A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma.

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).

Instability after reverse total shoulder arthroplasty: risk factors and how to avoid them.

Instability after RTSA (4'7%) remains a complication with limited salvage options... or not? We conducted a study of the incidence, predisposing factors, and treatment of RTSA instability to risk stratify patient and identify the most reliable treatment methods. We retrospectively searched for RTSAs performed between 2008 and 2017 at our institution by one surgeon using the same technique. We identified post- operative dislocations or symptoms of instability. 103 patients underwent 103 RTSAs (97 primary, 6 revision). 6 patients had 5 dislocations (3 in primary RTSAs, 3 in revision RTSAs). Mean time from surgery to diagnosis was 32.6 days (range, 10-60 days). One dislocation occurred immediately after surgery, 0 after falls, 3 from low-energy mechanisms of injury, and 2 without known inciting events. All dislocations were treated in the operating room; no dislocation was successfully treated with simple closed reduction in the clinic. Although dislocation after RTSA is uncommon, the risk is higher for patients with higher BMI and for patients undergoing revision surgery. The highest risk of instability occurs in RTSAs done for severe proximal humerus fracture; where the anatomy of the shoulder is changed. In these cases, approximately one in four patients will have a recurrent dislocation. In patients with persistent instability or with risk factors for instability, consideration should be given for use of larger glenospheres and increasing the lateral offset at the time of RTSA. Besides, peri- glenoid release, the suitable tension of the soft tissues tend to be the key of the stability.

Roles of Low Temperature Sputtered Indium Tin Oxide for Solar Photovoltaic Technology.

Different functionalities of materials based on indium tin oxide and fabricated at soft conditions were investigated with the goal of being used in a next generation of solar photovoltaic devices. These thin films were fabricated in a commercial UNIVEX 450B magnetron sputtering. The first studied functionality consisted of an effective n-type doped layer in an n-p heterojunction based on p-type crystalline silicon. At this point, the impact of the ITO film thickness (varied from 45 to 140 nm) and the substrate temperature (varied from room temperature to 250 °C) on the heterojunction parameters was evaluated separately. To avoid possible damages in the heterojunction interface, the applied ITO power was purposely set as low as 25 W; and to minimize the energy consumption, no heat treatment process was used. The second functionality consisted of indium-saving transparent conductive multicomponent materials for full spectrum applications. This was carried out by the doping of the ITO matrix with transition metals, as titanium and zinc. This action can reduce the production cost without sacrificing the optoelectronic film properties. The morphology, chemical, structural nature and optoelectronic properties were evaluated as function of the doping concentrations. The results revealed low manufactured and suitable films used successfully as conventional emitter, and near-infrared extended transparent conductive materials with superior performance that conventional ones, useful for full spectrum applications. Both can open interesting choices for cost-effective photovoltaic technologies.

AlxIn1-xN on Si (100) Solar Cells (x = 0-0.56) Deposited by RF Sputtering.

We investigate the photovoltaic performance of solar cells based on n-AlxIn1-xN (x = 0-0.56) on p-Si (100) hetero-junctions deposited by radio frequency sputtering. The AlxIn1-xN layers own an optical bandgap absorption edge tuneable from 1.73 eV to 2.56 eV within the Al content range. This increase of Al content results in more resistive layers (≈10-4-1 Ω·cm) while the residual carrier concentration drops from ~1021 to ~1019 cm-3. As a result, the top n-contact resistance varies from ≈10-1 to 1 MΩ for InN to Al0.56In0.44N-based devices, respectively. Best results are obtained for devices with 28% Al that exhibit a broad external quantum efficiency covering the full solar spectrum with a maximum of 80% at 750 nm, an open-circuit voltage of 0.39 V, a short-circuit current density of 17.1 mA/cm2 and a conversion efficiency of 2.12% under air mass 1.5 global (AM1.5G) illumination (1 sun), rendering them promising for novel low-cost III-nitride on Si photovoltaic devices. For Al contents above 28%, the electrical performance of the structures lessens due to the high top-contact resistivity.

Single GaAs nanowire based photodetector fabricated by dielectrophoresis.

Mechanical manipulation of nanowires (NWs) for their integration in electronics is still problematic because of their reduced dimensions, risking to produce mechanical damage to the NW structure and electronic properties during the assembly process. In this regard, contactless NW manipulation based methods using non-uniform electric fields, like dielectrophoresis (DEP) are usually much softer than mechanical methods, offering a less destructive alternative for integrating nanostructures in electronic devices. Here, we report a feasible and reproducible dielectrophoretic method to assemble single GaAs NWs (with radius 35-50 nm, and lengths 3-5 µm) on conductive electrodes layout with assembly yields above 90% per site, and alignment yields of 95%. The electrical characteristics of the dielectrophoretic contact formed between a GaAs NW and conductive electrodes have been measured, observing Schottky barrier like contacts. Our results also show the fast fabrication of diodes with rectifying characteristics due to the formation of a low-resistance contact between the Ga catalytic droplet at the tip of the NW when using Al doped ZnO as electrode. The current-voltage characteristics of a single Ga-terminated GaAs NW measured in dark and under illumination exhibit a strong sensitivity to visible light under forward bias conditions (around two orders of magnitude), mainly produced by a change on the series resistance of the device.

Long-Range Distributed Solar Irradiance Sensing Using Optical Fibers.

