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1.
Immunopharmacol Immunotoxicol ; : 1-14, 2024 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-39376102

RESUMO

OBJECTIVE: One of the most effective treatments for allergic respiratory diseases is allergen-specific sublingual immunotherapy (SLIT). While, mannose targeting has been applied in various immunostimulatory approaches, but it has not been investigated in sublingual allergen-specific immunosuppressive treatment. This study assesses mannose targeting for the ovalbumin (Ova) loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles(NPs). METHODS: The emulsion-solvent evaporation method was employed for the synthesis of PLGA NPs containing Ova, and subsequently they attached to D-mannose. Ova-sensitized mice underwent treatment in different ways: subcutaneous administration of 10 µg Ova, sublingual administration of 5 and 10 µg Ova loaded in PLGA NPs, 5 and 10 µg Ova loaded in mannose-targeted PLGA NPs, 10 µg Ova, and 10 µg Ova loaded in dendritic cell-specific aptamer-attached PLGA NPs. Serum Ova-specific IgE and IgG2a levels, as well as IFN-γ, IL-4, IL-10, and IL-17a levels in the supernatant of Ova-stimulated splenocytes were measured. Splenocyte proliferation was assessed using an MTT assay, and also lung histological examinations, and nasal lavage fluid cell counting were performed. RESULTS: Ova-specific IgE, IL-4, IL-17a levels, eosinophil cell count, and splenocyte proliferation were remarkably reduced in the mice treated with mannose or aptamer targeted NPs compared to other groups. Also, IL-10 and IFN-γ levels were remarkably increased in the targeted NPs groups. CONCLUSION: Our findings indicated that mannose targeting of PLGA NPs could decrease allergen dose and improve immunomodulatory effects of SLIT. However, this approach suggests an effective formulation for SLIT in the mice model, further studies with common allergens are needed for application in humans.

2.
Lett Appl Microbiol ; 77(9)2024 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-39237462

RESUMO

The antibacterial, antibiofilm, and cytotoxicity activity of cell-free supernatants (CFSs) from probiotics, including Lactobacillus plantarum, Bifidobacterium bifidum, and Saccharomyces cerevisiae against multi-drug resistant Escherichia coli evaluated in current research. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the CFSs were determined by analyzing inhibition zone formation using agar disk diffusion for antibacterial activity, microtiter plate for biofilm analysis, and auto-aggregation were done. CFSs substances were analyzed by GC-MS. The MTT assay on HEK293 cells investigated CFS's influence on cell viability. CFSs were examined for biofilm-related virulence genes, including aggR and fimH using real-time polymerase chain reaction (real-time PCR). All CFSs had bacteriostatic and bactericidal effects. The B. bifidum exhibited the highest antibiofilm activity compared to the others. Bifidobacterium bifidum, L. plantarum, and S. cerevisiae produce 19, 16, and 11 mm inhibition zones against E. coli, respectively. GC-MS indicated that Hydroxyacetone, 3-Hydroxybutyric acid, and Oxime-methoxy-phenyl-dominated CFSs from L. plantarum, B. bifidum, and S. cerevisiae CFSs, respectively. The MTT test demonstrated a cell viability rate of over 90%. Statistically, adding all CFSs lowered the relative expression of both aggR and fimH virulence genes.


Assuntos
Antibacterianos , Biofilmes , Farmacorresistência Bacteriana Múltipla , Escherichia coli , Testes de Sensibilidade Microbiana , Probióticos , Saccharomyces cerevisiae , Probióticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Humanos , Biofilmes/efeitos dos fármacos , Antibacterianos/farmacologia , Lactobacillus plantarum/metabolismo , Lactobacillus plantarum/genética , Células HEK293 , Bifidobacterium bifidum , Sobrevivência Celular/efeitos dos fármacos , Lactobacillales/metabolismo , Lactobacillales/genética
3.
Heliyon ; 10(14): e34692, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39149034

