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1.
Lancet Oncol ; 25(6): e270-e280, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38821101

RESUMEN

Although radiotherapy continues to evolve as a mainstay of the oncological armamentarium, research and innovation in radiotherapy in low-income and middle-income countries (LMICs) faces challenges. This third Series paper examines the current state of LMIC radiotherapy research and provides new data from a 2022 survey undertaken by the International Atomic Energy Agency and new data on funding. In the context of LMIC-related challenges and impediments, we explore several developments and advances-such as deep phenotyping, real-time targeting, and artificial intelligence-to flag specific opportunities with applicability and relevance for resource-constrained settings. Given the pressing nature of cancer in LMICs, we also highlight some best practices and address the broader need to develop the research workforce of the future. This Series paper thereby serves as a resource for radiation professionals.


Asunto(s)
Países en Desarrollo , Neoplasias , Oncología por Radiación , Humanos , Países en Desarrollo/economía , Neoplasias/radioterapia , Oncología por Radiación/economía , Investigación Biomédica/economía , Radioterapia/economía , Pobreza
2.
Hum Reprod ; 39(2): 413-424, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38059518

RESUMEN

STUDY QUESTION: To what extent do self-reported sleep duration and non-daytime work schedules in either partner affect the rate of spontaneous abortion (SAB)? SUMMARY ANSWER: Incidence of SAB had little association with female sleep duration and a modest positive association with male short sleep duration, female work at night, and discrepant work schedules among partners. WHAT IS KNOWN ALREADY: Several studies have reported an association between short sleep duration in either partner and reproductive health outcomes, including fecundability. Moreover, certain types of female occupational exposures during pregnancy have been associated with an increased risk of SAB. No studies have evaluated SAB risk in relation to male sleep and work schedules, or joint exposures within a couple. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9357 female participants and 2602 of their male partners residing in North America (June 2013 to April 2023). PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants enrolled when they were attempting pregnancy and completed self-administered baseline questionnaires about their average sleep duration and work schedules. Among those who conceived, we ascertained SAB and gestational age at loss via follow-up questionnaires. We used multivariable Cox proportional hazards models with gestational weeks as the time scale to estimate hazard ratios (HRs) and 95% CIs relating SAB with sleep duration and non-daytime work schedules for female and male participants, and the couple. We used inverse probability weighting to account for potential selection bias due to the possibility of differential participation of male partners with respect to the exposures. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to female participants with recommended sleep (7-8.9 h), those reporting short sleep duration (<6 h) did not have a higher rate of SAB (HR 0.88, 95% CI 0.69, 1.13). Short self-reported sleep duration among male participants was modestly associated with a higher rate of SAB (adjusted and weighted HR 1.30, 95% CI 0.96, 1.75). Female night work at night (adjusted HR 1.19, 95% CI 1.02, 1.38) and male non-daytime work (adjusted and weighted HR 1.26, 95% CI 1.00, 1.59) were associated with modestly higher rates of SAB, whereas female rotating shift work was not (adjusted HR 0.91, 0.78, 1.05) compared with daytime workers. Couples in which work schedules were discrepant had an elevated rate of SAB if the male partner worked a non-daytime shift (adjusted and weighted HR 1.46, 95% CI 1.13, 1.88) compared with couples in which both members worked during the day. The corresponding HR if only the female partner worked a non-daytime shift was 1.21 (95% CI 0.92, 1.58). LIMITATIONS, REASONS FOR CAUTION: Data on sleep duration and work schedules were based on self-report, which is vulnerable to misclassification, particularly since participants were asked to report their average sleep duration during the past month. Work exposures were heterogeneous, as many different types of employment may require night and shift work and may have different associations with SAB. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with previous research indicating that some types of female employment schedules may be associated with SAB incidence. This is the first study to indicate a relationship between SAB and male employment schedules, indicating that discrepant work schedules within a couple might be relevant. STUDY FUNDING/COMPETING INTEREST(S): This work was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development grants R01HD105863 (PIs: L.A.W. and M.L.E.), R01HD086742 (PIs: L.A.W. and E.E.H.), and R21HD072326 (PI: L.A.W.). PRESTO has received in-kind donations from Swiss Precision Diagnostics and Kindara.com for primary data collection. L.A.W. is a consultant for AbbVie, Inc. and the Gates Foundation. M.L.E. is an advisor for and holds stock in Ro, Hannah, Dadi, Underdog, Vseat, & Doveras. The other authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.


