RESUMEN
Tumors develop by invoking a supportive environment characterized by aberrant angiogenesis and infiltration of tumor-associated macrophages (TAMs). In a transgenic model of breast cancer, we found that TAMs localized to the tumor parenchyma and were smaller than mammary tissue macrophages. TAMs had low activity of the metabolic regulator mammalian/mechanistic target of rapamycin complex 1 (mTORC1), and depletion of negative regulator of mTORC1 signaling, tuberous sclerosis complex 1 (TSC1), in TAMs inhibited tumor growth in a manner independent of adaptive lymphocytes. Whereas wild-type TAMs exhibited inflammatory and angiogenic gene expression profiles, TSC1-deficient TAMs had a pro-resolving phenotype. TSC1-deficient TAMs relocated to a perivascular niche, depleted protein C receptor (PROCR)-expressing endovascular endothelial progenitor cells, and rectified the hyperpermeable blood vasculature, causing tumor tissue hypoxia and cancer cell death. TSC1-deficient TAMs were metabolically active and effectively eliminated PROCR-expressing endothelial cells in cell competition experiments. Thus, TAMs exhibit a TSC1-dependent mTORC1-low state, and increasing mTORC1 signaling promotes a pro-resolving state that suppresses tumor growth, defining an innate immune tumor suppression pathway that may be exploited for cancer immunotherapy.
Asunto(s)
Células Progenitoras Endoteliales , Proteínas Supresoras de Tumor , Animales , Humanos , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa/genética , Macrófagos Asociados a Tumores/metabolismo , Células Progenitoras Endoteliales/metabolismo , Receptor de Proteína C Endotelial , Diana Mecanicista del Complejo 1 de la Rapamicina , Neovascularización Patológica , MamíferosRESUMEN
In metazoan organisms, cell competition acts as a quality control mechanism to eliminate unfit cells in favour of their more robust neighbours1,2. This mechanism has the potential to be maladapted, promoting the selection of aggressive cancer cells3-6. Tumours are metabolically active and are populated by stroma cells7,8, but how environmental factors affect cancer cell competition remains largely unknown. Here we show that tumour-associated macrophages (TAMs) can be dietarily or genetically reprogrammed to outcompete MYC-overexpressing cancer cells. In a mouse model of breast cancer, MYC overexpression resulted in an mTORC1-dependent 'winner' cancer cell state. A low-protein diet inhibited mTORC1 signalling in cancer cells and reduced tumour growth, owing unexpectedly to activation of the transcription factors TFEB and TFE3 and mTORC1 in TAMs. Diet-derived cytosolic amino acids are sensed by Rag GTPases through the GTPase-activating proteins GATOR1 and FLCN to control Rag GTPase effectors including TFEB and TFE39-14. Depletion of GATOR1 in TAMs suppressed the activation of TFEB, TFE3 and mTORC1 under the low-protein diet condition, causing accelerated tumour growth; conversely, depletion of FLCN or Rag GTPases in TAMs activated TFEB, TFE3 and mTORC1 under the normal protein diet condition, causing decelerated tumour growth. Furthermore, mTORC1 hyperactivation in TAMs and cancer cells and their competitive fitness were dependent on the endolysosomal engulfment regulator PIKfyve. Thus, noncanonical engulfment-mediated Rag GTPase-independent mTORC1 signalling in TAMs controls competition between TAMs and cancer cells, which defines a novel innate immune tumour suppression pathway that could be targeted for cancer therapy.
Asunto(s)
Competencia Celular , Técnicas de Reprogramación Celular , Inmunidad Innata , Neoplasias , Macrófagos Asociados a Tumores , Animales , Ratones , Aminoácidos/metabolismo , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Competencia Celular/genética , Competencia Celular/inmunología , Proteínas en la Dieta/farmacología , Modelos Animales de Enfermedad , GTP Fosfohidrolasas/metabolismo , Lisosomas/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismoRESUMEN
OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.
