Volumetric hyperthermia delivery using the ExAblate Body MR-guided focused ultrasound system.

OBJECTIVES: To investigate image-guided volumetric hyperthermia strategies using the ExAblate Body MR-guided focused ultrasound ablation system, involving mechanical transducer movement and sector-vortex beamforming. MATERIALS AND METHODS: Acoustic and thermal simulations were performed to investigate volumetric hyperthermia using mechanical transducer movement combined with sector-vortex beamforming, specifically for the ExAblate Body transducer. The system control in the ExAblate Body system was modified to achieve fast transducer movement and MR thermometry-based hyperthermia control, mechanical transducer movements and electronic sector-vortex beamforming were combined to optimize hyperthermia delivery. The experimental validation was performed using a tissue-mimicking phantom. RESULTS: The developed simulation framework allowed for a parametric study with varying numbers of heating spots, sonication durations, and transducer movement times to evaluate the hyperthermia characteristics for mechanical transducer movement and sector-vortex beamforming. Hyperthermic patterns involving 2-4 sequential focal spots were analyzed. To demonstrate the feasibility of volumetric hyperthermia in the system, a tissue-mimicking phantom was sonicated with two distinct spots through mechanical transducer movement and sector-vortex beamforming. During hyperthermia, the average values of Tmax, T10, Tavg, T90, and Tmin over 200 s were measured within a circular ROI with a diameter of 10 pixels. These values were found to be 8.6, 7.9, 6.6, 5.2, and 4.5 °C, respectively, compared to the baseline temperature. CONCLUSIONS: This study demonstrated the volumetric hyperthermia capabilities of the ExAblate Body system. The simulation framework developed in this study allowed for the evaluation of hyperthermia characteristics that could be implemented with the ExAblate MRgFUS system.

Segmentation-Based Fusion of CT and MR Images.

In this paper, a segmentation-based image fusion method is proposed for the fusion of MR and CT images to obtain a high contrast fused image that contains complementary information from both input images. The proposed method uses the fuzzy C-mean method to extract information about the skull from the CT image. This skull information is used to extract soft tissue information from the MR image. Both the skull information and the soft tissue information are then fused using the fusion rule. The efficiency of the proposed method over other state-of-the-art fusion methods is analyzed and compared using qualitative and quantitative analysis methods. Qualitative analysis shows the improvement in the contrast between the bone and the soft tissue using the proposed method over other state-of-the-art methods without introducing any artifacts or distortions. Classical and gradient-based quantitative analysis also show significant improvement in the fused image obtained using the proposed method over the five state-of-the-art methods. The percentage improvement in the standard deviation, average gradient, entropy, spatial frequency, QABF, and LABF of the proposed method over the best value obtained by the five state-of-the-art methods is 27.11%, 12.06%, 23.64%, 11.30%, 5.59%, and 13.70% respectively.

Stereotactic biopsy for brain lesions: Doing more with less.

Objectives: Stereotactic biopsy (STB) is a potential diagnostic tool considering its minimal invasiveness, high diagnostic yield, and minimal associated complications. Over the years, various frame-based instrument systems and frameless stereotactic biopsy systems have emerged to be employed in clinical use. With this study, we intend to get more by doing less in the form of STB for the patients of doubtful intracranial lesions treated over the past 5 years. We also want to highlight the technique of performing the procedure under scalp block, which can be used as a versatile tool in many clinical scenarios. Stereotactic biopsies may be planned even in rural district-level health facilities. One-time investment to procure instruments and avail existing imaging can lead to establishing definitive diagnoses in many doubtful cases. This will result in lesser cost and early establishment of treatment. Independent risk factors determining the outcome, such as deep-seated lesions, associated edema, and intraoperative hypertension, were studied. Establishing the diagnosis helped in prognosticating the disease, explaining the natural progression of symptoms, and starting adjuvant therapy. This tissue biopsy would also help secure samples for research and molecular analysis. Materials and Methods: Twenty patients underwent STBs at our institution between January 2018 and December 2022. We retrospectively analyzed patient characteristics, tumor pathology, surgical procedures, and outcomes, including the diagnostic value and surgery-related complications. These patients were followed up, and their progression-free and overall survival were analyzed. The need for adjuvant treatment was noted and analyzed. All procedures were performed using Cosman Roberts Wells® stereotactic frame. Pre-procedure magnetic resonance scans were performed at the time of admission. Contrast-enhanced computerized tomography (CT) scan after frame application was performed to identify targets and calculate the coordinates. A post-procedure CT scan was done to confirm the accessibility of the targeted lesion. Results: The most common location of the tumor was a deep-seated thalamic lesion. A definitive diagnosis was established in 19 patients (95%) at the first STB. The diagnoses were glioma in 55% of cases, primary central nervous system lymphoma, tuberculosis, and demyelinating disorders in 10% of each, and a metastatic brain tumor in 1 (5%). The post-operative complications were all transient except in one patient with deterioration of motor weakness. The follow-up was noted, and modes of adjuvant treatment needed in these patients were recorded. Conclusion: Stereotactic biopsy is a useful and effective method for achieving a definitive diagnosis and aiding in treating multifocal or small deep-seated lesions in or around eloquent regions.

