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.     

Preterm infants’ early growth and brain white matter maturation at term age

Background

Normal intrauterine conditions are essential to normal brain growth and development; premature birth and growth restriction can interrupt brain maturation. Maturation processes can be studied using diffusion tensor imaging.

Objective

The aim of this study was to use tract-based spatial statistics to assess the effect that early postnatal growth from birth to 40 gestational weeks has on brain white matter maturation.

Materials and methods

A total of 36 preterm infants were accepted in the study. Postnatal growth was assessed by weight, length and head circumference. Birth weight z-score and gestational age were used as confounding covariates.

Results

Head circumference catch-up growth was associated with less mature diffusion parameters (P?<?0.05). No significant associations were observed between weight or length growth and diffusion parameters.

Conclusion

Growth-restricted infants seem to have delayed brain maturation that is not fully compensated at term, despite catch-up growth.     

Improved detection of localized prostate cancer using co-registered MRI and (11)C-acetate PET/CT

Objectives

We aimed to study the ability of contrast enhanced MRI at 1.5 T and ¹¹C-acetate PET/CT, both individually and using fused data, to detect localized prostate cancer.

Methods

Thirty-six men with untreated prostate cancer and negative for metastatic disease on pelvic CT and bone scan were prospectively enrolled. A pelvic ¹¹C-acetate PET/CT scan was performed in all patients, and a contrast enhanced MRI scan in 33 patients (6 examinations using both endorectal coil and surface coils, and 27 examinations using surface coils only). After the imaging studies 10 patients underwent prostatectomy and 26 were treated by image guided external beam radiation treatment. Image fusion of co-registered PET and MRI data was performed based on anatomical landmarks visible on CT and MRI using an advanced in-house developed software package. PET/CT, MRI and fused PET/MRI data were evaluated visually and compared with biopsy findings on a lobar level, while a sextant approach was used for patients undergoing prostatectomy.

Results

When using biopsy samples as method of reference, the sensitivity, specificity and accuracy for visual detection of prostate cancer on a lobar level by contrast enhanced MRI was 85%, 37%, 73% and that of ¹¹C-acetate PET/CT 88%, 41%, 74%, respectively. Fusion of PET with MRI data increased sensitivity, specificity and accuracy to 90%, 72% and 85%, respectively.

Conclusions

Fusion of sequentially obtained PET/CT and MRI data for the localization of prostate cancer is feasible and superior to the performance of each individual modality alone.     

Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial

Aims/hypothesis

Pancreatic fat accumulation may contribute to the development of beta cell dysfunction. Exercise training improves whole-body insulin sensitivity, but its effects on pancreatic fat content and beta cell dysfunction are unclear. The aim of this parallel-group randomised controlled trial was to evaluate the effects of exercise training on pancreatic fat and beta cell function in healthy and prediabetic or type 2 diabetic participants and to test whether the responses were similar regardless of baseline glucose tolerance.

Methods

Using newspaper announcements, a total of 97 sedentary 40–55-year-old individuals were assessed for eligibility. Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes were defined by ADA criteria. Of the screened candidates, 28 healthy men and 26 prediabetic or type 2 diabetic men and women met the inclusion criteria and were randomised into 2-week-long sprint interval or moderate-intensity continuous training programmes in a 1:1 allocation ratio using random permuted blocks. The primary outcome was pancreatic fat, which was measured by magnetic resonance spectroscopy. As secondary outcomes, beta cell function was studied using variables derived from OGTT, and whole-body insulin sensitivity and pancreatic fatty acid and glucose uptake were measured using positron emission tomography. The measurements were carried out at the Turku PET Centre, Finland. The analyses were based on an intention-to-treat principle. Given the nature of the intervention, blinding was not applicable.

Results

At baseline, the group of prediabetic or type 2 diabetic men had a higher pancreatic fat content and impaired beta cell function compared with the healthy men, while glucose and fatty acid uptake into the pancreas was similar. Exercise training decreased pancreatic fat similarly in healthy (from 4.4% [3.0%, 6.1%] to 3.6% [2.4%, 5.2%] [mean, 95% CI]) and prediabetic or type 2 diabetic men (from 8.7% [6.0%, 11.9%] to 6.7% [4.4%, 9.6%]; p?=?0.036 for time effect) without any changes in pancreatic substrate uptake (p?≥?0.31 for time effect in both insulin-stimulated glucose and fasting state fatty acid uptake). In prediabetic or type 2 diabetic men and women, both exercise modes similarly improved variables describing beta cell function.

Conclusions/interpretation

Two weeks of exercise training improves beta cell function in prediabetic or type 2 diabetic individuals and decreases pancreatic fat regardless of baseline glucose tolerance. This study shows that short-term training efficiently reduces ectopic fat within the pancreas, and exercise training may therefore reduce the risk of type 2 diabetes.

