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1.
Braz. j. biol ; 83: e247422, 2023. tab, graf
Artigo em Inglês | LILACS, VETINDEX | ID: biblio-1285631

RESUMO

Abstract Plasmodium falciparum resistance to Chloroquine (CQ) is a significant cause of mortality and morbidity worldwide. There is a paucity of documented data on the prevalence of CQ-resistant mutant haplotypes of Pfcrt and Pfmdr1 genes from malaria-endemic war effected Federally Administered Tribal Areas of Pakistan. The objective of this study was to investigate the prevalence of P. falciparum CQ-resistance in this area. Clinical isolates were collected between May 2017 and May 2018 from North Waziristan and South Waziristan agencies of Federally Administrated Trial Area. Subsequently, Giemsa-stained blood smears were examined to detect Plasmodium falciparum. Extraction of malarial DNA was done from microscopy positive P. falciparum samples, and P. falciparum infections were confirmed by nested PCR (targeting Plasmodium small subunit ribosomal ribonucleic acid (ssrRNA) genes). All PCR confirmed P. falciparum samples were sequenced by pyrosequencing to find out mutation in Pfcrt gene at codon K76T and in pfmdr1 at codons N86Y, Y184F, N1042D, and D1246Y. Out of 121 microscopies positive P. falciparum cases, 109 samples were positive for P. falciparum by nested PCR. Pfcrt K76T mutation was found in 96% of isolates, Pfmdr1 N86Y mutation was observed in 20%, and 11% harboured Y184F mutation. All samples were wild type for Pfmdr1 codon N1042D and D1246Y. In the FATA, Pakistan, the frequency of resistant allele 76T remained high despite the removal of CQ. However, current findings of the study suggest complete fixation of P. falciparum CQ-resistant genotype in the study area.


Resumo A resistência do Plasmodium falciparum à cloroquina (CQ) é uma causa significativa de mortalidade e morbidade em todo o mundo. Há uma escassez de dados documentados sobre a prevalência de haplótipos mutantes CQ-resistentes dos genes Pfcrt e Pfmdr1 da guerra endêmica da malária em áreas tribais administradas pelo governo federal do Paquistão. O objetivo deste estudo foi investigar a prevalência de resistência a CQ de P. falciparum nesta área. Isolados clínicos foram coletados entre maio de 2017 e maio de 2018 nas agências do Waziristão do Norte e do Waziristão do Sul da Área de Ensaio Administrada Federalmente. Posteriormente, esfregaços de sangue corados com Giemsa foram examinados para detectar Plasmodium falciparum. A extração do DNA da malária foi feita a partir de amostras de P. falciparum positivas para microscopia, e as infecções por P. falciparum foram confirmadas por nested PCR (visando genes de ácido ribonucleico ribossômico de subunidade pequena de Plasmodium (ssrRNA)). Todas as amostras de P. falciparum confirmadas por PCR foram sequenciadas por pirosequenciamento para descobrir a mutação no gene Pfcrt no códon K76T e em pfmdr1 nos códons N86Y, Y184F, N1042D e D1246Y. De 121 microscopias de casos positivos de P. falciparum, 109 amostras foram positivas para P. falciparum por nested PCR. A mutação Pfcrt K76T foi encontrada em 96% dos isolados, a mutação Pfmdr1 N86Y foi observada em 20% e 11% abrigou a mutação Y184F. Todas as amostras eram do tipo selvagem para o códon N1042D e D1246Y de Pfmdr1. No FATA, Paquistão, a frequência do alelo resistente 76T permaneceu alta apesar da remoção de CQ. No entanto, as descobertas atuais do estudo sugerem a fixação completa do genótipo resistente a CQ de P. falciparum na área de estudo.


Assuntos
Plasmodium falciparum/genética , Antimaláricos/farmacologia , Paquistão , Proteínas de Membrana Transportadoras/genética , Resistência a Medicamentos/genética , Proteínas de Protozoários/genética , Cloroquina/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Alelos
2.
JAMA ; 328(5): 460-471, 2022 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-35916842

