Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma

Osteosarcoma is the most common primary bone tumour in dogs but various forms of therapy have not significantly improved clinical outcomes. As dysregulation of kinase activity is often present in tumours, kinases represent attractive molecular targets for cancer therapy. The purpose of this study was to identify novel compounds targeting kinases with the potential to induce cell death in a panel of canine osteosarcoma cell lines. The ability of 80 well-characterized kinase inhibitor compounds to inhibit the proliferation of four canine osteosarcoma cell lines was investigated in vitro. For those compounds with activity, the mechanism of action and capability to potentiate the activity of doxorubicin was further evaluated. The screening showed 22 different kinase inhibitors that induced significant anti-proliferative effects across the four canine osteosarcoma cell lines investigated. Four of these compounds (RO 31-8220, 5-iodotubercidin, BAY 11-7082 and an erbstatin analog) showed significant cell growth inhibitory effects across all cell lines in association with variable induction of apoptosis. RO 31-8220 and 5-iodotubercidin showed the highest ability to potentiate the effects of doxorubicin on cell viability. In conclusion, the present study identified several potent kinase inhibitors targeting the PKC, CK1, PKA, ErbB2, mTOR and NF-κB pathways, which may warrant further investigations for the treatment of osteosarcoma in dogs

Potential improvement of pregnancy outcome through prenatal small for gestational age detection

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA. OBJECTIVE: To assess differences in mode of delivery and pregnancy outcome between prenatally detected and nonprenatally detected small for gestational age (SGA) neonates born at term.STUDY DESIGN: We performed a retrospective multicenter cohort study. All singleton infants, born SGA in cephalic position between 36(0/7) and 41(0/7) weeks gestation, were classified as either prenatally detected SGA or nonprenatally detected SGA. With propensity score matching we created groups with comparable baseline characteristics. We compared these groups for composite adverse perinatal outcome, labor induction, and cesarean section rates.RESULTS: We included 718 SGA infants, of whom 555 (77%) were not prenatally detected. Composite adverse neonatal outcome did not differ statistically significant between the matched prenatally detected and the nonprenatally detected group (5.5 vs. 7.4%, odds ratio [OR] 0.74, 95% confidence interval [CI]: 0.30-1.8). However, perinatal mortality only occurred in the nonprenatally detected group (1.8% [3/163] in the matched cohort, 1.3% [7/555] in the complete cohort). In the propensity matched prenatally detected SGA group both induction of labor (57 vs. 9%, OR 14.0, 95% CI: 7.4-26.2) and cesarean sections (20 vs. 8%, OR 2.9, 95% CI: 1.5-5.8) were more often performed compared with the nonprenatally detected SGA group.CONCLUSION: Prenatal SGA detection at term allows timely induction of labor and cesarean sections thus potentially preventing stillbirth

Graphene-porphyrin single-molecule transistors

We demonstrate a robust graphene-molecule-graphene transistor architecture. We observe remarkably reproducible single electron charging, which we attribute to insensitivity of the molecular junction to the atomic configuration of the graphene electrodes. The stability of the graphene electrodes allow for high-bias transport spectroscopy and the observation of multiple redox states at room-temperature

Cerebral autoregulation assessed by near-infrared spectroscopy:validation using transcranial Doppler in patients with controlled hypertension, cognitive impairment and controls

PURPOSE: Cerebral autoregulation (CA) aims to attenuate the effects of blood pressure variation on cerebral blood flow. This study assessed the criterion validity of CA derived from near-infrared spectroscopy (NIRS) as an alternative for Transcranial Doppler (TCD). METHODS: Measurements of continuous blood pressure (BP), oxygenated hemoglobin (O(2)Hb) using NIRS and cerebral blood flow velocity (CBFV) using TCD (gold standard) were performed in 82 controls, 27 patients with hypertension and 94 cognitively impaired patients during supine rest (all individuals) and repeated sit to stand transitions (cognitively impaired patients). The BP-CBFV and BP-O(2)Hb transfer function phase shifts (TF(φ)) were computed as CA measures. Spearman correlations (ρ) and Bland Altman limits of agreement (BAloa) between NIRS- and TCD-derived CA measures were computed. BAloa separation < 50° was considered a high absolute agreement. RESULTS: NIRS- and TCD-derived CA estimates were significantly correlated during supine rest (ρ = 0.22–0.30, N = 111–120) and repeated sit-to-stand transitions (ρ = 0.46–0.61, N = 19–32). BAloa separation ranged between 87° and 112° (supine rest) and 65°–77° (repeated sit to stand transitions). CONCLUSION: Criterion validity of NIRS-derived CA measures allows for comparison between groups but was insufficient for clinical application in individuals. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00421-021-04681-w

