Study finds macrophages talk to sensory nerves to elicit chronic pain caused by nerve damage

Study finds macrophages talk to sensory nerves to elicit chronic pain caused by nerve damage

The digital telco firm is also looking to enter new markets.

The post Warburg-backed Circles.Life wins slice of telco pie, targeting incumbents’ legacy systems appeared first on DealStreetAsia.

Mekari, which was formed out of the merger of four startups, snagged Series B and C funding last year.

The post Indonesia has room for multiple SaaS players targeting SMEs, says Mekari CEO Soh appeared first on DealStreetAsia.

Marketers fear ‘racist’ Trump supporters, says head of Hispanic advertising group

With Sales Accelerator, Del Monte can 'tweak the levers' during a campaign to boost reach and revenu

Lead scoring might remind you a bit of the “pursuit of happiness.” They are both hard to achieve. However, they are important for your well-being, […]

The post 5 Ways To Score Leads For Success By Targeting The eLearning Community appeared first on e-Learning Feeds.

The omnibus bill on job creation limits increases in the minimum wage and eases conditions for firing employees.

The post Indonesia halts job creation bill targeting foreign investment appeared first on DealStreetAsia.

Jessica Ennis-Hill joked she will spend her 30th birthday next Thursday in tears and admitted being preoccupied by the landmark age.

Kelly L. Dunlevy, Valentina Medvedeva, Jade E. Wilson, Mohammed Hoque, Trinity Pellegrin, Adam Maynard, Madison M. Kremp, Jason S. Wasserman, Andrey Poleshko, and Richard A. Katz

A large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via "tethering proteins" that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We identified previously a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify an evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We also show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation-dephosphorylation of the LBD. Furthermore, we identified a PP2A phosphatase recognition motif within the evolutionarily conserved PRR14 C-terminal Tantalus domain. Disruption of this motif affected PRR14 localization to the nuclear lamina. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two separable, modular domains. The findings also describe an optimal PRR14 LBD fragment that could be used for efficient targeting of fusion proteins to the nuclear lamina.

Source: Knox Henderson for Streetwise Reports   05/05/2020

News Update: A quick update since FansUnite Entertainment Inc. went live on Tuesday, May 5, because big things are happening in the industry, thus showing there is an enormous appetite for this kind of technology especially now, as we (very slowly) emerge out of this COVID pandemic. . .FansUnite is at a small-cap entry point with tremendous upside. After a financing at $0.35, the now-trading company rests slightly above that as a relatively new and unknown entity—so far—which is why now is great opportunity participate in a smaller scale, yet leveraged, consolidation play. "We have a great opportunity to use our stock as currency, and then grow and scale companies through our team and resources," says CEO Darius Eghdami. Read the entire update here.

Lets face it: gamers love games. While currently there's a dearth of real sports activity, that doesn't mean people aren't starving something to speculate on. No sports? No problem. Consider that there is $50 billion dollars placed online every year, according to ESPN. That's a lot of hungry money looking for a place to play.

So, despite the absence of the NFL, NHL, NBA and MLB, new online platforms are offering fun times for taking your chances on everything from reality TV shows, award shows, online gaming and virtual sports along with real in-the-flesh nail-biters like horse racing, table tennis and snooker. Who cares? It's all about the thrill of playing and winning. According to The The Guardian, just last week, "as coronavirus and the subsequent shelter-in-place orders have shut businesses around the globe and forced people to stay inside, some jobs have proven more stable than others," it said referring to online players. "The four U.S. states with legal sites—New Jersey, Nevada, Delaware, and Pennsylvania—reported record revenues in March." Meanwhile despite our current "modified behaviors" and "slowing of the economy," investors are also very keen on speculation in the gaming industry itself.

"FansUnite is at a small-cap entry point with tremendous upside."

