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1.
Ann Hematol ; 103(1): 73-88, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37917373

RESUMO

Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow, and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a trans-membrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. However, its role in chemotherapy response is still unknown; therefore, the aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy. The expression of CD45 on myeloid leukaemia primary cells and cell lines was heterogeneous with HEL and OCI-AML3 cells showing the highest level. Inhibition of CD45 resulted in increased cellular sensitivity to cytarabine and ruxolitinib, the two main therapies for AML and MPN. Bioinformatics analysis identified genes whose expression was correlated with CD45 expression such as JAK2, ACTR2, THAP3 Serglycin, and PBX-1 genes, as well as licensed drugs (alendronate, allopurinol, and balsalazide), which could be repurposed as CD45 inhibitors which effectively increases sensitivity to cytarabine and ruxolitinib at low doses. Therefore, CD45 inhibition could be explored as a potential therapeutic partner for treatment of myeloid malignancies in combination with chemotherapy such as cytarabine especially for elderly patients and those showing chemotherapy resistance.


Assuntos
Leucemia Mieloide Aguda , Leucemia Mieloide , Transtornos Mieloproliferativos , Humanos , Idoso , Leucemia Mieloide/tratamento farmacológico , Pirazóis/uso terapêutico , Nitrilas/uso terapêutico , Citarabina , Transtornos Mieloproliferativos/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo
2.
Int J Mol Sci ; 24(6)2023 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-36982791

RESUMO

Paediatric acute myeloid leukaemia (AML) continues to present treatment challenges, as no "standard approach" exists to treat those young patients reliably and safely. Combination therapies could become a viable treatment option for treating young patients with AML, allowing multiple pathways to be targeted. Our in silico analysis of AML patients highlighted "cell death and survival" as an aberrant, potentially targetable pathway in paediatric AML patients. Therefore, we aimed to identify novel combination therapies to target apoptosis. Our apoptotic drug screening resulted in the identification of one potential "novel" drug pairing, comprising the Bcl-2 inhibitor ABT-737 combined with the CDK inhibitor Purvalanol-A, as well as one triple combination of ABT-737 + AKT inhibitor + SU9516, which showed significant synergism in a series of paediatric AML cell lines. Using a phosphoproteomic approach to understand the apoptotic mechanism involved, proteins related to apoptotic cell death and cell survival were represented, in agreement with further results showing differentially expressed apoptotic proteins and their phosphorylated forms among combination treatments compared to single-agent treated cells such upregulation of BAX and its phosphorylated form (Thr167), dephosphorylation of BAD (Ser 112), and downregulation of MCL-1 and its phosphorylated form (Ser159/Thr 163). Total levels of Bcl-2 were decreased but correlated with increased levels of phosphorylated Bcl-2, which was consistent with our phosphoproteomic analysis predictions. Bcl-2 phosphorylation was regulated by extracellular-signal-regulated kinase (ERK) but not PP2A phosphatase. Although the mechanism linking to Bcl-2 phosphorylation remains to be determined, our findings provide first-hand insights on potential novel combination treatments for AML.


Assuntos
Leucemia Mieloide Aguda , Criança , Humanos , Linhagem Celular Tumoral , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Apoptose
3.
Int J Mol Sci ; 22(18)2021 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-34576326

RESUMO

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.


Assuntos
Sobrevivência Celular/fisiologia , Leucemia Mieloide Aguda/metabolismo , Antineoplásicos/uso terapêutico , Western Blotting , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Reposicionamento de Medicamentos , Citometria de Fluxo , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação/genética
7.
Nanomedicine ; 13(3): 921-932, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27979747