Asunto(s)
Aborto Espontáneo , Horario de Trabajo por Turnos , Embarazo , Niño , Humanos , Masculino , Femenino , Aborto Espontáneo/epidemiología , Aborto Espontáneo/etiología , Incidencia , Estudios Prospectivos , Duración del Sueño
3.
Lancet Oncol ; 24(8): e344-e354, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37541280

RESUMEN

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.


Asunto(s)
Investigación Biomédica , Neoplasias Encefálicas , Estados Unidos , Humanos , Calidad de Vida , National Cancer Institute (U.S.) , Consenso , Neoplasias Encefálicas/terapia
4.
Cytogenet Genome Res ; 163(3-4): 103-109, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37285811

RESUMEN

Radiation-related normal tissue injury sustained during cancer radiotherapy or in a radiological or mass casualty nuclear incident is a major health concern. Reducing the risk and mitigating consequences of radiation injury could have a broad impact on cancer patients and citizens. Efforts to discover biomarkers that can determine radiation dose, predict tissue damage, and aid medical triage are underway. Exposure to ionizing radiation causes changes in gene, protein, and metabolite expression that needs to be understood to provide a holistic picture for treating acute and chronic radiation-induced toxicities. We present evidence that both RNA (mRNA, microRNA, long noncoding RNA) and metabolomic assays may provide useful biomarkers of radiation injury. RNA markers may provide information on early pathway alterations after radiation injury that can predict damage and implicate downstream targets for mitigation. In contrast, metabolomics is impacted by changes in epigenetics, genetics, and proteomics and can be considered a downstream marker that incorporates all these changes to provide an assessment of what is currently happening within an organ. We highlight research from the past 10 years to understand how biomarkers may be used to improve personalized medicine in cancer therapy and medical decision-making in mass casualty scenarios.


Asunto(s)
MicroARNs , Neoplasias , Traumatismos por Radiación , Humanos , Traumatismos por Radiación/etiología , Traumatismos por Radiación/genética , MicroARNs/genética , Biomarcadores , Epigénesis Genética , Neoplasias/genética , Neoplasias/radioterapia , Radiometría
5.
Cancer Immunol Immunother ; 71(4): 839-850, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34435232

RESUMEN

The expression of immune-related genes in cancer cells can alter the anti-tumor immune response and thereby impact patient outcomes. Radiotherapy has been shown to modulate immune-related genes dependent on the fractionation regimen. To identify long-term changes in gene expression after irradiation, PC3 (p53 deleted) and LNCaP (p53 wildtype) prostate cancer cells were irradiated with either a single dose (SD, 10 Gy) or a fractionated regimen (MF) of 10 fractions (1 Gy per fraction). Whole human genome arrays were used to determine gene expression at 24 h and 2 months after irradiation. Immune pathway activation was analyzed with Ingenuity Pathway Analysis software. Additionally, 3D colony formation assays and T-cell cytotoxicity assays were performed. LNCaP had a higher basal expression of immunogenic genes and was more efficiently killed by cytotoxic T-cells compared to PC3. In both cell lines, MF irradiation resulted in an increase in multiple immune-related genes immediately after irradiation, while at 2 months, SD irradiation had a more pronounced effect on radiation-induced gene expression. Both immunogenic and immunosuppressive genes were upregulated in the long term in PC3 cells by a 10 Gy SD irradiation but not in LNCaP. T-cell-mediated cytotoxicity was significantly increased in 10 Gy SD PC3 cells compared to the unirradiated control and could be further enhanced by treatment with immune checkpoint inhibitors. Irradiation impacts the expression of immune-related genes in cancer cells in a fractionation-dependent manner. Understanding and targeting these changes may be a promising strategy for primary prostate cancer and recurrent tumors.