RESUMO

The emergence and development of antibiotic resistance in bacteria is a serious threat to global public health. Antibiotic resistance genes (ARGs) are often located on mobile genetic elements (MGEs). They can be transferred among bacteria by horizontal gene transfer (HGT), leading to the spread of drug-resistant strains and antibiotic treatment failure. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR-associated genes) is one of the many strategies bacteria have developed under long-term selection pressure to restrict the HGT. CRISPR-Cas systems exist in about half of bacterial genomes and play a significant role in limiting the spread of antibiotic resistance. On the other hand, bacteriophages and other MGEs encode a wide range of anti-CRISPR proteins (Acrs) to counteract the immunity of the CRISPR-Cas system. The Acrs could decrease the CRISPR-Cas system's activity against phages and facilitate the acquisition of ARGs and virulence traits for bacteria. This review aimed to assess the relationship between the CRISPR-Cas systems and Acrs with bacterial antibiotic resistance. We also highlighted the CRISPR technology and Acrs to control and prevent antibacterial resistance. The CRISPR-Cas system can target nucleic acid sequences with high accuracy and reliability; therefore, it has become a novel gene editing and gene therapy tool to prevent the spread of antibiotic resistance. CRISPR-based approaches may pave the way for developing smart antibiotics, which could eliminate multidrug-resistant (MDR) bacteria and distinguish between pathogenic and beneficial microorganisms. Additionally, the engineered anti-CRISPR gene-containing phages in combination with antibiotics could be used as a cutting-edge treatment approach to reduce antibiotic resistance.

4.
Mediators Inflamm ; 2024: 5821996, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39045230

RESUMO

Background: Psoriasis is a noncontagious auto-inflammatory chronic skin disease. So far, some of the inflammatory genes were upregulated in mouse model of psoriasis. This study examined changes in skin mRNA expression of L-kynureninase (Kynu), cathelicidin antimicrobial peptide (Camp), beta-defensin 2 (Defb2), and proenkephalin (Penk) in a mouse model of imiquimod-induced psoriasis. Materials and Methods: Tree groups of C57BL/6 female mice were allocated. The imiquimod (IMQ) cream was administered to the mice dorsal skin of the two groups to induce psoriatic inflammation. In the treatment group, IMQ was administered 10 min after hydrogel-containing M7 anti-IL-17A aptamer treatment. Vaseline (Vas) was administered to the negative control group. The psoriatic skin lesions were evaluated based on the psoriasis area severity index (PASI) score, histopathology, and mRNA expression levels of Kynu, Camp, Defb2, and Penk using real-time PCR. In order to assess the systemic response, the spleen and lymph node indexes were also evaluated. Results: The PASI and epidermal thickness scores were 6.01 and 1.96, respectively, in the IMQ group, and they significantly decreased after aptamer administration to 1.15 and 0.90, respectively (P < 0.05). Spleen and lymph node indexes showed an increase in the IMQ group, followed by a slight decrease after aptamer treatment (P > 0.05). Additionally, the mRNA expression levels of Kynu, Defb2, Camp, and Penk genes in the IMQ-treated region showed a significant 2.70, 4.56, 3.29, and 2.61-fold increase relative to the Vas mice, respectively (P < 0.05). The aptamer-treated region exhibited a significant decrease in these gene expression levels (P < 0.05). A positive correlation was found between Kynu, Penk, and Camp expression levels and erythema, as well as Camp expression with PASI, scaling, and thickness (P < 0.05). Conclusion: According to our results, it seems that Kynu, Camp, and Penk can be considered appropriate markers for the evaluation of psoriasis in IMQ-induced psoriasis. Also, the anti-IL-17 aptamer downregulated these important genes in this mouse model.


Assuntos
Catelicidinas , Modelos Animais de Doenças , Encefalinas , Imiquimode , Camundongos Endogâmicos C57BL , Precursores de Proteínas , Psoríase , beta-Defensinas , Psoríase/induzido quimicamente , Psoríase/metabolismo , Animais , Camundongos , Feminino , beta-Defensinas/metabolismo , beta-Defensinas/genética , Precursores de Proteínas/metabolismo , Precursores de Proteínas/genética , Encefalinas/metabolismo , Encefalinas/genética , Peptídeos Catiônicos Antimicrobianos/metabolismo , Pele/metabolismo , Pele/patologia , Pele/efeitos dos fármacos , Biomarcadores/metabolismo
5.
BMC Infect Dis ; 24(1): 554, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38831286

