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jesse-pinkman123 · 3 years

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Monobody Based Therapeutic Drugs Market Size Share Trends Forecast 2026

Monobody Based Therapeutic Drugs Market - Global Industry Insights, Trends, Outlook, and Opportunity Analysis, 2018-2026

Monobodies are synthetic binding proteins in which fibronectin type III domain (FN3) is used as a molecular scaffold. Monobodies are robust alternative to antibodies to create target-binding proteins. The term monobody was devised by Koide group in 1998. Monobody belong to a class called antibody mimics aiming to overcome the shortcomings of natural antibody. A major advantage of monobody is that it can be used as genetically encoded intracellular inhibitors. Adnexus (now a part of Bristol-Myers Squibb), uses monobody technology to inhibit tumor angiogenesis since 2007.

Monobody – a technology with great potential in Cancer Treatment

Monobody is a technology which has great potential in the treatment of cancer. Monobody is independent of their environment and can be used as genetically encoded inhibitors. When a monobody binds to a protein then it work as an inhibitor of that protein.

Pegdinetanib, also known as Adnectin, is an antagonist of vascular endothelial growth factor receptor 2 has entered in clinical trial II for the treatment of glioblastoma. Adnectins is based on 10th fibronectin type III domain designed to bind with high affinity and specificity to relevant targets. There are three solvent accessible loops (BC, DE, and FG) which are responsible for binding. Various monobody proteins have been developed for clinical efficacy against cancer and infections. The market of monobody will be high in developed region like America because of availability of advance medical technology, good medical facilities and medical infrastructure.

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Success of therapeutic antibodies has sparked a growing interest to create molecules that bind to the target molecule specifically and efficiently. A common alternative process is that the libraries of monobody being constructed which can be obtained by capturing natural diversity of an antibody.

Research in the field of Monobody

Researchers at the University of Illinois, Chicago identified a monobody, NS1, which can block oncogene activity. 30% of all cancers are due to RAS mutation. RAS mutation is also found in 90% of pancreatic cancers and frequently occurs in colon cancer, lung cancer and melanoma. The NS1 monobody bind to RAS protein molecule and inhibits its oncogenic activity.

Monobody – a better alternative

Antibodies are successful tools used in diagnostics, purification, and therapeutics. Antibodies have their limitations also like high product cost and low stability. Alternative tools based on nucleic acid (aptamers), polypeptides (engineered binding proteins) and inorganic matrices have received attention recently. With increasing research activities for drug development in cancer, more information would be gathered with respect to monobodies too. Because of high specificity and affinity monobodies have potential and can be used in organ transplant in near future and can affect the antibodies market. Successful outcomes will boost investors to develop this technology and address the unmet need of cancer patients undergoing antibody therapy. Use of monobodies as therapeutic drug improves patient situation and hence companies are striving to develop monobodies to be used as therapeutic drugs in the treatment of cancer.

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Introduction of monobody will have a major impact in developed regions

The rate of organ transplantation in the U.S. is high. According to National Kidney Foundation, there are currently 121,678 people waiting for organ transplant in the U.S of which 100,791 await kidney transplant. Monoclonal antibodies are used in successful transplant and are administered before transplant. It will become one of the major drivers for monobody based therapeutic drugs market. Monobody technology requires high investment to commercialize. The advancement of monobody technology to treat cancer will have an impact on the existing antibody treatment technologies.

Key Developments

Research and development in use of monobody-based therapies is expected to boost the market growth. For instance, in August 2019, researchers from The University of Chicago characterized 42 Flublok-induced monoclonal antibodiesand 38 Flucelvax-induced mAbs for avidity, cross reactivity, and any selectivity towards the head versus the stalk domain to compare the fine specificity of the antibodies induced by recombinant hemagglutinin vaccine produced in insect cells (Flublok) and Flucelvax, prepared from virions produced in mammalian cells.

Similarly, in August 2019, researchers from Icahn School of Medicine at Mount Sinai characterized monoclonal antibodies isolated from a patient with an active Zika virus infection that potently neutralized virus infection in Vero cells at the nanogram-per-milliliter range.

In June 2018, researchers from Bristol-Myers Squibb reported that 6200_A08, a novel gp41-binding Adnectin with potent anti-HIV activity is highly synergistic when linked to a CD4-binding Adnectin. Novel bispecific molecules of this type may serve as the next generation of potent antiviral agents.

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#Monobody Based Therapeutic Drugs Market Share #Monobody Based Therapeutic Drugs Market

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creativesage · 5 years

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(via Innovation in the Workplace: What's the Best Way to Prioritize It?)

