[Functional evaluation and quality of life in megaprostheses implanted by musculoskeletal tumors in the lower limb]. / Evaluación funcional y calidad de vida en megaprótesis implantadas por tumores musculoesqueléticos en miembro inferior.

INTRODUCTION: radical resection is the surgical treatment of choice in musculoskeletal malignancies, which often settle in the pelvis and lower limbs. Megaprothesis reconstruction has been imposed in recent years as the gold standard in limb preservation surgery. MATERIAL AND METHODS: descriptive retrospective study series of cases, including 30 patients operated between 2011 and 2019 of musculoskeletal pelvic and lower limb tumors at our institution that underwent limb-sparing reconstruction with the megaprosthesis. Functional results according to the MSTS (Musculoskeletal Tumor Society) index and complication rate were analyzed. RESULTS: the average follow-up was 40.8 months (12-101.7). Nine patients (30%) underwent pelvic resections and reconstructions, 11 patients (36.7%) underwent hip reconstruction with megaprothesis due to femoral involvement, in three patients (10%) complete femur resection was performed, and seven patients (23.3%) underwent prosthetic reconstruction of the knee. The mean MSTS score was 72.5% (range: 40-95%), and the complication rate was 56.7% (17 patients), being de tumoral recurrence (29%) the main complication. CONCLUSION: tumor megaprothesis give satisfying functional results, allowing the patients to realize a relatively normal life after a lower limb-sparing surgery.

INTRODUCCIÓN: la resección amplia es el tratamiento quirúrgico de elección en los tumores malignos musculoesqueléticos, que con frecuencia asientan en la pelvis y en los miembros inferiores. La reconstrucción mediante megaprótesis se ha impuesto en los últimos años como primera opción en la cirugía de preservación de la extremidad. MATERIAL Y MÉTODOS: estudio retrospectivo descriptivo serie de casos, incluye 30 pacientes intervenidos entre 2011 y 2019 de tumores musculoesqueléticos de pelvis y miembro inferior. En todos ellos valoramos la tasa de complicaciones y los resultados funcionales mediante el índice MSTS (Musculoskeletal Tumor Society). RESULTADOS: se realizó un seguimiento de 40.8 meses (12-101.7). En nueve pacientes (30%) se realizaron resecciones y reconstrucciones pélvicas, a 11 pacientes (36.7%) se les implantaron megaprótesis de cadera por afectación femoral, en tres de los pacientes (10%) se realizó resección del fémur completo y en siete pacientes (23.3%) reconstrucción protésica de la rodilla. El resultado funcional medio de la escala MSTS fue de 72.5% (rango: 40-95%) y la tasa de complicaciones de 56.7% (17 pacientes), siendo la recurrencia tumoral (29%) la principal complicación. CONCLUSIÓN: la reconstrucción mediante megaprótesis ofrece buenos resultados funcionales a los pacientes dentro de la cirugía de resección radical, permitiendo realizar una vida relativamente normal.

[Aneurysmal bone cyst located on the acetabular roof in an 11-year-old male]. / Quiste óseo aneurismático localizado en el techo acetabular en un varón de 11 años.

The aneurysmal bone cyst is a benign rare tumor, which usually develops during childhood and its more often found in limbs. The most accepted treatment consists in curetagge and filling with graft. However, certain locations may be inaccesible for surgery and represent therapeutical challenges. We present the case of an 11 year-old male patient with limping and right hip pain without any traumatic nor infectious record. In the image studies with CT and MRI a lytic and expansive lession was found in the upper part of the right acetabulum and right iliac wing, all of which suggested an aneurysmal bone cyst with an associated acetabular fracture. A biopsy was performed which confirmed the diagnosis. He was treated with a CT-guided embolization and, due to its size, curetagge and allograft filling afterwards. He was asymptomatic after1 year of follow-up.