Protocol for the value of urodynamics prior to stress incontinence surgery (VUSIS) study: a multicenter randomized controlled trial to assess the cost effectiveness of urodynamics in women with symptoms of stress urinary incontinence in whom surgical treatment is considered

BACKGROUND: Stress urinary incontinence (SUI) is a common problem. In the Netherlands, yearly 64.000 new patients, of whom 96% are women, consult their general practitioner because of urinary incontinence. Approximately 7500 urodynamic evaluations and approximately 5000 operations for SUI are performed every year. In all major national and international guidelines from both gynaecological and urological scientific societies, it is advised to perform urodynamics prior to invasive treatment for SUI, but neither its effectiveness nor its cost-effectiveness has been assessed in a randomized setting. The Value of Urodynamics prior to Stress Incontinence Surgery (VUSIS) study evaluates the positive and negative effects with regard to outcome, as well as the costs of urodynamics, in women with symptoms of SUI in whom surgical treatment is considered. METHODS/DESIGN: A multicentre diagnostic cohort study will be performed with an embedded randomized controlled trial among women presenting with symptoms of (predominant) SUI. Urinary incontinence has to be demonstrated on clinical examination and/or voiding diary. Physiotherapy must have failed and surgical treatment needs to be under consideration. Patients will be excluded in case of previous incontinence surgery, in case of pelvic organ prolapse more than 1 centimeter beyond the hymen and/or in case of residual bladder volume of more than 150 milliliter on ultrasound or catheterisation. Patients with discordant findings between the diagnosis based on urodynamic investigation and the diagnosis based on their history, clinical examination and/or micturition diary will be randomized to operative therapy or individually tailored therapy based on all available information. Patients will be followed for two years after treatment by their attending urologist or gynaecologist, in combination with the completion of questionnaires. Six hundred female patients will be recruited for registration from approximately twenty-seven hospitals in the Netherlands. We aspect that one hundred and two women with discordant findings will be randomized. The primary outcome of this study is clinical improvement of incontinence as measured with the validated Dutch version of the Urinary Distress Inventory (UDI). Secondary outcomes of this study include costs, cure of incontinence as measured by voiding diary parameters, complications related to the intervention, re-interventions, and generic quality of life changes. TRIAL REGISTRATION: Clinical Trials NCT0081474

Adverse drug reactions to tocolytic treatment for preterm labour: prospective cohort study

Objective To evaluate the incidence of serious maternal complications after the use of various tocolytic drugs for the treatment of preterm labour in routine clinical situations

Vibrational effects in charge transport through a molecular double quantum dot

Recent progress in the field of molecular electronics has revealed the fundamental importance of the coupling between the electronic degrees of freedom and specific vibrational modes. Considering the examples of a molecular dimer and a carbon nanotube double quantum dot, we here theoretically investigate transport through a two-site system that is strongly coupled to a single vibrational mode. Using a quantum master equation approach, we demonstrate that, depending on the relative positions of the two dots, electron-phonon interactions can lead to negative differential conductance and suppression of the current through the system. We also discuss the experimental relevance of the presented results and possible implementations of the studied system

Serum-based measurements of stromal activation through ADAM12 associate with poor prognosis in colorectal cancer.

BACKGROUND Recently it has been recognized that stromal markers could be used as a clinically relevant biomarker for therapy response and prognosis. Here, we report on a serum marker for stromal activation, A Disintegrin and Metalloprotease 12 (ADAM12) in colorectal cancer (CRC). METHODS Using gene expression databases we investigated ADAM12 expression in CRC and delineated the source of ADAM12 expression. The clinical value of ADAM12 was retrospectively assessed in the CAIRO2 trial in metastatic CRC with 235 patients (31% of total cohort), and an independent rectal cancer cohort (n = 20). RESULTS ADAM12 is expressed by activated CRC associated fibroblasts. In the CAIRO2 trial cohort, ADAM12 serum levels were prognostic (ADAM12 low versus ADAM12 high; median OS 25.3 vs. 17.1 months, HR 1.48 [95% CI 1.11-1.96], P = 0.007). The prognostic potential was specifically high for metastatic rectal cancer (HR 1.78 [95% CI 1.06-3.00], P = 0.030) and mesenchymal subtype tumors (HR 2.12 [95% CI 1.25-3.60], P = 0.004). ADAM12 also showed potential for predicting recurrence in an exploratory analysis of non-metastatic rectal cancers. CONCLUSIONS Here we describe a non-invasive marker for activated stroma in CRC which associates with poor outcome, especially for primary cancers located in the rectum