Response to trametinib, hydroxychloroquine, and bevacizumab in a young woman with NRAS-mutated metastatic intrahepatic cholangiocarcinoma: a case report.

Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient's condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors.

Branching Crisscross Polymerization of Single-Stranded DNA Slats.

Controlling where and when self-assembly happens is crucial in both biological and synthetic systems as it optimizes the utilization of available resources. We previously reported strictly seed-initiated linear crisscross polymerization with alternating recruitment of single-stranded DNA slats that are aligned in a parallel versus perpendicular orientation with respect to the double-helical axes. However, for some applications, it would be advantageous to produce growth that is faster than what a linear assembly can provide. Here, we implement crisscross polymerization with alternating sets of six parallel slats versus six perpendicular slats and use this framework to explore branching behavior. We present architectures that, respectively, are designed to exhibit primary, secondary, and hyperbranching growth. Thus, amplification via nonlinear crisscross polymerization can provide a route for applications such as low-cost, enzyme-free, and ultrasensitive detection.

Enzyme-Free Exponential Amplification via Growth and Scission of Crisscross Ribbons from Single-Stranded DNA Components.

The self-assembly of DNA-based monomers into higher-order structures has significant potential for realizing various biomimetic behaviors including algorithmic assembly, ultrasensitive detection, and self-replication. For these behaviors, it is desirable to implement high energetic barriers to undesired spurious nucleation, where such barriers can be bypassed via seed-initiated assembly. Joint-neighbor capture is a mechanism enabling the construction of such barriers while allowing for algorithmic behaviors, such as bit-copying. Cycles of polymerization with division could accordingly be used for implementing exponential growth in self-replicating materials. Previously, we demonstrated crisscross polymerization, a strategy that attains robust seed-dependent self-assembly of single-stranded DNA and DNA-origami monomers via joint-neighbor capture. Here, we expand the crisscross assembly to achieve autonomous, isothermal exponential amplification of ribbons through their concurrent growth and scission via toehold-mediated strand displacement. We demonstrate how this crisscross chain reaction, or 3CR, can be used as a detection strategy through coupling to single- and double-stranded nucleic acid targets and introduce a rule-based stochastic modeling approach for simulating molecular self-assembly behaviors such as crisscross-ribbon scission.

Tunable full-color emission of stilbazoles containing a 2-halo-3,4-dicyanopyridine acceptor.

Synthesis of a series of novel push-pull stilbazole-based chromophores containing a strong 2-halocinchomeronic dinitrile acceptor is reported. The photophysical properties of the compounds are described. Strong positive solvatofluorochromism typical of intramolecular charge transfer (ICT) dyes is observed for the synthesized stilbazoles. Their tunable multicolor emission ranges from 442 nm to 710 nm and covers the whole visible spectrum.

Crystal structure and Hirshfeld surface analysis of (22 RS,23 SR,25 RS,26 SR)-23,25,5-trimethyl-21-(2,2,2-tri-fluoro-acet-yl)-5-aza-2(2,6)-piperidina-1,3(2,5)-di-furana-cyclo-hexa-phan-24-one.

The title compound, C20H21F3N2O4, features a main twelve-membered difuryl ring with which the furan rings make dihedral angles of 76.14 (5) and 33.81 (5)°. The dihedral angle between the furan rings is 42.55 (7)°. The six-membered nitro-gen heterocycle has a twist-boat conformation. In the crystal, pairs of mol-ecules are connected by inter-molecular C-H⋯O inter-actions, generating an R 2 2(14) ring motif. These pairs of mol-ecules form zigzag chains along the a-axis direction by means of C-H⋯F inter-actions. Furthermore, C-H⋯π and C-F⋯π inter-actions link the mol-ecules into chains along the b-axis direction, forming sheets parallel to the (001) plane. These sheets are also connected by van der Waals inter-actions.

KRAS, NRAS, BRAF, HER2 and MSI Status in a Large Consecutive Series of Colorectal Carcinomas.