RESUMO

BACKGROUND AND OBJECTIVE(S): CRISPR-Cas is a prokaryotic adaptive immune system that protects bacteria and archaea against mobile genetic elements (MGEs) such as bacteriophages plasmids, and transposons. In this study, we aimed to assess the prevalence of the CRISPR-Cas systems and their association with antibiotic resistance in one of the most challenging bacterial pathogens, Klebsiella pneumoniae. MATERIALS AND METHODS: A total of 105 K. pneumoniae isolates were collected from various clinical infections. Extended-spectrum ß-lactamases (ESBLs) phenotypically were detected and the presence of ESBL, aminoglycoside-modifying enzymes (AME), and CRISPR-Cas system subtype genes were identified using PCR. Moreover, the diversity of the isolates was determined by enterobacterial repetitive intergenic consensus (ERIC)-PCR. RESULTS: Phenotypically, 41.9% (44/105) of the isolates were found to be ESBL producers. A significant inverse correlation existed between the subtype I-E CRISPR-Cas system's presence and ESBL production in K. pneumoniae isolates. Additionally, the frequency of the ESBL genes blaCTX-M1 (3%), blaCTX-M9 (12.1%), blaSHV (51.5%), and blaTEM (33.3%), as well as some AME genes such as aac(3)-Iva (21.2%) and ant(2'')-Ia (3%) was significantly lower in the isolates with the subtype I-E CRISPR-Cas system in comparison to CRISPR-negative isolates. There was a significant inverse correlation between the presence of ESBL and some AME genes with subtype I-E CRISPR-Cas system. CONCLUSION: The presence of the subtype I-E CRISPR-Cas system was correlated with the antibiotic-resistant gene (ARGs). The isolates with subtype I-E CRISPR-Cas system had a lower frequency of ESBL genes and some AME genes than CRISPR-negative isolates.


Assuntos
Antibacterianos , Sistemas CRISPR-Cas , Infecções por Klebsiella , Klebsiella pneumoniae , beta-Lactamases , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/efeitos dos fármacos , Humanos , beta-Lactamases/genética , Infecções por Klebsiella/microbiologia , Infecções por Klebsiella/epidemiologia , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana/genética , Prevalência , Masculino , Feminino , Pessoa de Meia-Idade
6.
Mol Cancer Ther ; : OF1-OF11, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38853421

RESUMO

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited because of dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for patients with LSCC. Moreover, other options for chemotherapy-ineligible patients are limited. As such, there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. In this study, we investigated inhibiting TRAF2- and NCK-interacting protein kinase (TNIK), which is amplified in 40% of patients with LSCC, as a strategy to sensitize LSCC tumors to chemotherapy and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in patients with LSCC with high TNIK expression.

7.
Semin Radiat Oncol ; 34(3): 344-350, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38880543

RESUMO

FLASH radiotherapy (RT) is emerging as a potentially revolutionary advancement in cancer treatment, offering the potential to deliver RT at ultra-high dose rates (>40 Gy/s) while significantly reducing damage to healthy tissues. Democratizing FLASH RT by making this cutting-edge approach more accessible and affordable for healthcare systems worldwide would have a substantial impact in global health. Here, we review recent developments in FLASH RT and present perspective on further developments that could facilitate the democratizing of FLASH RT. These include upgrading and validating current technologies that can deliver and measure the FLASH radiation dose with high accuracy and precision, establishing a deeper mechanistic understanding of the FLASH effect, and optimizing dose delivery conditions and parameters for different types of tumors and normal tissues, such as the dose rate, dose fractionation, and beam quality for high efficacy. Furthermore, we examine the potential for democratizing FLASH radioimmunotherapy leveraging evidence that FLASH RT can make the tumor microenvironment more immunogenic, and parallel developments in nanomedicine or use of smart radiotherapy biomaterials for combining RT and immunotherapy. We conclude that the democratization of FLASH radiotherapy represents a major opportunity for concerted cross-disciplinary research collaborations with potential for tremendous impact in reducing radiotherapy disparities and extending the cancer moonshot globally.