Development of pathophysiologically relevant models of sickle cell disease and ß-thalassemia for therapeutic studies.

Ex vivo cellular system that accurately replicates sickle cell disease and ß-thalassemia characteristics is a highly sought-after goal in the field of erythroid biology. In this study, we present the generation of erythroid progenitor lines with sickle cell disease and ß-thalassemia mutation using CRISPR/Cas9. The disease cellular models exhibit similar differentiation profiles, globin expression and proteome dynamics as patient-derived hematopoietic stem/progenitor cells. Additionally, these cellular models recapitulate pathological conditions associated with both the diseases. Hydroxyurea and pomalidomide treatment enhanced fetal hemoglobin levels. Notably, we introduce a therapeutic strategy for the above diseases by recapitulating the HPFH3 genotype, which reactivates fetal hemoglobin levels and rescues the disease phenotypes, thus making these lines a valuable platform for studying and developing new therapeutic strategies. Altogether, we demonstrate our disease cellular systems are physiologically relevant and could prove to be indispensable tools for disease modeling, drug screenings and cell and gene therapy-based applications.

Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches.

Sickle cell disease (SCD) is an autosomal recessive genetic disorder affecting millions of people worldwide. A reversible and selective DNMT1 inhibitor, GSK3482364, has been known to decrease the overall methylation activity of DNMT1, resulting in the increase of HbF levels and percentage of HbF-expressing erythrocytes in an in vitro and in vivo model. In this study, a structure-based virtual screening was done with GSK3685032, a co-crystalized ligand of DNMT1 (PDB ID: 6X9K) with an IC50 value of 0.036 µM and identified 3988 compounds from three databases (ChEMBL, PubChem and Drug Bank). Using this screening method, we identified around 15 compounds with XP docking scores greater than -8 kcal/mol. Further, prime MM-GBSA calculations have been performed and found compound SCHEMBL19716714 with the highest binding free energy of -83.31 kcal/mol. Finally, four compounds were identified based on glide energy and ΔG bind scores that have the most binding with DG7, DG19, DG20 bases and Lys1535, His1507, Trp1510, Ser1230, which were required for the target enzyme inhibition. Furthermore, molecular dynamics simulation studies of top ligands validate the stability of the docked complexes by examining root mean square deviations, root mean square fluctuations, solvent accessible surface area, and radius of gyration graphs from simulation trajectories. These findings suggest that the top four hit compounds may be capable of inhibiting DNMT1 and that additional in vitro and in vivo studies will be essential to prove the clinical effectiveness of the selected lead compounds.Communicated by Ramaswamy H. Sarma.

Scalable noninvasive amplicon-based precision sequencing (SNAPseq) for genetic diagnosis and screening of ß-thalassemia and sickle cell disease using a next-generation sequencing platform.

ß-hemoglobinopathies such as ß-thalassemia (BT) and Sickle cell disease (SCD) are inherited monogenic blood disorders with significant global burden. Hence, early and affordable diagnosis can alleviate morbidity and reduce mortality given the lack of effective cure. Currently, Sanger sequencing is considered to be the gold standard genetic test for BT and SCD, but it has a very low throughput requiring multiple amplicons and more sequencing reactions to cover the entire HBB gene. To address this, we have demonstrated an extraction-free single amplicon-based approach for screening the entire ß-globin gene with clinical samples using Scalable noninvasive amplicon-based precision sequencing (SNAPseq) assay catalyzing with next-generation sequencing (NGS). We optimized the assay using noninvasive buccal swab samples and simple finger prick blood for direct amplification with crude lysates. SNAPseq demonstrates high sensitivity and specificity, having a 100% agreement with Sanger sequencing. Furthermore, to facilitate seamless reporting, we have created a much simpler automated pipeline with comprehensive resources for pathogenic mutations in BT and SCD through data integration after systematic classification of variants according to ACMG and AMP guidelines. To the best of our knowledge, this is the first report of the NGS-based high throughput SNAPseq approach for the detection of both BT and SCD in a single assay with high sensitivity in an automated pipeline.