By Matias Rodsevich

Today one of the key challenges most companies face is being able to scale rapidly while still keeping their innovative startup edge. Startups have less decision-makers, making it easier to take the risks needed to prioritize innovation in the workplace. As these companies start to grow, they often experience a downturn in innovation as management layers increase. In fact, many larger corporations are now attempting to harvest the success of startups by creating small internal companies. This begs the question: do you have to stay small to increase innovation in the workplace?

According to the Economist’s study on organizational agility, the main obstacles to improved business responsiveness are slow decision-making, conflicting departmental goals and priorities, risk-averse cultures and silo-based information. This isn’t a problem that faces a select number of companies. A survey by McKinsey&Company found that 94 percent of managers are unhappy with their company’s innovation in the workplace performance. The good news is that you don’t have to stay small to avoid these common growth pitfalls. Instead follow these three performance management must haves:

Risk-taking

Create a culture in which risk-taking is encouraged. Fear of failure is one of the most common inhibitors of innovation in the workplace. Someone may have a great idea, but concern for their job security may keep them from taking the risk to try something new or challenge traditional strategies. Top companies are now taking the opposite approach. Google X, the company’s secret innovation lab, allows googlers to explore game-changing ideas consequence-free. It’s here that the fantasy of self-driving cars became a reality and inventions such as hoverboards and smart contact lenses have been tested. The criteria are that these ideas actually have to be radical sci-fi sounding inventions, which will help solve a global problem in the next 10 years.

To encourage employees to take risks, managers must give them more space and autonomy to develop early-stage ideas. To make this work, a high degree of accountability is also needed. One of the toughest tasks for managers is learning how to keep up accountability within the team, without micromanaging. Creating a set of goals your employees can work towards on their own will allow you to be hands-off, but still check in from time to time and offer guidance.

Increase Learning Agility

Exploring new ideas is not enough when working on innovation in the workplace. The key to being truly innovative is taking risks, and then learning from your experiences. People with a high learning agility are able to take feedback and adjust strategies accordingly, without becoming discouraged. For businesses, having a highly agile workforce means employees can be re-skilled quickly to meet new company goals and strategies based on industry trends. A study on learning agility in the workforce concluded that companies with the highest amount of high-learning agile executives produced 25 percent higher profit margins than their rivals. A series of studies by BTM Corporation on business agility concluded that companies with highly mature business characteristics demonstrated:

13 percent to 38 percent performance advantage in capital efficiency and value;

10 percent to 15 percent performance advantage in margins;

Up to 5 percent performance advantage in revenue and earnings growth.

Supporting continuous and disruptive learning centered on the competencies that characterize the company’s competitive nature will help managers ramp up their team’s performance. To create this type of work environment, managers must focus on metrics-driven skill development and real-time learning. The more training and practice employees get in giving and receiving feedback effectively, the better they’ll become at tracking their own performance and integrating feedback into their development game plan.

Creating Cross-functional Teams

Often large companies will find that different departments begin to become silos of information, leading to a duplication of work and inter-departmental conflicts. A lack of communication and knowledge-sharing across the organization leads to a failure to utilize all resources available on a project, thereby significantly lengthening timelines.

As a result, many companies are now harnessing the benefits of cross-functional teams. These teams consist of members with different skill sets and are grouped together on an ad hoc basis to tackle particular projects. Organizing teams in this way creates a smaller pool of decision-makers and allows the team to benefit from cross-departmental knowledge. Combining the strengths of each person allows these teams to come up with more insightful and out of the box ideas, thus increasing innovation in the workplace.

The ability to quickly form cross-functional teams can greatly increase organizational agility. However, managers need more accurate performance data to quickly identify the employees with the appropriate skills needed to meet the company’s shifting goals. At the same time, performance data also gives HR better insights into what’s missing so they can address skill gaps with more targeted training efforts. Over time, acquiring a growing library of data enables companies to more effectively deploy fast acting and effective teams.

The original version of this article was first published on blog.impraise.com

[Entire post, click on the title link to read it at Converge Tech Media.]

***

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#innovation #innovationmanagement #innovationteam #leadership #management #mgmt #crossfunctionalteam #risktaking #activelearning #lifelonglearning #agile #changemanagement #experimentation

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tumimmtxpapers · 4 years

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Engineering Stimuli-Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy.

