendage was partly excised. Ten patients (9%) were homozygous for the minor allele (AA, Group 1), 30 (28%) were heterozygous (AG, Group 2), and 68 (63%) were non-carriers (GG, Group 3). Ten age- and sex-matched tissue samples per group were analysed for Cx40 expression by: (i) real-time quantitative polymerase chain reaction (Q-PCR), (ii) western blotting, and (iii) immunohistochemistry on cryosections. Real-time quantitative polymerase chain reaction showed no significant differences of Cx40 mRNA among the groups. Western blot analysis, however, revealed a reduction in Cx40 protein in Groups 1 (-36.4%) and 2 (-39.5%) as compared with Group 3. Immunohistochemistry confirmed this reduction but indicated an unaltered subcellular distribution of the remaining Cx40. Incidence of post-operative AF (28%) was age-dependent but unrelated to the presence of the polymorphism or fibrosis. CONCLUSION: Presence of the Cx40 minor allele (-44 G â A) results in a uniform down-regulation of right atrial appendage Cx40 protein which was not significantly related to development of post-operative AF.
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Apêndice Atrial/metabolismo , Fibrilação Atrial/genética , Conexinas/metabolismo , Alelos , Fibrilação Atrial/metabolismo , Western Blotting , Conexinas/genética , Estudos Transversais , Regulação para Baixo , Feminino , Expressão Gênica , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Polimorfismo Genético , Reação em Cadeia da Polimerase em Tempo Real , Proteína alfa-5 de Junções ComunicantesRESUMO
Introduction: Pain is the most common and distressing medical symptom in hospitalized patients in all wards. Pain prevalence among hospitalized patients is an indicator of the quality of health care. Objective: The aim of this study is to describe pain prevalence in two Italian hospitals. Material and method: This is an observational study. It involved hospitalized patients of both sexes, able and unable to self-report. Descriptive analysis and multivariate analysis were applied. Results: A sample of 754 inpatients were included. In Terni Ho-spital (n = 255), pain prevalence was 80.8%. The mean pain severity was 5.2 (sd ± 3.33). At Rome's San Camillo Hospital (n=499), pain prevalence was 46.9%. Acute pain is more prevalent in women (OR= 0.65; CI 95% 0.43-0.99) and increases with age (OR= 0.97; CI 95% 0.96-0.99). Chronic pain is more prevalent in men (OR= 2.34; CI 95% 1.41-3.97) and increases with age (OR= 1.04; CI 95% 1.03-1.06). Discussion and conclusion.: San Camillo Hospital presents data showing reduced pain prevalence, and describing pain even in patients unable to self-report. It is reasonable to believe that pain control by the staff at San Camillo is better, even though both hospitals are equally important regional institutions.
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Hospitais , Dor , Estudos Transversais , Feminino , Humanos , Masculino , Dor/epidemiologia , Dor/etiologia , Medição da Dor , PrevalênciaRESUMO
T-cell dysfunction is a hallmark of B-cell Chronic Lymphocytic Leukemia (CLL), where CLL cells downregulate T-cell responses through regulatory molecules including programmed death ligand-1 (PD-L1) and Interleukin-10 (IL-10). Immune checkpoint blockade (ICB) aims to restore T-cell function by preventing the ligation of inhibitory receptors like PD-1. However, most CLL patients do not respond well to this therapy. Thus, we investigated whether IL-10 suppression could enhance antitumor T-cell activity and responses to ICB. Since CLL IL-10 expression depends on Sp1, we utilized a novel, better tolerated analogue of the Sp1 inhibitor mithramycin (MTMox32E) to suppress CLL IL-10. MTMox32E treatment inhibited mouse and human CLL IL-10 production and maintained T-cell effector function in vitro. In the Eµ-Tcl1 mouse model, treatment reduced plasma IL-10 and CLL burden and increased CD8+ T-cell proliferation, effector and memory cell prevalence, and interferon-γ production. When combined with ICB, suppression of IL-10 improved responses to anti-PD-L1 as shown by a 4.5-fold decrease in CLL cell burden compared to anti-PD-L1 alone. Combination therapy also produced more interferon-γ+, cytotoxic effector KLRG1+, and memory CD8+ T-cells, and fewer exhausted T-cells. Since current therapies for CLL do not target IL-10, this provides a novel strategy to improve immunotherapies.
