The intrinsic limits of conventional cancer therapies prompted the development and application of various nanotechnologies for more effective and safer cancer treatment, herein referred to as cancer nanomedicine. Considerable technological success has been achieved in this field, but the main obstacles to nanomedicine becoming a new paradigm in cancer therapy stem from the complexities and heterogeneity of tumour biology, an incomplete understanding of nano-bio interactions and the challenges regarding chemistry, manufacturing and controls required for clinical translation and commercialization. This Review highlights the progress, challenges and opportunities in cancer nanomedicine and discusses novel engineering approaches that capitalize on our growing understanding of tumour biology and nano-bio interactions to develop more effective nanotherapeutics for cancer patients.

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Cancer nanomedicine: progress, challenges and opportunities.

Much has been written about theory and practice in the law, and the tension between practitioners and theorists. Judges do not cite theoretical articles often; they rarely "apply" theories to particular cases. These arguments are not revisited. Instead the Essay explores the working and interaction of theory and practice, practitioners and theorists. The Essay starts with a story about solving a legal issue using our intellectual tools - theory, practice, and their progenies: experience and "gut." Next the Essay elaborates on the nature of theory, practice, experience and "gut." The third part of the Essay discusses theories that are helpful to practitioners and those that are less helpful. The Essay concludes that practitioners theorize, and theorists practice. They use these intellectual tools differently because the goals and orientations of theorists and practitioners, and the constraints under which they act, differ. Theory, practice, experience and "gut" help us think, remember, decide and create. They complement each other like the two sides of the same coin: distinct but inseparable.

Of Theory and Practice

This thesis explores transport phenomena in nanochannels on a chip. Fundamental nanofluidic ionic studies form the basis for novel separation and preconcentration applications for proteomic purposes. The measurements were performed with 50-nm-high 1D nanochannels, which are easily accessible from both sides by two microchannels. Nanometer characteristic apertures were manufactured in the bonded structure of Pyrex-amorphous silicon – Pyrex, in which the thickness of the amorphous silicon layer serves as a spacer to define the height of the nanochannels. The geometry of the nanometer-sized apertures is well defined, which simplifies the modeling of the transport across them. Compared to biological pores, the present nanochannels in Pyrex offer increased stability. Fundamental characteristics of nanometer-sized apertures were obtained by impedance spectroscopy measurements of the nanochannel at different ionic strengths and pH values. A conductance plateau (on a log-log scale) was modeled and measured, establishing due to the dominance of the surface charge density in the nanochannels, which induces an excess of mobile counterions to maintain electroneutrality. The nanochannel conductance can be regulated at low ionic strengths by pH adjustment, and by an external voltage applied on the chip to change the zeta potential. This field-effect allows the regulation of ionic flow which can be exploited for the fabrication of nanofluidic devices. Fluorescence measurements confirm that 50-nm-high nanochannels show an exclusion of co-ions and an enrichment of counterions at low ionic strengths. This permselectivity is related to the increasing thickness of the electrical double layer (EDL) with decreasing salt concentrations, which results in an EDL overlap in an aperture if the height of the nanochannel and the thickness of the EDL are comparable in size. The diffusive transport of charged species and therefore the exclusion-enrichment effect was described with a simple model based on the Poisson-Boltzmann equation. The negatively charged Pyrex surface of the nanometer characteristic apertures can be inversed with chemical surface pretreatments, resulting in an exclusion of cations and an enrichment of anions. When a pressure gradient is applied across the nanochannels, charged molecules are electrostatically rejected at the entrance of the nanometer-sized apertures, which can be used for separation processes. Proteomic applications are presented such as the separation and preconcentration of proteins. The diffusion of Lectin proteins with different isoelectric points and very similar compositions were controlled by regulating the pH value of the buffer. When the proteins are neutral at their pI value, the diffusion coefficient is maximal because the biomolecules does not interact electrostatically with the charged surfaces of the nanochannel. This led to a fast separation of three Lectin proteins across the nanochannel. The pI values measured in this experiment are slightly shifted compared to the values obtained with isoelectric focusing because of reversible adsorption of proteins on the walls which affects the pH value in the nanochannel. An important application in the proteomic field is the preconcentration of biomolecules. By applying an electric field across the nanochannel, anionic and cationic analytes were preconcentrated on the cathodic side of the nanometer-sized aperture whereas on the anodic side depletion of ions was observed. This is due to concentration polarization, a complex of effects related to the formation of ionic concentration gradients in the electrolyte solution adjacent to an ion-selective interface. It was measured that the preconcentration factor increased with the net charge of the molecule, leading to a preconcentration factor of > 600 for rGFP proteins in 9 minutes. Such preconcentrations are important in micro total analysis systems to achieve increased detection signals of analytes contained in dilute solutions. Compared to cylindrical pores, our fabrication process allows the realization of nanochannels on a chip in which the exclusion-enrichment effect and a big flux across the nanometer-sized aperture can be achieved, showing the interest for possible micro total analysis system applications. The described exclusion-enrichment effect as well as concentration polarization play an important role in transport phenomena in nanofluidics. The appendix includes preliminary investigations in DNA molecule separation and fluorescence correlation spectroscopy measurements, which allows investigating the behavior of molecules in the nanochannel itself.

