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Small Molecules Against IRE1 To Prevent Pd-L1 Upregulation

The strategy to treat cancer by modulating the immune response has been the subject of research for the last twenty years, including the use of vaccines or activating cytokine therapies. Recently, in the last few years, a breakthrough was achieved by the discovery of immune checkpoints, particularly the cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), programed cell death receptor-1 (PD-1), or programed cell death ligand-1 (PD-L1).   The blockade of the pathway for PD-L1 and PD-1 has been used therapeutically for the treatment of a variety of cancers and has achieved long-term remissions in some patients and there are a number of active clinical trials ongoing that target PD-1 and PD-L1. However, a number of cancers are resistant to checkpoint inhibitor-based immunotherapy. The majority of the drugs used for the blockade of the PD-1 and PD-L1 pathways are humanized antibodies. The fact that there have been immune related toxicities associated with PD pathway blockade using the current technologies suggests that an alternative approach may be necessary.

Pharmacological Mitigation of Late-Stage Toxemia

Anthrax disease, caused by Bacillus anthracis, is a highly lethal infection with patient fatality rate between 45-85% during fulminant, toxemia-related late-stages of infection. Systemic release of anthrax edema toxin during late-stage infection induces vascular collapse through endothelial barrier disruption, culminating in fatal hypovolemic shock, a hallmark of systemic anthrax infection. Existing therapeutic strategies to mitigate the effects of anthrax infections only target early-stage infection vis-à-vis bacterial clearance (antibiotics) and toxin-host cell interactions (anti-toxin antibodies), but are ineffective in preventing toxemic-shock which is induced even after pathogen clearance. In fact, patients with fulminant infection require aggressive, continuous fluid drainage and assisted breathing, and no effective therapeutic interventions exist currently for this critical stage of infection. Pathogen induced cell-cell barrier disruption (anthrax, cholera, traveler’s diarrhea, gastroenteritis, pertussis, pneumonia) account for significant socio-economic impacts each year. Stand-alone antitoxin therapies such as those mentioned here can fulfill the unmet medical need for measures that significantly improve the survival rate of patients with severe infections, and lower the risk for development of antibiotic resistance.   High fatality rate of anthrax infections, despite intense antibiotic and supportive therapies, are primarily due to the continuing activities of anthrax exotoxins (ET and LT) released in the patient's circulatory system. Edema toxin or ET, a highly active adenylate cyclase that induces uncontrolled, pathological elevation in cellular levels of the second messenger cAMP is a major virulence protein of Bacillus anthracis and mediates significant lethality during fulminant stages of infection. ET induces rapid disruption of the endothelial barrier, resulting in irreversible tissue damage and lethality due massive fluid loss resulting in cardiovascular collapse and hypovolemic shock. It is therefore imperative that new therapeutic measures be developed that effectively blocks the intracellular function of ET (i.e. cellular proteins/pathways co-opted to induce barrier instability), to reduce fatalities associated with anthrax toxemia.

Method To Implement A Crispr-Cas9 Copycat Gene Drive In Rodents

Currently, alleles at multiple loci in the mouse genome must be combined by Mendelian genetics in crosses of animals to one another to produce a desired compound mutant genotype. For example, to combine homozygous mutations at two loci, animals that are heterozygous for each gene must be produced by breeding, and these are subsequently crossed to one another. Since the frequency of homozygosity for each allele is 1:4 the frequency of homozygosity for both genes is 1:16. Since the average litter of mice is approximately 10 pups, and the generation time from conception to reproductive age is about 3 months, this requires a substantial number of animals and time. With the addition of each new locus (three, four, etc), the cost measured in animals, time, and money increases exponentially. These factors increase substantially more if two or more loci are genetically linked, which requires rare recombination events to combine engineered alleles on the same chromosome. The CRISPR-Cas9 gene drive system stands to revolutionize rodent breeding. If each desired allele is encoded as a gene drive element that contains an sgRNA designed to target the same genomic location in the wild type homologous chromosome, each locus will be “driven” to homozygosity in the presence of Cas9. Therefore, in order to combine three alleles, for example, a mouse with one gene drive element (A) would be crossed to a mouse that encodes Cas9. Offspring of this cross would then be crossed to mice carrying gene drive element B, and these offspring would be crossed to mice carrying gene drive element C. In the presence of Cas9 at each generation, these gene drive elements at three distinct loci will be converted to homozygosity such that 50% of offspring, those that inherit Cas9, will be triple homozygous after three generations, even if they are genetically linked loci. A CRISPR-Cas9 mediated gene drive leverages the native cellular mechanism of homology directed repair to copy a desired allele from one chromosome to another. This process can convert a heterozygous genotype to homozygosity in a single generation. While CRISPR-Cas9 gene drives have been implemented in two species of insects, flies and mosquitos, it has not been reported in any non-insect animal species. 

