Cascadia Journal of Biomedical Research - Articles

Chen, P., Chen, J., Zhan, P., Ye, X., Zhao, L., Zhang, Z., Zuo, J., Shi, H., Li, X., Wu, S., Fu, Y., Wang, H., Fu, S.

Prostate cancer can become difficult to treat when it adapts to therapy and spreads, leading to treatment-resistant disease. A key reason for this is that cancer cells do not act alone: they are supported by nearby “helper” cells that shape the tumor environment. Among these, cancer-associated fibroblasts can build a dense scaffold around tumors, release signals that fuel cancer growth, and weaken immune responses, which may reduce the effectiveness of medicines. This review aims to explain what these fibroblasts are, how they change during prostate cancer progression, and why different fibroblast types may require different treatment approaches. By summarizing recent biological insights and emerging therapeutic strategies, we highlight how targeting the tumor-supporting environment—rather than cancer cells alone—could help design more effective combination treatments and guide future research toward more personalized care.

Kurki, M., Karjalainen, J., Palta, P., Sipilä, T., Kristiansson, K., Donner, K., Reeve, M., Laivuori, H., Aavikko, M., Kaunisto, M., Loukola, A., Lahtela, E., Mattsson, H., Laiho, P., Della Briotta Parolo, P., Lehisto, A., Kanai, M., Mars, N., Rämö, J., Kiiskinen, T., Heyne, H., Veerapen, K., Rüeger, S., Lemmelä, S., Zhou, W., Ruotsalainen, S., Pärn, K., Hiekkalinna, T., Koskelainen, S., Paajanen, T., Llorens, V., Gracia-Tabuenca, J., Siirtola, H., Reis, K., Elnahas, A., Sun, B., Foley, C., Aalto-Setälä, K., Alasoo, K., Arvas, M., Auro, K., Biswas, S., Bizaki-Vallaskangas, A., Carpen, O., Chen, C., Dada, O., Ding, Z., Ehm, M., Eklund, K., Färkkilä, M., Finucane, H., Ganna, A., Ghazal, A., Graham, R., Green, E., Hakanen, A., Hautalahti, M., Hedman, Å., Hiltunen, M., Hinttala, R., Hovatta, I., Hu, X., Huertas-Vazquez, A., Huilaja, L., Hunkapiller, J., Jacob, H., Jensen, J., Joensuu, H., John, S., Julkunen, V., Jung, M., Junttila, J., Kaarniranta, K., Kähönen, M., Kajanne, R., Kallio, L., Kälviäinen, R., Kaprio, J., Kerimov, N., Kettunen, J., Kilpeläinen, E., Kilpi, T., Klinger, K., Kosma, V., Kuopio, T., Kurra, V., Laisk, T., Laukkanen, J., Lawless, N., Liu, A., Longerich, S., Mägi, R., Mäkelä, J., Mäkitie, A., Malarstig, A., Mannermaa, A., Maranville, J., Matakidou, A., Meretoja, T., Mozaffari, S., Niemi, M., Niemi, M., Niiranen, T., O´Donnell, C., Obeidat, M., Okafo, G., Ollila, H., Palomäki, A., Palotie, T., Partanen, J., Paul, D., Pelkonen, M., Pendergrass, R., Petrovski, S., Pitkäranta, A., Platt, A., Pulford, D., Punkka, E., Pussinen, P., Raghavan, N., Rahimov, F., Rajpal, D., Renaud, N., Riley-Gillis, B., Rodosthenous, R., Saarentaus, E., Salminen, A., Salminen, E., Salomaa, V., Schleutker, J., Serpi, R., Shen, H., Siegel, R., Silander, K., Siltanen, S., Soini, S., Soininen, H., Sul, J., Tachmazidou, I., Tasanen, K., Tienari, P., Toppila-Salmi, S., Tukiainen, T., Tuomi, T., Turunen, J., Ulirsch, J., Vaura, F., Virolainen, P., Waring, J., Waterworth, D., Yang, R., Nelis, M., Reigo, A., Metspalu, A., Milani, L., Esko, T., Fox, C., Havulinna, A., Perola, M., Ripatti, S., Jalanko, A., Laitinen, T., Mäkelä, T., Plenge, R., McCarthy, M., Runz, H., Daly, M., Palotie, A.

Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.

Stanek, T., Leung, W., Shaffer, C., Olaveja, I., Laughlin, A., Hester, J., Garrido, D., Oh, E., Volski, M., Panda, N., Mo, M., Cordes, E., Dalling, M., Kershaw, K., Arnott, M., Daly, S., Valenzuela, S., Thompson, P., Hastert, K., Sabb, D., Karpinski, K., Arora, M., Rius, N., LoBello, L., Jaramillo, S., Sonavane, O., Herrmann, A., Reed, L., Elgin, S., Arrigo, C., Ellison, C.

Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila, also known as the “Muller F element” or “dot chromosome”, as a model to investigate chromosome-specific size expansion. The F element of most Drosophila species is small (∼1.3 Mb) and almost entirely heterochromatic, yet harbors approximately 80 protein-coding genes. Here, we study D. kikkawai, D. takahashii, D. ananassae, and D. bipectinata, whose F elements are 2- to 15-fold larger in size compared to D. melanogaster. Through manual gene curation and comparative genomic analysis, we find that their F elements have expanded primarily via accumulation of transposable elements (TEs) in introns and intergenic regions. Natural selection appears less efficient on these expanded F elements: they have smaller effective population sizes and their genes exhibit reduced usage of optimal codons, compared to D. melanogaster. We propose that F element size variation is driven by differences in F element recombination rates. The ultra-long (∼20 Mb) F elements of D. ananassae and D. bipectinata display high rates of rearrangement and sequence evolution and exhibit independent TE-driven expansions. Our results suggest that F elements of most Drosophila species likely recombine enough to prevent size expansion, while F element recombination in D. ananassae and D. bipectinata is either absent or rare enough to allow TEs and other deleterious mutations to accumulate via Muller's ratchet; thus, these chromosomes evolve more like a Y chromosome than a typical Drosophila F element.

Johnson, L., Jamieson, L., Kubjane, M., Meyer-Rath, G.

Background High incidence rates of HIV, sexually transmitted infections (STIs), and teenage pregnancy are major challenges facing South Africa. The role of socio-economic factors in driving these incidence rates is complex, with high socio-economic status protecting against some risk behaviours (condomless sex, early sexual debut, and casual/transactional sex in females) but increasing other risk behaviours (e.g., male engagement in casual and commercial sex). We aimed to model the effect of socio-economic status, and associated economic strengthening interventions, in South Africa. Methods and findings We extended a previously-developed agent-based model of HIV, STIs, and fertility in South Africa to assess effects of education, employment, and per capita household income on sexual behaviours. We estimated these effects from literature and from calibration of the model to African randomized controlled trials of economic strengthening interventions. Population attributable fractions (PAFs) were calculated. We considered three intervention types, all targeting households with log per capita income below the national average: school support to reduce school dropout; vocational training for unemployed adults; and unconditional cash transfers. We estimate that low socio-economic status accounted for 13% of new HIV infections, 7% of incident STIs (gonorrhoea, chlamydia, and trichomoniasis) and 31% of teenage births in South Africa, over 2000−2020. However, because of uncertainties regarding effect sizes, confidence intervals around these PAFs are wide (1,50% for HIV; −1,19% for STIs; and 10,76% for teenage births). Over 2025−2040, none of the interventions are estimated to reduce HIV, STIs, or teenage births significantly, due to limited impact on secondary economic outcomes. The greatest impact would be that of school support on teenage births (a 5% reduction, 95% CI: −1,12%). Key limitations include the assumption of uniform STI treatment access across socio-economic strata, and the exclusion of possible socio-economic effects at a community level. Conclusions Although poverty is likely to be a significant driver of HIV, STIs, and teenage pregnancy in South Africa, precise quantification is challenging. Recently trialled economic strengthening interventions have insufficient impact on socio-economic status to reduce HIV and STIs significantly at a population level.

Jenvrin, A., Sartoris, R., Dokmak, S., Védie, A., Laurent, L., Tihy, M., Sauvanet, A., Rebours, V., Ronot, M., Bongrain, C., Couvelard, A., Cros, J., de Mestier, L.

Background: In non-metastatic pancreatic adenocarcinoma (PDAC), the appropriate evaluation of tumor response to neoadjuvant treatment (NAT) has a substantial prognostic impact, but the tools used to assess it are imperfect and sometimes discordant. Objectives: We aimed to explore the prognostic impact of morphological and pathological evaluations of tumor response to NAT. Design: Single-center retrospective observational study. Methods: We retrospectively studied all patients with borderline or locally advanced PDAC who underwent surgery after neoadjuvant chemotherapy (NAC) with FOLFIRINOX, ±additional chemoradiation (NACR) between 2016 and 2022 in a tertiary center. Morphological response was evaluated according to RECIST 1.1, and pathological response was assessed according to the CAP score and proportion of viable tumor cells (VTC). The primary endpoint was recurrence-free survival (RFS), and the secondary endpoint was overall survival (OS). Factors associated with the risk of recurrence were analyzed using ROC curves and multivariable Cox proportional hazard models. Results: We included 91 patients (52% male, median age 66, 83% with borderline PDAC) who underwent surgery following NAC with additional NACR in 85% of patients. Overall, 38% of patients had an objective morphological response according to RECIST 1.1, which was not associated with prolonged RFS HR 1.16, 95% CI (0.62–2.10), p = 0.64). Conversely, poor pathological response was associated with shorter RFS on multivariable analysis, notably VTC ⩾ 30% (HR 2.28, 95% CI [1.08–5.13], p = 0.037). Median OS was 62.2 months with VTC ⩾ 30% versus 45.1 months with VTC < 30% (p = 0.025). Identifying PDAC with VTC < or ⩾30% had a strong reproducibility (kappa 0.86). Conclusion: Morphological response per RECIST should not be the aim of NAT in patients with PDAC. Conversely, the proportion of VTC could be a reproducible, simple, and effective prognostic tool. Should this marker be further confirmed as valuable, it may help inform the adaptation of adjuvant treatment and follow-up in this setting.