Asunto(s)
Recurrencia Local de Neoplasia , Neoplasias de la Próstata , Apoptosis , Línea Celular Tumoral , Humanos , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia
6.
Nucleic Acids Res ; 48(3): 1314-1326, 2020 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-31822909

RESUMEN

Multifractionated irradiation is the mainstay of radiation treatment in cancer therapy. Yet, little is known about the cellular DNA repair processes that take place between radiation fractions, even though understanding the molecular mechanisms promoting cancer cell recovery and survival could improve patient outcome and identify new avenues for targeted intervention. To address this knowledge gap, we systematically characterized how cells respond differentially to multifractionated and single-dose radiotherapy, using a combination of genetics-based and functional approaches. We found that both cancer cells and normal fibroblasts exhibited enhanced survival after multifractionated irradiation compared with an equivalent single dose of irradiation, and this effect was entirely dependent on 53BP1-mediated NHEJ. Furthermore, we identified RIF1 as the critical effector of 53BP1. Inhibiting 53BP1 recruitment to damaged chromatin completely abolished the survival advantage after multifractionated irradiation and could not be reversed by suppressing excessive end resection. Analysis of the TCGA database revealed lower expression of 53BP1 pathway genes in prostate cancer, suggesting that multifractionated radiotherapy might be a favorable option for radio-oncologic treatment in this tumor type. We propose that elucidation of DNA repair mechanisms elicited by different irradiation dosing regimens could improve radiotherapy selection for the individual patient and maximize the efficacy of radiotherapy.


Asunto(s)
Supervivencia Celular/genética , Neoplasias de la Próstata/radioterapia , Proteínas de Unión a Telómeros/genética , Proteína 1 de Unión al Supresor Tumoral P53/genética , Animales , Supervivencia Celular/efectos de la radiación , Cromatina/efectos de la radiación , Reparación del ADN por Unión de Extremidades/genética , Reparación del ADN/genética , Reparación del ADN/efectos de la radiación , Fibroblastos/efectos de la radiación , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Células HeLa , Humanos , Masculino , Ratones , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Transducción de Señal/efectos de la radiación
7.
BMC Genomics ; 22(1): 643, 2021 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-34488624

RESUMEN

BACKGROUND: The lower Dipteran fungus fly, Sciara coprophila, has many unique biological features that challenge the rule of genome DNA constancy. For example, Sciara undergoes paternal chromosome elimination and maternal X chromosome nondisjunction during spermatogenesis, paternal X elimination during embryogenesis, intrachromosomal DNA amplification of DNA puff loci during larval development, and germline-limited chromosome elimination from all somatic cells. Paternal chromosome elimination in Sciara was the first observation of imprinting, though the mechanism remains a mystery. Here, we present the first draft genome sequence for Sciara coprophila to take a large step forward in addressing these features. RESULTS: We assembled the Sciara genome using PacBio, Nanopore, and Illumina sequencing. To find an optimal assembly using these datasets, we generated 44 short-read and 50 long-read assemblies. We ranked assemblies using 27 metrics assessing contiguity, gene content, and dataset concordance. The highest-ranking assemblies were scaffolded using BioNano optical maps. RNA-seq datasets from multiple life stages and both sexes facilitated genome annotation. A set of 66 metrics was used to select the first draft assembly for Sciara. Nearly half of the Sciara genome sequence was anchored into chromosomes, and all scaffolds were classified as X-linked or autosomal by coverage. CONCLUSIONS: We determined that X-linked genes in Sciara males undergo dosage compensation. An entire bacterial genome from the Rickettsia genus, a group known to be endosymbionts in insects, was co-assembled with the Sciara genome, opening the possibility that Rickettsia may function in sex determination in Sciara. Finally, the signal level of the PacBio and Nanopore data support the presence of cytosine and adenine modifications in the Sciara genome, consistent with a possible role in imprinting.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Cromosoma X , ADN , Femenino , Hongos , Humanos , Masculino , Análisis de Secuencia de ADN
8.
J Transl Med ; 19(1): 336, 2021 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-34364390