Related Articles Engineering Stimuli-Activatable Boolean Logic Prodrug Nanoparticles for Combination Cancer Immunotherapy. Adv Mater. 2020 Feb 12;:e1907210 Authors: Hou B, Zhou L, Wang H, Saeed M, Wang D, Xu Z, Li Y, Yu H Abstract Prodrug nanoparticles that codeliver the immune modulators to the tumor site are highly recommendable for cancer immunotherapy yet remain challenging. However, effective stimuli-responsive strategies that exploit the endogenous hallmarks of the tumor have paved the way for cancer immunotherapy. For the first time, the development of the Boolean logic prodrug nanoparticles (BLPNs) for tumor-targeted codelivery of immune modulators (e.g., immune activator and immune inhibitor) and combination immunotherapy is reported herein. A library of stimuli-activatable BLPNs is fabricated yielding YES/AND logic outputs by adjusting the input combinations, including extracellular matrix metalloproteins 2/9 (MMP-2/9), intracellular acidity (pH = 5.0-6.0), and reduction (glutathione) in the tumor microenvironment. Tunable and selective control over BLPNs dissociation and prodrug activation is achieved by specifying the connectivity of orthogonal stimuli-labile spacers while exploiting the endogenous signals at the tumor sites. The tumor-specific distribution of the BLPNs and stimuli-activation of the immune modulators for highly efficient cancer immunotherapy are further demonstrated. The results reported in this study may open a new avenue for tumor-specific delivery of immune therapeutics and precise cancer immunotherapy. PMID: 32048361 [PubMed - as supplied by publisher] http://dlvr.it/RPyJ77

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fiamh · 5 years

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SESSION 1: CANCER GENOMICS AND EPIGENOMICS

The 2014 Beyond the Genome meeting has a simple tweet policy: talks are assumed to be sharable unless the speaker says otherwise, hashtag of the conference is #btgcg14. As always, all errors are mine.

First talk by Gad Getz on Cancer genomics and evolution and completing the catalog of cancer genes who also multitasks as session chair. Quick summary of cancer mutations, driver events (which increase the fitness when it occurs), clonality, passenger events and Co. Cancer genes defined as genes that harbor driver events. Recap of the MutSig algorithm to assess mutation frequencies, adjusting for gene length; results in a long tail distribution of cancer genes. Studies with higher power continue to find more genes at lower frequencies, vast majority at <20% in patients.

Look at larger and larger studies and the gene list increases, including hundred of olfactory receptors which indicates false positives. Problem is algorithm assumes constant background mutation background (all patients, all regions of the genome with same rate). Mutation rate across cancers varies up to three orders of magnitude; mutation rate also varies with expression rate due to transcription-coupled repair . Most important factor is location in the genome; rate correlates with DNA replication time. The ‘fishy’ genes mentioned above tend to have low expresison rate and late replication time. New version MutSivCV takes these factors into account.

Use for pan-cancer study testing ~4700 tumor/normal pairs from 21 different tumours checking for genes mutated in more than 2% of patients. Combine evidence to ind cancer genes, e.g., for clustered mutations in conserved regions of a protein; yields 224 cancer genes. Combined all tumor types together identifies 114 significant genes (which may not have reached significance in the individual tumor tests) — combined list of 254 cancer genes. Study found ‘all’ previously known cancer genes, but also identified 33 novel genes at an FDR of 10%.

Tried to assess completeness of the gene list via downsampling; indicates with more data and more tumour types the list increases steadily. Stratifying by frequency it seems the >20% frequency genes are mostly discovered, but at frequency of less than 5% the list is still rising rapdily. Clearly more genes to find. Power calculations indicate (ballpark figure) 50 tumour types with 2000 samples each (ongoig effort to study 15,000 samples). This is just for point mutations in coding regions. More work to do for non-coding regions, amplifications, epigenetic changes, etc. Great introductory talk setting the scene for the rest of the meeting.

Had to skip the second talk from Jan Korbel on Origins and consequences of structural rearrangements due to the inevtibable conference calls but made it back for the third talk of the session by Nuria Lopez-Bigas on Therapeutic landscape of cancer drivers. Nuria gives a quick proof of concept using Vemurafenib for BRAF. ~7000 tumor samples from 28 tumors (ICGC and TCGA), what is the opportunity to identify therapeutic opportunities to target cancer drivers. Iterative approach to identify drivers, find drugs targeting drivers, assign targeted drugs to patients based on driver event (not sure how this then links back to the original cohort).

First step to find driver events identified via somatic mutations, CNVs, fusion gene information, links back to Gad’s talk and described approaches to find positive selection across tumours re-sequenced genomes (MutSigCV, MuSiC-SMG, also measure functional impact of mutations with OncodriveFM and check for clustered mutations. These feed into the Intogen mutations pipeline (pipeline available through the web interface or for local installs).

