Mechanical properties of wax-oleogels: Assessing their potential to mimic commercial margarine functionality under small and large deformations.

Utilizing waxes to gel oils presents a viable approach for diminishing trans and saturated fat levels in commercial fats such as margarines. This technique ensures that oleogels mimic traditional fats in terms of rheological properties, oil-binding capacity, and overall structure. Our study employed cooling-shear rates to finely adjust physical characteristics, evaluating rheology via SAOS-LAOS, oil retention, and crystal structure of wax oleogels, compared against commercial margarines as benchmarks. Findings indicate that wax oleogels, under specific cooling/shear conditions, exhibit softer yet more ductile-like behavior, akin to margarine, while retaining oil effectively. This similarity is evidenced through Lissajous curves and plastic dissipation ratio during yielding, reflecting a ductile yielding response characterized by square-like Lissajous curves and a plastic dissipation ratio index approximating one. Although these crystallization conditions influence the mechanical properties of wax oleogels, they do not alter oil losses or wax characteristics.

Effect of stress-based interventions on the quality of life of people with an intellectual disability and their caregivers.

PURPOSE: People with intellectual disabilities often show challenging behaviour, which can manifest itself in self-harm or aggression towards others. Real-time monitoring of stress in clients with challenging behaviour can help caregivers to promptly deploy interventions to prevent escalations, ultimately to improve the quality of life of client and caregiver. This study aimed to assess the impact of real-time stress monitoring with HUME, and the subsequent interventions deployed by the care team, on stress levels and quality of life. MATERIALS AND METHODS: Real-time stress monitoring was used in 41 clients with intellectual disabilities in a long-term care setting over a period of six months. Stress levels were determined at the start and during the deployment of the stress monitoring system. The quality of life of the client and caregiver was measured with the Outcome Rating Scale at the start and at three months of use. RESULTS: The results showed that the HUME-based interventions resulted in a stress reduction. The perceived quality of life was higher after three months for both the clients and caregivers. Furthermore, interventions to provide proximity were found to be most effective in reducing stress and increasing the client's quality of life. CONCLUSIONS: The study demonstrates that real-time stress monitoring with the HUME and the following interventions were effective. There was less stress in clients with an intellectual disability and an increase in the perceived quality of life. Future larger and randomized controlled studies are needed to confirm these findings.

Assistive technology such as real-time stress monitoring enables caregivers to timely intervene and contributes to the reduction of challenging behaviour.Real-time stress monitoring contributes to the quality of life of clients and caregivers in healthcare.There is a reduction in the levels of stress of people with an intellectual disability by using stress-monitoring technology.

Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.

Tackling the tumor microenvironment - how can complex tumor models in vitro aid oncology drug development?

INTRODUCTION: Identifying effective cancer drugs remains an inefficient process. Drug efficacy in traditional preclinical cancer models translates poorly into therapy in the clinic. Implementation of preclinical models that incorporate the tumor microenvironment (TME) is needed to improve selection of active drugs prior to clinical trials. AREAS COVERED: Progression of cancer results from the behavior of cancer cells in concert with the host's histopathological background. Nonetheless, complex preclinical models with a relevant microenvironment have yet to become an integral part of drug development. This review discusses existing models and provides a synopsis of active areas of cancer drug development where implementation would be of value. Their contribution to finding therapeutics in immune oncology, angiogenesis, regulated cell death and targeting tumor fibroblasts as well as optimization of drug delivery, combination therapy, and biomarkers of efficacy is considered. EXPERT OPINION: Complex tumor models in vitro (CTMIVs) that mimic the organotypic architecture of neoplastic tumors have boosted research into TME influence on traditional cytoreductive chemotherapy as well as the detection of specific TME targets. Despite advances in technical prowess, CTMIVs can only address specific aspects of cancer pathophysiology.

Hazard Detection During Simulated Driving in Glaucoma Patients.

