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Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Camundongos , Animais , Peróxido de Hidrogênio , Peróxidos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Proteômica , Acetilcisteína/farmacologia , Glucose , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genéticaRESUMO
Periosteal stem and progenitor cells (PSPCs) are major contributors to bone maintenance and repair. Deciphering the molecular mechanisms that regulate their function is crucial for the successful generation and application of future therapeutics. Here, we pinpoint Hox transcription factors as necessary and sufficient for periosteal stem cell function. Hox genes are transcriptionally enriched in periosteal stem cells and their overexpression in more committed progenitors drives reprogramming to a naïve, self-renewing stem cell-like state. Crucially, individual Hox family members are expressed in a location-specific manner and their stem cell-promoting activity is only observed when the Hox gene is matched to the anatomical origin of the PSPC, demonstrating a role for the embryonic Hox code in adult stem cells. Finally, we demonstrate that Hoxa10 overexpression partially restores the age-related decline in fracture repair. Together, our data highlight the importance of Hox genes as key regulators of PSPC identity in skeletal homeostasis and repair.
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Células-Tronco Adultas , Genes Homeobox , Humanos , Adulto , Genes Homeobox/genética , Proteínas de Homeodomínio/genética , Células-Tronco , Osso e OssosRESUMO
Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron (MN) degeneration. Various studies using cellular and animal models of ALS indicate that there is a complex interplay between MN and neighboring non-neuronal cells, such as astrocytes, resulting in noncell autonomous neurodegeneration. Astrocytes in ALS exhibit a lower ability to support MN survival than nondisease-associated ones, which is strongly correlated with low-mitochondrial respiratory activity. Indeed, pharmacological inhibition of pyruvate dehydrogenase kinase (PDK) led to an increase in the mitochondrial oxidative phosphorylation pathway as the primary source of cell energy in SOD1G93A astrocytes and restored the survival of MN. Among the four PDK isoforms, PDK2 is ubiquitously expressed in astrocytes and presents low expression levels in neurons. Herein, we hypothesize whether selective knockdown of PDK2 in astrocytes may increase mitochondrial activity and, in turn, reduce SOD1G93A-associated toxicity. To assess this, cultured neonatal SOD1G93A rat astrocytes were incubated with specific PDK2 siRNA. This treatment resulted in a reduction of the enzyme expression with a concomitant decrease in the phosphorylation rate of the pyruvate dehydrogenase complex. In addition, PDK2-silenced SOD1G93A astrocytes exhibited restored mitochondrial bioenergetics parameters, adopting a more complex mitochondrial network. This treatment also decreased lipid droplet content in SOD1G93A astrocytes, suggesting a switch in energetic metabolism. Significantly, PDK2 knockdown increased the ability of SOD1G93A astrocytes to support MN survival, further supporting the major role of astrocyte mitochondrial respiratory activity in astrocyte-MN interactions. These results suggest that PDK2 silencing could be a cell-specific therapeutic tool to slow the progression of ALS.
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Esclerose Lateral Amiotrófica , Astrócitos , Piruvato Desidrogenase Quinase de Transferência de Acetil , Animais , Ratos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Astrócitos/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Neurônios Motores/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil/metabolismo , Respiração , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
ALS is a human neurodegenerative disorder that induces a progressive paralysis of voluntary muscles due to motor neuron loss. The causes are unknown, and there is no curative treatment available. Mitochondrial dysfunction is a hallmark of ALS pathology; however, it is currently unknown whether it is a cause or a consequence of disease progression. Recent evidence indicates that glial mitochondrial function changes to cope with energy demands and critically influences neuronal death and disease progression. Aberrant glial cells detected in the spinal cord of diseased animals are characterized by increased proliferation rate and reduced mitochondrial bioenergetics. These features can be compared with cancer cell behavior of adapting to nutrient microenvironment by altering energy metabolism, a concept known as metabolic reprogramming. We focus on data that suggest that aberrant glial cells in ALS undergo metabolic reprogramming and profound changes in glial mitochondrial activity, which are associated with motor neuron death in ALS. This review article emphasizes on the association between metabolic reprogramming and glial reactivity, bringing new paradigms from the area of cancer research into neurodegenerative diseases. Targeting glial mitochondrial function and metabolic reprogramming may result in promising therapeutic strategies for ALS.
