Addition of exogenous sodium palmitate increases the IAPP/insulin mRNA ratio via GPR40 in human EndoC-βH1 cells

Background: Enhanced IAPP production may contribute to islet amyloid formation in type 2 diabetes. The objective of this study was to determine the effects of the saturated fatty acid palmitate on IAPP levels in human β-cells.

Methods: EndoC-βH1 cells and human islets were cultured in the presence of sodium palmitate. Effects on IAPP/insulin mRNA expression and secretion were determined using real-time qPCR/ELISA. Pharmacological activators and/or inhibitors and RNAi were used to determine the underlying mechanisms.

Results: We observed that EndoC-βH1 cells exposed to palmitate for 72?h displayed decreased expression of Pdx-1 and MafA and increased expression of thioredoxin-interacting protein (TXNIP), reduced insulin mRNA expression and glucose-induced insulin secretion, as well as increased IAPP mRNA expression and secretion. Further, these effects were independent of fatty acid oxidation, but abolished in response to GPR40 inhibition/downregulation. In human islets both a high glucose concentration and palmitate promoted increased IAPP mRNA levels, resulting in an augmented IAPP/insulin mRNA ratio. This was paralleled by elevated IAPP/insulin protein secretion and content ratios.

Conclusions: Addition of exogenous palmitate to human β-cells increased the IAPP/insulin expression ratio, an effect contributed to by activation of GPR40. These findings may be pertinent to our understanding of the islet amyloid formation process.     

Outcome of surgical treatment for bone metastases caused by colorectal cancer

BackgroundCancer of the lower intestinal tract, although relatively common, rarely metastasizes to the skeleton. The treatment of metastatic bone disease due to colorectal cancer has thus been poorly described and treatment decisions are therefore difficult. The aim of this study was to describe the outcome of orthopedic surgery in patients with pathological fractures from colorectal cancer and investigate factors that correlate with patient survival, since it influences treatment decisions.MethodsRetrospective review of data collected in a prospectively collected database. 36 patients (38 fractures) who underwent surgery between 2000 and 2019 for metastatic bone disease caused by colorectal cancer were included.ResultsMost metastases were localized in the axial skeleton and 33/36 patients already had visceral metastases. Patients with pathological fractures from colorectal cancer had poor prognosis, with only 5/36 surviving more than 1 year, median survival being 3 months. Patients presenting with a single skeletal metastasis had a superior overall survival (P≤0.001). Post-operative complications were common, noted in 11 patients, and the surgical failure rate was considerable.ConclusionsAlthough relatively rare, bone metastases should be suspected in patients with colorectal cancer presenting with signs and symptoms of spinal cord compression or skeletal pain. In this case, the presence of a solitary skeletal lesion is a favorable prognostic sign. Awareness for local complications after surgery should be high.     

Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer

Purpose

[¹⁸F]Fluciclovine (anti-[¹⁸F]FACBC) is a synthetic amino acid developed for PET assessment of the anabolic component of tumour metabolism in clinical routine. This phase 1 trial evaluated the safety, tracer stability and uptake kinetics of [¹⁸F]fluciclovine in patients.

Methods

Six patients with biopsy-proven prostate cancer were investigated with 3-T MRI and PET/CT. All underwent dynamic [¹⁸F]fluciclovine PET/CT of the pelvic area for up to 120 min after injection of 418?±?10 MBq of tracer with simultaneous blood sampling of radioactivity. The kinetics of uptake in tumours and normal tissues were evaluated using standardized uptake values (SUVs) and compartmental modelling.

Results

Tumour deposits as defined by MRI were clearly visualized by PET. Urine excretion was minimal and normal tissue background was low. Uptake of [¹⁸F]fluciclovine in tumour from the blood was rapid and the tumour-to-normal tissue contrast was highest between 1 and 15 min after injection with a 65 % reduction in mean tumour uptake at 90 min after injection. A one-compartment model fitted the tracer kinetics well. Early SUVs correlated well with both the influx rate constant (K ₁) and the volume of distribution of the tracer (V _T). There were no signs of tracer metabolite formation. The product was well tolerated in all patients without significant adverse events.

Conclusion

[¹⁸F]Fluciclovine shows high uptake in prostate cancer deposits and appears safe for use in humans. The production is robust and the formulation stable in vivo. An early imaging window seems to provide the best visual results. SUV measurements capture most of the kinetic information that can be obtained from more advanced models, potentially simplifying quantification in future studies.     

