A humanised tissue‐engineered bone model allows species‐specific breast cancer‐related bone metastasis in vivo

Bone metastases frequently occur in the advanced stages of breast cancer. At this stage, the disease is deemed incurable. To date, the mechanisms of breast cancer‐related metastasis to bone are poorly understood. This may be attributed to the lack of appropriate animal models to investigate the complex cancer cell–bone interactions. In this study, two established tissue‐engineered bone constructs (TEBCs) were applied to a breast cancer‐related metastasis model. A cylindrical medical‐grade polycaprolactone‐tricalcium phosphate scaffold produced by fused deposition modelling (scaffold 1) was compared with a tubular calcium phosphate‐coated polycaprolactone scaffold fabricated by solution electrospinning (scaffold 2) for their potential to generate ectopic humanised bone in NOD/SCID mice. While scaffold 1 was found not suitable to generate a sufficient amount of ectopic bone tissue due to poor ectopic integration, scaffold 2 showed excellent integration into the host tissue, leading to bone formation. To mimic breast cancer cell colonisation to the bone, MDA‐MB‐231, SUM1315, and MDA‐MB‐231BO breast cancer cells were cultured in polyethylene glycol‐based hydrogels and implanted adjacent to the TEBCs. Histological analysis indicated that the breast cancer cells induced an osteoclastic reaction in the TEBCs, demonstrating analogies to breast cancer‐related bone metastasis seen in patients.     

Role of hemodynamics in initiation/growth of intracranial aneurysms

Background

Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%‐3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood.

Design

PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications.

Results

Current knowledge about the relation between WSS and IA has been obtained from both computational fluid dynamic studies in patients and experimental models of IA formation and growth. It is increasingly recognized that a high wall shear stress (gradient) participates to IA formation and that both low and high WSS can drive IA growth. Primary cilia (PC) play an important role as mechanosensors as patients with polycystic kidney disease, which is characterized by the absence or dysfunction of PC, have increased risk to develop IAs as well as increased risk of rupture.

Conclusion

Wall shear stress is a key player in IA initiation and progression. It is involved in vascular wall remodelling and inflammation, processes underlying aneurysm pathophysiology.     

Time to consider neuroinflammation as a booster effect of cerebral venous sinus thrombosis in vaccine-induced immune thrombotic thrombocytopenia?

Journal of Thrombosis and Thrombolysis -     

High-dose chemoradiotherapy and autologous blood stem cell transplantation in multiple myeloma: results of a phase II trial involving 63 patients

Sixty-three patients with high tumor mass multiple myeloma were treated with high-dose chemotherapy and total body irradiation supported by autologous blood stem cell transplantation. After high-dose therapy, they were monitored for a median of 44 months. Seven patients died early from toxicity. All the other patients, including those whose disease was resistant to previous therapies, showed a tumor mass reduction. At 6 months postengraftment, 40 (71%) of the surviving patients had minimal residual disease and 11 (20%) were in apparent complete remission. During follow-up, 25 out of the 63 (39%) patients relapsed and 16 of these died; 31 (49%) had a sustained remission. The median overall and event-free survival times after transplantation were 59 and 43 months, respectively. The initial serum beta 2-microglobulin value (> or < 2.8 mg/L) and length of previous therapy (> or < 6 courses of chemotherapy) were the only significant prognostic factors. In all surviving patients, blood stem cell autograft provided satisfactory and sustained haematopoietic reconstitution most often within 15 days. High dose chemoradiotherapy followed by autologous blood stem cell transplantation is thus an important therapeutic option for young patients with aggressive multiple myeloma.     

Prenatal treatment of congenital adrenal hyperplasia.

Prenatal diagnosis of congenital adrenal hyperplasia (CAH) is accurate and prenatal therapy is effective in significantly reducing or even eliminating virilization of females affected by CAH, sparing these children the consequences of genital surgery, sex missassignment and gender confusion. However, both the physical and psychological development of these children and the possibility of long-range adverse effects in the mothers need to be evaluated further. Prospective multicentre studies covering several decades are being designed.     