RESUMO

HPV subtypes (16, 18) are associated with the development of cervical cancer, with oncoproteins E6 and E7 responsible for pathogenesis. The goal of this study was to evaluate our 'smart system' technology platform for DNA vaccination against cervical cancer. The vaccination platform brings together two main components; a peptide RALA which condenses DNA into cationic nanoparticles (NPs), and a polymeric polyvinylpyrrolidone (PVP) microneedle (MN) patch for cutaneous delivery of the loaded NPs. RALA condensed E6/E7 DNA into NPs not exceeding 100nm in diameter, and afforded the DNA protection from degradation in PVP. Sera from mice vaccinated with MN/RALA-E6/E7 were richer in E6/E7-specific IgGs, displayed a greater T-cell-mediated TC-1 cytotoxicity and contained more IFN-γ than sera from mice that received NPs intramuscularly. More importantly, MN/RALA-E6/E7 delayed TC-1 tumor initiation in a prophylactic model, and slowed tumor growth in a therapeutic model of vaccination, and was more potent than intramuscular vaccination.


Assuntos
Vacinas Anticâncer/administração & dosagem , Técnicas de Transferência de Genes/instrumentação , Oligopeptídeos/química , Infecções por Papillomavirus/prevenção & controle , Povidona/química , Neoplasias do Colo do Útero/prevenção & controle , Vacinação/instrumentação , Vacinas de DNA/administração & dosagem , Administração Cutânea , Animais , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Linhagem Celular , Colo do Útero/imunologia , Colo do Útero/patologia , Colo do Útero/virologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Papillomavirus Humano 16/genética , Papillomavirus Humano 16/imunologia , Papillomavirus Humano 18/genética , Papillomavirus Humano 18/imunologia , Humanos , Imunidade Humoral , Camundongos Endogâmicos C57BL , Agulhas , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias do Colo do Útero/virologia , Vacinas de DNA/genética , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico
8.
Mol Pharm ; 13(4): 1217-28, 2016 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-26954700

RESUMO

Bisphosphonates (BPs) are a class of bone resorptive drug with a high affinity for the hydroxyapatite structure of bone matrices that are used for the treatment of osteoporosis. However, clinical application is limited by a common toxicity, BP-related osteonecrosis of the jaw. There is emerging evidence that BPs possess anticancer potential, but exploitation of these antiproliferative properties is limited by their toxicities. We previously reported the utility of a cationic amphipathic fusogenic peptide, RALA, to traffic anionic nucleic acids into various cell types in the form of cationic nanoparticles. We hypothesized that complexation with RALA could similarly be used to conceal a BP's hydroxyapatite affinity, and to enhance bioavailability, thereby improving anticancer efficacy. Incubation of RALA with alendronate, etidronate, risedronate, or zoledronate provoked spontaneous electrostatic formation of cationic nanoparticles that did not exceed 100 nm in diameter and that were stable over a range of temperatures and for up to 6 h. The nanoparticles demonstrated a pH responsiveness, possibly indicative of a conformational change, that could facilitate release of the BP cargo in the endosomal environment. RALA/BP nanoparticles were more potent anticancer agents than their free BP counterparts in assays investigating the viability of PC3 prostate cancer and MDA-MB-231 breast cancer cells. Moreover, RALA complexation potentiated the tumor growth delay activity of alendronate in a PC3 xenograft model of prostate cancer. Taken together, these findings further validate the use of BPs as repurposed anticancer agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Difosfonatos/química , Nanopartículas/química , Peptídeos/química , Peptídeos/farmacologia , Alendronato/química , Alendronato/farmacologia , Alendronato/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Conservadores da Densidade Óssea/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Humanos , Imidazóis/química , Imidazóis/farmacologia , Masculino , Camundongos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Ácido Zoledrônico
9.
Int J Pharm ; 653: 123841, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38266939