Idea is to use complementary signals to obtain a comprehensive list of driver genes. Ended up with ~460 candidates (larger number than in Gad’s talk, but also additional tumor types sampled), again with a long tail distribution of mutation frequencies. Other findings are also similar, for example pooled analysis identified additional drivers, but misses drivers specific to a single tumor type. Needs both analysis. Next step is to distinguish loss of function from activation, key to drug development (activators easier to dampen, loss of function requires more thought). Estimate ~90% precision, 83 unclassified, 207 LoF, 170 Act. Further subset to focus on drivers dominating the clonal landscape, finds 73 major drivers. Includes CNA, fusion gene drivers to come up with list of ~480 driver events. Checking back on the original data it seems that ~90% of tumours have at least one of the recognized driver events, 68% have multiple events (median of 3). Differs a lot between different tumour types: most bladder samples have more than 1 (median 7).

Second step to identify and classify drugs targeting drivers (small molecule libraries, text search, etc). Only 96 targeted, most drugs through directed targeting. Classified remaining non-targeted drivers as druggable or not. Generated database with drug target interaction, dependency on specific mutation, recommended tumor types, repurposing suggestions to end up with ‘in silico drug prescriptions’ for 4068 patients as the third step. Estimate that 65% of patients could benefit from drugs already in clinical trials (again with the expected differences across various tumor types). Questions revolve around confidence of driver events, finding additional drivers, what to correct for (ignoring SNPs in CNV regions, cellularity adjustment, etc.).

Fourth full talk is from Michael Taylor on Epigenome alterations drive lethal posterior fossa ependymomas of infancy. Third most common childhood brain tumor, incurable in ~50 of the cases, Occur in almost any given part of the nervous system, treatment by surgery and radiotherapy, no chemo works. Morphological not distinguishable between site, but the transcriptomes differ quite a bit between sites. Extend of resection best indicator for good outcome, but with very negative impact on kids due to potential nerve/brain damage. Tumour transcriptome mimics cells of origin. Two distinct two groups (PF-A and PF-B) based on microarray profiles, replicated in Toronto and Heidelberg. PF-B much better survival rate than -A group, replace the surgery resection prognosis, PF-A vs -B tends to dominate prognosis estimates. Deep exome-seq on PF-A samples along with limited WGS. Zero recurrent SNVs in the samples they studied, lowest mutation rate among all tumours studied (PF-B have recurrent copy number events, in contrast). Cites Holmes on what to do when you eliminated impossible, so started checking for epigenetic changes. Found high rate of promoter CpG methylation along with gene silencing.

Checked methylated/silenced genes in two cohorts followed by pathway analysis. No convergence in PF-B, for PF-A PRC2-related genes, normally used by undifferentiated ES cells to prevent differentiation seem to be enriched. Can be reversed with demethylation agents. Identified good overlap of tri-methylation between PF-As and ES cells, no overlap with PF-B. Seems to be re-capitulatng embryonic program. No recurrent CNVs, indels, SVs, somatic mutations found so far. Lots of potential drugs that could replace highly damaging radiotherapy (e.g., 5-Aza-2’-Deoxycytidine), other drugs selective for EZH2 look promising as well (GSK EZH2 inhibitor). Moving through phase 1 clinical trial.

In the meantime revisiting prognosis estimates. Created PF cohort (with PF-A patients younger than PF-B, PF-B patients doing better than PF-A as expected). Look just at PF-A based on genomic tests it turns out that amount of resection does not matter. No difference between aggressive surgery that might put kids in wheelchairs vs less aggressive surgery. Likewise the effect of tumour grade on prognosis goes away once accounted for the two different tumor types. Huge impact on patient care, radiation plans and subsequently child development. Thinks these are not cancers, but ES-related neuron development disorder (balance of too many vs not enough neurons disturbed).

The session is conclucted by a two selected short talks, the first one from Ingegerd Elvers on Tumor/normal exome sequencing in dogs identifies known and novel lymphoma genes. Breeding resulted in landscape useful for studying somatic mutations in cancer. Live in the same environment as we do, but are more homogenic within breeds (and different across). Treatments dogs receive are similar to human treatment options, wel diagnosed. Picked golden retrievers (13% lymphoma over lifetime), boxers (20%), cocker spaniel (7%) to study disease across 3 unrelated breeds. MuTect/MuSIC to identify variants and significantly mutated genes, 10-50 events founds depending on breed and T/B-cell lymphona source. Little overlap between B-, T-cell lymphoma, usually specific for subtype. In addition, b-cell lymphomas between breeds are similar (share half of the significantly mutated genes), T-cell are not, indicating a genetic background role. A subset of the B-cell genes shared with human B-cell lymphoma or other cancers, reinforcing the concept of dog cancer studies as a useful model system. Expanding to additional breeds now and checking for germ-line predispositions.

