Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant

The pathogenesis of Hirschsprung disease is complex. Although the RET proto-oncogene is the most frequently affected gene in Hirschsprung disease, rare coding sequence variants explain only a small part of Hirschsprung disease cases. We aimed to assess the genetic background of Hirschsprung disease using a genome-wide association analysis combined with sequencing all RET exons in samples from 105 Hirschsprung disease cases (30 familial and 75 sporadic) and 386 controls.As expected, variants in or near RET showed the strongest overall association with Hirschsprung disease and the most statistically significant association was observed when using a recessive genetic model (rs2435357, NC_000010.10:g.43582056T?>?C; genotype TT, OR?=?17.31, P?=?1.462?×?10^?21). Previously published associations in variants in SEMA (rs11766001, NC_000007.13:g.84145202A?>?C; allele C, OR?=?2.268, P?=?0.009533) and NRG1 (rs4541858, NC_000008.10:g.32410309A?>?G; allele G, OR?=?1.567, P?=?0.015; rs7835688, NC_000008.10:g.32411499G?>?C; allele C, OR?=?1.567, P?=?0.015) were also replicated in the genome-wide association analysis. Sequencing revealed a total of 12 exonic RET rare variants. Of these, eight amino acid changing rare variants and two frameshift variants caused or possibly caused Hirschsprung disease.Only a minority of the Hirschsprung disease cases (9/30 familial; 7/75 sporadic) carried one of the rare variants. Excluding the rare variant carriers from the genome-wide association analysis did not appreciably change the association of rs2435357 with Hirschsprung disease. We estimate that approximately two thirds of the sporadic cases may be statistically attributed to the recessive action of the common non-coding RET variants. Thus, even though most cases do not carry rare RET variants, combinations of rare variants and the common non-coding RET variant cause the majority of the cases in our population.     

Outcome of clavicular fracture in 89 patients

Summary During 1982, 118 patients with clavicular fracture were treated in the Department of Orthopaedics and Traumatology, Helsinki University Central Hospital. Eighty-nine patients appeared for the follow-up examination in 1984. Eighty-three fractures were treated with immobilization in a sling. Four fractures were treated with plate fixation primarily and two patients were operated on for delayed union. The immobilization averaged 21 days, range 10–42 days. The follow-up was 2 years in all cases. The result was good in 65 cases, satisfactory in 20, and poor in 4 cases. Patients with primary dislocation of more than 15 mm or with shortening observed at the follow-up examination had statistically significantly more pain than patients without these findings.

---

Zusammenfassung An der Orthopädisch-traumatologischen Klinik der Universität Helsinki wurden 1982 118 Patienten mit Klavikulafraktur behandelt. Neunundachtzig dieser Patienten konnten im Jahre 1984 nachuntersucht werden. Dreiundachtzig Frakturen waren durch Immobilisation im Armtragetuch behandelt worden. Vier Frakturen wurden primär verplattet, und zwei Fälle wurden wegen verzögerter Heilung sekundär operiert. Die Dauer der Immobilisation betrug durchschnittlich 21 Tage (10–42 Tage). Die Beobachtungszeit war in allen Fällen zwei Jahre. Das Ergebnis der Behandlung war gut in 65 Fällen, befriedigend in 20 Fällen und schlecht in 4 Fällen. Patienten mit primärer Dislokation von mehr als 15 mm oder bei der Nachuntersuchung festgestellter Verkürzung hatten signifikant mehr Schmerzen als Patienten ohne derartige Befunde.

     

Gene variants as determinants of longevity: focus on the inflammatory factors

Human longevity is an extremely complex trait with various genetic, epigenetic and environmental factors acting upon the longevity phenotype. It is now becoming evident that whilst the genetic differences contribute only modestly to life expectancy before the age of 60 years, their impact on survival becomes more prominent at the extreme ages. Several longevity gene candidates have emerged during the past decade; the majority of them are related either to inflammatory functions, stress response or to lipid and glucose metabolism. The variants of inflammatory and immune response genes are of special interest since advancing ages is accompanied by a decline in several immune functions—a phenomenon called immunosenescence. Paradoxically, ageing is also characterised by chronic low-grade inflammation termed “inflammaging”, which manifests as a two- to fourfold increase in the production of proinflammatory cytokines and acute phase proteins. These contrasting phenomena provide a functional rationale of how the genetic differences in inflammatory mediators may modify the life span of the elderly. Besides describing the pre-existing inflammatory and immune-related longevity gene variants, in this review, we also explain some of the theoretical and practical challenges that genetic longevity studies often encounter.     

