Bone morphogenetic protein (BMP)1-3 enhances bone repair

Members of the astacin family of metalloproteinases such as human bone morphogenetic protein 1 (BMP-1) regulate morphogenesis by processing precursors to mature functional extracellular matrix (ECM) proteins and several growth factors including TGFβ, BMP2, BMP4 and GFD8. We have recently discovered that BMP1-3 isoform of the Bmp-1 gene circulates in the human plasma and is significantly increased in patients with acute bone fracture. We hypothesized that circulating BMP1-3 might have an important role in bone repair and serve as a novel bone biomarker. When administered systemically to rats with a long bone fracture and locally to rabbits with a critical size defect of the ulna, recombinant human BMP1-3 enhanced bone healing. In contrast, neutralization of the endogenous BMP1-3 by a specific polyclonal antibody delayed the bone union. Invitro BMP1-3 increased the expression of collagen type I and osteocalcin in MC3T3-E₁ osteoblast like cells, and enhanced the formation of mineralized bone nodules from bone marrow mesenchymal stem cells. We suggest that BMP1-3 is a novel systemic regulator of bone repair.     

Cell prestress. II. Contribution of microtubules

The tensegritymodel hypothesizes that cytoskeleton-based microtubules (MTs) carrycompression as they balance a portion of cell contractile stress. Totest this hypothesis, we used traction force microscopy to measuretraction at the interface of adhering human airway smooth muscle cellsand a flexible polyacrylamide gel substrate. The prediction is that ifMTs balance a portion of contractile stress, then, upon theirdisruption, the portion of stress balanced by MTs would shift to thesubstrate, thereby causing an increase in traction. Measurements weredone first in maximally activated cells (10 µM histamine) and thenagain after MTs had been disrupted (1 µM colchicine). We found that after disruption of MTs, traction increased on average by ~13%. Because in activated cells colchicine induced neither an increase inintracellular Ca²⁺ nor an increase in myosin light chainphosphorylation as shown previously, we concluded that the observedincrease in traction was a result of load shift from MTs to thesubstrate. In addition, energy stored in the flexible substrate wascalculated as work done by traction on the deformation of thesubstrate. This result was then utilized in an energetic analysis. Weassumed that cytoskeleton-based MTs are slender elastic rods supportedlaterally by intermediate filaments and that MTs buckle as the cellcontracts. Using the post-buckling equilibrium theory of Euler struts,we found that energy stored during buckling of MTs was quantitativelyconsistent with the measured increase in substrate energy afterdisruption of MTs. This is further evidence supporting the idea thatMTs are intracellular compression-bearing elements.

     

A Refined Model of the Prototypical Salmonella SPI-1 T3SS Basal Body Reveals the Molecular Basis for Its Assembly

The T3SS injectisome is a syringe-shaped macromolecular assembly found in pathogenic Gram-negative bacteria that allows for the direct delivery of virulence effectors into host cells. It is composed of a “basal body”, a lock-nut structure spanning both bacterial membranes, and a “needle” that protrudes away from the bacterial surface. A hollow channel spans throughout the apparatus, permitting the translocation of effector proteins from the bacterial cytosol to the host plasma membrane. The basal body is composed largely of three membrane-embedded proteins that form oligomerized concentric rings. Here, we report the crystal structures of three domains of the prototypical Salmonella SPI-1 basal body, and use a new approach incorporating symmetric flexible backbone docking and EM data to produce a model for their oligomeric assembly. The obtained models, validated by biochemical and in vivo assays, reveal the molecular details of the interactions driving basal body assembly, and notably demonstrate a conserved oligomerization mechanism.     

Multiple primary melanoma: epidemiological and prognostic implications; analysis of 36 cases

Patients who are already diagnosed with cutaneous melanoma are at increased risk of developing another primary melanoma. The occurrence of multiple primary melanoma is a rare phenomenon, varying in frequency, with an estimated incidence ranging from 0.2% to 8.6%. The authors are presenting data on the patients with multiple primary melanoma from the Croatian Referral Melanoma Centre. The clinical, histological and epidemiological characteristics of 36 (3.6%) patients, identified from 991 patients with histologically confirmed melanoma, are analyzed in this study. Twenty-eight of the patients (78%) had two primary melanomas, six had three melanomas (16.7%) and two (5,6%) had four melanomas. Diagnosis was established synchronously in 11 patients (30%) and, in the rest of the patients, time interval between the diagnosis of the first and second melanoma varied from 1 month to the longest interval of 16 years. However, the majority of subsequent melanomas were removed within 2 years of the initial operation. The mean Breslow's thickness of the first melanoma was significantly higher than the mean Breslow's thickness of the second primary melanoma. The proportion of in situ to invasive melanomas was greater for the second melanomas compared with the first melanomas. Therefore, we emphasize the importance of regular follow-up as well as the education in regular self--skin examinations in melanoma patients in order to detect subsequent primary melanomas in the early phase.     

Invasive alga <Emphasis Type="Italic">Caulerpa racemosa</Emphasis> var. <Emphasis Type="Italic">cylindracea</Emphasis> makes a strong impact on the Mediterranean sponge <Emphasis Type="Italic">Sarcotragus spinosulus</Emphasis>

Here we present the first observation of the impact of the invasive Caulerpa racemosa var. cylindracea on native photophilic sponge species in the Adriatic Sea, with special focus on Sarcotragus spinosulus. Caulerpa racemosa var. cylindracea is able to completely overgrow the sponge, developing an exceptionally thick canopy with a maximum measured density of 1,887 m of stolons m⁻² and 40,561 fronds m⁻². Necrosis of the sponge surface was significantly correlated with the algal dry biomass, frond number and stolon length. Dense algal canopy, penetration of the algal stolon and rhizoids into the sponge oscula and covering of the ostiae probably diminishes the seawater circulation through the sponge and consequently results in its smothering and even death. We suggest that chemotropism is the reason why C. racemosa penetrates the sponge oscula and establishes such dense canopy on the sponge.     

