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1.
Bioconjug Chem ; 2019 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-31584260

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among cancers. Chemotherapy is the standard first-line treatment, but only modest survival benefits are observed. With the advent of targeted therapies, epidermal growth factor receptor (EGFR) has been acknowledged as a prospective target in PDAC since it is overexpressed in up to 60% of cases. Similarly, the tyrosine-protein kinase Met (cMET) is also overexpressed in PDAC (27-60%) and is a prognostic marker for poor survival. Interestingly, EGFR and cMET share some common signaling pathways including PI3K/Akt and MAPK pathways. Small molecule inhibitors or bispecific antibodies that can target both EGFR and cMET are therefore emerging as novel options for cancer therapy. We previously developed a dual EGFR and cMET inhibitor (N19) that was able to inhibit tumor growth in nonsmall cell lung cancer models resistant to EGFR tyrosine kinase inhibitors (TKI). Here, we report the development of a novel liposomal formulation of N19 (LN19) and showed significant growth inhibition and increased sensitivity toward gemcitabine in the pancreatic adenocarcinoma orthotopic xenograft model. Taken together, our results suggest that LN19 can be valued as an effective combination therapy with conventional chemotherapy such as gemcitabine for PDAC patients.

2.
J Med Chem ; 62(16): 7543-7556, 2019 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-31381331

RESUMEN

A quaternary ammonium betaine 7 is described which shows exceptional potency and selectivity (1.4 to >3 logs) for the αvß6 integrin receptor over the other αv integrins as determined in cell adhesion assays. 7 is prepared by remarkably stereoselective methylation, the origins of which are discussed. The chemical, biological, physicochemical, and pharmacokinetic properties of 7 and its docking into αvß6 are described along with related analogues.

3.
Nat Hum Behav ; 2019 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-31406338

RESUMEN

Human children are frequently cared for by non-parental caregivers (alloparents), yet few studies have conducted systematic alternative hypothesis tests of why alloparents help. Here we explore whether predictions from kin selection, reciprocity, learning-to-mother and costly signalling hypotheses explain non-parental childcare among Agta hunter-gatherers from the Philippines. To test these hypotheses, we used high-resolution proximity data from 1,701 child-alloparent dyads. Our results indicated that reciprocity and relatedness were positively associated with the number of interactions with a child (our proxy for childcare). Need appeared more influential in close kin, suggesting indirect benefits, while reciprocity proved to be a stronger influence in non-kin, pointing to direct benefits. However, despite shared genes, close and distant kin interactions were also contingent on reciprocity. Compared with other apes, humans are unique in rapidly producing energetically demanding offspring. Our results suggest that the support that mothers require is met through support based on kinship and reciprocity.

4.
Sci Rep ; 9(1): 11080, 2019 Jul 31.
Artículo en Inglés | MEDLINE | ID: mdl-31367002

RESUMEN

High-fidelity transmission of information through imitation and teaching has been proposed as necessary for cumulative cultural evolution. Yet, it is unclear when and for which knowledge domains children employ different social learning processes. This paper explores the development of social learning processes and play in BaYaka hunter-gatherer children by analysing video recordings and time budgets of children from early infancy to adolescence. From infancy to early childhood, hunter-gatherer children learn mainly by imitating and observing others' activities. From early childhood, learning occurs mainly in playgroups and through practice. Throughout childhood boys engage in play more often than girls whereas girls start foraging wild plants from early childhood and spend more time in domestic activities and childcare. Sex differences in play reflect the emergence of sexual division of labour and the play-work transition occurring earlier for girls. Consistent with theoretical models, teaching occurs for skills/knowledge that cannot be transmitted with high fidelity through other social learning processes such as the acquisition of abstract information e.g. social norms. Whereas, observational and imitative learning occur for the transmission of visually transparent skills such as tool use, foraging, and cooking. These results suggest that coevolutionary relationships between human sociality, language and teaching have likely been fundamental in the emergence of human cumulative culture.

