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"Das, M"
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Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications
Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.
Journal Article
An open-source drug discovery platform enables ultra-large virtual screens
On average, an approved drug currently costs US$2–3 billion and takes more than 10 years to develop
1
. In part, this is due to expensive and time-consuming wet-laboratory experiments, poor initial hit compounds and the high attrition rates in the (pre-)clinical phases. Structure-based virtual screening has the potential to mitigate these problems. With structure-based virtual screening, the quality of the hits improves with the number of compounds screened
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. However, despite the fact that large databases of compounds exist, the ability to carry out large-scale structure-based virtual screening on computer clusters in an accessible, efficient and flexible manner has remained difficult. Here we describe VirtualFlow, a highly automated and versatile open-source platform with perfect scaling behaviour that is able to prepare and efficiently screen ultra-large libraries of compounds. VirtualFlow is able to use a variety of the most powerful docking programs. Using VirtualFlow, we prepared one of the largest and freely available ready-to-dock ligand libraries, with more than 1.4 billion commercially available molecules. To demonstrate the power of VirtualFlow, we screened more than 1 billion compounds and identified a set of structurally diverse molecules that bind to KEAP1 with submicromolar affinity. One of the lead inhibitors (iKeap1) engages KEAP1 with nanomolar affinity (dissociation constant (
K
d
) = 114 nM) and disrupts the interaction between KEAP1 and the transcription factor NRF2. This illustrates the potential of VirtualFlow to access vast regions of the chemical space and identify molecules that bind with high affinity to target proteins.
VirtualFlow, an open-source drug discovery platform, enables the efficient preparation and virtual screening of ultra-large ligand libraries to identify molecules that bind with high affinity to target proteins.
Journal Article
The Eagle has landed : 50 years of lunar science fiction
\"In celebration of the 50th anniversary of the Apollo 11 landing, the endlessly-mysterious moon is explored in this reprint short science fiction anthology from award-winning editor and anthologist Neil Clarke ... On July 20, 1969, mankind made what had only years earlier seemed like an impossible leap forward: when Apollo 11 became the first manned mission to land on the moon, and Neil Armstrong the first person to step foot on the lunar surface. While there have only been a handful of new missions since, the fascination with our planet's satellite continues, and generations of writers and artists have imagined the endless possibilities of lunar life. From adventures in the vast gulf of space between the earth and the moon, to journeys across the light face to the dark side, to the establishment of permanent residences on its surface, science fiction has for decades given readers bold and forward-thinking ideas about our nearest interstellar neighbor and what it might mean to humankind, both now and in our future. [This book] collects the best stories written in the fifty years since mankind first stepped foot on the lunar surface, serving as a shining reminder that the moon is and always has been our most visible and constant example of all the infinite possibility of the wider universe\"-- Provided by publisher.
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Apical Abscission Alters Cell Polarity and Dismantles the Primary Cilium During Neurogenesis
Withdrawal of differentiating cells from proliferative tissue is critical for embryonic development and adult tissue homeostasis; however, the mechanisms that control this cell behavior are poorly understood. Using high-resolution live-cell imaging in chick neural tube, we uncover a form of cell subdivision that abscises apical cell membrane and mediates neuron detachment from the ventricle. This mechanism operates in chick and mouse, is dependent on actin-myosin contraction, and results in loss of apical cell polarity. Apical abscission also dismantles the primary cilium, known to transduce sonic-hedgehog signals, and is required for expression of cell-cycle-exit gene p27/Kip1. We further show that N-cadherin levels, regulated by neuronal-differentiation factor Neurog2, determine cilium disassembly and final abscission. This cell-biological mechanism may mediate such cell transitions in other epithelia in normal and cancerous conditions.