El quiste óseo aneurismático es una tumoración benigna poco común, de aparición en la infancia generalmente y a nivel de extremidades. El tratamiento más habitual consiste en el curetaje y relleno con injerto. No obstante, localizaciones poco accesibles a la cirugía suponen un reto terapéutico. Se presenta el caso de un paciente de 11 años con cojera y dolor en cadera derecha sin antecedente traumático ni infeccioso. En los estudios de imagen con TAC y RM se evidencia una lesión lítica expansiva que ocupa todo el techo del acetábulo y pala ilíaca derecha, sugestiva de un quiste óseo aneurismático presentando fractura acetabular asociada. Se realizó una biopsia que confirmó el diagnóstico. Se trató mediante embolización guiada por angiografía debido al gran volumen y alto riesgo de fractura, después del curetaje y relleno con aloinjerto evolucionó satisfactoriamente y el paciente se encuentra asintomático al año de la intervención.

An antisense oligonucleotide targeting TGF-ß2 inhibits lung metastasis and induces CD86 expression in tumor-associated macrophages.

BACKGROUND: The transforming growth factor (TGF)-ß pathway is a well-described inducer of immunosuppression and can act as an oncogenic factor in advanced tumors. Several preclinical and clinical studies show that the TGF-ß pathway can be considered a promising molecular target for cancer therapy. The human genome has three TGF-ß isoforms and not much is known about the oncogenic response to each of the isoforms. Here, we studied the antitumor response to ISTH0047, a recently developed locked nucleic acid-modified antisense oligonucleotide targeting TGF-ß2. MATERIALS AND METHODS: We have studied the anticancer response to ISTH0047 using gymnotic delivery in tumor cell cultures and in in vivo preclinical orthotopic mouse models for primary tumors (breast and kidney tumors) and lung metastasis. RESULTS: We observed that ISTH0047 is able to significantly reduce TGF-ß2 mRNA and protein levels without altering the levels of TGF-ß1 and TGF-ß3. ISTH0047 prevented lung metastasis in syngeneic orthotopic renal cell carcinoma (RENCA) and breast cancer (4T1) tumor models. In addition, using an orthotopic xenograft model of a lung cancer cell line (CRL5807) that mainly expresses TGF-ß2, we observed that ISTH0047 had an important effect on the lung microenvironment inhibiting the growth of lung lesions. ISTH0047 treatment re-educated macrophages in the lung parenchyma to express the tumor-suppressive factor, CD86. CONCLUSION: Overall, our data point to TGF-ß2 as a therapeutic target and ISTH0047 as a novel anticancer drug to prevent lung metastasis by impacting on the tumor niche, in part, through the induction of CD86 in tumor-associated macrophages.

[Surgical treatment of malignant primary tumors of the pelvis on Ennekings zone II]. / Tratamiento quirúrgico de los tumores primarios malignos de pelvis de la zona II de Enneking.

INTRODUCTION: Surgical treatment of malignant bone tumors of the pelvis with periacetabular involvement is constantly evolving. Even though acetabular reconstructions improve quality of life without impairing cancer control, they are not complication free. Our purpose is to describe the functional outcomes and surgical complications of different reconstructive techniques for Enneking zone II tumors. MATERIAL AND METHODS: Fifteen patients underwent surgery for malignant pelvic bone tumors between 2002 and 2012. Seven patients were retrospectively evaluated according to the Enneking and Dunham classification and were found to have periacetabular involvement, as follows: 3 were type II; 1 types I + II; 2 types II + III, and one types I + II + III. Five patients had a standard chondrosarcoma and 2 osteosarcoma. Patients included 4 males and 3 females; mean age was 43 years. The minimum follow-up period was 12 months (mean 6.14 years). All of them underwent cancer resection with periacetabular reconstruction: massive osteochondral allograft in 3 patients, structural allograft and hip arthroplasty in 2 patients, and prosthesis with iliac anchoring in 2. They were clinically, radiologically and functionally evaluated with the MSTS scale (1993). RESULTS: The mean MSTS score 6 months after surgery was 20.71 (69%). Five patients (71.4%) had surgical complications: 2 dislocations of the native femoral head on the allograft; one aseptic prosthetic dislodgement, and 2 deep infections. All patients had free intraoperative borders. CONCLUSIONS: Acetabular reconstructions after oncologic resection for malignant bone tumors seem to provide good functional outcomes. However, only selected cases should undergo surgeries associated with a high complication rate.

