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1.
J Emerg Med ; 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34627638

RESUMO

BACKGROUND: Acquired arteriovenous fistulas (AVFs) are most commonly caused by direct arterial trauma, with 90% of traumatic AVFs due to penetrating trauma. Post-traumatic common carotid artery-internal jugular vein fistulae are rare, with an incidence of 4% to 7% of all traumatic AVFs. CASE REPORT: We present a case of delayed presentation of a patient with shortness of breath, neck pain, and worsening right upper extremity paresthesias 10 days after a blunt injury to the neck by an arrow. He was subsequently found to have a common carotid artery-internal jugular vein fistula and a common carotid pseudoaneurysm on computed tomography angiography. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Post-traumatic common carotid-jugular AVFs are uncommon, especially in patients with delayed presentations and a blunt injury mechanism. If left untreated, AVFs may progress to high-output cardiac failure, atrial fibrillation, and embolization. Clinicians must be aware of this finding, given the potential for significant morbidity.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34598376

RESUMO

OBJECTIVES: Insulin resistance may be associated with impaired lung function. The objective of this study was to examine the relationship between insulin resistance and lung function in asthmatic children. METHODS: We performed a cross-sectional study on asthmatic children aged 6-18 years at Tertiary Care Center, India. Fasting serum glucose and insulin levels were analyzed to calculate the homeostatic model assessment of insulin resistance (HOMA-IR) in 90 children. Lung function tests were performed. Spearman correlation was used to assess the relationship between insulin resistance and lung function. Linear regression was done to adjust the potential confounders. RESULTS: Insulin resistance was present in 15.5% of patients. We found a statistically significant inverse relationship between HOMA-IR and spirometric parameters such as forced expiratory volume in 1 s/forced vital capacity ratio and forced expiratory flow between 25 and 75% on Spearman correlation. However, adjusted regression for age, gender, and body mass index showed no significant association of lung function parameters with HOMA-IR. CONCLUSIONS: Insulin resistance may be considered for the decline in lung function in asthmatic children.

3.
Neurol India ; 69(4): 1018-1020, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34507433

RESUMO

A 45-year-old man presented with acute onset ataxia for last 1 week. On examination he had signs of left-sided cerebellar involement. MRI brain revealed asymmetric altered signal intensities in bilateral cerebellar hemispheres suggesting demyelinating lesions. ELISA for Human Immune Deficiency virus-1 was positive. CSF JC virus DNA PCR was positive. A diagnosis of Progressive Multifocal Leukoencephalopathy (PML) was made on the basis of clinico-radiological picture and JC virus DNA PCR presence in CSF. PML is unknown and under diagnosed CNS infection seen in HIV patients mostly seen with advanced disease. We present an unusual case report where isolated cerebellar involvement occurred as the first AIDS defining event in the absence of appreciable immunodeficiency in a patient with previously undiagnosed HIV infection.


Assuntos
Ataxia Cerebelar , Infecções por HIV , Leucoencefalopatia Multifocal Progressiva , Ataxia Cerebelar/etiologia , Infecções por HIV/complicações , Humanos , Leucoencefalopatia Multifocal Progressiva/complicações , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem
5.
Lupus ; : 9612033211045069, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34558344

RESUMO

AIM: To determine the clinicopathological characteristics and outcomes of children diagnosed with lupus nephritis in a tertiary hospital in western Rajasthan and compare it with the data available from other parts of India. MATERIAL AND METHODS: A retrospective review of children presenting to a tertiary care center in western Rajasthan, India, with a diagnosis of pediatric Systemic Lupus Erythematosus (p SLE), between July 2017 and July 2020 was done. Comparisons of pediatric lupus in western India to other parts of country were done. RESULTS: 19 children with SLE with Renal involvement were enrolled and followed up. The median age at presentation was 15 years (IQR-16-9.5) (73% females). 8/19 (42%) children presented with AKI, of which 62% children presented as rapidly progressive renal failure. Six (37.5%) patients required dialysis at presentation. 84.21% of children were evaluated with renal biopsy, 16 biopsies were done in 19 children, among which class II, III, and IV lupus nephritis were reported in 21%,42%, and 35% respectively(4 crescentic). Antiphospholipid antibodies were positive in 8/15(53%), children which is much higher than a reported incidence of 30% in other Indian studies. Ten patients (52%) had neurological involvement, with seizures being the most common form of presentation (60%). Seven patients (36%) developed hepatitis. We noted many uncommon presentations in the small group like Autoimmune Pancreatitis, Mononeuritis multiplex, and peripheral digital gangrene. Cyclophosphamide was used in 10 out of 19 patients for inducing remission with class 3 and 4 nephritis and MMF in 8 children. 55% patients attained remission (after completing induction), of which 4 relapsed during the follow up. Four patients were lost to follow-up. A total of 27% patients died and 10% patients developed end stage renal failure. It was seen that those who died had more cardiac and neurological involvement at presentation, higher grade of proteinuria, lower GFR, and need for dialysis at admission. CONCLUSION: We found a more severe form of clinical manifestation in pediatric SLE patients at the time of the first presentation in the form of severe renal and extrarenal manifestation compared to other parts of the country.