RESUMEN

BACKGROUND: Radiation therapy is integral to effective thoracic cancer treatments, but its application is limited by sensitivity of critical organs such as the heart. The impacts of acute radiation-induced damage and its chronic effects on normal heart cells are highly relevant in radiotherapy with increasing lifespans of patients. Biomarkers for normal tissue damage after radiation exposure, whether accidental or therapeutic, are being studied as indicators of both acute and delayed effects. Recent research has highlighted the potential importance of RNAs, including messenger RNAs (mRNAs), microRNAs (miRNAs), and long non-coding RNAs (lncRNAs) as biomarkers to assess radiation damage. Understanding changes in mRNA and non-coding RNA expression will elucidate biological pathway changes after radiation. METHODS: To identify significant expression changes in mRNAs, lncRNAs, and miRNAs, we performed whole transcriptome microarray analysis of mouse heart tissue at 48 h after whole-body irradiation with 1, 2, 4, 8, and 12 Gray (Gy). We also validated changes in specific lncRNAs through RT-qPCR. Ingenuity Pathway Analysis (IPA) was used to identify pathways associated with gene expression changes. RESULTS: We observed sustained increases in lncRNAs and mRNAs, across all doses of radiation. Alas2, Aplnr, and Cxc3r1 were the most significantly downregulated mRNAs across all doses. Among the significantly upregulated mRNAs were cell-cycle arrest biomarkers Gdf15, Cdkn1a, and Ckap2. Additionally, IPA identified significant changes in gene expression relevant to senescence, apoptosis, hemoglobin synthesis, inflammation, and metabolism. LncRNAs Abhd11os, Pvt1, Trp53cor1, and Dino showed increased expression with increasing doses of radiation. We did not observe any miRNAs with sustained up- or downregulation across all doses, but miR-149-3p, miR-6538, miR-8101, miR-7118-5p, miR-211-3p, and miR-3960 were significantly upregulated after 12 Gy. CONCLUSIONS: Radiation-induced RNA expression changes may be predictive of normal tissue toxicities and may indicate targetable pathways for radiation countermeasure development and improved radiotherapy treatment plans.


Asunto(s)
MicroARNs , ARN Largo no Codificante , 5-Aminolevulinato Sintetasa , Animales , Redes Reguladoras de Genes , Humanos , Ratones , MicroARNs/genética , ARN Largo no Codificante/genética , ARN Mensajero/genética , Irradiación Corporal Total
9.
Eur J Nucl Med Mol Imaging ; 49(1): 64-72, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34378064

RESUMEN

BACKGROUND: Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. METHODS: This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. RESULTS: NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. CONCLUSION: Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.


Asunto(s)
Neoplasias , Humanos , National Cancer Institute (U.S.) , Neoplasias/radioterapia , Radiometría , Radiofármacos , Estados Unidos
10.
J Radiol Prot ; 41(4)2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34153947

RESUMEN

With the end of the Cold War in 1991, U.S. Government (USG) investments in radiation science and medical preparedness were phased out; however, the events of 11 September, which involved a terroristic attack on American soil, led to the re-establishment of funding for both radiation preparedness and development of approaches to address injuries. Similar activities have also been instituted worldwide, as the global threat of a radiological or nuclear incident continues to be a concern. Much of the USG's efforts to plan for the unthinkable have centred on establishing clear lines of communication between agencies with responsibility for triage and medical response, and external stakeholders. There have also been strong connections made between those parts of the government that establish policies, fund research, oversee regulatory approval, and purchase and stockpile necessary medical supplies. Progress made in advancing preparedness has involved a number of subject matter meetings and tabletop exercises, publication of guidance documents, assessment of available resources, clear establishment of anticipated concepts of operation for multiple radiation and nuclear scenarios, and identification/mobilization of resources. From a scientific perspective, there were clear research gaps that needed to be addressed, which included the need to identify accurate biomarkers and design biodosimetry devices to triage large numbers of civilians, develop decorporation agents that are more amenable for mass casualty use, and advance candidate products to address injuries caused by radiation exposure and thereby improve survival. Central to all these activities was the development of several different animal constructs, since efficacy testing of these approaches requires extensive work in research models that accurately simulate what would be expected in humans. Recent experiences with COVID-19 have provided an opportunity to revisit aspects of radiation preparedness, and leverage those lessons learned to enhance readiness for a possible future radiation public health emergency.