El tratamiento quirúrgico de los tumores óseos malignos de pelvis con afectación periacetabular está en continua evolución. Las reconstrucciones acetabulares mejoran la calidad de vida sin perjudicar el control oncológico; sin embargo, no están exentas de complicaciones. Nuestro objetivo es describir los resultados funcionales y las complicaciones quirúrgicas de diferentes técnicas reconstructivas de la zona II de Enneking.

In vivo and in vitro evaluation of topical formulations containing physiological lipid mixture for replacement of skin barrier function.

AIM: The aim of the study was to describe a new in vivo and in vitro approach of the efficacy evaluation of cosmetic emollients to better understand the link between the formulation and the activity of cosmetic products. METHODS: Two long term in vivo studies were carried out on nine healthy Caucasian volunteers mean age 40±12 years to evaluate the protecting and repairing effects of the two different barrier repair cosmetic formulations. The application of the formulations was repeated once a day during 7 days and biophysical parameters (TEWL and Skin Hydration) were measured before and after Sodium laureth sulphate exposure The in vitro study was carried out by freeze substitution transmission electron microscopy (FSTEM) on stratum corneum samples obtained by sections of fresh skin from young pigs, depleted with a solvent mixture and treated with the two products RESULTS: The in vivo results demonstrated that daily product application provided a reinforcement of the skin barrier with protecting and repairing effects from chemical injuries the extent of which was dependent on the formulation features (product A>product B) The role of the technical form on the lipid availability was confirmed by the in vitro evaluation tests. CONCLUSION: The results point out that a daily application of physiological lipid mixture containing emulsion can protect healthy skin and promote the reparing effect on unpaired barrier skin, reducing TEWL and maintaining hydration of the stratum corneum. The efficacy degree is higher when the cosmetic form promotes the availability of active ingredients increasing the product performance.

New methodology for assessing the environmental burden of cement mortars with partial replacement of coal bottom ash and fly ash.

This paper assess the mechanical an environmental behaviour of cement mortars manufactured with addition of fly ash (FA) and bottom ash (BA), as partial cement replacement (10%, 25% and 35%). The environmental behaviour was studied by leaching tests, which were performed under several temperature (23 °C and 60 °C) and pH (5 and 10) conditions, and ages (1, 2, 4 and 7 days). Then, the accumulated amount of the different constituents leached was analysed. In order to obtain an environmental burden (EB) value of each cement mixture, a new methodology was developed. The EB value obtained is related to the amount leached and the hazardous level of each constituent. Finally, the integral study of compressive strength and EB values of cement mixtures allowed their classification. The results showed that mortars manufactured with ordinary Portland cement (OPC) and with coal BA had similar or even better environmental and mechanical behaviour than mortars with FA. Therefore, the partial replacement of cement by BA might be as suitable or even better as the replacement by FA.

Bicellar systems as vehicle for the treatment of impaired skin.

This study assesses the potential usefulness of bicellar systems to retard the penetration of drugs into damaged skin. The active compound used in this study was diclofenac diethylamine (DDEA). Initially, physicochemical characterisation of the DDEA bicellar systems was performed at different temperatures by small-angle X-ray scattering (SAXS), wide-angle X-ray scattering (WAXS) and differential scanning calorimetry (DSC) techniques. Subsequently, in vitro percutaneous absorption of bicellar systems into in vitro damaged skin was studied. SAXS results indicated a slight decrease in the width of their bilayers with increasing temperature, with no apparent stacking in those systems. WAXS patterns were compatible with an orthorhombic lateral packing of the nanoaggregates. The thermogram obtained by DSC indicated a decrease in gel-to-liquid crystalline transition temperature (Tm) when the drug was included into bicellar systems. A retardation effect for DDEA was detected by in vitro percutaneous absorption studies when DDEA was vehiculised in the bicellar systems with respect to an aqueous solution of the drug. It seems that the use of bicellar systems as a vehicle for topical application of DDEA on skin with an impaired barrier function may inhibit the penetration of DDEA to the systemic level. Such systems may consequently repair stratum corneum barrier function to some extent. The use of these systems could be considered a new alternative strategy to treat topically pathological skin with different drugs.

Tracking climate change in a dispersal-limited species: reduced spatial and genetic connectivity in a montane salamander.

