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Abstract Filamin-A (FLNA), also called actin-binding protein 280 (ABP-280), was originally identified as a non-muscle actin binding protein, which organizes filamentous actin into orthogonal networks and stress fibers. Filamin-A also anchors various transmembrane proteins to the actin cytoskeleton and provides a scaffold for a wide range of cytoplasmic and nuclear signaling proteins. Intriguingly, several studies have revealed that filamin-A associates with multiple non-cytoskeletal proteins of diverse function and is involved in several unrelated pathways. Mutations and aberrant expression of filamin-A have been reported in human genetic diseases and several types of cancer. In this review, we discuss the implications of filamin-A in cancer progression, including metastasis and DNA damage response.

Abstract Background The majority of non-syndromic colorectal cancers (CRCs) can be described as a complex disease. A two-stage case–control study on CRC susceptibility was conducted to assess the influence of the ancestral alleles in the polymorphisms previously associated with nutrition-related complex diseases. Methods In stage I, 28 single nucleotide polymorphisms (SNPs) were genotyped in a hospital-based Czech population (1025 CRC cases, 787 controls) using an allele-specific PCR-based genotyping system (KASPar®). In stage II, replication was carried out for the five SNPs with the lowest p values. The replication set consisted of 1798 CRC cases and 1810 controls from a population-based German study (DACHS). Odds ratios (ORs) and 95% confidence intervals (CIs) for associations between genotypes and CRC risk were estimated using logistic regression. To identify signatures of selection, Fay-Wu’s H and Integrated Haplotype Score (iHS) were estimated. Results In the Czech population, carriers of the ancestral alleles of AGT rs699 and CYP3A7 rs10211 showed an increased risk of CRC (OR 1.26 and 1.38, respectively; two-sided p≤0.05), whereas carriers of the ancestral allele of ENPP1 rs1044498 had a decreased risk (OR 0.79; p≤0.05). For rs1044498, the strongest association was detected in the Czech male subpopulation (OR 0.61; p=0.0015). The associations were not replicated in the German population. Signatures of selection were found for all three analyzed genes. Conclusions Our study showed evidence of association for the ancestral alleles of polymorphisms in AGT and CYP3A7 and for the derived allele of a polymorphism in ENPP1 with an increased risk of CRC in Czechs, but not in Germans. The ancestral alleles of these SNPs have previously been associated with nutrition-related diseases hypertension (AGT and CYP3A7) and insulin resistance (ENPP1). Future studies may shed light on the complex genetic and environmental interactions between different types of nutrition-related diseases.

Background: We recently reported that Mediterranean (MED) and green-MED diets significantly attenuated age-related brain atrophy by ∼50% within 18 mo., Objective: The objective of this study was to explore the contribution of specific diet-induced parameters to brain-volume deviation from chronologic age., Methods: A post hoc analysis of the 18-mo DIRECT PLUS trial, where participants were randomly assigned to the following groups: 1) healthy dietary guidelines, 2) MED diet, or 3) green-MED diet, high in polyphenols, and low in red meat. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The green-MED group further consumed green tea (3-4 cups/d) and Mankai green shake (Wolffia globosa aquatic plant) (+800 mg/d polyphenols). We collected blood samples through the intervention and followed brain structure volumes by magnetic resonance imaging (MRI). We used hippocampal occupancy (HOC) score (hippocampal and inferior lateral-ventricle volumes ratio) as a neurodegeneration marker and brain-age proxy. We applied multivariate linear regression models., Results: Of 284 participants [88% male; age = 51.1 y; body mass index = 31.2 kg/m 2 ; hemoglobin A1c (HbA1c) = 5.48%; APOE-ε4 genotype = 15.7%], 224 completed the trial with eligible whole-brain MRIs. Individuals with higher HOC deviations (i.e., younger brain age) presented lower body weight [r = -0.204; 95% confidence interval (CI): -0.298, -0.101], waist circumference (r = -0.207; 95% CI: -0.310, -0.103), diastolic (r = -0.186; 95% CI: -0.304, -0.072), systolic blood pressure (r = -0.189; 95% CI: -0.308, -0.061), insulin (r = -0.099; 95% CI: -0.194, -0.004), and HbA1c (r = -0.164; 95% CI: -0.337, -0.006) levels. After 18 mo, greater changes in HOC deviations (i.e., brain-age decline attenuation) were independently associated with improved HbA1c (β = -0.254; 95% CI: -0.392, -0.117), HOMA-IR (β = -0.200; 95% CI: -0.346, -0.055), fasting glucose (β = -0.155; 95% CI: -0.293, -0.016), and c-reactive protein (β = -0.153; 95% CI: -0.296, -0.010). Improvement in diabetes status was associated with greater HOC deviation changes than either no change in diabetes status (0.010; 95% CI: 0.002, 0.019) or with an unfavorable change (0.012; 95% CI: 0.002, 0.023). A decline in HbA1c was further associated with greater deviation changes in the thalamus, caudate nucleus, and cerebellum (P < 0.05). Greater consumption of Mankai and green tea (green-MED diet components) were associated with greater HOC deviation changes beyond weight loss., Conclusions: Glycemic control contributes to the neuroprotective effects of the MED and green-MED diets on brain age. Polyphenols-rich diet components as Mankai and green tea may contribute to a more youthful brain age. This trial was registered at clinicaltrials.gov at clinicaltrials.gov as NCT03020186., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