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Esclerose Lateral Amiotrófica , Animais , Humanos , Neurônios Motores , Neuroglia , Medula Espinal , Superóxido DismutaseRESUMO
OBJECTIVE: Up to 15% of patients with high-grade serous ovarian, tubal, or peritoneal carcinoma harbor a mutation in BRCA genes. Early notion of mutation status may facilitate counseling, predict prognosis, and increase access to Parp-inhibitors. The aim of this study was to examine the rate of germline genetic testing in a retrospective cohort of women with high-grade serous ovarian, tubal, or peritoneal carcinoma to determine if a new pilot project of gynecologic oncologist-initiated genetic testing improved the rate of testing, after 1 year of implementation. METHODS: Gynecologic oncology-initiated genetic testing was implemented at a single university hospital center with input and collaboration from gynecological oncologists, nurses, and genetic counselors. All patients diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma after August 2017 were offered gynecologic oncologist- initiated genetic testing for a panel of 13 hereditary breast and ovarian cancer susceptibility genes. Data from this group was then compared with a historic cohort of patients who received traditional genetic counseling between January 2014 and August 2017 (control group). Patients that had genetic testing through a clinical trial were excluded. The primary outcome was the uptake of genetic testing in both groups. Secondary outcomes included difference in time from diagnosis to genetic result between both cohorts. Data was analyzed using SPSS 25.0 and medians (ranges) were reported. RESULTS: A total of 152 women with high-grade serous ovarian, tubal, or peritoneal carcinoma were included in this study. Between January 2014 to July 2017 there were 108 patients with high-grade serous ovarian, tubal, or peritoneal carcinoma, among which 50.9% (n=54) underwent genetic testing following referral to genetics. The prevalence of BRCA pathogenic variants was 25.9% (14/54): 9.2% (5/54) in BRCA1 and 16.7% (9/54) in BRCA2. The median time from diagnosis to genetics referral was 53 days (range; 3-751), and median time from diagnosis to test result disclosure was 186 days (range; 15-938). After 1 year of implementation of the gynecologic oncologist-initiated genetic testing model, among 44 women diagnosed with high-grade serous ovarian, tubal, or peritoneal carcinoma, 86.2% underwent genetic testing. The median time from diagnosis to result disclosure decreased to 58 days, representing a reduction of 128 days, or 4.27 months (P<0.001). Reasons for non-testing included refusal, death, and follow-up at another hospital. The prevalence of germline BRCA1/2 pathogenic variants was 21% (8/38). CONCLUSION: Gynecologic oncologist-initiated genetic testing at the time of high-grade serous ovarian, tubal, or peritoneal carcinoma diagnosis leads to increased uptake and decreased delays in testing compared with referral for traditional genetic counseling.