PRCIS: In this cross-sectional study, glaucoma patients showed slower reaction times (RTs) to hazardous situations when compared with control subjects during simulated driving. Worse RTs were associated with a greater magnitude of visual field loss. PURPOSE: The purpose of this study was to evaluate the impact of different hazardous traffic conditions on driving performance in glaucoma patients using a high-fidelity driving simulator. METHODS: The cross-sectional study was performed with 52 glaucoma patients and 15 control subjects. A series of hazard scenarios were presented, such as pedestrians crossing the street unexpectedly or vehicles suddenly pulling into the driver's lane. RTs in seconds (s) from first the evidence of a hazard to the time it took the driver to take the foot off the gas pedal ("Gas Off") and the time it took to depress the brake pedal ("Brake On") were compared between groups. RESULTS: Overall, mean RTs were statistically significantly slower in glaucoma patients (3.39±3.88 s) compared with controls (2.39±1.99 s; P =0.005) for the "Brake On" task but not for the "Gas Off" task (2.74±3.42 vs. 2.13±1.91 s, respectively; P =0.120). For subjects with glaucoma, multivariable models adjusted for age, gender, race, and visual acuity demonstrated significantly slower RTs for worse values of binocular mean sensitivity for both "Gas Off" and "Brake On" tasks (1.12 and 1.14 s slower per 10 dB worse; P =0.009 and P <0.001, respectively). Subjects with glaucoma took significantly longer times to brake for smaller (low saliency) hazards compared with larger (high saliency) hazards ( P =0.027). CONCLUSIONS: RTs in response to hazardous driving situations were slower for glaucoma patients compared with controls. Individualized assessment of driving fitness using hazardous scenarios in driving simulators could be helpful in providing an assessment of driving risk in glaucoma patients.

Comparative study of cranial measurements between sexes from Brazil and The Netherlands: A cone-beam computed tomography study.

The objective of this study was to better understand human variation by comparing cone-beam computed tomography-based cranial measurements between both sexes of individuals from two distinct populations: Brazilian and Dutch. Cone-beam computed tomography volumes of 311 patients between 20 and 60 years from Brazil and The Netherlands were selected. Two radiologists performed 16 linear measurements in the maxillary sinuses and mandibular canal. Kruskall-Wallis test compared measurements of the two cranial structures between male and female for the two populations and four age ranges (20-30, 31-40, 41-50, 51-60). Mann-Whitney test compared individual measurements obtained from the cranial structures between male and female for each population, and between both populations for both sexes. Intra- and inter-observer reliability was assessed by intraclass correlation test (α = 0.05). No significant differences were found in the linear measurements among the experimental groups including sex, population and age group for both cranial structures (p > 0.05). Most of the cranial linear measurements were significantly higher for male than those for female irrespective of the population (p ≤ 0.05). When the populations were compared regardless of sex, Brazilians presented four significantly higher measurements, and Dutch presented seven significantly higher measurements (p ≤ 0.05). The assessed cranial structures did not differ between Brazilian and Dutch populations for both sexes and four age ranges. Multiple linear measurements differed between both populations with a predominance of larger dimensions for the Dutch population.

Chronic morphine induces adaptations in opioid receptor signaling in a thalamo-cortico-striatal circuit that are projection-dependent, sex-specific and regulated by mu opioid receptor phosphorylation.

Chronic opioid exposure induces tolerance to the pain-relieving effects of opioids but sensitization to some other effects. While the occurrence of these adaptations is well-understood, the underlying cellular mechanisms are less clear. This study aimed to determine how chronic treatment with morphine, a prototypical opioid agonist, induced adaptations to subsequent morphine signaling in different subcellular contexts. Opioids acutely inhibit glutamatergic transmission from medial thalamic (MThal) inputs to the dorsomedial striatum (DMS) and anterior cingulate cortex (ACC) via activity at µ-opioid receptors (MORs). MORs are present in somatic and presynaptic compartments of MThal neurons terminating in both the DMS and ACC. We investigated the effects of chronic morphine treatment on subsequent morphine signaling at MThal-DMS synapses, MThal-ACC synapses, and MThal cell bodies in male and female mice. Surprisingly, chronic morphine treatment increased subsequent morphine inhibition of MThal-DMS synaptic transmission (morphine facilitation), but decreased subsequent morphine inhibition of transmission at MThal-ACC synapses (morphine tolerance) in a sex-specific manner; these adaptations were present in male but not female mice. Additionally, these adaptations were not observed in knockin mice expressing phosphorylation-deficient MORs, suggesting a role of MOR phosphorylation in mediating both facilitation and tolerance to morphine within this circuit. The results of this study suggest that the effects of chronic morphine exposure are not ubiquitous; rather adaptations in MOR function may be determined by multiple factors such as subcellular receptor distribution, influence of local circuitry and sex.

