Oxidatively modified low-density lipoproteins are potential mediators of proteasome inhibitor resistance in multiple myeloma.

Proteasome inhibitor (PI) therapy has improved the survival of multiple myeloma (MM) patients. However, inevitably, primary or acquired resistance to PIs leads to disease progression; resistance mechanisms are unclear. Obesity is a risk factor for MM mortality. Oxidized LDL (OxLDL), a central mediator of atherosclerosis that is elevated in metabolic syndrome (co-occurrence of obesity, insulin resistance, dyslipidemia and hypertension), has been linked to an increased risk of solid cancers and shown to stimulate pro-oncogenic/survival signaling. We hypothesized that OxLDL is a mediator of chemoresistance and evaluated its effects on MM cell killing by PIs. OxLDL potently suppressed the ability of the boronic acid-based PIs bortezomib (BTZ) and ixazomib, but not the epoxyketone-based PI carfilzomib, to kill human MM cell lines and primary cells. OxLDL suppressed BTZ-induced inhibition of proteasome activity and induction of pro-apoptotic signaling. These cytoprotective effects were abrogated when lipid hydroperoxides (LOOHs) associated with OxLDL were enzymatically reduced. We also demonstrated the presence of OxLDL in the MM bone marrow microenvironment as well as numerous granulocytes and monocytes capable of cell-mediated LDL oxidation through myeloperoxidase. Our findings suggest that OxLDL may be a potent mediator of boronic acid-based PI resistance, particularly for MM patients with metabolic syndrome, given their elevated systemic levels of OxLDL. LDL cholesterol-lowering therapy to reduce circulating OxLDL, and pharmacologic targeting of LOOH levels or resistance pathways induced by the modified lipoprotein, could deepen the response to these important agents and offer clinical benefit to MM patients with metabolic syndrome.

The Prevention of Ischemia-Reperfusion Injury in Elderly Rats after Lower Limb Tourniquet Use.

Background: Lower limb ischemia-reperfusion injury (IRI-LL) is a common major complication of orthopedic surgery, especially in elderly patients. It has previously been demonstrated that folinic acid (FA) reduced IRI-LL damage in 3−4-month-old rats. This current work analyses the effect of FA in the prevention of IRI-LL in elderly animals. Methods: Forty-two 18-month-old male WAG/RijHsd rats were subjected to 3 h of ischemia. Eighteen animals received FA (2.5 mg/kg, ip) 20 min before the end of the ischemia period, while the other half received the same volume of saline solution. The animals were sacrificed after 3 h, 24 h, and 14 days of reperfusion for biochemical (tissue damage markers and electrolytes), histopathological studies of the gastrocnemius muscle and the daily assessment of the limb function by the Rota Rod test, respectively. Results: The administration of FA prior to the end of the ischemia period reduced the increase in LDH and CK observed in non-treated animals by 30−40% (p < 0.0001). When the histological sections were analyzed, FA was found to have reduced the number of damaged muscle fibers per field by 20% (60 ± 17.1 vs. 80.7 ± 16.4, p < 0.0001). The functional test revealed that FA also led to an improvement in the muscle function, assessed by the length of time that the animals kept running on the rod, compared to untreated animals. Conclusions: The administration of FA, prior to the end of the ischemic period, decreases the damage induced by IRI-LL, also achieving a faster recovery of mobility.

The complexity of verifying population protocols.

Population protocols (Angluin et al. in PODC, 2004) are a model of distributed computation in which indistinguishable, finite-state agents interact in pairs to decide if their initial configuration, i.e., the initial number of agents in each state, satisfies a given property. In a seminal paper Angluin et al. classified population protocols according to their communication mechanism, and conducted an exhaustive study of the expressive power of each class, that is, of the properties they can decide (Angluin et al. in Distrib Comput 20(4):279-304, 2007). In this paper we study the correctness problem for population protocols, i.e., whether a given protocol decides a given property. A previous paper (Esparza et al. in Acta Inform 54(2):191-215, 2017) has shown that the problem is decidable for the main population protocol model, but at least as hard as the reachability problem for Petri nets, which has recently been proved to have non-elementary complexity. Motivated by this result, we study the computational complexity of the correctness problem for all other classes introduced by Angluin et al., some of which are less powerful than the main model. Our main results show that for the class of observation models the complexity of the problem is much lower, ranging from Π 2 p to PSPACE.