RESUMO

Importance: Malaria is caused by protozoa parasites of the genus Plasmodium and is diagnosed in approximately 2000 people in the US each year who have returned from visiting regions with endemic malaria. The mortality rate from malaria is approximately 0.3% in the US and 0.26% worldwide. Observations: In the US, most malaria is diagnosed in people who traveled to an endemic region. More than 80% of people diagnosed with malaria in the US acquired the infection in Africa. Of the approximately 2000 people diagnosed with malaria in the US in 2017, an estimated 82.4% were adults and about 78.6% were Black or African American. Among US residents diagnosed with malaria, 71.7% had not taken malaria chemoprophylaxis during travel. In 2017 in the US, P falciparum was the species diagnosed in approximately 79% of patients, whereas P vivax was diagnosed in an estimated 11.2% of patients. In 2017 in the US, severe malaria, defined as vital organ involvement including shock, pulmonary edema, significant bleeding, seizures, impaired consciousness, and laboratory abnormalities such as kidney impairment, acidosis, anemia, or high parasitemia, occurred in approximately 14% of patients, and an estimated 0.3% of those receiving a diagnosis of malaria in the US died. P falciparum has developed resistance to chloroquine in most regions of the world, including Africa. First-line therapy for P falciparum malaria in the US is combination therapy that includes artemisinin. If P falciparum was acquired in a known chloroquine-sensitive region such as Haiti, chloroquine remains an alternative option. When artemisinin-based combination therapies are not available, atovaquone-proguanil or quinine plus clindamycin is used for chloroquine-resistant malaria. P vivax, P ovale, P malariae, and P knowlesi are typically chloroquine sensitive, and treatment with either artemisinin-based combination therapy or chloroquine for regions with chloroquine-susceptible infections for uncomplicated malaria is recommended. For severe malaria, intravenous artesunate is first-line therapy. Treatment of mild malaria due to a chloroquine-resistant parasite consists of a combination therapy that includes artemisinin or chloroquine for chloroquine-sensitive malaria. P vivax and P ovale require additional therapy with an 8-aminoquinoline to eradicate the liver stage. Several options exist for chemoprophylaxis and selection should be based on patient characteristics and preferences. Conclusions and Relevance: Approximately 2000 cases of malaria are diagnosed each year in the US, most commonly in travelers returning from visiting endemic areas. Prevention and treatment of malaria depend on the species and the drug sensitivity of parasites from the region of acquisition. Intravenous artesunate is first-line therapy for severe malaria.


Assuntos
Antimaláricos , Resistência a Medicamentos , Malária , Doença Relacionada a Viagens , Adulto , Antimaláricos/efeitos adversos , Antimaláricos/uso terapêutico , Artemisininas/efeitos adversos , Artemisininas/uso terapêutico , Artesunato/efeitos adversos , Artesunato/uso terapêutico , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Humanos , Malária/diagnóstico , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/prevenção & controle , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Malária Falciparum/epidemiologia , Malária Falciparum/prevenção & controle , Viagem/estatística & dados numéricos , Estados Unidos/epidemiologia
3.
Mol Cancer ; 21(1): 159, 2022 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-35922812

RESUMO

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated oncogene, occurring in a variety of tumor types. Targeting KRAS mutations with drugs is challenging because KRAS is considered undruggable due to the lack of classic drug binding sites. Over the past 40 years, great efforts have been made to explore routes for indirect targeting of KRAS mutant cancers, including KRAS expression, processing, upstream regulators, or downstream effectors. With the advent of KRAS (G12C) inhibitors, KRAS mutations are now druggable. Despite such inhibitors showing remarkable clinical responses, resistance to monotherapy of KRAS inhibitors is eventually developed. Significant progress has been made in understanding the mechanisms of drug resistance to KRAS-mutant inhibitors. Here we review the most recent advances in therapeutic approaches and resistance mechanisms targeting KRAS mutations and discuss opportunities for combination therapy.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas p21(ras) , Resistência a Medicamentos , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
4.
Biomater Adv ; 135: 212749, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35929221

RESUMO

Multiple myeloma (MM) is a hematological malignancy in which the patient's drug resistance is one of the main clinical problems. As 2D cultures do not recapitulate the cellular microenvironment, which has a key role in drug resistance, there is an urgent need for better biomimetic models. Here, a novel 3D platform is used to model MM. The semi-solid culture consists of a dynamic suspension of microspheres and MM cells, termed as microgel. Microspheres are synthesized with acrylic polymers of different sizes, compositions, and functionalities (fibronectin or hyaluronic acid). Optimal conditions for the platform in terms of agitation speed and microsphere size have been determined. With these parameters the system allows good proliferation of the MM cell lines RPMI8226, U226, and MM1.S. Interestingly, when used for drug resistance studies, culture of the three MM cell lines in microgels showed close agreement in revealing the role of acrylic acid in resistance to anti-MM drugs such as dexamethasone and bortezomib. This work presents a unique platform for the in vitro modeling of non-solid tumors since it allows keeping non-adherent cells in suspension conditions but in a 3D context that can be easily tuned with different functionalizations.