Take, for example, DraftKings (NASDAQ:DKNG), which launched as recently as April 23, in the thick of this stay-at-home pandemic. After completing a merger with Diamond Eagle, a special purpose acquisition company, and back-end technology provider SBTech, its stock soared. Not only did DraftKings' stock jump 14% in its first day of trading before closing up 10.38% at $19.35, but the company was also able to add another half a billion dollars on the balance sheet at a time when it's not easy to raise money. The company is currently nearing a $1 billion market capitalization.

In this game, consolidation is key. Another highly successful big gaming conglomerate over-the-pond is UK-based GVC Gaming Group, which has been consolidating gaming assets over the last 15 years and is now worth $7.5 billion.

This week on the Canadian Securities Exchange (CSE) an emerging player is launching its platform onto the public market. FansUnite Entertainment Inc. (FANS:CSE), a company active in the gaming industry since 2014, is led by industry veterans who are looking to unleash their own high-growth consolidation strategy. The company is focusing on technology related to regulated and lawful internet activity and other related products.

Its business is to consolidate business-to-business (B2B) partnerships worldwide, operate its FansUnite business-to-consumer (B2C) coined Sportsbook launching later this year, and operate its recently acquired (March 26) Scottish subsidiary, McBookie, an online white-label sportsbook licensed and regulated by the U.K. Commission. Even considering the "COVID" delays in traditional sports, the company expects to generate at least $1 million in 2020. Considering FansUnite's experience in the space and its established technologies in an industry that is truly trending, FansUnite has a long runway from its current $25 million market cap to the billions-dollar peers it's chasing, and that is why this looks be a great stock to hold right out of the gate.

When you consider "B2B" in this scenario, consider an entity that wants to create a sportsbook, to become "the house," if you will. That company would turn to FansUnite to set up a turnkey "white-label" (as in use FansUnite technology but with its own brand) online platform, complete with user onboarding, fan integration and access to fulfillment in fiat currency (hard dollars) or cryptocurrency. For this service FansUnite takes a percentage of the "house earnings" and also charges for its Software as a Service (SaaS) platform. In the B2C scenario, FansUnite itself is the "house," using its own sportsbook and technology platform, and executes the marketing efforts to on-board new users.

McBookie, the company's first acquisition, is a white-label sportsbook in the UK, focusing on the Scottish market. It offers 200,000 members active in sports, and virtual games and boasts over $100 million turnover cumulatively the last three years. "It's a great brand with an experienced team operating for over a decade," says FansUnite CEO Darius Eghdami. "We completed this acquisition late March, and our focus currently is going to continue building our presence in the Scottish market."

Moving forward, Eghdami says the team will be putting an emphasis on M&A activity. "We'll continue to look for strong assets with either great technology or a strong database of users where we can come in with our team and resources and really grow and scale the business," he says.

With strong financial backing, Eghdami is also looking at potential opportunities in the colossal U.S. market. "The big heavyweights are coming into the U.S.. We don't intend to be an operator in the U.S., so we're looking at other ways to get in the market and that includes social peer activity, fan engagement, as well as licensed affiliate opportunities."

Eghdami points to another big success story in Canada, Amaya (TSE:TSGI), which is now The Stars Group and has a market capitalization of $11.5 billion. "It's a tremendous story of how they built the company and started to acquire assets. It's a model that we would love to follow."

After a crushing dip into the pandemic, TSGI.T is big-board player that has catapulted to new highs once the reality set in that social isolation might not necessarily be a bad thing for online gaming providers. According to Bloomberg, "The Stars Group Inc. says it saw record revenue in its first quarter as COVID-19 led to an increase in online activity starting in March. And, it says, it has continued to see increased activity in its online playing into the second quarter. In an update to its expectations for the three-month period ended March 31, the company says it expects revenue of approximately US$735 million, up from US$580 million in the first quarter of 2019."

"The stay-at-home lifestyle we now face in 2020 could result in a massive shift in the habits of players," says Eghdami. "Players that are used to going to the physical house, or the horse track, may now shift their habits to online. The older generation now may be signing up on online platforms and realize they can do this a lot easier. We're getting new users on the platform every day, and players starting to turn to virtual sports as well."

