MGMT in TMZ-based glioma therapy: Multifaceted insights and clinical trial perspectives.

Temozolomide (TMZ) is the most preferred and approved chemotherapeutic drug for either first- or second-line chemotherapy for glioma patients across the globe. In glioma patients, resistance to treatment with alkylating drugs like TMZ is known to be conferred by exalted levels of MGMT gene expression. On the contrary, epigenetic silencing through MGMT gene promoter methylation leading to subsequent reduction in MGMT transcription and protein expression, is predicted to have a response favoring TMZ treatment. Thus, MGMT protein level in cancer cells is a crucial determining factor in indicating and predicting the choice of alkylating agents in chemotherapy or choosing glioma patients directly for a second line of treatment. Thus, in-depth research is necessary to achieve insights into MGMT gene regulation that has recently enticed a fascinating interest in epigenetic, transcriptional, post-transcriptional, and post-translational levels. Furthermore, MGMT promoter methylation, stability of MGMT protein, and related subsequent adaptive responses are also important contributors to strategic developments in glioma therapy. With applications to its identification as a prognostic biomarker, thus predicting response to advanced glioma therapy, this review aims to concentrate on the mechanistic role and regulation of MGMT gene expression at epigenetic, transcriptional, post-transcriptional, and post-translational levels functioning under the control of multiple signaling dynamics.

E3 ubiquitin ligases in lung cancer: Emerging insights and therapeutic opportunities.

Aim In this review, we have attempted to provide the readers with an updated account of the role of a family of proteins known as E3 ligases in different aspects of lung cancer progression, along with insights into the deregulation of expression of these proteins during lung cancer. A detailed account of the therapeutic strategies involving E3 ligases that have been developed or currently under development has also been provided in this review. MATERIALS AND METHODS: The review article employs extensive literature search, along with differential gene expression analysis of lung cancer associated E3 ligases using the DESeq2 package in R, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (http://gepia.cancer-pku.cn/). Protein expression analysis of CPTAC lung cancer samples was carried out using the UALCAN webtool (https://ualcan.path.uab.edu/index.html). Assessment of patient overall survival (OS) in response to high and low expression of selected E3 ligases was performed using the online Kaplan-Meier plotter (https://kmplot.com/analysis/index.php?p=background). KEY FINDINGS: SIGNIFICANCE: The review provides an in-depth understanding of the role of E3 ligases in lung cancer progression and an up-to-date account of the different therapeutic strategies targeting oncogenic E3 ligases for improved lung cancer management.

DDX5 (p68) orchestrates ß-catenin, RelA and SP1 mediated MGMT gene expression in human colon cancer cells: Implication in TMZ chemoresistance.

DDX5 (p68) upregulation has been linked with various cancers of different origins, especially Colon Adenocarcinomas. Similarly, across cancers, MGMT has been identified as the major contributor of chemoresistance against DNA alkylating agents like Temozolomide (TMZ). TMZ is an emerging potent chemotherapeutic agent across cancers under the arena of drug repurposing. Recent studies have established that patients with open MGMT promoters are prone to be innately resistant or acquire resistance against TMZ compared to its closed conformation. However, not much is known about the transcriptional regulation of MGMT gene in the context of colon cancer. This necessitates studying MGMT gene regulation which directly impacts the cellular potential to develop chemoresistance against alkylating agents. Our study aims to uncover an unidentified mechanism of DDX5-mediated MGMT gene regulation. Experimentally, we found that both mRNA and protein expression levels of MGMT were elevated in response to p68 overexpression in multiple human colon cancer cell lines and vice-versa. Since p68 cannot directly interact with the MGMT promoter, transcription factors viz., ß-catenin, RelA (p65) and SP1 were also studied as reported contributors. Through co-immunoprecipitation and GST-pull-down studies, p68 was established as an interacting partner of SP1 in addition to ß-catenin and NF-κB (p50-p65). Mechanistically, luciferase reporter and chromatin-immunoprecipitation assays demonstrated that p68 interacts with the MGMT promoter via TCF4-LEF, RelA and SP1 sites to enhance its transcription. To the best of our knowledge, this is the first report of p68 as a transcriptional co-activator of MGMT promoter and our study identifies p68 as a novel and master regulator of MGMT gene expression.