Assuntos
Microgéis , Mieloma Múltiplo , Bortezomib/farmacologia , Proliferação de Células , Resistência a Medicamentos , Humanos , Mieloma Múltiplo/tratamento farmacológico , Microambiente Tumoral
5.
Front Immunol ; 13: 918314, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35935969

RESUMO

Regulation of ubiquitination is involved in various processes in cancer occurrence and development, including cell cycle arrest, cell proliferation, apoptosis, invasion, metastasis, and immunity. Ubiquitination plays an important role not only at the transcriptional and post-translational levels but also at the protein level. When ubiquitination is in a pathological state, abnormally activated biological processes will not only induce cancer progression but also induce immune evasion. The main function of deubiquitinases (DUBs) is to remove ubiquitin chains from substrates, changing the biological activity of the substrates. It has great potential to improve the prognosis of cancer by targeting DUB to regulate proteome. Ubiquitin-specific peptidase 22 (USP22) belongs to the ubiquitin-specific protease (USP) family of DUBs and has been reported to be related to various physiological and pathological processes. USP22 is abnormally expressed in various malignant tumors such as prostate cancer, lung cancer, liver cancer, and colorectal cancer, which suggests that USP22 may play an important role in tumors. USP22 may stabilize programmed death ligand 1 (PD-L1) by deubiquitination while also regulating T-cell infiltration into tumors. Regulatory T cells (Tregs) are a unique class of immunosuppressive CD4+ T cells that primarily suppress the immune system by expressing the master transcription factor forkhead box protein 3 (FOXP3). USP22 was found to be a positive regulator of stable FOXP3 expression. Treg-specific ablation of USP22 leads to reduced tumor volume in multiple cancer models. This suggests that USP22 may regulate tumor resistance to immunotherapy. In this article, we review and summarize the biological functions of USP22 in multiple signal transduction pathways during tumorigenesis, immune evasion, and drug resistance. Furthermore, we propose a new possibility of combining USP22 with chemotherapeutic, targeted, and immunosuppressive drugs in the treatment of cancer.


Assuntos
Neoplasias , Tioléster Hidrolases , Resistência a Medicamentos , Fatores de Transcrição Forkhead/metabolismo , Humanos , Evasão da Resposta Imune , Masculino , Tioléster Hidrolases/metabolismo , Ubiquitina Tiolesterase/genética
6.
PLoS One ; 17(8): e0272459, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35913968

RESUMO

BACKGROUND: Mycobacterium tuberculosis (M. tuberculosis) remains one of the most significant causes of death and a major public health problem in the community. As a result, the aim of this study was to determine magnitude of Mycobacterium tuberculosis, its drug resistance, and associated factors among presumptive tuberculosis (TB) patients at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. METHODS: Cross-sectional study was conducted at St. Paul's Hospital Millennium Medical College (SPHMMC), Addis Ababa, Ethiopia from January to July 2019. Demographic and clinical data were collected by structured questionnaire through face to face interview. Using microscopic examination and GeneXpert MTB/RIF assay and culturing in the Lowenstein-Jensen (LJ) culture media, we collected and analyzed both pulmonary and extra-pulmonary clinical samples. Data were analyzed by SPSS version 23. Binary logistic regression was done to identify the associated risk factors and p-value less than 0.05 was taken as significant association. RESULTS: Of the total 436 respondents, 223(51%) were male. The mean ±SD age of the participants was 38±17years. Overall, 27/436(6.2%) of the participants had confirmed Mycobacterium tuberculosis using the GeneXpert MTB/RIF assay and LJ culture media, and two isolates were resistant to RIF and one to INH medication, with two (0.5%) being MDR-TB. MTB infection was associated with previous TB contact history, patient weight loss, and CD4+ T-cell counts of 200-350/mm3 of blood. CONCLUSION: The magnitude of M. tuberculosis and MDR-TB in this study underscores the need for improved early case detection and management of MDR-TB in order to reduce transmission and patient suffering.


Assuntos
Mycobacterium tuberculosis , Tuberculose dos Linfonodos , Tuberculose Resistente a Múltiplos Medicamentos , Adulto , Estudos Transversais , Meios de Cultura , Resistência a Medicamentos , Etiópia/epidemiologia , Feminino , Hospitais , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose Resistente a Múltiplos Medicamentos/diagnóstico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/epidemiologia , Adulto Jovem
7.
Med Trop Sante Int ; 2(2)2022 Jun 30.
Artigo em Francês | MEDLINE | ID: mdl-35919251