Asunto(s)
COVID-19 , Exposición a la Radiación , Terrorismo , Animales , Urgencias Médicas , Humanos , SARS-CoV-2 , Estados Unidos
11.
Diabet Med ; 37(1): 44-52, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31407377

RESUMEN

AIM: To assess the impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on renal and mortality outcomes in people with Type 2 diabetes and proteinuria. METHODS: A literature search up to 6 June 2019 was performed. We included randomized trials of ≥100 participants with Type 2 diabetes and micro- or macroalbuminuria comparing an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker with placebo ± background anti-hypertensives or non-angiotensin-converting enzyme inhibitor or angiotensin receptor blocker-containing anti-hypertensives, which included follow-up of ≥12 months. Endpoints included doubling of serum creatinine, end-stage renal disease, all-cause and cardiovascular mortality and progression and regression of proteinuria. A Hartung-Knapp random-effects model (between-study variance calculated using the Paule-Mandel estimator) producing a risk ratio with 95% confidence interval was employed. RESULTS: The use of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker was not associated with a significant reduction in the risk of a doubling in serum creatinine (n = 7 trials, RR = 0.77, 95% CI = 0.50-1.21). Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduced the risk of progressing to end-stage renal disease (n = 8, RR = 0.79, 95% CI = 0.75-0.83). No difference in all-cause (n = 11, RR = 0.98, 95% CI = 0.89-1.08) or cardiovascular mortality (n = 6 trials, RR = 1.08, 95% CI = 0.92-1.28), nor the composite outcome of doubling in serum creatinine, end-stage renal disease or mortality (n = 3 trials, RR = 0.87, 95% CI = 0.72-1.06), was observed. Progression of proteinuria was decreased with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use vs. control (n = 10, RR = 0.49, 95% CI = 0.33-0.74). Regression of proteinuria was not improved with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (n = 11, RR = 1.55, 95% CI = 0.93-2.58). CONCLUSION: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce the risk of end-stage renal disease and slow the progression of nephropathy, but they do not appear to decrease all-cause or cardiovascular mortality in people with Type 2 diabetes and proteinuria.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Diabetes Mellitus Tipo 2/mortalidad , Proteinuria/mortalidad , Anciano , Albuminuria , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Humanos , Riñón , Fallo Renal Crónico , Masculino , Persona de Mediana Edad , Proteinuria/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto
12.
Cancer ; 125(16): 2732-2746, 2019 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-31017664

RESUMEN

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.


Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/radioterapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Productos Biológicos , Proteínas HSP90 de Choque Térmico/metabolismo , Herpesvirus Humano 1 , Humanos , Inmunoterapia/métodos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Terapia Molecular Dirigida , National Cancer Institute (U.S.) , Proteína Quinasa C/antagonistas & inhibidores , Nucleósidos de Pirimidina/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Estados Unidos
13.
Diabet Med ; 35(8): 1105-1110, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29663521

RESUMEN

AIM: To assess the effectiveness and safety of rivaroxaban vs warfarin in people with non-valvular atrial fibrillation and diabetes treated in routine practice. METHODS: Using US MarketScan claims data for the period November 2011 to December 2016, we identified oral anticoagulation-naïve people with non-valvular atrial fibrillation and diabetes (Type 1 or Type 2) and ≥12 months of continuous insurance coverage prior to the qualifying oral anticoagulation dispensing time. Rivaroxaban users were 1:1 propensity score-matched to warfarin users. Participants were followed until an event, oral anticoagulation switch/discontinuation, insurance disenrolment or end of follow-up. Rates (events/100 person-years) of the composite of stroke or systemic embolism and major bleeding were compared using Cox regression and reported as hazard ratios and 95% CIs. RESULTS: We assessed 5517 rivaroxaban users (20% received the reduced dose) and 5517 warfarin users with non-valvular atrial fibrillation and diabetes (~97% with Type 2 diabetes) with a median (interquartile range) available follow-up of 1.5 (0.7, 2.7) years. Rivaroxaban was associated with nonsignificant reductions in stroke or systemic embolism (0.87 vs 1.35/100 person-years; hazard ratio 0.68, 95% CI 0.44-1.05) and ischaemic stroke (0.69 vs 0.93/100 person-years; hazard ratio 0.78, 95% CI 0.48-1.30) compared with warfarin. No differences in major bleeding (2.7 vs 3.0/100 person-years; hazard ratio 0.96, 95% CI 0.74-1.25) were observed. Similar results were seen when analysis was limited to standard-dose rivaroxaban. Reduced-dose rivaroxaban was associated with a significantly decreased hazard of stroke or systemic embolism and ischaemic stroke, without an increase in major bleeding risk. CONCLUSIONS: Rivaroxaban has effectiveness and safety at least as good as those of warfarin in people with diabetes and non-valvular atrial fibrillation treated in routine clinical practice.


