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Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

A new series of narrow orange emitting phosphors in 1:2 B-site cation ordered Eu3+ doped triple Perovskite Ba3CaNb2O9 was prepared by the conventional solid-state route. Powder X-ray diffraction analysis of these phosphors confirms the formation of trigonal perovskite-type structure with the space group P-3m1 and Z = 3. The weak intensity superlattice reflections at low 2θ angles support the idea of 1:2 ordering on the B-site. UV–visible absorption spectra show strong absorption below 325 nm. These phosphors exhibit dominant narrow orange emission with fwhm ~ 4 nm due to allowed magnetic dipole transition, 5D0–7F1 under near-UV (394 nm), or charge transfer band (288 nm) excitations. The intensity for the CT band excitation (x = 0.2) is double that of the direct Eu3+ excitation at 394 nm inferring good host sensitization by way of energy transfer to Eu3+ ions. The ordering on the B-site cations aids a high concentration quenching in the Ba3CaNb2O9:Eu3+ phosphor at 20 mol%. The low asymmetric ratio values and high lifetimes corroborate the environment of Eu3+ ions in most symmetrical surrounding of the host. The CIE color co-ordinates of Ba3CaNb2O9:0.2Eu3+ phosphor are (0.57, 0.41) that are close to the Nichia Corporation developed Amber LED NSPAR70BS. The above results demonstrate that the Ba3CaNb2O9:0.2Eu3+ phosphor is a potential candidate for near-ultraviolet-based phosphor-converted white light-emitting diodes.

Accurate component positioning is the key for successful outcome after total hip arthroplasty (THA). Positioning acetabular and femoral components in a safe zone of 25°–50° on the basis of combined anteversion (CA) has shown to reduce instability and impingement. This safe zone was described for THAs performed through the posterior approach and has not been validated for other surgical approaches. Seventy patients who underwent unilateral uncemented THA were included in the study; 35 patients—using posterior approach and the remaining 35—using trans-gluteal approach. All patients included had a stable and impingement-free THA at a mean follow-up of 39.2 ± 9.5 months. CT scan was performed to assess component positioning by calculating CA. The values were compared between the two groups to study possible differences. CA in the trans-gluteal group was significantly lower (32° ± 3.7° vs 38.4° ± 4.6°, P

A series of intense red-emission phosphors, Y3Mg2Nb3O14:Eu3+, with higher color purity were prepared via the conventional high-temperature ceramic route. The influence of Mg2+ ion incorporation in the highly symmetrical YNbO4 lattice on the luminescence properties was studied using powder x-ray diffraction, scanning electron microscopy with energy dispersive spectrometry, UV–visible absorption spectroscopy, and photoluminescence measurements. The developed phosphors crystallize into a monoclinic fergusonite-type structure with a C2/c space group even with the addition of Mg into the system. These phosphors display intense, sharp, red emission with a maximum at 613 nm under near-UV excitation. The photoluminescence studies suggest that Mg addition perturbs the A site network forming cation pairs of Eu3+-Y3+, Eu3+-Mg2+, and Eu3+-Eu3+ connected with O2− ions. The preferential occupation of cations in the A site network by the incorporation of Mg2+ ions in the YNbO4 host lattice induces Eu3+-Eu3+ separation and results in intense, sharp, red emission due to increased radiative probabilities. Moreover, the color purity of the Y3−xMg2Nb3O14:xEu3+ phosphor could achieve 92.4% that is attributed to the narrow full width at half maximum (FWHM ∼ 4 nm) of the red emission peaking at 613 nm. More importantly, the luminescence intensity of the developed phosphor is 9.4 times greater than that of the Philip’s red phosphor under near-UV excitation. Because of the intriguing red luminescence, phosphors exhibit Commission Internationale de l’Elcairage color coordinates (0.63, 0.35) close to the National Television System Committee standards, low correlated color temperature values for warm white lighting, and greater color purity (92.4%) for improving the color rendering index, which makes them a potential candidate for use in the fabrication of white light-emitting diodes.

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC., Li, Viswanadhapalli et al utilized multiple in vitro, ex vivo and in vivo models of TNBC to investigate LIFR inhibition. The authors reported that HDAC inhibition in TNBC cells led to an increase of LIFR expression and over activation of the downstream signaling elements (e.g., STAT3, mTOR, AKT), enhancing the aggressive potential of TNBC cells, and an LIFR inhibitor, EC359, synergistically enhanced the efficacy of HADC inhibitors in suppressing TNBC in vitro and in vivo.

Femoral neck nonunion in young patients has always been a difficult problem to deal with for surgeons. Numerous surgical procedures to address either the biological or mechanical issues at the nonunion have been described and most of them have been associated with variable results. Isolated biological augmentation is often associated with poor results and some techniques like vascularized grafting may require not so commonly available expertise. Valgus osteotomy is aimed to correct the abnormal fracture biomechanics associated with femoral neck fractures. By altering the nature of force transmission across the nonunion, shear forces are converted into compressive forces that lead to rapid osseous union without the need for bone grafting. Though the principles are sound and were described a long time ago, the technical aspects have evolved over time. Various modifications have been described to overcome shortcomings such as limb length discrepancy, reduction of femoral offset, alteration in mechanical axis, and the overall proximal femur anatomy. In this review, we look back at the fundamental principles and recent literature on the results of valgus intertrochanteric osteotomy for femoral neck pseudoarthrosis. We also highlight the important need for accurate preoperative planning and surgical execution. Lastly, we elaborate on the technical improvisations that have happened over time in order to improve functional results and to minimize complications and poor outcome after a valgus osteotomy.

