Reduced SH3RF3 may protect against Alzheimer's disease by lowering microglial pro-inflammatory responses via modulation of JNK and NFkB signaling.

Understanding how high-risk individuals are protected from Alzheimer's disease (AD) may illuminate potential therapeutic targets. A previously identified non-coding SNP in SH3RF3/POSH2 significantly delayed disease onset in a Caribbean Hispanic cohort carrying the PSEN1 G206A mutation sufficient to cause early-onset AD and microglial expression of SH3RF3 has been reported to be a key driver of late-onset AD. SH3RF3 acts as a JNK pathway scaffold and can activate NFκB signaling. While effects of SH3RF3 knockdown in human neurons were subtle, including decreased phospho-tau S422, knockdown in human microglia significantly reduced inflammatory cytokines in response to either a viral mimic or oligomeric Aß42. This was associated with reduced activation of JNK and NFκB pathways in response to these stimuli. Pharmacological inhibition of JNK or NFκB signaling phenocopied SH3RF3 knockdown. We also found PSEN1 G206A microglia have reduced inflammatory responses to oAß42. Thus, further reduction of microglial inflammatory responses in PSEN1 mutant carriers by protective SNPs in SH3RF3 might reduce the link between amyloid and neuroinflammation to subsequently delay the onset of AD.

Osteopontin drives neuroinflammation and cell loss in MAPT-N279K frontotemporal dementia patient neurons.

Frontotemporal dementia (FTD) is an incurable group of early-onset dementias that can be caused by the deposition of hyperphosphorylated tau in patient brains. However, the mechanisms leading to neurodegeneration remain largely unknown. Here, we combined single-cell analyses of FTD patient brains with a stem cell culture and transplantation model of FTD. We identified disease phenotypes in FTD neurons carrying the MAPT-N279K mutation, which were related to oxidative stress, oxidative phosphorylation, and neuroinflammation with an upregulation of the inflammation-associated protein osteopontin (OPN). Human FTD neurons survived less and elicited an increased microglial response after transplantation into the mouse forebrain, which we further characterized by single nucleus RNA sequencing of microdissected grafts. Notably, downregulation of OPN in engrafted FTD neurons resulted in improved engraftment and reduced microglial infiltration, indicating an immune-modulatory role of OPN in patient neurons, which may represent a potential therapeutic target in FTD.

Fostering partnerships and program success.

BACKGROUND: Fostering partnerships was critical to the success of the Colon Health Program (CHP) in Greater Seattle. The CHP was built on the Breast and Cervical Health Program (BCHP) framework. A replicable system to provide quality colorectal screening services for individuals with limited incomes and no health insurance was developed. METHODS: Partners were recruited and engaged during 3 programmatic phases: 1) development and start-up, 2) implementation, and 3) sustainability planning. Several tactics were used to develop trust and build bridges among the partners and to create an effective work group. RESULTS: The partners were critical to developing clinic policies, procedures, and systems to increase colorectal screening and improve follow-up; expanding access to colonoscopies; and initiating statewide dissemination of training and systems as well as policy change. The fecal occult blood test completion rate was 61%, and the colonoscopy completion rate was 78%. The colonoscopy navigation system was effective with a low "no show" rate (8%). The partners were instrumental in helping Washington State obtain funding from the Centers for Disease Control and Prevention to continue the CHP statewide. CONCLUSIONS: During implementation, key elements for success included: building the project on the successful BCHP framework, meticulous training of clinic staff about colorectal cancer and screening methods, frequent consultation to identify and solve problems, active support of the clinic administration, and the presence of a CHP champion in the clinic. Institutionalization of the CHP depended on: assessing progress after the first year, documenting experience with the program, disseminating lessons learned, engaging new partners, and determining steps to expand the program.

Clinical outcomes from the CDC's Colorectal Cancer Screening Demonstration Program.

BACKGROUND: Colorectal cancer remains the second leading cause of cancer-related deaths among US men and women. Screening rates have been slow to increase, and disparities in screening remain. METHODS: To address the disparity in screening for this high burden but largely preventable disease, the Centers for Disease Control and Prevention (CDC) designed and established a 4-year Colorectal Cancer Screening Demonstration Program (CRCSDP) in 2005 for low-income, under-insured or uninsured men and women aged 50 to 64 years in 5 participating US program sites. In this report, the authors describe the design of the CRCSDP and the overall clinical findings and screening test performance characteristics, including the positive fecal occult blood testing (FOBT) rate; the rates of polyp, adenoma, and cancer detection with FOBTs and colonoscopies; and the positive predicative value for polyps, adenomas, and cancers. RESULTS: In total, 5233 individuals at average risk and increased risk were screened for colorectal cancer across all 5 sites, including 44% who underwent screening FOBT and 56% who underwent screening colonoscopy. Overall, 77% of all individuals screened were women. The FOBT positivity rate was 10%. Results from all screening or diagnostic colonoscopies indicated that 75% had negative results and required a repeat screening colonoscopy in 10 years, 16% had low-risk adenomas and required surveillance colonoscopy in 5 to 10 years, 8% had high-risk adenomas and required surveillance colonoscopy in 3 years, and 0.6% had invasive cancers. CONCLUSIONS: This report documents the successes and challenges in implementing the CDC's CRCSDP and describes the clinical outcomes of this 4-year initiative, the patterns in program uptake and test choice, and the comparative test performance characteristics of FOBT versus colonoscopy. Patterns in final outcomes from the follow-up of positive screening tests were consistent with national registry data.

Lesbian health matters: a pap test education campaign nearly thwarted by discrimination.

The Pap test detects cell changes in the cervix that can be treated, preventing cancer from developing. Regular screening reduced cervical cancer deaths by 70% since 1950. Lesbians may not be adequately screened because of a misperception that they do not need Pap tests. The "Lesbian Health Matters" public and provider education campaign was implemented to address this problem. Paid advertisements were placed on two radio stations and in four newspapers. After 1 week, both radio stations cancelled the ads due to listener complaints about hearing the word "lesbian" on the radio. The community responded to this discriminatory action by demanding the campaign be completed, creating publicity that increased the campaign's reach to 34% of women in the region. A training program was implemented reaching 219 providers. Thirty-two hundred health providers were surveyed regarding lesbian-friendly practice. A database of 293 providers was created and 120 referrals made.