Asunto(s)
Fibrilación Atrial/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/tratamiento farmacológico , Rivaroxabán/uso terapéutico , Warfarina/uso terapéutico , Reclamos Administrativos en el Cuidado de la Salud/estadística & datos numéricos , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Bases de Datos Factuales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/epidemiología , Angiopatías Diabéticas/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento
14.
Biomarkers ; 23(7): 689-703, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29799276

RESUMEN

CONTEXT: Accidental exposure to life-threatening radiation in a nuclear event is a major concern; there is an enormous need for identifying biomarkers for radiation biodosimetry to triage populations and treat critically exposed individuals. OBJECTIVE: To identify dose-differentiating miRNA signatures from whole blood samples of whole body irradiated mice. METHODS: Mice were whole body irradiated with X-rays (2 Gy-15 Gy); blood was collected at various time-points post-exposure; total RNA was isolated; miRNA microarrays were performed; miRNAs differentially expressed in irradiated vs. unirradiated controls were identified; feature extraction and classification models were applied to predict dose-differentiating miRNA signature. RESULTS: We observed a time and dose responsive alteration in the expression levels of miRNAs. Maximum number of miRNAs were altered at 24-h and 48-h time-points post-irradiation. A 23-miRNA signature was identified using feature selection algorithms and classifier models. An inverse correlation in the expression level changes of miR-17 members, and their targets were observed in whole body irradiated mice and non-human primates. CONCLUSION: Whole blood-based miRNA expression signatures might be used for predicting radiation exposures in a mass casualty nuclear incident.


Asunto(s)
MicroARNs/sangre , Análisis por Micromatrices/métodos , Irradiación Corporal Total/efectos adversos , Animales , Relación Dosis-Respuesta en la Radiación , Perfilación de la Expresión Génica , Ratones , Exposición a la Radiación/efectos adversos , Factores de Tiempo
15.
J Neurooncol ; 134(3): 551-557, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28560665

RESUMEN

Glioblastoma is an aggressive disease characterized by moderate initial response rates to first-line radiation-chemotherapy intervention followed by low poor response rates to second-line intervention. This article discusses novel strategic platforms for the development of radiation-investigational agent combination clinical trials for primary and recurrent glioblastoma in a NCI-NCTN settings with simultaneous analysis of challenges in the drug development process.


Asunto(s)
Neoplasias Encefálicas/terapia , Quimioradioterapia , Glioblastoma/terapia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/metabolismo , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Glioblastoma/metabolismo , Humanos
16.
PLoS Genet ; 10(5): e1004336, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24784729

RESUMEN

Secondary metabolites are produced by numerous organisms and can either be beneficial, benign, or harmful to humans. Genes involved in the synthesis and transport of these secondary metabolites are frequently found in gene clusters, which are often coordinately regulated, being almost exclusively dependent on transcription factors that are located within the clusters themselves. Gliotoxin, which is produced by a variety of Aspergillus species, Trichoderma species, and Penicillium species, exhibits immunosuppressive properties and has therefore been the subject of research for many laboratories. There have been a few proteins shown to regulate the gliotoxin cluster, most notably GliZ, a Zn2Cys6 binuclear finger transcription factor that lies within the cluster, and LaeA, a putative methyltransferase that globally regulates secondary metabolism clusters within numerous fungal species. Using a high-copy inducer screen in A. fumigatus, our lab has identified a novel C2H2 transcription factor, which plays an important role in regulating the gliotoxin biosynthetic cluster. This transcription factor, named GipA, induces gliotoxin production when present in extra copies. Furthermore, loss of gipA reduces gliotoxin production significantly. Through protein binding microarray and mutagenesis, we have identified a DNA binding site recognized by GipA that is in extremely close proximity to a potential GliZ DNA binding site in the 5' untranslated region of gliA, which encodes an efflux pump within the gliotoxin cluster. Not surprisingly, GliZ and GipA appear to work in an interdependent fashion to positively control gliA expression.