St John's wort greatly reduces the concentrations of oral oxycodone

Background: Chronic pain is associated with depression. Self‐treatment of depression with herbal over‐the‐counter medicine St John's wort makes pain patients prone to drug interactions. Aims: The aim of this study was to assess the potential of St John's wort to alter the CYP3A‐mediated metabolism of a μ‐opioid receptor agonist, oxycodone. Methods: The study design was placebo‐controlled, randomized, cross‐over with two phases at intervals of 4 weeks and was conducted with 12 healthy participants. St John's wort (Jarsin®) or placebo was administered t.i.d. for 15 days and oral oxycodone hydrochloride 15 mg on day 14. Oxycodone pharmacokinetics and pharmacodynamics were compared after St John's wort or placebo. Behavioural and analgesic effects were assessed with subjective visual analogue scales and cold pressor test. Plasma drug concentrations were measured from 0 to 48 h, behavioural and analgesic effects from 0 to 12 h. Results: Following St John's wort administration the oxycodone AUC decreased 50% (p < 0.001). Oxycodone elimination half‐life shortened from a mean ± SD 3.8 ± 0.7 to 3.0 ± 0.4 h (p < 0.001). The self‐reported drug effect of oxycodone as measured by AUEC_0–12 decreased significantly (p = 0.004). Differences between St John's wort and placebo phases in cold pain threshold and intensity AUEC_0–12 were not observed. Conclusions: St John's wort greatly reduced the plasma concentrations of oral oxycodone. The self‐reported drug effect of oxycodone decreased significantly. This interaction may potentially be of some clinical significance when treating patients with chronic pain.     

Panoramic ultrasonography is a valid method to measure changes in skeletal muscle cross-sectional area

The purpose of this study was to examine the reliability and validity of the “panoramic” brightness mode ultrasonography (US) method to detect training-induced changes in muscle cross-sectional area (CSA) by comparison with results obtained using magnetic resonance imaging (MRI). Out of 27 young male volunteers, 20 subjects were assigned to training group and seven to non-training control group. Muscle CSAs of vastus lateralis were analyzed by MRI and US before and after 21 weeks of either heavy resistance training or control period. Measured by both the US and MRI, the resistance training induced significant increases (~13–14%, P < 0.001) in muscle CSA, whereas no changes were observed in control group. A high repeatability was found between the two consequent US measurements (intraclass correlation coefficient, ICC of 0.997) with standard error of measurement (SEM) of 0.38 cm² and smallest detectable difference of 1.1 cm². Validity of the US method against MRI in assessing CSA of VL produced ICC of 0.905 and SEM of 0.87 cm² with high limits of agreement analyzed by Bland and Altman method. However, the MRI produced systematically (10 ± 4%, P < 0.01) larger CSA values than the US method. The US showed high agreement against MRI in detecting changes in muscle CSA (ICC of 0.929, SEM of 0.94 cm²). The results of this study showed that the panoramic US method provides repeatable measures of a muscle CSA although MRI produced larger absolute CSA values. Moreover, this US method detects training-induced changes in muscle CSA with a comparable degree of precision to MRI.     

Foresight in medicine: current challenges with Haemophilus influenzae type b conjugate vaccines

Eskola J (National Institute for Health and Welfare, Helsinki). Foresight in medicine: current challenges with Haemophilus influenzae type b conjugate vaccines (Foresight). J Intern Med 2010; 267 : 241–250. Abstract. An effective vaccine to prevent invasive infections caused by Haemophilus influenzae type b (Hib) bacteria has been available for more than 20 years. Hib conjugate vaccine is safe, efficacious and easy to use, and its cost‐benefit ratio is high both in industrialized as well as in developing countries. In spite of this, WHO estimates that every year approximately 8 million children contract life‐threatening Haemophilus infections, especially meningitis or severe pneumonia. If we want to take seriously the Millenium Development Goal of reducing the mortality of under 5‐year‐old children by two‐thirds before the year 2015, an effective means to contribute to this would be more efficient use of Hib vaccines [ 1 ].