Assuntos
Neoplasias , Humanos , Neoplasias/radioterapia , Dosagem Radioterapêutica , Fracionamento da Dose de Radiação , Radioterapia/métodos , Microambiente Tumoral/efeitos da radiação
8.
J Pharm Biomed Anal ; 247: 116245, 2024 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-38810331

RESUMO

Interleukin (IL)-23 inhibitor monoclonal antibodies shown significant efficacy in treating autoimmune diseases. DNA or RNA aptamers exhibit comparable specificity to antibodies, are cost-effective, non-immunogenic, and do not have batch to batch variation. This study aimed to characterize a single-stranded DNA (ssDNA) aptamer targeting human IL-23. The alpha subunit of IL-23 (P19) and intact IL-23 were cloned, expressed, and the proteins finally were purified through Ni2+-iminodiacetic acid affinity chromatography. The selection and characterization of ssDNA aptamer against P19 were conducted using the protein-systematic evolution of ligands by exponential enrichment (SELEX). Dot blot assay was carried out to monitor binding of the aptamer output of SELEX rounds, to P19 protein. The dissociation constant (Kd) of aptamers with positive results in dot blot assay, determined based on their binding to IL-23 using an ELISA method. Recombinant P19 and IL-23 proteins were 26 and 72 kDa, respectively, observed on SDS-PAGE .12 %. The aptamers output from 7, 8, 9, 10, 11, and 12 rounds of the SELEX was monitored by dot blot assay, revealing that the aptamer from the round 8 has stronger luminescent signal and was selected for TA-cloning. After analyzing the biotinylated aptamers from clones, positive clones in dot blot assay and ELISA were sequenced. Finally, the Kd calculation revealed three aptamers with high affinity, named A23P3, A23P6, and A23P15 with Kd values of 1.37, 2.139, and 2.88 nM, respectively. Results of this study introduced three specific anti-IL-23 ssDNA aptamers with high affinity, which could be utilized for therapeutic and diagnostic purposes.


Assuntos
Aptâmeros de Nucleotídeos , DNA de Cadeia Simples , Técnica de Seleção de Aptâmeros , Aptâmeros de Nucleotídeos/química , Técnica de Seleção de Aptâmeros/métodos , Humanos , Interleucina-23/antagonistas & inibidores , Proteínas Recombinantes , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Cromatografia de Afinidade/métodos
9.
Mol Cancer Ther ; 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38670554

RESUMO

Most patients with lung squamous cell carcinoma (LSCC) undergo chemotherapy, radiotherapy, and adjuvant immunotherapy for locally advanced disease. The efficacy of these treatments is still limited due to dose-limiting toxicity or locoregional recurrence. New combination approaches and targets such as actionable oncogenic drivers are needed to advance treatment options for LSCC patients. Moreover, other options for chemotherapy-ineligible patients are also limited. As such there is a critical need for the development of selective and potent chemoradiosensitizers for locally advanced LSCC. Here, we investigated inhibiting TRAF2 and NCK-interacting protein kinase (TNIK), which is amplified in 40% of LSCC patients, as a strategy to sensitize LSCC tumors to chemo- and radiotherapy. Employing a range of human LSCC cell lines and the TNIK inhibitor NCB-0846, we investigated the potential of TNIK as a chemo- and radiosensitizing target with in vitro and in vivo preclinical models. The combination of NCB-0846 with cisplatin or etoposide was at best additive. Interestingly, pre-treating LSCC cells with NCB-0846 prior to ionizing radiation (IR) potentiated the cytotoxicity of IR in a TNIK-specific fashion. Characterization of the radiosensitization mechanism suggested that TNIK inhibition may impair the DNA damage response and promote mitotic catastrophe in irradiated cells. In a subcutaneous xenograft in vivo model, pretreatment with NCB-0846 significantly enhanced the efficacy of IR and caused elevated necrosis in TNIKhigh LK2 tumors but not TNIKlow KNS62 tumors. Overall, these results indicate that TNIK inhibition may be a promising strategy to increase the efficacy of radiotherapy in LSCC patients with high TNIK expression.