RESUMO

Background: Malaria is a parasitic disease caused by a hematozoan of the genus Plasmodium. Early diagnosis followed by effective treatment is one of the keys to control this disease. In Madagascar, after more than 60 years of use for the treatment of uncomplicated malaria, chloroquine (CQ) was abandoned in favor of artesunate + amodiaquine (ASAQ) combination because of high prevalence of CQ treatment failure. Surveillance based on the assessment of therapeutic efficacy and genetic markers of resistance to antimalarials is therefore essential in order to detect the emergence of potentially resistant parasites as early as possible. In this context, our study aimed to genotype the Plasmodium falciparum chloroquine resistance transporter gene or Pfcrt and Plasmodium falciparum multidrug resistance gene 1 or Pfmdr1 in isolates collected from children in the district of Vatomandry. Methods: A total of 142 P. falciparum isolates collected during active case detection of malaria in children under 15 years old, between February and March of 2016 and 2017 in Vatomandry district, were analyzed. Pfcrt (K76T codon) and Pfmdr1 (N86Y codon) genotyping was carried out by polymerase chain reaction followed by enzymatic digestion (restriction fragment length polymorphism) or PCR-RFLP. Results: The successful rates of amplification of Pfcrt and Pfmdr1 genes were low, around 27% and 39% respectively. The prevalence of isolates carrying the mutant Pfcrt K76T codon and the mutant Pfmdr1 N86Y codon was 2.6% [95% confidence interval (95% CI): 0.1 - 15.0%] and 36% [95% CI: 23.7 - 49.7%] respectively. Conclusion: Despite the limited number of samples analyzed, our study highlighted the circulation of isolates carrying both the mutant Pfcrt K76T and Pfmdr1 N86Y alleles. Although the prevalence of mutations in Pfcrt and Pfmdr1 genes that we observed was low, other studies should be carried out in order to follow the evolution of these markers in time and space. The use of more sensitive methods will better characterize P. falciparum strains circulating in Madagascar. Artesunate-amodiaquine is used as a first-line treatment for uncomplicated malaria in the country; it is also crucial to monitor the other codons, i.e. 184 and 1246 of the Pfmdr1 gene, implicated in the resistance of P. falciparum to amodiaquine in Africa.


Assuntos
Malária Falciparum , Malária , Adolescente , Amodiaquina/farmacologia , Artesunato/farmacologia , Criança , Cloroquina/farmacologia , Resistência a Medicamentos/genética , Genótipo , Humanos , Madagáscar/epidemiologia , Malária/epidemiologia , Malária Falciparum/diagnóstico , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium falciparum/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição
8.
Vopr Virusol ; 67(3): 193-205, 2022 07 13.
Artigo em Russo | MEDLINE | ID: mdl-35831962

RESUMO

HIV infection is incurable, but effective antiretroviral therapy (ART) makes it possible to achieve an undetectable viral load (VL), to preserve the function of the immune system and to prevent the patient's health. Due to the constant increase in the use of ART and the high variability of HIV, especially in patients receiving so-called suboptimal therapy for various reasons, the incidence of drug resistance (DR) is increasing. In turn, the presence of DR in an HIV-infected patient affects the effectiveness of therapy, which leads to a limited choice and an increase in the cost of treatment regimens, disease progression and, consequently, an increased risk of death, as well as transmission of infection to partners. The main problems of drug resistance, its types and causes, as well as factors associated with its development are considered. The main drug resistance mutations for each of the drug classes are described.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Resistência a Medicamentos , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Carga Viral
9.
J Chem Inf Model ; 62(15): 3676-3684, 2022 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-35838124

RESUMO

Noncoding RNA(ncRNA) is closely related to drug resistance. Identifying the association between ncRNA and drug resistance is of great significance for drug development. Methods based on biological experiments are often time-consuming and small-scale. Therefore, developing computational methods to distinguish the association between ncRNA and drug resistance is urgent. We develop a computational framework called GSLRDA to predict the association between ncRNA and drug resistance in this work. First, the known ncRNA-drug resistance associations are modeled as a bipartite graph of ncRNA and drug. Then, GSLRDA uses the light graph convolutional network (lightGCN) to learn the vector representation of ncRNA and drug from the ncRNA-drug bipartite graph. In addition, GSLRDA uses different data augmentation methods to generate different views for ncRNA and drug nodes and performs self-supervised learning, further improving the quality of learned ncRNA and drug vector representations through contrastive learning between nodes. Finally, GSLRDA uses the inner product to predict the association between ncRNA and drug resistance. To the best of our knowledge, GSLRDA is the first to apply self-supervised learning in association prediction tasks in the field of bioinformatics. The experimental results show that GSLRDA takes an AUC value of 0.9101, higher than the other eight state-of-the-art models. In addition, case studies including two drugs further illustrate the effectiveness of GSLRDA in predicting the association between ncRNA and drug resistance. The code and data sets of GSLRDA are available at https://github.com/JJZ-code/GSLRDA.


