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1.
Phys Med Biol ; 69(10)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38588671

RESUMO

Objective. A novel x-ray field produced by an ultrathin conical target is described in the literature. However, the optimal design for an associated collimator remains ambiguous. Current optimization methods using Monte Carlo calculations restrict the efficiency and robustness of the design process. A more generic optimization method that reduces parameter constraints while minimizing computational load is necessary. A numerical method for optimizing the longitudinal collimator hole geometry for a cylindrically-symmetrical x-ray tube is demonstrated and compared to Monte Carlo calculations.Approach. The x-ray phase space was modelled as a four-dimensional histogram differential in photon initial position, final position, and photon energy. The collimator was modeled as a stack of thin washers with varying inner radii. Simulated annealing was employed to optimize this set of inner radii according to various objective functions calculated on the photon flux at a specified plane.Main results. The analytical transport model used for optimization was validated against Monte Carlo calculations using Geant4 via its wrapper, TOPAS. Optimized collimators and the resulting photon flux profiles are presented for three focal spot sizes and five positions of the source. Optimizations were performed with multiple objective functions based on various weightings of precision, intensity, and field flatness metrics. Finally, a select set of these optimized collimators, plus a parallel-hole collimator for comparison, were modeled in TOPAS. The evolution of the radiation field profiles are presented for various positions of the source for each collimator.Significance. This novel optimization strategy proved consistent and robust across the range of x-ray tube settings regardless of the optimization starting point. Common collimator geometries were re-derived using this algorithm while simultaneously optimizing geometry-specific parameters. The advantages of this strategy over iterative Monte Carlo-based techniques, including computational efficiency, radiation source-specificity, and solution flexibility, make it a desirable optimization method for complex irradiation geometries.


Assuntos
Método de Monte Carlo , Raios X , Fótons , Modelos Teóricos
2.
Med Phys ; 51(1): 447-463, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37947472

RESUMO

BACKGROUND: Carbon nanotube-based cold cathode technology has revolutionized the miniaturization of X-ray tubes. However, current applications of these devices required optimization for large, uniform fields with low intensity. PURPOSE: This work investigated the feasibility and radiological characteristics of a novel conical X-ray target optimized for high intensity and high directionality to be used in a compact X-ray tube. METHODS: The proposed device uses an ultrathin, conical tungsten-diamond target that exhibits significant heat loading while maintaining a small focal spot size and promoting forward-directedness of the X-ray field through preferential attenuation of oblique-angled photons. The electrostatic and thermal properties of the theoretical tube were calculated and analyzed using COMSOL Multiphysics software. The production, transport, and calculation of radiological properties associated with the resultant X-ray field were performed using the Geant4 toolkit via its wrapper, TOPAS. RESULTS: Heat transfer analysis of this X-ray tube demonstrated the feasibility of a 200-kV electron beam bombarding the proposed target at a maximum current of 100 mA using a 1-ms symmetric duty cycle. The cathode of the X-ray tube was designed to be segmented into nine switchable electrical segments for modulation of the focal spot size from 0.4- to 10.8-mm. After importing the COMSOL-derived electron beam into TOPAS for X-ray production simulations, radiological analysis of the resultant field demonstrated high levels of intrinsic beam collimation while maintaining high intensity. A maximum dose rate of 17,887 cGy/min was calculated for 1-mm depth in water at 7-cm distance. CONCLUSIONS: The proposed X-ray tube design can create highly directional X-ray fields with superior fluence compared to that of current commercial X-ray tubes of comparable size.


Assuntos
Nanotubos de Carbono , Raios X , Radiografia , Fluoroscopia , Software , Método de Monte Carlo
3.
Indian J Community Med ; 48(1): 177-182, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37082391