Hilling as a cultural control strategy for soybean gall midge (Diptera: Cecidomyiidae).

Soybean gall midge, Resseliella maxima Gagné, was recently identified as a new species causing significant injury to soybean and is currently found in 164 counties across 7 midwestern states (NE, IA, SD, MN, MO, ND, and KS). Infestation of soybean begins in late spring, when adults emerge from last year's soybean field. Infestation of a new soybean crop depends on the presence of fissures which start to form at the base of the soybean plant around the V2 stage. Field observations indicate that these fissures are only present below the cotyledonary nodes or in the area within 3-5 cm above the soil surface. To determine the importance of these fissures for R. maxima infestation and plant injury, hilling or the movement of the soil to cover the base of soybean plants at the V2-V3 stage was compared with the standard practice (no-hilling). Field studies were conducted at 3 sites in east-central Nebraska during the 2021 growing season. The results showed a significant reduction in the frequency of infested plants, larval number per plant, and plant injury for hilled compared to no-hill treatment. This reduction in the presence of larvae and plant injury corresponded with a significantly greater yield for hilled compared to the no-hill treatment. These results highlight the importance of fissures on soybean for R. maxima adult infestation as well as the potential for hilling to be used as a management strategy for R. maxima.

Evaluation of the Role of Preoperative Oral Amisulpride as Part of a Multimodal Antiemetic Prophylaxis Regime on Postoperative Nausea and Vomiting in Patients Undergoing Craniotomy: A Prospective, Double-Blind, Randomized, Placebo-controlled Study.

BACKGROUND: Patients undergoing craniotomy are at high risk for postoperative nausea and vomiting (PONV) despite the use of prophylactic antiemetics. We hypothesized that a single preoperative oral dose of amisulpride as part of a multimodal antiemetic regimen would decrease the incidence of PONV in patients undergoing craniotomy for intracranial tumor surgery. METHODS: Adult patients scheduled for elective craniotomy requiring general anesthesia were enrolled and randomized to receive either oral amisulpride 25 mg or placebo 2 hours before surgery in addition to our institution's usual antiemetic regimen. The primary outcome of the study was the incidence of nausea and/or vomiting during the first 24 hours postoperatively. Secondary outcomes included severity of nausea, use of rescue antiemetic medications, and treatment-related adverse events. RESULTS: A total of 100 patients were included in the analysis. More patients in the amisulpride group had no episodes of nausea (90% vs. 40%; P<0.001) and no episodes of vomiting (94% vs. 46%; P<0.001) compared with the placebo group. The severity of nausea was lower in the amisulpride group than in the control group in the first 4 hours after surgery (P<0.05), and fewer patients receiving amisulpride required rescue antiemetics (P<0.001). The incidence of treatment-related adverse events was similar between groups. CONCLUSIONS: A single preoperative oral dose of amisulpride 25 mg as a component of a multimodal antiemetic regimen decreased the incidence and severity of PONV in patients undergoing craniotomy for intracranial tumor surgery, with no adverse effects.

Fermentation of biodiesel-derived crude glycerol to 1,3-propanediol with bio-wastes as support matrices: Polynomial prediction model.

Biodiesel production from used cooking oil is sustainable alternative, for bio-energy production. The process generates residual crude glycerol (RCG) as the major energy-rich waste which can be used to produce various bio-based chemicals like 1,3-propanediol (1,3-PDO) through biotechnological interventions. This RCG contains several impurities like methanol, soap, organic materials, salts non-transesterified fatty acids and metals in varied concentrations. These impurities significantly affect yield and productivity of the bio-process due to their marked microbial toxicity. In this work, previously isolated Clostridium butyricum L4 was immobilized on various abundantly available cheap bio-wastes (like rice straw, activated carbon and corn cob) to explore advantages offered and improve tolerance to various feed impurities. Amongst these, shredded rice straw was found most suitable candidate for immobilization and results in maximum improvement in 1,3-PDO production (18.4%) with highest porosity (89.28%), lowest bulk density (194.48Kg/m3), and highest cellular biofilm density (CFU/g-8.4 ×1010) amongst the three matrices. For practical purposes, recyclability was evaluated and it was concluded that even after reusing for five successive cycles the production retained to ∼82.4%. Subsequently, polynomial model was developed using 30 runs central composite factorial design experiments having coefficient of regression (R²) as 0.9520, in order to predict yields under different immobilization conditions for 1,3-PDO production. Plackett-Burman was employed (Accuracy= 99.17%) to screen significant toxic impurities. Based on statistical analysis six impurities were found to be significantly influential on PDO production in adverse manner. With negative coefficient of estimate (COE) varying in decreasing order: Linoleic acid >Oleic acid >Stearic acid >NaCl>K2SO4 >KCl. The study illustrates practical application for repurposing waste glycerol generated from biodiesel plants, thus developing improved agnostic process along with yield production models.