The E3 ubiquitin ligase CHIP drives monoubiquitylation-mediated nuclear import of the tumor suppressor PTEN.

Monoubiquitylation is a principal mechanism driving nuclear translocation of the protein PTEN (phosphatase and tensin homolog deleted on chromosome ten). In this study, we describe a novel mechanism wherein the protein CHIP (C-terminus of Hsc70-interacting protein) mediates PTEN monoubiquitylation, leading to its nuclear import. Western blot analysis revealed a rise in both nuclear and total cellular PTEN levels under monoubiquitylation-promoting conditions, an effect that was abrogated by silencing CHIP expression. We established time-point kinetics of CHIP-mediated nuclear translocation of PTEN using immunocytochemistry and identified a role of karyopherin α1 (KPNA1) in facilitating nuclear transport of monoubiquitylated PTEN. We further established a direct interaction between CHIP and PTEN inside the nucleus, with CHIP participating in either polyubiquitylation or monoubiquitylation of nuclear PTEN. Finally, we showed that oxidative stress enhanced CHIP-mediated nuclear import of PTEN, which resulted in increased apoptosis, and decreased cell viability and proliferation, whereas CHIP knockdown counteracted these effects. To the best of our knowledge, this is the first report elucidating non-canonical roles for CHIP on PTEN, which we establish here as a nuclear interacting partner of CHIP.

Observing temporal variation in hemolysis through photoacoustics with a low cost LASER diode based system.

Patients under hemolytic condition need continuous monitoring of lysis as depletion of Red Blood Cells (RBC) and the presence of antioxidant free hemoglobin (Hb) in excess amount due to hemolysis lead to severe deterioration of their health. Out of many modalities, Photoacoustics (PA) offers real time information noninvasively from deep lying blood vessels since Hb is the strongest chromophore in mammalian blood and the PA response of blood varies with the amount of Hb present. During hemolysis, total Hb content in blood however remains unchanged, thus, questions the use of PA in hemolysis detection. In this report, a hypothesis that the amplitude of the PA signal would not change with the amount of lysis is framed and tested by applying osmotic shock to the RBCs in hypotonic environment and the PA response is recorded over time using a low cost NIR based PA system. The experimental outcome indicates that PA amplitude falls off as lysis progresses in course of time consequently rejecting the hypothesis. The decaying PA response also carries the signature of RBC swelling during the early phase of lysis. The PA measurement can detect hemolysis as low as 1.7%. These findings further advocate transforming this NIR-PA system into a portable, noninvasive patient care device to monitor hemolysis in-vivo.

Neurological damages in COVID-19 patients: Mechanisms and preventive interventions.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, causes coronavirus disease 2019 (COVID-19) which led to neurological damage and increased mortality worldwide in its second and third waves. It is associated with systemic inflammation, myocardial infarction, neurological illness including ischemic strokes (e.g., cardiac and cerebral ischemia), and even death through multi-organ failure. At the early stage, the virus infects the lung epithelial cells and is slowly transmitted to the other organs including the gastrointestinal tract, blood vessels, kidneys, heart, and brain. The neurological effect of the virus is mainly due to hypoxia-driven reactive oxygen species (ROS) and generated cytokine storm. Internalization of SARS-CoV-2 triggers ROS production and modulation of the immunological cascade which ultimately initiates the hypercoagulable state and vascular thrombosis. Suppression of immunological machinery and inhibition of ROS play an important role in neurological disturbances. So, COVID-19 associated damage to the central nervous system, patients need special care to prevent multi-organ failure at later stages of disease progression. Here in this review, we are selectively discussing these issues and possible antioxidant-based prevention therapies for COVID-19-associated neurological damage that leads to multi-organ failure.

USP7 imparts partial EMT state in colorectal cancer by stabilizing the RNA helicase DDX3X and augmenting Wnt/ß-catenin signaling.