RESUMO

Introduction: Scrub typhus is one of the most underreported and fatal illnesses accounting for 23% of all febrile illness. Rajasthan reported cases during 2018-2019 in state reporting system but did not report any case to central Integrated Disease Surveillance Programme (IDSP) unit. We evaluated the Scrub typhus surveillance system in Alwar district, Rajasthan, with the objective of describing and evaluating the system and providing evidence-based recommendations to identify gaps. Material and Methods: In cross-sectional study, we reviewed records and conducted key informant interviews at district- and block-level health facilities. Using US Centers for Disease Control guidelines, we evaluated the system by framing indicators for selected attributes for a defined reference period. Overall performance was ranked as outstanding (90-100%), excellent (80-89%), very good (70-79%), good (60-69%), and poor (<60%). Results: Line list of confirmed cases was sent from district to block level for additional active case search (ACS) to implement control measures. We conducted 26 key informant interviews and reviewed records and calculated simplicity as 79%, flexibility 100%, data quality 46%, acceptability 92%, representativeness 48%, timeliness 43%, and stability 79%. Conclusions: Epidemiological surveillance (active and passive) is a core intervention under scrub typhus surveillance system. Lab reports were incompletely uploaded on IDSP portal. Surveillance reports should be updated after each ACS. Reporting format under IDSP should be uploaded timely, and lab reports from state should be sent within 48 hours of diagnosis so that case investigation is not delayed.

4.
Int J Radiat Oncol Biol Phys ; 116(2): 295-304, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35235854

RESUMO

PURPOSE: The American Association of Physicists in Medicine (AAPM) shares the results, conclusions, and recommendations from the initial Equity, Diversity, and Inclusion Climate Survey conducted in 2021. METHODS AND MATERIALS: The climate survey targeted medical physicists who are full members of the AAPM and included demographic inquiries and questions intended to assess the working environmental climate in terms of a sense of belonging and inclusion, experiences of discrimination and harassment, and obstacles to participation within the AAPM. The survey invitation was sent to 5,500 members. Responses were collected from 1385 members (response rate of 25%) between January and February 2021. RESULTS: Overall, the medical physics workplace climate was positive. However, some demographic and professional subgroups reported lower levels of agreement with positive characteristics of their workplace climates. Compared with men, women ranked lower 7 of 8 categories that characterized the workplace climate. Other subgroups that also ranked the workplace climate descriptors lower included individuals not originally from the United States and Canada (3/8). Most respondents strongly agreed/agreed that the climate within the AAPM was welcoming. However, 17% of respondents reported personally experiencing or witnessing microaggressions within the AAPM. Overall, medical physicists reported low levels of agreement that opportunities within the AAPM were available to them, from 34% to 60% among 8 categories, including opportunities to volunteer, join committees, and compete for leadership positions within the AAPM. Several subgroups reported even lower levels of agreement that these opportunities are available. Asian and Asian American respondents (3/8) and physicists with origins in countries outside the United States and Canada (7/8) reported fewer opportunities to participate in the AAPM. Medical physicists reported their experiences of discrimination and sexual harassment in their workplaces and within the AAPM. For those who reported personal experiences of sexual harassment, only 24% (15/63) felt comfortable reporting when it occurred within their workplaces, and 35% (9/26) felt comfortable reporting when it occurred within the AAPM. CONCLUSIONS: The report concludes with several recommendations for action.


Assuntos
Medicina , Assédio Sexual , Masculino , Humanos , Feminino , Estados Unidos , Física Médica , Diversidade, Equidade, Inclusão , Inquéritos e Questionários
5.
Emerg Infect Dis ; 28(13): S138-S144, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36502396

RESUMO

The India Field Epidemiology Training Program (FETP) has played a critical role in India's response to the ongoing COVID-19 pandemic. During March 2020-June 2021, a total of 123 FETP officers from across 3 training hubs were deployed in support of India's efforts to combat COVID-19. FETP officers have successfully mitigated the effect of COVID-19 on persons in India by conducting cluster outbreak investigations, performing surveillance system evaluations, and developing infection prevention and control tools and guidelines. This report discusses the successes of select COVID-19 pandemic response activities undertaken by current India FETP officers and proposes a pathway to augmenting India's pandemic preparedness and response efforts through expansion of this network and a strengthened frontline public health workforce.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Pandemias/prevenção & controle , Surtos de Doenças/prevenção & controle , Índia/epidemiologia
6.
Front Cell Infect Microbiol ; 12: 1011692, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36250048