6.
J Appl Genet ; 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535887

RESUMO

Rice false smut (RFS), an emerging major fungal disease worldwide caused by Ustilaginoidea virens, affects rice grain quality and yield. RFS cause 2.8-49% global yield loss depending upon disease severity and cultivars. In India, the yield loss due to RFS ranged from 2 to 75%. Identification of the genes or quantitative trait loci (QTLs) governing disease resistance would be of utmost importance towards mitigating the economic losses incurred due to RFS. Here, we report mapping of RFS resistance QTLs from a resistant breeding line RYT2668. The mapping population was evaluated for RFS resistance under the field condition in three cropping seasons 2013, 2015, and 2016. A positive correlation among infected panicle/plant, total smut ball/panicle, and disease score was observed in the years 2013, 2015, and the mean data. A total of seven QTLs were mapped on rice chromosomes 2, 4, 5, 7, and 9 using 2326 single nucleotide polymorphism markers. Of these, two QTLs, qRFSr5.3 and qRFSr7.1a, were associated with the infected panicle per plant, one QTL qRFsr9.1 with total smut ball per panicle, and four QTLs qRFSr2.2, qRFSr4.3, qRFSr5.4, and qRFSr7.1b with disease score. Among them, a novel QTL qRFSr9.1 on chromosome 9 exhibits the largest phenotypic effect. The prediction of putative candidate genes within the qRFSr9.1 revealed four nucleotide-binding sites-leucine-rich repeat (NBS-LRR) domain-containing disease resistance proteins. In summary, our findings mark the hotspot region of rice chromosomes carrying genes/QTLs for resistance to the RFS disease.

7.
J Trace Elem Med Biol ; 68: 126853, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34543780

RESUMO

BACKGROUND: In utero exposure to toxic metal substances can cause severe neurodevelopmental deficits in developing fetus and infant. METHODS: We evaluated the association of newborn umbilical cord blood lead concentration with early neurodevelopmental performance (cognitive, receptive language, expressive language, fine motor, gross motor and social-emotional development). The Bayley Scale of Infants Developments-III (BSID-III) was used to perform neurodevelopment outcomes at an average age of 6.5 months. In this prospective study, total of 167 mother-child pairs were enrolled from Western Rajasthan, India. Association between risk factors of lead contamination and newborn umbilical cord blood lead levels was observed. Multivariate regression was performed to see the association of cord blood lead level with infant neurodevelopment outcome. RESULTS: The obtained newborn umbilical cord blood lead concentration 5.0-10.5 µg/dL was negatively associated with the sub-scale score of gross motor development (ß-coefficient with 95 % CI; -0.29 (-5.0-0.11), p = 0.04). However, no associations were found with the score of cognitive, language, gross motor, and social-emotional development. The umbilical cord blood lead concentration <5.0 µg/dL was also not associated with the BSID-III scores. The mother's regular intake of calcium supplements during the antenatal period was significantly associated with a lower umbilical cord blood lead level (p-value 0.031). CONCLUSION: The data suggest that newborn umbilical cord blood lead concentration 0.5-10.5 µg/dL has a negative association with early gross motor development during infancy.