Asunto(s)
Aspergillus fumigatus/metabolismo , Proteínas Fúngicas/metabolismo , Factores de Transcripción/fisiología , Regiones no Traducidas 5' , Sitios de Unión , Proteínas Fúngicas/genética , Dosificación de Gen , Regiones Promotoras Genéticas
17.
Int J Clin Pract ; 70(1): 82-8, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26575855

RESUMEN

OBJECTIVE: To validate the In-hospital Mortality for PulmonAry embolism using Claims daTa (IMPACT) multivariable prediction rule using admission claims data. STUDY DESIGN: Retrospective claims database analysis. METHODS: This analysis was performed using Humana admission claims data from January 2007 to March 2014. We included adult patients admitted for their first PE during this period (International Classification of Diseases, ninth edition, Clinical Modification code of 415.1x in in the primary position or secondary position when accompanied by a primary code for a PE complication). The IMPACT rule, consisting of age plus 11 comorbidities, was used to estimate patients' probability of in-hospital mortality and classify risk. Low risk was defined as in-hospital mortality ≤ 1.5%. IMPACT was evaluated by evaluating prognostic test characteristic values and 95% confidence intervals (CIs). RESULTS: A total of 23,858 patients admitted for PE were included, and 3.3% died in-hospital. The IMPACT prediction rule classified 2371 (9.9%) as low-risk; with a sensitivity of 97.6%, 95% CI: 96.1-98.5, specificity of 10.2%, 95% CI: 9.8-10.6, negative and positive predictive values of 99.2% (95% CI: 98.7-99.5) and 3.5% (95% CI: 3.3-3.8) and c-statistic of 0.70, 95% CI: 0.0.68-0.72, for in-hospital mortality. IMPACT classified 42.7% of patients < 65 years old as low-risk; with a sensitivity, specificity and c-statistic of 85.0%, 95% CI: 77.4-90.5, 43.3%, 95% CI: 42.0-44.7 and 0.74, 95% CI: 0.69-0.78, respectively. CONCLUSION: The IMPACT prediction rule was valid when implemented in a database consisting largely of Medicare claims. Following further external validation and direct comparison to commonly used clinical prediction rules, IMPACT may become a valuable tool for payers and hospitals wishing to retrospectively assess whether their PE patients are being kept hospitalized for the optimal period of time.


Asunto(s)
Técnicas de Apoyo para la Decisión , Mortalidad Hospitalaria , Embolia Pulmonar/mortalidad , Reclamos Administrativos en el Cuidado de la Salud/estadística & datos numéricos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Comorbilidad , Femenino , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Retrospectivos
18.
Lancet ; 393(10175): 983-984, 2019 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-30860045
19.
Diabet Med ; 32(12): 1530-40, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26104021

