Gastrointestinal Polyps and Polyposis in Individuals Harboring Germline CHEK2 Mutations.

BACKGROUND: Checkpoint kinase 2 is a tumor suppressor gene in the deoxyribonucleic acid damage checkpoint system that may be mutated in several cancers. Patients with germline checkpoint kinase 2 mutations and multiple colon polyps were noted during routine care, and genetic testing is recommended for patients with as few as 10 lifetime polyps. OBJECTIVE: This study assessed whether checkpoint kinase 2 is associated with attenuated or oligopolyposis and characterized the gastrointestinal clinicopathologic profile. DESIGN: Retrospective observational study. SETTINGS: Records from patients harboring germline checkpoint kinase 2 mutations from 1999-2020 were reviewed. PATIENTS: A total of 45 patients with germline checkpoint kinase 2 mutations with endoscopic examinations. MAIN OUTCOME MEASURES: Description of clinicopathologic variables. RESULTS: Twenty-five of 45 patients had polyps: 3 with only upper gastrointestinal polyps, 17 with only lower gastrointestinal polyps and 5 with both upper and lower gastrointestinal polyps. The most common germline checkpoint kinase 2 mutations in patients with polyps were p.S428F (n = 10), p.I157T (n = 4) and p.T476M (n = 2), with other mutations present in 1 patient each. Among patients with lower gastrointestinal polyps, 9 had adenomas, 6 had serrated polyps, 1 had an inflammatory polyp and 6 had both adenomatous and serrated polyps. Three patients (p.I157T, n = 2; p.R117G, n = 1) had >10 adenomas, and 1 (p.G259fs) had 18 serrated polyps. Five patients (11.1%) developed colorectal adenocarcinoma, including 2 with >10 adenomas. Five patients with p.S428F (50%) exclusively had right- sided adenomas. LIMITATIONS: Single-center descriptive study. CONCLUSIONS: Germline checkpoint kinase 2 mutations should be considered in patients with polyposis. The preponderance of right- sided adenomas in patients with p.S428F mutations suggests the importance of right-sided colonoscopy in these patients. See Video Abstract.

Risk-reducing mastectomy decisions among women with mutations in high- and moderate- penetrance breast cancer susceptibility genes.

BACKGROUND: Women harboring mutations in breast cancer susceptibility genes are at increased lifetime risk of developing breast cancer and are faced with decisions about risk management, including whether to undergo high-risk screening or risk-reducing mastectomy (RRM). National guidelines recommend BRCA1 or BRCA2 mutation carriers consider RRM, but that carriers of moderate penetrance mutations (e.g., ATM or CHEK2) should be managed based on family history. We aimed to investigate determinants of decision for RRM, and hypothesized that mutation status, age, family history, partner status, and breast cancer would impact RRM decision making. METHODS: We performed a retrospective study assessing RRM decisions for 279 women. RESULTS: Women with BRCA and moderate penetrance gene mutations, a personal history of breast cancer, or a first degree relative with a history of breast cancer were more likely to undergo RRM. Breast cancer status and age showed an interaction effect such that women with breast cancer were less likely to undergo RRM with increasing age. CONCLUSION: Although national guidelines do not recommend RRM for moderate penetrance carriers, the rates of RRM for this population approached those for BRCA mutation carriers. Further insights are needed to better support RRM decision-making in this population.

Global reach of ageism on older persons' health: A systematic review.

OBJECTIVE: Although there is anecdotal evidence of ageism occurring at both the structural level (in which societal institutions reinforce systematic bias against older persons) and individual level (in which older persons take in the negative views of aging of their culture), previous systematic reviews have not examined how both levels simultaneously influence health. Thus, the impact of ageism may be underestimated. We hypothesized that a comprehensive systematic review would reveal that these ageism levels adversely impact the health of older persons across geography, health outcomes, and time. METHOD: A literature search was performed using 14 databases with no restrictions on region, language, and publication type. The systematic search yielded 13,691 papers for screening, 638 for full review, and 422 studies for analyses. Sensitivity analyses that adjusted for sample size and study quality were conducted using standardized tools. The study protocol is registered (PROSPERO CRD42018090857). RESULTS: Ageism led to significantly worse health outcomes in 95.5% of the studies and 74.0% of the 1,159 ageism-health associations examined. The studies reported ageism effects in all 45 countries, 11 health domains, and 25 years studied, with the prevalence of significant findings increasing over time (p < .0001). A greater prevalence of significant ageism-health findings was found in less-developed countries than more-developed countries (p = .0002). Older persons who were less educated were particularly likely to experience adverse health effects of ageism. Evidence of ageism was found across the age, sex, and race/ethnicity of the targeters (i.e., persons perpetrating ageism). CONCLUSION: The current analysis which included over 7 million participants is the most comprehensive review of health consequences of ageism to date. Considering that the analysis revealed that the detrimental impact of ageism on older persons' health has been occurring simultaneously at the structural and individual level in five continents, our systematic review demonstrates the pernicious reach of ageism.