Tropical montane taxa are often locally adapted to very specific climatic conditions, contributing to their lower dispersal potential across complex landscapes. Climate and landscape features in montane regions affect population genetic structure in predictable ways, yet few empirical studies quantify the effects of both factors in shaping genetic structure of montane-adapted taxa. Here, we considered temporal and spatial variability in climate to explain contemporary genetic differentiation between populations of the montane salamander, Pseudoeurycea leprosa. Specifically, we used ecological niche modelling (ENM) and measured spatial connectivity and gene flow (using both mtDNA and microsatellite markers) across extant populations of P. leprosa in the Trans-Mexican Volcanic Belt (TVB). Our results indicate significant spatial and genetic isolation among populations, but we cannot distinguish between isolation by distance over time or current landscape barriers as mechanisms shaping population genetic divergences. Combining ecological niche modelling, spatial connectivity analyses, and historical and contemporary genetic signatures from different classes of genetic markers allows for inference of historical evolutionary processes and predictions of the impacts future climate change will have on the genetic diversity of montane taxa with low dispersal rates. Pseudoeurycea leprosa is one montane species among many endemic to this region and thus is a case study for the continued persistence of spatially and genetically isolated populations in the highly biodiverse TVB of central Mexico.

Bicellar systems as new delivery strategy for topical application of flufenamic acid.

In this work, bicellar systems, bilayered disc-shaped nanoaggregates formed in water by phospholipids, are proposed as a novel strategy for delivery of the anti-inflammatory flufenamic acid (FFA) to the skin. A comparative percutaneous penetration study of this drug in bicellar systems and other vehicles was conducted. The effects induced on the skin by the application of FFA in the different vehicles were analyzed by attenuated total reflectance-fourier transform infrared (ATR-FTIR). Additionally, using the microscopic technique freeze-substitution transmission electron microscopy (FSTEM) and X-ray scattering technique using synchrotron radiation (SAXS-SR), we studied the possible microstructural and organizational changes that were induced in the stratum corneum (SC) lipids and the collagen of the skin by the application of FFA bicellar systems. Bicellar systems exhibited a retarder effect on the percutaneous absorption of FFA with respect to the other vehicles without promoting disruption in the SC barrier function of the skin. Given that skin disruption is one of the main effects caused by inflammation, prevention of disruption and repair of the skin microstructure should be prioritized in anti-inflammatory formulations.

Tratamiento de la infección recalcitrante de cadera mediante colgajo de músculo vasto lateral / Treatment of a recalcitrant hip infection with a vastus lateralis muscle flap

Introducción. La infección recalcitrante de cadera tras artroplastia es una complicación de difícil tratamiento para el cirujano ortopédico. El objetivo de este estudio es evaluar los resultados de estas infecciones de cadera recalcitrantes que hemos tenido en nuestro Servicio tratadas con el colgajo de vasto externo. Material y métodos. Estudio descriptivo retrospectivo de 5 pacientes con infecciones profundas de cadera mediante trasposición de colgajo del músculo vasto lateral. Edad media: 70,5 años. Tiempo medio de seguimiento: 30 meses (rango, 25-34 meses). Previamente todos los pacientes habían sido sometidos a distintos procedimientos quirúrgicos mayores (media de 3,7 procedimientos previos). Todos presentaban infecciones polimicrobianas previas a la cirugía. Se estudió los agentes patógenos involucrados mediante cultivo de la fístula, la evolución de la herida, así como controles analíticos, incluidos la proteína C-reactiva (PCR). Resultados. Se consiguió la curación de la herida en los 5 pacientes intervenidos, sin necesidad de realizar ningún otro procedimiento posterior ni aparición de fístula ni otros signos flogóticos de infección. La PCR se normalizó al mes de la intervención y no hubo morbi-mortalidad relacionada con la técnica quirúrgica. Conclusión. En nuestra experiencia, el colgajo de músculo vasto lateral como tratamiento para la infección profunda recalcitrante tras artroplastia de cadera ha presentado buenos resultados, siempre enmarcado dentro de un adecuado tratamiento antibiótico y desbridamiento quirúrgico, consiguiendo la curación de la herida y normalización de la PCR (AU)