RESUMO

The Plasmodium vivax reticulocyte invasion process is still poorly understood, with only a few receptor-ligand interactions identified to date. Individuals with the Southeast Asian ovalocytosis (SAO) phenotype have a deletion in the band 3 protein on the surface of erythrocytes, and are reported to have a lower incidence of clinical P. vivax malaria. Based on this observation, band 3 has been put forward as a receptor for P. vivax invasion, although direct proof is still lacking. In this study, we combined functional ex vivo invasion assays and transcriptome sequencing to uncover a band 3-mediated invasion pathway in P. vivax and potential band 3 ligands. Invasion by P. vivax field isolates was 67%-71% lower in SAO reticulocytes compared with non-SAO reticulocytes. Reticulocyte invasion was decreased by 40% and 27%-31% when blocking with an anti-band 3 polyclonal antibody and a PvTRAg38 peptide, respectively. To identify new band 3 receptor candidates, we mRNA-sequenced schizont-stage isolates used in the invasion assays, and observed high transcriptional variability in multigene and invasion-related families. Transcriptomes of isolates with low or high dependency on band 3 for invasion were compared by differential expression analysis, which produced a list of band 3 ligand candidates with high representation of PvTRAg genes. Our ex vivo invasion assays have demonstrated that band 3 is a P. vivax invasion receptor and confirm previous in vitro studies showing binding between PvTRAg38 and band 3, although the lower and variable inhibition levels observed suggest the involvement of other ligands. By coupling transcriptomes and invasion phenotypes from the same isolates, we identified a list of band 3 ligand candidates, of which the overrepresented PvTRAg genes are the most promising for future research.


Assuntos
Malária Vivax , Plasmodium vivax , Proteína 1 de Troca de Ânion do Eritrócito/metabolismo , Antígenos de Protozoários , Eliptocitose Hereditária , Eritrócitos , Humanos , Ligantes , Malária Vivax/genética , Peptídeos/metabolismo , Proteínas de Protozoários/metabolismo , RNA Mensageiro/metabolismo , Reticulócitos/metabolismo
7.
Sensors (Basel) ; 22(18)2022 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-36146135

RESUMO

(1) Background: The Exradin W2 is a commercially available scintillator detector designed for reference and relative dosimetry in small fields. In this work, we investigated the performance of the W2 scintillator in a 10 MV flattening-filter-free photon beam and compared it to the performance of ion chambers designed for small field measurements. (2) Methods: We measured beam profiles and percent depth dose curves with each detector and investigated the linearity of each system based on dose per pulse (DPP) and pulse repetition frequency. (3) Results: We found excellent agreement between the W2 scintillator and the ion chambers for beam profiles and percent depth dose curves. Our results also showed that the two-voltage method of calculating the ion recombination correction factor was sufficient to correct for the ion recombination effect of ion chambers, even at the highest DPP. (4) Conclusions: These findings show that the W2 scintillator shows excellent agreement with ion chambers in high DPP conditions.


Assuntos
Fótons , Plásticos , Radiometria/métodos
8.
Med Phys ; 49(9): 5742-5751, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35866442

RESUMO

PURPOSE: To fully automate CT-based cervical cancer radiotherapy by automating contouring and planning for three different treatment techniques. METHODS: We automated three different radiotherapy planning techniques for locally advanced cervical cancer: 2D 4-field-box (4-field-box), 3D conformal radiotherapy (3D-CRT), and volumetric modulated arc therapy (VMAT). These auto-planning algorithms were combined with a previously developed auto-contouring system. To improve the quality of the 4-field-box and 3D-CRT plans, we used an in-house, field-in-field (FIF) automation program. Thirty-five plans were generated for each technique on CT scans from multiple institutions and evaluated by five experienced radiation oncologists from three different countries. Every plan was reviewed by two of the five radiation oncologists and scored using a 5-point Likert scale. RESULTS: Overall, 87%, 99%, and 94% of the automatically generated plans were found to be clinically acceptable without modification for the 4-field-box, 3D-CRT, and VMAT plans, respectively. Some customizations of the FIF configuration were necessary on the basis of radiation oncologist preference. Additionally, in some cases, it was necessary to renormalize the plan after it was generated to satisfy radiation oncologist preference. CONCLUSION: Approximately, 90% of the automatically generated plans were clinically acceptable for all three planning techniques. This fully automated planning system has been implemented into the radiation planning assistant for further testing in resource-constrained radiotherapy departments in low- and middle-income countries.