Assuntos
Redes Neurais de Computação , RNA não Traduzido , Biologia Computacional/métodos , Resistência a Medicamentos , RNA não Traduzido/genética , Aprendizado de Máquina Supervisionado
10.
J Int AIDS Soc ; 25(7): e25941, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35775502

RESUMO

INTRODUCTION: Universal HIV testing and treatment (UTT) has individual and public health benefits. HPTN 071 (PopART), a community-randomized trial in Zambia and South Africa, demonstrated that UTT decreased HIV incidence. This endpoint was assessed in a cohort of >48,000 randomly selected adults in the study communities. We evaluated the impact of UTT on HIV drug resistance in this cohort and compared other resistance-related outcomes in participants with recent versus non-recent HIV infection. METHODS: Two years after the start of HPTN 071 (2016-2017), 6259 participants were HIV positive and 1902 were viremic (viral load >400 copies/ml). HIV genotyping and antiretroviral (ARV) drug testing were performed for viremic participants in three groups: seroconverters (infected <1 year), non-seroconverters (infected >1 year, random subset) and participants with unknown duration of infection (random subset). A two-stage cluster-based approach was used to assess the impact of the study intervention on drug resistance. Treatment failure was defined as being viremic with ARV drugs detected. Participants were classified as ARV naïve based on self-report and ARV drug testing. RESULTS: Genotyping results were obtained for 758 participants (143 seroconverters; 534 non-seroconverters; and 81 unknown duration of infection). The estimated prevalence of resistance in the study communities was 37% for all viremic persons and 11% for all HIV-positive persons. There was no association between UTT and drug resistance. Resistance was detected in 14.0% of seroconverters and 40.8% of non-seroconverters (non-nucleoside reverse transcriptase inhibitor resistance: 14.0% and 39.9%; nucleoside/nucleotide reverse transcriptase inhibitor resistance: 0.7% and 15.5%; protease inhibitor resistance: 0% and 1.9%; multi-class resistance: 0.7% and 16.1%, respectively). ARV drugs were detected in 2/139 (1.4%) of seroconverters and 94/534 (17.6%) of non-seroconverters tested. These participants were classified as failing ART; 88 (93.6%) of the non-seroconverters failing ART had resistance. Mutations used for surveillance of transmitted drug resistance were detected in 10.5% of seroconverters and 15.1% of non-seroconverters who were ARV naive. CONCLUSIONS: UTT was not associated with an increase in drug resistance in this cohort. Higher rates of drug resistance and multi-class resistance were observed in non-seroconverters compared to seroconverters.


Assuntos
Infecções por HIV , Adulto , Antirretrovirais/uso terapêutico , Resistência a Medicamentos , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Humanos , Inibidores da Transcriptase Reversa/uso terapêutico , Carga Viral , Viremia/tratamento farmacológico
11.
Int J Mol Sci ; 23(15)2022 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-35897796

RESUMO

B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.


Assuntos
Neoplasias , Complexo Repressor Polycomb 1 , Animais , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Resistência a Medicamentos , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias/etiologia , Neoplasias/genética , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo
12.
BMC Urol ; 22(1): 114, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35879749

RESUMO

BACKGROUND: MUC1 is a type I transmembrane protein that plays an important role in tumor cell signal transduction. Although current studies have shown that MUC1 is upregulated in bladder cancer (BC), the specific mechanism is still unclear. METHODS: We performed expression analysis, gene set enrichment analysis, survival analysis, immune infiltration analysis, drug sensitivity analysis, and metabolism-related gene expression analysis on TCGA-BLCA, GES31684 and GSE13507. RESULTS: The expression of MUC1 in the tumor and lymphatic metastasis positive samples was significantly increased. Genes related to MUC1 expression were significantly enriched in immune response, ribosomes, exosomes, and energy metabolism. The results of the immune infiltration analysis showed that M1 macrophages in BC with high MUC1 expression were significantly decreased. Expression of MUC1 increases drug resistance in BC patients. In addition, MUC1 increases glycolysis, glucose uptake, and lactate production by inducing metabolic reprogramming. CONCLUSION: MUC1 has a significant effect on the metabolism and immune cell infiltration of BC, which may be the cause of increased drug resistance, and can be used as a molecular target for the diagnosis and treatment of BC.