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Cistadenocarcinoma Seroso/genética , Testes Genéticos/normas , Neoplasias Ovarianas/genética , Neoplasias Peritoneais/genética , Encaminhamento e Consulta/normas , Proteína BRCA1 , Proteína BRCA2 , Feminino , Testes Genéticos/estatística & dados numéricos , Mutação em Linhagem Germinativa , Humanos , Padrões de Prática Médica , Encaminhamento e Consulta/estatística & dados numéricos , Estudos RetrospectivosRESUMO
Cellular senescence is an endpoint of chemotherapy, and targeted therapies in melanoma and the senescence-associated secretory phenotype (SASP) can affect tumor growth and microenvironment, influencing treatment outcomes. Metabolic interventions can modulate the SASP, and an enhanced mitochondrial energy metabolism supports resistance to therapy in melanoma cells. Herein, we assessed the mitochondrial function of therapy-induced senescent melanoma cells obtained after exposing the cells to temozolomide (TMZ), a methylating chemotherapeutic agent. Senescence induction in melanoma was accompanied by a substantial increase in mitochondrial basal, ATP-linked, and maximum respiration rates and in coupling efficiency, spare respiratory capacity, and respiratory control ratio. Further examinations revealed an increase in mitochondrial mass and length. Alterations in mitochondrial function and morphology were confirmed in isolated senescent cells, obtained by cell-size sorting. An increase in mitofusin 1 and 2 (MFN1 and 2) expression and levels was observed in senescent cells, pointing to alterations in mitochondrial fusion. Silencing mitofusin expression with short hairpin RNA (shRNA) prevented the increase in mitochondrial length, oxygen consumption rate and secretion of interleukin 6 (IL-6), a component of the SASP, in melanoma senescent cells. Our results represent the first in-depth study of mitochondrial function in therapy-induced senescence in melanoma. They indicate that senescence increases mitochondrial mass, length and energy metabolism; and highlight mitochondria as potential pharmacological targets to modulate senescence and the SASP.
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Senescência Celular , Metabolismo Energético , GTP Fosfo-Hidrolases/metabolismo , Melanoma Experimental/metabolismo , Mitocôndrias/metabolismo , Proteínas de Neoplasias/metabolismo , Animais , GTP Fosfo-Hidrolases/genética , Inativação Gênica , Interleucina-6/genética , Interleucina-6/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Mitocôndrias/genética , Mitocôndrias/patologia , Dinâmica Mitocondrial/efeitos dos fármacos , Dinâmica Mitocondrial/genética , Proteínas de Neoplasias/genética , Temozolomida/farmacologiaRESUMO
GATA2 deficiency is an inherited bone marrow failure syndrome that can manifest with myelodysplasia (myelodysplastic syndrome) with chromosomal aberrations and high risk of evolution to leukemia (particularly, acute myeloid leukemia); immunodeficiency with opportunistic infections; and/or lymphedema. It can be transmitted in families in autosomal-dominant fashion, or present de novo as sporadic disease in adults or children. The authors report a case of an adolescent male with features of GATA2 deficiency resulting from a complete monoallelic deletion, review chromosomal anomalies associated with this disorder, and discuss the management implications.
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Aberrações Cromossômicas , Deficiência de GATA2/genética , Fator de Transcrição GATA2/genética , Deleção de Genes , Síndromes Mielodisplásicas/genética , Adolescente , Deficiência de GATA2/patologia , Humanos , Masculino , Síndromes Mielodisplásicas/patologiaRESUMO
As marine tropical ecosystems deteriorate and lose biodiversity, their communities are shifting to being dominated by a few species, altering ecosystem's functioning and services. Macroalgae are becoming dominant on coral reefs, and are frequently observed outcompeting corals. Turf algal assemblages are the base of energy flow in these systems and one of the most abundant types of macroalgae on coral reefs, but little is known about their biology and diversity. Through molecular and morphological analyses, we identified the turf-forming species Laurencia cervicornis, and by studying seasonal recruitment and the impact of herbivorous fishes on its abundance, we describe its survival strategy. The molecular analyses used a total of 45 rbcL gene sequences including eight current genera within the Laurencia complex and two new sequences of L. cervicornis and strongly support the new combination of Palisada cervicornis comb. nov. In addition, a detailed morphological characterization including the description of reproductive structures is provided. Palisada cervicornis was seen recruiting in all seasons but was typically in low abundance. Specimens grown on tiles in fish exclosure cages were devoured in less than 4 h when offered to fishes. Even though many species of the Laurencia complex have chemicals that deter herbivory, species within the genus Palisada lack feeding deterrents and thus are highly palatable. We suggest that P. cervicornis is a palatable species that seems to survive in the community by obtaining a size-refuge from herbivory within turf communities.
