Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiation therapy (SABR), are rapidly becoming accepted practice for the radiation ...therapy of certain tumors. Typically, SRS and SBRT involve the delivery of 1 or a few large-dose fractions of 8 to 30 Gy per fraction: a major paradigm shift from radiation therapy practice over the past 90 years, when, with relatively large amounts of normal tissues receiving high doses, the goal was to maximize tumor response for an acceptable level of normal tissue injury. The development of SRS and SBRT have come about because of technologic advances in image guidance and treatment delivery techniques that enable the delivery of large doses to tumors with reduced margins and high gradients outside the target, thereby minimizing doses to surrounding normal tissues. Because the results obtained with SRS and SBRT have been impressive, they have raised the question whether classic radiobiological modeling, and the linear-quadratic (LQ) model, are appropriate for large doses per fraction. In addition to objections to the LQ model, the possibility of additional biological effects resulting from endothelial cell damage, enhanced tumor immunity, or both have been raised to account for the success of SRS and SBRT. In this review, we conclude that the available preclinical and clinical data do not support a need to change the LQ model or to invoke phenomena over and above the classic 5 Rs of radiobiology and radiation therapy, with the likely exception that for some tumors high doses of irradiation may produce enhanced antitumor immunity. Thus, we suggest that for most tumors, the standard radiobiology concepts of the 5 Rs are sufficient to explain the clinical data, and the excellent results obtained from clinical studies are the result of the much larger biologically effective doses that are delivered with SRS and SBRT.
•Novel devices are posing challenges to existing spike sorting pipelines.•Spike sorting methodology is expanding to handle thousands to millions of neurons.•Multi-stage procedures enhance robustness ...and reliability in sorting.•Evaluation without ground truth remains an issue but is receiving increased attention.
Engineering efforts are currently attempting to build devices capable of collecting neural activity from one million neurons in the brain. Part of this effort focuses on developing dense multiple-electrode arrays, which require post-processing via ‘spike sorting’ to extract neural spike trains from the raw signal. Gathering information at this scale will facilitate fascinating science, but these dreams are only realizable if the spike sorting procedure and data pipeline are computationally scalable, at or superior to hand processing, and scientifically reproducible. These challenges are all being amplified as the data scale continues to increase. In this review, recent efforts to attack these challenges are discussed, which have primarily focused on increasing accuracy and reliability while being computationally scalable. These goals are addressed by adding additional stages to the data processing pipeline and using divide-and-conquer algorithmic approaches. These recent developments should prove useful to most research groups regardless of data scale, not just for cutting-edge devices.
We explore the dynamical response of dissipative Kerr solitons to changes in pump power and detuning and show how thermal and nonlinear processes couple these parameters to the frequency-comb degrees ...of freedom. Our experiments are enabled by a Pound-Drever-Hall (PDH) stabilization approach that provides on-demand, radio-frequency control of the frequency comb. PDH locking not only guides Kerr-soliton formation from a cold microresonator but opens a path to decouple the repetition and carrier-envelope-offset frequencies. In particular, we demonstrate phase stabilization of both Kerr-comb degrees of freedom to a fractional frequency precision below 10^{-16}, compatible with optical-time-keeping technology. Moreover, we investigate the fundamental role that residual laser-resonator detuning noise plays in the spectral purity of microwave generation with Kerr combs.
The biological effectiveness of proton beams relative to photon beams in radiation therapy has been taken to be 1.1 throughout the history of proton therapy. While potentially appropriate as an ...average value, actual relative biological effectiveness (RBE) values may differ. This Task Group report outlines the basic concepts of RBE as well as the biophysical interpretation and mathematical concepts. The current knowledge on RBE variations is reviewed and discussed in the context of the current clinical use of RBE and the clinical relevance of RBE variations (with respect to physical as well as biological parameters).
The following task group aims were designed to guide the current clinical practice:
Assess whether the current clinical practice of using a constant RBE for protons should be revised or maintained.
Identifying sites and treatment strategies where variable RBE might be utilized for a clinical benefit.
Assess the potential clinical consequences of delivering biologically weighted proton doses based on variable RBE and/or LET models implemented in treatment planning systems.
Recommend experiments needed to improve our current understanding of the relationships among in vitro, in vivo, and clinical RBE, and the research required to develop models. Develop recommendations to minimize the effects of uncertainties associated with proton RBE for well‐defined tumor types and critical structures.