8.
Phys Eng Sci Med ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34468965

RESUMO

Being one of the most prevalent neurological disorders, epilepsy affects the lives of patients through the infrequent occurrence of spontaneous seizures. These seizures can result in serious injuries or unexpected deaths in individuals due to accidents. So, there exists a crucial need for an automatic prediction of epileptic seizures to alert the patients well before the onset of seizures, enabling them to have a healthier quality of life. In this era, the Internet of Things (IoT) technologies are being used in a cloud-fog integrated environment to address such healthcare challenges using deep learning approaches. The present paper also proposes a smart health monitoring approach for automated prediction of epileptic seizures using deep learning-based spectral analysis of EEG signals. This approach processes EEG signals using filtering, segmentation into short duration segments and spectral-domain transformation. These signals are then analysed spectrally by separating them into several spectral bands, such as delta, theta, alpha, beta, and sub-bands of gamma. Furthermore, the mean spectral amplitude and spectral power features are retrieved from each spectral band to characterize various seizure states, which are fed to the proposed LSTM and CNN models. The results of the proposed CNN model show a maximum accuracy of 98.3% and 97.4% to obtain a binary classification of preictal and interictal seizure states for two different spectral band combinations respectively. Thus, the proposed CNN architecture accompanied by spectral analysis of EEG signals provides a viable method for reliable and real-time prediction of epileptic seizures.

9.
Ann Plast Surg ; 87(3): 291-297, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34397517

RESUMO

BACKGROUND: Small recalcitrant defects of the mandible and maxilla may be secondary to tumor, trauma, infection, and congenital origin. Vascularized bone grafting has been shown to effectively manage these defects; however, donor sites are limited. The vascularized medial femoral condyle (MFC) provides adequate cortical cancellous bone with the option of a skin island, consistent anatomy, and minimal donor site morbidity. This article outlines the use of the MFC flap for maxillomandibular reconstruction. METHODS: A retrospective chart review of patients who required segmental maxillomandibular reconstruction with the MFC flap was conducted. A total of 9 patients (5 men and 5 women) with an average age of 45.3 years were identified. The etiology of the defects, flap sizes, and postoperative outcomes were recorded. RESULTS: Three patients had osteoradionecrosis of the neomandible after irradiation of the free fibula reconstruction, 3 patients had defects after cancer extirpation (1 mandible, 2 maxillary), 1 patient had a maxillary defect from trauma, and 2 patients had a residual cleft palate defect. All defects failed initial treatment with nonvascularized bone grafts. The average dimensions of the MFC flaps were 1.2 × 2.5 × 4 cm. Two of 9 flaps included a skin island. Eight flaps survived completely, but 1 patient suffered from flap failure requiring debridement and resulted in an oroantral fistula. Four patients received endosseous dental implants. Average time to union was 6.7 months, and average time to implant was 6.75 months. The average follow-up time was 24.9 months. CONCLUSIONS: The MFC flap is useful in the reconstruction of small segmental maxillomandibular defects and for the salvage of a neomandible after osteoradionecrosis. The MFC flap provides a reliable platform for endosseous dental implants and serves as an alternative source of vascularized bone reconstruction in the head and neck.


Assuntos
Retalhos de Tecido Biológico , Procedimentos Cirúrgicos Reconstrutivos , Transplante Ósseo , Feminino , Fêmur , Humanos , Masculino , Mandíbula/cirurgia , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Molecules ; 26(16)2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34443598

RESUMO

Apocynin (APO) is a known multi-enzymatic complexed compound, employed as a viable NADPH oxidase (NOX) inhibitor, extensively used in both traditional and modern-day therapeutic strategies to combat neuronal disorders. However, its therapeutic efficacy is limited by lower solubility and lesser bioavailability; thus, a suitable nanocarrier system to overcome such limitations is needed. The present study is designed to fabricate APO-loaded polymeric nanoparticles (APO-NPs) to enhance its therapeutic efficacy and sustainability in the biological system. The optimized APO NPs in the study exhibited 103.6 ± 6.8 nm and -13.7 ± 0.43 mV of particle size and zeta potential, respectively, along with further confirmation by TEM. In addition, the antioxidant (AO) abilities quantified by DPPH and nitric oxide scavenging assays exhibited comparatively higher AO potential of APO-NPs than APO alone. An in-vitro release profile displayed a linear diffusion pattern of zero order kinetics for APO from the NPs, followed by its cytotoxicity evaluation on the PC12 cell line, which revealed minimal toxicity with higher cell viability, even after treatment with a stress inducer (H2O2). The stability of APO-NPs after six months showed minimal AO decline in comparison to APO only, indicating that the designed nano-formulation enhanced therapeutic efficacy for modulating NOX-mediated ROS generation.