10.
Diagn Microbiol Infect Dis ; 109(2): 116229, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38507962

RESUMO

Some strains of Escherichia coli are known to be involved in the pathogenesis of colorectal cancer (CRC). The aim of current study was to compare the general characteristics of the E. coli from CRC patients and healthy participants. A total of 96 biopsy samples from 48 CRC patients and 48 healthy participants, were studied. The clonality of the E. coli isolates was analyzed by Enterobacterial repetitive intergenic consensus-based PCR (ERIC-PCR) method. The strains were tested by PCR to determine the prevalence of different virulence factors. According to the results of ERIC-PCR analysis, (from the 860 E. coli isolates) 60 strains from CRC patients and 41 strains from healthy controls were identified. Interestingly, the majority of the strains of both groups were in the same cluster. Enteropathogenic E. coli (EPEC) was detected significantly more often in CRC patients (21.6 %) than in healthy participants (2.4 %) (p < 0.05). The Enteroaggregative E. coli (EAEC) was found in 18.33 % of the strains of CRC patients. However, other pathotypes were not found in the E. coli strains of both groups. Furthermore, all the studied genes encoding for virulence factors seemed to be more prevalent in the strains belonging to CRC patients. Among the virulence genes, the statistical difference regarding the frequency of fuyA, chuA, vat, papC, hlyA and cnf1 genes was found significant (p < 0.05). In conclusion, E. coli strains that carry extraintestinal pathogenic E. coli (ExPEC) and diarrheagenic E. coli (DEC) multiple virulence factors colonize the gut mucosa of CRC patients.


Assuntos
Neoplasias Colorretais , Infecções por Escherichia coli , Escherichia coli , Mucosa Intestinal , Fatores de Virulência , Humanos , Neoplasias Colorretais/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Fatores de Virulência/genética , Idoso , Escherichia coli/genética , Escherichia coli/patogenicidade , Escherichia coli/isolamento & purificação , Escherichia coli/classificação , Infecções por Escherichia coli/microbiologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Adulto , Idoso de 80 Anos ou mais , Reação em Cadeia da Polimerase , Escherichia coli Enteropatogênica/genética , Escherichia coli Enteropatogênica/patogenicidade , Escherichia coli Enteropatogênica/isolamento & purificação , Escherichia coli Enteropatogênica/classificação
11.
Heliyon ; 10(5): e26809, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38449645

RESUMO

Role of clustered regularly interspaced short palindromic repeats (CRISPR)-like sequences in antibiotic resistance and biofilm formation isn't clear. This study investigated association of CRISPR-like sequences with antibiotic resistance and biofilm formation in H. pylori isolates. Thirty-six of H. pylori isolates were studied for existence of CRISPR-like sequences using PCR method and their correlation with biofilm formation and antibiotic resistance. Microtiter-plate technique was utilized for investigating antibiotic resistance profile of isolates against amoxicillin, tetracycline, metronidazole and clarithromycin. Biofilm formation of isolates was analyzed by microtiter-plate-based-method. Out of 23 CRISPR-like positive isolates, 19 had ability of biofilm formation and 7 of 13 CRISPR-like negative isolates were able to form biofilm (Pvalue = 0.445). In CRISPR-like positive isolates, 11 (48%), 18 (78%), 18 (78%) and 23 (100%) were resistant to amoxicillin, tetracycline, metronidazole and clarithromycin, respectively. Since CRISPR-like sequences have role in antibiotic resistance, may be applied as genetic markers of antibiotic resistance. But there was no substantial correlation between biofilm formation and existence of CRISPR-like sequences. These results indicate possible importance of CRISPR-like sequences on acquisition of resistance to antibiotics in this bacterium.

