Influence of mild and moderate hepatic impairment on axitinib pharmacokinetics

Objective: To evaluate the effects of hepatic impairment on the pharmacokinetics and safety of a single, oral axitinib dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel-group study, a total of 24 subjects with either normal hepatic function (n = 8) or with mild (n = 8) or moderate (n = 8) hepatic impairment were administered a single, oral dose of axitinib (5 mg). Blood samples were collected at intervals up to 144 h following dosing, and plasma pharmacokinetics and safety were assessed. Changes in axitinib plasma exposures in subjects with mild or moderate hepatic impairment were predicted using computer simulations and used to guide initial dosing in the clinical study. Results: Axitinib exposure was similar in subjects with normal hepatic function and those with mild hepatic impairment, but approximately twofold higher in subjects with moderate hepatic impairment. Axitinib exposure weakly correlated with measures of hepatic function but was not affected by smoking status. Axitinib protein binding was similar in the three treatment groups. No significant treatment-related adverse events were reported. Conclusions: Compared with subjects with normal hepatic function, moderate hepatic impairment increased axitinib exposure, suggesting that the oral clearance of axitinib is altered in these subjects. In addition, these data indicate a possible need for a dose reduction in subjects who develop moderate or worse hepatic impairment during axitinib treatment. A single 5-mg dose of axitinib was well tolerated in subjects with mild or moderate hepatic impairment

Sequencing of diverse mandarin, pummelo and orange genomes reveals complex history of admixture during citrus domestication

Cultivated citrus are selections from, or hybrids of, wild progenitor species whose identities and contributions to citrus domestication remain controversial. Here we sequence and compare citrus genomes-a high-quality reference haploid clementine genome and mandarin, pummelo, sweet-orange and sour-orange genomes-and show that cultivated types derive from two progenitor species. Although cultivated pummelos represent selections from one progenitor species, Citrus maxima, cultivated mandarins are introgressions of C. maxima into the ancestral mandarin species Citrus reticulata. The most widely cultivated citrus, sweet orange, is the offspring of previously admixed individuals, but sour orange is an F1 hybrid of pure C. maxima and C. reticulata parents, thus implying that wild mandarins were part of the early breeding germplasm. A Chinese wild 'mandarin' diverges substantially from C. reticulata, thus suggesting the possibility of other unrecognized wild citrus species. Understanding citrus phylogeny through genome analysis clarifies taxonomic relationships and facilitates sequence-directed genetic improvement

Sequencing of diverse mandarin, pummelo and orange genomes reveals complex history of admixture during citrus domestication

Cultivated citrus are selections from, or hybrids of, wild progenitor species whose identities and contributions to citrus domestication remain controversial. Here we sequence and compare citrus genomes-a high-quality reference haploid clementine genome and mandarin, pummelo, sweet-orange and sour-orange genomes-and show that cultivated types derive from two progenitor species. Although cultivated pummelos represent selections from one progenitor species, Citrus maxima, cultivated mandarins are introgressions of C. maxima into the ancestral mandarin species Citrus reticulata. The most widely cultivated citrus, sweet orange, is the offspring of previously admixed individuals, but sour orange is an F1 hybrid of pure C. maxima and C. reticulata parents, thus implying that wild mandarins were part of the early breeding germplasm. A Chinese wild 'mandarin' diverges substantially from C. reticulata, thus suggesting the possibility of other unrecognized wild citrus species. Understanding citrus phylogeny through genome analysis clarifies taxonomic relationships and facilitates sequence-directed genetic improvement. (Résumé d'auteur

A Realistic Roadmap to Formation Flying Space Interferometry

The ultimate astronomical observatory would be a formation flying space interferometer, combining sensitivity and stability with high angular resolution. The smallSat revolution offers a new and maturing prototyping platform for space interferometry and we put forward a realistic plan for achieving first stellar fringes in space by 2030

Immune Checkpoint Inhibitors for Genitourinary Cancers: Treatment Indications, Investigational Approaches and Biomarkers

Cancers of the genitourinary (GU) tract are common malignancies in both men and women and are a major source of morbidity and mortality. Immune checkpoint inhibitors (ICI) targeting CTLA-4, PD-1 or PD-L1 have provided clinical benefit, particularly in renal cell and urothelial carcinoma, and have been incorporated into standard of care treatment in both localized and metastatic settings. However, a large fraction of patients do not derive benefit. Identification of patient and tumor-derived factors which associate with response have led to insights into mechanisms of response and resistance to ICI. Herein, we review current approvals and clinical development of ICI in GU malignancies and discuss exploratory biomarkers which aid in personalized treatment selection

Assessing the Effect of an Intensive 2-Week Surgical Training and Innovation Program for High-School Students.