Journal Article
Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta—Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons
The ketogenic diet (KD), a high-lipid and low-carbohydrate diet, has been used in the treatment of epilepsy, neurodegenerative disorders, inborn errors of metabolism and cancer; however, the exact mechanism/s of its therapeutic effect is not completely known. We hypothesized that sirtuins (SIRT)—a group of seven NAD-dependent enzymes and important regulators of energy metabolism may be altered under KD treatment. HT22 hippocampal murine neurons were incubated with two important KD metabolites–beta-hydroxybutyrate (BHB) (the predominant ketone body) and decanoic acid (C10), both accumulating under KD. Enzyme activity, protein, and gene expressions of SIRT 1-4, enzyme capacities of the mitochondrial respiratory chain complexes (MRC), citrate synthase (CS) and gene expression of monocarboxylate transporters were measured in control (untreated) and KD-treated cells. Incubation with both–BHB and C10 resulted in significant elevation of SIRT1 enzyme activity and an overall upregulation of the MRC. C10 incubation showed prominent increases in maximal activities of complexes I + III and complex IV of the MRC and ratios of their activities to that of CS, pointing towards a more efficient functioning of the mitochondria in C10-treated cells.
Journal Article
Exploring various metal-ligand coordination bond formation in elastomers: Mechanical performance and self-healing behavior
Dynamic covalent crosslinking such as disulfide bonds, Diels-Alder (DA) reactions are widely used for healing applications. Herein, we report a simple approach involving the metal-ligand reversible interactions in diverse nature, which helps in developing a robust and self-healable carboxylated nitrile (XNBR) rubber by employing low cost and the commercially obtainable materials. Self-healing performance and mechanical properties were organized by introducing the various metal-ligand domains into the XNBR rubber. The network of XNBR, in-situ cross-linked via metal-ligand complexes, consists of strong and weak coordination bonds. The strength of various metal-ligand modified coordination bonds, healing performance, and mechanical properties primarily depend on the type of metal ions. The Fourier transform infrared spectroscopy (FTIR) makes the various metal-ligand coordination bond formation into the XNBR rubber visible. The coordination crosslinked XNBR rubber with 4 phr of Zn and Co metal ion exhibits high tensile strength (4.3±0.6 and 10.3±1.1 MPa) with excellent healing efficiency (100 and 88%), which is far higher than the most reported non-covalent supramolecular modified elastomers. The various metal-ligand coordination bonds are fully reconstructed during the rebuilding process and exhibiting excellent self-healing property.
Journal Article
Occipital condyle syndrome: a rare manifestation of skull base tuberculosis
A man in his 30s from South Asia presented with progressive neck pain, occipital headache and right-sided tongue deviation (occipital condyle syndrome). Initial imaging identified a destructive skull base lesion involving the right clivus, occipital condyle and C1 vertebra with compression of the hypoglossal nerve, raising concerns for malignancy. Concurrent necrotic mediastinal lymphadenopathy prompted endobronchial ultrasound-guided biopsy, which confirmed necrotising granulomatous lymphadenitis with Mycobacterium tuberculosis complex DNA. Quadruple antituberculous therapy and adjunctive corticosteroids gave significant clinical and radiological improvement at 6 months. This case highlights the importance of considering tuberculosis in the differential diagnosis of destructive skull base lesions even in non-endemic regions and in patients with previously negative TB screening.
Journal Article
Investigation of large-amplitude ion acoustic solitary waves in a warm magnetoplasma with positive ions and relativistic electrons
The Sagdeev pseudopotential (SP) method is used to study ion acoustic solitary waves (IASWs) in a warm, magnetized plasma with relativistic electrons. Employing the pseudopotential approach allows for the investigation of solitary wave (SW) structures across arbitrary amplitudes. The study highlights the simultaneous occurrence of compressive
N
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subsonic
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solitons, as well as rarefactive
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subsonic and supersonic
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solitons, under specific parametric conditions. Notably, it is seen that as the direction cosine of wave propagation
k
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increases, both the amplitude of SWs and the depth of the potential well decrease. The reduction in amplitude indicates a closer alignment between the magnetic field lines and the direction of wave propagation. The coexistence of compressive subsonic, rarefactive subsonic, and supersonic solitons in this plasma model is a rich and complex phenomenon that has both fundamental and practical implications in plasma physics. It reflects the intricate interplay of nonlinear effects, particle dynamics, and wave propagation in plasmas, with potential applications in both laboratory and astrophysical contexts.
Journal Article