5.
BJU Int ; 2019 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-31287613

RESUMEN

OBJECTIVE: To evaluate the ability of prostate-specific membrane antigen (PSMA)-positron-emission tomography (PET)/computed tomography (CT) to detect intermediate-grade intra-prostatic prostate cancer (PCa), and to determine if PSMA-PET improves the diagnostic accuracy of multiparametric magnetic resonance imaging (mpMRI). PATIENTS AND METHODS: A total of 56 consecutive patients with International Society of Urological Pathology (ISUP) grade 2-3 PCa after radical prostatectomy, who underwent both mpMRI and PSMA-PET CT (hereafter PSMA-PET) preoperatively, were enrolled in this study. The accuracy of PSMA-PET, mpMRI alone, and the two procedures in combination was analysed for identifying ISUP grades 1-3 within a 12-segment model. The accuracy of a combined predictive model (PSMA-PET and mpMRI) was determined. Receiver-operating characteristic curve analysis to determine the optimal standardized uptake value (SUVmax ) for PSMA-PET in discriminating between ISUP grades 1 and ≥2 was performed. RESULTS: On a per-patient basis, the sensitivities for PSMA-PET and mpMRI in identifying ISUP grades 2-3 PCa were 100% and 97%, respectively. Assessing ISUP grade ≥2 PCa using a 12-segment analysis, PSMA-PET demonstrated greater diagnostic accuracy (area under the curve), sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV), with values of 0.91, 88%, 93%, 95% and 85%, respectively, than did mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] 3-5), at 0.79, 68%, 91%, 87%, and 75%, respectively. When used in combination (PSMA-PET and mpMRI PIRADS 4-5), sensitivity, specificity, NPV and PPV were 92%, 90%, 96% and 81%, respectively. The sensitivity for both techniques reduced markedly when assessing ISUP grade 1 PCa (18% for PSMA-PET, 10% for mpMRI). An SUVmax value of 3.95 resulted in 94% sensitivity and 100% specificity. CONCLUSION: PSMA-PET is accurate in detecting segments containing intermediate-grade intra-prostatic PCa (ISUP grade ≥ 2), compared with and complementary to mpMRI. By contrast the detection rate for ISUP grade 1 disease for both PSMA-PET and mpMRI was low.

6.
Phys Rev Lett ; 122(23): 233602, 2019 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-31298915

RESUMEN

We propose a scheme for continuously measuring the evolving quantum phase of a collective spin composed of N pseudospins. Quantum nondemolition measurements of a lossy cavity mode interacting with an atomic ensemble are used to directly probe the phase of the collective atomic spin without converting it into a population difference. Unlike traditional Ramsey measurement sequences, our scheme allows for real-time tracking of time-varying signals. As a bonus, spin-squeezed states develop naturally, providing real-time phase estimation significantly more precise than the standard quantum limit of Δϕ_{SQL}=1/sqrt[N] rad.

7.
Dev Neuropsychol ; 44(5): 417-428, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31288587

RESUMEN

The current study examines associations between neural activation to the receipt of monetary reward in a rewarding game task and bias toward immediate reward measured in a behavioral delay discounting task among early adolescents (N = 58, 12-14 years). As expected, heightened brain activation in reward-related regions were correlated with higher bias toward immediate reward. This suggests that bias toward immediate reward in delay discounting tasks may be linked to heightened activation to reward in reward processing regions. This interplay between neural reward processing and bias toward immediate reward might explain the sharp increases in bias toward immediate reward that occur in early adolescence.


Asunto(s)
Encéfalo/fisiología , Toma de Decisiones/fisiología , Descuento por Demora/fisiología , Recompensa , Adolescente , Anticipación Psicológica/fisiología , Mapeo Encefálico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Pruebas Neuropsicológicas
8.
J Nucl Med ; 2019 Jun 14.
Artículo en Inglés | MEDLINE | ID: mdl-31201250