13.
DNA (Basel) ; 4(1): 34-51, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38282954

RESUMO

Motivation: Clustered DNA-lesions are predominantly induced by ionizing radiation, particularly by high-LET particles, and considered as lethal damage. Quantification of this specific type of damage as a function of radiation parameters such as LET, dose rate, dose, and particle type can be informative for the prediction of biological outcome in radiobiological studies. This study investigated the induction and complexity of clustered DNA damage for three different types of particles at an LET range of 0.5-250 keV/µm. Methods: Nanometric volumes (36.0 nm3) of 15 base-pair DNA with its hydration shell was modeled. Electron, proton, and alpha particles at various energies were simulated to irradiate the nanometric volumes. The number of ionization events, low-energy electron spectra, and chemical yields for the formation of °OH, H°, eaq-, and H2O2 were calculated for each particle as a function of LET. Single- and double-strand breaks (SSB and DSB), base release, and clustered DNA-lesions were computed from the Monte-Carlo based quantification of the reactive species and measured yields of the species responsible for the DNA lesion formation. Results: The total amount of DNA damage depends on particle type and LET. The number of ionization events underestimates the quantity of DNA damage at LETs higher than 10 keV/µm. Minimum LETs of 9.4 and 11.5 keV/µm are required to induce clustered damage by a single track of proton and alpha particles, respectively. For a given radiation dose, an increase in LET reduces the number of particle tracks, leading to more complex clustered DNA damage, but a smaller number of separated clustered damage sites. Conclusions: The dependency of the number and the complexity of clustered DNA damage on LET and fluence suggests that the quantification of this damage can be a useful method for the estimation of the biological effectiveness of radiation. These results also suggest that medium-LET particles are more appropriate for the treatment of bulk targets, whereas high-LET particles can be more effective for small targets.

14.
Cancers (Basel) ; 16(1)2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38201648

RESUMO

BACKGROUND: This study aims to present the feasibility of developing a synchrotron-based proton ultra-high dose rate (UHDR) pencil beam scanning (PBS) system. METHODS: The RF extraction power in the synchrotron system was increased to generate 142.4 MeV pulsed proton beams for UHDR irradiation at ~100 nA beam current. The charge per spill was measured using a Faraday cup. The spill length and microscopic time structure of each spill was measured with a 2D strip transmission ion chamber. The measured UHDR beam fluence was used to derive the spot dwell time for pencil beam scanning. Absolute dose distributions at various depths and spot spacings were measured using Gafchromic films in a solid-water phantom. RESULTS: For proton UHDR beams at 142.4 MeV, the maximum charge per spill is 4.96 ± 0.10 nC with a maximum spill length of 50 ms. This translates to an average beam current of approximately 100 nA during each spill. Using a 2 × 2 spot delivery pattern, the delivered dose per spill at 5 cm and 13.5 cm depth is 36.3 Gy (726.3 Gy/s) and 56.2 Gy (1124.0 Gy/s), respectively. CONCLUSIONS: The synchrotron-based proton therapy system has the capability to deliver pulsed proton UHDR PBS beams. The maximum deliverable dose and field size per pulse are limited by the spill length and extraction charge.

15.
Med Phys ; 51(2): 1474-1483, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37458068

RESUMO

PURPOSE: Most current research toward ultra-high dose rate (FLASH) radiation is conducted with advanced proton and electron accelerators, which are of limited accessibility to basic laboratory research. An economical alternative to charged particle accelerators is to employ high-capacity rotating anode x-ray tubes to produce kilovoltage x-rays at FLASH dose rates at short source-to-surface distances (SSD). This work describes a comprehensive dosimetric evaluation of a rotating anode x-ray tube for potential application in laboratory FLASH study. METHODS AND MATERIALS: A commercially available high-capacity fluoroscopy x-ray tube with 75 kW input power was implemented as a potential FLASH irradiator. Radiochromic EBT3 film and thermoluminescent dosimeters (TLDs) were used to investigate the effects of SSD and field size on dose rates and depth-dose characteristics in kV-compatible solid water phantoms. Custom 3D printed accessories were developed to enable reproducible phantom setup at very short SSD. Open and collimated radiation fields were assessed. RESULTS: Despite the lower x-ray energy and short SSD used, FLASH dose rates above 40 Gy/s were achieved for targets up to 10-mm depth in solid water. Maximum surface dose rates of 96 Gy/s were measured in the open field at 47 mm SSD. A non-uniform high-to-low dose gradient was observed in the planar dose distribution, characteristic of anode heel effects. With added collimation, beams up to 10-mm diameter with reasonable uniformity can be produced. Typical 80%-20% penumbra in the collimated x-ray FLASH beams were less than 1 mm at 5-mm depth in phantom. Ramp-up times at the maximum input current were less than 1 ms. CONCLUSION: Our dosimetric characterization demonstrates that rotating anode x-ray tube technology is capable of producing radiation beams in support of preclinical FLASH radiobiology research.