The second short talk is given by Chai Bandlamudi on Pan-cancer gene fusion discovery across 7,470 primary tumor transcriptomes using MOJO. Quick intro to typical fusion events, frequently hallmarks of cancer with a minimal number of secondary hits. Interesting since they often can present novel therapeutic targets. Went through COSMIC and identified ~200 events in more than 3 samples based on FiSH and more recently sequencing. As always very different frequency across tumor types, enriched in blood and sarcoma, depleted in solid types. Not a case of event frequency but detection bias. Extended analysis to ~8000 tumor transcriptomes from TCGA, detected by discordant reads (using MOJO, Minimal Overlap Junction Optimizer, to be released soon). Ran it in a ‘high sensitivity mode’ with subsequent false positive filtering. Most fusions found between genes less than 1MB apart, fair amount still inter-chromosomal. Number of fusion events differs, highest in ovarian cancers, least in colorectal cancers. Quick comparison to TCGA indicates a number of noval fusion events they are now following up on.

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1.28.2014 GENOME IN A BOTTLE 2014: FIGURES OF MERIT WORKING GROUP NOTES

Love the RTG approach, but general consensus is that we need an Open Source version of the variant comparison framework, and under a suitable license. Nils Homer to explore and make recommendations.

Will require some sort of default settings (given the target audience), at least for phase 1. Balance between getting a useful framework out sooner rather than later, and allowing lots of tweaking. Comparison between variant calls currently unsolved problem, lots of implementations out there (Complete Genomics, GeT-RM, bcbio.variation, RTG). Different truth sets, different regions of interest, different comparisons metrics (variant call vs getting the genotype right, boundaries of SVs, etc.).

Definition of the comparison metrics might have to wait for phase 2. Getting something out early to the community early makes sense, though it might mean we have to throw away the codebase at some point if the underlying framework do not meet the community needs (i.e., limited lifespan).

Long discussion about how to best handle truth sets and discrepancies. How to encourage users to submit evidence that the truth set is wrong in place? Wouldn’t they rather just re-run the analysis until the data converges better, even though that might be biased? Part of this will be submission of raw data as much as possible and iterative re-processing of all data to refine the truth set continuously.

Can we afford to ignore complex variants a little bit longer? Genome centers, tools developers want the more systematic comparisons along with APIs; the clinicians might be okay with just looking for rare variants for a bit. We also need community feedback on how to actually evaluate some of the more complex variants and structural changes.

Command line version obviously required (offline) for groups that cannot upload data, ability to define own truth set (not as a standard, but as a gVCF/BED file combination to re-run). Do we need some sort of meta-analysis (variance between VCFs)? Not required for the first round.

What variant classes are supported? Different layers, region by region, genotype by genotype, summarized top level. Not even getting started on phasing. Software needs to include all variants present and defined in the GiaB truth set; big CNVs/SVs off the table right now.

✳ software ✳ ngs ✳ giab ✳ workshop

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1.28.2014 GENOME IN A BOTTLE 2014: USAGE AND RELEASE OF REFERENCE MATERIALS

Several versions of RM released throughout the pilot have been used already:

Part of the FDA approval for Illumina sequencer

Variant caller and workflow assessment at HSPH

Tracing variant call changes over the development of a variant caller (FreeBayes, work with Marth lab)

Personalis categorizing exome regions, titrate coverage to compare different exome capturing methods, target sizes, etc; error rates outside of high-confidence regions can go up by an order of magnitude (poster (PDF))

Clinical pipeline validation at Mt Sinai (with internal validation), tuning of workflow to find better cutoffs (VQSR and Co)

Qiagen used material to identify PCR artifcacts, compare PCR enriched amplicon sequencing to whole exome sequencing, tuned workflows

Claritas Genomics to chase false negatives in assay development (Nils Homer)

Call for pedigree calls as another very valuable resource; better annotation for the non-high confidence calls to be able to have context on why they failed to make the high confident call set. Algorithm callibration (for example for tissue frequency) another use case (NA12878 as a spike in, ContEST and Co as modified downstream tools).

releasing rm and future plans

Quick update towards establishing call sets and DNA as NIST (Certified) Reference Materials. Needs to go through various assessments (homogenous, stability, etc.). Difficult to do — needs lots of sequencing samples to reach statistical significance.

Confidence that the sample tested in a year is the same as the one tested this year. Protect against changes to the ‘physical form’ of the DNA (size distribution stable even under accelerated aging tests, see notes from day 1).

Might have to sequence batches side by side from Coriell each time new samples are released, trace changes over time. Again, need lots of sequencing to detect minor differences with confidence. Could be a repository for non-NIST lots; capture data from labs that run NA12878 routinely anyway. Automated process to upload BAM, run standard workflow, capture variant changes over time. [Could even be used to detect workflow specific signatures…]. Interest / support for this from DNAnexus.