RESUMEN

Expression of the chemokine receptor chemokine C-X-C motif receptor 4 (CXCR4) plays an important role in cancer metastasis, autoimmune diseases and during stem cell based repair processes after stroke and myocardial infarction. Previously reported positron emission tomography (PET) imaging agents targeting CXCR4 suffer from either high non-specific uptake or only bind to the human form of the receptor. The objective of this study is to develop a high stability copper-64 labelled small molecule PET agent for imaging both human and murine CXCR4 chemokine receptors. METHODS: Synthesis, radiochemistry, stability and radioligand binding assays were performed for the novel tracer 64Cu-CuCB-Bicyclam. In vivo dynamic PET studies were carried out on mice bearing U87 (CXCR4low) and U87.CXCR4 (CXCR4high) tumors. Biodistribution and receptor blocking studies were carried out on CD1-IGS immunocompetent mice. CXCR4 expression on tumor and liver disaggregates was confirmed using a combination of immunohistochemistry, quantitative polymerase chain reaction (qPCR) and western blot. RESULTS: 64Cu-CuCB-Bicyclam has a high affinity for both the human and murine variants of the CXCR4 receptor (IC50 = 10 nM) and can be obtained from the parent chelator that has low affinity. In vitro and in vivo studies demonstrate specific uptake in CXCR4 expressing cells that can be blocked by >90% using a higher affinity antagonist, with limited uptake in non-CXCR4 expressing organs and high in vivo stability. The tracer was also able to selectively displace the CXCR4 antagonists AMD3100 and AMD3465 from the liver. CONCLUSIONS: The application of the tetraazamacrocyclic small molecule 64Cu-CuCB-Bicyclam is demonstrated as an imaging agent for the CXCR4 receptor that is likely to be applicable across a range of species. It has high affinity and stability and is suitable for preclinical research in immunocompetent murine models.

9.
Eur Urol Oncol ; 2019 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-31103721

RESUMEN

BACKGROUND: Focal irreversible electroporation (IRE) can be used to treat men with localised prostate cancer (PCa) with reduced impact on quality of life (QoL). OBJECTIVE: To assess oncological and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: To report on a prospective database of patients undergoing primary IRE between February 2013 and August 2018. A minimum of 12-mo follow-up was available for 123 patients. Median follow-up was 36 mo (interquartile range [IQR] 24-52 mo). A total of 112 (91%) patients had National Comprehensive Cancer Network intermediate risk and 11 (9%) had low risk. A total of 12 (9.8%) had International Society of Urological Pathology (ISUP) grade 1, 88 (71.5%) had ISUP 2, and 23 (18.7%) had ISUP 3. INTERVENTION: Focal IRE ablation of PCa lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Follow-up involved serial prostate-specific antigen (PSA), multiparametric magnetic resonance imaging (mpMRI), and transperineal template mapping biopsy (TTMB) at 12 mo. Failure-free survival (FFS) was defined as progression to whole-gland or systemic treatment or metastasis/death. Functional outcomes were assessed. RESULTS AND LIMITATIONS: Median age was 68yr (IQR 62-73yr). Median preoperative PSA was 5.7ng/ml (IQR 3.8-8.0ng/ml). On post-treatment TTMB, in-field recurrence was present in 2.7-9.8% of patients. FFS at 3yr was 96.75%, metastasis-free survival 99%, and overall survival 100%. A total of 18 patients required salvage treatment (12 had repeat IRE; six had whole-gland treatment). The negative predictive value of mpMRI was 94% and sensitivity 40% for detecting in-field residual disease 6 mo after treatment. Among patients who returned questionnaires, 80/81 (98.8%) remained pad free and 40/53 (76%) had no change in erectile function. CONCLUSIONS: Focal IRE in select patients with localised clinically significant PCa has satisfactory short-term oncological outcomes with a minimal impact on patient QoL. PATIENT SUMMARY: In this study, 123 patients underwent focal therapy using irreversible electroporation. Follow-up biopsy was clear of residual disease in 90.2-97.3% of patients. Of patients, 96.75% avoided whole gland treatment at 3yr.

10.
Int Rev Psychiatry ; 31(1): 95-110, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-31043106

RESUMEN

Post-traumatic stress disorder (PTSD) is one of the common mental disorders in military and veteran populations. Considerable research and clinical opinion has been focused on understanding the relationship between PTSD and military service and the implications for prevention, treatment, and management. This paper examines factors associated with the development of PTSD in this population, considers issues relating to engagement in treatment, and discusses the empirical support for best practice evidence-based treatment. The paper goes on to explore the challenges in those areas, with particular reference to treatment engagement and barriers to care, as well as treatment non-response. The final section addresses innovative solutions to these challenges through improvements in agreed terminology and definitions, strategies to increase engagement, early identification approaches, understanding predictors of treatment outcome, and innovations in treatment. Treatment innovations include enhancing existing treatments, emerging non-trauma-focused interventions, novel pharmacotherapy, personalized medicine approaches, advancing functional outcomes, family intervention and support, and attention to physical health.

