PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Upconversion amplification through dielectric superlensing modulation.

Achieving efficient photon upconversion under low irradiance is not only a fundamental challenge but also central to numerous advanced applications spanning from photovoltaics to biophotonics. However, to date, almost all approaches for upconversion luminescence intensification require stringent controls over numerous factors such as composition and size of nanophosphors. Here, we report the utilization of dielectric microbeads to significantly enhance the photon upconversion processes in lanthanide-doped nanocrystals. By modulating the wavefront of both excitation and emission fields through dielectric superlensing effects, luminescence amplification up to 5 orders of magnitude can be achieved. This design delineates a general strategy to converge a low-power incident light beam into a photonic hotspot of high field intensity, while simultaneously enabling collimation of highly divergent emission for far-field accumulation. The dielectric superlensing-mediated strategy may provide a major step forward in facilitating photon upconversion processes toward practical applications in the fields of photobiology, energy conversion, and optogenetics.

Fibro-Neuronal Guidance on Common, 3D-Printed Textured Substrates.

Ability to direct neuronal growth not only carries great potential for treating neural conditions-for example, bridging traumatically shattered connections-but would also be an exquisite tool for bionic applications that require a physical interface between neurons and electronics. A testing platform is needed to better understand axonal guidance in the context of a specific in vivo application. Versatility of 3D printing technology allows tailoring to researcher needs, both in vitro and in vivo. In this paper, we establish a fibro-neuronal co-culture inspired by our neural interface research and demonstrate axon alignment on a textured substrate fabricated with a common, versatile 3D-printing set-up.

All-inorganic perovskite nanocrystal scintillators.

The rising demand for radiation detection materials in many applications has led to extensive research on scintillators1-3. The ability of a scintillator to absorb high-energy (kiloelectronvolt-scale) X-ray photons and convert the absorbed energy into low-energy visible photons is critical for applications in radiation exposure monitoring, security inspection, X-ray astronomy and medical radiography4,5. However, conventional scintillators are generally synthesized by crystallization at a high temperature and their radioluminescence is difficult to tune across the visible spectrum. Here we describe experimental investigations of a series of all-inorganic perovskite nanocrystals comprising caesium and lead atoms and their response to X-ray irradiation. These nanocrystal scintillators exhibit strong X-ray absorption and intense radioluminescence at visible wavelengths. Unlike bulk inorganic scintillators, these perovskite nanomaterials are solution-processable at a relatively low temperature and can generate X-ray-induced emissions that are easily tunable across the visible spectrum by tailoring the anionic component of colloidal precursors during their synthesis. These features allow the fabrication of flexible and highly sensitive X-ray detectors with a detection limit of 13 nanograys per second, which is about 400 times lower than typical medical imaging doses. We show that these colour-tunable perovskite nanocrystal scintillators can provide a convenient visualization tool for X-ray radiography, as the associated image can be directly recorded by standard digital cameras. We also demonstrate their direct integration with commercial flat-panel imagers and their utility in examining electronic circuit boards under low-dose X-ray illumination.

Gunslinger Effect and Müller-Lyer Illusion: Examining Early Visual Information Processing for Late Limb-Target Control.

The multiple process model contends that there are two forms of online control for manual aiming: impulse regulation and limb-target control. This study examined the impact of visual information processing for limb-target control. We amalgamated the Gunslinger protocol (i.e., faster movements following a reaction to an external trigger compared with the spontaneous initiation of movement) and Müller-Lyer target configurations into the same aiming protocol. The results showed the Gunslinger effect was isolated at the early portions of the movement (peak acceleration and peak velocity). Reacted aims reached a longer displacement at peak deceleration, but no differences for movement termination. The target configurations manifested terminal biases consistent with the illusion. We suggest the visual information processing demands imposed by reacted aims can be adapted by integrating early feedforward information for limb-target control.

Regulation of later neurogenic stages of adult-derived neural stem/progenitor cells by L-type Ca2+ channels.