Assessment of Audio-Tactile Sensory Substitution Training in Participants with Profound Deafness Using the Event-Related Potential Technique.

This paper examines the application of electroencephalogram-based methods to assess the effects of audio-tactile substitution training in young, profoundly deaf (PD) participants, with the aim of analyzing the neural mechanisms associated with vibrotactile complex sound discrimination. Electrical brain activity reflects dynamic neural changes, and the temporal precision of event-related potentials (ERPs) has proven to be key in studying time-locked processes while performing behavioral tasks that involve attention and working memory. The current protocol was designed to study electrophysiological activity in PD subjects while they performed a continuous performance task (CPT) using complex-sound stimuli, consisting of five different animal sounds delivered through a portable stimulator system worn on the right index finger. As a repeated-measures design, electroencephalogram (EEG) recordings in standard conditions were performed before and after a brief training program (five 1 h sessions over 15 days), followed by offline artifact correction and epoch averaging, to obtain individual and grand-mean waveforms. Behavioral results show a significant improvement in discrimination and a more robust P3-like centroparietal positive waveform for the target stimuli after training. In this protocol, ERPs contribute to the further understanding of learning-related neural changes in PD subjects associated with audio-tactile discrimination of complex sounds.

Exploring Metabolic Signatures of Ex Vivo Tumor Tissue Cultures for Prediction of Chemosensitivity in Ovarian Cancer.

Predicting patient response to treatment and the onset of chemoresistance are still major challenges in oncology. Chemoresistance is deeply influenced by the complex cellular interactions occurring within the tumor microenvironment (TME), including metabolic crosstalk. We have previously shown that ex vivo tumor tissue cultures derived from ovarian carcinoma (OvC) resections retain the TME components for at least four weeks of culture and implemented assays for assessment of drug response. Here, we explored ex vivo patient-derived tumor tissue cultures to uncover metabolic signatures of chemosensitivity and/or resistance. Tissue cultures derived from nine OvC cases were challenged with carboplatin and paclitaxel, the standard-of-care chemotherapeutics, and the metabolic footprints were characterized by LC-MS. Partial least-squares discriminant analysis (PLS-DA) revealed metabolic signatures that discriminated high-responder from low-responder tissue cultures to ex vivo drug exposure. As a proof-of-concept, a set of potential metabolic biomarkers of drug response was identified based on the receiver operating characteristics (ROC) curve, comprising amino acids, fatty acids, pyrimidine, glutathione, and TCA cycle pathways. Overall, this work establishes an analytical and computational platform to explore metabolic features of the TME associated with response to treatment, which can leverage the discovery of biomarkers of drug response and resistance in OvC.

The Amsterdam UMC protocol for computer-assisted mandibular and maxillary reconstruction; A cadaveric study.