Background. Recalcitrant hip infection after arthroplasty presents a reconstructive challenge to orthopedic surgeons. The aim of this study is to evaluate the results with a vastus lateralis muscle flap used to treat these recalcitrant hip infections in our Department. Material and methods. A retrospective descriptive study was conducted on five patients with deep hip infections by transposition of the vastus lateralis muscle flap. Average age: 70.5 years. Mean follow-up: 30 months (range, 25-34 months). All patients had previously undergone other major surgical procedures (mean of 3.7 previous procedures). All had multiple microbial infections before surgery. The pathogens involved using cultures of the fistula, the outcome of the wound and laboratory results, including C-reactive protein (CRP), were analysed. Results. Healing was achieved in the five patients who underwent surgery without requiring any further procedures or inflammatory signs of infection. CRP returned to normal one month after surgery, and there was no morbidity or mortality related to surgical technique. Conclusion. In our experience, the vastus lateralis muscle flap as a treatment for recalcitrant deep infection after arthroplasty has presented good results, provided there is appropriate antibiotic therapy and surgical debridement, thus achieving wound healing and a return to normal of the CRP (AU)

Bicellar systems as a new colloidal delivery strategy for skin.

The presented work evaluates the use of bicellar systems as new delivery vectors for controlled release of compounds through the skin. Two different active principles were introduced into the bicellar systems: diclofenac diethylamine (DDEA) and flufenamic acid (Ffa). Bicellar systems are discoidal aggregates formed by long and short alkyl chain phospholipids. Characterization of the bicellar systems by dynamic light scattering (DLS) and cryogenic transmission electron microscopy (Cryo-TEM) showed that particle size decreased when DDEA was encapsulated and increased when Ffa was included in the bicellar systems. Percutaneous absorption studies demonstrated a lower penetration of DDEA and Ffa through the skin when the drugs were included in the bicellar systems than when the drugs were applied in an aqueous solution (DDEA) and in an ethanolic solution (Ffa); the reduction in penetration was more pronounced with Ffa. These bicellar systems may have retardant effects on percutaneous absorption, which result in a promising strategy for future drug or cosmetic delivery applications.

[Treatment of a recalcitrant hip infection with a vastus lateralis muscle flap]. / Tratamiento de la infección recalcitrante de cadera mediante colgajo de músculo vasto lateral.

BACKGROUND: Recalcitrant hip infection after arthroplasty presents a reconstructive challenge to orthopedic surgeons. The aim of this study is to evaluate the results with a vastus lateralis muscle flap used to treat these recalcitrant hip infections in our Department. MATERIAL AND METHODS: A retrospective descriptive study was conducted on five patients with deep hip infections by transposition of the vastus lateralis muscle flap. Average age: 70.5 years. Mean follow-up: 30 months (range, 25-34 months). All patients had previously undergone other major surgical procedures (mean of 3.7 previous procedures). All had multiple microbial infections before surgery. The pathogens involved using cultures of the fistula, the outcome of the wound and laboratory results, including C-reactive protein (CRP), were analysed. RESULTS: Healing was achieved in the five patients who underwent surgery without requiring any further procedures or inflammatory signs of infection. CRP returned to normal one month after surgery, and there was no morbidity or mortality related to surgical technique. CONCLUSION: In our experience, the vastus lateralis muscle flap as a treatment for recalcitrant deep infection after arthroplasty has presented good results, provided there is appropriate antibiotic therapy and surgical debridement, thus achieving wound healing and a return to normal of the CRP.

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer.

There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation.

Skin efficacy of liposomes composed of internal wool lipids rich in ceramides.

Ceramides from intercellular lipids of skin stratum corneum are known to play an essential role in maintaining and structuring the lipid barrier of the skin. Internal wool lipids (IWL), which are also rich in ceramides, have a composition similar to that of the stratum corneum lipids. IWL extracted with chloroform/methanol azeotrope at the laboratory scale have been shown to be capable of forming liposomes with a stable bilayer structure. Furthermore, topical application of these IWL liposomes on intact and compromised skin has been demonstrated to improve barrier skin properties.In this study we evaluated the effect on human skin repair of different IWL extract compositions obtained by two extraction methodologies. The formation and characteristics of the liposomes prepared were greatly influenced by the IWL composition, primarily the sterol sulfate content. The IWL liposomes improved skin barrier integrity and increased skin hydration when applied onto intact skin. These improvements were slightly enhanced in the case of IWL liposomes that were richer in polar lipids.