Epithelial mesenchymal transition (EMT) is a fundamental and highly regulated process that is normally observed during embryonic development and tissue repair but is deregulated during advanced cancer. Classically, through the process of EMT, cancer cells gradually transition from a predominantly epithelial phenotype to a more invasive mesenchymal phenotype. Increasing studies have, however, brought into light the existence of unique intermediary states in EMT, often referred to as partial EMT states. Through our studies we have found the deubiquitinase USP7 to be strongly associated with the development of such a partial EMT state in colon cancer cells, characterized by the acquisition of mesenchymal characteristics but without the reduction in epithelial markers. We found USP7 to be overexpressed in colon adenocarcinomas and to be closely associated with advancing tumor stage. We found that functional inhibition or knockdown of USP7 is associated with a marked reduction in mesenchymal markers and in overall migration potential of cancer cells. Starting off with a proteomics-based approach we were able to identify and later on verify the DEAD box RNA helicase DDX3X to be an interacting partner of USP7. We then went on to show that USP7, through the stabilization of DDX3X, augments Wnt/ß-catenin signaling, which has previously been shown to be greatly associated with colorectal cancer cell invasiveness. Our results indicate USP7 as a novel key player in establishing a partial mesenchymal phenotype in colorectal cancer.

Hybrid resonant cavities: A route towards phase engineered THz metasurfaces.

Coupled resonant cavities can enable strong photon energy confinement to facilitate the miniaturization of functional photonic devices for applications in designs of sensors, modulators, couplers, waveguides, color filters etc. Typically, the resonances in subwavelength plasmonic cavities rely on the excitation of surface plasmons at specific phase-matching conditions, usually determined by the lattice parameters and constituent material properties. Contrary to this notion, we experimentally demonstrate the control and manipulation of cavity resonances via suitably modifying the split ring resonator geometry in hybrid plasmonic-metasurface (dipole cavity-SRR) configuration without altering the lattice parameters. This results to the excitation of dual resonance peaks. Such dual channel characteristics demonstrate high quality (Q) factor, multi-band resonances, not permissible with typical (unhybridized) plasmonic dipole cavities. We envisage such hybrid meta-cavity designs can become important ingredients for futuristic terahertz devices that can hold the key for sixth generation (6G) communications, designer filters, dual channel sensors etc.

Resonant toroidal metasurface as a platform for thin-film and biomaterial sensing.

Toroidal resonances with weak free-space coupling have recently garnered significant research attraction toward the realization of advanced photonic devices. As a natural consequence of weak free-space coupling, toroidal resonances generally possess a high quality factor with low radiative losses. Because of these backgrounds, we have experimentally studied thin-film sensing utilizing toroidal resonance in a subwavelength planar metasurface, whose unit cell consists of near-field coupled asymmetric dual gap split-ring resonators (ASRRs). These ASRRs are placed in a mirrored configuration within the unit cell. The near-field coupled ASRRs support circulating surface currents in both resonators with opposite phases, resulting in excitation of the toroidal mode. In such a way, excited toroidal resonance can support strong light-matter interactions with external materials (analytes to be detected) placed on top of the metasurface. Further, our study reveals a sensitivity of 30 GHz/RIU while sensing AZ4533 photoresist film utilizing the toroidal mode. Such detection of thin films can be highly beneficial for the development of sensing devices for various biomolecules and dielectric materials that can be spin coated or drop casted on metasurfaces. Hence, the toroidal mode is further theoretically explored towards the detection of avian influenza virus subtypes, namely, H5N2 and H9N2. Our study reveals 6 and 9 GHz of frequency redshifts for H5N2 and H9N2, respectively, in comparison to the bare sample. Therefore, this work shows that toroidal metasurfaces can be a useful platform to sense thin films of various materials including biomaterials.

Wnt/ß-catenin signaling and p68 conjointly regulate CHIP in colorectal carcinoma.