Cancer in the Norwegian printing industry

OBJECTIVES: The aim of this study was to investigate cancer risk among Norwegian workers in the printing industry, particularly lung and bladder cancer. METHODS: Cancer incidence was investigated from 1953 through 1998 in a cohort of 10 549 male members of a trade union in the printing industry in Oslo and nearby areas. Rates from the region, were used to calculate standardized incidence ratios (SIR) separately for the skilled and unskilled workers. Smoking data from a sample of the cohort were utilized for evaluating the risk estimates of smoking-related cancers. Specific exposure data were not available. RESULTS: Among the skilled workers, significantly elevated risks of cancer of the urinary bladder [standardized incidence ratio (SIR) 1.47, 95% confidence interval (95% CI) 1.19-1.79], liver (SIR 1.92, 95% CI 1.15-2.99), pancreas (SIR 1.46, 95% CI 1.07-1.94) and colon (SIR 1.27, 95% CI 1.05-1.55) were observed, whereas an increased risk of lung cancer in this group was confined to those born before 1910. Among the unskilled workers, there were significantly increased risks of cancer of the mouth, esophagus, stomach, larynx, lung, and all sites. CONCLUSIONS: The study showed that workers in the printing industry were at increased risk of several types of cancer. In particular the increased risk of bladder cancer among the skilled workers is suggestive of an occupational cause. However, no specific agent could be identified as an occupational carcinogen. The results did not support the hypothesis of a generally increased risk of lung cancer. The risk pattern for unskilled workers may reflect confounding by nonoccupational factors.     

Intake of dietary fiber, especially from cereal foods, is associated with lower incidence of colon cancer in the HELGA cohort

The role of dietary fiber on the risk of colon and rectal cancer has been investigated in numerous studies, but findings have been inconsistent. The purpose of this study was to examine associations between intake of dietary fiber and risk of incident colon (including distal and proximal colon) and rectal cancer in the prospective Scandinavian HELGA cohort and to determine if fiber source (vegetables, fruits, potatoes, cereals) impacted the association. We included 1,168 incident cases (691 colon, 477 rectal cancer), diagnosed during a median of 11.3 years, among 108,081 cohort members. Sex-specific incidence rate ratios (IRRs) of colon and rectal cancer were related to intake of total or specific fiber source using Cox proportional hazards models. For men, an inverse association was observed between intake of total fiber and the risk of colon cancer per an incremental increase of 10 g day(-1) , IRR (95% CI): 0.74 (0.64-0.86). Intake of cereal fiber per 2 g day(-1) was associated with an IRR of 0.94 (0.91-0.98), which was also seen for intake of cereal fiber from foods with high fiber content (≥ 5 g per 100 g product), where the IRR per 2 g day(-1) was 0.94 (0.90-0.98). In women, intake of cereal fiber per 2 g day(-1) was also associated with lower risk of colon cancer, 0.97 (0.93-1.00). No clear associations were seen for rectal cancer. Our data indicate a protective role of total and cereal fiber intake, particularly from cereal foods with high fiber content, in the prevention of colon cancer.     

Collagen antibody–induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency

Objective

Pain is one of the most debilitating symptoms reported by rheumatoid arthritis (RA) patients. While the collagen antibody–induced arthritis (CAIA) model is used for studying the effector phase of RA pathologic progression, it has not been evaluated as a model for studies of pain. Thus, this study was undertaken to examine pain‐like behavior induced by anticollagen antibodies and to assess the effect of currently prescribed analgesics for RA. In addition, the involvement of spinal glia in antibody‐induced pain was explored.

Methods

CAIA was induced in mice by intravenous injection of a collagen antibody cocktail, followed by intraperitoneal injection of lipopolysaccharide. Disease severity was assessed by visual and histologic examination. Pain‐like behavior and the antinociceptive effect of diclofenac, buprenorphine, gabapentin, pentoxifylline, and JNK‐interacting protein 1 were examined in mechanical stimulation experiments. Spinal astrocyte and microglia reactivity were investigated by real‐time polymerase chain reaction and immunohistochemistry.

Results

Following the induction of CAIA, mice developed transient joint inflammation. In contrast, pain‐like behavior was observed prior to, and outlasted, the visual signs of arthritis. Whereas gabapentin and buprenorphine attenuated mechanical hypersensitivity during both the inflammatory and postinflammatory phases of arthritis, diclofenac was antinociceptive only during the inflammatory phase. Spinal astrocytes and microglia displayed time‐dependent signs of activation, and inhibition of glial activity reversed CAIA‐induced mechanical hypersensitivity.

Conclusion

CAIA represents a multifaceted model for studies exploring the mechanisms of pain induced by inflammation in the articular joint. Our findings of a time‐dependent prostaglandin and spinal glial contribution to antibody‐induced pain highlight the importance of using appropriate disease models to assess joint‐related pain.