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Recifes de Corais , Características de História de Vida , Rodófitas/fisiologia , Alga Marinha/fisiologia , Proteínas de Algas/genética , Florida , Filogenia , Dinâmica Populacional , Rodófitas/classificação , Rodófitas/genética , Ribulose-Bifosfato Carboxilase/genética , Estações do Ano , Alga Marinha/classificação , Alga Marinha/genética , Análise de Sequência de DNARESUMO
BACKGROUND: In the SOD1(G93A) mutant rat model of amyotrophic lateral sclerosis (ALS), neuronal death and rapid paralysis progression are associated with the emergence of activated aberrant glial cells that proliferate in the degenerating spinal cord. Whether pharmacological downregulation of such aberrant glial cells will decrease motor neuron death and prolong survival is unknown. We hypothesized that proliferation of aberrant glial cells is dependent on kinase receptor activation, and therefore, the tyrosine kinase inhibitor masitinib (AB1010) could potentially control neuroinflammation in the rat model of ALS. METHODS: The cellular effects of pharmacological inhibition of tyrosine kinases with masitinib were analyzed in cell cultures of microglia isolated from aged symptomatic SOD1(G93A) rats. To determine whether masitinib prevented the appearance of aberrant glial cells or modified post-paralysis survival, the drug was orally administered at 30 mg/kg/day starting after paralysis onset. RESULTS: We found that masitinib selectively inhibited the tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R) at nanomolar concentrations. In microglia cultures from symptomatic SOD1(G93A) spinal cords, masitinib prevented CSF-induced proliferation, cell migration, and the expression of inflammatory mediators. Oral administration of masitinib to SOD1(G93A) rats starting after paralysis onset decreased the number of aberrant glial cells, microgliosis, and motor neuron pathology in the degenerating spinal cord, relative to vehicle-treated rats. Masitinib treatment initiated 7 days after paralysis onset prolonged post-paralysis survival by 40 %. CONCLUSIONS: These data show that masitinib is capable of controlling microgliosis and the emergence/expansion of aberrant glial cells, thus providing a strong biological rationale for its use to control neuroinflammation in ALS. Remarkably, masitinib significantly prolonged survival when delivered after paralysis onset, an unprecedented effect in preclinical models of ALS, and therefore appears well-suited for treating ALS.
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Esclerose Lateral Amiotrófica/complicações , Encefalite/tratamento farmacológico , Encefalite/etiologia , Paralisia/tratamento farmacológico , Paralisia/etiologia , Inibidores de Proteínas Quinases/uso terapêutico , Tiazóis/uso terapêutico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/mortalidade , Animais , Benzamidas , Morte Celular , Modelos Animais de Doenças , Progressão da Doença , Humanos , Masculino , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Piperidinas , Piridinas , Ratos , Ratos Transgênicos , Medula Espinal/patologia , Superóxido Dismutase/genéticaRESUMO
Motoneuron loss and reactive astrocytosis are pathological hallmarks of amyotrophic lateral sclerosis (ALS), a paralytic neurodegenerative disease that can be triggered by mutations in Cu-Zn superoxide dismutase (SOD1). Dysfunctional astrocytes contribute to ALS pathogenesis, inducing motoneuron damage and accelerating disease progression. However, it is unknown whether ALS progression is associated with the appearance of a specific astrocytic phenotype with neurotoxic potential. Here, we report the isolation of astrocytes with aberrant phenotype (referred as "AbA cells") from primary spinal cord cultures of symptomatic rats expressing the SOD1(G93A) mutation. Isolation was based on AbA cells' marked proliferative capacity and lack of replicative senescence, which allowed oligoclonal cell expansion for 1 y. AbA cells displayed astrocytic markers including glial fibrillary acidic protein, S100ß protein, glutamine synthase, and connexin 43 but lacked glutamate transporter 1 and the glial progenitor marker NG2 glycoprotein. Notably, AbA cells secreted soluble factors that induced motoneuron death with a 10-fold higher potency than neonatal SOD1(G93A) astrocytes. AbA-like aberrant astrocytes expressing S100ß and connexin 43 but lacking NG2 were identified in nearby motoneurons, and their number increased sharply after disease onset. Thus, AbA cells appear to be an as-yet unknown astrocyte population arising during ALS progression with unprecedented proliferative and neurotoxic capacity and may be potential cellular targets for slowing ALS progression.