Towards efficient verification of population protocols.

Population protocols are a well established model of computation by anonymous, identical finite-state agents. A protocol is well-specified if from every initial configuration, all fair executions of the protocol reach a common consensus. The central verification question for population protocols is the well-specification problem: deciding if a given protocol is well-specified. Esparza et al. have recently shown that this problem is decidable, but with very high complexity: it is at least as hard as the Petri net reachability problem, which is TOWER-hard, and for which only algorithms of non-primitive recursive complexity are currently known. In this paper we introduce the class WS 3 of well-specified strongly-silent protocols and we prove that it is suitable for automatic verification. More precisely, we show that WS 3 has the same computational power as general well-specified protocols, and captures standard protocols from the literature. Moreover, we show that the membership and correctness problems for WS 3 reduce to solving boolean combinations of linear constraints over N . This allowed us to develop the first software able to automatically prove correctness for all of the infinitely many possible inputs.

Complications in the surgical treatment of craniosynostosis and craniofacial syndromes: apropos of 306 transcranial procedures.

OBJECTIVE: To review the complications in the surgical treatment of craniosynostosis in 306 consecutive transcranial procedures between June 1999 and June 2007. PATIENTS AND METHODS: Surgical series consist of 306 procedures done in 268 patients: 155 scaphocephalies, 50 trigonocephalies, 28 anterior plagiocephalies, one occipital plagiocephaly, 20 non-syndromic multisutural synostosis and 32 craniofacial syndromes (11 Crouzon, 12 Apert, seven Pfeiffer and two Saethre-Chotzen) Complications and time of hospitalisation were reckoned. Surgical procedures were classified in 12 different types according to the technique: Type I: frontal-orbital distraction (26 cases); Type II: endoscopic assisted osteotomies in sagittal synostosis (39 cases); Type III: sagittal suturectomy and expansive osteotomies (44 cases); Type IV: same as type III, but including frontal dismantling or frontal osteotomies in scaphocephalies (59 cases); Type V: complete cranial vault remodelling (holocranial dismantling) in scaphocephalies (13 cases); Type VI: frontal-orbital remodelling without frontal-orbital bandeau in trigonocephaly (50 cases); Type VII: frontal-orbital remodelling without frontal-orbital bandeau in plagiocephaly (14 cases); Type VIII: frontal-orbital remodelling with frontal-orbital bandeau in plagiocephaly (14 cases); Type IX: Occipital advancement in posterior plagiocephaly (one case); Type X: Standard bilateral front-orbital advancement with expansive osteotomies (28 cases); Type XI: holocranial dismantling (complete cranial vault remodelling) in multisutural craniosynostosis (12 cases); Type XII: occipital and suboccipital craniectomies in multiple suture craniosynostosis (six cases). RESULTS: There was no mortality and all complications resolved without permanent deficit. Mean age at surgery was 6.75 months. Most frequent complication was non-filiated postoperative hyperthermia (13.17% of the cases) followed by infection (8.10%), subcutaneous haematoma (6.08%), dural tears (5.06%) and cerebrospinal fluid (CSF) leakage (2.7%). Number and type of complications was higher among the group of reoperated patients (12.8% of all): 62.5% of all the series infections, 93% of all dural tears and 75% of all CSF leaks. In relation to surgical procedures, endoscopic assisted osteotomies reported the lowest rate of complications, followed by standard frontal-orbital advancement in multiple synostosis, trigonocephalies and plagiocephalies. Highest number of complications was related to complete cranial vault remodelling (holocranial dismantling) in scaphocephalies and multiple synostoses and after the use of internal osteogenic distractors. Special consideration deserves two cases of iatrogenic basal encephaloceles after combined frontal-facial distraction. Finally, we establish considerations based on the complications related to every specific technique. CONCLUSIONS: Percentage and severity of complications relates to the surgical procedure and is higher among patients going for re-operation. Mean time of hospitalization is also modified by these issues.