RESUMO

A dry powder inhaled liposomal azithromycin formulation was developed for the treatment of chronic respiratory diseases such as cystic fibrosis and bronchiectasis. Key properties including liposome size, charge and encapsulation efficiency powder size, shape, glass transition temperature (Tg), water content and in vitro respiratory deposition were determined. Antimicrobial activity against cystic fibrosis (CF) respiratory pathogens was determined by MIC, MBC and biofilm assays. Cytotoxicity and cellular uptake studies were performed using A549 cells. The average liposome size was 105 nm, charge was 55 mV and encapsulation efficiency was 75 %. The mean powder particle size d[v,50] of 4.54 µm and Mass Median Aerodynamic Diameter (MMAD) was 5.23 µm with a mean Tg of 76˚C and water content of 2.1 %. These excellent physicochemical characteristics were maintained over one year. Liposomal loaded azithromycin demonstrated enhanced activity against P. aeruginosa clinical isolates grown in biofilm. The formulation was rapidly delivered into bacterial cells with > 75 % uptake in 1 h. Rapid uptake into A549 cells via a cholesterol-dependent endocytosis pathway with no cytotoxic effects apparent. These data demonstrate that this formulation could offer benefits over current treatment regimens for people with chronic respiratory infection.


Assuntos
Fibrose Cística , Infecções Respiratórias , Humanos , Azitromicina , Antibacterianos , Lipossomos/uso terapêutico , Pós , Fibrose Cística/tratamento farmacológico , Administração por Inalação , Infecções Respiratórias/tratamento farmacológico , Água , Tamanho da Partícula , Inaladores de Pó Seco
10.
Cell Signal ; 114: 111004, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38048856

RESUMO

Acute myeloid leukemia (AML) is a type of blood cancer that is characterized by the rapid growth of abnormal myeloid cells. The goal of AML treatment is to eliminate the leukemic blasts, which is accomplished through intensive chemotherapy. Cytarabine is a key component of the standard induction chemotherapy regimen for AML. However, despite a high remission rate, 70-80% of AML patients relapse and develop resistance to Cytarabine, leading to poor clinical outcomes. Mitocurcumin (MitoC), a derivative of curcumin that enters mitochondria, leading to a drop in mitochondrial membrane potential and mitophagy induction. Further, it activates oxidative stress-mediated JNK/p38 signaling to induce apoptosis. MitoC demonstrated a preferential ability to kill leukemic cells from AML cell lines and patient-derived leukemic blasts. RNA sequencing data suggests perturbation of DNA damage response and cell proliferation pathways in MitoC-treated AML. Elevated reactive oxygen species (ROS) in MitoC-treated AML cells resulted in significant DNA damage and cell cycle arrest. Further, MitoC treatment resulted in ROS-mediated enhanced levels of p21, which leads to suppression of CHK1, RAD51, Cyclin-D and c-Myc oncoproteins, potentially contributing to Cytarabine resistance. Combinatorial treatment of MitoC and Cytarabine has shown synergism, increased apoptosis, and enhanced DNA damage. Using AML xenografts, a significant reduction of hCD45+ cells was observed in AML mice bone marrow treated with MitoC (mean 0.6%; range0.04%-3.56%) compared to control (mean 38.2%; range10.1%-78%), p = 0.03. The data suggest that MitoC exploits stress-induced leukemic oxidative environment to up-regulate JNK/p38 signaling to lead to apoptosis and can potentially overcome Cytarabine resistance via ROS/p21/CHK1 axis.


Assuntos
Curcumina , Leucemia Mieloide Aguda , Animais , Camundongos , Humanos , Citarabina/farmacologia , Citarabina/uso terapêutico , Espécies Reativas de Oxigênio , Leucemia Mieloide Aguda/genética , Apoptose , Estresse Oxidativo
11.
Cureus ; 16(4): e58024, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38738124

