Disposition of flavonoids via enteric recycling: enzyme stability affects characterization of prunetin glucuronidation across species, organs, and UGT isoforms

We characterized the in vitro glucuronidation of prunetin, a prodrug of genistein that is a highly active cancer prevention agent. Metabolism studies were conducted using expressed human UGT isoforms and microsomes/S9 fractions prepared from intestine and liver of rodents and humans. The results indicated that human intestinal microsomes were more efficient than liver microsomes in glucuronidating prunetin, but rates of metabolism were dependent on time of incubation at 37 degrees C. Human liver and intestinal microsomes mainly produced metabolite 1 (prunetin-5- O-glucuronide) and metabolite 2 (prunetin-4'- O-glucuronide), respectively. Using 12 human UGT isoforms, we showed that UGT1A7, UGT1A8, and UGT1A9 were mainly responsible for the formation of metabolite 1, whereas UGT1A1, UGT1A8, and UGT1A10 were mainly responsible for the formation of metabolite 2. This isoform-specific metabolism was consistent with earlier results obtained using human liver and intestinal microsomes, as the former (liver) is UGT1A9-rich whereas the latter is UGT1A10-rich. Surprisingly, we found that the thermostability of the microsomes was isoform- and organ-dependent. For example, human liver microsomal UGT activities were much more heat-stable (37 degrees C) than intestinal microsomal UGT activities, consistent with the finding that human UGT1A9 is much more thermostable than human UGT1A10 and UGT1A8. The organ-specific thermostability profiles were also evident in rat microsomes and mouse S9 fractions, even though human intestinal glucuronidation of prunetin differs significantly from rodent intestinal glucuronidation. In conclusion, prunetin glucuronidation is species-, organ-, and UGT-isoform-dependent, all of which may be impacted by the thermostability of specific UGT isoforms involved in the metabolism.     

Variations in the Anatomy of Spinal Accessory Nerve and its Landmarks for Identification in Neck Dissection: A Clinical Study

PurposeTo assess the anatomy of the spinal accessory nerve (SAN), its variations and the landmark of level II B lymph nodes.MethodsProspective study included 50 patients from 2016 to 2018.The predictor variables were drawn from demographic details of the patients; SAN was analyzed intraoperatively with the parameters like the nerve relationship with the IJV, SCM muscle, contributions of cervical plexus and a new parameter of length from midpoint of clavicle to entry of nerve in the trapezius muscle in the lower part of neck which was studied for the first time and forms the prime identification landmark to preserve the nerve. Outcome variables were details of anatomic variations and branches and utility of these landmarks in prevention of nerve injury.ResultsSample consisted of 38 (76%) male and 12 (24%) female patients. The SAN with respect to the IJV was dorsal in 42% patients and ventral in 58%. In 54% cases, SAN gave a branch to the SCM without penetrating the muscle and in 46% gave a branch to the SCM penetrating the muscle. SAN received contributions from the C2 root of the cervical plexus in 68%, both C2 and C3 in 54% and C3 in 50% cases. Mean length from measurements recorded between mid-line of clavicle to insertion of SAN to trapezius muscle and entry of SAN into trapezius muscle was 59 mm with variations recorded in gender and short/long neck.ConclusionThe result of this study suggests that parameters used are simple clinical tools for identification of the SAN and its variations resulting in no nerve injury. It is prudent for the surgeon to have knowledge of sound anatomical landmarks with the variations in the SAN course which avoids morbidity and improves the quality of life.     

