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"Mukherjee, Siddhartha"
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The emperor of all maladies : a biography of cancer
A \"biography\" of cancer from its origins to the epic battle to cure, control, and conquer it.
Book
Synthesis and investigation of properties of nanostructured cubic PMN ceramics for possible applications in electronics
The pure phase of Pb(Mg
1/3
Nb
2/3
)O
3
was synthesized by two-stage chemical process at 800 °C. Thermal analysis of precursors was done by TG-DSC. XRD, Raman spectroscopy, FESEM and HRTEM analyses were done to characterize synthesized material and also to observe the microstructure. XRD studies revealed the formation of pure crystalline PMN ceramics (JCPDS PDF# 00-081-0861) having crystallite size around 28 nm. The particle size was examined to be around 19 nm by HRTEM. The nanocrystalline PMN ceramics exhibited a bandgap around 3.28 eV using diffuse reflectance spectroscopy. Dielectric nature was inspected using impedance analyzer between 40 Hz and 110 MHz. Dielectric constant (
ϵ
r
) and
tan
δ
were investigated where unusual negative values of
ϵ
r
were observed beyond 41.26 MHz. A peak in
tan
δ
near 41.26 MHz was also obtained.
Journal Article
إمبراطور المآسي : سيرة للسرطان
(إمبراطور المآسي) كتاب أخاذ وإنساني وعميق، هو سيرة لمرض السرطان منذ أول توثيق لظهوره قبل آلاف السنين والمعارك الأسطورية التي حدثت في القرن العشرين للسيطرة عليه، إلى الفهم الأصيل لجوهر هذا العرض، وقصة مرض السرطان هي قصة عن براعة البشر، ومرونتهم وقدرتهم على البقاء، ومثابرتهم، وأيضا عن غطرستهم وتسلطهم وسوء فهمهم وتقديرهم.
BOOK
Suppression of insulin feedback enhances the efficacy of PI3K inhibitors
Mutations in
PIK3CA
, which encodes the p110α subunit of the insulin-activated phosphatidylinositol-3 kinase (PI3K), and loss of function mutations in
PTEN
, which encodes a phosphatase that degrades the phosphoinositide lipids generated by PI3K, are among the most frequent events in human cancers
1
,
2
. However, pharmacological inhibition of PI3K has resulted in variable clinical responses, raising the possibility of an inherent mechanism of resistance to treatment. As p110α mediates virtually all cellular responses to insulin, targeted inhibition of this enzyme disrupts glucose metabolism in multiple tissues. For example, blocking insulin signalling promotes glycogen breakdown in the liver and prevents glucose uptake in the skeletal muscle and adipose tissue, resulting in transient hyperglycaemia within a few hours of PI3K inhibition. The effect is usually transient because compensatory insulin release from the pancreas (insulin feedback) restores normal glucose homeostasis
3
. However, the hyperglycaemia may be exacerbated or prolonged in patients with any degree of insulin resistance and, in these cases, necessitates discontinuation of therapy
3
–
6
. We hypothesized that insulin feedback induced by PI3K inhibitors may reactivate the PI3K–mTOR signalling axis in tumours, thereby compromising treatment effectiveness
7
,
8
. Here we show, in several model tumours in mice, that systemic glucose–insulin feedback caused by targeted inhibition of this pathway is sufficient to activate PI3K signalling, even in the presence of PI3K inhibitors. This insulin feedback can be prevented using dietary or pharmaceutical approaches, which greatly enhance the efficacy/toxicity ratios of PI3K inhibitors. These findings have direct clinical implications for the multiple p110α inhibitors that are in clinical trials and provide a way to increase treatment efficacy for patients with many types of tumour.
Glucose–insulin feedback can reactivate PI3K in tumours treated with PI3K inhibitors, reducing therapeutic efficacy, but this effect can be reduced by using drugs or diet to suppress the insulin response.
Journal Article
The laws of medicine : field notes from an uncertain science
One of the world's premiere cancer researchers reveals an urgent philosophy on the little-known principles that govern medicine--and how understanding these principles can empower everyone.