Assuntos
Acetofenonas/química , Acetofenonas/farmacologia , Peróxido de Hidrogênio/farmacologia , NADPH Oxidases/metabolismo , Nanopartículas/química , Neurônios/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Sobrevivência Celular/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Células PC12 , Ratos
11.
Abdom Radiol (NY) ; 46(11): 5114-5124, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34379149

RESUMO

PURPOSE: To determine the diagnostic performance of an abbreviated non-contrast MRI protocol in diagnosing acute appendicitis. METHODS: Prospectively, a total of 67 consenting consecutive patients with clinical suspicion of acute appendicitis (Alvarado score ≥ 5) were evaluated with an abbreviated three-sequence non-contrast MRI protocol (axial T2WI, coronal T2WI, axial DWI) at a single tertiary care center. MRI was interpreted by two radiologists blinded to the clinical details, other investigations, and outcome of the patients. Diagnostic performance of MRI was determined using either histopathological examination (HPE) results as the reference standard in surgical cases (n = 39), or final clinical diagnosis at discharge and 3-months follow-up in non-operatively managed cases (n = 28). RESULTS: Sixty-seven patients comprising 42 males, 25 females including 1 pregnant patient were enrolled (median age 24 years; age range 6-70 years). The median acquisition duration of the MRI protocol was 12.5 min. In the analysis of the complete cohort including both surgical and non-operatively managed cases (n = 67), MRI showed sensitivity of 93.3% (95% CI 81.7-98.6%), specificity of 86.4% (95% CI 65.1-97.1%), and diagnostic accuracy of 91.0% (95% CI 81.5-96.6%) (p < 0.001). In the subset of surgical cases with HPE as the reference standard (n = 39), MRI showed sensitivity of 97.1% (95% CI 84.7-99.9%), specificity of 100% (95% CI 47.8-100%), and diagnostic accuracy of 98% (95% CI 87.5-100%) (p < 0.001). CONCLUSION: MRI may be performed to diagnose acute appendicitis or alternative causes of right iliac fossa pain. An abbreviated MRI protocol consisting of only three sequences without IV contrast, patient preparation, or antiperistaltic agents could shorten the examination duration while retaining diagnostic accuracy.

12.
Genomics ; 113(5): 3198-3215, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34293475

RESUMO

A genome-wide association study (GWAS) was conducted using six different multi-locus GWAS models and 35K SNP array to demarcate genomic regions underlying reproductive stage salinity tolerance. Marker-trait association analysis was performed for salt tolerance indices (STI) of 11 morpho-physiological traits, and the actual concentrations of Na+ and K+, and the Na+/K+ ratio in flag leaf. A total of 293 significantly associated quantitative trait nucleotides (QTNs) for 14 morpho-physiological traits were identified. Of these 293 QTNs, 12 major QTNs with R2 ≥ 10.0% were detected in three or more GWAS models. Novel major QTNs were identified for plant height, number of effective tillers, biomass, grain yield, thousand grain weight, Na+ and K+ content, and the Na+/K+ ratio in flag leaf. Moreover, 48 candidate genes were identified from the associated genomic regions. The QTNs identified in this study could potentially be targeted for improving salinity tolerance in wheat.

14.
Rev Sci Instrum ; 92(6): 063303, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34243544

RESUMO

A tuner is an important element of a superconducting radio frequency (SCRF) cavity, which is used to tune the cavity at resonance frequency. The measurement and control of the pulsed detuning phenomenon is very challenging and can be measured in the superconducting state of the cavity at a high voltage gradient. This paper describes an innovative method and unique approach for the measurement of dynamic changes in resonance frequency of the SCRF cavity even at room temperature. For this purpose, a 1.3 GHz nine-cell prototype dressed cavity with RRCAT's designed X-link tuning device is used. A test setup for measurements of dynamic changes in resonance frequency of the RF cavity has been designed and developed. The cavity response for piezo-excitation at various pulse widths has been determined. In order to simulate the Lorentz force detuning (LFD) effect, the source frequency has been modulated similar to the superconducting scenario in the SCRF cavity. To compensate the simulated detuning, a fast tuner is operated with half sinusoidal pulses at various combinations of pulse width and time advance to find out an optimum waveform. This optimized waveform will be used with a fast tuning control system to control LFD under actual operation conditions of the SCRF cavity.

