What is Geo-Targeting? This is a form of location specific targeting where you literally choose specific locations to market your services or products too. A simple way to understand this objective is to think of it as local listing services that show local results in the search engines. But the main difference is that you […]

Israel says its targets are legitimate, but critics say it is aiming at Hezbollah's social base.

The following article, ‘Blatant Weaponization’: FEMA Facing Investigations For Targeting Suffering Trump Supporters, was first published on Conservative Firing Line.

Republicans are calling for investigations, or are already launching their own, into charges that the federal government deliberately and willfully discriminated against supporters of President-elect Donald Trump following a hurricane disaster in Florida. It was the Daily Wire that initially documented how Marn’I Washington, a Federal Emergency Management Agency supervisor, instructed employees under her authority …

Continue reading ‘Blatant Weaponization’: FEMA Facing Investigations For Targeting Suffering Trump Supporters ...

Leukocidin ED (LukED) is a pore-forming toxin produced by Staphylococcus aureus, which lyses host cells and promotes virulence of the bacteria. LukED enables S. aureus to acquire iron by lysing erythrocytes, which depends on targeting the host receptor Duffy antigen receptor for chemokines (DARC). The toxin also targets DARC on the endothelium, contributing to the lethality observed during bloodstream infection in mice. LukED is comprised of two monomers: LukE and LukD. LukE binds to DARC and facilitates hemolysis, but the closely related Panton–Valentine leukocidin S (LukS-PV) does not bind to DARC and is not hemolytic. The interaction of LukE with DARC and the role this plays in hemolysis are incompletely characterized. To determine the domain(s) of LukE that are critical for DARC binding, we studied the hemolytic function of LukE–LukS-PV chimeras, in which areas of sequence divergence (divergence regions, or DRs) were swapped between the toxins. We found that two regions of LukE's rim domain contribute to hemolysis, namely residues 57–75 (DR1) and residues 182–196 (DR4). Interestingly, LukE DR1 is sufficient to render LukS-PV capable of DARC binding and hemolysis. Further, LukE, by binding DARC through DR1, promotes the recruitment of LukD to erythrocytes, likely by facilitating LukED oligomer formation. Finally, we show that LukE targets murine Darc through DR1 in vivo to cause host lethality. These findings expand our biochemical understanding of the LukE–DARC interaction and the role that this toxin-receptor pair plays in S. aureus pathophysiology.

Postoperative recurrence from microscopic residual disease must be prevented to cure intractable cancers, including pancreatic cancer. Key to this goal is the elimination of cancer stem cells (CSCs) endowed with tumor-initiating capacity and drug resistance. However, current therapeutic strategies capable of accomplishing this are insufficient. Using in vitro models of CSCs and in vivo models of tumor initiation in which CSCs give rise to xenograft tumors, we show that dexamethasone induces expression of MKP-1, a MAPK phosphatase, via glucocorticoid receptor activation, thereby inactivating JNK, which is required for self-renewal and tumor initiation by pancreatic CSCs as well as for their expression of survivin, an anti-apoptotic protein implicated in multidrug resistance. We also demonstrate that systemic administration of clinically relevant doses of dexamethasone together with gemcitabine prevents tumor formation by CSCs in a pancreatic cancer xenograft model. Our study thus provides preclinical evidence for the efficacy of dexamethasone as an adjuvant therapy to prevent postoperative recurrence in patients with pancreatic cancer.

Single-domain antibodies (sdAbs) demonstrate favorable pharmacokinetic profiles for molecular imaging applications. However, their renal excretion and retention are obstacles for applications in targeted radionuclide therapy (TRT). Methods: Using a click-chemistry–based pretargeting approach, we aimed to reduce kidney retention of a fibroblast activation protein α (FAP)–targeted sdAb, 4AH29, for ¹⁷⁷Lu-TRT. Key pretargeting parameters (sdAb-injected mass and lag time) were optimized in healthy mice and U87MG (FAP⁺) xenografts. A TRT study in a pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (PDX) model was performed as a pilot study for sdAb-based pretargeting applications. Results: Modification of 4AH29 with trans-cyclooctene (TCO) moieties did not modify the sdAb pharmacokinetic profile. A 200-µg injected mass of 4AH29-TCO and an 8-h lag time for the injection of [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine resulted in the highest kidney therapeutic index (2.0 ± 0.4), which was 5-fold higher than that of [¹⁷⁷Lu]Lu-DOTA-4AH29 (0.4 ± 0.1). FAP expression in the tumor microenvironment was validated in a PDAC PDX model with both immunohistochemistry and PET/CT imaging. Mice treated with the pretargeting high-activity approach (4AH29-TCO + [¹⁷⁷Lu]Lu-DOTA-PEG₇-tetrazine; 3 x 88 MBq, 1 injection per week for 3 wk) demonstrated prolonged survival compared with the vehicle control and conventionally treated ([¹⁷⁷Lu]Lu-DOTA-4AH29; 3 x 37 MBq, 1 injection per week for 3 wk) mice. Mesangial expansion was reported in 7 of 10 mice in the conventional cohort, suggesting treatment-related kidney morphologic changes, but was not observed in the pretargeting cohort. Conclusion: This study validates pretargeting to mitigate sdAbs’ kidney retention with no observation of morphologic changes on therapy regimen at early time points. Clinical translation of click-chemistry–based pre-TRT is warranted on the basis of its ability to alleviate toxicities related to biovectors’ intrinsic pharmacokinetic profiles. The absence of representative animal models with extensive stroma and high FAP expression on cancer-associated fibroblasts led to a low mean tumor-absorbed dose even with high injected activity and consequently to modest survival benefit in this PDAC PDX.