Exploration of low field magnetic states in Nd1-xCexCrO3.

We report the structural and magnetic properties of Nd1-xCexCrO3(x=0.05-0.175) single-phase samples to classify the influence of Ce substitution on the Nd-site. The electron density profile indicates the possible covalent nature of Cr-O bonds. The x-ray photoelectron spectroscopy confirms a mixed Ce valency with a constant ratio of Ce3+/Ce4+ions in all substituted compounds and the charge neutralization through the oxygen vacancies. The magnetization measurements reveal an increase in antiferromagnetic ordering temperature (TN) and spin-reorientation transition temperature (TSR) and unfold soft spin-reorientation attributed to diluted superexchange interactions upon Ce incorporation. The presence of mixed Ce ions induces the merging of the hysteresis loop with a significant exchange bias (EB) field. We demonstrate for the first time that the magnitude of the magnetization is different for the same applied field in positive and negative directions, indicating the existence of two different magnetic states. The difference between these two magnetic states possibly arises from the pinning of Cr3+spins, which requires an additional Zeeman energy for it to rotate. This maximum Zeeman energy from the normalized magnetic susceptibility vs. temperature curves correlates with the maximum EB field, validating unusual EB in these compounds.

Surfactant Assisted In Situ Synthesis of Nanofibrillated Cellulose/Polymethylsilsesquioxane Aerogel for Tuning Its Thermal Performance.

Nanofibrillated cellulose (NFC) and polymethylsilsesquioxane (PMSQ) based aerogel are prepared by the sol-gel method. The objective of this work is to study the impact of surfactant and base catalyst on the thermal and mechanical performance of the corresponding aerogel. The rheological premonitory assists in predicting the bulk properties of the aerogel. The chemical structure of the aerogel is studied by Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and solid-state nuclear magnetic resonance (NMR). X-ray microtomographic (XMT) analysis confirms the homogeneous and monolithic structure of the aerogel. The lowest thermal conductivity is achieved as 23.21 mW m-1 K-1 with V-0 and HBF rating through UL-94 test. Thermal performance of aerogels is cross-verified through modeling and simulation in COMSOL multiphysics platform. The mechanical properties of aerogel are evaluated by monolithic compression test in axial and radial compression test up to 90% strain, cyclic compression loading-unloading, and reloading test, flexural test, and dynamic mechanical analysis. The time-temperature analysis has shown around 5 °C temperature difference in the middle of the room after using the aerogel panel at the exposed surface, which assists in the practical application of the synthesized aerogel panel.

A cross talk based critical analysis of solvent free microwave extraction to accentuate it as the new normal for extraction of essential oil: an attempt to overhaul the science of distillation through a comprehensive tutelage.

Microwave-assisted extraction (MAE) is a sustainable non-contact heating source and has been extensively researched for extraction of plant bioactives. There are various derivatives or modules available for MAE and solvent free microwave extraction (SFME) is one of them where by operational aspects of MAE have been maneuvered to make it compatible for extraction of essential oil (EO). This article makes an attempt to overhaul the science of distillation by revisiting SFME and trying to learn through a comprehensive tutelage comprising of 20 years of published literature in Web of Science so that a shrewd decision can be obtained through a cross talk based critical analysis on the science SFME. A total of 312 articles within the time frame of 2001-2020 were extracted from WOS and critically analyzed. Considering the various uncertainties involved with SFME the articles establishes some global working standards and tries to explore the dynamic relationship between plant part/genus and microwave power, microwave power and time, microwave power and extracted volatile principles, prioritizes plant family selection and also presents a research blueprint of SFME. A techno-commercial feasibility study has been presented for smooth industrial transition of SFME. The tutelage presented decodes the publication trends and SFME blueprint.

A Simple, Cost-Effective, and Extraction-Free Molecular Diagnostic Test for Sickle Cell Disease Using a Noninvasive Buccal Swab Specimen for a Limited-Resource Setting.

