A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver
occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and ...safety of tepotinib, a highly selective MET inhibitor, in this patient population.
In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed
exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a
exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.
As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval CI, 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.
Among patients with advanced NSCLC with a confirmed
exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck Darmstadt, Germany; VISION ClinicalTrials.gov number, NCT02864992.).
Nanomaterials, such as nanoparticles, nanorods, nanosphere, nanoshells, and nanostars, are very commonly used in biomedical imaging and cancer therapy. They make excellent drug carriers, imaging ...contrast agents, photothermal agents, photoacoustic agents, and radiation dose enhancers, among other applications. Recent advances in nanotechnology have led to the use of nanomaterials in many areas of functional imaging, cancer therapy, and synergistic combinational platforms. This review will systematically explore various applications of nanomaterials in biomedical imaging and cancer therapy. The medical imaging modalities include magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computerized tomography, optical imaging, ultrasound, and photoacoustic imaging. Various cancer therapeutic methods will also be included, including photothermal therapy, photodynamic therapy, chemotherapy, and immunotherapy. This review also covers theranostics, which use the same agent in diagnosis and therapy. This includes recent advances in multimodality imaging, image-guided therapy, and combination therapy. We found that the continuous advances of synthesis and design of novel nanomaterials will enhance the future development of medical imaging and cancer therapy. However, more resources should be available to examine side effects and cell toxicity when using nanomaterials in humans.
A defining property of cytotoxic lymphocytes is their expression and regulated secretion of potent toxins, including the pore-forming protein perforin and serine protease granzymes. Until recently, ...mechanisms of pore formation and granzyme transfer into the target cell were poorly understood, but advances in structural and cellular biology have now begun to unravel how synergy between perforin and granzymes brings about target cell death. These and other advances are demonstrating the surprisingly broad pathophysiological roles of the perforin–granzyme pathway, and this has important implications for understanding immune homeostasis and for developing immunotherapies for cancer and other diseases. In particular, we are beginning to define and understand a range of human diseases that are associated with a failure to deliver active perforin to target cells. In this Review, we discuss the current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology.
Intestinal microbial metabolites are conjectured to affect mucosal integrity through an incompletely characterized mechanism. Here we showed that microbial-specific indoles regulated intestinal ...barrier function through the xenobiotic sensor, pregnane X receptor (PXR). Indole 3-propionic acid (IPA), in the context of indole, is a ligand for PXR in vivo, and IPA downregulated enterocyte TNF-α while it upregulated junctional protein-coding mRNAs. PXR-deficient (Nr1i2−/−) mice showed a distinctly “leaky” gut physiology coupled with upregulation of the Toll-like receptor (TLR) signaling pathway. These defects in the epithelial barrier were corrected in Nr1i2−/−Tlr4−/− mice. Our results demonstrate that a direct chemical communication between the intestinal symbionts and PXR regulates mucosal integrity through a pathway that involves luminal sensing and signaling by TLR4.
•Pregnane X receptor (PXR) is a physiologic regulator of intestinal permeability•Microbial-derived indoles can regulate intestinal barrier function through PXR•PXR regulates intestinal barrier function through TLR4•Specific indole-producing bacteria can reduce intestinal inflammation
How commensal microbial metabolites affect mucosal integrity and barrier function is unclear. Mani and colleagues show that indole 3 propionic acid regulates intestinal barrier permeability through the PXR-TLR4 pathway.
Recent research has emphasized the promise of Immersive Virtual Reality (IVR) to bolster empathy. The underlying mechanisms of such an intriguing outcome are, however, underexplored. The present ...study examines the effect of distinct but interrelated user experiences (UX) dimensions underlying the bolstering effect of IVR on empathy. Sixty-five young adults participated in five 1-h weekly programs encompassing a total of 25 IVR experiences of different nature. Following each session, participants rated their UX of immersion-presence, illusion of body ownership, illusion of agency, engagement, and IVR-triggered mind-wandering for each IVR experience. Baseline empathy, operationalized in a multifaceted fashion, was measured both before and after the IVR program, spanning a total of seven weeks. Empathy significantly increased after the program with a moderate effect size (d = .52). Further, 27.6% of the variance in empathy change was explained by the combined effect of the UX variables. The largest predictors were illusion of body ownership and agency. The pattern of results was the same across types of IVR experience, suggesting that media content (whether empathy-evoking or not), did not moderate the relationship between UX and empathy. Together, this study highlights that IVR is more an effective “perspective taking-machine” than “empathy machine” per se.