OBJECTIVES: In this cadaveric study, the accuracy of CAS guided mandibular and maxillary reconstruction including immediate dental implant placement in different Brown defect classes is assessed. MATERIALS AND METHODS: The virtual planning and surgical procedure was conducted according to a newly proposed Amsterdam UMC reconstruction protocol. Postoperative evaluation was performed according to a previously proposed evaluation guideline. RESULTS: Fourteen mandibular and 6 maxillary reconstructions were performed. Average mandibular angle deviations were 1.52°±1.32, 1.85°±1.58, 1.37°±1.09, 1.78°±1.37, 2.43°±1.52 and 2.83°±2.37, respectively for the left and right axial angles, left and right coronal angles and left and right sagittal angles. A total of 62 dental implants were placed in neomandibles with an average dXYZ values of 3.68 ± 2.21 mm and 16 in neomaxillas with an average dXYZ values of 3.24 ± 1.7 mm. CONCLUSION: Promising levels of accuracy were achieved for all mandibular angles. Dental implant positions approached the preoperative preferred positions well, within the margin to manufacture prosthetic devices.

Pathophysiologic and Pharmacologic Considerations to Improve the Design and Application of Antibody-Drug Conjugates.

Antibody-drug conjugates (ADC) have emerged as one of the pillars of clinical disease management in oncology. The biggest hurdle to widespread development and application of ADCs has been a narrow therapeutic index. Advances in antibody technologies and formats as well as novel linker and payload chemistries have begun to facilitate structural improvements to ADCs. However, the interplay of structural characteristics with physiologic and pharmacologic factors determining therapeutic success has garnered less attention. This review elaborates on the pharmacology of ADCs, the pathophysiology of cancerous tissues, and the reciprocal consequences on ADC properties and functions. While most currently approved ADCs utilize either microtubule inhibition or DNA damage as primary mechanisms of action, we present arguments to expand this repertoire and highlight the need for payload mechanisms that exploit disease-specific vulnerabilities. We promote the idea that the choice of antibody format, targeting antigen, linker properties, and payload of an ADC should be deliberately fit for purpose by taking the pathophysiology of disease and the specific pharmacology of the drug entity into account, thus allowing a higher probability of clinical success.

Pevonedistat and azacitidine upregulate NOXA (PMAIP1) to increase sensitivity to venetoclax in preclinical models of acute myeloid leukemia.

Dysregulation of apoptotic machinery is one mechanism by which acute myeloid leukemia (AML) acquires a clonal survival advantage. B-cell lymphoma protein-2 (BCL2) overexpression is a common feature in hematologic malignancies. The selective BCL2 inhibitor, venetoclax (VEN) is used in combination with azacitidine (AZA), a DNAmethyltransferase inhibitor (DNMTi), to treat patients with AML. Despite promising response rates to VEN/AZA, resistance to the agent is common. One identified mechanism of resistance is the upregulation of myeloid cell leukemia-1 protein (MCL1). Pevonedistat (PEV), a novel agent that inhibits NEDD8-activating enzyme, and AZA both upregulate NOXA (PMAIP1), a BCL2 family protein that competes with effector molecules at the BH3 binding site of MCL1. We demonstrate that PEV/AZA combination induces NOXA to a greater degree than either PEV or AZA alone, which enhances VEN-mediated apoptosis. Herein, using AML cell lines and primary AML patient samples ex vivo, including in cells with genetic alterations linked to treatment resistance, we demonstrate robust activity of the PEV/VEN/AZA triplet. These findings were corroborated in preclinical systemic engrafted models of AML. Collectively, these results provide rational for combining PEV/VEN/AZA as a novel therapeutic approach in overcoming AML resistance in current therapies.

Patient-Derived Explants of Colorectal Cancer: Histopathological and Molecular Analysis of Long-Term Cultures.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Although short-term cultures of tumour sections and xenotransplants have been used to determine drug efficacy, the results frequently fail to confer clinically useful information. Biomarker discovery has changed the paradigm for advanced CRC, though the presence of a biomarker does not necessarily translate into therapeutic success. To improve clinical outcomes, translational models predictive of drug response are needed. We describe a simple method for the fast establishment of CRC patient-derived explant (CRC-PDE) cultures from different carcinogenesis pathways, employing agitation-based platforms. A total of 26 CRC-PDE were established and a subset was evaluated for viability (n = 23), morphology and genetic key alterations (n = 21). CRC-PDE retained partial tumor glandular architecture and microenvironment features were partially lost over 4 weeks of culture. Key proteins (p53 and Mismatch repair) and oncogenic driver mutations of the original tumours were sustained throughout the culture. Drug challenge (n = 5) revealed differential drug response from distinct CRC-PDE cases. These findings suggest an adequate representation of the original tumour and highlight the importance of detailed model characterisation. The preservation of key aspects of the CRC microenvironment and genetics supports CRC-PDE potential applicability in pre- and co-clinical settings, as long as temporal dynamics are considered.