Assuntos
Radioterapia Conformacional , Radioterapia de Intensidade Modulada , Neoplasias do Colo do Útero , Feminino , Humanos , Órgãos em Risco , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Radioterapia Conformacional/métodos , Radioterapia de Intensidade Modulada/métodos , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/radioterapia
9.
J Appl Clin Med Phys ; 23(8): e13647, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35580067

RESUMO

PURPOSE: To determine the most accurate similarity metric when using an independent system to verify automatically generated contours. METHODS: A reference autocontouring system (primary system to create clinical contours) and a verification autocontouring system (secondary system to test the primary contours) were used to generate a pair of 6 female pelvic structures (UteroCervix [uterus + cervix], CTVn [nodal clinical target volume (CTV)], PAN [para-aortic lymph nodes], bladder, rectum, and kidneys) on 49 CT scans from our institution and 38 from other institutions. Additionally, clinically acceptable and unacceptable contours were manually generated using the 49 internal CT scans. Eleven similarity metrics (volumetric Dice similarity coefficient (DSC), Hausdorff distance, 95% Hausdorff distance, mean surface distance, and surface DSC with tolerances from 1 to 10 mm) were calculated between the reference and the verification autocontours, and between the manually generated and the verification autocontours. A support vector machine (SVM) was used to determine the threshold that separates clinically acceptable and unacceptable contours for each structure. The 11 metrics were investigated individually and in certain combinations. Linear, radial basis function, sigmoid, and polynomial kernels were tested using the combinations of metrics as inputs for the SVM. RESULTS: The highest contouring error detection accuracies were 0.91 for the UteroCervix, 0.90 for the CTVn, 0.89 for the PAN, 0.92 for the bladder, 0.95 for the rectum, and 0.97 for the kidneys and were achieved using surface DSCs with a thickness of 1, 2, or 3 mm. The linear kernel was the most accurate and consistent when a combination of metrics was used as an input for the SVM. However, the best model accuracy from the combinations of metrics was not better than the best model accuracy from a surface DSC as an input. CONCLUSIONS: We distinguished clinically acceptable contours from clinically unacceptable contours with an accuracy higher than 0.9 for the targets and critical structures in patients with cervical cancer; the most accurate similarity metric was surface DSC with a thickness of 1, 2, or 3 mm.


Assuntos
Aprendizado Profundo , Algoritmos , Feminino , Humanos , Linfonodos , Pelve , Planejamento da Radioterapia Assistida por Computador/métodos , Tomografia Computadorizada por Raios X/métodos
11.
Mutat Res ; 824: 111772, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34923215

RESUMO

The study of radiation effects on biological tissues is a diverse field of research with direct applications to improve human health, in particular in the contexts of radiation therapy and space exploration. Understanding the DNA damage response following radiation exposure, which is a key determinant for mutagenesis, requires reproducible methods for delivering known doses of ionizing radiation (IR) in a controlled environment. Multiple IR sources, including research X-ray and gamma-ray irradiators are routinely used in basic and translational research with cell and animal models. These systems are however not ideal when a high temporal resolution is needed, for example to study early DNA damage responses with live cell microscopy. Here, we characterize the dose rate and beam properties of a commercial, miniature, affordable, and versatile X-ray source (Mini-X). We describe how to use Mini-X on the stage of a fluorescence microscope to deliver high IR dose rates (up to 29 Gy/min) or lower dose rates (≤ 0.1 Gy/min) in live cell imaging experiments. This article provides a blueprint for radiation biology applications with high temporal resolution, with a step-by-step guide to implement a miniature X-ray system on an imaging platform, and the information needed to characterize the system.


Assuntos
Microscopia , Radiobiologia , Animais , Radiação Ionizante , Raios X
12.
Lancet Oncol ; 22(12): 1732-1739, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34717797