Electronic Device and Method for Scheduling for Enhanced Transmission Efficiency Over a Wireless Communication Network

Existing cellular networks assume that interference from neighboring cells is treated as noise and mobile devices are selected (scheduled) to communicate based on performance metrics for each device. When sliding-window coded modulation (SWCM) is used however, the performance metrics depend on those of interfering devices in neighboring cells, and hence scheduling has to be performed simultaneously over multiple cells.

Apparatus and Method For Transmitting Signal Using Sliding-Window Coded Modulation In A Wireless Network

To meet the demand for wireless data traffic having increased since deployment of 4G communication systems, efforts have been made to develop an improved 5G or pre-5G communication system. Therefore, the 5G or pre-5G communication system is also called a 'Beyond 4G Network' or a 'Post LTE System'.   The 5G communication system is considered to be implemented in higher frequency (mm Wave) bands, e.g., 60GHz bands, so as to accomplish higher data rates. To decrease propagation loss of the radio waves and increase the transmission distance, the beamforming, massive multiple-input multiple-output (MIMO), Full Dimensional MIMO (FD-MIMO), array antenna, an analog beam forming, large scale antenna techniques are discussed in 5G communication systems.   In addition, in 5G communication systems, development for system network improvement is under way based on advanced small cells, cloud Radio Access Networks (RANs), ultra-dense networks, device-to-device (D2D) communication, wireless backhaul, moving network, cooperative communication, Coordinated Multi-Points (CoMP), reception-end interference cancellation and the like.   In the 5G system, Hybrid FSK and QAM Modulation (FQAM) and sliding window superposition coding (SWSC) as an advanced coding modulation (ACM), and filter bank multi carrier(FBMC), non-orthogonal multiple access(NOMA), and sparse code multiple access (SCMA) as an advanced access technology have been developed.   The sliding-window superposition coding (SWSC) is a coding method capable of reaching a theoretical critical value performance of a physical layer in an additive white Gaussian noise (A WGN) interference environment where a fading is not generated, and thus the SWSC has a high efficiency

Learning Predictive Models Of Drug Response That Translate Across Biological Contexts

Translating biomarkers from basic research to clinical utility involves transfer of information across a series of contexts (from cells to disease animal models to humans) in which data are progressively harder to obtain. It is known that biomarkers identified in cell lines often do not translate to clinical settings and that is one of the main roadblocks in Translational Medicine. Presently, the state-of-the-art machine learning models require a number of training samples. The inventors show that conventional machine learning models, such as Random Forest, Linear Regression Model, Nearest Neighbors, cannot achieve accurate predictions and therefore there is a need for more accurate models.

“Polyp-Print”: A Methodology To Identify Which Colon Polyps Are Likely To Proceed To Colorectal Cancers

Colorectal cancer (CRC) is the second leading cause of cancer deaths in men and women combined in the United States, according to the American Cancer Society. Every day, patients undergo routine screening colonoscopies around the world for assessment of their risk of CRC. CRCs always arise from precursor lesions, called polyps. Since most patients with polyps are asymptomatic, tracking these lesions through fecal occult blood, rectosigmoidoscopy and colonoscopy enables the suspicion, detection and removal of the lesion. Since 2000, colonoscopy has become the most important examination to track polyps and CRC. Nowadays, in the USA, one out of four colonoscopies aim to track polyps. Besides detecting polyps, their removal through endoscopic polypectomy has proved to be effective to reduce the incidence of this tumor. Anatomopathological analysis enables the histological classification of adenomas, and also allows checking for dysplasia or neoplasm, as well as vascular and/or lymphatic invasion. This assessment determines if polypectomy and/or mucosectomy were effective to heal the patient who presented with polyp or CRC, or if therapeutics will be necessary. Typically, screening colonoscopies begin at age 50, and are done every 10 years. If polyps are encountered, based on their size and number and location, the risk is determined to be high vs low (completely arbitrarily, with no molecular basis at all). Bottomline, right now, there is no way to tell which polyp will become a cancer and which will not. Hence, some patients may be receiving over Rx and some may be under Rx. Clearly, what is needed is an invention that can predict the timing and consequences of multiple host events during CRC initiation and progression.

A Wide Dynamic Range Current Measurement Front-End

Accurate current measurement is crucial in many biosensing applications, such as the detection of neurotransmitters and the monitoring of intercellular molecular dynamics. This need has become even more critical recently with single molecule biosensors where sub-pA signal currents are superimposed on a slowly varying nA to µA background current, as is the case with nanopores. As such, the readout circuitry requires wide dynamic range (>120dB) and high linearity (>14b) albeit often with low bandwidth (a few Hz to kHz).