Strontium ranelate: New data on fracture prevention and mechanisms of action

Osteoporosis treatments need to combine an unequivocally demonstrated reduction of fractures, at various skeletal sites, long-term safety, and a user-friendly profile that optimizes therapeutic adherence. Strontium ranelate is the first compound to simultaneously decrease bone resorption and stimulate bone formation. Its anti-fracture efficacy at various skeletal sites has been established for as long as 5 years through studies of the highest methodological standards. Increases in bone mineral density observed after 1 year of treatment are predictive of the long-term fracture efficacy, suggesting for the first time in osteoporosis that bone densitometry can be used as a monitoring tool. Due to a positive risk/benefit ratio, strontium ranelate is now considered as a first-line treatment in the management of osteoporosis.     

Acinar cell carcinoma of the pancreas with predominant intraductal growth: report of a case

Acinar cell carcinoma (ACC) of the pancreas accounts for approximately 1% of all exocrine pancreatic tumours. We report a rare form of ACC in a 66-year-old man. This tumour was revealed by epigastric pain and weight loss. Abdominal computed tomography showed a hypodense, well-demarcated, heterogeneous lesion, in the head of the pancreas, measuring 4.2 cm in diameter. There was a marked dilatation of the main pancreatic duct upstream, with tumour spreading within this duct. The diagnosis of ACC was made on the fine needle aspiration cytology performed during endoscopic ultrasound examination. On the pancreaticoduodenectomy specimen, the dilated main pancreatic duct (2.5 cm in diameter) was filled by an exophytic tumour. Histological examination showed an ACC, with predominant intraductal growth (main and accessory pancreatic ducts), with pancreatic parenchymal and duodenal invasion. Neuroendocrine markers were negative. To our knowledge, this is the second report of an ACC with predominant intraductal spread. These rare forms of ACC can be confused with intraductal papillary-mucinous neoplasms. In our report, fine needle aspiration cytology performed during endoscopic ultrasound examination was a valuable tool in the diagnostic assessment.     

Cycling performance and mechanical variables using a new prototype chainring

The primary aim of our study was to examine supra-maximal cycling performance and related mechanical variables in trained cyclists using a new prototype chainring (PC) designed to produce a higher mean net torque (T _{N mean}) than a standard chainring (SC). The main feature of the PC is that crank-arm alignment and lever-arm length change as a function of the crank angle during the pedaling cycle. The PC presents two features theorized to effect cycling performance: (1) out of line of pedal cranks resulting in an decrease in the dead points, and (2) a change in crank arm length inducing a torque different from that of SC during the down- and up-stroke of the pedaling cycle. To investigate this theory, we examined eight male cyclists who performed a 1-km “all-out” cycling test in the following order: SC, PC, and SC. Performance was measured as the time (s) to complete the 1-km test. Mechanical variables included torque (N m⁻¹), crank velocity (rad s⁻¹), and power output (W). We performed our statistical analysis using a two-way ANOVA for repeated measurements and Newman–Keuls post hoc assessment. Our results showed that performance was similar for SC (69.41 ± 6.69 s) and PC (73.33 ± 4.58 s). Torque, crank velocity, and power output were also similar throughout (P > 0.05). We conclude that despite the theoretically benefits proposed by the inventors the new PC investigated in our study failed to improve cycling performance or mechanical variables during a supramaximal test when compared with SC.     

When should a liver resection be performed in patients with liver metastases from neuroendocrine tumours? A systematic review with practice recommendations

Aim

To determine the benefits and risks of hepatic resection versus non-resectional liver-directed treatments in patients with potentially resectable neuroendocrine liver metastases.

Methods

A systematic review identified 1594 reports which alluded to a possible liver resection for neuroendocrine tumour metastases, of which 38 reports (all retrospective), comprising 3425 patients, were relevant.

Results

Thirty studies reported resection alone, and 16 studies reported overall survival (OS). Only two studies addressed quality-of-life (QoL) issues. Five-year overall survival was reported at 41–100%, whereas 5-year progression-free survival (PFS) was 5–54%. We identified no robust evidence that a liver resection was superior to any other liver-directed therapies in improving OS or PFS. There was no evidence to support the use of a R2 resection (debulking), with or without tumour ablation, to improve either OS or QoL. There was little evidence to guide sequencing of surgery for patients presenting in Stage IV with resectable disease, and none to support a resection of asymptomatic primary tumours in the presence of non-resectable liver metastases.

Conclusion

Low-level recommendations are offered to assist in the management of patients with neuroendocrine liver metastases, along with recommendations for future studies.     

