Machine-learning-derived classifier predicts absence of persistent pain after breast cancer surgery with high accuracy

Purpose

To define the mutational spectrum of several candidate gene mutations in Israeli male breast cancer cases.

Methods

MBC cases counselled at the Oncogenetics unit, Sheba Medical Center from January 1998 to June 2017 were included. Relevant clinical and oncological data and cancer phenotype were retrieved. All participants were genotyped for the predominant Jewish BRCA1 and BRCA2 germline mutations using a chip-based assay. Those who tested negative were further genotyped for three recurring mutations in CHEK2 (c.1100delC, p.S428F, p.I157T), and single mutations in the FANCM (c.5791C>T), and RAD51D (c.556C>T) genes, by direct sequencing. The ethics committee approved the study.

Results

Overall, 61 MBC were identified and genotyped, 41 (67.2%) were Ashkenazim, age at diagnosis was 58.1?±?12.6 years, and 31 (50.8%) had a family history of cancer. Of genotyped individuals, one (1.6%) harboured the 185delAG* BRCA1 mutation, 7 (11.4%) the 6174delT*BRCA2 mutation and 2 (3.2%) other recurring mutations in BRCA2 (overall 10/61–16.4% BRCA1/BRCA2 mutation carriers). Of BRCA-negative cases, 3/51 (5.9%) carried the p.S428F *CHEK2 mutation. None was a carrier of the other genotyped mutations in CHEK2, FANCM or RAD51D.

Conclusion

BRCA1, BRCA2 and CHEK2 germline mutations contribute to inherited predisposition to MBC in Israel.

     

Systemic circulating microRNA landscape in Lynch syndrome

Circulating microRNAs (c-miRs) are small noncoding RNA molecules that migrate throughout the body and regulate gene expression. Global c-miR expression patterns (c-miRnomes) change with sporadic carcinogenesis and have predictive potential in early detection of cancers. However, there are no studies that have assessed whether c-miRnomes display similar potential in carriers of inherited pathogenic mismatch-repair gene variants (path_MMR), known as Lynch syndrome (LS), who are predisposed to highly increased cancer risk. Using high-throughput sequencing and bioinformatic approaches, we conducted an exploratory analysis to characterize systemic c-miRnomes of path_MMR carriers, sporadic rectal cancer patients and non-LS controls. We showed for the first time that cancer-free path_MMR carriers have a systemic c-miRnome of 40 differentially expressed c-miRs that can distinguish them from non-LS controls. The systemic c-miRnome of cancer-free path_MMR carriers also resembles the systemic c-miRnomes of cancer patients with or without path_MMR. Our pathway analysis linked the found differentially expressed c-miRs to carcinogenesis. A total of 508 putative target genes were identified for 32 out of 40 differentially expressed c-miRs, and 238 of them were enriched in cancer-related pathways. The most enriched c-miR-target genes include well-known oncogenes and tumor suppressor genes such as BCL2, AKT3, PIK3CA, KRAS, NRAS, CDKN1A and PIK3R1. Taken together, our findings suggest that LS and sporadic carcinogenesis share common biological pathways and alterations in these pathways can produce a c-miR signature which can track potential oncogenic stress in cancer-free path_MMR carriers. Therefore, c-miRs hold potential in monitoring the LS risk stratification patterns during clinical surveillance or cancer management.     

Disodium clodronate in the treatment of diffuse sclerosing osteomyelitis (DSO) of the mandible

Diffuse sclerosing osteomyelitis (DSO) of the mandible is a chronic condition, the cause of which is not known. Jaw pain, occurring irregularly, is a typical symptom. The aim of the study was to assess the effectiveness of disodium clodronate for relieving pain in patients with DSO. Disodium clodronate is a bisphosphonate used to treat diseases of bone and calcium metabolism. Ten DSO patients experiencing pain received disodium clodronate or placebo intravenously on a randomized double-blind basis. Both minimum (300 mg) and maximum (900 mg) doses were well tolerated. Disodium clodronate administration did not result in better immediate pain relief than placebo administration. However, 6 months after treatment there was a statistically significant difference in pain intensity between the groups, with the disodium clodronate group experiencing significantly less pain.     

Effects of the wood extractives dehydroabietic acid and betulinol on reproductive physiology of zebrafish (Danio rerio)-a two-generation study

Two wood extractives, dehydroabietic acid (DHAA) and betulinol (BET), present in wood industry effluents were evaluated for their potential effects on the reproductive physiology of zebrafish. Adult zebrafish (F0) were exposed in a continuous flow-through system to 50 microg/l DHAA, 5 microg/l BET and 0.27 microg/l (1 nM) 17beta-estradiol (E2) for 3 months. Eggs were collected from F0 fish and the following F1 generation was exposed for 6 months. Biomarkers analyzed in both F0 and F1 fish were plasma vitellogenin (Vtg), testosterone (T), E2 (only females) and gonadal histology. DHAA and BET affected growth in terms of increased condition factor, and spawning was stimulated in BET-exposed fish of the F0 generation. F0 males exposed to DHAA and F0 females exposed to BET showed lower plasma Vtg concentration, but F1 males exposed to BET showed an increase in Vtg. In fish exposed to E2, the positive control for estrogenic effects, a pronounced increase in Vtg concentration was observed. Plasma sex steroids were not significantly affected by the wood extractives. However, although not statistically significant, the T concentration tended to be lower in fish of all BET treatments. The histological study revealed alterations in spermatogenic stages of F0 males exposed to DHAA and BET, which were different from those caused by E2. In F1 females, the percentage of vitellogenic oocytes was decreased in DHAA, BET and E2 exposures. This study shows that DHAA and BET may contribute to growth alterations and reproductive disturbances reported in fish exposed to pulp and paper mill effluents. Further, these wood extractives may have different effects in F0 and F1 generation fish, which highlights the value of two-generation studies in investigations regarding endocrine disrupting compounds.     