Diesel particulate matter (DPM) has been classified as a carcinogen to humans by the International Agency for Research on Cancer. As a result of its potential carcinogenic nature, DPM exposure is regulated by the Mine Safety and Health Administration. Currently, diesel emissions in the workplace are monitored by collecting the aerosol onto filters, which are then sent to a laboratory for thermal-optical analysis using the NIOSH method 5040. This process can take days or even weeks, and workers can potentially be exposed to excessive levels of DPM before the problem is identified. Moreover, the delay involved in getting the loaded filter to the lab inevitably means the loss of some of the more volatile organic carbon. To remedy this delay, researchers from the National Institute for Occupational Safety and Health are seeking to develop a field-portable, real-time method for measuring elemental and organic carbons in DPM aerosols. In the current study, the use of mid-infrared spectrometry was investigated. It is believed that mid-infrared spectroscopy is more suitable for use in a real-time field-portable device than thermo-optical analysis methods. This article presents a method for measuring organic carbon (OC) and elemental carbon (EC) in DPM for a broad range of OC/EC ratios. The method has been successfully applied to laboratory-generated and mine samples.

A series of Eu3+ activated xenotime type rare earth phosphate NaYP2O7 based orange–red emitting phosphors have been prepared via solid state (SS) and citrate gel (CG) methods. The morphological variation of the developed phosphors concerning synthesis method and heat treatment has significantly influenced the luminescence properties. The phosphors synthesized by the CG route reveals the formation of homogeneous powder with small particles along with uniform size. The developed phosphors exhibit intense orange–red emission under 394 nm near UV excitation with a full width half maximum ~ 2 nm. Compared with the phosphors synthesized by SS route, the phosphors obtained by CG method possess enhanced and sharper orange–red emission with longer lifetimes due to the 5D0–7F1–2 transitions. The developed narrow red emitting phosphors have better emission intensity in comparison with commercially available Y2O3:Eu3+ red phosphors. Thus, these phosphors could be a suitable candidate for solid state lighting applications for the fabrication of white light emitting diodes.

The proposed study examined the preparation of chitosan (CS)–polyvinylpyrrolidone (PVP)–bovine serum albumin (BSA)-coated magnetic iron oxide (Fe3O4) nanoparticles (Fe3O4–CS–PVP–BSA) to use as potential drug delivery carriers for delivery of tamoxifen drug (TAM) . The anticancer drug selected in this study was tamoxifen which can be used for the human breast cancer treatment. These prepared nanoparticles were characterized by FTIR, XRD, SEM, AFM, TEM, CD and VSM techniques. The swelling studies have been measured at different (10, 20, 30, 40, 50%) drug loading. The mean particle size of the tamoxifen-loaded nanoparticles system (Fe3O4–CS–TAM, Fe3O4–CS–TAM–PVP and Fe3O4–CS–TAM–PVP–BSA) as measured by Malvern Zetasizer ranged between 350 ± 2.3 and 601 ± 1.7 nm. As well as these drug-loaded nanoparticles were positively charged. The zeta potential was in the range of 28.9 ± 3.5 and 50.8 ± 3.9 mV. The encapsulation efficiency was between 63.60 ± 2.11 and 96.45 ± 2.12%. Furthermore, in vitro release and drug loading efficiency from the nanoparticles were investigated. The cytotoxicity of prepared nanoparticles was verified by MTT assay. In vitro release studies were executed in 4.0 and 7.4 pH media to simulate the intestinal and gastric conditions and different temperature (37 and 42 °C). Hence, the prepared tamoxifen-loaded nanoparticles system (Fe3O4–CS–TAM, Fe3O4–CS–TAM–PVP and Fe3O4–CS–TAM–PVP–BSA) could be a promising candidate in cancer therapy.

Non-ionic polyethylene glycol dodecyl ether (Brij 76) template novel single-step process is successfully evolved for preparation of mesoporous cesium salt of phosphotungstic acid (PTA) with tunable porosity. Hybrid proton exchange membranes are prepared by embedding mesoporous cesium salt of PTA into chitosan (CS) polymer and are characterized by FTIR, TGA, and SEM mapping studies. To elucidate advantages of mesoporous structure, a series of CS hybrid membranes comprising non-porous cesium salt of phosphotungstic acid is also prepared and their functional properties are compared with mesoporous counterparts. Mesoporous nature helps to integrate membrane network creating maximum intermolecular interaction between organic and inorganic components. Both selective water sorption feature of CS and highly hydrophilic nature of mesoporous cesium salt of PTA together play a vital role in selective proton transport process through CS/m-PTA hybrid membranes. At optimal loading of m-PTA, maximum peak power density of 83 mW cm−2 was achievable with 2 M methanol as a fuel feed. On the basis of thermal stability, low methanol crossover, and appropriate proton conductivity, CS/m-PTA-5 wt% hybrid membrane could be proposed as novel polyelectrolytes for direct methanol fuel cell.

In underground metal/nonmetal mines, repeated localized short-term exposure to high levels of airborne contaminants can become a serious health issue. Currently, there are no common mechanisms to control or mitigate these short-term high exposures to contaminants. To improve miners’ health and safety, the U.S. National Institute for Occupational Safety and Health’s Spokane Mining Research Division (SMRD) is developing a smart monitoring and control (SMAC) system for the real-time monitoring of mine air quality, with integrated countermeasures to reduce high concentrations of airborne contaminants in localized sections of mines. To develop and test a SMAC system capable of being implemented in an underground mine, SMRD researchers built a test apparatus incorporating a fan, louver, ducting and sensors combined with atmospheric monitoring and control software. This system will institute effective countermeasures to reduce contaminant levels, improving miner safety and health.

