Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at an advanced stage, with systemic therapy being the mainstay of treatment. Survival continues to be limited, typically less than ...1 year. The PDAC microenvironment is characterized by a paucity of malignant epithelial cells, abundant stroma with predominantly immunosuppressive T cells and myelosuppressive-type macrophages (M2), and hypovascularity. The current treatment options for metastatic PDAC are modified (m)FOLFIRINOX /FOLFIRINOX or nab-paclitaxel and gemcitabine in patients with good performance status (PS) (ECOG 0-1/KPS 70-100%) and gemcitabine with or without a second agent for those with ECOG PS 2-3. New therapies are emerging, and the current guidelines endorse both germline and somatic testing in PDAC to evaluate actionable findings. Important themes related to new therapeutic approaches include DNA damage repair strategies, immunotherapy, targeting the stroma, and cancer-cell metabolism. Targeted therapy alone (outside small genomically defined subsets) or in combination with standard cytotoxic therapy, thus far, has proven disappointing in PDAC; however, novel therapies are evolving with increased integration of genomic profiling along with a better understanding of the tumor microenvironment and immunology. A small but important sub-group of patients have some of these agents available in the clinics for use. Olaparib was recently approved by the US Food and Drug Administration for maintenance therapy in germline
BRCA1/2
mutated PDAC following demonstration of survival benefit in a phase 3 trial
.
Pembrolizumab is approved for patients with defects in mismatch repair/microsatellite instability. PDAC with wild-type
KRAS
represents a unique subgroup who have enrichment of potentially targetable oncogenic drivers. Small-molecule inhibitors including ERBB inhibitors (e.g., afatinib, MCLA-128), TRK inhibitors (e.g., larotrectinib, entrectinib),
ALK/ROS
inhibitor (e.g., crizotinib), and
BRAF/MEK
inhibitors are in development. In a small subset of patients with the
KRASG12C
mutation, a
KRASG12C
inhibitor, AMG510, and other agents are being investigated. Major efforts are underway to effectively target the tumor microenvironment and to integrate immunotherapy into the treatment of PDAC, and although thus far the impact has been modest to ineffective, nonetheless, there is optimism that some of the challenges will be overcome.
Remotely powered microrobots are proposed as next‐generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft ...tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites. In this work, bubble‐based microrobots with complex geometries are shown to efficiently swim with non‐linear trajectories in a mouse bladder, robustly pin to the epithelium, and slowly release therapeutic drugs. The asymmetric fins on the exterior bodies of the microrobots induce a rapid rotational component to their swimming motions of up to ≈150 body lengths per second. Due to their fast speeds and sharp fins, the microrobots can mechanically pin themselves to the bladder epithelium and endure shear stresses commensurate with urination. Dexamethasone, a small molecule drug used for inflammatory diseases, is encapsulated within the polymeric bodies of the microrobots. The sustained release of the drug is shown to temper inflammation in a manner that surpasses the performance of free drug controls. This system provides a potential strategy to use microrobots to efficiently navigate large volumes, pin at soft tissue boundaries, and release drugs over several days for a range of diseases.
Bubble‐containing microrobots with asymmetric fins propel within a mouse bladder at ultrafast speeds. Due to their fast speeds and sharp fins, microrobots can mechanically pin themselves to the bladder epithelium. The sustained release of drugs from the microrobots tempers inflammatory phenotypes of immune cells in a manner that surpasses the performance of the free drug.
Microrobots are being explored for biomedical applications, such as drug delivery, biological cargo transport, and minimally invasive surgery. However, current efforts largely focus on ...proof-of-concept studies with nontranslatable materials through a “design-and-apply” approach, limiting the potential for clinical adaptation. While these proof-of-concept studies have been key to advancing microrobot technologies, we believe that the distinguishing capabilities of microrobots will be most readily brought to patient bedsides through a “design-by-problem” approach, which involves focusing on unsolved problems to inform the design of microrobots with practical capabilities. As outlined below, we propose that the clinical translation of microrobots will be accelerated by a judicious choice of target applications, improved delivery considerations, and the rational selection of translation-ready biomaterials, ultimately reducing patient burden and enhancing the efficacy of therapeutic drugs for difficult-to-treat diseases.
This paper explores a recent application of the computational fluid dynamics technique “CFD” for wind analysis and its comparisons with the conventional wind tunnel experimentations. This study is ...centered on the wind response of square and corner cut-shaped building models and its optimization caused by the variation of the wind incidence angle. Extensive rigid model experiments of two building models of length scale 1:100 have been performed in the boundary layer wind tunnel. The numerical analysis has been carried out with the standard k-ε turbulence model to evaluate the force coefficients, base moments, power spectra, external surface pressure coefficients, and flow field characteristics of the models with variable wind angles of incidence. The comparisons between experimental results and CFD analysis suggest the computational approach's viability in wind analysis of tall structures efficiently and accurately. A case study of aerodynamic mitigation by corner cut suggests minor modification techniques performance, efficiency, and limitations.
Multiple networks-on-chip is a popular on-chip interconnect. This parallel communication infrastructure uses more than one NoCs to facilitate customized traffic distribution. Parallel architectures ...improve performance, however, at the cost of huge power dissipation. We propose power efficient customized placement of network selector hardware unit in the control plane at router. A network selector hardware unit is essentially used to distribute traffic between NoCs. Conventionally, this unit is placed in the data plane at network interface. We place network selector at switch allocator and at the routing unit of the router. The placement at switch allocator is more efficient than placement at routing unit or network interface. It improves 21% static power, 29% dynamic power, and 33% critical path delay of the circuit over network interface placement.