ObjectiveThe summer surgery program (SSP) was founded in 2012 as an educational program for students at the critical juncture between high school and college to engender interest in medicine, science, and innovation. This program has a distinct emphasis on innovation and problem solving based on real-life operative challenges identified by students during surgical observation in the operating room. The effect of the SSP regarding postsecondary education and career goals was evaluated by participants using a follow-up questionnaire.DesignRetrospective cohort study using web-based survey administered to students at least 1 year after participation in the SSP. Associations between demographics and survey responses were made using Fisher's exact test and a Bonferonni correction was used to account for multiple comparisons.ParticipantsBetween July 2012 and August 2015, 119 students enrolled in the SSP. We sent a web-based questionnaire link to all participants who completed the program. The questionnaire contained 80 questions assessing the participant's interest in studying medicine or science in college, knowledge of health care, and their appreciation and understanding of innovation.SettingUC Irvine Medical Center, Orange, CA; Institutional tertiary care center.ResultsIn total, 77 (64.7%) of 119 students who matriculated in the SSP completed the follow-up survey; the mean number of years after the program was 2.09 years. Nearly all students reported the program increased their interest in studying medicine or science in college (97.4%), led them to a better understanding of their own career goals (93.5%) and made them more confident in their ability to succeed in a career in health care (88.3%). The majority indicated the program led them to better understand the training and schooling required of doctors and surgeons (94.8%), and led them to better appreciate the roles of different medical specialties (96.1%). Overall 96% of students reported that the program led them to better understand the importance of innovation and 86% of the respondents noted they better understood the process of innovation. Participants in the SSP were confident they would be able to become a health professional (p < 0.0001). Of note, there was no drop off in the ratings for the program when comparing classes that were 1, 2, 3, or 4 years after their SSP experience.ConclusionsThe follow-up survey revealed that the 2 week SSP had a markedly, long lasting positive effect on participants in areas of academic, career, and innovation-related variables

Photodynamic Therapy Effectively Treats Actinic Keratoses Without Pre-Illumination Incubation Time.

BACKGROUND: Actinic keratoses (AKs) are dysplastic lesions of the epidermis that have the potential to progress to non-melanoma skin cancers (NMSC). Traditional photodynamic therapy (PDT) requires a pre-illumination incubation time, which adds to overall in-office time and has been linked to pain. Our group has found a novel protocol to effectively treat AKs with PDT that eliminates the pre-illumination incubation period and uses 2 back-to-back cycles of 16 minute 40 seconds. METHODS: The patient was prepped with soapy water and isopropyl alcohol, and thick AKs were descaled with a curette. Next, 5-aminolevulinic acid (ALA) was applied to the treatment areas and the patient was immediately placed under the blue light for 33 minutes and 20 seconds (two cycles of 16m/40s). RESULTS: During therapy, the patient reported no pain. At one week, treated areas revealed a good reaction. The procedure was repeated at one month to treat residual AKs. At a 4-month follow-up, the patient's face and scalp showed near clearance of any AKs. CONCLUSION: During PDT, the photosensitizer aminolevulinic acid (ALA), or in Europe methyl aminolevulinate (MAL), is utilized as a synthetic precursor that preferentially accumulates in dysplastic cells. The precursor then converts to PpIX via the heme pathway and causes apoptosis of the cells when excited, most commonly by either blue-violet (400-430 nm) or red (630-635 nm) light. Shorter incubation times are associated with reduced pain because less PpIX will have accumulated in the treated tissue by the start of the exposure to the light. The doubling of the light exposure time allows comparable levels of the photosensitizing molecule to accumulate and be activated so as to produce an equivalent reaction. The associated reduction in pain along with a more convenient treatment schedule makes this PDT protocol more tolerable and convenient to some patients. J Drugs Dermatol. 2017;16(3):275-278.