Part I of the paper discussed the temperature dependencies of the electrical resistivities, thermal conductivities, thermal diffusivities and total hemispherical emissivities of several vacuum plasma-sprayed (VPS) and cold-sprayed (CS) copper alloy monolithic coatings, VPS NiAl, VPS NiCrAlY, extruded GRCop-84 and as-cast Cu-17(wt.%)Cr-5%Al. Part II discusses the temperature dependencies of the constant-pressure specific heat capacities, C P, of these coatings. The data were empirically regression-fitted with the equation: $${\varvec{C}}_{\mathbf{P}} = {\mathbf{ AT}}^{\mathbf 4} + {\mathbf{BT}}^{\mathbf 3} + {\mathbf{CT}}^{\mathbf 2} + {\mathbf{DT}} + \varvec{E}$$ where T is the absolute temperature and A, B, C, D and E are regression constants. The temperature dependencies of the molar enthalpy, molar entropy and Gibbs molar free energy determined from experimental values of molar specific heat capacity are reported. Calculated values of C P using the Neumann–Kopp (NK) rule were in poor agreement with experimental data. Instead, a modification of the NK rule was found to predict values closer to the experimental data with an absolute deviation less than 6.5%. The specific molar heat capacities for all the alloys did not agree with the Dulong–Petit law, and C P > 3R, where R is the universal gas constant, were measured for all the alloys except NiAl for which C P

This two-part paper reports the thermophysical properties of several cold- and vacuum plasma-sprayed monolithic Cu- and Ni-based alloy coatings. Part I presents the electrical and thermal conductivity, thermal diffusivity, and total hemispherical emissivity data, while Part II reports the specific heat capacity data for these coatings. Metallic copper alloys and stoichiometric NiAl and NiCrAlY coatings were fabricated by either the cold spray or the vacuum plasma spray deposition processes for thermal property measurements between 77 and 1223 K. The temperature dependencies of the thermal conductivities, thermal diffusivities, electrical conductivities, and total hemispherical emissivities of these cold- and vacuum-sprayed monolithic coatings are reported in this paper. The electrical and thermal conductivity data correlate reasonably well for Cu-8%Cr-1%Al, Cu-23%Cr-5%Al, and NiAl in accordance with the Wiedemann–Franz (WF) law although a better fit is obtained using the Smith–Palmer relationship. The Lorentz numbers determined from the WF law are close to the theoretical value.

Aluminum and its alloys are widely used in almost all industries and for marine and medical applications. However, their surfaces are easily colonized by bacteria that form biofilms and corroded by chemical reactions. We report here a simple method to fabricate polyaniline/chitosan/zinc stearate superhydrophobic coatings on aluminum with a micro–nanosurface structure by polymerization of aniline and deposition of chitosan and zinc stearate coating. The fabricated coatings have been characterized by ATR-IR, XRD, FE-SEM, and EDX. The superhydrophobic surface shows the highest water-repellent property with contact angle of 150.7°, which is responsible for antiadhesion of bacteria, antiicing property, and excellent corrosion resistance of aluminum. The corrosion behavior of the coating in the 3.5% NaCl solution was investigated by EIS and potentiodynamic polarization. The efficacies of the different coatings against bacteria that are commonly encountered in marine (Desulfovibrio desulfuricans) and medical applications (Staphylococcus aureus and Escherichia coli) are demonstrated.

Background CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) are approved for the treatment of ER+ advanced breast cancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. We previously reported a novel therapeutic agent, ERX-11, that binds to the estrogen receptor (ER) and modulates ER-coregulator interactions. Here, we tested if the combination of ERX-11 with agents approved for ER+ BCa would be more potent. Methods We tested the effect of combination therapy using BCa cell line models, including those that have acquired resistance to tamoxifen, letrozole, or CDK4/6 inhibitors or have been engineered to express mutant forms of the ER. In vitro activity was tested using Cell Titer-Glo, MTT, and apoptosis assays. Mechanistic studies were conducted using western blot, reporter gene assays, RT-qPCR, and mass spectrometry approaches. Xenograft, patient-derived explants (PDEs), and xenograft-derived explants (XDE) were used for preclinical evaluation and toxicity. Results ERX-11 inhibited the proliferation of therapy-resistant BCa cells in a dose-dependent manner, including ribociclib resistance. The combination of ERX-11 and CDK4/6 inhibitor was synergistic in decreasing the proliferation of both endocrine therapy-sensitive and endocrine therapy-resistant BCa cells, in vitro, in xenograft models in vivo, xenograft-derived explants ex vivo, and in primary patient-derived explants ex vivo. Importantly, the combination caused xenograft tumor regression in vivo. Unbiased global mass spectrometry studies demonstrated profound decreases in proliferation markers with combination therapy and indicated global proteomic changes in E2F1, ER, and ER coregulators. Mechanistically, the combination of ERX-11 and CDK4/6 inhibitor decreased the interaction between ER and its coregulators, as evidenced by immunoprecipitation followed by mass spectrometry studies. Biochemical studies confirmed that the combination therapy significantly altered the expression of proteins involved in E2F1 and ER signaling, and this is primarily driven by a transcriptional shift, as noted in gene expression studies. Conclusions Our results suggest that ERX-11 inhibited the proliferation of BCa cells resistant to both endocrine therapy and CDK4/6 inhibitors in a dose-dependent manner and that the combination of ERX-11 with a CDK4/6 inhibitor may represent a viable therapeutic approach.