Bicellar systems for in vitro percutaneous absorption of diclofenac.

This work evaluates the effect of different bicellar systems on the percutaneous absorption of diclofenac diethylamine (DDEA) using two different approaches. In the first case, the drug was included in bicellar systems, which were applied on the skin and, in the second case, the skin was treated by applying bicellar systems without drug before to the application of a DDEA aqueous solution. The characterization of bicellar systems showed that the particle size decreased when DDEA was encapsulated. Percutaneous absorption studies demonstrated a lower penetration of DDEA when the drug was included in bicellar systems than when the drug was applied in an aqueous solution. This effect was possibly due to a certain rigidity of the bicellar systems caused by the incorporation of DDEA. The absorption of DDEA on skin pretreated with bicelles increased compared to the absorption of DDEA on intact skin. Bicelles without DDEA could cause certain disorganization of the SC barrier function, thereby facilitating the percutaneous penetration of DDEA subsequently applied. Thus, depending on their physicochemical parameters and on the application conditions, these systems have potential enhancement or retardant effects on percutaneous absorption that result in an interesting strategy, which may be used in future drug delivery applications.

Liposome formation with wool lipid extracts rich in ceramides.

Internal wool lipids (IWLs) are rich in cholesterol, free fatty acids, cholesteryl sulfate, and, mainly, ceramides. The repairing effect of these lipids structured as liposomes was demonstrated by reinforcing the skin-barrier integrity and increasing the water-holding capacity when applied onto the skin. This work was focused on the formation of liposomes with IWLs rich in ceramides, obtained at pilot plant level with organic solvent extraction by using methanol and acetone. The lipid composition of the two extracts was quantitatively analyzed. IWL extracts containing different amounts of sterol sulfate were used to form liposomes at physiologic p(H). Vesicle size distribution, polydispersity index, and zeta potential of all liposomes were determined to characterize them and to study their stability. The results obtained showed that IWL extract composition, which was different depending on the extraction methodologies used, greatly influences the characteristics of the liposomes formed. Vesicular size and polydispersity index liposomes were smaller when the extract composition contained a higher proportion of either free fatty acids or sterol sulfate. Moreover, liposome stability was improved when some amount of sterol sulfate was added to the composition of methanol and acetone extracts. This natural mixture with keratinaceous origin could have a special interest for cosmetic or dermopharmaceutical companies.

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity.

Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

Lamellar rearrangement of internal lipids from human hair.

The internal lipids were extracted from untreated hair without surface lipids. Liposomes were formed with the internal lipids at different hydration levels to determine the organization of these lipids and the influence of the water content on the lamellar structure of the hair fibres by X-ray Scattering (SAXS). Two structures of hair lipids were observed at 4.5 and approximately 9.0 nm with a different behaviour as a function of water content: the largest bilayer being the one that showed a capacity to retain water inside its structure. SAXS was also applied directly to three samples: a packed swatch of hair fibres at 60% RH, fibres soaked in water and delipidized fibres. Only the lamella at 9.0 nm was slightly affected by water content. Moreover, there was a small diminution in intensity probably due to a high permeability of wet fibres which could give rise to a disorder of the lipid structure. These two lamellar rearrangements are probably made up of lipids with a different and specific hydrophilic/hydrophobic balance.

Cosmetic effectiveness of topically applied hydrolysed keratin peptides and lipids derived from wool.