Shiaoching Gong
Sep 12, 2007; 27:9817-9823
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In the aftermath of the bombing in North Pakistan, OM Pakistan begins to help those most vulnerable.

Proptech refers to the use of technology and software to assist the real estate market with its needs.

The Delaware Judiciary, Delaware Department of Justice, Department of Correction and Delaware State Police are warning the public of a phone scam that is apparently targeting probationers. The Delaware State Police have received information about fraudulent callers threatening individuals on probation with re-arrest for allegedly committing new crimes. In at least one case, the caller […]

Attorney General Kathy Jennings has joined a coalition of 25 states and territories in filing a letter with the U.S. Treasury Department’s Financial Crimes Enforcement Network (FinCEN) in support of proposed rules entitled “Anti-Money Laundering Regulations for Residential Real Estate Transactions.”     The April 16 letter expresses staunch support for the would-be regulations, which will […]

There's no question that we're all increasingly, and often exclusively, interacting with brands digitally. Consumers are now online through countless mechanisms – from laptops and mobile apps to AI-enabled voice assistants and sensor-based wearables. Engagement is diversifying in fascinating new ways. And when organizations can't see their customers interacting in [...]

SAS Customer Intelligence 360: Behavioral event tracking, targeting & engagement analysis was published on Customer Intelligence Blog.

the hague, netherlands — Dozens of people armed with sticks and firecrackers set a tram on fire in Amsterdam on Monday, police said, while the city is facing tensions following violence last week targeting fans of an Israeli soccer club. Police said the fire was quickly extinguished and riot officers cleared the square. Images online showed people damaging property and setting off firecrackers. Police said it was not clear who started the unrest or whether it was related to what happened last week. But they noted the tense atmosphere since five people were treated in the hospital and dozens detained Thursday following a Maccabi Tel Aviv-Ajax match. Youths on scooters and on foot went in search of Israeli fans, punching and kicking them and then fleeing to evade police, according to Amsterdam’s mayor. Dutch police announced five new arrests Monday in their investigation into that earlier violence. The suspects are men aged 18 to 37 and are from Amsterdam or surrounding cities. Four are still in custody; the fifth has been released but remains a suspect. Earlier, police said that four other men who had been arrested last week would remain in custody while the investigation continued. Two of those are minors, a 16-year-old and a 17-year-old from Amsterdam. The other two men are from Amsterdam and a nearby city. Police said they have identified over 170 witnesses and have taken forensics evidence from dozens. Prime Minister Dick Schoof said they were also examining videos posted to social media. Reports of antisemitic speech, vandalism and violence have been on the rise in Europe since the start of the war in Gaza, and tensions mounted in Amsterdam ahead of Thursday night’s match. Pro-Palestinian demonstrators were banned by local authorities from gathering outside the stadium. Before the match, Maccabi fans also tore a Palestinian flag off a building in Amsterdam and chanted anti-Arab slogans on their way to the stadium. There were also reports of Maccabi fans starting fights. The mayor has banned all demonstrations in the city and declared several parts of Amsterdam risk zones where police can stop and check anyone. Dozens were detained on Sunday for taking part in a pro-Palestinian demonstration in central Amsterdam that had been outlawed. Israeli Foreign Minister Gideon Saar rushed to the Netherlands on Friday and offered Israel’s help in the police investigation. He met on Saturday with the Dutch prime minister and said in a statement that the attacks and demands to show passports “were reminiscent of dark periods in history.”

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid-β peptide (Aβ), culminating in cognitive decline and dementia. The connection between the SRIF and AD further extends to the neuropsychiatric symptoms, seizure activity, and inflammation, whereas preclinical AD investigations show SRIF or SRIF receptor agonist administration capable of enhancing cognition. SRIF receptor subtype-4 activation in particular presents unique attributes, with the potential to mitigate learning and memory decline, reduce comorbid symptoms, and enhance enzymatic degradation of Aβ in the brain. Here, we review the links between SRIF and AD along with the therapeutic implications.

Shameless scammers trick veterans into giving personal info or cash. Tech expert Kurt “CyberGuy" Knutsson explores five common scams.

As Latino voters are a key voting bloc in the 2024 presidential election in battleground states like Nevada, Arizona and Pennsylvania, they have been targeted by a rise in Spanish-language misinformation. Most of the false messaging disparages Kamala Harris and supports Donald Trump, says Pulitzer Prize-winning journalist Maria Hinojosa, host of Latino USA, which investigated the phenomenon in a new episode called “The Misinformation Web.” She interviewed some of the content creators in this “blob” of online vitriol and says there is almost no effective content moderation online, nor many reliable fact-checking sources in Spanish to counter the lies.

Showjumper Tim Stockdale is setting his sights on competing at the Rio Olympic Games of 2016 at the age of 52.

Highlights: Interest in re-purposing neutralizing antibodies for therapeutic use against related viruses has been w

People who work night shifts or irregular hours and eat at inconsistent times are more susceptible to weight gain and diabetes, likely because their eating

Acute and chronic liver diseases continue to be major clinical problems because of their high rates of morbidity and mortality. Acetaminophen (APAP)

The hackers who reportedly hit more than 130 organizations last year and stole the credentials of almost 10,000 employees are still targeting several tech and video game companies, according to a report obtained by TechCrunch. The report, prepared by cybersecurity firm CrowdStrike, calls the hackers “Scattered Spider.” In a previous publicly available report, the company […]

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National Bureau of Economic Research

National Bureau of Economic Research

National Bureau of Economic Research

European Central Bank

Shakeri is an Islamic Revolutionary Guard Corps (IRGC) asset, remains at large and is believed to reside in Tehran, Iran