Background Virtually all patients with metastatic prostate cancer (PCa) will relapse and develop lethal castration-resistant prostate cancer (CRPC). Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements of many cellular biological processes, and may serve as therapeutic targets for combating PCa progression. Here, we have discovered in a high-throughput RNAi screen a novel lncRNA in PCa, and assessed the oncogenic effects of this lncRNA. Methods Rapid amplification of cDNA ends and sequencing was utilized to identify a previously unannotated lncRNA lying within exon six and the 3’UTR of the lymphocyte-specific protein tyrosine kinase (LCK) gene. The levels of HULLK in the presence or absence of hormone and/or enzalutamide or coregulator inhibitors were measured by quantitative PCR (qPCR). The determination of HULLK transcription and localization were characterized by strand-specific qPCR and cellular fractionation followed by qPCR, respectively. The correlation between HULLK expression and prostate cancer Gleason score was analyzed by droplet digital PCR. CyQuant assays were conducted to evaluate the effects of knocking down HULLK with shRNAs or overexpressing HULLK on cell growth. Results In this study, a previously unannotated lncRNA lying within exon six and 3’UTR of the LCK gene was dramatically upregulated by androgen in a dose-dependent manner, and the anti-androgen enzalutamide completely blocked this hormone-induced increase. Therefore, we labeled this lncRNA “HULLK” for Hormone-Upregulated lncRNA within LCK. Binding sites for two AR coregulators p300 and Brd4 reside near the HULLK transcriptional start site (TSS), and inhibitors of these coregulators downregulated HULLK. HULLK is transcribed from the sense strand of DNA, and predominantly localizes to the cytoplasm. HULLK transcripts are not only expressed in prostate cancer cell lines, but also prostate cancer patient tissue. Remarkably, there was a significant positive correlation between HULLK expression and high-grade PCa in multiple cohorts. shRNAs targeting HULLK significantly decreased PCa cell growth. Moreover, cells overexpressing HULLK were hypersensitive to androgen stimulation. Conclusions HULLK is a novel lncRNA situated within the LCK gene that may serve as an oncogene in PCa. Our data enhances our understanding of lncRNA biology and may assist in the development of additional biomarkers or more effective therapeutic targets for advanced PCa. Electronic supplementary material The online version of this article (10.1186/s12943-019-1039-6) contains supplementary material, which is available to authorized users.

Salvage haploidentical hematopoietic cell transplantation for graft rejection following a prior haploidentical allograft

Background: The clinical significance of pressure-dependent intra-beat changes in local pulse-wave velocity (C) has recently come to light [1]. While reported methods require arterial pressure and diameter measurements from a single site to assess intra-beat changes in C, we present an image-free fast ultrasound device that performs this by capturing diameter waveforms from two proximal locations on an artery.. Methods: The functionality was assessed on eight normotensive participants (26 ± 4 years). By perturbing blood pressure through a short duration moderate lower body negative pressure intervention [2], CD and CF pulse wave velocities corresponding to diastolic and 80% of peak pressure were measured from the carotid artery. Human NIBP system (ADInstruments, India) was used for monitoring continuous pressure. Results: The device captured dual-diameter waveforms and evaluated CD and CF, with a beat-to-beat variation 0.6, p < 0.001) of CD and CF with the diastolic and systolic pressures for each individual was preserved even after adjusting for heart-rate. Conclusions: The device demonstrated its functionality and reliably measured the incremental nature of C. Its pressure-dependent intra-beat variations and inter-beat dynamics during the intervention concurred with literature. Further studies are underway to demonstrate the potential use of the device in vascular research and clinical applications.

Interpenetrating polymer network (IPN) using chitosan and egg white cross linked with polyvinylpyrrolidone and polyethylene glycol was prepared by heat coagulation method. 5-Fluorouracil (5-FU) was chosen as a model drug which is effective for several cancer treatments. Eleven formulations were prepared by keeping chitosan concentration constant and varying the concentration of egg white and heating time. The prepared nanoparticles were characterized using FE-SEM, FT-IR, P-XRD and TG/DTG studies. FE-SEM analysis indicated that the IPN nanoparticles exhibit a uniform and compact dense morphology. FTIR spectroscopy confirmed the formation of interpenetrating network and the chemical stability of 5-FU after penetration into IPN nanoparticles. P-XRD results demonstrated that the drugs were distributed in amorphous state in the IPN nanoparticles. Particle size, poly-dispersity index and zeta potential were evaluated. The entrapment efficiency and in vitro drug release behavior of drug loaded IPN nanoparticles were also studied. Entrapment efficiency is high for F-3 formulation. The release rate is relatively higher at alkaline pH 7.4 as compared to acidic pH 1.2 and this feature is desirable from perspective of site specific drug delivery. Cell cytotoxicity was assessed using MTT assay into HT 29 cell line and found that 5-FU loaded IPN nanoparticles prolonged the cytotoxic effect on HT-29 colon cancer cell lines in comparison to free 5-FU. This work provides a promising delivery system for sustained release of 5-FU.