Local application of a proteasome inhibitor enhances fracture healing in rats.

The ubiquitin/proteasome system plays an important role in regulating the activity of osteoblast precursor cells. Proteasome inhibitors (PSIs) have been shown to stimulate the differentiation of osteoblast precursor cells and to promote bone formation. This raises the possibility that PSIs might be useful for enhancing fracture healing. In this study, we examined the effect of the local administration of PSI on fracture repair in rats. The effects of treatment on the healing of a fractured femur were assessed based on radiographs, micro-computed tomography (µCT) analysis, biomechanical testing, and histological analysis. PSI enhanced osteogenic differentiation in bone marrow- and periosteum-derived mesenchymal progenitor cells in vitro. Moreover, the local administration of PSI in vivo promoted fracture healing in rats, as demonstrated by an increased fracture callus volume in radiographs at 2 weeks post-fracture, and improved radiographic scores. By week 4, PSI treatment had enhanced biomechanical strength and mineral density in the callus as assessed using bending tests, and µCT, respectively. Histological sections demonstrated that PSI treatment accelerated endochondral ossification during the early stages of fracture repair. Although further investigations are necessary to assess its clinical use, the local administration of PSIs might be a novel, and effective therapeutic approach for fracture repair.

Synthesis and molecular modeling of new 1-aryl-3-[4-arylpiperazin-1-yl]-1-propane derivatives with high affinity at the serotonin transporter and at 5-HT(1A) receptors.

It has been proposed that 5-HT(1A) receptor antagonists augment the antidepressant efficacy of selective serotonin (5-HT) reuptake inhibitors. In a search toward new and efficient antidepressants, 1-(aryl)-3-[4-arylpiperazin-1-yl]-1-propane molecular hybrids were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT(1A) receptor affinity. The design was based in coupling structural moieties related to inhibition of serotonin reuptake, such as benzo[b]thiophene derivatives to arylpiperazines, typical 5-HT(1A) receptor ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and at 5-HT(1A) receptors. Molecular modeling studies predicted the pharmacophore elements required for high affinity binding and the features that enable to discriminate between agonist, partial agonist, or antagonist action at 5-HT(1A) receptors and 5-HT transporter inhibition. Solvent interactions in desolvation prior to the binding step along with enthalpy and enthropy compensations might be responsible to explain agonist, partial agonist, and antagonist character. Hydrogen-bonding capability seems to be important to break hydrogen interhelical hydrogen bonds or alternatively to form other bonds upon ligand binding. Partial agonists and antagonists are unable to do this as the full agonist, which interacts closely by long-range forces or directly. The compounds showing the higher affinity at both the 5-HT transporter (K(i) < 50 nM) and the 5-HT(1A) receptors (K(i) < 20 nM) were further explored for their ability to stimulate [(35)S]GTPgammaS binding or to antagonize 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT)-stimulated [(35)]GTPgammaS binding to rat hippocampal membranes, an index of agonist/antagonist action at 5-HT(1A) receptors, respectively. Compound 8g exhibited agonist activity (EC(50) = 30 nM) in this assay, whereas compounds 7g and 8h,i behaved as weak partial agonists and 7h-j and 8j,l antagonized the R(+)-8-OH-DPAT-stimulated GTPgammaS binding. Functional characterization was performed by measuring the antagonism to 8-OH-DPAT-induced hypothermia in mice.

Laser resurfacing of darkly pigmented patients.