Stereotactic radiosurgery for patients with breast cancer brain oligometastases — molecular subtypes and clinical outcomes

BackgroundWe sought to determine the clinical outcomes of patients with breast cancer (BC) who had undergone stereotactic radiosurgery (SRS) for a limited number of brain metastases (BM) and to identify factors influencing overall survival (OS) and local control.Materials and methodsThe records of 45 patients who underwent SRS for 72 brain lesions were retrospectively evaluated. Statistics included the chi-squared test, Kaplan-Meier method, and the multivariate Cox model.ResultsThe median number of treated BM was 2 (range 1–10). Median OS from BM diagnosis and post-SRS were 27.6 [95% confidence interval (CI): 14.8–40.5) and 18.5 months (95% CI: 11.1–25.8), respectively. One-year and two-year survival rates after BM diagnosis were 55% and 41%, respectively. In a univariate analysis, the Luminal-B-human-epidermal-growth-receptor-positive (HER2+) subtype had the longest median OS at 39.1 months (95% CI: 34.1–44.1, p = 0.004). In an adjusted analysis, grade 2 [hazard ratio (HR): 0.1; 95% CI: 0.1–0.6, p = 0.005), craniotomy (HR: 0.3; 95% CI: 0.1–0.7; p = 0.006), and ≥ 2 systemic therapies received (HR: 0.3; 95% CI: 0.1–0.9, p = 0.028) were associated with improved OS. One-year and two-year intracranial progression-free survival rates were 85% and 63%, respectively. Four factors for a higher risk of any intracranial recurrence remained significant in the adjusted analysis, as follows: age < 50 years (HR: 4.2; 95% CI: 1.3–36.3; p = 0.014), grade 3 (HR: 3.7; 95% CI: 1.1–13.2; p = 0.038), HER2+ (HR: 6.9; 95% CI: 1.3–36.3; p = 0.023), and whether the brain was the first metastatic site (HR: 4.7; 95% CI: 1.6–14.5; p = 0.006).ConclusionIntrinsic BC characteristics are important determinants for both survival and intracranial control for patients undergoing SRS for oligometastatic brain disease.     

Present state and possibilities for improvement of cancer prevention and early detection in the Osijek-Baranya county

Cancer morbidity and mortality are on a steady increase in Croatia. Technologic possibilities for appropriate management are available for four cancer sites, i.e. cancer of the breast, cervix uteri, colorectum and prostate, and include cancer prevention and early detection in individuals yet free from manifest signs of the disease. The magnitude of the problem, the experience acquired to date, health care personnel available, and additional resources required to launch a systematic program of early detection of the disease are presented. The program should be initially launched in a county with greatest experience in early detection of cancer, where health care service is ready to immediately start its implementation. The role of family physician, gynecologic service at primary health care level, and polyclinic-consultation hospital service in program implementation is described. The following three possible options for early detection of cancer are analyzed and proposed: minimal program (early detection every 3 years), medium program (the same individuals examined every 2 years), and optimal program proposed by the American Cancer Society and other national and international organizations.     

Protected areas and prime hoverfly areas: Safe haven for hoverflies or not?

The efficiency of protected areas (PAs) has often been questioned due to global decline of biodiversity. Invertebrates, especially insects, have been historically underrepresented in conservation studies. Our study focuses on hoverflies, an important group of insect pollinators and proven to be good bioindicators. Research was focused in Serbia, one of Europe's hotspots of hoverfly diversity, with a long tradition of hoverfly research, which provided sufficient information for achieving our aims: identifying areas of high hoverfly diversity, evaluating the efficiency of PAs and prime hoverfly areas (PHAs) in the conservation of hoverflies, determining how well they cover the distribution of hoverfly species, especially those of conservation concern, and testing the importance of the size of the area for conservation of hoverfly diversity. We applied weighting of the species to help stress the importance of species of conservation concern. The results indicated that PHAs cover the areas with high hoverfly diversity better than PA networks, especially when it comes to species of conservation concern. Generalized linear model results showed that the area size was a significant predictor of number of species in both PA and PHA. This indicates that area size is key when designating new areas important for conservation, but there are also other factors that need to be taken into account, such as habitat quality or suitability. Studies like this are useful in aiding designation of new areas important for conservation of certain species and in identifying sampling gaps, which could potentially aim future research in that direction.     

Detailed chromosomal and radiation hybrid mapping in the proximal part of rat Chromosome 10 and gene order comparison with mouse and human

The rat provides valuable and sometimes unique models of human complex diseases. To fully exploit the rat models in biomedical research, it is important to have access to detailed knowledge of the rat genome organization as well as its relation to the human genome. Rat Chromosome 10 (RNO10) harbors several important cancer-related genes. Deletions in the proximal part of RNO10 were repeatedly found in a rat model for endometrial cancer. To identify functional and positional candidate genes in the affected region, we used radiation hybrid (RH) mapping and single- and dual-color fluorescence in situ hybridization (FISH) techniques to construct a detailed chromosomal map of the proximal part of RNO10. The regional localization of 14 genes, most of them cancer-related (Grin2a, Gspt1, Crebbp, Gfer, Tsc2, Tpsb1, Il9r, Il4, Irf1, Csf2, Sparc, Tp53, Thra1, Gh1), and of five microsatellite markers (D10Mit10, D10Rat42, D10Rat50, D10Rat72, and D10Rat165) was determined on RNO10. For a fifteenth gene, Ppm1b, which had previously been assigned to RNO10, the map position was corrected to RNO6q12-q13.