RESUMO

BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide and are considered silent killers that threaten different age groups. The stressful lifestyle of resident physicians might make them vulnerable to CVDs. Since 2021, Egypt has recently reported more frequent sudden deaths of junior physicians after long shifts. Many factors can be associated with this prevalence, such as diabetes mellitus, increased blood pressure, or a sedentary lifestyle. Therefore, this study aimed to estimate the risk of developing heart attack and stroke within 10 years among resident physicians in Egypt with the goal of informing health policymakers to improve the healthcare systems for Egyptian physicians. METHODS: This cross-sectional study was conducted at six university teaching hospitals around Egypt: Cairo, Al-Azhar, Zagazig, Menoufia, South Valley, and Sohag. Data were collected on the ground using a questionnaire developed from a validated tool, the QRISK3 calculator, developed by the National Health Service, and used to measure the development of CVDs and stroke over the next 10 years. RESULTS: Four hundred twenty-eight resident physicians filled out the study questionnaire, including 224 (52.3%) females. The mean age of the participants was 28.22 years (±2.54). The study revealed that 258 (60.3%), with a median (IQR) = 0.2% (0.1%-0.5%), of the resident physicians are at high risk of having a heart attack or stroke within 10 years. Migraine symptoms (n=65, 15.2%) and angina or heart attack in a first-degree relative (n=26, 6.1%) were the most reported risk factors. The risk was variable among the six university hospitals, with a significant P-value <0.001, where Menoufia University hospitals ranked first, followed by Zagazig University hospitals. However, the percentage of each specialty differs from others. The highest risk was among anesthesiology and ICU residents (n=18, 78.3%), followed by surgery residents (n=44, 62.9%). CONCLUSION: About 258 (60.3%) of the resident physicians are at risk of having a heart attack or stroke within 10 years. There is an urgent need to increase resident physicians' awareness about their heart attack and stroke risks and for health policymakers to ensure a better lifestyle and friendly training environment for resident physicians in Egypt.

12.
Diagn Cytopathol ; 51(10): 589-595, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37335285

RESUMO

BACKGROUND: Primary lung cancer is the leading cause of cancer death in the United States. Most lung cancers are diagnosed in an outpatient setting, but a subset requires intraoperative diagnosis. Two intraoperative diagnostic methods are available, frozen section (FS) and fine needle aspiration (FNA) cytology. This study compares intraoperative FNA cytology and FS based diagnosis in thoracic malignancies within the same clinical practice. METHODS: Pathology reports from thoracic intraoperative FNA cytology or FS (January 2017-December 2019) were reviewed. Resection diagnosis was the gold standard. If unavailable, concurrent biopsy and final FNA cytology diagnosis were the gold standard. RESULTS: Of 300 FNA specimens (155 patients), 142 (47%) cases were benign, and 158 (53%) were malignant. Adenocarcinoma was the most common malignant diagnosis (40%), followed by squamous cell carcinoma (26%), neuroendocrine tumors (18%), and other (16%). Intraoperative FNA yielded 88% sensitivity, 99% specificity, and 92% accuracy (p < .001). Of 298 FS specimens (252 patients), 215 (72%) cases were malignant and 83 (28%) were benign. Adenocarcinomas was the most common malignant diagnosis (48%), followed by squamous cell carcinoma (25%), metastatic carcinomas (13%), and other (14%). FS yielded 97% sensitivity, 99% specificity, and 97% accuracy (p < .001). CONCLUSION: Our findings confirm FS is the gold standard for intraoperative diagnosis. FNA cytology may be useful as a non-invasive, inexpensive initial diagnostic tool intraoperatively, given the similar specificity (99% FNA, 99% FS) and accuracy (92% FNA, 97% FS). Negative FNA could be followed by the costlier and invasive FS. We encourage surgeons to utilize intraoperative FNA first.


Assuntos
Adenocarcinoma , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Biópsia por Agulha Fina/métodos , Secções Congeladas , Sensibilidade e Especificidade , Adenocarcinoma/diagnóstico , Neoplasias Pulmonares/diagnóstico
13.
Cureus ; 14(6): e25946, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35855223

RESUMO

Adherence to either continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) therapy in patients with obstructive sleep apnea syndrome (OSAS) represents a real challenge to sleep medicine physicians. Many risk factors/predictors for nonadherence exist, and usually, it is multifactorial. Long-term nonadherence with CPAP therapy has been associated with the use of CPAP for <4 hours/night during early treatment, moderate to severe obstructive sleep apnea (OSA), poor self-efficacy, and unsupportive bed partner. The American Academy of Sleep Medicine (AASM) recommends follow-up of patients with OSA within the first two weeks of CPAP use to optimize adherence. Measures to improve adherence to positive airway pressure (PAP) therapy go through an integrated approach that involves behavioral therapy and prompt management of side effects. Pharmacologic therapy in the form of a sedative-hypnotic sleep aid has a minor role in managing nonadherence to CPAP based on the greater risk of side effects. This article will briefly discuss the risk factors and management of nonadherence to PAP therapy in patients with OSAS.