Assuntos
Radiometria , Água , Raios X , Radiometria/métodos , Dosagem Radioterapêutica , Fluoroscopia
16.
J Glob Antimicrob Resist ; 36: 151-159, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38154746

RESUMO

OBJECTIVES: Plasmid genes, termed mobile colistin resistance-1 (mcr-1) and mobile colistin resistance-2 (mcr-2), are associated with resistance to colistin in Escherichia coli (E. coli). These mcr genes result in a range of protein modifications contributing to colistin resistance. This study aims to discern the proteomic characteristics of E. coli-carrying mcr-1 and mcr-2 genes. Furthermore, it evaluates the expression levels of various proteins under different conditions (with and without colistin). METHODS: Plasmid extraction was performed using an alkaline lysis-based plasmid extraction kit, whereas polymerase chain reaction was used to detect the presence of mcr-1 and mcr-2 plasmids. The E. coli DH5α strain served as the competent cell for accepting and transforming mcr-1 and mcr-2 plasmids. We assessed proteomic alterations in the E. coli DH5α strain both with and without colistin in the growth medium. Proteomic data were analysed using mass spectrometry. RESULTS: The findings revealed significant protein changes in the E. coli DH5α strain following cloning of mcr-1 and mcr-2 plasmids. Of the 20 proteins in the DH5α strain, expression in 8 was suppressed following transformation. In the presence of colistin in the culture medium, 39 new proteins were expressed following transformation with mcr-1 and mcr-2 plasmids. The proteins with altered expression play various roles. CONCLUSION: The results of this study highlight numerous protein alterations in E. coli resulting from mcr-1 and mcr-2-mediated resistance to colistin. This understanding can shed light on the resistance mechanism. Additionally, the proteomic variations observed in the presence and absence of colistin might indicate potential adverse effects of indiscriminate antibiotic exposure on treatment efficacy and heightened pathogenicity of microorganisms.


Assuntos
Colistina , Proteínas de Escherichia coli , Colistina/farmacologia , Escherichia coli/genética , Escherichia coli/metabolismo , Proteoma , Proteômica , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Farmacorresistência Bacteriana/genética , Antibacterianos/farmacologia , Clonagem Molecular
17.
BMC Infect Dis ; 23(1): 765, 2023 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-37932679

RESUMO

BACKGROUND: Neutropenia is the most important cause of life-threatening invasive fungal infections (IFIs). Here, we studied the frequency and antifungal susceptibility profiles of Candida species that colonized or caused infections among neutropenic patients with solid or hematological malignancies. METHODS: A total of 362 clinical samples were collected from 138 patients. After initial isolation using a mix of mycological methods, isolates were screened using chromogenic culture media. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied for molecular identification. Positive or suspected cases were confirmed using the reference method of sequencing. Antifungal susceptibility testing for voriconazole and caspofungin was carried out using the microbroth dilution method. An in-silico assay was applied for phylogenetic analysis. RESULTS: Thirty-four Candida strains were isolated. C. albicans (47.06%) and C. glabrata (29.41%) were the most frequent strains. Antifungal treatment reduced the chance of Candida colonization by almost 76% in neutropenic patients (OR: 1.759; 95% CI: 1.349 to 2.390; p value: 0.000). An unusual and non-resistant strain, C. lambica, was reported from the bloodstream of a 56-year-old man with hematologic malignancy (HM). Eight isolates were non-susceptible, and one isolate was resistant to voriconazole. Also, four isolates were non-susceptible to caspofungin. CONCLUSION: We can conclude that there is a cause-and-effect relationship between neutropenia, HM background, and Candida species separated from neutropenic patients, which can lead to possible infections. Further and repetitive studies are recommended using different molecular methods for better prediction and management of fungal infections in neutropenic patients.