Triple-negative breast cancer (TNBC), the most aggressive breast cancer subtype, occurs in younger women and is associated with poor prognosis. Gain-of-function mutations in TP53 are a frequent occurrence in TNBC and have been demonstrated to repress apoptosis and up-regulate cell cycle progression. Even though TNBC responds to initial chemotherapy, resistance to chemotherapy develops and is a major clinical problem. Tumor recurrence eventually occurs and most patients die from their disease. An urgent need exists to identify molecular-targeted therapies that can enhance chemotherapy response. In the present study, we report that targeting PELP1, an oncogenic co-regulator molecule, could enhance the chemotherapeutic response of TNBC through the inhibition of cell cycle progression and activation of apoptosis. We demonstrate that PELP1 interacts with MTp53, regulates its recruitment, and alters epigenetic marks at the target gene promoters. PELP1 knockdown reduced MTp53 target gene expression, resulting in decreased cell survival and increased apoptosis upon genotoxic stress. Mechanistic studies revealed that PELP1 depletion contributes to increased stability of E2F1, a transcription factor that regulates both cell cycle and apoptosis in a context-dependent manner. Further, PELP1 regulates E2F1 stability in a KDM1A-dependent manner, and PELP1 phosphorylation at the S1033 residue plays an important role in mediating its oncogenic functions in TNBC cells. Accordingly, depletion of PELP1 increased the expression of E2F1 target genes and reduced TNBC cell survival in response to genotoxic agents. PELP1 phosphorylation was significantly greater in the TNBC tumors than in the other subtypes of breast cancer and in the normal tissues. These findings suggest that PELP1 is an important molecular target in TNBC, and that PELP1-targeted therapies may enhance response to chemotherapies.

Thermal expansion measurements were conducted on hot-pressed CrSi2, TiSi2, WSi2 and a two-phase Cr-Mo-Si intermetallic alloy between 303 and 1523 K during three heat-cool cycles. The corrected thermal expansion, (ΔL/L 0)thermal, varied with the absolute temperature, T, as $$\left( {\Delta L/L_{0} } \right)_{\text{thermal}} = \, A\left( {T - 293} \right)^{3} + \, B\left( {T - 293} \right)^{2} + \, C\left( {T - 293} \right) \, + D$$ where, A, B, C, and D are regression constants. Excellent reproducibility was observed for most of the materials after the first heat-up cycle. In some cases, the data from first heat-up cycle deviated from those determined in the subsequent cycles. This deviation was attributed to the presence of residual stresses developed during processing, which are relieved after the first heat-up cycle.

Impact of haploidentical hematopoietic cell transplantation conditioning intensity on the incidence and severity of post-transplantation viral infections

Molecularly targeted therapies for advanced prostate cancer include castration modalities that suppress ligand-dependent transcriptional activity of the androgen receptor (AR). However, persistent AR signalling undermines therapeutic efficacy and promotes progression to lethal castration-resistant prostate cancer (CRPC), even when patients are treated with potent second-generation AR-targeted therapies abiraterone and enzalutamide. Here we define diverse AR genomic structural rearrangements (AR-GSRs) as a class of molecular alterations occurring in one third of CRPC-stage tumours. AR-GSRs occur in the context of copy-neutral and amplified AR and display heterogeneity in breakpoint location, rearrangement class and sub-clonal enrichment in tumours within and between patients. Despite this heterogeneity, one common outcome in tumours with high sub-clonal enrichment of AR-GSRs is outlier expression of diverse AR variant species lacking the ligand-binding domain and possessing ligand-independent transcriptional activity. Collectively, these findings reveal AR-GSRs as important drivers of persistent AR signalling in CRPC., Castration-resistant prostate cancer frequently presents with persistent androgen receptor signalling. Here, the authors find that the androgen receptor is subject to genetic rearrangements, resulting in variants with ligand-independent activity.

A 24-year-old woman presented with a 45 cm complex cystic renal mass, which was resected. The tumor was a type-2 papillary renal cell carcinoma (pRCC-2), and several nodules remained. The patient was treated with mammalian target of rapamycin complex 1 (mTORC1) inhibitors, but after 5 months the tumor had progressed. Genetic testing of the patient revealed a novel heterozygous germline mutation in the gene encoding fumarate hydratase (FH), an enzyme of the tricarboxylic acid (TCA) cycle. As the tumor exhibited loss of heterozygosity for FH and markedly reduced FH activity, and in the absence of other established therapies, treatment with the glycolytic inhibitor 2DG (2-deoxy-D-glucose) was explored.CT, histology, immunohistochemistry, genetic studies, 2-deoxy-2-(¹⁸F)fluoro-D-glucose (¹⁸FDG)-PET/CT, FH enzymatic assays, reconstitution experiments and in vitro studies of the effects of 2DG on FH-deficient tumor cells.pRCC-2 arising in a patient with a novel germline FH mutation and de novo hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome progressing after mTORC1 inhibitor therapy.Surgical resection of the renal mass, treatment with mTORC1 inhibitors followed by 2DG. Unfortunately, 2DG was not effective, and the patient died several weeks later.

A detailed quantitative microstructural analyses of primarily open cell FeCrAlY and 314 stainless steel metal foams with different relative densities and pores per inch (p.p.i.) were undertaken in the present investigation to determine the effect of microstructural parameters on the relative densities of metal foams. Several elements of the microstructure, such as major and minor cell sizes, cell areas and perimeters, ligament dimensions, cell shapes, and area fractions of closed and open cells, were measured. The cross-sections of the foam ligaments showed numerous pores, and their circularity factors and average sizes were determined. The area fractions of the open cells and ligaments decreased, whereas that of the closed cells increased linearly with increasing relative density. The relative densities and p.p.i. were not significantly dependent on cell size, cell perimeter, and ligament dimensions within the limits of experimental scatter. A phenomenological model is proposed to rationalize the present microstructural observations.