In the adult hippocampus, new neurons are continuously generated and incorporated into the local circuitry in a manner dependent on the network activity. Depolarization evoked by neurotransmitters has been assumed to activate L-type Ca2+ channels (LTCC) which regulate the intracellular Ca2+ -dependent signaling cascades. The process of neurogenesis contains several stages such as proliferation, fate determination, selective death/survival and maturation. Here, we investigated which stage of neurogenesis is under the regulation of LTCC using a clonal line of neural stem/progenitor cells, PZ5, which was derived from adult rat hippocampus. Although undifferentiated PZ5 cells were type 1-like cells expressing both nestin and glial fibrillary acidic protein, they generated neuronal, astrocytic and oligodendrocytic populations in differentiation medium containing retinoic acid. Proliferation of undifferentiated PZ5 cells was dependent on neither the LTCC antagonist, nimodipine (Nimo) nor the LTCC agonists, Bay K 8644 (BayK) or FPL 64176 (FPL), whereas the fraction of neuronal population that expressed both ßIII-tubulin and MAP2 was reduced by Nimo but increased by BayK or FPL. At an earlier period of differentiation (e.g., day 4), the fraction of PZ5 cells expressing HuC/D, pan-neuronal marker, was not affected either by the LTCC activation or inhibition. At a later period of differentiation (e.g., day 9), the fraction of dying neurons was decreased by LTCC activation and increased by LTCC inhibition. It is suggested that the LTCC activation facilitates the survival and maturation of immature neurons, and that its inhibition facilitates the neuronal death.

The gunslinger effect: why are movements made faster when responding to versus initiating an action?

The authors replicated and extended results from the gunfight paradigm (A. Welchman, J. Stanley, M. Schomers, R. Miall, & H. Bulthoff, 2010a) in which participants moved faster when reacting to the perceived initiation of an opponent compared to initiating an action themselves. In addition to replicating these movement time effects, the authors found that time to peak velocity, peak velocity, and movement-endpoint dispersions were similarly impacted. The findings are discussed in terms of a triggering mechanism involved in ballistic and internally generated movements.

Image-guided focused ultrasound ablation of breast cancer: current status, challenges, and future directions.

Image-guided focussed ultrasound (FUS) ablation is a non-invasive procedure that has been used for treatment of benign or malignant breast tumours. Image-guidance during ablation is achieved either by using real-time ultrasound (US) or magnetic resonance imaging (MRI). The past decade phase I studies have proven MRI-guided and US-guided FUS ablation of breast cancer to be technically feasible and safe. We provide an overview of studies assessing the efficacy of FUS for breast tumour ablation as measured by percentages of complete tumour necrosis. Successful ablation ranged from 20% to 100%, depending on FUS system type, imaging technique, ablation protocol, and patient selection. Specific issues related to FUS ablation of breast cancer, such as increased treatment time for larger tumours, size of ablation margins, methods used for margin assessment and residual tumour detection after FUS ablation, and impact of FUS ablation on sentinel node procedure are presented. Finally, potential future applications of FUS for breast cancer treatment such as FUS-induced anti-tumour immune response, FUS-mediated gene transfer, and enhanced drug delivery are discussed. Currently, breast-conserving surgery remains the gold standard for breast cancer treatment.

MRI-guided needle localization of suspicious breast lesions: results of a freehand technique.

Magnetic resonance imaging (MRI) can detect clinically and mammographically occult breast lesions. In this study we report the results of MRI-guided needle localization of suspicious breast lesions by using a freehand technique. Preoperative MRI-guided single-needle localization was performed in 220 patients with 304 MRI-only breast lesions at our hospital between January 1997 and July 2004. Procedures were performed in an open 0.5-T Signa-SP imager allowing real-time monitoring, with patient in prone position, by using a dedicated breast coil. MRI-compatible hookwires were placed in a noncompressed breast by using a freehand technique. MRI findings were correlated with pathology and follow-up. MRI-guided needle localization was performed for a single lesion in 150 patients, for two lesions in 56 patients, and for three lesions in 14 patients. Histopathologic analysis of these 304 lesions showed 104 (34%) malignant lesions, 51 (17%) high-risk lesions, and 149 (49%) benign lesions. The overall lesion size ranged from 2.0-65.0 mm (mean 11.2 mm). No direct complications occurred. Follow-up MRI in 54 patients showed that two (3.7%) lesions were missed by surgical biopsy. MRI-guided freehand needle localization is accurate and allows localization of lesions anterior in the breast, the axillary region, and near the chest wall.

First use of a truly-hybrid X-ray/MR imaging system for guidance of brain biopsy.

The use of a new hybrid imaging system for guidance of a brain biopsy is described. The system combines the strengths of MRI (soft-tissue contrast, arbitrary plane selection) with those of x-ray fluoroscopy (high-resolution real-time projection images, clear portrayal of bony structures) and allows switching between the imaging modalities without moving the patient. The biopsy was carried out using x-ray guidance for direction of the needle through the foramen ovale and MR guidance to target the soft-tissue lesion. Appropriate samples were acquired. The system could be particularly effective for guidance of those cases where motion, swelling, resection and other intra-operative anatomical changes cannot be accounted for using traditional stereotactic-based imaging approaches.

Temperature mapping of frozen tissue using eddy current compensated half excitation RF pulses.