Sickle cell disease (SCD) is the most prevalent life-threatening blood monogenic disorder. Currently, there is no cure available, apart from bone marrow transplantation. Early and efficient diagnosis of SCD is key to disease management, which would make considerable strides in alleviating morbidity and reducing mortality. However, the cost and complexity of diagnostic procedures, such as the Sanger sequencing method, impede the early detection of SCD in a resource-limited setting. To address this, the current study demonstrates a simple and efficient proof-of-concept assay for the detection of patients and carriers using extraction-free non-invasive buccal swab samples by isothermal DNA Amplification coupled Restrictase-mediated cleavage (iDAR). This study is a first of its kind reporting the use of buccal swab specimens for iDA in molecular diagnosis of a genetic disease, all the while being cost effective and time saving, with the total assay time of around 150 min at a cost of USD 5. Further, iDAR demonstrates 91.5% sensitivity and 100% specificity for detecting all three alleles: SS, AS, and AA, having a 100% concordance with Sanger sequencing. The applicability of the iDAR assay is further demonstrated with its adaptation to a one-pot reaction format, which simplifies the assay system. Overall, iDAR is a simple, cost-effective, precise, and non-invasive assay for SCD screening, with the potential for use in a limited resource setting.

Development of an efficient single-cell cloning and expansion strategy for genome edited induced pluripotent stem cells.

BACKGROUND: Disease-specific human induced pluripotent stem cells (hiPSCs) can be generated directly from individuals with known disease characteristics or alternatively be modified using genome editing approaches to introduce disease causing genetic mutations to study the biological response of those mutations. The genome editing procedure in hiPSCs is still inefficient, particularly when it comes to homology directed repair (HDR) of genetic mutations or targeted transgene insertion in the genome and single cell cloning of edited cells. In addition, genome editing processes also involve additional cellular stresses such as poor cell viability and genetic stability of hiPSCs. Therefore, efficient workflows are desired to increase genome editing application to hiPSC disease models and therapeutic applications. METHODS AND RESULTS: To this end, we demonstrate an efficient workflow for feeder-free single cell clone generation and expansion in both CRISPR-mediated knock-out (KO) and knock-in (KI) hiPSC lines. Using StemFlex medium and CloneR supplement in conjunction with Matrigel cell culture matrix, we show that cell viability and expansion during single-cell cloning in edited and unedited cells is significantly enhanced. Keeping all factors into account, we have successfully achieved hiPSC single-cell survival and cloning in both edited and unedited cells with rates as maximum as 70% in less than 2 weeks. CONCLUSION: This simplified and efficient workflow will allow for a new level of sophistication in generating hiPSC-based disease models to promote rapid advancement in basic research and also the development of novel cellular therapeutics.

Fermentative reforming of crude glycerol to 1,3-propanediol using Clostridium butyricum strain L4.

Repurposed used cooking oil is a sustainable alternative to other feedstocks for biodiesel production offering enviro-economic benefits. Residual crude glycerol (RCG) from such biodiesel production plants is difficult to utilize due to presence of numerous toxic impurities with various inhibitory effects on biological fermentative reforming process. However, it is a new industrial feedstock for bio-based production of 1,3-propanediol. In this work, a new Clostridium butyricum strain L4 was isolated from biogas reactor leachate after rigorous adaption and 35 subcultures under increasing stress conditions and studied for green production of 1,3-propanediol (PDO) from RCG and further process development. Evaluation of fermentative reforming kinetics was performed and the optimal reaction conditions are pH 7.0, temperature 30 °C, 2 g yeast extract/L and 15 g ammonium sulphate/L. Glycerol-glucose co-fermentation (10:1) enhanced cell growth and thus, PDO output by 11.6 g/L. In comparison to batch fermentation (24.8 g PDO/L; 0.58 mol PDO/mol glycerol) there was 2.8-fold improvement with fed-batch process resulting in accumulation of 70.1 g PDO/L (Yield = 0.65 mol PDO/mol glycerol) using the studied biocatalyst in 150 h. In order to predict yields under different operational conditions a multiple linear regression model was developed (r2 = 0.783) with six independent variables (p < 0.05), where biomass (g/L) and temperature (oC) were forecasted as top contributors to PDO yield. Finally, this biocatalyst appears as a potential candidate for industrial use due to its non-pathogenic nature, ability to grow in wide pH and temperature conditions, tolerance to high substrate and product concentration, insignificant generation of by-products and Coenzyme B12 independent biotransformation. The study can add value to bio-utilization of RCG to produce green 1,3-propanediol.