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Esclerose Lateral Amiotrófica/patologia , Astrócitos/patologia , Modelos Animais de Doenças , Neurônios Motores/patologia , Esclerose Lateral Amiotrófica/enzimologia , Animais , Proliferação de Células , Humanos , Mutação , Fenótipo , Ratos , Superóxido Dismutase/genéticaRESUMO
In the framework of precision viticulture, satellite data have been demonstrated to significantly support many tasks. Specifically, they enable the rapid, large-scale estimation of some viticultural parameters like vine stem water potential (Ψstem) and intercepted solar radiation (ISR) that traditionally require time-consuming ground surveys. The practice of covering table grape vineyards with plastic films introduces an additional challenge for estimation, potentially affecting vine spectral responses and, consequently, the accuracy of estimations from satellites. This study aimed to address these challenges with a special focus on the exploitation of Sentinel-2 Level 2A and meteorological data to monitor a plastic-covered vineyard in Southern Italy. Estimates of Ψstem and ISR were obtained using different algorithms, namely, Ordinary Least Square (OLS), Multivariate Linear Regression (MLR), and machine learning (ML) techniques, which rely on Random Forest Regression, Support Vector Regression, and Partial Least Squares. The results proved that, despite the potential spectral interference from the plastic coverings, ISR and Ψstem can be locally estimated with a satisfying accuracy. In particular, (i) the OLS regression-based approach showed a good performance in providing accurate ISR estimates using the near-infrared spectral bands (RMSE < 8%), and (ii) the MLR and ML algorithms could estimate both the ISR and vine water status with a higher accuracy (RMSE < 7 for ISR and RMSE < 0.14 MPa for Ψstem). These results encourage the adoption of medium-high resolution multispectral satellite imagery for deriving satisfying estimates of key crop parameters even in anomalous situations like the ones where plastic films cover the monitored vineyard, thus marking a significant advancement in precision viticulture.
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We report a first case of hallux rigidus successfully treated in an elderly patient by intra-articular infiltration of cross-linked hyaluronic acid (HA) 21 mg/mL with mannitol (Desirial Plus) and review the previous literature on the different compositions of HA infiltrative treatment applied to hallux rigidus. A 77-year-old female patient with moderate unilateral pain of 6 months of evolution and stiffness of the movement of the first metatarsophalangeal joint of the left foot, corresponding to grade 2 of the classification proposed by Coughlin and Shurnas. The objective of the study was to perform a pilot test to (a) evaluate the correct technique of intra-articular infiltration as well as (b) the use of a commercial cross-linked HA 21 mg/mL with mannitol, to a voluntary patient diagnosed with hallux rigidus. A single cross-linked HA infiltration is applied to the first metatarsophalangeal joint with an administered amount of 1 mL. The loaded dorsiflexion, the unloaded dorsiflexion, and the unloaded plantarflexion angles of the first metatarsophalangeal joint improved from 15°, 20°, and 10°, respectively, before injection to 45°, 52°, and 22°, respectively, at 14 days after injection. Moreover, these improvements maintained until the final follow-up (400 days). The intensity of pain, according to the visual analog scale, improved from 7 of 10 before the injection, passing through 4 of 10 at 14 days after the injection, to 1 of 10 at 60 days after the injection. Cross-linked HA 21 mg/mL with mannitol improves symptomatology, joint mobility of the first metatarsophalangeal joint, and quality of life in the patient with stiff hallux submitted to the pilot test. These effects have been maintained for more than 14 months.