Low-cost particulate matter (PM) sensors are promising
tools for supplementing existing air quality monitoring networks. However,
the performance of the new generation of low-cost PM sensors under ...field
conditions is not well understood. In this study, we characterized the
performance capabilities of a new low-cost PM sensor model (Plantower model
PMS3003) for measuring PM2.5 at 1 min, 1 h, 6 h, 12 h, and 24 h
integration times. We tested the PMS3003 sensors in both low-concentration suburban
regions (Durham and Research Triangle Park (RTP), NC, US) with 1 h
PM2.5 (mean ± SD) of 9±9 and 10±3 µg m−3, respectively, and a high-concentration urban
location (Kanpur, India) with 1 h PM2.5 of 36±17 and 116±57 µg m−3 during monsoon and post-monsoon
seasons, respectively. In Durham and Kanpur, the sensors were compared to a
research-grade instrument (environmental β attenuation monitor, E-BAM) to determine how these sensors perform across
a range of PM2.5 concentrations and meteorological factors (e.g., temperature and relative
humidity, RH). In RTP, the sensors were compared to three Federal
Equivalent Methods (FEMs) including two Teledyne model T640s and a
Thermo Scientific model 5030 SHARP to demonstrate the importance of the type
of reference monitor selected for sensor calibration. The decrease in 1 h
mean errors of the calibrated sensors using univariate linear models from
Durham (201 %) to Kanpur monsoon (46 %) and post-monsoon (35 %)
seasons showed that PMS3003 performance generally improved as ambient
PM2.5 increased. The precision of reference instruments (T640:
±0.5 µg m−3 for 1 h; SHARP: ±2 µg m−3 for
24 h, better than the E-BAM) is critical in evaluating sensor performance,
and β-attenuation-based monitors may not be ideal for testing PM
sensors at low concentrations, as underscored by (1) the less dramatic error
reduction over averaging times in RTP against optically based T640 (from 27 % for 1 h to 9 % for 24 h) than in Durham (from 201 % to 15 %);
(2) the lower errors in RTP than the Kanpur post-monsoon season (from 35 % to
11 %); and (3) the higher T640–PMS3003 correlations (R2≥0.63) than SHARP–PMS3003 (R2≥0.25). A major RH influence was
found in RTP (1 h RH =64±22 %) due to the relatively high
precision of the T640 measurements that can explain up to ∼30 % of the variance in 1 min to 6 h PMS3003 PM2.5 measurements. When
proper RH corrections are made by empirical nonlinear equations after using
a more precise reference method to calibrate the sensors, our work suggests
that the PMS3003 sensors can measure PM2.5 concentrations within
∼10 % of ambient values. We observed that PMS3003 sensors
appeared to exhibit a nonlinear response when ambient PM2.5 exceeded
∼125 µg m−3 and found that the quadratic fit is
more appropriate than the univariate linear model to capture this
nonlinearity and can further reduce errors by up to 11 %. Our results
have substantial implications for how variability in ambient PM2.5 concentrations, reference monitor types, and meteorological factors can
affect PMS3003 performance characterization.
Many tumors are dependent on de novo fatty acid synthesis to maintain cell growth. Fatty acid synthase (FASN) catalyzes the final synthetic step of this pathway, and its upregulation is correlated ...with tumor aggressiveness. The consequences and adaptive responses of acute or chronic inhibition of essential enzymes such as FASN are not fully understood. Herein we identify Fasnall, a thiophenopyrimidine selectively targeting FASN through its co-factor binding sites. Global lipidomics studies with Fasnall showed profound changes in cellular lipid profiles, sharply increasing ceramides, diacylglycerols, and unsaturated fatty acids as well as increasing exogenous palmitate uptake that is deviated more into neutral lipid formation rather than phospholipids. We also showed that the increase in ceramide levels contributes to some extent in the mediation of apoptosis. Consistent with this mechanism of action, Fasnall showed potent anti-tumor activity in the MMTV-Neu model of HER2+ breast cancer, particularly when combined with carboplatin.
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•Fasnall is a thiophenopyrimidine targeting fatty acid synthase•Fasnall has anti-proliferative activity and induces apoptosis in breast cancer cells•Fasnall promotes fatty acid uptake, ceramide and diacylglycerol accumulation•Fasnall is well tolerated and shows efficacy against HER2+ breast tumors in vivo
Many tumors are dependent on de novo fatty acid synthesis. Using a chemoproteomic screen, Alwarawrah et al. identified Fasnall, a thiophenopyrimidine fatty acid synthase inhibitor that displays anti-neoplastic activity against breast cancer in vitro and in vivo.
Next-generation sequencing technology is rapidly transforming the landscape of evolutionary biology, and has become a cost-effective and efficient means of collecting exome information for non-model ...organisms. Due to their taxonomic diversity, production of interesting venom and silk proteins, and the relative scarcity of existing genomic resources, spiders in particular are excellent targets for next-generation sequencing (NGS) methods. In this study, the transcriptomes of six entelegyne spider species from three genera (Cicurina travisae, C. vibora, Habronattus signatus, H. ustulatus, Nesticus bishopi, and N. cooperi) were sequenced and de novo assembled. Each assembly was assessed for quality and completeness and functionally annotated using gene ontology information. Approximately 100 transcripts with evidence of homology to venom proteins were discovered. After identifying more than 3,000 putatively orthologous genes across all six taxa, we used comparative analyses to identify 24 instances of positively selected genes. In addition, between ~ 550 and 1,100 unique orphan genes were found in each genus. These unique, uncharacterized genes exhibited elevated rates of amino acid substitution, potentially consistent with lineage-specific adaptive evolution. The data generated for this study represent a valuable resource for future phylogenetic and molecular evolutionary research, and our results provide new insight into the forces driving genome evolution in taxa that span the root of entelegyne spider phylogeny.
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