Assuntos
Neoplasias da Bexiga Urinária , Biologia Computacional , Resistência a Medicamentos , Glicólise , Humanos , Mucina-1/genética , Mucina-1/metabolismo , Prognóstico , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética
13.
Methods Mol Biol ; 2470: 11-17, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35881334

RESUMO

P. falciparum causes the most severe form of malaria in younger children and pregnant women. In vitro culture systems allow researchers to understand parasite biology, elucidate mechanism of host immunity and test efficacy of antimalarial agents or vaccines in preclinical studies. Most laboratory-adapted parasite strains predate the emergence of artemisinin-based drug combinations and mainly originate from Asia or Europe. To fully understand the biochemical and phenotypic characteristics of parasites, it is imperative that researchers are able to culture parasites circulating in an area to unravel any geographical differences at the population level. Ex vivo culturing of clinical isolates can be challenging when collecting samples in the field and requires technical expertise and equipment. To overcome this challenge, clinical isolates are cryopreserved in the field and transported to a laboratory for in vitro studies. In this protocol, we describe different methods of cryopreserving P. falciparum isolates in the field and thawing them for subsequent in vitro culture.


Assuntos
Antimaláricos , Malária Falciparum , Malária , Parasitos , Animais , Antimaláricos/uso terapêutico , Criança , Criopreservação , Resistência a Medicamentos , Feminino , Humanos , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Plasmodium falciparum , Gravidez
14.
Lancet HIV ; 9(8): e544-e553, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35905753

RESUMO

BACKGROUND: Many countries are now replacing non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) with a regimen containing tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). Recognising laboratory limitations, Malawi opted to transition those on NNRTI-based first-line ART to TLD without viral load testing. We aimed to assess viral load and HIV drug resistance during 1 year following transition to TLD without previous viral load testing. METHODS: In this prospective cohort study, we monitored 1892 adults transitioning from NNRTI-based first-line ART to the TLD regimen in the Médecins Sans Frontières-supported decentralised HIV programme in Chiradzulu District, Malawi. Eligible adults were enrolled between Jan 17 and May 11, 2019, at Ndunde and Milepa health centres, and between March 8 and May 11, 2019, at the Boma clinic. Viral load at the start of the TLD regimen was assessed retrospectively and measured at month 3, 6, and 12, and additionally at month 18 for those ever viraemic (viral load ≥50 copies per mL). Dolutegravir minimal plasma concentrations (Cmin) were determined for individuals with viraemia. Drug-resistance testing was done at the start of TLD regimen and at viral failure (viral load ≥50 copies per mL, followed by viral load ≥500 copies per mL; resistance defined as Stanford score ≥15). FINDINGS: Of 1892 participants who transitioned to the TLD regimen, 101 (5·3%) were viraemic at TLD start. 89 of 101 had drug-resistance testing with 31 participants (34·8%) with Lys65Arg mutation, 48 (53·9%) with Met184Val/Ile, and 42 (40·4%) with lamivudine and tenofovir disoproxil fumerate dual resistance. At month 12 (in the per-protocol population), 1725 (97·9% [95% CI 97·1-98·5]) of 1762 had viral loads of less than 50 copies per mL, including 83 (88·3% [80·0-94·0]) of 94 of those who were viraemic at baseline. At month 18, 35 (97·2% [85·5-99·9]) of 36 who were viraemic at TLD start with lamivudine and tenofovir disoproxil fumarate resistance and 27 (81·8% [64·5-93·0]) of 33 of those viraemic at baseline without resistance had viral load suppression. 14 of 1838 with at least two viral load tests upon transitioning had viral failure (all with at least one dolutegravir Cmin value <640 ng/mL; active threshold), suggesting suboptimal adherence. High baseline viral load was associated with viral failure (adjusted odds ratio [aOR] 14·1 [2·3-87·4] for 1000 to <10 000 copies per mL; aOR 64·4 [19·3-215·4] for ≥10 000 copies per mL). Two people with viral failure had dolutegravir resistance at 6 months (Arg263Lys or Gly118Arg mutation), both were viraemic with lamivudine and tenofovir disoproxil fumarate resistance at baseline. INTERPRETATION: High viral load suppression 1 year after introduction of the TLD regimen supports the unconditional transition strategy in Malawi. However, high pre-transition viral load, ongoing adherence challenges, and possibly existing nucleoside reverse transcriptase inhibitor resistance can lead to rapid development of dolutegravir resistance in a few individuals. This finding highlights the importance of viral load monitoring and dolutegravir-resistance surveillance after mass transitioning to the TLD regimen. FUNDING: Médecins Sans Frontières. TRANSLATIONS: For the French and Portuguese translations of the abstract see Supplementary Materials section.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Soropositividade para HIV , HIV-1 , Adulto , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Antirretrovirais/uso terapêutico , Resistência a Medicamentos , Infecções por HIV/tratamento farmacológico , Soropositividade para HIV/tratamento farmacológico , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Malaui , Oxazinas , Piperazinas , Estudos Prospectivos , Piridonas , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/uso terapêutico , Carga Viral
15.
Comput Math Methods Med ; 2022: 5989889, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35813416

