Dace Pjanova

EDUCATION

University of Latvia

Scopus Publications

IgA class-switched CD27^-CD21⁺B cells in IgA nephropathy
Anna Popova, Baiba Slisere, Karlis Racenis, Viktorija Kuzema, Roberts Karklins, Mikus Saulite, Janis Seilis, Anna Jana Saulite, Aiga Vasilvolfa, Kristine Vaivode,et al.
Oxford University Press (OUP)
ABSTRACT Background Immunoglobulin A nephropathy (IgAN) is characterized by the production of galactose-deficient IgA1 (GdIgA1) antibodies. As the source of pathogenic antibodies, B cells are central to IgAN pathogenesis, but the B cell activation pathways as well as the potential B cell source of dysregulated IgA secretion remain unknown. Methods We carried out flow cytometry analysis of peripheral blood B cells in patients with IgAN and control subjects with a focus on IgA-expressing B cells to uncover the pathways of B cell activation in IgAN and how these could give rise to pathogenic GdIgA1 antibodies. Results In addition to global changes in the B cell landscape—expansion of naïve and reduction in memory B cells—IgAN patients present with an increased frequency of IgA-expressing B cells that lack the classical memory marker CD27, but are CD21+. IgAN patients furthermore have an expanded population of IgA+ antibody-secreting cells, which correlate with serum IgA levels. Both IgA+ plasmabalsts and CD27− B cells co-express GdIgA1. Implicating dysregulation at mucosal surfaces as the driver of such B cell differentiation, we found a correlation between lipopolysaccharide in the serum and IgA+CD27− B cell frequency. Conclusion We propose that dysregulated immunity in the mucosa may drive de novo B cell activation within germinal centres, giving rise to IgA+CD27− B cells and subsequently IgA-producing plasmablasts. These data integrate B cells into the paradigm of IgAN pathogenesis and allow further investigation of this pathway to uncover biomarkers and develop therapeutic interventions.


Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex- and age-dependent manner
R. Dovhyi, A. Dvukhriadkina, K. Ostrovska, M. Rudyk, Irina Verhovcova, Kristine Vaivode, D. Pjanova, L. Ostapchenko, and L. Skivka
Elsevier BV



Bacteriophage–derived double-stranded rna (larifan) exerts variable effects on human blood monocytes depending on age and sex of donors
, R. Dovhyi, M. Rudyk, , T. Serhiichuk, , Yu. Yumyna, , A. Dvukhriadkina, ,et al.
National Academy of Sciences of Ukraine (Co. LTD Ukrinformnauka) (Publications)
To date, great attention is paid to sex and age differences in the therapeutic effectiveness of drugs, including those that impact the immune system. Bacteriophage-derived dsRNA is the main component of the medicinal product Larifan, which exhibits interferonogenic activity. This study aimed to estimate the effect of Larifan on the activation status of human peripheral blood monocytes collected from donors of different ages and sex. Blood samples were obtained from the healthy volunteers, divided into 4 groups: young men and young women aged from 20 to 39 years, aged men and aged women from 54 to 69 years old. EDTA-anticoagulated blood samples were exposed to 200 μg/ml Larifan for 30 min, cells were washed and treated to study phagocytic index, ROS generation and expression of phenotypic markers. Only live monocytes selected by flow cytometry were included in the analysis. It was shown that monocytes from young as well as from aged females turned out to be quite inert to the treatment with Larifan. Monocytes from young males after the treatment demonstrated a minor decrease in phagocytic activity and significant down-regulation of ROS generation. Monocytes from aged adults showed clear sex-based differences in the basal cell phenotype. Thus, compared to monocytes from women, the monocytes from men over 50 after the treatment with Larifan showed decreased phagocytic activity and CD86 expression along with increased CD206 expression. Taken together, these results indicate the need for further studies of Larifan focused on developing personalized treatment depending on the age and sex of an individual. Keywords: double-stranded RNA, Larifan, monocytes, phagocytosis, reactive oxygen species, sex and age differences


Immunomodulatory properties of bacteriophage derived dsRNA of different size and their use as anticancer vaccine adjuvants
Neringa Dobrovolskienė, Ramojus Balevičius, Agata Mlynska, Karolina Žilionytė, Jan Aleksander Krasko, Marius Strioga, Ilva Lieknina, Dace Pjanova, and Vita Pašukonienė
Elsevier BV