Hyperpigmentation following laser resurfacing in darker-skinned individuals is common but treatable. This pigmentation is usually heralded by persistent erythema and can be prevented in most patients if aggressive laser resurfacing is curtailed and conservative or single-pass techniques are applied. Avoiding excessive intraoperative frictional trauma when removing the desiccated tissue Avoiding excessive intraoperative frictional trauma when removing the desiccated tissue and potentially irritating agents or infections in the pre- or postoperative period is also instrumental in avoiding long-term complications.

Focal cerebral involvement by neurobrucellosis: pathological and MRI findings.

Central nervous system involvement by brucellosis is infrequent and usually presents as acute meningoencephalitis. Neurobrucellosis presenting as a focal brain mass has rarely been demonstrated on imaging studies. We describe the imaging and pathologic findings in a child affected by neurobrucellosis with focal cortico-subcortical involvement.

Local injection of lovastatin in biodegradable polyurethane scaffolds enhances bone regeneration in a critical-sized segmental defect in rat femora.

Statins, a class of naturally-occurring compounds that inhibit HMG-CoA reductase, are known to increase endogenous bone morphogenetic protein-2 (BMP-2) expression. Local administration of statins has been shown to stimulate fracture repair in in vivo animal experiments. However, the ability of statins to heal more challenging critical-sized defects at the mid-diaphyseal region in long bones has not been investigated. In this study, we examined the potential of injectable lovastatin microparticles combined with biodegradable polyurethane (PUR) scaffolds in preclinical animal models: metaphyseal small plug defects and diaphyseal segmental bone defects in rat femora. Sustained release of lovastatin from the lovastatin microparticles was achieved over 14 days. The released lovastatin was bioactive, as evidenced by its ability to stimulate BMP-2 gene expression in osteoblastic cells. Micro-computed tomography (CT) and histological examinations showed that lovastatin microparticles, injected into PUR scaffolds implanted in femoral plug defects, enhanced new bone formation. Furthermore, bi-weekly multiple injections of lovastatin microparticles into PUR scaffolds implanted in critical-sized femoral segmental defects resulted in increased new bone formation compared to the vehicle control. In addition, bridging of the defect with newly formed bone was observed in four of nine defects in the lovastatin microparticle treatment group, whereas none of the defects in the vehicle group showed bridging. These observations suggest that local delivery of lovastatin combined with PUR scaffold can be an effective approach for treatment of orthopaedic bone defects and that multiple injections of lovastatin may be useful for large defects.

A new measurement of scientific creativity: The study of its psychometric properties / Una nueva medida de la creatividad científica: El estudio de sus propiedades psicométricas

The purpose of this paper is to study the psychometric proprieties of a new test aimed to measure scientific creativity, the Creative Scientific Ability Test (C-SAT, Sak & Ayas, 2011). The test has been validated in different Turkish samples, showing an adequate reliability (α = .87, Ayas & Sak, 2014). The test is composed of five tasks that measure scientific creativity in different areas of knowledge: Biology, Chemistry, Physics, Ecology and an interdisciplinary task. For each task, a Creative Quotient (CQ) is calculated as a combination of Fluency (number of valid answers) and Flexibility (different approaches in the solution). The test also allows us to differentiate three scientific-creative thinking processes (hypothesis generation, hypothesis evaluation and evidence verification). 344 students from Compulsory Secondary Education took part in this study. The results point out a good reliability (α = .705) and an adequate inter-rater agreement (ranging from average ICC .80 to .98). In addition, the unifactorial structure of the test was verified using CFA, which agree with the authors’ previous results (Ayas & Sak, 2014; Sak & Ayas, 2013), even when a structure of three creative process can be considered