Application of LDH assay for therapeutic efficacy evaluation of ex vivo tumor models.

The current standard preclinical oncology models are not able to fully recapitulate therapeutic targets and clinically relevant disease biology, evidenced by the 90% attrition rate of new therapies in clinical trials. Three-dimensional (3D) culture systems have the potential to enhance the relevance of preclinical models. However, the limitations of currently available cellular assays to accurately evaluate therapeutic efficacy in these models are hindering their widespread adoption. We assessed the compatibility of the lactate dehydrogenase (LDH) assay in 3D spheroid cultures against other commercially available readout methods. We developed a standardized protocol to apply the LDH assay to ex vivo cultures, considering the impact of culture growth dynamics. We show that accounting for growth rates and background release levels of LDH are sufficient to make the LDH assay a suitable methodology for longitudinal monitoring and endpoint assessment of therapeutic efficacy in both cell line-derived xenografts (xenospheres) and patient-derived explant cultures. This method has the added value of being non-destructive and not dependent on reagent penetration or manipulation of the parent material. The establishment of reliable readout methods for complex 3D culture systems will further the utility of these tumor models in preclinical and co-clinical drug development studies.

A large beam high efficiency radio frequency neutron spin flipper.

A design for a radio frequency (RF) neutron spin flipper obtained from magneto-static and neutron spin transport simulations is presented. The RF flipper constructed from this design provides a flipping probability of 0.999 or better for a beam size 6 cm wide and 15 cm high and a wavelength band between 0.4 and 0.6 nm. Three permanent magnet guide field sections with air gaps provide a linear field gradient along the beam propagation direction over a large cross-sectional area. An RF oscillator based on coupling the resonant coil of a Hartley oscillator to the excitation coil was developed, which provides a higher current and, thereby, a larger RF amplitude, as compared to a conventional RF power amplifier. Two opaque He3 neutron spin filters were employed to measure the flipping probability of the flipper with very high precision. A spatially uniform flipping probability of 0.9995(2) or higher was measured over the large cross-sectional area neutron guide. This RF neutron spin flipper will be employed in a polychromatic beam reflectometer at the National Institute of Standards and Technology Center for Neutron Research. This design can be applied to other polarized neutron instruments or applications requiring a very high continuous flipping probability of the neutron spin for a large cross-sectional area beam.

Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

PURPOSE: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic. METHODS: The efficacy of ADCs, antibodies, TMZ and radiation was tested in xenograft models of GBM, U-87MG and U-87MG EGFRvIII. Both models express EGFR. U-87MG EGFRvIII was transduced to express EGFRvIII. Changes in tumor volume, biomarkers of cell death and apoptosis after treatment were used to measure efficacy of the various treatments. Synergism of depatux-m and TMZ was verified in three-dimensional cultures of U-87MG and U-87MG EGFRvIII by the method of Chou and Talalay. RESULTS: Combined with TMZ and radiotherapy (RT), depatux-m inhibited xenograft growth of U-87MG and U-87MG EGFRvIII more than either treatment with depatux-m or TMZ + RT. Durability of the response to depatux-m + TMZ + RT or depatux-m + TMZ was more pronounced in U-87MG EGFRvIII than in U-87MG. Efficacy of depatux-m + TMZ was synergistic in U-87MG EGFRvIII and additive in U-87MG. CONCLUSION: Adding depatux-m enhances the efficacy of standard of care therapy in preclinical models of GBM. Durability of response to depatux-m + TMZ in vivo and synergy of the drug-drug interaction correlates with the amount of antigen expressed by the tumor cells.