Chemical signature of magnetotactic bacteria

There are longstanding and ongoing controversies about the abiotic or biological origin of nanocrystals of magnetite. On Earth, magnetotactic bacteria perform biomineralization of intracellular magnetite nanoparticles under a controlled pathway. These bacteria are ubiquitous in modern natural environments. However, their identification in ancient geological material remains challenging. Together with physical and mineralogical properties, the chemical composition of magnetite was proposed as a promising tracer for bacterial magnetofossil identification, but this had never been explored quantitatively and systematically for many trace elements. Here, we determine the incorporation of 34 trace elements in magnetite in both cases of abiotic aqueous precipitation and of production by the magnetotactic bacterium Magnetospirillum magneticum strain AMB-1. We show that, in biomagnetite, most elements are at least 100 times less concentrated than in abiotic magnetite and we provide a quantitative pattern of this depletion. Furthermore, we propose a previously unidentified method based on strontium and calcium incorporation to identify magnetite produced by magnetotactic bacteria in the geological record.Magnetite (Fe₃O₄) is a widespread iron oxide found in geological sedimentary deposits such as banded iron formations, carbonate platforms, or paleosols (1). It can be produced through abiotic or biotic pathways. Magnetotactic bacteria (MTB) and dissimilatory iron-reducing bacteria are known to synthetize magnetite nanoparticles (2).MTB are magnetite- or greigite (Fe₃S₄)-producing bacteria found in both freshwater and marine environments. They inhabit the oxic–anoxic transition zone under microaerophilic conditions required for their growth. Magnetite or greigite crystals are actively precipitated through biological mechanisms in intracellular organelles called magnetosomes (e.g., refs. 3 and 4). Magnetosomes are assembled in chains inside the cell (Fig. 1) and provide the microorganism with a permanent magnetic dipole. This arrangement allows the bacteria to align themselves along the Earth’s geomagnetic field and to reach the optimal position along vertical chemical gradients (5, 6). When the cell dies, magnetosomes may be deposited and trapped into sediments. Magnetite can then be fossilized if the redox conditions are appropriate (1). This mineral may thus be an indirect bacterial fossil. Magnetotactic bacteria have been proposed to represent one of the most ancient biomineralizing organisms (1, 7). Thus, the identification of fossil magnetotactic bacteria, hereafter named bacterial magnetofossils, would provide strong constraints on the evolution of life and of biomineralization over geological times.Open in a separate windowFig. 1.Transmission electron microscopy images of (A) bacteria cultivated in bottles and (B) in fermentor, (C) extracted chain of magnetosomes, (D) magnetosomes treated with SDS-Triton-phenol preparation, (E) bacterial magnetite leached with EDTA, and (F) untreated magnetosome. Extracted magnetosomes display chain structures assembled by magnetosome membranes and proteins (arrows in C). In contrast with magnetite treated with SDS-Triton-phenol (E), untreated magnetosomes show traces of organic matter (arrow in F). Once treated, magnetite from AMB-1 agglomerated, as shown in D. We also observed such agglomeration in abiotic magnetite. Magnetite did not seem to be affected by EDTA leaching.Magnetite produced by MTB shows highly controlled crystallographic structure (8). It displays narrow size distributions and is in the magnetic stable single-domain range. Magnetosome chains have remarkable magnetic properties (5, 6, 9), which have been used to identify bacterial magnetofossils in sediments. Although previous studies demonstrated that observations by electron microscopy and/or magnetic measurements could detect bacterial magnetofossils in natural samples (9–13), the chain structure is generally lost during sediment aging owing to degradation of organic matter assembling magnetosomes (9, 14). This strongly complicates the identification of the bacterial magnetofossils. Moreover, those magnetites undergo variable transformations ranging from isomorphic conversion to maghemite, all the way to crystals that just barely preserve the structural integrity (15). Thus, for bacterial magnetofossil identification in ancient rock samples reliable biosignatures surviving these modifications are still needed for distinguishing biogenic from abiotic magnetite (1, 2).Geochemical fingerprints can be used as a potential tool for identifying fossilized biominerals (2, 16). For instance, chemical purity has been suggested as a common feature of minerals produced by living organisms (2). The chemical purity of magnetite from MTB has been discussed for many years (e.g., ref. 17). Although not without controversy, it was suggested that low concentrations in minor elements observed in magnetite from Martian meteorite {"type":"entrez-protein","attrs":{"text":"ALH84001","term_id":"937293154","term_text":"ALH84001"}}ALH84001 could indicate a biological origin for magnetite (18). This interpretation was supported by abiotic formation of magnetite in the laboratory, leading to high levels of elements other than iron in the crystal products (19, 20), except if initial materials highly depleted in doping elements were used (21). However, the degree of magnetite chemical purity in these previous studies was estimated by energy dispersive x-ray spectroscopy (EDXS) coupled with transmission electron microscopy, which is usually limited to the quantification of relatively elevated elemental concentrations, typically higher than 0.1–1% (22). Moreover, EDXS analyses have been used to evaluate single-element incorporations into magnetite crystals produced by MTB (23–26). These experiments tested only high element concentrations, which may not be representative of natural conditions. A detailed measurement of the low levels of trace elements likely present in trace amounts in magnetite from MTB, together with the knowledge of the concentrations of these elements in the surrounding fluids, thus remain to be established. Indeed, rather than the low or high level of impurity in the magnetite, the important point would be to establish whether differential incorporation of elements exists between biotic and abiotic magnetites. In this work, we thus determined multielement partitioning between aqueous solution and either abiotic magnetite or magnetite from magnetosomes to provide reliable signatures of biological origin.Abiotic magnetite nanoparticles were synthetized in adapting previous work (27) by mixing Fe³⁺ and Fe²⁺ to which were added 34 trace elements at concentrations of 100 ppb of each element by weight in the solution. This magnetite chemical precipitation is related to an extensive previous literature reporting studies designed for decontamination of wastewaters (e.g., refs. 28 and 29). Our experiments were performed in a glove box to prevent Fe(II) and magnetite oxidation. Biomagnetite was produced from Magnetospirillum magneticum strain AMB-1 (ATCC700264) under two different conditions: (i) in a fermentor as described in ref. 30 and (ii) in bottles following ATCC recommendations. The initial growth media of the two experiments were different. In contrast with bottle cultures, pH and pO₂ were maintained constant in the fermentor and the medium was continuously homogenized by stirring. These contrasting conditions allow us to evaluate the variability possibly induced by the biosynthesis. In either case, the bacterial growth medium was doped with the same 34 trace elements at 100 ppb each, (i.e., at the same doping level as in the abiotic syntheses). Chains of magnetosomes were extracted from cells with a high-pressure homogenizer. Magnetosome membranes surrounding magnetite were removed using a Triton-SDS-phenol solution heated at 70 °C overnight. Magnetite nanoparticles were leached with ultrapure water and contaminant-free EDTA solution to chelate and remove any element adsorbed on mineral surface (Fig. 1). Abiotic and biotic bottle experiments were carried out in duplicate. Mineralogical characterization (i.e., size, shape, and structure) of the magnetite samples was obtained from X-ray diffraction and transmission electron microscopy (Fig. 1 and Fig. S1). The element concentrations in all experimental products were measured by high-resolution inductively coupled plasma mass spectrometry.     

Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases

Background:

Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC).

Methods:

We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012.

Results:

mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs Cohort: 60 months; DFS: KRAS G12V: 15 months vs Cohort: 24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28–0.65), P<0.0001 for OS; HR: 0.67 (0.48–0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001–0.08), P<0.0001).

Conclusions:

mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.     

Quantitative elastography of renal transplants using supersonic shear imaging: a pilot study

Purpose

To evaluate the reliability of quantitative ultrasonic measurement of renal allograft elasticity using supersonic shear imaging (SSI) and its relationship with parenchymal pathological changes.

Materials and methods

Forty-three kidney transplant recipients (22 women, 21 men) (mean age, 51?years; age range, 18–70?years) underwent SSI elastography, followed by biopsy. The quantitative measurements of cortical elasticity were performed by two radiologists and expressed in terms of Young’s modulus (kPa). Intra- and inter-observer reproducibility was assessed (Kruskal-Wallis test and Bland-Altman analysis), as well as the correlation between elasticity values and clinical, biological and pathological data (semi-quantitative Banff scoring). Interstitial fibrosis was evaluated semi-quantitatively by the Banff score and measured by quantitative image analysis.

Results

Intra- and inter-observer variation coefficients of cortical elasticity were 20?% and 12?%, respectively. Renal cortical stiffness did not correlate with any clinical parameters, any single semi-quantitative Banff score or the level of interstitial fibrosis; however, a significant correlation was observed between cortical stiffness and the total Banff scores of chronic lesions and of all elementary lesions (R?=?0.34, P?=?0.05 and R?=?0.41, P?=?0.03,respectively).

Conclusion

Quantitative measurement of renal cortical stiffness using SSI is a promising non-invasive tool to evaluate global histological deterioration.

Key Points

? Supersonic shear imaging elastography can measure cortical stiffness in renal transplants ? The level of cortical stiffness is correlated with the global degree of tissue lesions ? The global histological deterioration of transplanted kidneys can be quantified using elastography