14.
Drug Deliv Transl Res ; 12(4): 931-943, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34302273

RESUMO

Chronic fungal infection of the cornea could lead to blindness if not treated properly. Topical amphotericin B (AMP-B) is considered the first treatment of choice for ocular fungal infection. However, factors related to its poor solubility and penetration through intact cornea lead to poor bioavailability. Microneedles (MNs) are emerging as a minimally invasive method to enhance ocular drug delivery. This study aims to investigate the potential use of biodegradable poly(vinylpyrrolidone) (PVP) and hyaluronic acid (HA)-based rapidly dissolving MNs for delivery of AMP-B to treat fungal infection. The data obtained illustrates PVP/HA MN arrays' reproducibility, good mechanical strength, and faster dissolution with 100% drug recovery. Multiphoton microscopic results revealed that MNs successfully penetrate the corneal tissue and enhance AMP-B permeation through corneal layers. Furthermore, PVP/HA MN arrays showed high solubility. Both PVP and HA successfully decreased AMP-B cytotoxicity when compared to free drug. More interestingly, the biocompatible MN formulations preserved the antifungal activity of AMP-B, as demonstrated by significant inhibition of fungal growth. Therefore, this study shows the feasibility of ocular delivery of the poorly soluble AMP-B using a fast-dissolving MN patch.


Assuntos
Anfotericina B , Infecções Oculares Fúngicas , Humanos , Administração Cutânea , Sistemas de Liberação de Medicamentos/métodos , Infecções Oculares Fúngicas/tratamento farmacológico , Ácido Hialurônico/uso terapêutico , Agulhas , Reprodutibilidade dos Testes
15.
Am J Clin Pathol ; 158(6): 692-701, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-36197800

RESUMO

OBJECTIVES: Monitoring of frozen section diagnostic performance provides an important quality improvement measure. METHODS: Surgical specimens involving a frozen section diagnosis over a 3-year period were retrospectively reviewed. Glass slides were reviewed on cases with discordance. Discordance and deferral rates were calculated. RESULTS: Of 3,675 frozen section diagnoses included, 96 (2.7%) were discordant with the final diagnosis. Additionally, 114 frozen section diagnoses (3.1%) were deferred. The organ-specific discordance rates were lowest in breast and genitourinary specimens and highest for pancreas, lymph node, and gynecologic specimens. Deferral rates were highest in musculoskeletal, breast, and hepatobiliary cases and lowest in thyroid, parathyroid, and neuropathology cases. Discordance was explained by block-sampling error (45%), specimen-sampling error (27%), or interpretation error (27%). Discordant frozen section diagnoses from gynecologic specimens were responsible for 81% of specimen-sampling errors; frozen section diagnoses of lymph nodes, head and neck, and pancreas were responsible for 54% of interpretation errors; 51% of block-sampling errors involved lymph node evaluation for metastatic carcinoma. CONCLUSIONS: Careful gross evaluation and microscopic examination of multiple levels should minimize specimen-sampling error and block-sampling error, respectively. Periodic review of accuracy and deferral rates may help reduce errors and improve the overall performance of this essential procedure.