Jarratt, R., Clough, H., Wilkinson, E., Vivancos, R., Decraene, V.

Our study assessed the link between gastrointestinal (GI) infections in England and the Eat Out to Help Out scheme (EOHO), a government subsidy created to encourage people to eat out during COVID-19 pandemic (03–30 August 2020). We studied national laboratory data between January 2015 and December 2020. We used time series change point analysis to see if there were shifts in reported cases of specific GI infections (Campylobacter spp., Escherichia coli O157, and non-typhoidal Salmonella spp.) associated with the timing of the scheme. Our analysis uniquely applied the Pruned Exact Linear Time method, with generalized linear models to a national dataset of GI infections. This revealed increases in cases closely aligned to the timing of the easing of COVID-19 restrictions, prior to the introduction of the EOHO scheme. Our study showed the scheme had no measurable impact, as there was no significant change on reported cases. Substantial reductions in cases after the first lockdown, followed by an increase as restrictions were phased out, show the wider impact of COVID-19 control measures, for example, public information campaigns aimed at improving hand-hygiene. These findings highlight the complicated interactions between COVID-19 control measures, the public’s behaviour, and the spread of GI infections.

Petrov, V., Ahmadi, N., Rossi, C., Rahman, R., Bellini, R.

Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila , also known as the “Muller F element” or “dot chromosome”, as a model to investigate chromosome-specific size expansion. The F element of most Drosophila species is small (∼1.3 Mb) and almost entirely heterochromatic, yet harbors approximately 80 protein-coding genes. Here, we study D. kikkawai , D. takahashii , D. ananassae , and D. bipectinata , whose F elements are 2- to 15-fold larger in size compared to D. melanogaster . Through manual gene curation and comparative genomic analysis, we find that their F elements have expanded primarily via accumulation of transposable elements (TEs) in introns and intergenic regions. Natural selection appears less efficient on these expanded F elements: they have smaller effective population sizes and their genes exhibit reduced usage of optimal codons, compared to D. melanogaster . We propose that F element size variation is driven by differences in F element recombination rates. The ultra-long (∼20 Mb) F elements of D. ananassae and D. bipectinata display high rates of rearrangement and sequence evolution and exhibit independent TE-driven expansions. Our results suggest that F elements of most Drosophila species likely recombine enough to prevent size expansion, while F element recombination in D. ananassae and D. bipectinata is either absent or rare enough to allow TEs and other deleterious mutations to accumulate via Muller's ratchet; thus, these chromosomes evolve more like a Y chromosome than a typical Drosophila F element.

Cho, C., O’Farrell, P.

Collisions between advancing replication forks and elongating transcripts pose a universal threat. During the rapid nuclear division cycles in early Drosophila embryos, coordinating transcription and replication is critical to reduce the risk of collisions. In each cycle, replication begins immediately after mitosis, while transcription starts 3 min later, overlapping replication for the remainder of interphase. We previously showed that transcription depends on Brd4, which forms hubs at active genes. Here, we show that Brd4 persists on mitotic chromosomes as bookmarks of transcriptional activation. Upon anaphase entry, the replication initiation factor Cdc7 forms Brd4-dependent foci that promote early replication in the following interphase. Additionally, Cdc7 activity disperses Brd4 such that post-mitotic transcription occurs only after a new round of Brd4 hub assembly. Early initiation of replication in conjunction with deferred transcription is proposed to allow unimpeded transcriptional elongation behind advancing replication forks. Supporting this, inhibiting Cdc7 delayed replication, stabilized Brd4 bookmarks, and resulted in premature transcription with elongation defects. We propose that Cdc7 triggers a functional switch in Brd4 that enforces temporal ordering of the initiation of replication and transcription, thereby minimizing collisions. This switching process might underlie the widespread correlation between transcriptional activity and early replication.

Cho, C., O’Farrell, P.

Collisions between advancing replication forks and elongating transcripts pose a universal threat. During the rapid nuclear division cycles in early Drosophila embryos, coordinating transcription and replication is critical to reduce the risk of collisions. In each cycle, replication begins immediately after mitosis, while transcription starts 3 min later, overlapping replication for the remainder of interphase. We previously showed that transcription depends on Brd4, which forms hubs at active genes. Here, we show that Brd4 persists on mitotic chromosomes as bookmarks of transcriptional activation. Upon anaphase entry, the replication initiation factor Cdc7 forms Brd4-dependent foci that promote early replication in the following interphase. Additionally, Cdc7 activity disperses Brd4 such that post-mitotic transcription occurs only after a new round of Brd4 hub assembly. Early initiation of replication in conjunction with deferred transcription is proposed to allow unimpeded transcriptional elongation behind advancing replication forks. Supporting this, inhibiting Cdc7 delayed replication, stabilized Brd4 bookmarks, and resulted in premature transcription with elongation defects. We propose that Cdc7 triggers a functional switch in Brd4 that enforces temporal ordering of the initiation of replication and transcription, thereby minimizing collisions. This switching process might underlie the widespread correlation between transcriptional activity and early replication.

Okeke, K.