Asymmetrical flow field-flow fractionation to probe the dynamic association equilibria of ß-D-galactosidase.

Protein dynamics play a significant role in many aspects of enzyme activity. Monitoring of structural changes and aggregation of biotechnological enzymes under native conditions is important to safeguard their properties and function. In this work, the potential of asymmetrical flow field-flow fractionation (AF4) to study the dynamic association equilibria of the enzyme ß-D-galactosidase (ß-D-Gal) was evaluated. Three commercial products of ß-D-Gal were investigated using carrier liquids containing sodium chloride or ammonium acetate, and the effect of adding magnesium (II) chloride to the carrier liquid was assessed. Preservation of protein structural integrity during AF4 analysis was essential and the influence of several parameters, such as the focusing step (including use of frit-inlet), cross flow, and injected amount, was studied. Size-exclusion chromatography (SEC) and dynamic light scattering (DLS) were used to corroborate the in-solution enzyme oligomerization observed with AF4. In contrast to SEC, AF4 provided sufficiently mild separation conditions to monitor protein conformations without disturbing the dynamic association equilibria. AF4 analysis showed that ammonium acetate concentrations above 40 mM led to further association of the dimers ("tetramerization") of ß-D-Gal. Magnesium ions, which are needed to activate ß-D-Gal, appeared to induce dimer association, raising justifiable questions about the role of divalent metal ions in protein oligomerization and on whether tetramers or dimers are the most active form of ß-D-Gal.

Patient-derived ovarian cancer explants: preserved viability and histopathological features in long-term agitation-based cultures.

Ovarian carcinoma (OvC) remains a major therapeutic challenge due to its propensity to develop resistance after an initial response to chemotherapy. Interactions of tumour cells with the surrounding microenvironment play a role in tumour survival, invasion capacity and drug resistance. Cancer models that retain tissue architecture and tumour microenvironment components are therefore essential to understand drug response and resistance mechanisms. Herein, our goal was to develop a long-term OvC patient-derived explant (OvC-PDE) culture strategy in which architecture and cell type heterogeneity of the original tumour would be retained. Samples from 25 patients with distinct OvC types and one with a benign tumour, were cultured for 30 days in agitation-based culture systems with 100% success rate. OvC-PDE cultures retained the original tumour architecture and main cellular components: epithelial cells, fibroblasts and immune cells. Epithelial cells kept their original levels of proliferation and apoptosis. Moreover, the major extracellular components, such as collagen-I and -IV, were retained in explants. OvC-PDE cultures were exposed to standard-of-care chemotherapeutics agents for 2 weeks, attesting the ability of the platform for drug assays employing cyclic drug exposure regimens. We established an OvC-PDE dynamic culture in which tumour architecture and cell type heterogeneity were preserved for the different OvC types, replicating features of the original tumour and compatible with long-term drug exposure for drug efficacy and resistance studies.

Optimizing magnetically shielded solenoids.

An important consideration when designing a magnetostatic cavity for various applications is to maximize the ratio of the volume of field homogeneity to the overall size of the cavity. We report a design of a magnetically shielded solenoid that significantly improves the transverse field gradient averaged over a volume of 1000 cm3 by placing compensation coils around the holes in the mu-metal end caps rather than the conventional design in which the compensation coils are placed on the main solenoid. Our application is polarized 3He-based neutron spin filters, and our goal was to minimize the volume-averaged transverse field gradient, thereby the gradient induced relaxation time, over a 3He cell. For solenoids with end cap holes of different sizes, additional improvements in the field gradient were accomplished by introducing non-identical compensation coils centered around the non-identical holes in the end caps. The improved designs have yielded an overall factor of 7 decrease in the gradient in the solenoid, hence a factor of 50 increase in the gradient induced relaxation time of the 3He polarization. The results from both simulation and experiments for the development of several such solenoids are presented. Whereas our focus is on the development of magnetically shielded solenoids for 3He neutron spin filters, the approach can be applied for other applications demanding a high level of field homogeneity over a large volume.

Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor.

Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.