RESUMO

BACKGROUND: The role of radiotherapy in metastatic renal cell carcinoma is controversial. We prospectively tested the feasibility and efficacy of radiotherapy to defer systemic therapy for patients with oligometastatic renal cell carcinoma. METHODS: This single-arm, phase 2, feasibility trial was done at one centre in the USA (The MD Anderson Cancer Center, Houston, TX, USA). Patients (aged ≥18 years) with five or fewer metastatic lesions, an Eastern Cooperative Oncology Group status of 0-2, and no more than one previous systemic therapy (if this therapy was stopped at least 1 month before enrolment) without limitations on renal cell carcinoma histology were eligible for inclusion. Patients were treated with stereotactic body radiotherapy (defined as ≤5 fractions with ≥7 Gy per fraction) to all lesions and maintained off systemic therapy. When lesion location precluded safe stereotactic body radiotherapy, patients were treated with hypofractionated intensity-modulated radiotherapy regimes consisting of 60-70 Gy in ten fractions or 52·5-67·5 Gy in 15 fractions. Additional rounds of radiotherapy were allowed to treat subsequent sites of progression. Co-primary endpoints were feasibility (defined as all planned radiotherapy completed with <7 days unplanned breaks) and progression-free survival. All efficacy analyses were intention-to-treat. Safety was analysed in the as-treated population. A second cohort, with the aim of assessing the feasibility of sequential stereotactic body radiotherapy alone in patients with low-volume metastatic disease, was initiated and will be reported separately. This study is registered with ClinicalTrials.gov, NCT03575611. FINDINGS: 30 patients (six [20%] women) were enrolled from July 13, 2018, to Sept 18, 2020. All patients had clear cell histology and had a nephrectomy before enrolment. All patients completed at least one round of radiotherapy with less than 7 days of unplanned breaks. At a median follow-up of 17·5 months (IQR 13·2-24·6), median progression-free survival was 22·7 months (95% CI 10·4-not reached; 1-year progression-free survival 64% [95% CI 48-85]). Three (10%) patients had severe adverse events: two grade 3 (back pain and muscle weakness) and one grade 4 (hyperglycaemia) adverse events were observed. There were no treatment-related deaths. INTERPRETATION: Sequential radiotherapy might facilitate deferral of systemic therapy initiation and could allow sustained systemic therapy breaks for select patients with oligometastatic renal cell carcinoma. FUNDING: Anna Fuller Foundation, the Cancer Prevention and Research Institute of Texas (CPRIT), and the National Cancer Institute.


Assuntos
Carcinoma de Células Renais/radioterapia , Neoplasias Renais/radioterapia , Radioterapia de Intensidade Modulada/mortalidade , Idoso , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Neoplasias Renais/epidemiologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Texas/epidemiologia
13.
Nat Commun ; 11(1): 6159, 2020 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-33268801

RESUMO

Malaria is spread by the transmission of sexual stage parasites, called gametocytes. However, with Plasmodium falciparum, gametocytes can only be detected in peripheral blood when they are mature and transmissible to a mosquito, which complicates control efforts. Here, we identify the set of genes overexpressed in patient blood samples with high levels of gametocyte-committed ring stage parasites. Expression of all 18 genes is regulated by transcription factor AP2-G, which is required for gametocytogenesis. We select three genes, not expressed in mature gametocytes, to develop as biomarkers. All three biomarkers we validate in vitro using 6 different parasite lines and develop an algorithm that predicts gametocyte production in ex vivo samples and volunteer infection studies. The biomarkers are also sensitive enough to monitor gametocyte production in asymptomatic P. falciparum carriers allowing early detection and treatment of infectious reservoirs, as well as the in vivo analysis of factors that modulate sexual conversion.


Assuntos
Estágios do Ciclo de Vida/genética , Malária Falciparum/transmissão , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Fator de Transcrição AP-2/genética , Transcriptoma , Animais , Biomarcadores/sangue , Portador Sadio , Eritrócitos/parasitologia , Gametogênese/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Ontologia Genética , Humanos , Malária Falciparum/diagnóstico , Malária Falciparum/parasitologia , Anotação de Sequência Molecular , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/metabolismo , Fator de Transcrição AP-2/metabolismo
14.
Int J Part Ther ; 7(2): 11-20, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33274253