11.
Cognition ; 190: 212-220, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31121404

RESUMEN

Previous research on temporal and spatial discounting has largely focused on temporal discounting in which responses to reward stimuli are altered by the time taken to reach the reward. However, there is currently minimal research on the behavioral effects of spatial discounting. In addition, contrary to the current findings, previous research on reward discounting has suggested a correlation between temporal and spatial discounting. Here we present results from three studies, all of which employed a spatial and temporal discounting task in which subjects were immersed in a virtual reality environment and were presented with a choice between two monetary rewards, each reward varying in distance and duration. In addition, in experiments 2 and 3, the speed at which a subject could move within the virtual environment was manipulated. Our findings indicate some of the first evidence that space and time may in fact be estimated independently when discounting rewards.

12.
Phys Med Biol ; 64(13): 135018, 2019 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-31117062

RESUMEN

Approximately 50% of all colorectal cancer (CRC) patients will develop metastasis to the liver. 90Y selective internal radiation therapy (SIRT) is an established treatment for metastatic CRC. There is still a fundamental lack of understanding regarding the radiobiology underlying the dose response. This study was designed to determine the radiosensitivity of two CRC cell lines (DLD-1 and HT-29) to 90Y ß - radiation exposure, and thus the relative effectiveness of 90Y SIRT in relation to external beam radiotherapy (EBRT). A 90Y-source dish was sandwiched between culture dishes to irradiate DLD-1 or HT-29 cells for a period of 6 d. Cell survival was determined by clonogenic assay. Dose absorbed per 90Y disintegration was calculated using the PENELOPE Monte Carlo code. PENELOPE simulations were benchmarked against relative dose measurements using EBT3 GAFchromic™ film. Statistical regression based on the linear-quadratic model was used to determine the radiosensitivity parameters [Formula: see text] and [Formula: see text] using R. These results were compared to radiosensitivity parameters determined for 6 MV clinical x-rays and 137Cs γ-ray exposure. Equivalent dose of EBRT in 2 Gy ([Formula: see text]) and 10 Gy ([Formula: see text]) fractions were derived for 90Y dose. HT-29 cells were more radioresistant than DLD-1 for all treatment modalities. Radiosensitivity parameters determined for 6 MV x-rays and 137Cs γ-ray were equivalent for both cell lines. The [Formula: see text] ratio for 90Y ß --particle exposure was over an order of magnitude higher than the other two modalities due to protraction of dose delivery. Consequently, an 90Y SIRT absorbed dose of 60 Gy equates to an [Formula: see text] of 28.7 and 54.5 Gy and an [Formula: see text] of 17.6 and 19.3 Gy for DLD-1 and HT-29 cell lines, respectively. We derived radiosensitivity parameters for two CRC cell lines exposed to 90Y ß --particles, 6 MV x-rays, and 137Cs γ-ray irradiation. These radiobiological parameters are critical to understanding the dose response of CRC lesions and ultimately informs the efficacy of 90Y SIRT relative to other radiation therapy modalities.

13.
Vaccine ; 37(25): 3326-3334, 2019 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-31079849

RESUMEN

BACKGROUND: We evaluated safety and immunogenicity of the first mRNA vaccines against potentially pandemic avian H10N8 and H7N9 influenza viruses. METHODS: Two randomized, placebo-controlled, double-blind, phase 1 clinical trials enrolled participants between December 2015 and August 2017 at single centers in Germany (H10N8) and USA (H7N9). Healthy adults (ages 18-64 years for H10N8 study; 18-49 years for H7N9 study) participated. Participants received vaccine or placebo in a 2-dose vaccination series 3 weeks apart. H10N8 intramuscular (IM) dose levels of 25, 50, 75, 100, and 400 µg and intradermal dose levels of 25 and 50 µg were evaluated. H7N9 IM 10-, 25-, and 50-µg dose levels were evaluated; 2-dose series 6 months apart was also evaluated. Primary endpoints were safety (adverse events) and tolerability. Secondary immunogenicity outcomes included humoral (hemagglutination inhibition [HAI], microneutralization [MN] assays) and cell-mediated responses (ELISPOT assay). RESULTS: H10N8 and H7N9 mRNA IM vaccines demonstrated favorable safety and reactogenicity profiles. No vaccine-related serious adverse event was reported. For H10N8 (N = 201), 100-µg IM dose induced HAI titers ≥ 1:40 in 100% and MN titers ≥ 1:20 in 87.0% of participants. The 25-µg intradermal dose induced HAI titers > 1:40 in 64.7% of participants compared to 34.5% of participants receiving the IM dose. For H7N9 (N = 156), IM doses of 10, 25, and 50 µg achieved HAI titers ≥ 1:40 in 36.0%, 96.3%, and 89.7% of participants, respectively. MN titers ≥ 1:20 were achieved by 100% in the 10- and 25-µg groups and 96.6% in the 50-µg group. Seroconversion rates were 78.3% (HAI) and 87.0% (MN) for H10N8 (100 µg IM) and 96.3% (HAI) and 100% (MN) in H7N9 (50 µg). Significant cell-mediated responses were not detected in either study. CONCLUSIONS: The first mRNA vaccines against H10N8 and H7N9 influenza viruses were well tolerated and elicited robust humoral immune responses. ClinicalTrials.gov NCT03076385 and NCT03345043.