FansUnite is the brainchild of three entrepreneurs who have each already carved out more than a decade of in-the-trenches experience in the industry. Two of them including founder Eghdami and his former associate at KMPG, Graeme Moore, are chartered accountants, while co-founder Duncan McIntyre is a practicing lawyer schooled in mergers, acquisitions and corporate development. The teams' first success was the development of the FansUnite B2C social platform, which they eventually sold to a public company in 2016. FansUnite Social uses a free virtual currency for members to simulate the real thing while following and learning from their online heroes. The endgame, of course, is toward transferring the activity to the real-dollar platforms.

FansUnite Technology—B2C Social Platform

After the sale of the social peer platform, Eghdami and company decided to maintain the "FansUnite" brand equity in their new venture, launched in 2017. "We had the idea of getting into real-money sports gaming, spun it out of the pubic company, raised money in 2018 and started down this path. For the last year and a half we've been building our own technology to launch our sportsbook from a B2C perspective as well as prepare it for a full turn-key B2B solution. An option on the B2B platform will be a "smart contract sports book" whereby the funds are held "in-trust" and not accessible to FansUnite or end users until the event is completed and funds are directly sent to the winning party. The FansUnite platform is expected to accept cryptocurrency and regular fiat currency on its sportsbooks.

As part of FansUnite's roll-up strategy of entering into other world markets, acquiring yet maintaining well-established brands is the key to building its global B2B customers and B2C end users. The company is well funded with access to capital. Much of its support comes from industry leaders on the board like Shafin Diamond, CEO of Victory Square since 2015, a venture builder that builds start-ups in web, mobile, gaming, AI and AR/VR. Diamond has launched 40 start-ups in 24 countries, employed more than 350 people, and has generated over $100 million in annual revenues. He has received numerous awards, including the BC Tech Person of the Year Award, BC Angel Investor of the Year in 2014, and Business in Vancouver's Top 40 under 40.

FansUnite recently completed a financing of $3.1 million at $0.35 (free trading upon listing) and used $500,000 cash for the McBookie transaction before launching its IPO on the CSE. Total consideration for the McBookie deal was for approximately CAD$2.2 million, composed of the $500,000 cash up front, and $500,000 cash to be paid within 12 months, the rest in stock, at $0.35 a share, vesting and unrestricting over a course of 36 months.

Currently, management and insiders hold about 20% of the 70 million shares outstanding, and there are 3.5 million options and 1.4 million warrants with a weighted average price of $0.48 and $0.17 respectively, so no scary skeletons in the closet. Eghdami says the company is now sitting on about a $2 million war chest and burning about $175,000 per month. Should investor speculation lift its share price (as predicted here), it should be able to execute is M&A activity with a much stronger currency.

With $1 trillion waged annually, according to UK-based Football Report, the global market for this kind of technology is insane. Apparently, due to "COVID self-containment," it's "trending" even more as digital consumers are quarantined in their homes with nothing better to do but play on their computers.

As we hopefully ease out of this economic situation, FansUnite will have to execute fast and furiously. Now launching on the CSE at C$0.35 with a current market capitalization of $25 million, it has a long way to go, and much to prove, toward reaching the billion-dollar heights of its gaming peers, but the pie is big and the appetite is certainly there.

This is one race worth watching.

Knox Henderson is a journalist and capital markets communications consultant. He has advised for a broad range of small cap companies in the resource, life sciences and technology sectors for more than 25 years.