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cancersfakianakis1 · 5 years

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Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells toward Taxanes, ATR, and PARP Inhibitors In Vitro and In Vivo

Purpose:

The catalytic function of BUB1 is required for chromosome arm resolution and positioning of the chromosomal passenger complex for resolution of spindle attachment errors and plays only a minor role in spindle assembly checkpoint activation. Here, we present the identification and preclinical pharmacologic profile of the first BUB1 kinase inhibitor with good bioavailability.

Experimental Design:

The Bayer compound library was screened for BUB1 kinase inhibitors and medicinal chemistry efforts to improve target affinity and physicochemical and pharmacokinetic parameters resulting in the identification of BAY 1816032 were performed. BAY 1816032 was characterized for kinase selectivity, inhibition of BUB1 signaling, and inhibition of tumor cell proliferation alone and in combination with taxanes, ATR, and PARP inhibitors. Effects on tumor growth in vivo were evaluated using human triple-negative breast xenograft models.

Results:

The highly selective compound BAY 1816032 showed long target residence time and induced chromosome mis-segregation upon combination with low concentrations of paclitaxel. It was synergistic or additive in combination with paclitaxel or docetaxel, as well as with ATR or PARP inhibitors in cellular assays. Tumor xenograft studies demonstrated a strong and statistically significant reduction of tumor size and excellent tolerability upon combination of BAY 1816032 with paclitaxel or olaparib as compared with the respective monotherapies.

Conclusions:

Our findings suggest clinical proof-of-concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors to enhance their efficacy and potentially overcome resistance.

http://bit.ly/2GOvXZn

#Oncology-Sfakianakis

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we-arnold-lockshin-blog · 6 years

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Dictatorship USA – A Personal History – Part 41

The American Gestapo blocks a promising cancer treatment (2)...

It is worth describing my research in some detail and the sabotage ordered by the FBI.

Solving the thymidine concentration problem was actually quite straightforward (see previous post). No one at the Stehlin Foundation or anywhere in the US had actually determined the maximum (at saturation) solubility of the compound! Only intellectual sloppiness can explain this gross oversight.

As a naturally occurring – and, in fact, essential – biological compound, thymidine in normal bodily concentration is not at all cytotoxic. Moreover, breakdown and excretion mechanisms for the compound are well known. It would have been logical to expect that only infusion of a highly concentrated thymidine solution could overwhelm the normal biological degradation mechanisms and thus have therapeutic effect.

I set about determining the actual maximum solubility of thymidine in infusion fluid and found out that the saturation concentration was considerably higher than that which had been arbitrarily selected for the clinial trials. Moreover, in conformity with the behavior of most solutes, the saturation concentration increases with higher temperatures: warming the physiological buffer solution to or near normal body temperature significantly increased the maximum dissolved thymidine concentration.

In planning laboratory experiments, I selected as the test model a rapidly-proliferating human melanoma inoculated into nude mice (see previous post). The results were quite amazing. Repeated infusions were necessary to achieve an observable therapeutic effect, but for the majority of these fragile experimental animals, tumor regression (disappearance) was complete. In most cases, the implanted tumor shrunk and then was entirely resorbed, leaving a benign scar and a healthy mouse.

It is widely considered that the nude mouse model for human tumors is the best preclinical predictor of clinical effectiveness.

When I presented the summary of my research to Giovanella, usually a cool customer, he became livid. “You'll kill the patient by clogging up his veins,” he belched. Hardly likely, as the concentrated thymidine would immediately become enormously diluted upon entering the blood stream. In any case, a fine filter could be attached to the infusor to be doubly and triply sure that no particles entered.

In “Silent Terror,” I described Giovanella's repeated attempt to sabotage my publications:

“To discourage me from publishing scientific papers, Giovanella kept my manuscripts on his desk for weeks or months without reading them. When I reminded him about a manuscript, he often 'forgot' that I had handed it to him, even though as laboratory director, he usually was listed as a co-author. Normally, any scientist is eager to expedite publication of research from his laboratory and gives this priority. Concurrently, Giovanella pointedly read unrelated papers and would willingly discuss these at length. Giovanella had no scientific basis for downgrading my research...” (p. 92)

In this way, Giovanella held up publication of the concentrated thymidine results for several months. Eventually, I threatened to send the manuscript without his co-authorship to the scientific journal, and only then did he “find the time” to read it. And the peer-reviewed manuscript eventually was published.

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Dirty FBI deception, lies – and miscalculation - from the word “go”...

What was at stake here was the secret political police directive to find a plausible excuse to precipitously fire me at the appropriate time. And from a psychological warfare perspective, to convince me personally that I had been a “failure,” thus sapping my self-confidence and readiness to combat all the lies splattered about me throughout the US mass media after my forced exile.