Until recently, the amount of solar irradiance reaching the Earth surface was considered to be a steady value over the years. However, there is increasing observational evidence showing that this quantity undergoes substantial variations over time, which need to be addressed in different scenarios ranging from climate change to solar energy applications. With the growing interest in developing solar energy technology with enhanced efficiency and optimized management, the monitoring of solar irradiance at the ground level is now considered to be a fundamental input in the pursuit of that goal. Here, we propose the first fiber-based distributed sensor able of monitoring ground solar irradiance in real time, with meter scale spatial resolutions over distances of several tens of kilometers (up to 100 km). The technique is based on an optical fiber reflectometry technique (CP-ϕOTDR), which enables real time and long-range high-sensitivity bolometric measurements of solar radiance with a single optical fiber cable and a single interrogator unit. The method is explained and analyzed theoretically. A validation of the method is proposed using a solar simulator irradiating standard optical fibers, where we demonstrate the ability to detect and quantify solar irradiance with less than a 0.1 W/m2 resolution.

New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth.

For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 (IDH1), Isocitrate Dehydrogenase-2 (IDH2), and Tumor Supressor P53 (TP53) and deletion of Cyclin Dependent Kinase Inhibitor 2A (CDKN2A) were detected both in cell lines and tumor samples. In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog (MDM2) arose during cell culture in CDS17 cells. Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth. Altogether, this work expanded the panel of clinically and genetically-annotated chondrosarcoma lines amenable for in vivo studies and cancer stem cell (CSC) characterization. Moreover, it provided clues of the genetic drift of chondrosarcoma cells during the adaptation to grow conditions.

The multikinase inhibitor EC-70124 synergistically increased the antitumor activity of doxorubicin in sarcomas.

Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.

A Novel Growth Method To Improve the Quality of GaAs Nanowires Grown by Ga-Assisted Chemical Beam Epitaxy.

The successful synthesis of high crystalline quality and high aspect ratio GaAs nanowires (NWs) with a uniform diameter is needed to develop advanced applications beyond the limits established by thin film and bulk material properties. Vertically aligned GaAs NWs have been extensively grown by Ga-assisted vapor-liquid-solid (VLS) mechanism on Si(111) substrates, and they have been used as building blocks in photovoltaics, optoelectronics, electronics, and so forth. However, the nucleation of parasitic species such as traces and nanocrystals on the Si substrate surface during the NW growth could affect significantly the controlled nucleation of those NWs, and therefore the resulting performance of NW-based devices. Preventing the nucleation of parasitic species on the Si substrate is a matter of interest, because they could act as traps for gaseous precursors and/or chemical elements during VLS growth, drastically reducing the maximum length of grown NWs, affecting their morphology and structure, and reducing the NW density along the Si substrate surface. This work presents a novel and easy to develop growth method (i.e., without using advanced nanolithography techniques) to prevent the nucleation of parasitic species, while preserving the quality of GaAs NWs even for long duration growths. GaAs NWs are grown by Ga-assisted chemical beam epitaxy on oxidized Si(111) substrates using triethylgallium and tertiarybutylarsine precursors by a two-step-based growth method presented here; this method includes a growth interruption for an oxidation on air between both steps of growth, reducing the nucleation of parasitic crystals on the thicker SiO x capping layer during the second and longer growth step. VLS conditions are preserved overtime, resulting in a stable NW growth rate of around 6 µm/h for growth times up to 1 h. Resulting GaAs NWs have a high aspect ratio of 85 and average radius of 35 nm. We also report on the existence of characteristic reflection high-energy electron diffraction patterns associated with the epitaxial growth of GaAs NWs on Si(111) substrates, which have been analyzed and compared to the morphological characterization of GaAs NWs grown for different times under different conditions.

Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS).

Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.

Protein kinase C theta is highly expressed in gastrointestinal stromal tumors but not in other mesenchymal neoplasias.

PURPOSE: Gastrointestinal stromal tumors (GIST) are a distinctive group of mesenchymal neoplasms of the gastrointestinal tract. The oncogene KIT has a central role in the pathogenesis of GIST, with c-kit receptor tyrosine kinase (KIT) protein expression being the gold standard in its diagnosis. The identification of GIST patients has become crucial, because the tyrosine kinase inhibitor Imatinib is effective in the treatment of this malignancy. However, a small set of GISTs remain unrecognized, because KIT protein expression is not always evident. The aim of this study was the identification of new markers for the differential diagnosis of GIST. EXPERIMENTAL DESIGN: By analyzing publicly available data from transcriptional profiling of sarcomas, we found that protein kinase C theta (PKC-theta), a novel PKC isotype involved in T-cell activation, is highly and specifically expressed in GIST. PKC-theta expression in GIST was confirmed by reverse transcription-PCR and Western blot. PKC-theta was analyzed by immunohistochemistry in a panel of 26 GIST, 12 non-GIST soft-tissue sarcomas, and 35 tumors from other histologies. RESULTS: We found that all of the GISTs expressed PKC-theta, whereas this protein was undetectable in other mesenchymal or epithelial tumors, including non-GIST KIT-positive tumors. PKC-theta immunoreactivity was also observed in interstitial cells of Cajal. CONCLUSIONS: Our results show that PKC-theta is easily detected by immunohistochemistry in GIST specimens and that it could be a sensitive and specific marker for the diagnosis of this malignancy.