Methods to measure calcitonin receptor activity, up-regulated in cell stress, apoptosis and autophagy.

The expression of the calcitonin receptor (CT Receptor) is widespread throughout the life cycle of mammals and in many diseases, and in these contexts the functions of the common isoforms is largely unknown. The relatively recent development of anti-CT Receptor antibodies that bind separate epitopes on the CT a Receptor and CT b Receptor isoforms has advanced our knowledge and understanding of these events. CT Receptor at the protein level is upregulated in programmed cell death including apoptosis (as described in a previous publication) and autophagy, which is discussed in our upcoming, unpublished review. Incomplete data sets are cited in this review on the upregulation of CACLR (encoding CT Receptor) mRNA, in particular the insert-positive isoform (CT b Receptor), in response to cell stress. Cell stress is induced by growth in depleted foetal bovine serum (dFBS) or without FBS, both of which induce degrees of starvation and autophagy, or dFBS plus staurosporine, which induces apoptosis. Details of the methods deployed to generate these data are described here including measurement of the upregulation of CT b Receptor mRNA with qPCR and nanopore long range sequencing. An anti-CT Receptor antibody also known as CalRexin TM, which binds an epitope in the N-terminal domain, was conjugated to either fluorophore 568, which is accumulated into apoptotic cells as previously reported, or pHrodo Red, a pH dependent fluorescent dye, which is accumulated into autophagic and apoptotic cells.  These conjugates are under development to image programmed cell death. The methods for conjugation and high content imaging on the Operetta platform are described. The high fluorescence intensity at low pH of CalRexin:pHrodo Red in both autophagic and apoptotic cells suggests localisation in autophago-lysosomes and lysosomes respectively. Overall, these observations and the methods that underpin them have contributed to our understanding of the widespread expression of CT Receptor isoforms.

Strategic Development of an Immunotoxin for the Treatment of Glioblastoma and Other Tumours Expressing the Calcitonin Receptor.

New strategies aimed at treatment of glioblastoma are frequently proposed to overcome poor prognosis. Recently, research has focused on glioma stem cells (GSCs), some quiescent, which drive expansion of glioblastoma and provide the complexity and heterogeneity of the tumour hierarchy. Targeting quiescent GSCs is beyond the capability of conventional drugs such as temozolomide. Here, we discuss the proposal that the calcitonin receptor (CT Receptor), expressed in 76-86% of patient biopsies, is expressed by both malignant glioma cells and GSCs. Forty-two percent (42%) of high-grade glioma (HGG; representative of GSCs) cell lines available from one source express CT Receptor protein in cell culture. The pharmacological calcitonin (CT)-response profiles of four of the HGG cell lines were reported, suggesting mutational/splicing inactivation. Alternative splicing, commonly associated with cancer cells, could result in the predominant expression of the insert-positive isoform and explain the atypical pharmacology exhibited by CT non-responders. A role for the CT Receptor as a putative tumour suppressor and/or oncoprotein is discussed. Both CT responders and non-responders were sensitive to immunotoxins based on an anti-CT Receptor antibody conjugated to ribosomal-inactivating proteins. Sensitivity was increased by several logs with the triterpene glycoside SO1861, an endosomal escape enhancer. Under these conditions, the immunotoxins were 250-300 times more potent than an equivalent antibody conjugated with monomethyl auristatin E. Further refinements for improving the penetration of solid tumours are discussed. With this knowledge, a potential strategy for effective targeting of CSCs expressing this receptor is proposed for the treatment of GBM.

Spin induced exchange bias and lattice modulation in Nd1-x Eu x CrO3.

We report the evolution of coupled phonons and exchange bias (EB) in perovskite-type Nd1-x Eu x CrO3 (x = 0.0, 0.05, and 0.10) samples by means of temperature-dependent Raman spectroscopy and dc magnetization measurements. We observed a non-monotonic behavior of the EB field around the temperature T *, which lies between the antiferromagnetic ordering temperature (T N) and spin-reorientation transition temperature (T SR). The temperature dependence of phonon modes related to antistretching and bending of CrO6 octahedra and Nd3+/Eu3+ ion vibration below T N confirms the strong spin-phonon coupling. The T * found from the non-monotonicity of the EB is imprinted with the additional anomaly observed in the low-temperature spin-phonon behavior. The phonon modes and phonon anomaly are also verified using the density functional theory-based calculations.