RESUMO

PURPOSE: To determine the clinical outcomes and toxicities of proton beam therapy (PBT) versus 3D-conformal photon radiation therapy (XRT) in patients with testicular seminoma. MATERIALS AND METHODS: This observational study evaluated consecutive patients with testicular seminoma who were treated with inguinal orchiectomy and radiation therapy at a single, tertiary, high-volume center in 2008-19. Acute toxicity was scored with the Common Terminology Criteria for Adverse Events V 4.0. Organs at risk were contoured retrospectively by 2 investigators. Recurrences and secondary malignancies were based on routine follow-up imaging, either computed tomography or magnetic resonance imaging. RESULTS: Fifty-five patients were treated with radiation therapy, 11 in the PBT-arm and 44 in the XRT-arm, with a median follow-up interval of 61 months (interquartile range [IQR]: 32-79 months). Acute treatment-related diarrhea, grade 1 to 2, was more common among XRT-treated patients (0% vs 29.5%, P = .039), and dermatitis, grade 1, was more likely among PBT-treated patients (27.3% vs 2.3%, P = .004). Dosimetrically, PBT-treated patients, relative to XRT-treated patients, had lower dose to organs at risk including the kidney, bladder, femoral head, spinal cord, bowel, pancreas, and stomach. The 5-year overall survival rate was 100% and disease-free survival rate was 96.4% for all patients. Two patients, all in the XRT-arm, had disease recurrence: 1 in the pelvis and 1 in the lung. Three patients, all in the XRT-arm, were diagnosed with a secondary malignancy: 1 in-field pancreaticoblastoma, 1 in-field colon adenocarcinoma, and a stage IV T-cell lymphoma. CONCLUSION: Proton beam therapy for testicular seminoma resulted in excellent clinical outcomes and was associated with lower rates of acute diarrhea but higher rates of acute dermatitis. Proton beam therapy resulted in no in-field secondary malignancies and a more favorable dosimetric profile for organs at risk relative to XRT. Reduced dose to organs at risk, such as the kidneys, may result in long-term improvement in function.

15.
J Radiosurg SBRT ; 6(2): 161-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31641553

RESUMO

Splenic metastases from oligometastatic ovarian carcinoma are a rare occurrence. Usual treatment for splenic metastases includes splenectomy, but some patients are either unable or unwilling to undergo surgery. Stereotactic body radiotherapy (SBRT) is an effective ablative modality for treating metastatic disease. SBRT to abdominopelvic tumors has been shown to be safe and effective for properly-selected patients and is particularly attractive in the oligometastatic setting as an alternative to radical resection. In this case study, we report a patient with an isolated splenic metastasis from ovarian carcinoma treated with 50 Gy in 10 fractions.

16.
PLoS Pathog ; 15(6): e1007809, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31185066

RESUMO

Malaria is caused by Plasmodium parasites, which invade and replicate in erythrocytes. For Plasmodium falciparum, the major cause of severe malaria in humans, a heterotrimeric complex comprised of the secreted parasite proteins, PfCyRPA, PfRIPR and PfRH5 is essential for erythrocyte invasion, mediated by the interaction between PfRH5 and erythrocyte receptor basigin (BSG). However, whilst CyRPA and RIPR are present in most Plasmodium species, RH5 is found only in the small Laverania subgenus. Existence of a complex analogous to PfRH5-PfCyRPA-PfRIPR targeting BSG, and involvement of CyRPA and RIPR in invasion, however, has not been addressed in non-Laverania parasites. Here, we establish that unlike P. falciparum, P. knowlesi and P. vivax do not universally require BSG as a host cell invasion receptor. Although we show that both PkCyRPA and PkRIPR are essential for successful invasion of erythrocytes by P. knowlesi parasites in vitro, neither protein forms a complex with each other or with an RH5-like molecule. Instead, PkRIPR is part of a different trimeric protein complex whereas PkCyRPA appears to function without other parasite binding partners. It therefore appears that in the absence of RH5, outside of the Laverania subgenus, RIPR and CyRPA have different, independent functions crucial for parasite survival.


Assuntos
Basigina/metabolismo , Malária/metabolismo , Complexos Multiproteicos/metabolismo , Plasmodium knowlesi/metabolismo , Proteínas de Protozoários/metabolismo , Basigina/genética , Humanos , Malária/genética , Complexos Multiproteicos/genética , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Plasmodium knowlesi/genética , Plasmodium vivax/genética , Plasmodium vivax/metabolismo , Proteínas de Protozoários/genética , Especificidade da Espécie
17.
Sci Rep ; 9(1): 8943, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31221984