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Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD8-Positivos/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-10/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/imunologia , Plicamicina/farmacologia , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Estudos de Casos e Controles , Proliferação de Células , Modelos Animais de Doenças , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
T cell-specific adapter (TSAd) protein is an Src homology 2 (SH2) domain-containing adapter molecule implicated in T cell receptor for antigen (TCR)-mediated interleukin 2 (IL-2) secretion in T cells. Here, we demonstrate that a substantial fraction of TSAd is found in the T cell nucleus. Nuclear import of TSAd is an active process that depends on TSAd SH2 domain recognition of a phosphotyrosine-containing ligand. Importantly, we show that TSAd can act as a potent transcriptional activator in T cells. Furthermore, the TSAd SH2 domain appears to be essential for this transcription-activating function independent of its role in nuclear import. Biochemical analyses suggest that a single TSAd SH2 domain ligand of 95-100 kD may be involved in these processes. Consistent with a role as a transcription activator, cotransfection of TSAd with an IL-2 promoter-reporter gene construct results in a considerable upregulation of IL-2 promoter activity. Further, we show that this augmentation requires a functional TSAd SH2 domain. However, TSAd does not appear to modulate the activity of the major recognized IL-2 gene transcription factors, nuclear factor kappaB (NF-kappaB), nuclear factor of activated T cells (NFAT), or activator protein 1 (AP-1). These findings point to the function of TSAd as a novel transcription-regulatory protein in T cells and illustrate the importance of the TSAd SH2 domain in this role.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Proteínas de Transporte/química , Proteínas de Transporte/fisiologia , Linfócitos T/imunologia , Transporte Ativo do Núcleo Celular , Animais , Células COS , Linhagem Celular , Núcleo Celular/metabolismo , Genes Reporter , Humanos , Interleucina-2/genética , Células Jurkat , Regiões Promotoras Genéticas , Fatores de Transcrição/química , Fatores de Transcrição/fisiologia , Ativação Transcricional , Domínios de Homologia de srcRESUMO
OBJECTIVE: To analyze clinical records of cardiac surgery patients in an attempt to identify factors associated with mortality in the postoperative critical care units of the public health service hospitals in the Community of Valencia, Spain, in 2007. METHODS: Retrospective study of cases from January 1, 2007 to December 31, 2007. The charts of all patients who underwent cardiac surgery with or without extracorporeal circulation were reviewed. A data collection protocol was followed to obtain information on age, sex, body mass index (BMI), presurgical risk factors, type of surgery, duration of extracorporeal circulation, duration of ischemia, cause of death, and length of stay in the postoperative critical care unit. RESULTS: The study population consisted of 2113 patients at 5 public hospitals; 124 patients (70 men, 54 women) died. The mean (SD) age was 70 (9.43) years (range, 36-91 years). The mean BMI was 28.19 kg/m2 (maximum, 42 kg/m2). The mean Euroscore was 21.92 (maximum, 94.29). Hypertension was present as a preoperative risk factor in most patients (74.2%); dyslipidemia was present in 51.6%, diabetes mellitus in 38.7%, stroke in 73%, and renal failure in 2.4%. It was noteworthy was that the group who underwent coronary revascularization had the highest mortality rate (nearly 35% of the 124 patients). The next highest mortality rate (19.4%) was in patients who had combined procedures (valve repair or substitution plus coronary revascularization). Mortality was 18.5% in the group undergoing aortic valve surgery and 11.3% in those undergoing mitral valve surgery. The mean duration of extracorporeal circulation was 148.63 minutes. The mean duration of myocardial ischemia was 94.91 minutes. The most frequent cause of death was cardiogenic shock (54.8%). This was followed by distributive shock (29.8%) and hemorrhagic shock (8.9%). The mean length of stay in the postoperative critical care unit was 13.6 days. Overall mortality was 5.87%. CONCLUSIONS: The highest mortality rate among cardiac surgery patients in postoperative critical care units in hospitals in the Community of Valencia in 2007 was in patients who underwent coronary revascularization. The most prevalent preoperative risk factor was hypertension. Cardiogenic shock and distributive shock were the most frequent causes of death in these patients. A system for classifying risk is needed in order to predict mortality in critical care units and improve perioperative care.