Cryosurgery has been shown to be an effective therapy for prostate cancer. Temperature monitoring throughout the cryosurgical iceball could dramatically improve efficacy, since end temperatures of at least -40 degrees C are required. The results of this study indicate that MR thermometry based on tissue R(*)(2) has the potential to provide this information. Frozen tissue appears as a complete signal void on conventional MRI. Ultrashort echo times (TEs), achievable with half pulse excitation and a short spiral readout, allow frozen tissue to be imaged and MR characteristics to be measured. However, half pulse excitation is highly sensitive to eddy current distortions of the slice-select gradient. In this work, the effects of eddy currents on the half pulse technique are characterized and methods to overcome these effects are developed. The methods include: 1) eddy current compensated slice-select gradients, and 2) a correction for the phase shift between the first and second half excitations at the center of the slice. The effectiveness of these methods is demonstrated in R(*)(2) maps calculated within the frozen region during cryoablation.

Potential role of magnetic resonance imaging and other modalities in ductal carcinoma in situ detection.

Ductal Carcinoma In Situ (DCIS) is the earliest form of ductal cancer, with a high rate of care if treated early. This article outlines the use of breast imaging in DCIS diagnosis, including mammography, MR imaging, and nuclear medicine studies. While MR imaging and nuclear medicine show great promise in DCIS diagnosis, mammography remains the mainstay of DCIS detection by the presence of microcalcifications in early tumors on the mammogram.

Freehand iMRI-guided large-gauge core needle biopsy: a new minimally invasive technique for diagnosis of enhancing breast lesions.

The lack of reliable methods for minimally invasive biopsy of suspicious enhancing breast lesions has hindered the utilization of contrast-enhanced magnetic resonance imaging (MRI) for the detection and diagnosis of breast cancer. In this study, a freehand method was developed for large-gauge core needle biopsy (LCNB) guided by intraprocedural MRI (iMRI). Twenty-seven lesions in nineteen patients were biopsied using iMRI-guided LCNB without significant complications. Diagnostic tissue was obtained in all cases. Nineteen of the 27 lesions were subsequently surgically excised. Histopathologic analysis confirmed that iMRI-guided LCNB correctly distinguished benign lesions from malignancy in 18 of the 19 lesions. The histology revealed by core biopsy was partially discrepant with surgical biopsy in 2 of the other 19 lesions. Freehand iMRI-guided LCNB of enhancing breast lesions is promising. Larger studies are needed to determine the smallest lesion that can be sampled reliably and to precisely measure the accuracy of iMRI-guided LCNB as a minimally invasive tool to diagnose suspicious lesions found by breast MRI. J. Magn. Reson. Imaging 2001;13:896-902.

Intensity-modulated parametric mapping for simultaneous display of rapid dynamic and high-spatial-resolution breast MR imaging data.

Contrast material-enhanced magnetic resonance (MR) imaging of the breast has variable specificity for differentiation of breast cancer from other enhancing conditions. Two principal strategies to improve its specificity are rapid dynamic MR imaging and high-spatial-resolution MR imaging. A method was developed of combining contemporaneously acquired dynamic and high-spatial-resolution MR imaging data into a single integrated display. Whole-breast rapid dynamic data were condensed into a color map by using pharmacokinetic analysis. The pharmacokinetic results were combined with the high-spatial-resolution images with a new technique that preserves underlying morphologic details. This new method was evaluated by five radiologists for eight breast lesions, and the results were compared with those of the standard method of overlaying parametric map data. The radiologists' ratings showed a statistically significant preference for the intensity-modulated parametric map display method over the overlaid parametric display method for 10 of the 12 evaluation criteria. The new method enabled simultaneous visualization of pharmacokinetic and morphologic information, facilitated assessment of lesion extent, and improved the suppression of noise in the pharmacokinetic data. The ability to simultaneously assess both dynamic and high-spatial-resolution features may ultimately improve the specificity of breast MR imaging.

Temperature quantitation and mapping of frozen tissue.

A method was developed for quantitating the temperature within frozen tissue with the magnetic resonance (MR) parameter R2*. The pulse sequence uses half-pulse excitation and a short spiral readout to achieve echo times as short as 0.2 msec. Fiber-optic temperature sensors were inserted into bovine liver tissue. The tissue was frozen at one end while being held warm at the other end. Once steady state was reached, the parameter R2* was measured. A linear dependence of R2* on temperature was demonstrated. R2* is independent of freeze number and of the orientation of the temperature gradient with respect to the main magnetic field. Feasibility in a canine prostate during cryosurgery is demonstrated. J. Magn. Reson. Imaging 2001;13:99-104.