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Enfermedad de Graves , Oftalmopatía de Graves , Hipertiroidismo , Hipotiroidismo , Adulto , Antitiroideos/uso terapéutico , Enfermedad de Graves/radioterapia , Humanos , Hipertiroidismo/radioterapia , Hipotiroidismo/tratamiento farmacológico , Radioisótopos de Yodo/uso terapéutico , Estudios Retrospectivos , Tirotropina , Tiroxina/uso terapéuticoRESUMEN
Autistic youth display difficulties in emotion recognition, yet little research has examined behavioral and neural indices of vocal emotion recognition (VER). The current study examines behavioral and event-related potential (N100, P200, Late Positive Potential [LPP]) indices of VER in autistic and non-autistic youth. Participants (N = 164) completed an emotion recognition task, the Diagnostic Analyses of Nonverbal Accuracy (DANVA-2) which included VER, during EEG recording. The LPP amplitude was larger in response to high intensity VER, and social cognition predicted VER errors. Verbal IQ, not autism, was related to VER errors. An interaction between VER intensity and social communication impairments revealed these impairments were related to larger LPP amplitudes during low intensity VER. Taken together, differences in VER may be due to higher order cognitive processes, not basic, early perception (N100, P200), and verbal cognitive abilities may underlie behavioral, yet occlude neural, differences in VER processing.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Adolescente , Humanos , Trastorno Autístico/diagnóstico , Electroencefalografía , Potenciales Evocados/fisiología , Emociones/fisiologíaRESUMEN
How genetic lesions drive cell transformation and whether they can be circumvented without compromising function of non-transformed cells are enduring questions in oncology. Here we show that in mature T cells-in which physiologic clonal proliferation is a cardinal feature- constitutive MYC transcription and Tsc1 loss in mice modeled aggressive human malignancy by reinforcing each other's oncogenic programs. This cooperation was supported by MYC-induced large neutral amino acid transporter chaperone SLC3A2 and dietary leucine, which in synergy with Tsc1 deletion overstimulated mTORC1 to promote mitochondrial fitness and MYC protein overexpression in a positive feedback circuit. A low leucine diet was therapeutic even in late-stage disease but did not hinder T cell immunity to infectious challenge, nor impede T cell transformation driven by constitutive nutrient mTORC1 signaling via Depdc5 loss. Thus, mTORC1 signaling hypersensitivity to leucine as an onco-nutrient enables an onco-circuit, decoupling pathologic from physiologic utilization of nutrient acquisition pathways.
RESUMEN
With the creation of public health management cadre in the state, district, and block levels of India, there is a need for a comprehensive, synergistic education system to ensure efficient public health across the country. This scoping review, therefore, aims to examine the characteristics of public health education programs available in India's varied geographical and regional contexts. It examines 16 program-related descriptors across public health Doctoral, Masters, Bachelors, Post-graduate Diploma, and Diploma education programs offered. Data was retrieved through institutional websites. Results of our analysis showed 84 unique institutions in 20 states and 3 UTs currently offering 116 public health programs across India's 28 states and 8 UTs. Private and public institutes were 65% (n = 75) and 35% (n = 41) respectfully. The majority of universities mainly provided Masters of Public Health (n = 73, 63%) programs followed by Postgraduate Diploma (PGD) and Diploma (n = 17, 15%), BPHSc (n = 14, 12%), and Ph.D. (n = 12, 10%). The majority of Ph.D. programs in public health are offered in Maharashtra, Karnataka, and Haryana, while Masters in Public Health programs are offered highest in Karnataka, Bachelors in Public Health programs in Rajasthan, Post Graduate Diploma in Public Health program in Delhi, and Tamil Nadu had the most number of Diploma in Public Health programs. Thirty-one percent (n = 36) of the public health programs are offered across the south, 28% (n = 32) across the north, and 22% (n = 26) across the west Analyzed descriptors provide comprehensive information on program characteristics, mainly admission, format, and tuition fee. The review offers five suggestions to improve collaborative public health education and prepare a workforce with the skills, knowledge, and expertise to respond to the twentyfirst century's public health threats and challenges in India.
Asunto(s)
Educación en Salud , Salud Pública , India , Administración en Salud Pública , Recursos HumanosRESUMEN
BACKGROUND: Expenditure for rehabilitation following knee arthroplasty for osteoarthritis- and rehabilitation-related challenges following discharge to home after surgery is not available in the Indian context. OBJECTIVES: To estimate cost of rehabilitation and document challenges in following rehabilitation advices, from a patient perspective. METHODS: We conducted a hospital-based cross-sectional study of patients visiting the orthopedic department at a tertiary care public-funded hospital in New Delhi and included those who recently (less than 4 months) underwent primary knee arthroplasty for osteoarthritis. A trained physiotherapist not involved in clinical care collected information on expenditures incurred after discharge from hospital, patient's ability to recall the advices given by the physician and challenges they experienced using a semi-structured questionnaire. We report median costs by category of direct and indirect cost and used linear regression to explore determinants of cost. RESULTS: We interviewed 82 consecutive patients (mean age 60.8 years and 68% females) with median time since surgery of 28 days. More than half (52%) sought some support for physiotherapy. The median cost of rehabilitation was INR 18,395 (Interquartile-range 11,325-27,775). Direct medical cost contributed to 74% of total cost (32% fee for services, 21% medications and lab investigations, 21% assistive devices). Twenty percent higher costs were incurred among those undergoing bilateral knee surgery after adjusting for age, sex, income, and type of physiotherapy support sought. Challenges were related to recall of advices, not understanding the recovery process and pain management. CONCLUSION: About half patients undergoing knee arthroplasty seek support for rehabilitation after discharge to home contributing to a major portion of expenses incurred during rehabilitation. Cost-effective support mechanism for home-based rehabilitation is required for improving patient rehabilitation experiences. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43465-021-00405-6.