RESUMO

Background: Isothermal signal amplification technique is developed based on the rolling ring amplification mechanism of cyclic DNA molecules in nature. This technique plays an extremely beneficial role in gonorrhea pathogen identification and drug resistance gene detection. Aims: This study analyzes the isothermal signal amplification techniques in the etiological diagnosis of gonorrhea and drug resistance gene detection. Materials and Methods: Urethral, cervical secretion, or prostatic fluid samples from 322 cases of gonorrhea collected from January 2018 to December 2021 at the STD clinic of our hospital dermatology department were selected for direct smear examination and gonococcal culture examination; DNA was extracted from urethral, cervical secretion, or prostatic fluid samples and then used for pathogen identification by SAT assay and rolling loop nucleic acid amplification technique, smear examination and pathogen culture examination methods, SAT assay, and isothermal signal amplification technique for comparative sensitivity and specificity analysis. Results: The highest rate of gonorrhea positivity was for the urine rolling loop nucleic acid amplification technique, followed by the swab rolling loop nucleic acid amplification technique, and the lowest rate of gonorrhea positivity was for the urine SAT test. The difference in the positivity rate between the two urine testing methods was statistically significant (P < 0.05). The highest sensitivity of the urine rolling loop nucleic acid amplification technique method for the detection of gonorrhea pathogens and the lowest sensitivity of the urine SAT method were statistically significant (P < 0.01). The differences in sensitivity and specificity between the swab rolling loop nucleic acid amplification technique and the swab SAT method were not statistically significant (P > 0.05). ROC curves were plotted based on sensitivity and specificity, with swab SAT assay (AUC = 0.998) > rolling loop nucleic acid amplification technique (AUC = 0.981). Comparing the negative rates of urine and swab rolling loop nucleic acid amplification technique and urine SAT assay, the differences were not statistically significant (P > 0.05). Conclusion: The isothermal signal amplification technique improves the shortcomings of gonorrhea pathogen identification means and drug resistance gene detection methods, with good detection sensitivity and specificity, simple operation, low price, and easy promotion, which has obvious advantages in clinical applications and epidemiological studies.


Assuntos
Gonorreia , Resistência a Medicamentos , Gonorreia/diagnóstico , Gonorreia/urina , Humanos , Neisseria gonorrhoeae/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Sensibilidade e Especificidade
16.
Clin. transl. oncol. (Print) ; 24(7): 1250-1261, julio 2022.
Artigo em Inglês | IBECS | ID: ibc-203826

RESUMO

Drug resistance is the drug-effectiveness reduction in treatment and is a serious problem in oncology and infections. In oncology, drug resistance is a complicated process resulting from enhancing the function of a pump that transports drugs out of tumor cells, or acquiring mutations in drug target. Surprisingly, most drugs are very effective in the early stages, but the response to the drug wears off over time and resistance eventually develops. Drug resistance is caused by genetic and epigenetic changes that affect cancer cells and the tumor environment. The study of inherited changes in the phenotype without changes in the DNA sequence is called epigenetics. Because of reversible changes in epigenetics, they are an attractive target for therapy. Some of these epigenetic drugs are effective in treating cancers like acute myeloid leukemia (AML), which is characterized by the accumulation and proliferation of immature hematopoietic cells in the blood and bone marrow. In this article, we outlined the various contributing factors involved in resistance or sensitivity to epigenetic drugs in the treatment of AML.


Assuntos
Humanos , Medula Óssea/patologia , Epigênese Genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Cromatina , Mutação , Resistência a Medicamentos
17.
Nat Commun ; 13(1): 4121, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35840578

RESUMO

The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to define the myeloma surfaceome at baseline, in drug resistance, and in response to acute drug treatment. We provide a scoring system for surface antigens and identify CCR10 as a promising target in this disease expressed widely on malignant plasma cells. We engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting CCR10 using its natural ligand CCL27. In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. We find that acute lenalidomide treatment increases activity of MUC1-targeting CAR-T cells through antigen upregulation. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.


Assuntos
Mieloma Múltiplo , Resistência a Medicamentos , Humanos , Imunoterapia/métodos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Proteômica , Microambiente Tumoral
18.
BMC Vet Res ; 18(1): 277, 2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35836230