Role of the endolysosomal system in Parkinson's disease.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting 1-1.5% of the total population. While progress has been made in understanding the neurodegenerative mechanisms that lead to cell death in late stages of PD, mechanisms for early, causal pathogenic events are still elusive. Recent developments in PD genetics increasingly point at endolysosomal (E-L) system dysfunction as the early pathomechanism and key pathway affected in PD. Clathrin-mediated synaptic endocytosis, an integral part of the neuronal E-L system, is probably the main early target as evident in auxilin, RME-8, and synaptojanin-1 mutations that cause PD. Autophagy, another important pathway in the E-L system, is crucial in maintaining proteostasis and a healthy mitochondrial pool, especially in neurons considering their inability to divide and requirement to function an entire life-time. PINK1 and Parkin mutations severely perturb autophagy of dysfunctional mitochondria (mitophagy), both in the cell body and synaptic terminals of dopaminergic neurons, leading to PD. Endolysosomal sorting and trafficking is also crucial, which is complex in multi-compartmentalized neurons. VPS35 and VPS13C mutations noted in PD target these mechanisms. Mutations in GBA comprise the most common risk factor for PD and initiate pathology by compromising lysosomal function. This is also the case for ATP13A2 mutations. Interestingly, α-synuclein and LRRK2, key proteins involved in PD, function in different steps of the E-L pathway and target their components to induce disease pathogenesis. In this review, we discuss these E-L system genes that are linked to PD and how their dysfunction results in PD pathogenesis. This article is part of the Special Issue "Synuclein".

Critical Size Limit of Biodegradable Nanoparticles for Enhanced Lymph Node Trafficking and Paracortex Penetration.

Lymph node (LN) targeting through interstitial drainage of nanoparticles (NPs) is an attractive strategy to stimulate a potent immune response, as LNs are the primary site for lymphocyte priming by antigen presenting cells (APCs) and triggering of an adaptive immune response. NP size has been shown to influence the efficiency of LN-targeting and retention after subcutaneous injection. For clinical translation, biodegradable NPs are preferred as carrier for vaccine delivery. However, the selective "size gate" for effective LN-drainage, particularly the kinetics of LN trafficking, is less well defined. This is partly due to the challenge in generating size-controlled NPs from biodegradable polymers in the sub-100-nm range. Here, we report the preparation of three sets of poly(lactic-co-glycolic)-b-poly(ethylene-glycol) (PLGA-b-PEG) NPs with number average diameters of 20-, 40-, and 100-nm and narrow size distributions using flash nanoprecipitation. Using NPs labeled with a near-infrared dye, we showed that 20-nm NPs drain rapidly across proximal and distal LNs following subcutaneous inoculation in mice and are retained in LNs more effectively than NPs with a number average diameter of 40-nm. The drainage of 100-nm NPs was negligible. Furthermore, the 20-nm NPs showed the highest degree of penetration around the paracortex region and had enhanced access to dendritic cells in the LNs. Together, these data confirmed that small, size-controlled PLGA-b-PEG NPs at the lower threshold of about 30-nm are most effective for LN trafficking, retention, and APC uptake after s.c. administration. This report could inform the design of LN-targeted NP carrier for the delivery of therapeutic or prophylactic vaccines.

Synergistic inhibition of head and neck tumor growth by green tea (-)-epigallocatechin-3-gallate and EGFR tyrosine kinase inhibitor.

One of the mechanisms of the antitumor activity of green tea (-)-epigallocatechin-3-gallate (EGCG) is associated with its effect on epidermal growth factor receptor (EGFR)-mediated signaling transduction pathways. We investigated whether combining EGCG with the EGFR-tyrosine kinase inhibitor (EGFR-TKI) erlotinib may augment erlotinib-induced cell growth inhibition of squamous cell carcinoma of the head and neck (SCCHN) in a mouse xenograft model. In vitro studies with 5 head and neck cancer cell lines revealed that synergistic cell growth inhibition by the combination of EGCG and erlotinib was associated with significantly greater inhibition of pEGFR and pAKT, increased activation of caspases 9, 3 and PARP compared to the inhibition induced by EGCG or erlotinib alone. Erlotinib inhibited phosphorylation of EGFR, stabilizing EGFR at the plasma membrane, whereas EGCG induced EGFR internalization and ubiquitin-degradation, ultimately undermining EGFR signaling. The efficacy of the combination treatment was investigated with nude mice (n = 25) orally gavaged with vehicle control, EGCG, erlotinib or the combination at the same doses for 7 days, followed by subcutaneous injection with Tu212 cells. Animals were continuously administered the agents 5 days weekly for 7 weeks. The combined treatment resulted in significantly greater inhibition of tumor growth and delayed tumor progression as a result of increased apoptosis, decreased cell proliferation and reduced pEGFR and pAKT compared to the single agent treatment groups. Our results suggest a synergistic antitumor effect of a combined treatment with EGCG and erlotinib, and provide a promising regimen for future chemoprevention and treatment of SCCHN.