Immature integration and segregation of emotion-related brain circuitry in young children

The human brain undergoes protracted development, with dramatic changes in expression and regulation of emotion from childhood to adulthood. The amygdala is a brain structure that plays a pivotal role in emotion-related functions. Investigating developmental characteristics of the amygdala and associated functional circuits in children is important for understanding how emotion processing matures in the developing brain. The basolateral amygdala (BLA) and centromedial amygdala (CMA) are two major amygdalar nuclei that contribute to distinct functions via their unique pattern of interactions with cortical and subcortical regions. Almost nothing is currently known about the maturation of functional circuits associated with these amygdala nuclei in the developing brain. Using intrinsic connectivity analysis of functional magnetic resonance imaging data, we investigated developmental changes in functional connectivity of the BLA and CMA in twenty-four 7- to 9-y-old typically developing children compared with twenty-four 19- to 22-y-old healthy adults. Children showed significantly weaker intrinsic functional connectivity of the amygdala with subcortical, paralimbic, and limbic structures, polymodal association, and ventromedial prefrontal cortex. Importantly, target networks associated with the BLA and CMA exhibited greater overlap and weaker dissociation in children. In line with this finding, children showed greater intraamygdala connectivity between the BLA and CMA. Critically, these developmental differences were reproducibly identified in a second independent cohort of adults and children. Taken together, our findings point toward weak integration and segregation of amygdala circuits in young children. These immature patterns of amygdala connectivity have important implications for understanding typical and atypical development of emotion-related brain circuitry.     

Role of Neuropilin-2-mediated signaling axis in cancer progression and therapy resistance

Neuropilins (NRPs) are transmembrane proteins involved in vascular and nervous system development by regulating angiogenesis and axon guidance cues. Several published reports have established their role in tumorigenesis. NRPs are detectable in tumor cells of several cancer types and participate in cancer progression. NRP2 is also expressed in endothelial and immune cells in the tumor microenvironment and promotes functions such as lymphangiogenesis and immune suppression important for cancer progression. In this review, we have taken a comprehensive approach to discussing various aspects of NRP2-signaling in cancer, including its regulation, functional significance in cancer progression, and how we could utilize our current knowledge to advance the studies and target NRP2 to develop effective cancer therapies.

     

Analysis of Demographic and Educational Backgrounds of Interventional Neuroradiology Fellowship Program Director Workforce in North America

PurposeTo analyse the demographics, academic background, and scholarly activity of Interventional Neuroradiology (INR)/Endovascular Surgical Neuroradiology (ESN) program directors (PDs) in the United States (US) and Canada.MethodsA list of all INR/ESN fellowships was obtained from the Accreditation Council for Graduate Medical Education, the Committee on Advanced Subspecialty Training, maintained by Society of Neurological Surgeons, the NeuroInterventional Training list website maintained by the Society of NeuroInterventional Surgery, and the Neurosurgical Fellowship Training Program Directory website maintained by the American Association of Neurological Surgeons. Online search was performed to identify PDs for these programs. Publicly available sources used to gather information about each PD included the program websites, the HealthGrades and Doximity websites, and Elsevier's Scopus database. Demographic and educational data including age, gender, educational background, subspecialty, appointment age, interval between residency completion and appointment as PD, additional degrees, academic rank, prior leadership positions, and metrics of scholarly activity were recorded. One-way analysis of variance was used to determine differences between the means of different groups.ResultsA total of 78 PDs from 72 programs were included, of which 72 (92.3%) were male with the mean age of 49.59 years (SD 7.25). Specialty division of PDs was neurosurgery (40, 51.3%), radiology (26, 33.3%), and neurology (10, 12.8%), whereas 2 PDs were dual board-certified in neurology and radiology. Twenty-five (32.1%) PDs attended an international medical school. All PDs received an MD degree or foreign equivalent, with no PD holding a DO degree. Eleven PDs received a PhD degree and 16 PDs received fellowship from a professional medical society. The mean ± SD publications, citations, and h-indexes of PDs were 111.32 ± 121.18, 2985.0 ± 1459.0 and 22.27 ± 15.45, respectively. There was no statistical difference in scholarly activity among PDs when stratified on the basis of specialty, gender, and US region.ConclusionINR/ESN PDs are predominantly male, with a majority from neurosurgery background, and thirty percent having graduated from international medical schools.