BACKGROUND/PURPOSE: Skin moisturisation, elasticity, feel and appearance can all be improved through the topical application of protein hydrolysates. Recent studies suggest that supplementing intercellular lipids of the stratum corneum can enhance the functioning of the skin. METHODS: In this study, a hydrolysed keratin peptide (molecular weight <1000 Da) was prepared from wool and tested on skin in two different formulations: an aqueous solution and an internal wool lipids (IWL) liposome suspension. In vivo long-term studies were performed to evaluate the water barrier function of the skin after topical application of different formulations. During the treatment period, hydration and elasticity were determined. A sorption-desorption test was also performed to assess the hygroscopic properties and water-holding capacity of the different treated skin sites. RESULTS: Significant differences were found between the control and treated sites, with the treated areas showing an increase in hydration and elasticity as a result of keratin peptide application. Measurements also indicated that the keratin formulations reinforce the skin barrier integrity, improving its water-holding capacity. CONCLUSION: A combination of the keratin peptide with the IWL showed beneficial effects, indicating that this combination is suitable for designing new cosmetics products.

Tratamiento de las fracturas vertebrales mediante cifoplastia / Treatment of vertebral fractures by kyphoplasty

Objetivo. Análisis retrospectivo clínico y radiológico sobre los primeros casos intervenidos mediante cifoplastia en un centro de la Comunidad de Madrid. Material y método. Se revisaron 30 pacientes (43 vértebras) intervenidos entre diciembre 2002 y mayo 2005. La distribución etiológica fue: 24 pacientes con fractura osteoporótica y 6 con implantes tumorales líticos (1 caso de cáncer de pulmón, 2 de mama, un hipernefroma y 2 mielomas). El seguimiento medio fue de 13,2 meses. Se valoró la escala analógica visual (EAV), el índice de Karnosfky y la analgesia empleada antes del proceso y tras el seguimiento. También se midió el porcentaje de aplastamiento, el ángulo de Cobb local y la corrección de ambos. Resultados. El 93,2% de los pacientes mejoraron. La media de la EAV aumentó 5 puntos (p < 0,05). El índice de Karnosfky pasó de 70,63 a 90 puntos (p < 0,05). El 53% usaba opiáceos mayores antes de la cirugía, pasando el porcentaje después de la cirugía al 6,6% (p < 0,05). Veinte casos (46,5%) mejoraron radiológicamente. Excluyendo aquellas vértebras que no se corrigieron, la mejora obtenida fue de 21,7% de aplastamiento (rango 5-70%) y 13,86° de corrección ángulo de Cobb (rango 3-30°) respectivamente. Hubo 6 extravasaciones anterolaterales, todas asintomáticas. Se detectaron 2 fracturas adyacentes (ambas en los tres primeros meses tras la cirugía), una con repercusión clínica. En el subgrupo de pacientes tumorales los resultados finales fueron comparables a la serie general. Conclusiones. La mayoría de los casos mejoran sustancialmente sin complicaciones asociadas. La cifoplastia es una técnica de baja morbilidad y alta eficacia

Purpose. To conduct a retrospective clinical and radiological study of the first few cases operated by kyphoplasty at one center of Madrid. Materials and methods. Thirty patients were reviewed (43 vertebrae) who were operated between December 2002 and May 2005. The etiological distribution was as follows: 24 patients with an osteoporotic fracture and 6 with osteolytic tumors (lung cancer, 1 case; breast cancer, 2; hypernephroma, 1; and myeloma, 2). Mean follow-up was 13.2 months. Pain reduction was assessed by means of the Visual Analog Scale (VAS), the Karnosfky score and the amount of analgesia used before the procedure and during follow-up. Pre- and postoperative endplate angles were measured to assess the restoration of the sagittal alignment. Results. A 93.2% of patients improved. Mean VAS increased by 5 points (p < 0.05). Karnosfky score went from 70.63 to 90 points (p < 005). Patients using major opioids went from 53% befofre surgery to 6.6% postoperatively (p < 0.05). 20 cases (46.5%) showed radiological improvement. If we exclude uncorrected vertebrae, the improvement obtained was 21.7% as regards crushing (range: 5-70%) and 13.86° as regards Cobb's angle (range: 3-30°). There were 6 instances of anterolateral cement extravasation, all of them asymptomatic. Two adjoining fractures were detected (both in the first three months post-op), one of them with clinical repercussions. In the group of patients with tumors, final results were comparable to the general series. Conclusions. Most cases show a significant improvement with no associated complications. Kyphoplasty is a highly effective minimally invasive technique with a low degree of morbidity