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Background: Microglial dysfunction plays a causative role in Alzheimer's disease (AD) pathogenesis. Here we focus on a germline insertion/deletion variant mapping SIRPß1, a surface receptor that triggers amyloid-ß(Aß) phagocytosis via TYROBP. Objective: To analyze the impact of this copy-number variant in SIRPß1 expression and how it affects AD molecular etiology. Methods: Copy-number variant proxy rs2209313 was evaluated in GERALD and GR@ACE longitudinal series. Hippocampal specimens of genotyped AD patients were also examined. SIRPß1 isoform-specific phagocytosis assays were performed in HEK393T cells. Results: The insertion alters the SIRPß1 protein isoform landscape compromising its ability to bind oligomeric Aß and its affinity for TYROBP. SIRPß1 Dup/Dup patients with mild cognitive impairment show an increased cerebrospinal fluid t-Tau/Aß ratio (pâ=â0.018) and a higher risk to develop AD (ORâ=â1.678, pâ=â0.018). MRIs showed that Dup/Dup patients exhibited a worse initial response to AD. At the moment of diagnosis, all patients showed equivalent Mini-Mental State Examination scores. However, AD patients with the duplication had less hippocampal degeneration (pâ<â0.001) and fewer white matter hyperintensities. In contrast, longitudinal studies indicate that patients bearing the duplication allele show a slower cognitive decline (pâ=â0.013). Transcriptional analysis also shows that the SIRPß1 duplication allele correlates with higher TREM2 expression and an increased microglial activation. Conclusions: The SIRPß1 internal duplication has opposite effects over MCI-to-Dementia conversion risk and AD progression, affecting microglial response to Aß. Given the pharmacological approaches focused on the TREM2-TYROBP axis, we believe that SIRPß1 structural variant might be considered as a potential modulator of this causative pathway.
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Doença de Alzheimer , Disfunção Cognitiva , Receptores de Superfície Celular , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/genética , Disfunção Cognitiva/metabolismo , Microglia/metabolismo , Fagocitose , Receptores de Superfície Celular/metabolismoRESUMO
BACKGROUND: Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported. CASE PRESENTATION: Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband's sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants. CONCLUSION: This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband's affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.
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Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Receptores ErbB/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Pulmão/patologia , MutaçãoRESUMO
BACKGROUND: Insulin feedback is a critical mechanism responsible for the poor clinical efficacy of phosphatidylinositol 3-kinase (PI3K) inhibition in cancer, and hyperglycemia is an independent factor associated with poor prognosis in glioblastoma (GBM). We investigated combination anti-hyperglycemic therapy in a mouse model of GBM and evaluated the association of glycemic control in clinical trial data from patients with GBM. METHODS: The effect of the anti-hyperglycemic regimens, metformin and the ketogenic diet, was evaluated in combination with PI3K inhibition in patient-derived GBM cells and in an orthotopic GBM mouse model. Insulin feedback and the immune microenvironment were retrospectively evaluated in blood and tumor tissue from a Phase 2 clinical trial of buparlisib in patients with recurrent GBM. RESULTS: We found that PI3K inhibition induces hyperglycemia and hyperinsulinemia in mice and that combining metformin with PI3K inhibition improves the treatment efficacy in an orthotopic GBM xenograft model. Through examination of clinical trial data, we found that hyperglycemia was an independent factor associated with poor progression-free survival in patients with GBM. We also found that PI3K inhibition increased insulin receptor activation and T-cell and microglia abundance in tumor tissue from these patients. CONCLUSION: Reducing insulin feedback improves the efficacy of PI3K inhibition in GBM in mice, and hyperglycemia worsens progression-free survival in patients with GBM treated with PI3K inhibition. These findings indicate that hyperglycemia is a critical resistance mechanism associated with PI3K inhibition in GBM and that anti-hyperglycemic therapy may enhance PI3K inhibitor efficacy in GBM patients.