RESUMEN

AIM: To assess the efficacy and safety of third-line adjuvant antihyperglycaemic agents in people with Type 2 diabetes mellitus failing metformin and sulphonylurea combination therapy. METHODS: We searched MEDLINE, CENTRAL, clinicaltrials.gov and regulatory websites, and conducted a manual search of references in the identified studies. Randomized trials evaluating antihyperglycaemic agents in adults with Type 2 diabetes experiencing poor glycaemic control despite optimized metformin and sulphonylurea therapy (≥ 1500 mg metformin or maximum tolerated dose; ≥ 50% of maximum sulphonylurea dose for ≥ 3 weeks) were included. Data extraction included: study characteristics; change in HbA1c concentration; weight; systolic blood pressure; and relative risk of hypoglycaemia, urinary tract infections; and genital tract infections. A network meta-analysis was performed. RESULTS: A total of 20 trials evaluating 13 antihyperglycaemic agents were included. Compared with placebo/control, all antihyperglycaemic agents reduced HbA1c levels, albeit by differing magnitudes [range 7 mmol/mol (0.6%) for acarbose to 13 mmol/mol (1.20%) for liraglutide]. Sodium glucose cotransporter-2 inhibitors reduced weight (1.43-2.07 kg) whereas thiazolidinediones, glargine and sitagliptin caused weight gain (1.48-3.62 kg) compared with placebo/control. Sodium glucose cotransporter-2 inhibitors, rosiglitazone and liraglutide decreased systolic blood pressure compared with placebo/control, pioglitazone, glargine and sitagliptin (2.41-8.88 mm Hg). Glargine, thiazolidinediones, liraglutide, sitagliptin and canagliflozin increased hypoglycaemia risk compared with placebo/control (relative risk 1.92-7.47), while glargine and rosiglitazone increased hypoglycaemia compared with most antihyperglycaemic agents (relative risk 2.81-7.47). No antihyperglycaemic agent increased the risk of urinary tract infection, but canagliflozin increased the risk of genital tract infection by 3.9-fold compared with placebo/control. CONCLUSIONS: When added to metformin and a sulphonylurea, antihyperglycaemic agents had varying effects on efficacy and safety endpoints. These conclusions should be considered when clinicians choose between possible adjunctive agents.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Resistencia a Medicamentos , Medicina Basada en la Evidencia , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Medicina de Precisión , Compuestos de Sulfonilurea/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Monitoreo de Drogas , Quimioterapia Combinada/efectos adversos , Hemoglobina Glucada/análisis , Humanos , Hiperglucemia/prevención & control , Hipoglucemiantes/efectos adversos , Metformina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Compuestos de Sulfonilurea/efectos adversos
20.
Int J Clin Pract ; 69(11): 1221-35, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26215321

RESUMEN

AIMS: Determine the efficacy and safety of antidiabetic agents added-on to metformin and a thiazolidinedione (TZD) in patients with inadequately controlled type 2 diabetes (T2D). METHODS: MEDLINE and CENTRAL were searched for randomised controlled trials (RCTs) evaluating the addition of an antidiabetic agent in patients with T2D inadequately controlled on stable, optimised metformin and TZD therapy (≥ 1500 mg metformin and ≥ 50% maximum TZD dose for ≥ 4 weeks). Frequentist network meta-analysis was performed on identified studies. RESULTS: Eleven RCTs evaluating dipeptidyl peptidase-4 inhibitors (linagliptin, sitagliptin), sulfonylureas (SUs) (glibenclamide, glimepiride), glucagon-like peptide-1 (GLP-1) analogues (exenatide, liraglutide, dulaglutide, taspoglutide) and sodium-glucose cotransporter2 (SGLT2) inhibitors (canagliflozin, empagliflozin) were identified. The mean reduction in HbA1c from baseline was significant for all agents (range, 0.55-1.17%) vs. placebo. SUs were associated with weight gain (range, 3.31-7.29 kg), while weight loss was seen with all GLP-1 analogues (range, 1.53-2.20 kg) and SGLT2 inhibitors (range, 2.08-2.95 kg) vs. placebo. Relative risk of hypoglycaemia was increased with dulaglutide, exenatide and glimepiride vs. placebo (RR range, 2.65-6.17); and trended higher with all other agents except linagliptin. GLP-1 analogues and canagliflozin reduced systolic blood pressure vs. placebo (range, 2.39-5.05 mmHg). No agent with available data increased the risk of urinary or genital tract infection vs. placebo. CONCLUSION: When added to stable, optimised metformin and TZD, all evaluated antidiabetic agents reduced HbA1c; albeit not to the same degree. Moreover, agents differed in their effects on body weight, hypoglycaemia and systolic blood pressure.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Tiazolidinedionas/uso terapéutico , Diabetes Mellitus Tipo 2/sangre , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto
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