15.
J Trop Pediatr ; 67(3)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34152424

RESUMO

INTRODUCTION: There is a lack of large multicentric studies in children with COVID-19 from developing countries. We aimed to describe the clinical profile and risk factors for severe disease in children hospitalized with COVID-19 from India. METHODS: In this multicentric retrospective study, we retrieved data related to demographic details, clinical features, including the severity of disease, laboratory investigations and outcome. RESULTS: We included 402 children with a median (IQR) age of 7 (2-11) years. Fever was the most common symptom, present in 38.2% of children. About 44% had underlying comorbidity. The majority were asymptomatic (144, 35.8%) or mildly symptomatic (219, 54.5%). There were 39 (9.7%) moderate-severe cases and 13 (3.2%) deaths. The laboratory abnormalities included lymphopenia 25.4%, thrombocytopenia 22.1%, transaminitis 26.4%, low total serum protein 34.7%, low serum albumin 37.9% and low alkaline phosphatase 40%. Out of those who were tested, raised inflammatory markers were ferritin 58.9% (56/95), c-reactive protein 33.3% (41/123), procalcitonin 53.5% (46/86) and interleukin-6 (IL-6) 76%. The presence of fever, rash, vomiting, underlying comorbidity, increased total leucocyte count, thrombocytopenia, high urea, low total serum protein and raised c-reactive protein was factors associated with moderate to severe disease. CONCLUSION: Fever was the commonest symptom. We identified additional laboratory abnormalities, namely lymphopenia, low total serum protein and albumin and low alkaline phosphatase. The majority of the children were asymptomatic or mildly symptomatic. We found high urea and low total serum protein as risk factors for moderate to severe disease for the first time.


Assuntos
COVID-19 , SARS-CoV-2 , Criança , Humanos , Índia/epidemiologia , Estudos Retrospectivos , Fatores de Risco
16.
Indian J Pediatr ; 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117623

RESUMO

OBJECTIVE: To explore the association of symptoms of sleep-related breathing disorders (SRBD) with asthma control in Indian children. METHODS: This study was carried out in the pediatric chest clinic of a tertiary care center in western India. Children from 6 to 18 y of age with a physician-diagnosed case of asthma were included in the study. A validated pediatric sleep questionnaire, SRBD scale, was used to screen the symptoms of SRBD. At the same time, Asthma Control Questionnaire (ACQ) was administered to assess asthma control. RESULTS: A total of 207 (73% boys) children with asthma were enrolled; the median age was 10 (7, 13) y. Asthma symptoms were well controlled (ACQ ≤ 0.75) in 102 (49.3%) and partly or poorly controlled (ACQ > 0.75) in 105 (50.7%) children. Inattention and/or hyperactivity was the most common SRBD symptom observed in 125 (60.4%) children; daytime sleepiness, mouth breathing, snoring, and night-time breathing problems were observed in 92 (44.5%), 91 (44%), 77 (37.2%), and 68 (32.8%) children, respectively. SRBD score showed a near-linear correlation with ACQ score (r = 0.28, p < 0.001). The score was positive in 52 (25.1%) children. A positive SRBD score was statistically more common in partly or poorly controlled asthma (aOR 2.5; 95% CI: 1.2-5.0; p = 0.01). However, the positive score did not show a statistically significant association with gender, being underweight, obesity, allergic rhinitis, compliance to therapy, and inhalation technique. CONCLUSION: SRBD symptoms are common in children with asthma. They showed a statistically significant association with partly or poorly controlled asthma. Therefore, it would be interesting to look for SRBD symptoms in children with partly or poorly controlled asthma.

17.
PLoS One ; 16(5): e0251891, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34003869

RESUMO

Quick identification and isolation of SARS-CoV-2 infected individuals is central to managing the COVID-19 pandemic. Real time reverse transcriptase PCR (rRT-PCR) is the gold standard for COVID-19 diagnosis. However, this resource-intensive and relatively lengthy technique is not ideally suited for mass testing. While pooled testing offers substantial savings in cost and time, the size of the optimum pool that offers complete concordance with results of individualized testing remains elusive. To determine the optimum pool size, we first evaluated the utility of pool testing using simulated 5-sample pools with varying proportions of positive and negative samples. We observed that 5-sample pool testing resulted in false negativity rate of 5% when the pools contained one positive sample. We then examined the diagnostic performance of 4-sample pools in the operational setting of a diagnostic laboratory using 500 consecutive samples in 125 pools. With background prevalence of 2.4%, this 4-sample pool testing showed 100% concordance with individualized testing and resulted in 66% and 59% reduction in resource and turnaround time, respectively. Since the negative predictive value of a diagnostic test varies inversely with prevalence, we re-tested the 4-sample pooling strategy using a fresh batch of 500 samples in 125 pools when the prevalence rose to 12.7% and recorded 100% concordance and reduction in cost and turnaround time by 36% and 30%, respectively. These observations led us to conclude that 4-sample pool testing offers the optimal blend of resource optimization and diagnostic performance across difference disease prevalence settings.