Assuntos
Secções Congeladas , Patologia Cirúrgica , Feminino , Humanos , Secções Congeladas/métodos , Patologia Cirúrgica/métodos , Período Intraoperatório , Estudos Retrospectivos , Erros de Diagnóstico/prevenção & controle
16.
J Control Release ; 348: 849-869, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35728715

RESUMO

Photodynamic therapy (PDT) to manage non-melanoma skin cancers has garnered great attention over the past few years. Hypericin (Hy) is a potent lipid-soluble photosensitiser with promising anticancer therapeutic activities. Nevertheless, its poor water-solubility, aggregation in biological systems and insufficient skin penetration restricted its effective exploitation. Herein, we report for the first-time encapsulation of Hy into lipid nanocapsules (Hy-LNCs), and then application of an AdminPen™ hollow microneedles (Ho-MNs) array and an in-house fabricated Ho-MN to enable efficient intradermal delivery. The physicochemical properties, photoactivity, ex vivo drug distribution and cellular uptake were evaluated. Results showed that Hy-LNCs were successfully formed with a particle size of 47.76 ± 0.49 nm, PDI of 0.12 ± 0.02, high encapsulation efficiency (99.67% ± 0.35), 396 fold higher photoactivity, 7 fold higher skin drug deposition, significantly greater cellular uptake and higher photocytotoxicity compared to free Hy. The therapeutic effect of Hy-LNCs was finally assessed in vivo using a nude mouse model with transplanted tumours. Interestingly, Hy-LNCs delivered by Ho-MN exhibited remarkable anti-tumour destruction (85.84%) after irradiation with 595 nm. This study showed that Ho-MNs-driven delivery of Hy-LNCs followed by irradiation could form a promising minimally invasive, effective and site-specific approach for managing non-melanoma skin cancers.


Assuntos
Nanocápsulas , Fotoquimioterapia , Neoplasias Cutâneas , Animais , Antracenos , Lipídeos/química , Camundongos , Nanocápsulas/química , Perileno/análogos & derivados , Fotoquimioterapia/métodos , Neoplasias Cutâneas/tratamento farmacológico
17.
Viruses ; 14(2)2022 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-35215919

RESUMO

SARS-CoV-2 can efficiently infect both children and adults, albeit with morbidity and mortality positively associated with increasing host age and presence of co-morbidities. SARS-CoV-2 continues to adapt to the human population, resulting in several variants of concern (VOC) with novel properties, such as Alpha and Delta. However, factors driving SARS-CoV-2 fitness and evolution in paediatric cohorts remain poorly explored. Here, we provide evidence that both viral and host factors co-operate to shape SARS-CoV-2 genotypic and phenotypic change in primary airway cell cultures derived from children. Through viral whole-genome sequencing, we explored changes in genetic diversity over time of two pre-VOC clinical isolates of SARS-CoV-2 during passage in paediatric well-differentiated primary nasal epithelial cell (WD-PNEC) cultures and in parallel, in unmodified Vero-derived cell lines. We identified a consistent, rich genetic diversity arising in vitro, variants of which could rapidly rise to near fixation within two passages. Within isolates, SARS-CoV-2 evolution was dependent on host cells, with paediatric WD-PNECs showing a reduced diversity compared to Vero (E6) cells. However, mutations were not shared between strains. Furthermore, comparison of both Vero-grown isolates on WD-PNECs disclosed marked growth attenuation mapping to the loss of the polybasic cleavage site (PBCS) in Spike, while the strain with mutations in Nsp12 (T293I), Spike (P812R) and a truncation of Orf7a remained viable in WD-PNECs. Altogether, our work demonstrates that pre-VOC SARS-CoV-2 efficiently infects paediatric respiratory epithelial cells, and its evolution is restrained compared to Vero (E6) cells, similar to the case of adult cells. We highlight the significant genetic plasticity of SARS-CoV-2 while uncovering an influential role for collaboration between viral and host cell factors in shaping viral evolution and ultimately fitness in human respiratory epithelium.


