If Virchow and Ehrlich Had Dreamt Together: What the Future Holds for KRAS-Mutant Lung Cancer

Non-small-cell lung cancer (NSCLC) with Kirsten rat sarcoma (KRAS) mutations has notoriously challenged oncologists and researchers for three notable reasons: (1) the historical assumption that KRAS is “undruggable”, (2) the disease heterogeneity and (3) the shaping of the tumor microenvironment by KRAS downstream effector functions. Better insights into KRAS structural biochemistry allowed researchers to develop direct KRAS(G12C) inhibitors, which have shown early signs of clinical activity in NSCLC patients and have recently led to an FDA breakthrough designation for AMG-510. Following the approval of immune checkpoint inhibitors for PDL1-positive NSCLC, this could fuel yet another major paradigm shift in the treatment of advanced lung cancer. Here, we review advances in our understanding of the biology of direct KRAS inhibition and project future opportunities and challenges of dual KRAS and immune checkpoint inhibition. This strategy is supported by preclinical models which show that KRAS(G12C) inhibitors can turn some immunologically “cold” tumors into “hot” ones and therefore could benefit patients whose tumors harbor subtype-defining STK11/LKB1 co-mutations. Forty years after the discovery of KRAS as a transforming oncogene, we are on the verge of approval of the first KRAS-targeted drug combinations, thus therapeutically unifying Paul Ehrlich’s century-old “magic bullet” vision with Rudolf Virchow’s cancer inflammation theory.     

Centroid index: Cluster level similarity measure

In clustering algorithm, one of the main challenges is to solve the global allocation of the clusters instead of just local tuning of the partition borders. Despite this, all external cluster validity indexes calculate only point-level differences of two partitions without any direct information about how similar their cluster-level structures are. In this paper, we introduce a cluster level index called centroid index. The measure is intuitive, simple to implement, fast to compute and applicable in case of model mismatch as well. To a certain extent, we expect it to generalize other clustering models beyond the centroid-based k-means as well.     

K-means: Clustering by gradual data transformation

Traditional approach to clustering is to fit a model (partition or prototypes) for the given data. We propose a completely opposite approach by fitting the data into a given clustering model that is optimal for similar pathological data of equal size and dimensions. We then perform inverse transform from this pathological data back to the original data while refining the optimal clustering structure during the process. The key idea is that we do not need to find optimal global allocation of the prototypes. Instead, we only need to perform local fine-tuning of the clustering prototypes during the transformation in order to preserve the already optimal clustering structure.     

A study of 3D Network-on-Chip design for data parallel H.264 coding

In this paper, we implement, analyze and compare different Network-on-Chip (NoC) architectures aiming at higher efficiencies for MPEG-4/H.264 coding. Two-dimensional (2D) and three-dimensional (3D) NoCs based on Non-Uniform Cache Access (NUCA) are analyzed. We present results using a full system simulator with realistic workloads. Experiments show the average network latencies in two 3D NoCs are reduced by 28% and 34% respectively, comparing with 2D design. It is also shown that heat dissipation is a trade-off in improving performance of 3D chips. Our analysis and experiment results provide a guideline to design efficient 3D NoCs for data parallel H.264 coding applications.     

Diffractive backlight grating array for mobile displays

Abstract— The display backlight unit (BLU) is the most power‐consuming subunit in mobile liquid‐crystal displays. The state‐of‐the‐art BLUs utilize scattering, refractive, and reflective microstructures to generate a uniform distribution of white light through the display. More effective means of transmitting light through the display color filters could be obtained by using diffraction, but previously proposed diffractive backlights do not fully utilize all the possibilities to design gratings effectively for optimal color separation and outcoupling. This paper presents a new pixelated diffractive backlight grating array as an approach for overcoming these obstacles in BLU design. A model array was fabricated to couple out red, green, and blue primary colors from the respective subpixel locations. The results show that it is possible to manufacture such an array and that the light couples out as intended, giving a starting point to design mobile‐display modules with low light‐transmission losses.     

Bridging the physical and virtual worlds by local connectivity-based physical selection

The prevalent visions of ambient intelligence emphasise natural interaction between user and functions and services embedded in the environment or available through mobile devices. In these scenarios the physical and virtual worlds seamlessly gear into each other, making crossing the border between these worlds natural or even invisible to the user. The bottleneck in reaching these scenarios appear in the natural mapping between the physical objects and their virtual counterparts. The emergence of local connectivity in mobile devices opens possibilities for implementing novel user interface paradigms to enhance this mapping. We present physical selection paradigm for implementing an intuitive human technology interaction for mobile devices. In order to demonstrate the feasibility of the paradigm we implemented two experimental set-ups using commercially available smart phones with IrDA connectivity. The experiments involved selecting a website by physically pointing at its symbol and making a phone call by pointing at an icon representing the person to be called. In tentative user experiments the physical selection method was more time-efficient and it was perceived more positively by the users than a conventional method.

BOAR: an advanced HW/SW coemulation environment for DSP system development

The BOAR emulation system is targeted to hardware/software (HW/SW) codevelopment of advanced embedded DSP and telecom systems. The challenge of the BOAR system is efficient customization of programmable hardware, and dedicated partitioning routine to target applications and structures, which allows quite high overall system performance. The system allows multiple configurations for communication between processors and field programmable gate arrays (FPGAs) making the BOAR system an efficient tool for real-time HW/SW coverification. The reprogrammable hardware of the emulation tool is based on four Xilinx 4000-series devices, two Texas TMS320C50 signal processors and one Motorola MC68302 microcontroller. With current devices the BOAR hardware provides approximately 40–70 kgates of logic capacity in DSP applications. The emulation capacity can be expanded by connecting several similar boards in chain. The system has also a versatile internal reprogrammable test environment for test bench development, performance evaluations and design debugging. The logic development environment is based on the Synopsys synthesis tools and an automatic design management software, which performs resource mapping and performance-driven design partitioning between FPGAs. The emulation hardware is currently connected to logic and software development environments via an RS-232C bus. The BOAR emulation system has been found a very efficient platform for real-life prototyping of different types of DSP algorithms and systems, and validating correct functionality of a VHDL macro library.     

Effect of Austenite Pancaking on the Microstructure,Texture, and Bendability of an Ultrahigh-Strength Strip Steel

The effect of austenite pancaking in the non-recrystallization regime on microstructure and texture evolution and thereby on bendability was investigated in an ultrahigh-strength strip steel with a martensitic-bainitic microstructure. The results indicate that an increase in rolling reduction (R _tot) below the non-recrystallization temperature, which improves the strength and toughness properties, increases the intensities of the ~{554}〈225〉 _α and ~{112}〈110〉 _α texture components along the strip centerline and of the ~{112}〈111〉 _α component at the surface region. Even with the highest R _tot of 79 pct, the bendability along the rolling direction was good, but the preferred alignment of rod-shaped MA constituents along the rolling direction led to a dramatic decrease in the bendability transverse to the rolling direction, with severe cracking occurring even at small bending angles. The early cracking is attributed to localization of the strain in narrow shear bands. It is concluded that the R_tot value has to be limited to guarantee successful bendability.     

A review of motion planning algorithms for intelligent robots

Journal of Intelligent Manufacturing - Principles of typical motion planning algorithms are investigated and analyzed in this paper. These algorithms include traditional planning algorithms,...