Assuntos
Antifúngicos , Neutropenia , Humanos , Masculino , Pessoa de Meia-Idade , Antifúngicos/farmacologia , Candida , Candida albicans , Candida glabrata , Caspofungina , Farmacorresistência Fúngica , Testes de Sensibilidade Microbiana , Neutropenia/tratamento farmacológico , Filogenia , Voriconazol
18.
Artigo em Inglês | MEDLINE | ID: mdl-37877143

RESUMO

In recent years, one of the most critical topics in microbiology that can be addressed is microbiome and microbiota. The term microbiome contains both the microbiota and structural elements, metabolites/signal molecules, and the surrounding environmental conditions, and the microbiota consists of all living members forming the microbiome. Among; the intestinal microbiota is one of the most important microbiota, also called the gut microbiota. After colonization, the gut microbiota can have different functions, including resistance to pathogens, maintaining the intestinal epithelium, metabolizing dietary and pharmaceutical compounds, and controlling immune function. Recently, studies have shown that the gut microbiota can prevent the formation of fat in the body. In this study, we examined the gut microbiota in various animals, including dogs, cats, dairy cows, sheep, chickens, horses, and people who live in urban and rural areas. Based on the review of various studies, it has been determined that the population of microbiota in animals and humans is different, and various factors such as the environment, nutrition, and contact with animals can affect the microbiota of people living in urban and rural areas.

19.
Heliyon ; 9(7): e17880, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37539246

RESUMO

Sepsis is a complex clinical disorder with heterogeneous etiological factors. Given its high mortality rate, it is considered a global health issue. Recently, the link between gut microbiota and their metabolites, especially short-chain fatty acids, in the pathophysiology of sepsis has been reported. However, there are few findings to confirm this relationship. This study aimed to evaluate some key gut microbiota members, pathogenic bacteria, and short-chain fatty acids in non-ICU patients with sepsis caused by bacteremia compared to a control group. In this case-control study, 45 stool samples from patients with sepsis and 15 healthy persons were collected from October 2021 to August 2022 in Tabriz, Iran. The position of some gut microbiota members and the main short-chain fatty acids concentration were assessed in the two groups by the Q-PCR and the high-performance liquid chromatography system. Faecalibacterium prausnitzii and Bifidobacterium sp. As bacterial with protective features in non-ICU patients with sepsis decreased significantly. Moreover, the concentrations of acetic acid and propionic acid significantly decreased in this group compared to the healthy volunteers. In contrast, the pathogenic bacteria members such as Enterobacteriaceae and Bacteroides sp. Increased significantly in the patients compared to the healthy individuals. The concentration of butyric acid decreased in the patients, but this change was not significant in the two groups. Protective and immune functions of F. prausnitzii and Bifidobacterium sp., as well as acetate and propionate, are evident. In this investigation, this profile was significantly reduced in non-ICU patients with sepsis compared to the control group.

20.
Egypt J Med Hum Genet ; 24(1): 3, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37519898

RESUMO

Background: Tuberculosis (TB) is considered one of the most infectious diseases in the world. In this study, we intended to examine the epidemiology of tuberculosis by MIRU-VNTR to define the changes that occur in the transmission of tuberculosis in the region during the COVID-19 era. A total of 120 Mycobacterium tuberculosis isolates were collected from sputum samples of patients referred to East Azerbaijan Center TB from December 2020 to August 2021. Demographic information such as age, sex, place of birth, previous TB history, and relevant medical data was collected. The proportion method was performed for drug susceptibility testing, and the PCR-based MIRU-VNTR method was applied to identify molecular epidemiology relationships. Results: The isolates were collected from 78 male (65%) and 39 female (32.5%) Iranian patients and 3 (2.5%) Azerbaijani patients. Ninety-three distinct patterns were identified including 15 clustered patterns and 36 unique patterns. The largest cluster was composed of seven isolates. Furthermore, one cluster with 5 members, four clusters with 3 members, and nine clusters with 2 members. In MIRU-VNTR typing, 75 clusters belonged to the Tabriz region and just 3 to the Republic of Azerbaijan. All isolates were sensitive to rifampin, isoniazid, and ethambutol. Conclusions: Results of the current study showed COVID-19 pandemic had a direct effect on the transmission and diagnosis of tuberculosis. Less diagnosis and less clustering can indicate public controls and hygiene, and the use of masks had a direct effect on the transmission and diagnosis of tuberculosis. However, misidentification and less focus on other respiratory infections are expected during the pandemic. Studies on the co-infection of COVID-19 and tuberculosis and the role of mask and sanitization against TB are strongly recommended.

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