Emerging evidences suggest abundant expression of Carboxy terminus of Hsc70 Interacting Protein or CHIP (alias STIP1 Homology and U-box Containing Protein 1 or STUB1) in colorectal carcinoma, but the mechanistic detail of this augmented expression pattern is unclear. The signature driver of canonical Wnt pathway, ß-catenin, and its co-activator RNA helicase p68, are also overexpressed in colorectal carcinoma. In this study, we describe a novel mechanism of Wnt/ß-catenin and p68 mediated transcriptional activation of CHIP gene leading to enhanced proliferation of colorectal carcinoma cells. Bioinformatic analyses reconfirmed an elevated CHIP expression level in colorectal carcinoma datasets. Wnt3A treatment and pharmacological activation of canonical Wnt signaling pathway resulted in increased nuclear translocation of ß-catenin, augmenting CHIP expression. Likewise, immunoblotting and Real time PCR following overexpression and knockdown of ß-catenin and p68 demonstrated upregulated and downregulated CHIP expression, respectively, at both mRNA and protein levels. p68 along with ß-catenin were found to occupy Transcription Factor 4 (TCF4) binding sites on endogenous CHIP promoter and regulate its transcription. After cloning CHIP promoter, the increased and decreased promoter activities of CHIP induced by overexpression and knockdown of either ß-catenin or p68 further confirmed transcriptional regulation of CHIP gene by Wnt/ß-catenin signaling cascade. Finally, enhanced cellular propagation and migration of colorectal carcinoma cells induced by 'Wnt/ß-catenin-p68-CHIP' axis established the significance of this pathway in oncogenesis. To the best of our knowledge, this is the first report elucidating the mechanistic details of transcriptional regulation of CHIP (STUB1) gene expression.

Localized surface plasmon resonance-enhanced solar-blind Al0.4Ga0.6N MSM photodetectors exhibiting high-temperature robustness.

The appealing properties of tunable direct wide bandgap, high-temperature robustness and chemical hardness, make AlxGa1-xN a promising candidate for fabricating robust solar-blind photodetectors (PDs). In this work, we have utilized the optical phenomenon of localized surface plasmon resonance (LSPR) in metal nanoparticles (NPs) to significantly enhance the performance of solar-blind Al0.4Ga0.6N metal-semiconductor-metal PDs that exhibit high-temperature robustness. We demonstrate that the presence of palladium (Pd) NPs leads to a remarkable enhancement by nearly 600, 300, and 462%, respectively, in the photo-to-dark current ratio (PDCR), responsivity, and specific detectivity of the Al0.4Ga0.6N PD at the wavelength of 280 nm. Using the optical power density of only 32µW cm-2at -10 V, maximum values of ∼3 × 103, 2.7 AW-1, and 2.4 × 1013Jones are found for the PDCR, responsivity and specific detectivity, respectively. The experimental observations are supported by finite difference time domain simulations, which clearly indicate the presence of LSPR in Pd NPs decorated on the surface of Al0.4Ga0.6N. The mechanism behind the enhancement is investigated in detail, and is ascribed to the LSPR induced effects, namely, improved optical absorption, enhanced local electric field and LSPR sensitization effect. Moreover, the PD exhibits a stable operation up to 400 K, thereby exhibiting the high-temperature robustness desirable for commercial applications.

Magnetic wire: transverse magnetism in a one-dimensional plasmonic system.

We experimentally demonstrate magnetic wire in a coupled, cut-wire pair-based metasurface operating at the terahertz frequencies. A dominant transverse magnetic dipole (non-axial circulating conduction current) is excited in one of the plasmonic wires that constitute the coupled system, whereas the other wire remains electric. Despite having large asymmetry-induced strong radiation channels in such a metasurface, non-radiative current distributions are obtained as a direct consequence of interaction between the electric and magnetic wire(s). We demonstrate a versatile platform to transform an electric to a magnetic wire and vice-versa through asymmetry-induced polymorphic hybridization with potential applications in photonic/electrical integrated circuits.

Acquiring photoacoustic signature of hematocrit variation from plexus layer ofin-silicohuman skin phantom.