Disclosure:
1) 1) Knox Henderson: I, or members of my immediate household or family, own shares of the following companies mentioned in this article: None. I personally am, or members of my immediate household or family are, paid by the following companies mentioned in this article: FansUnite Entertainment Inc. My company has a financial relationship with the following companies mentioned in this article: None. I determined which companies would be included in this article based on my research and understanding of the sector.
2) The following companies mentioned in this article are billboard sponsors of Streetwise Reports: None. Click here for important disclosures about sponsor fees. As of the date of this article, an affiliate of Streetwise Reports has a consulting relationship with FansUnite. Please click here for more information. An affiliate of Streetwise Reports is conducting a digital media marketing campaign for this article on behalf of FansUnite. Please click here for more information. The information provided above is for informational purposes only and is not a recommendation to buy or sell any security.
3) Statements and opinions expressed are the opinions of the author and not of Streetwise Reports or its officers. The author is wholly responsible for the validity of the statements. The author was not paid by Streetwise Reports for this article. Streetwise Reports was not paid by the author to publish or syndicate this article. Streetwise Reports requires contributing authors to disclose any shareholdings in, or economic relationships with, companies that they write about. Streetwise Reports relies upon the authors to accurately provide this information and Streetwise Reports has no means of verifying its accuracy.
4) This article does not constitute investment advice. Each reader is encouraged to consult with his or her individual financial professional and any action a reader takes as a result of information presented here is his or her own responsibility. By opening this page, each reader accepts and agrees to Streetwise Reports' terms of use and full legal disclaimer. This article is not a solicitation for investment. Streetwise Reports does not render general or specific investment advice and the information on Streetwise Reports should not be considered a recommendation to buy or sell any security. Streetwise Reports does not endorse or recommend the business, products, services or securities of any company mentioned on Streetwise Reports.
5) From time to time, Streetwise Reports and its directors, officers, employees or members of their families, as well as persons interviewed for articles and interviews on the site, may have a long or short position in securities mentioned. Directors, officers, employees or members of their immediate families are prohibited from making purchases and/or sales of those securities in the open market or otherwise from the time of the interview or the decision to write an article until three business days after the publication of the interview or article. The foregoing prohibition does not apply to articles that in substance only restate previously published company releases. As of the date of this article, officers and/or employees of Streetwise Reports LLC (including members of their household) own securities of FansUnite, a company mentioned in this article.

( Companies Mentioned: FANS:CSE, )

Agri-environmental measures (AEM) are designed to encourage farmers to protect and enhance the environment on their farmland by paying them for the provision of environmental services. This study suggests that AEM would be more effective if payments were targeted to areas under the greatest environmental pressures, such as intensive agricultural regions — to gain maximum environmental benefits.

The group has been very active during the last five years, especially in 2019-20.

Facebook has revealed that it removed a network of 37 Facebook accounts, 32 Pages, 11 Groups and 42 Instagram accounts that originated in India and used fake accounts masquerading as media outlets to target the Gulf region, the US, the UK and Canada.

The group has been very active during the last five years, especially in 2019-20.

The Justice Department and the Drug Enforcement Administration (DEA) today announced the results of Project Python, a DEA-led interagency operation encompassing all global investigations and related disruption activities targeting the Cártel de Jalisco Nueva Generación (CJNG).

A 14-count indictment has been unsealed today in San Antonio, Texas, charging five individuals with coordinating an identify-theft and fraud scheme targeting servicemembers and veterans.

Fredrick Brown, 38, of Las Vegas, Nevada, a former civilian medical records administrator for the U.S. Army at the 65th Medical Brigade, Yongsan Garrison, South Korea, admitted yesterday to his role in an identity-theft and fraud scheme that victimized thousands of U.S. servicemembers and veterans.

South Korea-based company Jier Shin Korea Co. Ltd., and its president, Sang Joo Lee, have agreed to pay $2 million to the United States for civil antitrust and False Claims Act violations for their involvement in a bid-rigging conspiracy that targeted contracts to supply fuel to U.S. military bases in South Korea, the Department of Justice announced today.

A sheriff's deputy in North Carolina is facing criminal charges after authorities say he led a group of armed people to wrong home in a search for a missing girl.

Over at All Things Photo, I’ve shared a video detailing a scam targeting photographers selling prints online. Also included in the video are 7 tips to avoid being scammed online. While the video is on the long side it’s worth a listen to protect yourself and learn the limitations of fraud protection with your bank and insurance companies. If you’re driving you can also listen to the podcast recording via the All Things Photo podcast. If you haven’t already I welcome you to follow All Things Photo on YouTube, Twitter and Facebook.