Assuntos
Evolução Molecular , Mucosa Respiratória/virologia , SARS-CoV-2/genética , Animais , Células Cultivadas , Criança , Chlorocebus aethiops , Genótipo , Humanos , Mutação , Nariz/citologia , Nariz/virologia , Fenótipo , SARS-CoV-2/classificação , SARS-CoV-2/crescimento & desenvolvimento , Células Vero , Sequenciamento Completo do Genoma
18.
PLoS One ; 17(4): e0266412, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35436306

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the coronavirus disease-19 (COVID-19) pandemic, was identified in late 2019 and caused >5 million deaths by February 2022. To date, targeted antiviral interventions against COVID-19 are limited. The spectrum of SARS-CoV-2 infection ranges from asymptomatic to fatal disease. However, the reasons for varying outcomes to SARS-CoV-2 infection are yet to be elucidated. Here we show that an endogenously activated interferon lambda (IFNλ1) pathway leads to resistance against SARS-CoV-2 infection. Using a well-differentiated primary nasal epithelial cell (WD-PNEC) culture model derived from multiple adult donors, we discovered that susceptibility to SARS-CoV-2 infection, but not respiratory syncytial virus (RSV) infection, varied. One of four donors was resistant to SARS-CoV-2 infection. High baseline IFNλ1 expression levels and associated interferon stimulated genes correlated with resistance to SARS-CoV-2 infection. Inhibition of the JAK/STAT pathway in WD-PNECs with high endogenous IFNλ1 secretion resulted in higher SARS-CoV-2 titres. Conversely, prophylactic IFNλ treatment of WD-PNECs susceptible to infection resulted in reduced viral titres. An endogenously activated IFNλ response, possibly due to genetic differences, may be one explanation for the differences in susceptibility to SARS-CoV-2 infection in humans. Importantly, our work supports the continued exploration of IFNλ as a potential pharmaceutical against SARS-CoV-2 infection.


Assuntos
COVID-19 , Infecções por Vírus Respiratório Sincicial , Antivirais/farmacologia , Células Epiteliais/metabolismo , Humanos , Interferons/metabolismo , Interferons/farmacologia , Janus Quinases/metabolismo , SARS-CoV-2 , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais
19.
J Clin Pathol ; 74(9): 548-552, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34039664

RESUMO

The leucocyte common antigen, protein tyrosine phosphatase receptor type C (PTPRC), also known as CD45, is a transmembrane glycoprotein, expressed on almost all haematopoietic cells except for mature erythrocytes, and is an essential regulator of T and B cell antigen receptor-mediated activation. Disruption of the equilibrium between protein tyrosine kinase and phosphatase activity (from CD45 and others) can result in immunodeficiency, autoimmunity, or malignancy. CD45 is normally present on the cell surface, therefore it works upstream of a large signalling network which differs between cell types, and thus the effects of CD45 on these cells are also different. However, it is becoming clear that CD45 plays an essential role in the innate immune system and this is likely to be a key area for future research. In this review of PTPRC (CD45), its structure and biological activities as well as abnormal expression of CD45 in leukaemia and lymphoma will be discussed.


Assuntos
Antígenos Comuns de Leucócito , Humanos
20.
PeerJ ; 9: e11611, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34178471

RESUMO

OBJECTIVES: To assess the knowledge about cervical cancer and HPV infection and the awareness towards and perceived barriers of HPV vaccination amid medical students in Jordan. METHODS: The present study is a cross-sectional survey that was conducted for a period of three months in the College of Medicine at six different universities in Jordan. Third-year to sixth-year students from these medical colleges in Jordan were invited to participate in the study. RESULTS: There were 504 students that took part in the study with 42.3% being males and 57.7% females. The mean knowledge score of students in our survey was 21.4 ± 4.4 out of 34, which was categorized as a moderate level of knowledge regarding cervical cancer and HPV. Only 40.5% knew about the availability of the HPV vaccine in Jordan, and 65.9% accepted the idea that it is necessary to introduce the HPV vaccine for school girls in Jordan. CONCLUSIONS: This study highlights that there is inadequate knowledge about cervical cancer and its screening among medical students in Jordan. Despite the limited awareness about the HPV vaccine among the study's participants, there is a favorable opinion towards the introduction of the vaccine for school girls in Jordan. The data provide a benchmark on the level of knowledge about cervical cancer and awareness about HPV, which can be used to formulate an effective awareness program.

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