Book
Droplet–turbulence interactions and quasi-equilibrium dynamics in turbulent emulsions
We perform direct numerical simulations (DNS) of emulsions in homogeneous isotropic turbulence using a pseudopotential lattice-Boltzmann (PP-LB) method. Improving on previous literature by minimizing droplet dissolution and spurious currents, we show that the PP-LB technique is capable of long stable simulations in certain parameter regions. Varying the dispersed-phase volume fraction$\\unicode[STIX]{x1D719}$, we demonstrate that droplet breakup extracts kinetic energy from the larger scales while injecting energy into the smaller scales, increasingly with higher$\\unicode[STIX]{x1D719}$, with approximately the Hinze scale (Hinze, AIChE J. , vol. 1 (3), 1955, pp. 289–295) separating the two effects. A generalization of the Hinze scale is proposed, which applies both to dense and dilute suspensions, including cases where there is a deviation from the$k^{-5/3}$inertial range scaling and where coalescence becomes dominant. This is done using the Weber number spectrum$We(k)$, constructed from the multiphase kinetic energy spectrum$E(k)$, which indicates the critical droplet scale at which$We\\approx 1$. This scale roughly separates coalescence and breakup dynamics as it closely corresponds to the transition of the droplet size ($d$) distribution into a$d^{-10/3}$scaling (Garrett et al. , J. Phys. Oceanogr. , vol. 30 (9), 2000, pp. 2163–2171; Deane & Stokes, Nature , vol. 418 (6900), 2002, p. 839). We show the need to maintain a separation of the turbulence forcing scale and domain size to prevent the formation of large connected regions of the dispersed phase. For the first time, we show that turbulent emulsions evolve into a quasi-equilibrium cycle of alternating coalescence and breakup dominated processes. Studying the system in its state-space comprising kinetic energy$E_{k}$, enstrophy$\\unicode[STIX]{x1D714}^{2}$and the droplet number density$N_{d}$, we find that their dynamics resemble limit cycles with a time delay. Extreme values in the evolution of$E_{k}$are manifested in the evolution of$\\unicode[STIX]{x1D714}^{2}$and$N_{d}$with a delay of${\\sim}0.3{\\mathcal{T}}$and${\\sim}0.9{\\mathcal{T}}$respectively (with${\\mathcal{T}}$the large eddy timescale). Lastly, we also show that flow topology of turbulence in an emulsion is significantly more different from single-phase turbulence than previously thought. In particular, vortex compression and axial straining mechanisms increase in the droplet phase.
Journal Article
Disease-associated mutation in SRSF2 misregulates splicing by altering RNA-binding affinities
Mutations in genes encoding proteins that function in splicing of mRNA precursors occur frequently in myelodysplastic syndromes (MDS) and certain leukemias. However, the mechanism by which the mutated splicing factors function has begun to be elucidated only recently. Here we use genome-editing techniques to introduce a common MDS mutation in the gene Serine/arginine-rich splicing factor 2 ( SRSF2 ), which encodes an RNA-binding splicing regulator, in cultured blood cells. We show that splicing of several hundred transcripts, including some with possible relevance to disease, is altered. We further show that mutant SRSF2 is sufficient to induce these changes and does so by binding to RNA sequence elements in the misregulated mRNAs with altered specificity. Serine/arginine-rich splicing factor 2 (SRSF2) is an RNA-binding protein that plays important roles in splicing of mRNA precursors. SRSF2 mutations are frequently found in patients with myelodysplastic syndromes and certain leukemias, but how these mutations affect SRSF2 function has only begun to be examined. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 nuclease to introduce the P95H mutation to SRSF2 in K562 leukemia cells, generating an isogenic model so that splicing alterations can be attributed solely to mutant SRSF2. We found that SRSF2 (P95H) misregulates 548 splicing events (<1% of total). Of these events, 374 involved the inclusion of cassette exons, and the inclusion was either increased (206) or decreased (168). We detected a specific motif (UCCA/UG) enriched in the more-included exons and a distinct motif (UGGA/UG) in the more-excluded exons. RNA gel shift assays showed that a mutant SRSF2 derivative bound more tightly than its wild-type counterpart to RNA sites containing UCCAG but bound less tightly to UGGAG sites. Thus in most cases the pattern of exon inclusion or exclusion correlated with stronger or weaker RNA binding, respectively. We further show that the P95H mutation does not affect other functions of SRSF2, i.e., protein–protein interactions with key splicing factors. Our results thus demonstrate that the P95H mutation positively or negatively alters the binding affinity of SRSF2 for cognate RNA sites in target transcripts, leading to misregulation of exon inclusion. Our findings shed light on the mechanism of the disease-associated SRSF2 mutation in splicing regulation and also reveal a group of misspliced mRNA isoforms for potential therapeutic targeting.
Journal Article
SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes
SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ∼25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 WT and mutant cell lines, normal human CD34 cells, and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature down-regulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia, and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.
Journal Article