The rates of alkaline bleaching of triphenylmethane dyes crystal violet (CV), malachite green (MG) and rosaniline (RA) have been measured spectrophotometrically in an aqueous medium at 30°C in the presence of β-cyclodextrin (CD). At lower concentrations of CD, CV forms productive 1: 1 (G: H) complex. At higher concentrations of CD, it forms unproductive 1: 2 (G: H) complex. For the bleaching of MG, CD accelerates or decelerates the rate depending on pH of the medium by forming 1: 1 (G: H) inclusion complex. Analysis of rate data shows that MG undergoes fading by mixed order process. CD decelerates the water reaction and accelerates hydroxide ion reaction. In the case of RA, both water reaction as well as hydroxide ion reaction are retarded by CD by the formation of inclusion complex.

The isothermal oxidation kinetics of as-cast Cu–17%Cr and Cu–17%Cr–5%Al in air were studied between 773 and 1,173 K under atmospheric pressure. Details of the oxidation kinetics of these alloys were discussed in Part I. This paper analyzes the microstructures of the scale and its composition in an attempt to elucidate the oxidation mechanisms in these alloys. The scales formed on Cu–17%Cr specimens oxidized between 773 and 973 K consisted of external CuO and subsurface Cu2O layers. The total thickness of these scales varied from about 10 μm at 773 K to about 450 μm at 973 K. In contrast, thin scales formed on Cu–17%Cr–5%Al alloys oxidized between 773 and 1,173 K. The exact nature of these scales could not be determined by X-ray diffraction but energy dispersive spectroscopy analyses were used to construct a scale composition map. Phenomenological oxidation mechanisms are proposed for the two alloys.

Kinetics of cleavage of phenylphenyl acetates (PPA) and several para-substituted PPAs in basic aqueous sodium carbonate-bicarbonate buffer containing β-cyclodextrin (CD) have been studied. The reaction exhibits saturation type kinetics and CD accelerates the rate of cleavage by the formation of 1G: 1H inclusion complex. The kinetic results indicate that aryloxy moiety of PPA is included in the hydrophobic cavity of CD. The overall rate constants for the cleavage of the [CD-ester] complex correlate with the Hammett σ-consdtants and Hansch hydrophobicity parameters π. At higher concentrations of CD, there is an additional catalysis due to the formation of weak 1G:2H complex.

Background: To assess pathological correlations and temporal trends of Angiopoietin-2 (ANGPT2), vascular endothelial growth factor (VEGF) and M2 Pyruvate kinase (TuM2PK), markers of tumor vascular development and metabolism, in patients with renal cell carcinoma (RCC). Methods: We prospectively collected plasma samples from 89 patients who underwent surgical/ablative therapy for RCC and 38 patients with benign disease (nephrolithiasis, hematuria without apparent neoplastic origin, or renal cysts). In RCC patients, marker levels were compared between at least 1 preoperative and 1 postoperative time point generally 3 weeks after surgery. Marker temporal trends were assessed using the Wilcoxon sign-rank test. Plasma VEGF, ANGPT2, and TuM2PK levels were determined by ELISA and tested for association with pathological variables. Results: Median age was comparable between groups. 83/89 (93%) of the cohort underwent surgical extirpation. 82% of the tumors were organ confined (T ≤2, N0). Only ANGPT2 exhibited significantly elevated preoperative levels in patients with RCC compared to benign disease (p= 0.046). Elevated preoperative levels of ANGPT2 and TuM2PK significantly correlated with increased tumor size and advanced grade (p< 0.05). Chromophobe RCC exhibited higher levels of ANGPT2 compared to other histologies (p < 0.05). A decline in marker level after surgery was not observed, likely due to the timing of the analyses. Conclusion: Our results suggest that ANGPT2 is a marker of RCC. Additionally, ANGPT2 and TuM2PK significantly correlated with several adverse pathological features. Further studies are needed to determine clinical applicability.

Surgeon–scientists have made fundamental discoveries that have revolutionized medicine. A recent report raises the spectre of a future without surgeon–scientists, owing to an increasing need for clinical productivity and burdensome administrative responsibilities. A pathway forward is needed, to protect and nurture the surgeon–scientist — a critical participant in academic medicine.

Directionally solidified (DS) Ni-33(at. pct)Al-33Cr-1Mo and Ni-33(at. pct)Al-31Cr-3Mo eutectic alloys were grown at different rates varying from 7.6 to 508 mm h−1. The microstructures consisted of eutectic colonies with parallel lamellar NiAl/(Cr,Mo) plates for solidification rates at and below 12.7 mm h−1. Cellular eutectic microstructures were observed at higher solidification rates, where the plates exhibited a radial pattern. Room-temperature fracture-toughness tests were conducted using a modified ASTM E-399 technique. The average fracture-toughness values for specimens with planar eutectic and cellular microstructures were about 12 to 15 and 17 MPa\(\sqrt m \), respectively, for both alloys. However, the Ni-33(at. pct)Al-33Cr-1Mo specimens grown at and above 254 mm h−1 exhibited fracture toughness values of about 8 MPa\(\sqrt m \) due to the presence of short (Cr,Mo) plates. The fracture toughness values for the Ni-33(at. pct)Al-31Cr-3Mo alloy were also correlated with quantitative microstructural data in an attempt to identify the relevant elements of the microstructure determining resistance to fracture. A phenomenological fracture model is presented in an attempt to rationalize the present observations.