This study aimed to analyze clinical and regional factors influencing the distribution of actionable genetic alterations in a large consecutive series of colorectal carcinomas (CRCs). KRAS, NRAS and BRAF mutations, HER2 amplification and overexpression, and microsatellite instability (MSI) were tested in 8355 CRC samples. KRAS mutations were detected in 4137/8355 (49.5%) CRCs, with 3913 belonging to 10 common substitutions affecting codons 12/13/61/146, 174 being represented by 21 rare hot-spot variants, and 35 located outside the "hot" codons. KRAS Q61K substitution, which leads to the aberrant splicing of the gene, was accompanied by the second function-rescuing mutation in all 19 tumors analyzed. NRAS mutations were detected in 389/8355 (4.7%) CRCs (379 hot-spot and 10 non-hot-spot substitutions). BRAF mutations were identified in 556/8355 (6.7%) CRCs (codon 600: 510; codons 594-596: 38; codons 597-602: 8). The frequency of HER2 activation and MSI was 99/8008 (1.2%) and 432/8355 (5.2%), respectively. Some of the above events demonstrated differences in distribution according to patients' age and gender. In contrast to other genetic alterations, BRAF mutation frequencies were subject to geographic variation, with a relatively low incidence in areas with an apparently warmer climate (83/1726 (4.8%) in Southern Russia and North Caucasus vs. 473/6629 (7.1%) in other regions of Russia, p = 0.0007). The simultaneous presence of two drug targets, BRAF mutation and MSI, was observed in 117/8355 cases (1.4%). Combined alterations of two driver genes were detected in 28/8355 (0.3%) tumors (KRAS/NRAS: 8; KRAS/BRAF: 4; KRAS/HER2: 12; NRAS/HER2: 4). This study demonstrates that a substantial portion of RAS alterations is represented by atypical mutations, KRAS Q61K substitution is always accompanied by the second gene-rescuing mutation, BRAF mutation frequency is a subject to geographical variations, and a small fraction of CRCs has simultaneous alterations in more than one driver gene.

Multi-micron crisscross structures grown from DNA-origami slats.

Living systems achieve robust self-assembly across a wide range of length scales. In the synthetic realm, nanofabrication strategies such as DNA origami have enabled robust self-assembly of submicron-scale shapes from a multitude of single-stranded components. To achieve greater complexity, subsequent hierarchical joining of origami can be pursued. However, erroneous and missing linkages restrict the number of unique origami that can be practically combined into a single design. Here we extend crisscross polymerization, a strategy previously demonstrated with single-stranded components, to DNA-origami 'slats' for fabrication of custom multi-micron shapes with user-defined nanoscale surface patterning. Using a library of ~2,000 strands that are combinatorially arranged to create unique DNA-origami slats, we realize finite structures composed of >1,000 uniquely addressable slats, with a mass exceeding 5 GDa, lateral dimensions of roughly 2 µm and a multitude of periodic structures. Robust production of target crisscross structures is enabled through strict control over initiation, rapid growth and minimal premature termination, and highly orthogonal binding specificities. Thus crisscross growth provides a route for prototyping and scalable production of structures integrating thousands of unique components (that is, origami slats) that each is sophisticated and molecularly precise.

Robust nucleation control via crisscross polymerization of highly coordinated DNA slats.

Natural biomolecular assemblies such as actin filaments or microtubules can exhibit all-or-nothing polymerization in a kinetically controlled fashion. The kinetic barrier to spontaneous nucleation arises in part from positive cooperativity deriving from joint-neighbor capture, where stable capture of incoming monomers requires straddling multiple subunits on a filament end. For programmable DNA self-assembly, it is likewise desirable to suppress spontaneous nucleation to enable powerful capabilities such as all-or-nothing assembly of nanostructures larger than a single DNA origami, ultrasensitive detection, and more robust algorithmic assembly. However, existing DNA assemblies use monomers with low coordination numbers that present an effective kinetic barrier only for slow, near-reversible growth conditions. Here we introduce crisscross polymerization of elongated slat monomers that engage beyond nearest neighbors which sustains the kinetic barrier under conditions that promote fast, irreversible growth. By implementing crisscross slats as single-stranded DNA, we attain strictly seed-initiated nucleation of crisscross ribbons with distinct widths and twists.

Facile synthesis of pyrrolo[2,1-a]isoquinolines by domino reaction of 1-aroyl-3,4-dihydroisoquinolines with conjugated ketones, nitroalkenes and nitriles.

A convenient protocol for the synthesis of 5,6-dihydropyrrolo[2,1-a]isoquinolines with various electron-withdrawing substituents at C-2 atom is described. This approach is based on the two-component domino reaction of 1-aroyl-3,4-dihydroisoquinolines with α,ß-unsaturated ketones, nitroalkenes and acrylonitrile. Depending on the selected substrates, the reaction was performed in TFE under reflux or under microwave irradiation. Only for the two examples, a transition metal catalyst was used.