Abstract: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Climate change increasingly impacts health, particularly of rural populations in sub-Saharan Africa due to their limited resources for adaptation. Understanding these impacts remains a challenge, as continuous monitoring of vital signs in such populations is limited. Wearable devices (wearables) present a viable approach to studying these impacts on human health in real time., Objective: The aim of this study was to assess the feasibility and effectiveness of consumer-grade wearables in measuring the health impacts of weather exposure on physiological responses (including activity, heart rate, body shell temperature, and sleep) of rural populations in western Kenya and to identify the health impacts associated with the weather exposures., Methods: We conducted an observational case study in western Kenya by utilizing wearables over a 3-week period to continuously monitor various health metrics such as step count, sleep patterns, heart rate, and body shell temperature. Additionally, a local weather station provided detailed data on environmental conditions such as rainfall and heat, with measurements taken every 15 minutes., Results: Our cohort comprised 83 participants (42 women and 41 men), with an average age of 33 years. We observed a positive correlation between step count and maximum wet bulb globe temperature (estimate 0.06, SE 0.02; P=.008). Although there was a negative correlation between minimum nighttime temperatures and heat index with sleep duration, these were not statistically significant. No significant correlations were found in other applied models. A cautionary heat index level was recorded on 194 (95.1%) of 204 days. Heavy rainfall (>20 mm/day) occurred on 16 (7.8%) out of 204 days. Despite 10 (21%) out of 47 devices failing, data completeness was high for sleep and step count (mean 82.6%, SD 21.3% and mean 86.1%, SD 18.9%, respectively), but low for heart rate (mean 7%, SD 14%), with adult women showing significantly higher data completeness for heart rate than men (2-sided t test: P=.003; Mann-Whitney U test: P=.001). Body shell temperature data achieved 36.2% (SD 24.5%) completeness., Conclusions: Our study provides a nuanced understanding of the health impacts of weather exposures in rural Kenya. Our study's application of wearables reveals a significant correlation between physical activity levels and high temperature stress, contrasting with other studies suggesting decreased activity in hotter conditions. This discrepancy invites further investigation into the unique socioenvironmental dynamics at play, particularly in sub-Saharan African contexts. Moreover, the nonsignificant trends observed in sleep disruption due to heat expose the need for localized climate change mitigation strategies, considering the vital role of sleep in health. These findings emphasize the need for context-specific research to inform policy and practice in regions susceptible to the adverse health effects of climate change., (©Ina Matzke, Sophie Huhn, Mara Koch, Martina Anna Maggioni, Stephen Munga, Julius Okoth Muma, Collins Ochieng Odhiambo, Daniel Kwaro, David Obor, Till Bärnighausen, Peter Dambach, Sandra Barteit. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 04.07.2024.)