Trial registration

ClinicalTrials.gov NCT01344928

Funding

This study was funded by the Emil Aaltonen Foundation, the European Foundation for the Study of Diabetes, the Finnish Diabetes Foundation, the Orion Research Foundation, the Academy of Finland (grants 251399, 256470, 281440, and 283319), the Ministry of Education of the State of Finland, the Paavo Nurmi Foundation, the Novo Nordisk Foundation, the Finnish Cultural Foundation, the Hospital District of Southwest Finland, the Turku University Foundation, and the Finnish Medical Foundation.

     

Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r?=?–0.66, p?=?0.04) and myocyte hypertrophy (r?=?–0.68, p?=?0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with ¹¹C-labeled acetate positron emission tomography (r?=?–0.71, p?=?0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.     

Measuring Value in Postacute Care

The value of postacute care (PAC) is unclear. While experienced clinicians understand the appropriateness of each specific site of PAC, clear evidence-based guidelines are not available, and many referrals to PAC today are made based on bed availability rather than patient need. Measuring value (value=outcomes/cost) for the entire episode of care has been proposed as an effective method to both evaluate and enable faster innovation in care. Instituting value-based care will increase patient engagement, improve quality and reduce cost with the potential of unifying the goals for all stakeholders—patients and families, providers, and payers. To achieve a goal of value-based care, rehabilitation researchers will need to measure outcomes and cost for the entire episode of care. Recent laudable efforts by the Centers for Medicare & Medicaid Services (CMS) to standardize data across PAC may not include the entire episode of care since outpatient care and measurement from home are not included. In addition, the true cost of services delivered is rarely measured. To implement value-based care in rehabilitation and facilitate cost-effective care improvements, outcomes research in PAC should focus on 4 areas. First, outcome measures need to reflect the patient’s perspective. Second, new methods must be implemented to acquire comparable valid and reliable data from all postacute settings and the home. Third, a predictive model for individual patients should be utilized to guide patient referral from acute care to PAC and monitor progress. And fourth, timely specific measures of true cost (resources consumed) for the outcomes achieved are needed.     

Dysfunctional family functioning in high socioeconomic status families as a risk factor for the development of psychiatric disorders in adoptees: the Finnish Adoptive Family Study of Schizophrenia

Purpose

Earlier findings indicate that socioeconomic status (SES) of family associates with family functioning. This study examined the impacts of family functioning and genetic risk for schizophrenia on psychiatric morbidity of adoptees in families of high SES (HSES) and low SES (LSES).

Methods

The study population is a subgroup of the Finnish Adoptive Family Study of Schizophrenia. Of the adoptees, 152 had high genetic risk for schizophrenia spectrum disorders (HR) and 151 adoptees had low risk (LR). Of the adoptees, 185 (HR = 94, LR = 91) were raised in high-SES (HSES) families and 118 (HR = 58, LR = 60) in low-SES (LSES) families. The family SES was determined by the occupational status of the main provider of the family. The functioning of adoptive families was assessed based on Global Family Ratings (GFRs) and psychiatric disorders on DSM-III-R criteria.

Results

In the HSES families, the psychiatric morbidity of the adoptees was emphasized by HR (OR = 4.28, CI 2.14–8.56) and dysfunctional family processes (OR = 6.44, CI 2.75–15.04). In the LSES families, the adoptees´ psychiatric morbidity was almost significantly increased by HR (OR = 2.10, CI 0.99–4.45), but not by dysfunctional family processes (OR = 1.33, CI 0.53–3.34).

Conclusions

This study showed that in HSES families, dysfunctional family processes and HR for schizophrenia increased the likelihoods for the development of psychiatric disorders in adoptees. The results can be utilized in identifying risk factors in the development of psychiatric disorders and focusing preventative strategies on risk groups with acknowledging the importance of family functioning.

     

Differentiation of adoptees at high versus low genetic risk for schizophrenia by adjusted MMPI indices.

The aim of this study was to find potential signs of genetic vulnerability to schizophrenia. The differences between adoptees at high genetic risk for schizophrenia (their biological mother had a schizophrenia spectrum disorder) and control adoptees of non-schizophrenia spectrum biological mothers were assessed. The comparisons between these groups were based on the Minnesota Multiphasic Personality Inventory (MMPI) test's subscale scores adjusted by gender, age at MMPI assessment, age at placement into the adoptive family and social class. The subjects were a subsamples of a total of 182 tested adoptees and 136 mentally healthy adoptees in the Finnish Adoptive Family Study. The high-risk group was found to be distinguishable from the low-risk group based on deviant scores on the Hostility, Hypomania and Lie scales. These scales may measure genetic vulnerability and also possibly be indicative of psychometric deviance predicting future onset of schizophrenia.