Influence of a Methanogenic Flora on the Breath H2 and Symptom Response to Ingestion of Sorbitol or Oat Fiber

Background and Objectives: We investigated the possibility that a variant of the normal colonic flora, a high concentration of methanogeas, influences the host's response to ingestion of nonabsorbable, fermentable materials. Methods: To better evaluate symptomatic and breath H₂ and methane (CH₄) responses, subjects were placed on a basal diet (primarily rice and hamburger) that contained minimal amounts of nonabsorbable, fermentable substrate. A breath CH₄/H₂ ratio of greater or less than 1 on the second day of the basal diet was used to categorize subjects as high (N = 9) or low (N = 25) CH₄ producers. After stabilization of the breath gas excretion (day 3 or 4 on the basal diet), the subjects ingested either sorbitol (8.8 g) or oat fiber (10.2 g). Results: The low CH₄ producers had a signficantly higher ( p < 0.05) breath H₂ concentration than the high producers on the basal diet and after ingestion of sorbitol (27.1 ± 2.7 ppm vs 15.8 ± 3.6 ppm) or oat fiber (13.1 ± 0.08 ppm vs 9.6 ± 1.2 ppm). Low producers of methane reported significantly increased bloating and cramping after sorbitol ingestion and increased bloating after fiber ingestion, whereas high CH₄ producers reported no signficant increase in these symptoms. Conclusion: The presence of a methanogenic flora is associated with a reduced symptomatic response to ingestion of nonabsorbable, fermentable material in healthy subjects. Manipulation of the normal flora could be of therapeutic value in nonmethanogenic patients with irritable bowel syndrome.     

Effect of reduced myristoylated alanine-rich C kinase substrate expression on hippocampal mossy fiber development and spatial learning in mutant mice: Transgenic rescue and interactions with gene background

The myristoylated alanine-rich C kinase substrate (MARCKS) is a prominent protein kinase C (PKC) substrate in brain that is expressed highly in hippocampal granule cells and their axons, the mossy fibers. Here, we examined hippocampal infrapyramidal mossy fiber (IP-MF) limb length and spatial learning in heterozygous Macs mutant mice that exhibit an ≈50% reduction in MARCKS expression relative to wild-type controls. On a 129B6(N3) background, the Macs mutation produced IP-MF hyperplasia, a significant increase in hippocampal PKC expression, and proficient spatial learning relative to wild-type controls. However, wild-type 129B6(N3) mice exhibited phenotypic characteristics resembling inbred 129Sv mice, including IP-MF hypoplasia relative to inbred C57BL/6J mice and impaired spatial-reversal learning, suggesting a significant contribution of 129Sv background genes to wild-type and possibly mutant phenotypes. Indeed, when these mice were backcrossed with inbred C57BL/6J mice for nine generations to reduce 129Sv background genes, the Macs mutation did not effect IP-MF length or hippocampal PKC expression and impaired spatial learning relative to wild-type controls, which now showed proficient spatial learning. Moreover, in a different strain (B6SJL(N1), the Macs mutation also produced a significant impairment in spatial learning that was reversed by transgenic expression of MARCKS. Collectively, these data indicate that the heterozygous Macs mutation modifies the expression of linked 129Sv gene(s), affecting hippocampal mossy fiber development and spatial learning performance, and that MARCKS plays a significant role in spatial learning processes.     

Pharmacokinetic study of beta-lactam antibiotics in bronchial secretions.

The objective of the study was to evaluate the concentrations obtained in serum and bronchial secretions after administration of five beta-lactam antibiotics: cephradin (1 g per os) and cefoxitin (2 g i.v. infusion), amoxycillin (1.0 g per os), bacampicillin (0.4 g and 0.8 g per os) and ampicillin (1.0 g per os). 123 adult patients were included in the study and received a single dose of the tested drug. Serum and mucus samples were collected simultaneously 30 minutes, 1, 2 or 4 hours after administration of the drugs. Mucus samples were taken by fibroscopy but in some patients the samples were collected through a tracheostomy cannula which allowed sampling at different time intervals. The results show that the concentrations of penicillins in bronchial secretions increase progressively between one and four hours after administration of the drugs. Bronchial levels obtained after oral administration of ampicillin are low, not more than 5 to 10% of serum levels. The other antibiotics tested show worthwhile concentrations in bronchial secretions, especially with cephalosporins and bacampicillin which exhibits higher serum and bronchial concentrations than ampicillin.