The cell type specificity of the regulation of expression of the potent growth inhibitory cytokine transforming growth factor-beta (TGF-beta), prompted our analyses of the regulation of TGF-beta1 gene expression in glial cells by viral and cellular oncoproteins. We have shown that SV40 T-antigen diminished TGF-beta1 expression in glial cells and this repression was dependent on the ability of T-antigen to interact with the tumor suppressor protein, pRb, and two structurally related proteins, p107 and p130. The cellular transcription factor E2F-1, which is a downstream effector of T-antigen, was unable to influence expression from the TGF-beta1 promoter by itself. Interestingly, E2F-1 could overcome viral T-antigen-mediated repression of the TGF-beta1 promoter, suggesting potential feedback loop between TGF-beta and E2F in virally transformed glial cells. Using deletion analyses, we have mapped two E2F-1-responsive regions on the TGF-beta1 promoter: a T-antigen-dependent negative regulatory sequence (TdNRS) between -323 and -175, and a T-antigen-independent positive regulatory sequence (TiPRS) between -34 and +10 on the TGF-beta1 promoter. Further examination of TiPRS revealed the presence of a functional E2F binding site. Interestingly, the amino terminus of E2F-1 was required for its activation of TGF-beta1 expression, as mutations in that domain abolished the ability of E2F-1 to increase TGF-beta1 expression. These data suggest that yet-uncharacterized interaction between the amino terminus of E2F-1 and cellular proteins regulates TGF-beta1 expression. The mechanism for E2F-1-mediated T-antigen-dependent regulation of TGF-beta1 expression from TdNRS awaits further characterization.

Extruded NiAl and NiAlZr alloys often show discontinuous yielding on strain aging in compression at room temperature. Two sets of experiments were conducted to understand the reasons for this yield-point behavior. First, strain-aging experiments were carried out on NiAl alloys containing O to 0.1 at. % Zr. The specimens were all deformed in compression at room temperature at a nominal initial strain rate of 1.1 × 10−4S−1, and the effect of annealing at 700 and 1200 K on the stress-strain curves and the yield strength was studied after an initial prestrain. While annealing at 700 and 1200 K consistently reduced the yield strength of both NiAl and NiAlZr, the effects were quite different. In the case of NiAl, annealing at 1200 K did not result in discontinuous yielding, whereas it generally resulted in a sharp yield point for the Zr containing alloys. Second, the PUCOT (piezoelectric ultrasonic composite oscillator technique) was used to measure the dynamic Young modulus, breakaway strain amplitude, and damping for the alloys. Only small differences were observed in the values of Young's modulus, but the breakaway strain was at least a factor of 2 to 3 lower for NiAl than for NiAlZr. The experimentally determined values of damping were used in the Granato-Lücke model to estimate the binding energy for NiAl. While the binding energy values were found to be in agreement with the calculated values of dislocation kink nucleation and migration energies in this material, to within an order of magnitude, other effects, such as dislocation pinning by quenched-in vacancies, cannot be ruled out. The observations made in this study suggest that the yield-point behavior in NiAl may be due to several factors, such as difficulties in double kink nucleation, and single kink migration, as well as dislocation-vacancy interactions; whereas, the yield-point behavior in the Zr-alloyed material is due at least in part to dislocation-solute interaction.

Although a NbAl3 alloy containing Cr, W, and Y has excellent oxidation resistance above 1440 K, it suffers from severe environmental attack during deformation at intermediate temperatures between 900 and 1100 K. Specimens tested in constant velocity and constant load direct compression tests showed varying degrees of degradation depending on environment (i.e., air or argon), surface finish, stress, and temperature. As a result, there were corresponding differences in mechanical behavior and in the observed microstructures. At high stresses and strain rates, specimens with as-machined surfaces were brittle at and below 1100 K when tested in air but showed fracture strains above 4% when deformed in argon. However, reproducible compressive ductility of 2–3% was attained on polished specimens tested in air. At intermediate stresses, the creep curves showed sudden and periodic increases in strain before the specimens failed catastrophically after about 80 h. Microstructural examination of these specimens revealed extensive oxidation within cracks. Constant load tests conducted at lower stresses below 100 MPa showed an apparent incubation period where the change in the length of the specimen was immeasurably small. Following the incubation period, which typically lasted between 10 and 110 h depending on stress, temperature, and surface condition, specimens increased significantly in length due to oxide growth. In this case, considerable oxide spalling occurred during the course of the test, often leading to a substantial decrease in the cross-sectional area of the specimen. Microstructural observations revealed extensive cracking in the oxide layer and in the matrix, where the cracks had originated at the oxide-metal interface. The effects of environment on the mechanical properties are rationalized with the help of a schematic environmental-deformation mechanism map.

A multiphase oxidation resistant composition (Nb–67Al–7Cr–0.5Y–0.25W) based on NbAl3 was prepared by both induction melting and rapid solidification processing (RSP), followed by grinding to 75 μm powder and consolidating by powder metallurgy techniques (hot pressing, hot isostatic pressing, and Ceracon pressing). Constant strain rate compression tests conducted on consolidated materials in the temperature range 300–1300 K indicated that the RSP material exhibited significantly higher strength and ductility than the induction melted alloy up to 1200 K. Bend strengths measured on induction melted material were significantly lower than the corresponding compressive strengths, suggesting the brittle, flaw-sensitive nature of this alloy. The NbAlCrYW alloy exhibits a brittle-to-ductile transition around 1000 K. The constant load creep tests conducted on the induction melted alloy in the 1200–1300 K temperature range indicated that this alloy shows a power law creep dependency with a stress exponent, n, of 3.2. It was found that the specific strength of this alloy is competitive with other aluminide intermetallics.