14.
Brain Behav ; 9(6): e01311, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-31087785

RESUMEN

INTRODUCTION: Adolescence is a time of heightened sensitivity in biological stress systems and the emergence of stress-related psychopathology. Thus, understanding environmental factors in adolescence that might be associated with adolescents'' stress systems is important. Maternal stress levels may be involved. However, the relationship between maternal stress and the adolescent brain is unknown. METHOD: The present study examined the association between mothers' self-reported stress levels and mothers' cortisol stress reactivity and their early adolescents' brain structure and functional activation to stressful negative emotional images. Participants included 66 mothers and their 12- to 14-year old adolescents. Mother's perceived stress and salivary cortisol reactivity to a stressful task were collected. Then, adolescents' brain structure and function were assessed in a magnetic resonance imaging session. RESULTS: Functional whole-brain analyses revealed that mothers' higher reported perceived stress, but not cortisol reactivity, predicted adolescents' higher responses in the medial prefrontal cortex (mPFC) to stressful negative emotional stimuli. There were no statistically significant associations for structural analyses. CONCLUSIONS: Given the finding of maternal stress reactivity related to adolescent mPFC function-an integral structure related to stress responses-parent stress may play a role in the development of neural stress systems in adolescence, with potential implications for development of psychopathology.

15.
BMC Med Res Methodol ; 19(1): 82, 2019 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-31014243

RESUMEN

BACKGROUND: Multiple neonatal and pediatric disorders have been linked to older paternal ages. Combining these findings with the evidence that many men are having children at much later ages generates considerable public health concern. The risk of paternal age has been difficult to estimate and interpret because children often have parents whose ages are similar and likely to be confounded. Epidemiologic studies often model the conditional effects of paternal age using regression models that typically treat maternal age as linear, curvilinear or as age-band categories. Each of these approaches has limitations. As an alternative, the current study measures age to the nearest year, and fits a Bayesian model in which each parent's age is given a conditional autoregressive prior (CAR). METHODS: Data containing approximately 12,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2016. Date were cross-tabulated for maternal ages 15-49 years and for paternal ages 15-65 years. A Bayesian logistic model was implemented using conditional autoregressive priors for both maternal and paternal ages modeled separately and jointly for both Down syndrome and chromosomal disorders other than Down syndrome. RESULTS: Models with maternal and paternal ages given CAR priors were judged to be better fitting than traditional models. For Down syndrome, the approach attributed a very large risk to advancing maternal age with the effect of advancing paternal age having a very small sparing effect on birth prevalence. Maternal age was also related to the birth prevalence of chromosomal disorders other than Down syndrome while paternal age was not. CONCLUSIONS: Advancing paternal age was not associated with an increase in risk for either Down syndrome or chromosomal disorders other than Down syndrome.