The Price of Human Evolution: Cancer-Testis Antigens, the Decline in Male Fertility and the Increase in Cancer
Jekaterina Erenpreisa, Ninel Miriam Vainshelbaum, Marija Lazovska, Roberts Karklins, Kristine Salmina, Pawel Zayakin, Felikss Rumnieks, Inna Inashkina, Dace Pjanova, and Juris Erenpreiss
MDPI AG
The increasing frequency of general and particularly male cancer coupled with the reduction in male fertility seen worldwide motivated us to seek a potential evolutionary link between these two phenomena, concerning the reproductive transcriptional modules observed in cancer and the expression of cancer-testis antigens (CTA). The phylostratigraphy analysis of the human genome allowed us to link the early evolutionary origin of cancer via the reproductive life cycles of the unicellulars and early multicellulars, potentially driving soma-germ transition, female meiosis, and the parthenogenesis of polyploid giant cancer cells (PGCCs), with the expansion of the CTA multi-families, very late during their evolution. CTA adaptation was aided by retrovirus domestication in the unstable genomes of mammals, for protecting male fertility in stress conditions, particularly that of humans, as compensation for the energy consumption of a large complex brain which also exploited retrotransposition. We found that the early and late evolutionary branches of human cancer are united by the immunity-proto-placental network, which evolved in the Cambrian and shares stress regulators with the finely-tuned sex determination system. We further propose that social stress and endocrine disruption caused by environmental pollution with organic materials, which alter sex determination in male foetuses and further spermatogenesis in adults, bias the development of PGCC-parthenogenetic cancer by default.


The Role of Mitotic Slippage in Creating a “Female Pregnancy-like System” in a Single Polyploid Giant Cancer Cell
Kristine Salmina, Ninel Miriam Vainshelbaum, Madara Kreishmane, Inna Inashkina, Mark Steven Cragg, Dace Pjanova, and Jekaterina Erenpreisa
MDPI AG
In our recent work, we observed that triple-negative breast cancer MDA-MB-231 cells respond to doxorubicin (DOX) via “mitotic slippage” (MS), discarding cytosolic damaged DNA during the process that provides their resistance to this genotoxic treatment. We also noted two populations of polyploid giant cells: those budding surviving offspring, versus those reaching huge ploidy by repeated MS and persisting for several weeks. Their separate roles in the recovery from treatment remained unclear. The current study was devoted to characterising the origin and relationship of these two sub-populations in the context of MS. MS was hallmarked by the emergence of nuclear YAP1/OCT4A/MOS/EMI2-positivity featuring a soma-germ transition to the meiotic-metaphase-arrested “maternal germ cell”. In silico, the link between modules identified in the inflammatory innate immune response to cytosolic DNA and the reproductive module of female pregnancy (upregulating placenta developmental genes) was observed in polyploid giant cells. Asymmetry of the two subnuclei types, one repairing DNA and releasing buds enriched by CDC42/ACTIN/TUBULIN and the other persisting and degrading DNA in a polyploid giant cell, was revealed. We propose that when arrested in MS, a “maternal cancer germ cell” may be parthenogenetically stimulated by the placental proto-oncogene parathyroid-hormone-like-hormone, increasing calcium, thus creating a ”female pregnancy-like” system within a single polyploid giant cancer cell.