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•Histones with specific PTMs can be synthesised and assembled in designer nucleosomes.•Codon suppression, semisynthesis or chemical mutagenesis allows controlled insertion of ...PTMs.•Designer nucleosomes can probe stability and/or PTM-specific interaction partners.•In cellulo techniques show potential for locus-specific incorporation of PTM.
Chromatin is the physiological template of genetic information in all eukaryotic cells, a highly organised complex of DNA and histone proteins central in regulating gene expression and genome organisation. A multitude of histone post-translational modifications (PTMs) have been discovered, providing a glance into the complex interplay of these epigenetic marks in cellular processes. In the last decade, synthetic and chemical biology techniques have emerged to study these modifications, including genetic code expansion, histone semisynthesis and post-translational chemical mutagenesis. These methods allow for the creation of histones carrying synthetic modifications which can in turn be assembled into designer nucleosomes. Their application in vitro and in vivo is now beginning to have an important impact on chromatin biology. Efforts towards introducing multiple labile modifications in histones as well as expanding their use in cellular biology promise new powerful tools to study epigenetics.
Diffusiophoresis refers to the phenomenon where colloidal particles move in response to solute concentration gradients. Existing studies on diffusiophoresis, both experimental and theoretical, ...primarily focus on the movement of colloidal particles in response to one-dimensional solute gradients. In this work, we numerically investigate the impact of two-dimensional solute gradients on the distribution of colloidal particles,
i.e.
, colloidal banding, induced
via
diffusiophoresis. The solute gradients are generated by spatially arranged sources and sinks that emit/absorb a time-dependent solute molar rate. First we study a dipole system,
i.e.
, one source and one sink, and discover that interdipole diffusion and molar rate decay timescales dictate colloidal banding. At timescales shorter than the interdipole diffusion timescale, we observe a rapid enhancement in particle enrichment around the source due to repulsion from the sink. However, at timescales longer than the interdipole diffusion timescale, the source and sink screen each other, leading to a slower enhancement. If the solute molar rate decays at the timescale of interdipole diffusion, an optimal separation distance is obtained such that particle enrichment is maximized. We find that the partition coefficient of solute at the interface between the source and bulk strongly impacts the optimal separation distance. Surprisingly, the diffusivity ratio of solute in the source and bulk has a much weaker impact on the optimal dipole separation distance. We also examine an octupole configuration,
i.e.
, four sinks and four sources, arranged in a circle, and demonstrate that the geometric arrangement that maximizes enrichment depends on the radius of the circle. If the radius of the circle is small, it is preferred to have sources and sinks arranged in an alternating fashion. However, if the radius of the circle is large, a consecutive arrangement of sources and sinks is optimal. Our numerical framework introduces a novel method for spatially and temporally designing the banded structure of colloidal particles in two dimensions using diffusiophoresis and opens up new avenues in a field that has primarily focused on one-dimensional solute gradients.
We numerically explore diffusiophoretic banding of colloidal particles in two dimensions by spatio-temporally designing solute sources and sinks. We discover an optimal design set by a balance of interpole diffusion and molar rate decay timescales.
In this article, we consider the optimal control problem governed by the wave equation in a 2-dimensional domain
Ω
ϵ
in which the state equation and the cost functional involves highly oscillating ...periodic coefficients
A
ϵ
and
B
ϵ
, respectively. This paper aims to examine the limiting behavior of optimal control and state and identify the limit optimal control problem, which involves the influences of the oscillating coefficients.
Herein, we report synthesis of thermoresponsive poly(
N
-isopropylaccrylamide) (PNIPAM) microgels with short oligo(ethylene glycol) (OEG) chain comonomers (1 to 4/5 repeating unit) by surfactant-free ...precipitation copolymerization. The efficient incorporation of the comonomers was confirmed by a complete set of characterization methods
viz.
, FTIR,
1
H NMR, TEM, DLS, and viscometry. The structural heterogeneity and the distribution of the comonomers within the microgels were determined by means of
1
H high-resolution transverse relaxation magnetization measurements. Interestingly, the incorporation of these short OEG chain comonomers led to the formation of a core-corona structure, in which the comonomers were mainly located in the core of the polymeric network with PNIPAM dangling chains at the microgel periphery. The experimental investigations of deswelling behaviours revealed that the OEG chains allowed precise control over the colloidal properties, including phase transition, particles size, swelling degree and polydispersity of the microgels. The tuneability of these properties that was interpreted in terms of polymeric hydrophobic/hydrophilic balance as well as structural diversity, could be achieved by changing the OEG chain length, comonomer feed and crosslinking density. Further, we found that the microgels with more hydrophilic OEG chains were able to show a higher relative swelling, and the same solid content thus led to a higher viscosity at all temperatures. The OEG chains remarkably improved the colloidal stability of the microgels in electrolyte solutions even at higher temperatures, thereby paving the way for the use of these microgels in a range of applications.
This work reports the synthesis, structural analysis and colloidal properties in aqueous medium of thermoresponsive PNIPAM-based microgels incorporating short oligo(ethylene glycol) methacrylate comonomers.
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