Assuntos
Teste de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , SARS-CoV-2/genética , Manejo de Espécimes , COVID-19/virologia , Humanos , RNA Viral/análise , Reação em Cadeia da Polimerase em Tempo Real , SARS-CoV-2/isolamento & purificação
18.
Sci Rep ; 11(1): 7254, 2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790381

RESUMO

Phenylketonuria (PKU) is an autosomal recessive inborn error of L-phenylalanine (Phe) metabolism. It is caused by a partial or complete deficiency of the enzyme phenylalanine hydroxylase (PAH), which is necessary for conversion of Phe to tyrosine (Tyr). This metabolic error results in buildup of Phe and reduction of Tyr concentration in blood and in the brain, leading to neurological disease and intellectual deficits. Patients exhibit retarded body growth, hypopigmentation, hypocholesterolemia and low levels of neurotransmitters. Here we report first attempt at creating a homozygous Pah knock-out (KO) (Hom) mouse model, which was developed in the C57BL/6 J strain using CRISPR/Cas9 where codon 7 (GAG) in Pah gene was changed to a stop codon TAG. We investigated 2 to 6-month-old, male, Hom mice using comprehensive behavioral and biochemical assays, MRI and histopathology. Age and sex-matched heterozygous Pah-KO (Het) mice were used as control mice, as they exhibit enough PAH enzyme activity to provide Phe and Tyr levels comparable to the wild-type mice. Overall, our findings demonstrate that 6-month-old, male Hom mice completely lack PAH enzyme, exhibit significantly higher blood and brain Phe levels, lower levels of brain Tyr and neurotransmitters along with lower myelin content and have significant behavioral deficit. These mice exhibit phenotypes that closely resemble PKU patients such as retarded body growth, cutaneous hypopigmentation, and hypocholesterolemia when compared to the age- and sex-matched Het mice. Altogether, biochemical, behavioral, and pathologic features of this novel mouse model suggest that it can be used as a reliable translational tool for PKU preclinical research and drug development.

19.
Oncoimmunology ; 10(1): 1881268, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33796402

RESUMO

Immune checkpoint blockade elicits durable anti-cancer responses in the clinic, however a large proportion of patients do not benefit from treatment. Several mechanisms of innate and acquired resistance to checkpoint blockade have been defined and include mutations of MHC I and IFNγ signaling pathways. However, such mutations occur in a low frequency of patients and additional mechanisms have yet to be elucidated. In an effort to better understand acquired resistance to checkpoint blockade, we generated a mouse tumor model exhibiting in vivo resistance to anti-PD-1 antibody treatment. MC38 tumors acquired resistance to PD-1 blockade following serial in vivo passaging. Lack of sensitivity to PD-1 blockade was not attributed to dysregulation of PD-L1 or ß2M expression, as both were expressed at similar levels in parental and resistant cells. Similarly, IFNγ signaling and antigen processing and presentation pathways were functional in both parental and resistant cell lines. Unbiased gene expression analysis was used to further characterize potential resistance mechanisms. RNA-sequencing revealed substantial differences in global gene expression, with tumors resistant to anti-PD-1 displaying a marked reduction in expression of immune-related genes relative to parental MC38 tumors. Indeed, resistant tumors exhibited reduced immune infiltration across multiple cell types, including T and NK cells. Pathway analysis revealed activation of TGFß and Notch signaling in anti-PD-1 resistant tumors, and activation of these pathways was associated with poorer survival in human cancer patients. While pharmacological inhibition of TGFß and Notch in combination with PD-1 blockade decelerated tumor growth, a local mRNA-based immunotherapy potently induced regression of resistant tumors, resulting in complete tumor remission, and resensitized tumors to treatment with anti-PD-1. Overall, this study describes a novel anti-PD-1 resistant mouse tumor model and underscores the role of two well-defined signaling pathways in response to immune checkpoint blockade. Furthermore, our data highlights the potential of intratumoral mRNA therapy in overcoming acquired resistance to PD-1 blockade.


Assuntos
Imunoterapia , Neoplasias , Animais , Apresentação do Antígeno , Modelos Animais de Doenças , Humanos , Camundongos , RNA Mensageiro/genética
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