RESUMO

Plasmodium vivax parasites preferentially invade reticulocyte cells in a multistep process that is still poorly understood. In this study, we used ex vivo invasion assays and population genetic analyses to investigate the involvement of complement receptor 1 (CR1) in P. vivax invasion. First, we observed that P. vivax invasion of reticulocytes was consistently reduced when CR1 surface expression was reduced through enzymatic cleavage, in the presence of naturally low-CR1-expressing cells compared with high-CR1-expressing cells, and with the addition of soluble CR1, a known inhibitor of P. falciparum invasion. Immuno-precipitation experiments with P. vivax Reticulocyte Binding Proteins showed no evidence of complex formation. In addition, analysis of CR1 genetic data for worldwide human populations with different exposure to malaria parasites show significantly higher frequency of CR1 alleles associated with low receptor expression on the surface of RBCs and higher linkage disequilibrium in human populations exposed to P. vivax malaria compared with unexposed populations. These results are consistent with a positive selection of low-CR1-expressing alleles in vivax-endemic areas. Collectively, our findings demonstrate that CR1 availability on the surface of RBCs modulates P. vivax invasion. The identification of new molecular interactions is crucial to guiding the rational development of new therapeutic interventions against vivax malaria.


Assuntos
Membrana Eritrocítica/metabolismo , Plasmodium vivax/fisiologia , Receptores de Complemento/metabolismo , Reticulócitos/parasitologia , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Malária Vivax/parasitologia , Malária Vivax/transmissão , Receptores de Complemento/genética
19.
Nat Commun ; 10(1): 2140, 2019 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-31086187

RESUMO

Plasmodium sexual differentiation is required for malaria transmission, yet much remains unknown about its regulation. Here, we quantify early gametocyte-committed ring (gc-ring) stage, P. falciparum parasites in 260 uncomplicated malaria patient blood samples 10 days before maturation to transmissible stage V gametocytes using a gametocyte conversion assay (GCA). Seventy six percent of the samples have gc-rings, but the ratio of gametocyte to asexual-committed rings (GCR) varies widely (0-78%). GCR correlates positively with parasitemia and is negatively influenced by fever, not hematocrit, age or leukocyte counts. Higher expression levels of GDV1-dependent genes, ap2-g, msrp1 and gexp5, as well as a gdv1 allele encoding H217 are associated with high GCR, while high plasma lysophosphatidylcholine levels are associated with low GCR in the second study year. The results provide a view of sexual differentiation in the field and suggest key regulatory roles for clinical factors and gdv1 in gametocytogenesis in vivo.


Assuntos
Interações Hospedeiro-Parasita/fisiologia , Malária Falciparum/parasitologia , Plasmodium falciparum/fisiologia , Proteínas de Protozoários/fisiologia , Diferenciação Sexual/fisiologia , Fatores Etários , Criança , Pré-Escolar , Feminino , Gametogênese/fisiologia , Genes de Protozoários/fisiologia , Gana , Humanos , Lisofosfatidilcolinas/sangue , Malária Falciparum/sangue , Masculino , Parasitemia/parasitologia , Plasmodium falciparum/isolamento & purificação
20.
Antimicrob Agents Chemother ; 59(5): 2548-53, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25691626

RESUMO

Malaria treatment in Southeast Asia is threatened with the emergence of artemisinin-resistant Plasmodium falciparum. Genome association studies have strongly linked a locus on P. falciparum chromosome 13 to artemisinin resistance, and recently, mutations in the kelch13 propeller region (Pfk-13) were strongly linked to resistance. To date, this information has not been shown in Indian samples. Pfk-13 mutations were assessed in samples from efficacy studies of artemisinin combination treatments in India. Samples were PCR amplified and sequenced from codon 427 to 727. Out of 384 samples, nonsynonymous mutations in the propeller region were found in four patients from the northeastern states, but their presence did not correlate with ACT treatment failures. This is the first report of Pfk-13 point mutations from India. Further phenotyping and genotyping studies are required to assess the status of artemisinin resistance in this region.


Assuntos
Artemisininas/farmacologia , Resistência a Medicamentos/genética , Plasmodium falciparum/genética , Proteínas de Protozoários/genética , Di-Hidropteroato Sintase/genética , Di-Hidropteroato Sintase/metabolismo , Índia , Dados de Sequência Molecular , Mutação , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/metabolismo , Mutação Puntual/genética , Proteínas de Protozoários/metabolismo
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