•Empathy is a fundamental dimension of human development.•Immersive Virtual Reality (IVR) Experiences are related to increase in empathy.•The contribution of IVR user experience dimensions on empathy change is examined.•Illusion of Virtual Body Ownership and Agency best predict empathy change.•User experience is more predictive of empathy change than media content.
A Bose-Einstein condensate is the ground state of a dilute gas of bosons, such as atoms cooled to temperatures close to absolute zero
. With much smaller mass, excitons (bound electron-hole pairs) ...are expected to condense at considerably higher temperatures
. Two-dimensional van der Waals semiconductors with very strong exciton binding are ideal systems for the study of high-temperature exciton condensation. Here we study electrically generated interlayer excitons in MoSe
-WSe
atomic double layers with a density of up to 10
excitons per square centimetre. The interlayer tunnelling current depends only on the exciton density, which is indicative of correlated electron-hole pair tunnelling
. Strong electroluminescence arises when a hole tunnels from WSe
to recombine with an electron in MoSe
. We observe a critical threshold dependence of the electroluminescence intensity on exciton density, accompanied by super-Poissonian photon statistics near the threshold, and a large electroluminescence enhancement with a narrow peak at equal electron and hole densities. The phenomenon persists above 100 kelvin, which is consistent with the predicted critical condensation temperature
. Our study provides evidence for interlayer exciton condensation in two-dimensional atomic double layers and opens up opportunities for exploring condensate-based optoelectronics and exciton-mediated high-temperature superconductivity
.
Ecological community assembly is governed by a combination of (i) selection resulting from among-taxa differences in performance; (ii) dispersal resulting from organismal movement; and (iii) ...ecological drift resulting from stochastic changes in population sizes. The relative importance and nature of these processes can vary across environments. Selection can be homogeneous or variable, and while dispersal is a rate, we conceptualize extreme dispersal rates as two categories; dispersal limitation results from limited exchange of organisms among communities, and homogenizing dispersal results from high levels of organism exchange. To estimate the influence and spatial variation of each process we extend a recently developed statistical framework, use a simulation model to evaluate the accuracy of the extended framework, and use the framework to examine subsurface microbial communities over two geologic formations. For each subsurface community we estimate the degree to which it is influenced by homogeneous selection, variable selection, dispersal limitation, and homogenizing dispersal. Our analyses revealed that the relative influences of these ecological processes vary substantially across communities even within a geologic formation. We further identify environmental and spatial features associated with each ecological process, which allowed mapping of spatial variation in ecological-process-influences. The resulting maps provide a new lens through which ecological systems can be understood; in the subsurface system investigated here they revealed that the influence of variable selection was associated with the rate at which redox conditions change with subsurface depth.
Global climate change linked to the accumulation of greenhouse gases has caused concerns regarding the use of fossil fuels as the major energy source. To mitigate climate change while keeping energy ...supply sustainable, one solution is to rely on the ability of microorganisms to use renewable resources for biofuel synthesis. In this Review, we discuss how microorganisms can be explored for the production of next-generation biofuels, based on the ability of bacteria and fungi to use lignocellulose; through direct CO2 conversion by microalgae; using lithoautotrophs driven by solar electricity; or through the capacity of microorganisms to use methane generated from landfill. Furthermore, we discuss how to direct these substrates to the biosynthetic pathways of various fuel compounds and how to optimize biofuel production by engineering fuel pathways and central metabolism.
As the population of cancer survivors has grown into the millions, there has been increasing emphasis on understanding how the late effects of treatment affect survivors' ability to return to work ...school, their capacity to function and live independently, and their overall quality of life. This review focuses on cognitive change associated with cancer and cancer treatments. Research in this area has progressed from a pharmacotoxicology perspective to a view of the cognitive change as a complex interaction of aspects of the treatment, vulnerability factors that increase risk for posttreatment cognitive decline, cancer biology, and the biology of aging. Methodological advances include the development of (
a
) measurement approaches that assess more fine-grained subcomponents of cognition based on cognitive neuroscience and (
b
) advanced statistical approaches. Conceptual issues that arise from this multidimensional perspective are described in relation to future directions, understanding of mechanisms, and development of innovative interventions.
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