Optical penetration inside human skin is constrained by the wavelength dependent scattering and absorption losses by tissue microstructure and chromophores. This computational study investigates whether the signature of hematocrit variation from plexus i.e., the first skin layer having very small blood volume percentage distributed in capillary vessels, is retained by the detected photoacoustic response. Thein-silicoskin phantom is irradiated by a light source equivalent to a small footprint and low power (below 5 W) continuous wave LASER diode. As the low fluence can be compensated by exploiting strong absorption by targeted chromophores (hemoglobin molecules), an irradiation of wavelength 405 nm has been used to generate detectable pressure from capillary blood vessels of plexus. Optical energy deposition inside the tissue has been modelled using Monte Carlo technique and the pressure wave is computed using k-wave. It is found that with the increase in hematocrit from 10% to 50%, photoacoustic amplitude monotonically increases and gets almost doubled. The increment is about 30% in the range of hematocrit of physiological interest (from 30% to 50%). The variation follows a quadratic relationship for the entire hematocrit range. This photoacoustic signature of hematocrit variation has further been validated against minimum detectable pressure (800 Pa). This numerical model is expected to be an important basis to realize the idea of low cost small footprintin-vivophotoacoustic hematocrit measurement device.

Lattice-induced plasmon hybridization in metamaterials.

We explore an inherent connection between two fundamental concepts of physics-resonance (eigen mode) hybridization and lattice effect in sub-wavelength periodic structures. Our study reveals that coupling with lattice mode is the prime deciding factor to determine the nature, position, and line shape of the hybridized states. Modulating lattice modes can effectively control mode hybridization and tune the relative position of hybridized modes [symmetric (electric), anti-symmetric (magnetic)] without changing any other structural dimensions in subwavelength plasmonic metamaterials. Outcomes of this study can be exploited in designing linear and nonlinear photonic structures toward futuristic meta devices.

TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review.

During the course of evolution, multicellular organisms have been orchestrated with an efficient and versatile immune system to counteract diverse group of pathogenic organisms. Pathogen recognition is considered as the most critical step behind eliciting adequate immune response during an infection. Hitherto Toll-like receptors (TLRs), especially the surface ones viz. TLR2 and TLR4 have gained immense importance due to their extreme ability of identifying distinct molecular patterns from invading pathogens. These pattern recognition receptors (PRRs) not only act as innate sensor but also shape and bridge innate and adaptive immune responses. In addition, they also play a pivotal role in regulating the balance between Th1 and Th2 type of response essential for the survivability of the host. In this work, major achievements rather findings made on the typical signalling and immunopathological attributes of TLR2 and TLR4 mediated host response against the major infectious diseases have been reviewed. Infectious diseases like tuberculosis, trypanosomiasis, malaria, and filariasis are still posing myriad threat to mankind. Furthermore, increasing resistance of the causative organisms against available therapeutics is also an emerging problem. Thus, stimulation of host immune response with TLR2 and TLR4 agonist can be the option of choice to treat such diseases in future.

Dual mode ratiometric recognition of zinc acetate: nanomolar detection with in vitro tracking of endophytic bacteria in rice root tissue.

Several naphthalene-based aldazine derivatives were developed as efficient colorimetric and fluorescence probes for selective ratiometric recognition of traces of zinc acetate. The derivative structures were characterized by single-crystal X-ray diffraction. The probes were used for in vitro tracking of zinc acetate in endophytic bacteria within rice root tissue and to image zinc acetate in human breast cancer cells (MCF7) by normal and fluorescence microscopy. Density functional theoretical studies were in close agreement with the experimental findings.

Photoacoustic imaging of nanoparticle- containing cells using single-element focused transducer: a simulation study.