El objetivo del trabajo es estudiar las propiedades psicométricas de un nuevo test para medir la creatividad científica, ‘The Creative Scientific Ability Test’ (C-SAT; Sak & Ayas, 2011). El test había sido validado para distintas muestras de alumnos en Turquía, obteniendo una adecuada fiabilidad (α = .87; Ayas & Sak, 2014). El test está compuesto de cinco tareas que miden la creatividad científica en distintas aéreas de conocimiento: Biología, Química, Física, Ecología y una tarea interdisciplinar. Para cada tarea se calcula un Compuesto Creativo (CQ) que resulta de la combinación de la fluidez (número de respuestas válidas) y la flexibilidad (enfoques utilizados en la solución). El test permite además diferenciar entre los procesos del pensamiento científico-creativo (generación de hipótesis, evaluación de la hipótesis y verificación de la evidencia). En esta investigación, han participado 344 estudiantes de Educación Secundaria Obligatoria. Nuestros resultados indican una buena fiabilidad (α = .705) y un buen acuerdo interjueces (oscilando el ICC promedio de .80 a .98). También se ha verificado a través de AFC la estructura unifactorial de la prueba, según la propuesta de los autores (Ayas & Sak, 2014; Sak & Ayas, 2013), pero considerando factible la estructura de tres procesos creativos compuestos de distintas tareas cada uno

A sustained release of lovastatin from biodegradable, elastomeric polyurethane scaffolds for enhanced bone regeneration.

Scaffolds prepared from biodegradable polyurethanes (PUR) have been investigated as a supportive matrix and delivery system for skin, cardiovascular, and bone tissue engineering. In this study, we combined reactive two-component PUR scaffolds with lovastatin (LV), which has been reported to have a bone anabolic effect especially when delivered locally, for effective bone tissue regeneration. To incorporate LV into PUR scaffolds, LV was combined with the hardener component before scaffold synthesis. The PUR scaffolds containing LV (PUR/LV) demonstrated a highly porous structure with interconnected pores, which supported in vitro cell attachment and proliferation and in vivo osteoconductive potential. The PUR/LV scaffolds showed sustained release of biologically active LV, as evidenced by the fact that LV releasates significantly enhanced osteogenic differentiation of osteoblastic cells in vitro. A study of bone formation in vivo using a rat plug defect model showed that the PUR/LV scaffolds were biocompatible. Further, locally delivered LV enhanced new bone formation in the PUR scaffolds at week 4, while there were no obvious effects at week 2. These results suggest that the sustained LV delivery system from PUR scaffolds is a potentially safe and effective device for bone regeneration.

Inhibition of TGF-ß signaling by 1D11 antibody treatment increases bone mass and quality in vivo.

Transforming growth factor ß (TGF-ß) is an abundant bone matrix protein that influences osteoblast and osteoclast interactions to control bone remodeling. As such, TGF-ß represents an obvious pharmacologic target with the potential to regulate both bone formation and resorption to improve bone volume and strength. To investigate the skeletal effect of TGF-ß inhibition in vivo, we used an antibody (1D11) specifically directed at all three isoforms of TGF-ß. Normal mice were treated with 1D11 or control antibody (4 weeks), and cortical and trabecular bone was assessed by micro-computed tomographic (µCT) scanning. Bone volume and cellular distribution were determined by histomorphometric analysis of vertebrae and long bones. Also, whole-bone strength was assessed biomechanically by three-point bend testing, and tissue-level modulus and composition were analyzed by nanoindentation and Raman microspectroscopy, respectively. TGF-ß blockade by 1D11 increased bone mineral density (BMD), trabecular thickness, and bone volume by up to 54%, accompanied by elevated osteoblast numbers and decreased osteoclasts. Biomechanical properties of bone also were enhanced significantly by 1D11 treatment, with increased bending strength and tissue-level modulus. In addition, Raman microspectroscopy demonstrated that 1D11-mediated TGF-ß inhibition in the bone environment led to an 11% increase in the mineral-to-collagen ratio of trabecular bone. Together these studies demonstrate that neutralizing TGF-ß with 1D11 increases osteoblast numbers while simultaneously decreasing active osteoclasts in the marrow, resulting in a profound increase in bone volume and quality, similar to that seen in parathyroid hormone (PTH)-treated rodent studies.

