Evolution, Medicine, and Public Health最新文献

Current cancer therapies often fail due to tumor heterogeneity and rapid resistance evolution. A new evolutionary framework, 'selection for function,' proposes that tumor progression is driven by group phenotypic composition (GPC) and its interaction with the microenvironment, not by individual cell traits. This perspective opens new therapeutic avenues: targeting the tumor's functional networks rather than individual cells. Real-time tracking of GPC changes could inform adaptive treatments, delaying progression and resistance. By integrating evolutionary and ecological principles with conventional therapies, this strategy aims to transform cancer from a fatal to a manageable chronic disease. Crucially, it does not necessarily require new drugs but offers a way to repurpose existing therapies to impair a tumor's evolutionary potential. By steering tumor evolution toward less aggressive states, this approach could improve prognosis and long-term patient survival compared to current methods. We argue that leveraging GPC dynamics represents a critical, yet underexplored, opportunity in oncology.

Background and objectives: Control of cell division is tightly regulated in eukaryotic cells, and dysfunction in cell cycle checkpoints is a key hallmark of malignant transformation that promotes a fitness advantage over non-cancer cells. One of the most critical mechanisms of cell cycle regulation is via the cyclin-dependent kinases (CDKs), which connect resource availability sensing and growth signaling with cell division and transcription elongation processes. Novel combination therapy approaches to co-target cell cycle and transcriptional CDKs may improve cancer-specific targeting of CDK dysfunction. In the current study, we assessed the effectiveness of fadraciclib, a new CDK2/9 inhibitor, for the treatment of advanced colorectal cancer (CRC).

Methodology: A panel of eighteen CRC patient-derived organoids (PDOs) was used to assess the efficacy of fadraciclib. Efficacy was further validated in patient-derived xenografts (PDXs). CDK2/9 target inhibition, cell cycle arrest, and cell killing mechanisms were investigated using western blotting, flow cytometry, and immunofluorescence staining, respectively.

Results: CRC PDOs exhibited greater sensitivity to fadraciclib compared to chemotherapy and palbociclib. This efficacy was validated in vivo using three matched PDXs, showing significant tumor growth inhibition with fadraciclib compared to vehicle (P < .05) and no serious adverse effects. Fadraciclib induced G2/M cell cycle arrest, leading to multipolar mitosis and anaphase catastrophe.

Conclusions and implications: Our results using patient-derived models suggest that fadraciclib is a promising therapy for advanced CRC by inhibiting CDKs 2 and 9, which affects critical pathways in cell cycle regulation and transcription.

Primitive emunctory functions to expel harmful substances from cells and the interstitial space of multicellular organisms evolved over the past billion and a half years into the complex physiology of the metanephric kidney. Integrative biology allows empirical testing of hypotheses of the origins of renal structures from homologous single-celled precursors. Emunctory cell complexes called nephridia evolved in metazoan (cnidarian) ancestors 750 million years ago (mya). The pronephric kidney was a metameric structure that evolved some 700 mya in early bilaterians to excrete waste products through nephridial slits in the body wall from head to tail. The mesonephric kidney evolved 635 mya when pharyngeal slits differentiated into filter-feeding gills and a heart-kidney evolved in later bilaterians. The mesonephric filtering glomeruli lost their external exits through the body wall and now drained through an internal mesonephric duct into the coelom. When chordates moved into fresh water from the sea 588 mya the high-pressure glomerulus evolved in the mesonephros, increasing water excretion. Tetrapods moved onto land losing the buoyancy of water. Blood pressure and glomerular filtration rose and the metanephric kidney evolved in amniotes. The high pressure-flow glomerulus predisposes podocytes to injury and detachment leading to sclerosis, whereas the high mitochondrial activity of the tubule contributes to susceptibility to ischemia, hypoxia, and oxidative injury. The kidney evolved a counter-current mechanism and urea cycle to optimize water retention. Perturbations in the complex development of the metanephric kidney, which parallels its phylogeny, explain many renal pathologies, which are traceable to these adaptations.

Background: Reproduction affects health and longevity among females across the life course. While significant focus has been devoted to the role of menarche, menopause remains understudied. Most menopause research is conducted in industrialized populations, where the risk of cardiovascular diseases increases progressively during the menopausal transition.