The fracture behavior of a B2 Ni-30Al-20Fe-0.05Zr (at. pct) alloy was investigated using results of tensile tests conducted in the temperature range 300-1300 K under initial strain rates that varied between 10 exp -6 and 10 exp -3/sec, together with results of deformation measurements reported by Raj et al. (1992). Microstructural observations revealed that the alloy had failed by transgranular cleavage fracture below 873 K and by ductile fracture, power-law cavitation, triple point cracking, and rupture above this temperautre. The fracture map constructed using fracture results is compared with those for other classes of materials, showing that the atomic bonding plays a significant role in the low-temperature ductility of NiAl-based alloys.

The creep properties of single-phase Cu-30% Zn alpha brass were investigated in the intermediate temperature range 573–823 K (0.48–0.70T m, whereT m is the absolute melting point). Inverse, linear, and sigmoidal primary creep transients were usually observed above 573 K under stresses resulting in minimum creep rates between 10−7 and 2×10−4s−1, while normal primary creep occurred under all other conditions. The creep stress exponent decreased from about 5.4 at 573 K to about 4.1 above 623 K, and the activation energy for creep varied between 170 and 180 kJ mol−1. A detailed analysis of the data, as well as a review of the literature, suggests that no clearly defined class M to class A to class M transition exists in this alloy, although the characteristics of both class A and class M behaviour are observed under nominally similar stresses and temperatures. It is concluded that Cu-30% Zn does not conform to the normally accepted characterization of class A or class M solid solution alloys.

The role of grain boundary sliding in copper and Cu-30% Zn in the temperature range 0.50 to 0.72T m, whereT m is the absolute melting point of the material, is examined. First, sliding data obtained on these materials are presented. These results indicate that the stress exponent for sliding,n gbs, is similar to that for lattice deformation, while the activation energy for sliding,Q gbs, varies between about 0·5Q c and 1.6Q c, whereQ c is the activation energy for creep. Next, a comparison of the published values ofQ gbs for bicrystals and polycrystals suggests that grain boundary sliding in polycrystalline materials requires the accommodation of the sliding process, whereas in bicrystals, the absence of triple points and other grain boundaries results in intrinsic sliding. Finally, several models proposed for grain boundary sliding are discussed, and it is shown that they do not account for the observed results on copper and alpha brass. A phenomenological model is proposed, where it is assumed that grain boundary sliding results from the glide of dislocations on secondary slip planes.

Young's and shear moduli and damping were measured for as-cast polycrystalline LiF-(22 mol pct)CaF2 eutectic specimens as a function of temperature using the piezoelectric ultrasonic composite oscillator technique. The shear modulus decreased with increasing temperature from about 40 GPa at 295 K to about 30 GPa at 1000 K, while the Young modulus decreased from about 115 GPa at 295 K to about 35 GPa at 900 K. These values are compared with those derived from the rule of mixtures using elastic moduli data for LiF and CaF2 single crystals. It is shown that, while the shear modulus data agree reasonably well with the predicted trend, there is a large discrepancy between the theoretical calculations and the Young modulus values, where this disagreement increases with increasing temperature.

Nature 523, 313–317 (2015); doi:10.1038/nature14583 In this Article, author Aurelien A. Serandour should have been listed with one middle initial only. This has been corrected in the online versions.

The Ni-33Al-33Cr-1Mo eutectic has been directionally solidified by a modified Bridgeman technique at growth rates ranging from 7.6 to 508 mm/h to produce grain/cellular microstructures containing alternating plates of NiAl and Cr alloyed with Mo. The grains had sharp boundaries for slower growth rates (≤ 12.7 mm/h), while faster growth rates (≥ 25.4 mm/h) lead to cells bounded by intercellular regions. Compressive testing at 1300 K indicated that alloys DS'ed at rates between 25.4 to 254 mm/h possessed the best strengths which exceed that for the as-cast alloy.

A statistical design of experiments (DOE) strategy was implemented to optimize alloys based on the Ni-33AI-31Cr-3Mo eutectic system using small amounts of potential strengthening elements (Hf, Si, Ta, Ti). Following the analysis of the DOE results, several alloys were selected for directionally solidification (DS) utilizing a modified Bridgeman technique. The as-grown alloys were microstructurally examined by optical and scanning electron microscopy. They were also evaluated for fracture toughness at room temperature and compressive properties at 1300K. The microstructures and mechanical properties of these DS DOE alloys are discussed and compared to the directionally solidified Ni–33Al–3lCr–3Mo base composition.

Experimental measurements of the apparent activation volume for creep, V-asterisk, of Cu and Cu-30 pct Zn conducted at intermediate temperatures showed two types of strain dependencies. At the lower temperatures and higher stresses, V-asterisk decreased with increasing creep strain, while at higher temperatures and lower stresses, V-asterisk was essentially independent of strain. The low temperature-high stress behavior for Cu and Cu-30 pct Zn was found to be consistent with the dominance of a dislocation intersection mechanism. The high temperature-low stress data for the pure metals suggest that the rate-controlling process involves the nonconservative motion of jogs on screw dislocations. For the latter conditions, an additional contribution from solute drag-limited dislocation glide also appears to be important in governing the creep behavior of the alloy.

Etude experimentale dans l'alliage Cu-30,5% Zn, predeforme puis soumis a des essais de fluage a 773 K. La vitesse de fluage a l'etat stable est plus basse pour un degre de predeformation de 10%. Une predeformation superieure a 10% conduit a une augmentation de la vitesse de fluage qui atteint une valeur constante avec un degre de predeformation egal a 15%. Explication des resultats par la variation de la contrainte interne due aux differentes microstructures