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Transport phenomena in nanofluidics

An object is to provide a semiconductor device of which a manufacturing process is not complicated and by which cost can be suppressed, by forming a thin film transistor using an oxide semiconductor film typified by zinc oxide, and a manufacturing method thereof. For the semiconductor device, a gate electrode is formed over a substrate; a gate insulating film is formed covering the gate electrode; an oxide semiconductor film is formed over the gate insulating film; and a first conductive film and a second conductive film are formed over the oxide semiconductor film. The oxide semiconductor film has at least a crystallized region in a channel region.

Semiconductor device, and manufacturing method thereof

The formulation and delivery of biopharmaceutical drugs, such as monoclonal antibodies and recombinant proteins, poses substantial challenges owing to their large size and susceptibility to degradation. In this Review we highlight recent advances in formulation and delivery strategies — such as the use of microsphere-based controlled-release technologies, protein modification methods that make use of polyethylene glycol and other polymers, and genetic manipulation of biopharmaceutical drugs — and discuss their advantages and limitations. We also highlight current and emerging delivery routes that provide an alternative to injection, including transdermal, oral and pulmonary delivery routes. In addition, the potential of targeted and intracellular protein delivery is discussed.

Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies

The present invention provides a microfluidic purification chip for capturing a biomarker from a physiological solution. The present invention also provides a method of capturing and releasing a biomarker, wherein the biomarker is originally in a physiological solution. The present invention further provides a method of pre-purifying and measuring the concentration of a biomarker in a physiological solution.

Physiologic sample preparation for nanosensors

Les cauchemars chroniques ont un impact majeur sur la santé mentale et le risque suicidaire. Ils présentent une prévalence élevée dans les populations psychiatriques, notamment chez les patients souffrants d’un trouble de stress post-traumatique (TSPT) et également chez les patients atteints de troubles de l’humeur (trouble dépressif unipolaire et troubles bipolaire) ou de schizophrénie. La thérapie par répétition d’imagerie mentale (ou RIM) est considérée à ce jour comme le traitement de référence de la maladie des cauchemars. À l’aide d’éducation thérapeutique et de restructuration cognitive, la RIM consiste à retravailler le scénario des cauchemars en journée, en usant d’imagerie mentale, afin de les modifier la nuit. Cette courte revue propose une description de la thérapie par répétition d’imagerie mentale ainsi qu’un résumé des éléments fondamentaux pour sa mise en place pratique, en s’appuyant notamment sur un exemple concret de mise en place d’un groupe thérapeutique pour le traitement des cauchemars par RIM en 4 brèves séances. 

Traitement des cauchemars par la thérapie par répétition d’imagerie mentale (ou RIM) : mise en place pratique

Background Macroprolactin is an immunoglobulin-prolactin complex that is not bioactive in vivo but the prolactin component remains immunoreactive. The complex is a universal source of interference in prolactin immunoassays and commonly results in misdiagnosis of hyperprolactinemia with consequent clinical mismanagement of patients. Removal of macroprolactin by precipitation with polyethylene glycol (PEG) is an effective technique for identifying such patients but unfortunately not universally employed due to the manual nature of the procedure. Methods We developed a modified PEG precipitation technique using magnetic nanoparticles that we termed Magnetically Assisted PEG Precipitation (MAPP). This procedure was verified against an established PEG precipitation procedure. Results The MAPP procedure we developed was robust, reproducible, and affords the potential for automation of macroprolactin screening in clinical laboratories. Comparisons of prolactin levels obtained following MAPP in sera from patients with either true hyperprolactinemia or macroprolactinemia generated results comparable to that of conventional PEG precipitation. Conclusions The MAPP technique yields results comparable to those of traditional PEG precipitation. Elimination of the need for centrifugation affords the possibility of automation and hence more widespread adoption of routine PEG screening by clinical laboratories.

Macroprolactinemia Detection by Magnetically Assisted Polyethylene Glycol Precipitation: Potential for Automation.

The present invention provides, among other things, a master cartridge for effective storage and transportation of antimicrobials, the master cartridge comprising multiple reservoir units for placing a plurality of antimicrobials at high concentration from which multiple patient cartridges could be generated for testing a plurality of biological samples, and methods for using the same.

Antimicrobial Cartridges and Processes for Antimicrobial Susceptibility Testing

The use of metabolic probes is well-established for determining cell viability and assessing drug cytotoxicity. Resazurin-based formulations, in particular, have found utility for determining susceptibilities of microorganisms to antimicrobials, specifically through their use in antibiotic susceptibility testing (AST). There is a strong need currently to shorten AST durations, thus resazurin formulations that produce signals earlier are advantageous. This need results from the slow state of clinical microbiology testing, which may leave patients exposed to unnecessary or ineffective broad-spectrum agents for prolonged periods of time. Another slow microbiology test is Gram staining, still most often performed manually in sequential steps. Speeding Gram typing, preferably with an automated platform, would also speed time-to-results and decrease manual workloads on medical technologists in clinical microbiology laboratories.

Eric Stern

Papers

Physiologic sample preparation for nanosensors

Traitement des cauchemars par la thérapie par répétition d’imagerie mentale (ou RIM) : mise en place pratique

Macroprolactinemia Detection by Magnetically Assisted Polyethylene Glycol Precipitation: Potential for Automation.

Antimicrobial Cartridges and Processes for Antimicrobial Susceptibility Testing

Metabolic assay for bacterial growth and gram typing