RESUMO

BACKGROUND: Coccidiosis is a poultry disease that occurs worldwide and is caused by Eimeria species. The infection is associated with reduced feed efficiency, body weight gain, and egg production. This study aimed to investigate the current status of coccidiosis and anticoccidial resistance to anticoccidial drugs used as part of control strategies for this disease in Korean chicken farms. RESULTS: An overall prevalence of 75% (291/388) was found. Positive farms contained several Eimeria species (mean = 4.2). Of the positive samples, E. acervulina (98.6%), E. maxima (84.8%), and E. tenella (82.8%) were the most prevalent species. Compared with cage-fed chickens, broilers and native chickens reared in free-range management were more at risk of acquiring an Eimeria infection. Sensitivities to six anticoccidial drugs (clopidol, diclazuril, maduramycin, monensin, salinomycin, and toltrazuril) were tested using nine field samples. Compared with untreated healthy control chickens, the body weight gains of infected chickens and treated/infected chickens were significantly reduced in all groups. Fecal oocyst shedding was significantly reduced in four clopidol-treated/infected groups, three diclazuril-treated/infected groups, two toltrazuril-treated/infected groups, one monensin-treated/infected group, and one salinomycin-treated/infected group, compared with the respective untreated/infected control groups. Intestinal lesion scores were also reduced in three clopidol-treated/infected groups, one monensin-treated/infected group, and one toltrazuril-treated/infected group. However, an overall assessment using the anticoccidial index, percent optimum anticoccidial activity, relative oocyst production, and reduced lesion score index found that all field samples had strong resistance to all tested anticoccidial drugs. CONCLUSION: The results of this large-scale epidemiological investigation and anticoccidial sensitivity testing showed a high prevalence of coccidiosis and the presence of severe drug resistant Eimeria species in the field. These findings will be useful for optimizing the control of coccidiosis in the poultry industry.


Assuntos
Coccidiose , Coccidiostáticos , Eimeria , Doenças das Aves Domésticas , Animais , Galinhas , Clopidol , Coccidiose/tratamento farmacológico , Coccidiose/epidemiologia , Coccidiose/veterinária , Coccidiostáticos/farmacologia , Coccidiostáticos/uso terapêutico , Resistência a Medicamentos , Fazendas , Monensin , Oocistos , Doenças das Aves Domésticas/tratamento farmacológico , Doenças das Aves Domésticas/epidemiologia , República da Coreia/epidemiologia , Aumento de Peso
19.
J Exp Clin Cancer Res ; 41(1): 218, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35821160

RESUMO

Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis, primarily caused by metastatic lesions. Improved understanding of GC metastasis at the molecular level yields meaningful insights into potential biomarkers and therapeutic targets. Covalently closed circular RNAs (circRNAs) have emerged as crucial regulators in diverse human cancers including GC. Furthermore, accumulating evidence has demonstrated that circRNAs exhibit the dysregulated patterns in GC and have emerged as crucial regulators in GC invasion and metastasis. However, systematic knowledge regarding the involvement of circRNAs in metastatic GC remains obscure. In this review, we outline the functional circRNAs related to GC metastasis and drug resistance and discuss their underlying mechanisms, providing a comprehensive delineation of circRNA functions on metastatic GC and shedding new light on future therapeutic interventions for GC metastases.


Assuntos
RNA Circular , Neoplasias Gástricas , Biomarcadores Tumorais/genética , Resistência a Medicamentos , Humanos , RNA Circular/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
20.
Sci Rep ; 12(1): 11459, 2022 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-35794459

RESUMO

Global control of hookworm infections relies on periodic Mass Drug Administration of benzimidazole drugs to high-risk groups, regardless of infection status. Mutations in the isotype-1 ß-tubulin gene have been identified in veterinary nematodes, resulting in structural changes and reduced drug-binding. In Ghana, previous studies have demonstrated significant variability in albendazole effectiveness among people infected with the hookworm Necator americanus, although the mechanisms underlying deworming response have not been defined. Using hookworm egg samples from a cross-sectional study in Ghana, we developed a multiplex amplicon deep sequencing (MAD-seq) method to screen genomic regions encapsulating putative drug-resistance markers in N. americanus isotype-1 ß-tubulin gene. Three single nucleotide polymorphisms (SNPs) corresponding to resistance-associated mutations (F167Y, E198A, F200Y) within the coding region of the isotype-1 ß-tubulin gene were characterized using MAD-seq in 30 matched pre- and post-treatment samples from individuals with persistent infection following therapy. Post-sequence analysis showed that the highest mean alternative nucleotide allele at each PCR amplicon was 0.034% (167amplicon) and 0.025% (198/200amplicon), suggesting minimal allelic variation. No samples contained the F167Y SNP, while one contained low-frequency reads associated with E198A (3.15%) and F200Y (3.13%). This MAD-seq method provides a highly sensitive tool to monitor the three putative benzimidazole resistance markers at individual and community levels. Further work is required to understand the association of these polymorphisms to treatment response.


Assuntos
Necator americanus , Tubulina (Proteína) , Animais , Benzimidazóis , Biomarcadores , Estudos Transversais , Resistência a Medicamentos/genética , Humanos , Isotipos de Imunoglobulinas , Tubulina (Proteína)/genética
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