Effects of Radolmidine, A Novel α2-Adrenergic Agonist Compared with Dexmedetomidine in Different Pain Models in the Rat

Background: Intrathecally administered [alpha]2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel [alpha]2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls.

Methods: Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 [mu]g, 2.5 [mu]g, 5 [mu]g, and 10 [mu]g.

Results: In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 [mu]g or 5 [mu]g of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 [mu]g dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine.     

Blood metabolism of [methyl- 11C]choline; implications for in vivo imaging with positron emission tomography

[methyl-¹¹C]Choline (¹¹C-choline) is a radioligand potentially useful for oncological positron emission tomography (PET). As a first step towards the development of a kinetic model for quantification of ¹¹C-choline uptake, blood metabolism of ¹¹C-choline during PET imaging was studied in humans. High-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) were used for the analysis of ¹¹C-choline and its radioactive metabolites. Prior to human PET imaging we studied ex vivo the biodistribution and metabolism of intravenously administered ¹¹C-choline in rats. Our results revealed that the radioactivity accumulated particularly in kidney, lung, adrenal gland and liver. Chromatographic analysis showed that the level of unmetabolized ¹¹C-choline in rat plasma decreased from 42%±20% (mean±SD) at 5 min to 21%±10% at 15 min after injection. In accordance with these findings, in humans the unmetabolized ¹¹C-choline represents 62%±19% of the total radioactivity in arterial plasma at 5 min after injection and 27%±12% at 15 min. In human venous plasma the corresponding values were 85%±12% and 48%±12% at 5 and 10 min, respectively. The major metabolite observed in both human and rat plasma was identified as ¹¹C-betaine. In human arterial plasma this maximally represented 82%±9% of the total radioactivity at 25 min after radiotracer injection. By 20 min after injection, the ¹¹C-choline and ¹¹C-betaine in human arterial plasma reached a plateau, and their fractional activities remained nearly constant thereafter. Although most of the circulating ¹¹C-choline in blood is transported to tissues, it does not disappear totally from blood within the first 40 min after tracer injection. Received 7 July and in revised form 16 September 1999     

Slow vasomotor fluctuation in fMRI of anesthetized child brain

Signal intensity changes in fMRI during rest caused by vasomotor fluctuations were investigated in this work. Resting‐state baseline fluctuations were evaluated in 12 children anesthetized with thiopental. Five subjects had fluctuations related to subvoxel motion. In seven subjects without significant motion, slow signal fluctuation at 0.025–0.041 Hz near one or more primary sensory cortices was observed. In each subject the amplitude and frequency of the fluctuations were stable. It is hypothesized that thiopental, which reduces blood pressure and flow in the cortex, alters the feedback in neurovascular coupling leading to an increase in the magnitude and a reduction in the frequency of these fluctuations. The use of anesthesia in fMRI may provide new insight into neural connectivity and the coupling of blood flow and neural metabolism. Magn Reson Med 44:373–378, 2000. © 2000 Wiley‐Liss, Inc.     

Advanced pancreatic cancer- how to choose an adequate treatment option

The prognosis of pancreatic adenocarcinoma is poor, making it one of the leading causes of cancer-related death. The 5-year overall survival rate remains below 5% and little progress is made during the past decade. Only about 10%-20% of patients are eligible for curative-intent surgery and the majority end up having recurring disease even after radical surgery and postoperative adjuvant chemotherapy. Chemotherapy in metastatic disease is palliative at best, aiming at disease and symptom control and prolongation of life. Treatment always causes side effects, the degree of which varies from patient to patient, depending on the patient’s general condition, concomitant morbidities as well as on the chosen treatment modality. Why is pancreatic cancer so resistant to treatment? How to best help the patient to reach the set treatment goals?     

A dental look at the autistic patient through orofacial pain

Abstract Autism is a neurodevelopmental disorder characterized by impaired social interaction and restricted interests, compromised communication skills, and repetitive patterns of behavior. Both social and behavioral problems, which may include hyperactivity and quick frustration, may hinder the detection of other important pathologies such as orofacial pain. This is aggravated by the invasive nature of oral exploration, which may trigger violent and self-injurious responses, such as temper tantrums and/or head banging, which make the work of professionals extremely difficult during diagnoses, follow-up examinations, and dental treatments. In addition, mercury-containing amalgams used to treat dental caries (the most common form of acute orofacial pain) have been associated with higher rates of severe autism in children. The purpose of this review is to describe the current state of the art regarding the co-occurrence of orofacial pain and autism spectrum disorder, and how these conditions may interrelate clinically and neurobiologically.