A new theoretical approach for photoacoustic (PA) image simulation of an ensemble of cells with endocytosed gold nanoparticles is presented. Each cell was approximated as a fluid sphere and suspended in a nonabsorbing fluid medium. It was assumed that the cellular optical absorption coefficient changed greatly because of endocytosis of nanoparticles; however, thermophysical parameters remained unchanged because nanoparticles occupied negligible intracellular volume. A frequency-domain method was used to obtain a PA signal from a single cell and resultant signal detected by a focused single-element transducer was evaluated by convolving signals from many cells with the spatial impulse response function of the receiver. The proposed model was explored to simulate PA images of numerical phantoms. It was observed that features of the phantoms are retained precisely in those simulated images. Also, speckles in PA images are significantly suppressed because of strong boundary buildup when cells are bounded to a region. Nevertheless, speckle visibility increases when cells are not bounded to a region. This approach may be developed as a realistic simulation tool for PA imaging of tissue medium utilizing its cellular feature.

Orientation enhancement in early visual processing can explain time course of brightness contrast and White's illusion.

Dynamics of orientation tuning in V1 indicates that computational model of V1 should not only comprise of bank of static spatially oriented filters but also include the contribution for dynamical response facilitation or suppression along orientation. Time evolution of orientation response in V1 can emerge due to time- dependent excitation and lateral inhibition in the orientation domain. Lateral inhibition in the orientation domain suggests that Ernst Mach's proposition can be applied for the enhancement of initial orientation distribution that is generated due to interaction of visual stimulus with spatially oriented filters and subcortical temporal filter. Oriented spatial filtering that appears much early (<70 ms) in the sequence of visual information processing can account for many of the brightness illusions observed at steady state. It is therefore expected that time evolution of orientation response might be reflecting in the brightness percept over time. Our numerical study suggests that only spatio-temporal filtering at early phase can explain experimentally observed temporal dynamics of brightness contrast illusion. But, enhancement of orientation response at early phase of visual processing is the key mechanism that can guide visual system to predict the brightness by "Max-rule" or "Winner Takes All" (WTA) estimation and thus producing White's illusions at any exposure.

Computational investigation on the photoacoustics of malaria infected red blood cells.

A computer simulation study on the possibility of using photoacoustic (PA) technique to differentiate intraerythrocytic stages of malarial parasite is reported. This parasite during its development substantially converts hemoglobin into hemozoin. This conversion is expected to alter the cellular absorption leading to changes in the PA emission of a red blood cell (RBC) at certain incident optical wavelengths. The PA signals from blood samples corresponding to ring, trophozoite and schizont stages were computed and compared with that of normal blood. A Monte Carlo algorithm was implemented generating random locations of RBCs in 3D to simulate blood samples. The average PA amplitude for wide bandwidth signals decreases for 434 nm incident radiation, but increases for 700 nm as the parasite matures. The spectral power at 7.5 MHz for the blood sample at the schizont stage compared to the normal blood is nearly reduced by 6 dB and enhanced by 22 dB at those incident wavelengths, respectively. Bandlimited signals for transducers of 15 and 50 MHz center frequencies were studied and found to exhibit similar characteristics. The presence of hemozoin inside the cells was examined and an excellent estimation was made. The simulation results suggest that intraerythrocytic stages of malarial parasite may be assessed using the PA technique.

Validity of a theoretical model to examine blood oxygenation dependent optoacoustics.

A theoretical model investigating the dependence of optoacoustic (OA) signal on blood oxygen saturation (SO(2)) is discussed. The derivations for the nonbandlimited and bandlimited OA signals from many red blood cells (RBCs) are presented. The OA field generated by many RBCs was obtained by summing the OA field emitted by each RBC approximated as a fluid sphere. A Monte Carlo technique was employed generating the spatial organizations of RBCs in two-dimensional. The RBCs were assumed to have the same SO(2) level in a simulated configuration. The fractional number of oxyhemoglobin molecules, confined in a cell, determined the cellular SO(2) and also defined the blood SO(2). For the nonbandlimited case, the OA signal amplitude decreased and increased linearly with blood SO(2) when illuminated by 700 and 1000 nm radiations, respectively. The power spectra exhibited similar trends over the entire frequency range (MHz to GHz). For the bandlimited case, three acoustic receivers with 2, 10, and 50 MHz as the center frequencies were considered. The linear variations of the OA amplitude with blood SO(2) were also observed for each receiver at those laser sources. The good agreement between simulated and published experimental results validates the model qualitatively.