Prior to my arriving at the Stehlin Foundation, Stehlin, Giovanella and the other US Gestapo-recruited scientists had concluded (a) that the thymidine (concentration) problem could not be solved; (b) that Lockshin would flounder in frustration; and (c) that his “failure” would serve as the pretext for the FBI-Stehlin-Giovanella consortium to peremptorily fire me as a key element in the harassment and terror campaign that forced me to exit the US for the USSR.

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Concentrated thymidine remains a promising drug for metastatic melanoma...

Only controlled clinical trials can determine whether or not a particular drug or treatment is efficacious. However, given the refractory response to established therapies and the very poor patient prognosis for metastatic melanoma (see previous post), the experimental preclinical evidence argues strongly in favor of conducting trials with concentrated thymidine. Clinical experimentation with this preparation was blocked entirely because of the dirty – incredibly filthy, and possibly murderous – directive of the US secret political police to smash Lockshin and not because of any scientific or medical consideration or any thought of the well-being of the many hundreds of thousands of human beings afflicted with this terrible disease.

It is reasonable to postulate that the mechanism of action of the potential drug relates to greatly overloading the in vivo thymidine/cytosine ratio and inducing a DNA mismatch in a critical gene's Watson-Crick base pair.

Evidence supporting such a postulate is the synergistic# effect of 3-deazauridine, a cytosine synthetase inhibitor##, with thymidine on tumor cells###.

It is entirely conceivable that such a drug combination could further reduce the volume of thymidine-containing infusate required for treatment.

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# synergistic: relating to the interaction or cooperation of two or more organizations, substances, or other agents to produce a combined effect greater than the sum of their separate effects.

## “3-Deazauridine is a synthetic analogue of nucleoside uridine lacking a ring nitrogen in the 3-position. 3-deazauridine inhibits cytidine synthase, thereby reducing intracellular levels of cytidine and deoxycytidine and disrupting DNA and RNA synthesis.” (National Center for Biotechnology Information, U.S. National Library of Medicine)

### Cytotoxic and Biochemical Effects of Thymidine and 3-Deazauridine on Human Tumor Cells, Cancer Research 44, 2534-2539 (1984), A.Lockshin et al.

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Перед нами сейчас - коварный и опасный мошенник, расист, лжец и фашист Дональд Трамп, порочный Конгресс, нацистские ФБР - ЦРУ, кровавые милитаристы США и НАТО >>> а также и лживые, вредоносные американские СМ»И».

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Правительство США жестоко нарушало мои права человека при проведении кампании террора, которая заставила меня покинуть свою родину и получить политическое убежище в СССР. См. книгу «Безмолвный террор — История политических гонений на семью в США» - "Silent Terror: One family's history of political persecution in the United States» - http://arnoldlockshin.wordpress.com

Правительство США еще нарушает мои права, в течении 14 лет отказывается от выплаты причитающейся мне пенсии по старости. Властители США воруют пенсию!!

ФСБ - Федеральная служба «безопасности» России - вслед за позорным, предавшим страну предшественником КГБ, мерзко выполняет приказы секретного, кровавого хозяина (boss) - американского ЦРУ (CIA). Среди таких «задач» - мне запретить выступать в СМИ и не пропускать большинства отправленных мне комментариев. А это далеко не всё...

Арнольд Локшин, политэмигрант из США

BANNED – ЗАПРЕЩЕН!!

ЦРУ - ФСБ забанили все мои посты и комментарии в Вконтакте!

… и в Макспарке!

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abbkineeu · 6 years

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New Post has been published on Biotech Advisers

New Post has been published on http://www.bioadvisers.com/combination-aptamer-drug-reversible-anticoagulation-cardiopulmonary-bypass/

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass

Content introduction:

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass

De novo DNA synthesis using polymerase-nucleotide conjugates

Efficient generation of targeted large insertions by microinjection into two-cell-stage mouse embryos

Precise, automated control of conditions for high-throughput growth of yeast and bacteria with eVOLVER

Encoding human serine phosphopeptides in bacteria for proteome-wide identification of phosphorylation-dependent interactions

1. Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia–associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, Ruwan Gunaratne at Duke University in Durham, North Carolina, USA and his colleagues solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. They demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer–drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Their results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