A truly hybrid interventional MR/X-ray system: feasibility demonstration.

A system enabling both x-ray fluoroscopy and MRI in a single exam, without requiring patient repositioning, would be a powerful tool for image-guided interventions. We studied the technical issues related to acquisition of x-ray images inside an open MRI system (GE Signa SP). The system includes a flat-panel x-ray detector (GE Medical Systems) placed under the patient bed, a fixed-anode x-ray tube overhead with the anode-cathode axis aligned with the main magnetic field and a high-frequency x-ray generator (Lunar Corp.). New challenges investigated related to: 1) deflection and defocusing of the electron beam of the x-ray tube; 2) proper functioning of the flat panel; 3) effects on B0 field homogeneity; and 4) additional RF noise in the MR images. We have acquired high-quality x-ray and MR images without repositioning the object using our hybrid system, which demonstrates the feasibility of this new configuration. Further work is required to ensure that the highest possible image quality is achieved with both MR and x-ray modalities.

Truly hybrid interventional MR/X-ray system: investigation of in vivo applications.

RATIONALE AND OBJECTIVES: The purpose of this study was to provide in vivo demonstrations of the functionality of a truly hybrid interventional x-ray/magnetic resonance (MR) system. MATERIALS AND METHODS: A digital flat-panel x-ray system (1,024(2) array of 200 microm pixels, 30 frames per second) was integrated into an interventional 0.5-T magnet. The hybrid system is capable of MR and x-ray imaging of the same field of view without patient movement. Two intravascular procedures were performed in a 22-kg porcine model: placement of a transjugular intrahepatic portosystemic shunt (TIPS) (x-ray-guided catheterization of the hepatic vein, MR fluoroscopy-guided portal puncture, and x-ray-guided stent placement) and mock chemoembolization (x-ray-guided subselective catheterization of a renal artery branch and MR evaluation of perfused volume). RESULTS: The resolution and frame rate of the x-ray fluoroscopy images were sufficient to visualize and place devices, including nitinol guidewires (0.016-0.035-inch diameter) and stents and a 2.3-F catheter. Fifth-order branches of the renal artery could be seen. The quality of both real-time (3.5 frames per second) and standard MR images was not affected by the x-ray system. During MR-guided TIPS placement, the trocar and the portal vein could be easily visualized, allowing successful puncture from hepatic to portal vein. CONCLUSION: Switching back and forth between x-ray and MR imaging modalities without requiring movement of the patient was demonstrated. The integrated nature of the system could be especially beneficial when x-ray and MR image guidance are used iteratively.

Magnetic resonance imaging of breast cancer: clinical indications and breast MRI reporting system.

Magnetic resonance imaging (MRI) is well suited to the investigation of breast cancer by virtue of its noninvasive nature and its multiplanar imaging abilities. MRI investigations showed high sensitivity but modest specificity for breast cancer detection and diagnosis. Most early studies tested the ability of MRI to evaluate and diagnose findings in the breast discovered by other imaging tests or by breast physical examination (1-4). When it was discovered that MRI identified small breast cancers undetected by mammography or breast ultrasound, MRI was used to estimate breast cancer extent in known cancer cases for surgical planning (5,6). These investigations led to the use of MRI in a multitude of breast imaging applications, raising further questions about the use of MRI in everyday practice: What are the indications for breast MRI in general practice? What is its role in light of other imaging tests? What are its benefits and limitations in each setting? How do I report these studies? The purpose of this article is to review the clinical background regarding indications for the use of MRI and relevant cases in which MRI can impact patient management in breast disease, and to describe new developments in reporting breast MRI studies. J. Magn. Reson. Imaging 2000;12:975-983.

Single-shot fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging of the bladder.

The purpose of this study was to reduce artifacts and increase imaging speed in fluid-attenuated inversion recovery (FLAIR) imaging of the urinary bladder. An existing half-Fourier, single-shot fast spin-echo imaging sequence was modified to allow presaturation with a non-slice-selective inversion recovery pulse (NSI SSFLAIR). Four independent, blinded readers rated severity of bladder artifacts and image quality in six normal male volunteers. NSI SSFLAIR effectively suppressed bladder urine signal in all six cases using a TI of 2900-3100 msec. Although NSI SSFLAIR images were noisier than standard fast spin-echo images, imaging time was only 10 seconds per slice location. Furthermore, perceived image sharpness was only minimally reduced, and conspicuity of the seminal vesicles and peripheral zone of the prostate were nearly equivalent. NSI SSFLAIR provides rapid T2-weighted imaging of the bladder wall and perivesicular tissues with nearly complete negation of signal from urine in the bladder.