16.
BMC Pregnancy Childbirth ; 19(1): 126, 2019 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-30975086

RESUMEN

BACKGROUND: Maternal obesity has a wide range of health effects on both the pregnant woman and developing fetus. The clinical significance of these disorders, combined with a dramatically increasing prevalence of obesity among pregnant women has precipitated a major health crisis in the United States. The most commonly used recommendations for gestational weight gain were established by the Institute of Medicine (IOM) in 2009 and have become well known and often adopted. The authors of the IOM report acknowledged that the recommended gestational weight gain of 5 to 9 kg for obese women whose body mass index was greater than 30 kg/m2 was based on very little empirical evidence. The objective of this study was to evaluate whether a 5 to 9 kg weight gain, for obese women, optimized a set of maternal and neonatal health outcomes. METHODS: Data containing approximately 12,000,000 birth records were obtained from the United States Natality database for the years 2014 to 2016. A Bayesian modeling approach was used to estimate the controlled direct effects of pre-pregnancy body mass index and gestational weight gain. RESULTS: Obese women gaining less than 5 kg during pregnancy had reduced maternal risks for gestational hypertension, eclampsia, induction of labor and Caesarian section. In contrast, maternal gestational weight gain of less than 5 kg was associated with increased risks for multiple adverse neonatal outcomes with macrosomia the exception. Obese women who gained more than 9 kg during pregnancy had increased risk for multiple maternal and neonatal adverse outcomes. CONCLUSIONS: Obese women who were observed to gain less than 5 kg during gestation had reduced odds of several peripartum disorders. However, this lower gestational weight gain was associated with an increase in multiple risks for the neonate.


Asunto(s)
Ganancia de Peso Gestacional , Obesidad/fisiopatología , Complicaciones del Embarazo/fisiopatología , Resultado del Embarazo/epidemiología , Adulto , Teorema de Bayes , Índice de Masa Corporal , Cesárea/estadística & datos numéricos , Bases de Datos Factuales , Femenino , Macrosomía Fetal/epidemiología , Macrosomía Fetal/etiología , Humanos , Hipertensión Inducida en el Embarazo/epidemiología , Hipertensión Inducida en el Embarazo/etiología , Salud del Lactante , Recién Nacido , Obesidad/complicaciones , Obesidad/epidemiología , Embarazo , Complicaciones del Embarazo/epidemiología , Complicaciones del Embarazo/etiología , Factores de Riesgo , Estados Unidos/epidemiología
17.
Oncologist ; 24(9): 1253-1258, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-30944185

RESUMEN

BACKGROUND: The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Multiple clinical trials have demonstrated that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now offered to select patients in routine clinical care. In order to better support patient decision making, we explored patients' views on TKI discontinuation and the factors patients consider when making this decision. MATERIALS AND METHODS: Patients were recruited from three U.S. academic cancer centers. Qualitative interviews were recorded, transcribed, and content analyzed. RESULTS: We interviewed 22 patients, half of whom wanted to try TKI discontinuation. Eleven factors relevant to the decision emerged, and patients weighed these factors differently. Commonly mentioned factors included perceived risk of relapse, TKI side effects, financial considerations, polypharmacy, and willingness to change something that was working (status quo). There were notable differences in patients' understanding of the likelihood of achieving a treatment-free remission, with patients who did not want to stop TKIs more accurately reporting the risk of relapse than patients who wanted to stop. CONCLUSION: This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for patient education and decision support so that patients and providers can make shared decisions that are informed and values based. IMPLICATIONS FOR PRACTICE: The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Clinical trials have shown that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now being offered to patients outside of clinical trials. This study explored factors that patients who are eligible to try TKI discontinuation considered when making this decision. Factors relevant to the decision included risk of relapse, side effects, financial considerations, polypharmacy, and willingness to change something that was working. This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for decision support and outline the factors that should be included so that patients and providers can make shared decisions that are informed and values based.

18.
Phys Chem Chem Phys ; 21(15): 8152-8160, 2019 Apr 21.
Artículo en Inglés | MEDLINE | ID: mdl-30933211

RESUMEN

We report the first excited state dynamics study of gas-phase 5,6-dihydroxyindole (5,6-DHI), a key building block of eumelanin pigments that are found throughout nature and serve as important photo-protective compounds. Time-resolved ion-yield measurements over the 241-296 nm ultraviolet photoexcitation region revealed non-adiabatic processes occurring on up to three distinct timescales. These reflect ultrafast (i.e. sub-picosecond) internal conversion within the excited state singlet manifold, and much longer-lived processes ranging from 10 ps to in excess of 1 ns. Our investigation paves the way for precisely targeted future studies of 5,6-DHI that exploit more differential measurement techniques. The work was facilitated by the use of soft laser-based thermal desorption to introduce 5,6-DHI samples into the gas phase. This approach, based on low-cost, readily available diode lasers, is straightforward, easily controllable and potentially applicable to a wide range of non-volatile molecular species.

19.
J Am Vet Med Assoc ; 254(9): 1042-1044, 2019 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-30986160
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