Methodology: We worked with the Tsimane, Indigenous Bolivian forager-farmers with physically active lifestyles, and the Moseten, genetically and culturally related horticulturalists experiencing greater market integration. We assessed relationships between menopause status and lipid biomarkers (HDL, LDL, non-HDL, total cholesterol, triglycerides, and apolipoprotein-B). Using linear mixed-effects models, in an all-age sample of n = 1,121 women (15-92 years) we found positive associations between menopausal status and most lipid levels.

Results: Menopause was associated with 5.0% higher total cholesterol (b = 7.038 mg/dL, P = .001), 9.4% higher LDL (b = 5.147 mg/dL, P = .017), 5.9% higher non-HDL cholesterol (b = 8.071 mg/dL, P < .001), 11.3% higher triglycerides (b = 19.119 mg/dL, P < .001), and 1.5% higher apolipoprotein-B (b = 0.248 mg/dL, P = .001), controlling for age, body mass index (BMI), year of data collection, and population. In contrast, HDL did not vary with menopause status.

Conclusions: After controlling for age, BMI, and year of data collection, post-menopausal lipid profiles among the Tsimane across six biomarkers are 2-7 times lower than those documented in U.S./U.K. populations. These results support existing literature that documents distinct shifts in lipid profiles during and after the menopause transition in industrialized populations. Further, our results suggest lipids increase post-menopause similarly to those of industrialized populations, despite the differential diet, physical activity, fertility, and hormone exposure in industrialized environments.

Lay summary: Menopause is a relatively rare life history trait primarily studied in industrial populations. We examined relationships between menopause and cardiovascular disease risk biomarkers in two forager-horticulturalist populations. We found positive associations between menopause and total cholesterol, HDL, LDL, non-HDL, triglycerides, and apolipoprotein-B, suggesting lipid increases post-menopause are a human universal.

Background and objectives: Water is essential for proper physiological function. As temperatures increase, populations may struggle to meet water needs despite adaptations or acclimation; chronic dehydration can cause kidney damage. We evaluate how daily water requirements are associated with ambient temperature (ambT), wet bulb globe temperature (WBGT), urine specific gravity (USG; marker of hydration status), and albumin:creatinine ratio (ACR; kidney function biomarker) among Daasanach pastoralists living in a hot, dry northern Kenyan climate.

Methodology: Water turnover (WT), USG, and ACR were measured using deuterium depletion (WT), refractometry (USG), and urine dipstick (ACR) for 76 participants aged 5-68 years in June 2022-23. Relationships between WT, ambT, WBGT, USG, and ACR were evaluated using linear and generalized linear models.

Results: Adult WT was higher than mean values worldwide, peaking around 7 l/day. Water demands increase from childhood through middle age before falling in later life. Adult WT was not correlated with ambT or WBGT. About 2/11 children's and 7/36 adults' USG indicated dehydration; USG was not correlated with child WT but was negatively correlated with adult WT when accounting for body size. WT was lower among adults with high (≥30 mg/g) ACR; high ACR was associated with higher USG.

Conclusions and implications: High Daasanach WT is likely driven by hot, semi-arid conditions, and lifestyle, rather than by compromised kidney function. Most participants were well-hydrated. Despite nonsignificant correlations between temperature and adult WT, high WT highlights the physiological demands of hot, dry climates. As climate change increases the global population exposed to hotter temperatures, global water needs will likely increase.

Caesarean birth has multiple, interrelated, and often mutually reinforcing bio-social etiologies. Evolutionary consequences of caesarean are uncertain. The goal of this study is to determine if caesarean births are more likely within family lineages by connecting and comparing lifetime birth experience (caesarean, vaginal) of individual women and generations of their families. A secondary goal is to identify potential parity differences between birth modes. Qualitative and quantitative methods were used to evaluate women's birth narratives of their own births and births to their maternal relatives: grandmothers, mothers, sisters, daughters. Participant data was analysed by birth year cohort and by familial generation (Grandmother, Mother, Index, and Daughter). 107 women participated in the study. Parous daughters of women who experienced any caesarean were more likely to experience caesarean than were daughters of women experiencing all vaginal birth (P = .0002; relative risk 2.1 [1.53-2.88]). Prevalence of any caesarean per mother is higher than the per-birth caesarean rate (44/107, 41.12% versus 71/229, 31.00%; P = .03). Parity was higher for women experiencing all vaginal births than all caesarean (2.14 versus 1.79; P = .03), yet highest for those experiencing any caesarean (2.75; P = .01). Caesarean for any indication is more common among daughters of mothers who themselves experienced any caesarean than those who experienced all vaginal births. Individual lifetime caesarean experience is more prevalent than commonly construed based on caesarean per live birth rate. Clustering of cesarean within families suggests that operative birth is altering our bio-social selves in potentially heritable ways.

