To compare gene expression profiles and drug permeability differences in Caco-2 cell culture and human duodenum.
Gene expression profiles in Caco-2 cells and human duodenum were determined by ...GeneChip analysis. In vivo drug permeability measurements were obtained through single-pass intestinal perfusion in human subjects, and correlated with in vitro Caco-2 transport permeability.
GeneChip analysis determined that 37, 47, and 44 percent of the 12,559 gene sequences were expressed in 4-day andl6-day Caco-2 cells and human duodenum, respectively. Comparing human duodenum with Caco-2 cells, more than 1,000 sequences were determined to have at least a 5-fold difference in expression. There were 26, 38, and 44 percent of the 443 transporters, channels, and metabolizing enzymes detected in 4-day, 16-day Caco-2 cells, and human duodenum, respectively. More than 70 transporters and metabolizing enzymes exhibited at least a 3-fold difference. The overall coefficient of variability of the 10 human duodenal samples for all expressed sequences was 31% (range 3% to 294%) while that of the expressed transporters and metabolizing enzymes was 33% (range 3% to 87%). The in vivo / in vitro drug permeability measurements correlated well for passively absorbed drugs (R2 = 85%). The permeability correlation for carrier-mediated drugs showed 3- 35-fold higher in human above the correlation of passively absorbed drugs. The 2- 595-fold differences in gene expression levels between the Caco-2 cells and human duodenum correlated with the observed 3- 35-fold difference in permeability correlation between carrier-mediated drugs and passively absorbed drugs. CONCLUSIONS; Significant differences in gene expression levels in Caco-2 cells and human duodenum were observed. The observed differences of gene expression levels were consistent with observed differences in carrier mediated drug permeabilities. Gene expression profiling is a valuable new tool for investigating in vitro and in vivo permeability correlation.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra‐renal abnormalities. Using trio exome ...sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one‐day‐old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post‐zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow‐up studies for presumed de novo and low‐level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
A crystallographic investigation of a series of host–guest complexes in which small‐molecule organic guests occupy the central cavity of an approximately cubic M8L12 coordination cage has revealed ...some unexpected behaviour. Whilst some guests form 1:1 H⋅G complexes as we have seen before, an extensive family of bicyclic guests—including some substituted coumarins and various saturated analogues—form 1:2 H⋅G2 complexes in the solid state, despite the fact that solution titrations are consistent with 1:1 complex formation, and the combined volume of the pair of guests significantly exceeds the Rebek 55±9 % packing for optimal guest binding, with packing coefficients of up to 87 %. Re‐examination of solution titration data for guest binding in two cases showed that, although conventional fluorescence titrations are consistent with 1:1 binding model, alternative forms of analysis—Job plot and an NMR titration—at higher concentrations do provide evidence for 1:2 H⋅G2 complex formation. The observation of guests binding in pairs in some cases opens new possibilities for altered reactivity of bound guests, and also highlights the recently articulated difficulties associated with determining stoichiometry of supramolecular complexes in solution.
What a bind: Despite solution titrations showing binding of one guest inside the cavity of an octanuclear cubic coordination cage, in the solid‐state many guests (such as coumarin, illustrated) bind as pairs with up to 87 % of cavity volume being occupied—amongst the highest packing coefficients known. With this knowledge from crystallography, evidence for formation of H⋅G2 species can be found in solution under forcing conditions.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
Isocitrate dehydrogenase (IDH) mutation status is recommended used for diagnosis and prognostication of glioblastoma patients. We studied efficacy and safety of stereotactic radiosurgery ...(SRS) for patients with recurrent IDH-wt glioblastoma.
Methods
Consecutive patients treated with SRS for IDH-wt glioblastoma were pooled for this retrospective observational international multi-institutional study from institutions participating in the International Radiosurgery Research Foundation.
Results
Sixty patients (median age 61 years) underwent SRS (median dose 15 Gy and median treatment volume: 7.01 cm
3
) for IDH-wt glioblastoma. All patients had histories of surgery and chemotherapy with temozolomide, and 98% underwent fractionated radiation therapy. MGMT status was available for 42 patients, of which half of patients had MGMT mutant glioblastomas. During median post-SRS imaging follow-up of 6 months, 52% of patients experienced tumor progression. Median post-SRS progression free survival was 4 months. SRS prescription dose of > 14 Gy predicted longer progression free survival HR 0.357 95% (0.164–0.777) p = 0.009. Fifty-percent of patients died during post-SRS clinical follow-up that ranged from 1 to 33 months. SRS treatment volume of > 5 cc emerged as an independent predictor of shorter post-SRS overall survival HR 2.802 95% CI (1.219–6.444) p = 0.02. Adverse radiation events (ARE) suggestive of radiation necrosis were diagnosed in 6/55 (10%) patients and were managed conservatively in the majority of patients.
Conclusions
SRS prescription dose of > 14 Gy is associated with longer progression free survival while tumor volume of > 5 cc is associated with shorter overall survival after SRS for IDH-wt glioblastomas. AREs are rare and are typically managed conservatively.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Pontine tegmental cap dysplasia is a rare neurologic condition first described by Barth et al. in 2007. It is characterized by a vaulted pontine tegmentum projecting into the fourth ...ventricle and ventral pontine hypoplasia. Patients present with developmental delay, cerebellar and pyramidal abnormalities, cranial nerve dysfunction, and various extracranial malformations. The condition is thought to occur as a result of aberrant neuronal axonal guidance during embryologic development. Its genetic etiology has not been identified. We describe a further case of this rare condition with several features not previously reported, including aortic arch hypoplasia and mirror movements.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Invited for the cover of this issue is the group of Michael D. Ward at the University of Warwick. The image depicts structures of the host cage containing one guest or two guests. Read the full text ...of the article at 10.1002/chem.201905499.
“The moral is that evaluating the stoichiometry of supramolecular complexes cannot be entrusted to one analytical technique under one set of conditions but, ideally, requires a range of techniques applied under different experimental conditions” Read more about the story behind the cover in the Cover Profile and about the research itself on page 3054 ff. (DOI: 10.1002/chem.201905499).
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