Read more, please click https://www.nature.com/articles/nbt.4153

2. De novo DNA synthesis using polymerase-nucleotide conjugates Oligonucleotides are almost exclusively synthesized using the nucleoside phosphoramidite method, even though it is limited to the direct synthesis of ∼200 mers and produces hazardous waste. Here, Sebastian Palluk at Joint BioEnergy Institute in California, USA and his colleagues describe an oligonucleotide synthesis strategy that uses the template-independent polymerase terminal deoxynucleotidyl transferase (TdT). Each TdT molecule is conjugated to a single deoxyribonucleoside triphosphate (dNTP) molecule that it can incorporate into a primer. After incorporation of the tethered dNTP, the 3′ end of the primer remains covalently bound to TdT and is inaccessible to other TdT–dNTP molecules. Cleaving the linkage between TdT and the incorporated nucleotide releases the primer and allows subsequent extension. They demonstrate that TdT–dNTP conjugates can quantitatively extend a primer by a single nucleotide in 10–20 s, and that the scheme can be iterated to write a defined sequence. This approach may form the basis of an enzymatic oligonucleotide synthesizer.

Read more, please click https://www.nature.com/articles/nbt.4173

3. Efficient generation of targeted large insertions by microinjection into two-cell-stage mouse embryos Rapid, efficient generation of knock-in mice with targeted large insertions remains a major hurdle in mouse genetics. Here, Bin Gu at Hospital for Sick Children in Toronto, Ontario, Canada and his colleagues describe two-cell homologous recombination (2C-HR)-CRISPR, a highly efficient gene-editing method based on introducing CRISPR reagents into embryos at the two-cell stage, which takes advantage of the open chromatin structure and the likely increase in homologous-recombination efficiency during the long G2 phase. Combining 2C-HR-CRISPR with a modified biotin–streptavidin approach to localize repair templates to target sites, they achieved a more-than-tenfold increase (up to 95%) in knock-in efficiency over standard methods. They targeted 20 endogenous genes expressed in blastocysts with fluorescent reporters and generated reporter mouse lines. They also generated triple-color blastocysts with all three lineages differentially labeled, as well as embryos carrying the two-component auxin-inducible degradation system for probing protein function. They suggest that 2C-HR-CRISPR is superior to random transgenesis or standard genome-editing protocols, because it ensures highly efficient insertions at endogenous loci and defined ‘safe harbor’ sites.

Read more, please click https://www.nature.com/articles/nbt.4166

4. Precise, automated control of conditions for high-throughput growth of yeast and bacteria with eVOLVER Precise control over microbial cell growth conditions could enable detection of minute phenotypic changes, which would improve our understanding of how genotypes are shaped by adaptive selection. Although automated cell-culture systems such as bioreactors offer strict control over liquid culture conditions, they often do not scale to high-throughput or require cumbersome redesign to alter growth conditions. Brandon G Wong at Boston University in Boston, Massachusetts, USA and his colleagues report the design and validation of eVOLVER, a scalable do-it-yourself (DIY) framework, which can be configured to carry out high-throughput growth experiments in molecular evolution, systems biology, and microbiology. High-throughput evolution of yeast populations grown at different densities reveals that eVOLVER can be applied to characterize adaptive niches. Growth selection on a genome-wide yeast knockout library, using temperatures varied over different timescales, finds strains sensitive to temperature changes or frequency of temperature change. Inspired by large-scale integration of electronics and microfluidics, they also demonstrate millifluidic multiplexing modules that enable multiplexed media routing, cleaning, vial-to-vial transfers and automated yeast mating.

Read more, please click https://www.nature.com/articles/nbt.4151

5. Encoding human serine phosphopeptides in bacteria for proteome-wide identification of phosphorylation-dependent interactions Post-translational phosphorylation is essential to human cellular processes, but the transient, heterogeneous nature of this modification complicates its study in native systems. Karl W Barber at Yale University in New Haven, Connecticut, USA and his colleagues developed an approach to interrogate phosphorylation and its role in protein-protein interactions on a proteome-wide scale. They genetically encoded phosphoserine in recoded E. coli and generated a peptide-based heterologous representation of the human serine phosphoproteome. They designed a single-plasmid library encoding >100,000 human phosphopeptides and confirmed the site-specific incorporation of phosphoserine in >36,000 of these peptides. They then integrated their phosphopeptide library into an approach known as Hi-P to enable proteome-level screens for serine-phosphorylation-dependent human protein interactions. Using Hi-P, they found hundreds of known and potentially new phosphoserine-dependent interactors with 14-3-3 proteins and WW domains. These phosphosites retained important binding characteristics of the native human phosphoproteome, as determined by motif analysis and pull-downs using full-length phosphoproteins. This technology can be used to interrogate user-defined phosphoproteomes in any organism, tissue, or disease of interest.

Read more, please click https://www.nature.com/articles/nbt.4150

#eVOLVER #Post-translational phosphorylation #TdT-dNTP conjugates #two-cell homologous recombination #Unfractionated heparin

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bioadvisers · 6 years

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