[This retracts the article DOI: 10.1093/emph/eoaf001.].

Background and objectives: Rituals have been reported to serve as a vital mechanism for expressing grief and fostering communal support worldwide. Despite these benefits, use of rituals in Indigenous communities is threatened by missionization, globalization, and westernization. This study sought to examine the relevance of traditional mourning rituals in community morality and well-being. Anchored in cultural evolutionary theory, the study employed an ethnographic research design.

Methodology: Data were collected from 45 community elders, 30 bereaved adults, 30 bereaved adolescents, and 8 religious leaders through focus group discussions and interviews.

Results: The study established five mourning rituals practiced by the Luhya people, each potentially serving an evolutionary function for community survival and well-being. Our findings show that Luhya traditional mourning rituals play an important role in community well-being, though not all members may benefit equally from these effects.

Conclusions and implications: The study established conflict over rituals with differing viewpoints from religious leaders, cultural leaders, and the western biomedical approach to mental well-being. Yet, the bereaved reported that both Luhya and religious rituals helped them process their grief. To address mental health issues fully, it is important to establish collaboration between western models, religious approaches, and cultural approaches.

Background and objectives: Copper is an essential micronutrient and a widely used antimicrobial, yet its widespread application may accelerate microbial resistance. We investigated how long-term copper (II) sulfate (CuSO₄) exposure drives genetic and phenotypic changes in Escherichia coli, focusing on survival, resistance mechanisms, and antibiotic cross-resistance.

Methodology: Fifty E. coli populations were evolved for 55 days under progressively increasing CuSO₄ concentrations. Whole-genome sequencing (WGS) identified genetic adaptations, while phenotypic changes were assessed using minimum inhibitory concentration (MIC) and fitness assays across CuSO₄ and antibiotic gradients.

Results: CuSO₄ imposed strong selective pressure, with only 16% of populations surviving prolonged exposure. Survivors exhibited up to eight-fold increases in CuSO₄ resistance, though some reverted to ancestral resistance levels when selective pressure was removed. Fitness assays showed that CuSO₄-selected populations maintained significantly higher fitness in high CuSO₄ environments than controls and ancestors (P < .001). WGS revealed diverse mutations in stress-response and metal-tolerance genes (cusA, acrB, corA, fur, and ybhA) without a single resistance signature. Although antibiotic cross-resistance was not observed, some CuSO₄-selected populations displayed elevated MICs for levofloxacin, colistin, trimethoprim, fosfomycin, and meropenem. Similar trends in controls suggest that additional factors, such as adaptation to laboratory media, also contribute to resistance.

Conclusions and implications: CuSO₄ exerts strong and variable selective pressure on E. coli populations, promoting diverse resistance pathways through distinct genetic and physiological mechanisms. While some CuSO₄-selected strains exhibited increased antibiotic resistance, trends in controls highlight the complexity of resistance evolution. These findings emphasize the need to monitor copper-driven antimicrobial resistance.

Background and objectives: Drug resistance is a major contributor to tuberculosis (TB) deaths worldwide. Understanding the dynamics of in-host evolution of Mycobacterium tuberculosis (MTB) drug resistance can help to improve treatment success rates.

Methodology: The microevolution of drug-resistant MTB was studied in three patients with long-standing, extensively drug-resistant TB (XDR-TB) by analyzing whole genome sequences of serial isolates collected during treatment.

Results: We identified three patterns of in vivo MTB microevolution during long-term, ineffective treatment: (i) new drug-resistant subpopulations emerge and compete with other subpopulations during treatment; (ii) drug resistance profiles remaining stable without the emergence of new drug-resistant subpopulations; and (iii) after a drug is stopped, new drug-resistant subpopulations continue to emerge and compete with existing subpopulations.

Conclusions and implications: The microevolution of drug-resistant MTB within patients on long-term ineffective treatment is complex. Subpopulations with different resistance-conferring mutations can compete with each other and with newly emerged subpopulations. Often, one subpopulation eventually dominates and achieves long-term stability. This work deepens the understanding of MTB microevolution in XDR-TB patients.