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Scheffer, K. C.

Publications and source records attributed to Scheffer, K. C..

2 recordsLinked to original sources

Selective Pyroptosis in NF1-Deficient Cells through PKCδ Agonism

Pyroptosis, a lytic and immunogenic form of cell death, holds broad therapeutic potential, yet its selective induction in specific cell populations remains a fundamental challenge. Loss of the NF1 tumor suppressor, one of the most frequent events across pediatric and adult cancers, elevates RAS-GTP and drives tumorigenesis through hyperactivated RAS signaling. Here we demonstrate that protein kinase C{delta} (PKC{delta}) agonism selectively triggers pyroptosis in NF1-deficient cells by exploiting their dependency on KRAS. PKC{delta} directly phosphorylates KRAS at S39 and S181, inducing KRAS-GDP accumulation and driving endoplasmic reticulum translocation. The dually phosphorylated KRAS-GDP interacts with caspase-8 and competitively displaces inhibitory BCL2, promoting caspase-8/caspase-3/gasdermin-E-mediated pyroptosis. This vulnerability is conserved across multiple NF1-deficient tumor types, and PKC agonism suppresses NF1-deficient neurofibroma and malignant peripheral nerve sheath tumor growth in vivo. These findings establish the inactive KRAS-GDP as a functionally active signaling molecule and PKC{delta} agonism as a selective therapeutic strategy for NF1-deficient cancers.

cancer biology↗

Factors associated with adherence to annual rabies vaccination in dogs and cats in the municipality of Curuca, Eastern Amazon

Dogs and cats maintain the urban cycle of rabies, and vaccination is the main form of prevention and control of the disease. Brazil has seen human rabies cases transmitted by dogs and cats infected with the bat variant in regions where annual campaigns no longer take place. Although the municipality of Curuca has no cases of urban rabies and viral circulation in wild animals is unknown, there are informal reports of contact of animals and people with vampire bats. This study aimed to identify factors associated with immune response against the rabies virus in dogs and cats in this municipality. A total of 352 dogs and 46 cats were randomly selected for blood collection and their owners answered a questionnaire. The animals were mostly males, aged between 1-3 years, and with unrestricted access to the street. A total of 48.8% of dogs and 32% of cats were not vaccinated in the last anti-rabies campaign, and 4.7% of dogs had been attacked by bats. Among the analyzed samples, only 21.1% had a titration [≥] 0.5 IU/mL. Risk factors for not participating in vaccination campaigns included species, presence of veterinary care, and participation in annual vaccination campaigns (OR = 0.46, 2.55, and 15.67 respectively). The animal population was estimated at 18,620 dogs and 4,556 cats. The human:dog ratio was 2.1:1 and the human:cat ratio was 8.7:1. This study revealed that the estimated population of dogs based on the human population was an underestimate for communities in the Amazon region. This was the first time that the number of dogs attacked by bats was determined. Health education with an emphasis on responsible ownership and periodic and biannual rabies vaccinations are recommended for the municipality. AUTHOR SUMMARYRabies is a viral disease characterized by brain and spinal cord inflammation. It affects all mammals, being almost 100% lethal. Hematophagous bats are one of the main wild reservoirs responsible for outbreaks of human rabies in the state of Para and other regions of Brazil. Vaccination is the most effective form of control and prevention, even where rabies is believed to be under control. The levels of antibodies that fight the rabies virus must be constantly monitored through serological analysis to assess the effectiveness of vaccination programs. In the municipality of Curuca, Para, bats commonly attack people and their pets, and anti-rabies campaigns are not promoted every year. In the present study, we determined the number of attacks by bats on domestic dogs and estimated vaccination coverage and the canine and feline population in the municipality, which was underestimated. This information can be useful for future vaccination campaigns. The study identified factors associated with responsible ownership that interfere with the protective titration of animals against rabies and suggests promoting more than one annual anti-rabies campaign in this location.

scientific communication and education↗