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Neoplasias Encefálicas , Glioblastoma , Hiperglicemia , Metformina , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Fosfatidilinositol 3-Quinase/farmacologia , Fosfatidilinositol 3-Quinase/uso terapêutico , Fosfatidilinositol 3-Quinases , Insulina/farmacologia , Insulina/uso terapêutico , Retroalimentação , Estudos Retrospectivos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Proliferação de Células , Hiperglicemia/tratamento farmacológico , Metformina/farmacologia , Metformina/uso terapêutico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
BACKGROUND: The presence of hallux limitus in adulthood is frequently encountered in clinical practice, generating other biomechanical, structural, and functional compensations in dynamics secondary to blockage of the main pivot in the sagittal plane, the first metatarsophalangeal joint. In addition, the presence of functional hallux limitus (FHL) in school-age children is also increasing. Currently, there is a lack of scientific literature about this condition in the pediatric population, and early diagnosis is necessary to reduce future biomechanical disorders and avoid the development of foot arthritis. The purpose of this research was to identify static plantar pressures in school-age children with and without hallux limitus. METHODS: A total sample of 106 children aged between six and twelve years old was divided into two groups: the case group (53 subjects with functional hallux limitus) and the control group (53 subjects without functional hallux limitus). Data were acquired with the participants in a standing barefoot position on the pressure platform, and the hallux limitus functional test was performed in a sitting position to classify the individuals into the determined study group. The variables analyzed in the research were: plantar pressure, bilateral forefoot and rearfoot surface area, bilateral forefoot and rearfoot ground reaction forces, bilateral forefoot and rearfoot distribution of body weight, total left and right surface area, maximum pressure of the left foot and right foot, medium pressure of the left foot and right foot, ground reaction forces of the left foot and right foot, and the weight of each foot. RESULTS: Age was the only descriptive quantitative variable that showed a significant difference between the two study groups, with a p-value of 0.031. No statistically significant differences were found between groups in the bilateral forefoot and rearfoot surface area, ground reaction forces, distribution of body weight, or maximum and medium plantar pressure in the left and right foot. CONCLUSIONS: Changes in the location of the maximum pressure were observed, particularly in older participants with FHL, but these results were not significant. The findings of this study did not show significant differences between the static plantar pressures of school-age individuals with and without functional hallux limitus.
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BACKGROUND: Hallux limitus is a common foot disorder whose incidence has increased in the school-age population. Hallux limitus is characterized by musculoskeletal alteration that involves the metatarsophalangeal joint causing structural disorders in different anatomical areas of the locomotor system, affecting gait patterns. The aim of this study was to analyze dynamic plantar pressures in a school-aged population both with functional hallux and without. METHODS: A full sample of 100 subjects (50 male and 50 female) 7 to 12 years old was included. The subjects were identified in two groups: the case group (50 subjects characterized as having hallux limitus, 22 male and 28 female) and control group (50 subjects characterized as not having hallux limitus, 28 male and 22 female). Measurements were obtained while subjects walked barefoot in a relaxed manner along a baropodometric platform. The hallux limitus test was realized in a seated position to sort subjects out into an established study group. The variables checked in the research were the surface area supported by each lower limb, the maximum peak pressure of each lower limb, the maximum mean pressure of each lower limb, the body weight on the hallux of each foot, the body weight on the first metatarsal head of each foot, the body weight at the second metatarsal head of each foot, the body weight at the third and fourth metatarsal head of each foot, the body weight at the head of the fifth metatarsal of each foot, the body weight at the midfoot of each foot, and the body weight at the heel of each foot. RESULTS: Non-significant results were obtained in the variable of pressure peaks between both study groups; the highest pressures were found in the hallux with a p-value of 0.127 and in the first metatarsal head with a p-value 0.354 in subjects with hallux limitus. A non-significant result with a p-value of 0.156 was obtained at the second metatarsal head in healthy subjects. However, significant results were observed for third and fourth metatarsal head pressure in healthy subjects with a p-value of 0.031 and regarding rearfoot pressure in subjects with functional hallux limitus with a p-value of 0.023. CONCLUSIONS: School-age subjects with hallux limitus during gait exhibit more average peak plantar pressure in the heel and less peak average plantar pressure in the third and fourth metatarsal head as compared to healthy children aged between 7 and 12 years old.