A single software project in an integrated development environment (IDE) may be built for multiple target environments in a single build episode. Multiple different output artifacts may be generated by the build process for each of the target environments. The output artifacts are then deployed to the target environments, which may be homogeneous or heterogeneous environments. The same source project may be used to generate multiple output artifacts for the same target environment.

The present invention concerns a TCTP antagonist, in particular a nucleic acid targeting an m RNA encoding Translationally-Controlled Tumor Protein (TCTP), wherein said nucleic acid is capable of reducing the amount of TCTP in cells, for use in the treatment or prevention of hormone-independent cancer or chemo-resistant cancer, such as an androgen-independent prostate cancer.

Disclosed herein are methods and reagents for determining the responsiveness of cancer to an epidermal growth factor receptor (EGFR) targeting treatment. The detection of these mutations will allow for the administration of gefitinib, erlotinib and other tyrosine kinase inhibitors to those patients most likely to respond to the drug.

The present invention relates to oligomer compounds (oligomers) for the treatment and prevention of acute myeloid leukemia, which target GLI2 mRNA in a cell, leading to reduced expression of GLI2.

The presently disclosed subject matter provides compositions that selectively bind cyclooxygenase-2 and comprise a therapeutic and/or diagnostic moiety. Also provided are methods for using the disclosed compositions for diagnosing (i.e., by imaging) a target cell and/or treating a disorder associated with a cyclooxygenase-2 biological activity.

The present disclosure relates to a Co-029 inhibitor for inhibiting the migration of cancer cells which express Co-029. The disclosure relates to a Co-029 inhibitor for the treatment of cancer and/or the prevention of cancer metastasis and pharmaceutical compositions comprising said inhibitor and provides Co-029 antibodies. The disclosure provides a method for predicting the response of a patient afflicted with or susceptible to be afflicted with cancer to a medical treatment with a Co-029 inhibitor, a method for diagnosing a cancer in a patient and a method for predicting the survival in a cancer patient.

A targeting jig apparatus for targeting interlocking holes of an intramedullary nail. The targeting jig includes a support-arm extending substantially parallel to the intramedullary nail. A targeting mechanism including a pair of targeting mechanism drill-guide orifices is adjustably disposed on the support arm for aligning the targeting mechanism drill-guide orifice with the interlocking holes of the intramedullary nail. The targeting mechanism includes a saddle having a U-shape including a base and parallel legs that are slidable along the support-arm. A connection mechanism includes a horizontal slot on the support-arm aligned with a vertical slot on the targeting mechanism and a pivot screw extending through the slots for facilitating adjustment of the targeting mechanism relative to the support arm.

A molecule comprising a lipid, a peptide and a linker to bind the lipid to the peptide which have specific amino acid sequence to bind to Epidermal Growth Factor Receptor (EGFR) of tumor cells, and a liposomal composition which is targeted by the molecule, and method for preparing thereof is disclosed.

The present invention relates to methods and compositions for treating, preventing, and diagnosing Alzheimer's Disease or other tauopathies in a subject by administering an immunogenic tau peptide or an antibody recognizing the immunogenic tau epitope under conditions effective to treat, prevent, or diagnose Alzheimer's Disease or other tauopathies. Also disclosed are methods of promoting clearance of aggregates from the brain of the subject and of slowing progression of tau-pathology related behavioral phenotype in a subject.

The invention provides compositions and methods for treating leukemia, for example, acute myeloid leukemia (AML) and B-cell acute lymphoid leukemia (B-ALL). The invention also relates to at least one chimeric antigen receptor (CAR) specific to CD123, vectors comprising the same, and recombinant T cells comprising the CD123 CAR. The invention also includes methods of administering a genetically modified T cell expressing a CAR that comprises a CD123 binding domain. The invention also includes methods of bone marrow ablation for use in treatments necessitating bone marrow reconditioning or transplant.