Increasing Wnt signaling in the bone marrow microenvironment inhibits the development of myeloma bone disease and reduces tumor burden in bone in vivo.

There is increasing evidence to suggest that the Wnt signaling pathway plays a critical role in the pathogenesis of myeloma bone disease. In the present study, we determined whether increasing Wnt signaling within the bone marrow microenvironment in myeloma counteracts development of osteolytic bone disease. C57BL/KaLwRij mice were inoculated intravenously with murine 5TGM1 myeloma cells, resulting in tumor growth in bone and development of myeloma bone disease. Lithium chloride (LiCl) treatment activated Wnt signaling in osteoblasts, inhibited myeloma bone disease, and decreased tumor burden in bone, but increased tumor growth when 5TGM1 cells were inoculated subcutaneously. Abrogation of beta-catenin activity and disruption of Wnt signaling in 5TGM1 cells by stable overexpression of a dominant-negative TCF4 prevented the LiCl-induced increase in subcutaneous growth but had no effect on LiCl-induced reduction in tumor burden within bone or on osteolysis in myeloma-bearing mice. Together, these data highlight the importance of the local microenvironment in the effect of Wnt signaling on the development of myeloma bone disease and demonstrate that, despite a direct effect to increase tumor growth at extraosseous sites, increasing Wnt signaling in the bone marrow microenvironment can prevent the development of myeloma bone disease and inhibit myeloma growth within bone in vivo.

Stimulation of new bone formation by the proteasome inhibitor, bortezomib: implications for myeloma bone disease.

Impaired bone formation contributes to the lack of bone healing in multiple myeloma and there is a need for agents with bone anabolic properties to reverse the bone deficit in patients. Bortezomib, a proteasome inhibitor with antitumour efficacy in myeloma patients, enhanced new bone formation in mouse calvarial cultures; this effect was blocked by dickkopf 1(Dkk1), an antagonist of Wnt signalling implicated in myeloma bone disease. Bortezomib inhibited Dkk1 expression in calvariae and bone marrow-derived stromal cells, suggesting a novel mechanism by which bortezomib exerts its effects in bone. Clinical trials in patients with myeloma bone disease are needed to validate these results.

Nonablative radiofrequency for facial and neck rejuvenation. A faster, safer, and less painful procedure based on concentrating the heat in key areas: the ThermaLift concept.

Nonablative radiofrequency was the first method of noninvasive tissue contraction. It is a safe and effective method, although the results are modest when compared with plastic surgery. Patients like the fact that it requires no down time, it is performed with topical anesthesia, and it can be combined with numerous other modalities of skin rejuvenation. Technique and results are discussed.

Near [corrected] painless, nonablative, immediate skin contraction induced by low-fluence irradiation with new infrared device: a report of 25 patients.

BACKGROUND: Nonablative radiofrequency (NARF) has been the only method for producing noninvasive skin tightening. Nevertheless, significant pain during the procedure is an important downside of this technology. A new nonablative medical device, Titan (Cutera, Inc., Brisbane, CA, USA), capable of fluences much lower than those possible with NARF, was tested as a less painful alternative. OBJECTIVES: To produce skin contraction leading to lifting of eyebrows and/or improvement of lower face and neck skin laxity using fluences below pain levels. PATIENTS AND METHODS: Twenty-five patients were treated. Standardized photographs were obtained preoperatively, after a few days, a few weeks, and up to 12 months after the procedure. RESULTS: Immediate changes were obtained in 22 of 25 patients. Examination of photographs revealed that the initial improvement was maintained throughout the follow-up period. CONCLUSION: Immediate true skin contraction persisting through the immediate, intermediate, and long-term follow-up was found in the vast majority of patients in this group. Edema as an artifact simulating immediate improvement was excluded by serial photographs taken during the follow-up period. Skin contraction occurred at low fluences, below the threshold of pain. This, to the best of our knowledge, has not been previously described in the medical literature.