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Background: Functional Hallux Limitus (FHL) is a dynamic foot dysfunction characterized by a limitation of hallux dorsiflexion when the first metatarsal head is under load. FHL plays a role in the development of osteoarthrosis in the first metatarsophalangeal joint (IMTPJ). Forefoot disorders can significantly impact an individual's quality of life, leading to dysfunction and pain. The aim of this project was to evaluate the quality of life of school-aged individuals with and without FHL using the Foot Health Status Questionnaire (FHSQ). Methods: A case-control study was conducted to evaluate the outcomes in paediatric age. A total sample of 116 children between 6 and 12 years old was used to conduct this research. The sample was divided into two groups: (i) the healthy group (n = 58) and the FHL group (n = 58). The FHSQ was completed and the FHL test was performed in a seated position to classify the patients into the selected group. Results: Non-significant changes were observed when the mean values of the FHSQ domains were compared between the groups with and without FHL, except for the "general foot health" domain (p = 0,024) associated with the specific foot health section (section 1) of the Questionnaire. For the domains linked with the general well-being section (section 2), there was not a statistically difference in the mean of the scores obtained between the two school-aged groups with and without FHL, being slightly lower in the group with the presence of FHL for the overall health and physical function domains. Both the healthy and case groups obtained and identical range of scores (10-100) for the "foot pain" domain. Nevertheless, the mean of the score was lower for the participants with FHL. Conclusions: The perception of the quality of general foot health was poorer in the school-aged group with FHL. Variables such as foot pain and footwear are likely contributors influencing the perception of foot health quality. The school-aged population with FHL faces a decline in the quality of foot life. Ensuring adequate foot control in children and implementing future foot programs for this population are imperative for enhancing school children's perception of foot health and managing the development of pain and footwear-related issues.
RESUMO
Family history questionnaires (FHQ) are useful tools for cancer genetic counseling, providing an informational basis for pedigree construction and individualized cancer risk assessment. Reported return rates of mailed FHQs amongst familial cancer clinics that utilize them are lower than desired however, and it is unknown whether patients perceive required completion of a FHQ as a barrier to access of cancer genetics services. This study critically evaluated the use of a mailed FHQ for all routine new patient referrals to a single hereditary cancer clinic in Quebec, Canada. Reasons for response/non-response to a FHQ and the effect of administration of a questionnaire on patients' self-reported level of motivation to pursue genetic counseling, were examined. Of 112 eligible individuals referred during the study period, 86 completed a semi-structured telephone survey; of these, 45% had returned the mailed FHQ prior to the telephone survey (Responders) and 55% had not (Non-responders). Overall, the majority of participants indicated a FHQ is an acceptable and understandable method of collecting family history information. Most prevalent reasons for not returning the FHQ were (bad) timing (56%), and difficulty accessing family history information (46%). Non-response was significantly associated with difficulty in asking relatives for the requested information (p = 0.011), and Non-responders cited fewer overall perceived benefits of cancer genetic counseling as compared with Responders (p < 0.0001). One quarter of Non-responders returned the mailed FHQ following administration of the telephone survey, suggesting implementation of a follow-up prompt is a cost-effective way to increase response.
Assuntos
Aconselhamento Genético , Anamnese , Neoplasias/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
Glucagonomas are rare pancreatic neuroendocrine tumors (pNETs), malignant in 80% of cases, thus highlighting the importance of early diagnosis and treatment. Primary manifestations are diabetes, dermatosis, depression, weight loss, and deep vein thrombosis. Unlike other pNETs, glucagonomas are associated with a higher incidence of thromboembolic events, often resulting in death. We present the case of a glucagonoma patient whose primary manifestation was cerebral sinus venous thrombosis (CS-VT). Early diagnosis enabled curative resection. The purpose of this paper is to review the underlying mechanisms associated with increased coagulopathy in glucagonomas.