Described herein are doppel-targeting molecules useful for inhibiting pathological angiogenesis and treating diseases and conditions associated with pathological angiogenesis, such as tumors, cancers, atherosclerosis, tuberculosis, asthma, pulmonary arterial hypertension (PAH), neoplasms and neoplasm-related conditions, and for detecting doppel expression in a subject. Related compositions and methods also are described.

The invention relates to polynucleotide agents targeting the complement component C5 gene, and methods of using such polynucleotide agents to inhibit expression of C5 and to treat subjects having a complement component C5-associated disease, e.g., paroxysmal nocturnal hemoglobinuria.

Hundreds of Indigenous people living in communities across the West Australian desert are being signed up to loans by a Gold Coast-based lender they can neither afford nor understand, advocacy groups say.

A clever little baiting device is being hailed as groundbreaking for the way in which it tempts foxes to take a poison bait while discouraging other wildlife.

The feminist parade kicked off last year in Los Angeles.

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents.

Detection and treatment of cancer have progressed, but neither is as precise as doctors would like. For example, tumors can change shape or location between pre-operative diagnosis and treatment so that radiation is aimed at a target which may have moved. Geometry, partial differential equations, and integer linear programming are three areas of mathematics used to process data in real-time, which allows doctors to inflict maximum damage to the tumor, with minimum damage to healthy tissue. One promising area of investigation is virotherapy: using viruses to destroy cancerous cells. Researchers are using mathematical models to discover how to use the viruses most beneficially.The models provide numerical outcomes for each of the many possibilities, thereby eliminating unsuccessful approaches and identifying candidates for further experimentation.Testing by simulation, which led to the development of anti-HIV cocktails, means good medicine is developed faster and cheaper than it can be by lab experiments and clinical trials alone. For More Information: Treatment Planning for Brachytherapy, Eva Lee, et al, Physics in Medicine and Biology, 1999.

Palestinian officials said Friday that Israel is forcing banks in the occupied West Bank to close accounts held by the families of prisoners in Israeli jails to prevent the Palestinian Authority from providing stipends to them. Israel has long objected to the Palestinian Authority's payments to the families of prisoners and those killed in the conflict, including militants, saying it rewards terrorism. The Palestinians view the payments as a social safety net for those living under decades of military occupation.

Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematological malignancy. Despite new treatments and protocols including high doses chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. Alpha-radioimmunotherapy (alpha-RIT) represents an attractive treatment strategy due to the high linear energy transfer and short path length of alpha-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of alpha-RIT with ²¹²Pb-Daratumumab (anti-CD38), in both in vitro and in vivo models, as well as an anti-mouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of RPMI8226 cell line with increasing activities (0.185-3.7 kBq/ml) of ²¹²Pb-isotypic control or ²¹²Pb-Daratumumab was evaluated. Biodistribution was performed in vivo by SPECT-CT imaging and post-mortem. Dose range finding (DRF) and acute toxicity studies were conducted. As Daratumumab does not bind the murine CD38, biodistribution and DRF were also determined using an anti-murine CD38 antibody. To evaluate in vivo efficacy of ²¹²Pb-Daratumumab, mice were engrafted subcutaneously with 5.106 RPMI8226 cells. Mice were treated 13 days post-engraftment with an intravenous injection of ²¹²Pb-Daratumumab or control solutions. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after three days of incubation with ²¹²Pb-Daratumumab compared to ²¹²Pb-Isotypic Control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of Daratumumab. No toxicity was observed with ²¹²Pb-Daratumumab up to 370 kBq due to the lack of cross-reactivity. Nevertheless, acute toxicity experiments with ²¹²Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of ²¹²Pb-Daratumumab. Marked tumor growth inhibition compared to controls was observed, with a median survival of 55 days for 277.5 kBq of ²¹²Pb-Daratumumab instead of 11 for PBS control groups. Conclusion: These results showed ²¹²Pb-Daratumumab efficacy on xenografted mice with significant tumor regression and increased survival. This study highlights alpha-RIT potency in MM treatment.

The overexpression of integrin αvβ6 in pancreatic cancer makes it a promising target for noninvasive positron emission tomography (PET) imaging. However, currently, most integrin αvβ6-targeting radiotracers are based on linear peptides, which are quickly degraded in the serum by proteinases. Herein, we aimed to develop and assess a ⁶⁸Ga-labeled integrin αvβ6-targeting cyclic peptide (⁶⁸Ga-cycratide) for PET imaging of pancreatic cancer. Methods: ⁶⁸Ga-cycratide was prepared, and its PET imaging profile was compared with that of the linear peptide (⁶⁸Ga-linear-pep) in an integrin αvβ6-positive BxPC-3 human pancreatic cancer mouse model. Five healthy volunteers (two women and three men) underwent whole-body PET/CT imaging after injection of ⁶⁸Ga-cycratide, and biodistribution and dosimetry calculations were determined. PET/CT imaging of two patients was performed to investigate the potential role of ⁶⁸Ga-cycratide in pancreatic cancer diagnosis and treatment monitoring. Results: ⁶⁸Ga-cycratide exhibited significantly higher tumor uptake than did ⁶⁸Ga-linear-pep in BxPC-3 tumor-bearing mice, owing—at least in part—to markedly improved in vivo stability. ⁶⁸Ga-cycratide could sensitively detect the pancreatic cancer lesions in an orthotopic mouse model and was well tolerated in all healthy volunteers. Preliminary PET/CT imaging in patients with pancreatic cancer demonstrated that ⁶⁸Ga-cycratide was comparable to ¹⁸F-fludeoxyglucose for diagnostic imaging and post-surgery tumor relapse monitoring. Conclusion: ⁶⁸Ga-cycratide is an integrin αvβ6-specific PET radiotracer with favorable pharmacokinetics and dosimetry profile. ⁶⁸Ga-cycratide is expected to provide an effective noninvasive PET strategy for pancreatic cancer lesion detection and therapy response monitoring.

Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. Gallium-68–labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to positron emission tomography (PET) imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an ¹⁸F–labeled glycosylated FAP inhibitor ([¹⁸F]FGlc-FAPI). Methods: An alkyne-bearing precursor was synthesized and subjected to click chemistry–based radiosynthesis of [¹⁸F]FGlc-FAPI by two-step ¹⁸F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [¹⁸F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small animal PET studies of [¹⁸F]FGlc-FAPI compared to [⁶⁸Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. Results: [¹⁸F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of >99%. In HT1080hFAP cells, [¹⁸F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared to FAPI-04 (IC50 = 32 nM), the glycoconjugate, FGlc-FAPI (IC50 = 167 nM), showed slightly lower affinity for FAP in vitro, while plasma protein binding was higher for [¹⁸F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [¹⁸F]FGlc-FAPI; however, small animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [¹⁸F]FGlc-FAPI (4.5 % injected dose per gram of tissue [ID/g]) compared to [⁶⁸Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor–bearing mice, both tracers showed similar tumor uptake, but [¹⁸F]FGlc-FAPI showed a higher tumor retention. Interestingly, [¹⁸F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. Conclusion: [¹⁸F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of F-18. The availability of [¹⁸F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

Triple-negative breast cancer (TNBC) is characterized by its aggressive biology, early metastatic spread, and poor survival outcomes. TNBC lacks expression of the targetable receptors found in other breast cancer subtypes, mandating use of cytotoxic chemotherapy. However, resistance to chemotherapy is a significant problem, encountered in about two-thirds of TNBC patients, and new strategies are needed to mitigate resistance. In this issue of the Journal of Biological Chemistry, Geck et al. report that TNBC cells are highly sensitive to inhibition of the de novo polyamine synthesis pathway and that inhibition of this pathway sensitizes cells to TNBC-relevant chemotherapy, uncovering new opportunities for addressing chemoresistance.

In 2012, Eleni Linos, professor of dermatology at Stanford university, published a systematic review and meta-analysis of the link between non-melanoma cancer and sun-beds. That bit of pretty standard research, and a particular rapid response to it, has kicked of years of work - and in this podcast I talk to Eleni and her colleagues Stanton...