Effects of BRAF V600E and NRAS mutational status on the progression-free survival and clinicopathological characteristics of patients with melanoma
Tatjana Zablocka, Madara Kreismane, Dace Pjanova, and Sergejs Isajevs
Spandidos Publications
Hotspot mutations of the BRAF and NRAS genes are the most common genetic alterations in invasive cutaneous melanoma; however, the prognostic significance of BRAF and NRAS co-mutations remains controversial. The present study aimed to determine the association between NRAS and BRAF mutation status and the clinicopathological characteristics of patients with stage IA-IIC melanoma. A total of 118 patients who underwent surgical treatment for stage IA-IIC melanoma at the Riga East University Hospital between 2012 and 2018 were retrospectively enrolled in the present study. BRAF and NRAS mutation status was assessed by digital droplet PCR using the BRAFV600, NRAS Q61 and NRAS G12/G13 Screening Assays. The association between mutation status and clinicopathological features and progression-free survival (PFS) was then analyzed. The BRAF V600 mutation was detected in 67 out of 118 patients (56.8%). The PFS did not differ between patients with BRAF wild-type and BRAF-mutant melanoma. NRAS mutations were detected in 35 out of 118 patients (29.6%). The NRAS mutational status was associated with Breslow thickness (P=0.035), tumor type (P=0.020; χ2=0.20), mitotic rate (P=0.025) and lymphovascular invasion (P=0.02; χ2=0.20). Patients with NRAS-mutant melanoma had significantly worse PFS compared with NRAS wild-type melanoma (HR=12.30; 95% CI=5.78-26.21, P<0.0001). Furthermore, BRAF and NRAS co-mutant melanoma was associated with a significantly worse PFS compared with BRAF-mutant melanoma (HR=6.30; 95% CI=3.10-12.70, P<0.0001). In conclusion, NRAS-mutant and NRAS/BRAF co-mutant stage IA-IIC melanoma was associated with worse PFS compared with NRAS wild-type and BRAF-mutant melanoma. The assessment of NRAS mutation status in melanoma in routine clinical practice may be beneficial for the risk stratification of disease progression for primary non-metastatic malignant melanoma.


The Transcriptome and Proteome Networks of Malignant Tumours Reveal Atavistic Attractors of Polyploidy-Related Asexual Reproduction
Ninel M. Vainshelbaum, Alessandro Giuliani, Kristine Salmina, Dace Pjanova, and Jekaterina Erenpreisa
MDPI AG
The expression of gametogenesis-related (GG) genes and proteins, as well as whole genome duplications (WGD), are the hallmarks of cancer related to poor prognosis. Currently, it is not clear if these hallmarks are random processes associated only with genome instability or are programmatically linked. Our goal was to elucidate this via a thorough bioinformatics analysis of 1474 GG genes in the context of WGD. We examined their association in protein–protein interaction and coexpression networks, and their phylostratigraphic profiles from publicly available patient tumour data. The results show that GG genes are upregulated in most WGD-enriched somatic cancers at the transcriptome level and reveal robust GG gene expression at the protein level, as well as the ability to associate into correlation networks and enrich the reproductive modules. GG gene phylostratigraphy displayed in WGD+ cancers an attractor of early eukaryotic origin for DNA recombination and meiosis, and one relative to oocyte maturation and embryogenesis from early multicellular organisms. The upregulation of cancer–testis genes emerging with mammalian placentation was also associated with WGD. In general, the results suggest the role of polyploidy for soma–germ transition accessing latent cancer attractors in the human genome network, which appear as pre-formed along the whole Evolution of Life.


Bacteriophage-Derived Double-Stranded RNA Exerts Anti-SARS-CoV-2 Activity In Vitro and in Golden Syrian Hamsters In Vivo
Kristine Vaivode, Irina Verhovcova, Dace Skrastina, Ramona Petrovska, Madara Kreismane, Daira Lapse, Zane Kalnina, Kristine Salmina, Diana Rubene, and Dace Pjanova
MDPI AG
Bacteriophage-derived dsRNA, known as Larifan, is a nationally well-known broad-spectrum antiviral medication. This study aimed to ascertain the antiviral activity of Larifan against the novel SARS-CoV-2 virus. Larifan’s effect against SARS-CoV-2 in vitro was measured in human lung adenocarcinoma (Calu3) and primary human small airway epithelial cells (HSAEC), and in vivo in the SARS-CoV-2 infection model in golden Syrian hamsters. Larifan inhibited SARS-CoV-2 replication both in vitro and in vivo. Viral RNA copy numbers and titer of infectious virus in the supernatant of Calu3 cells dropped significantly: p = 0.0296 and p = 0.0286, respectively. A reduction in viral RNA copy number was also observed in HSAEC, especially when Larifan was added before infection (p = 0.0218). Larifan markedly reduced virus numbers in infected hamsters’ lungs post-infection, with a more pronounced effect after intranasal administration (p = 0.0032). The administration of Larifan also reduced the amount of infections virus titer in the lungs (p = 0.0039). Improvements in the infection-induced pathological lesion severity in the lungs of animals treated with Larifan were also demonstrated. The inhibition of SARS-CoV-2 replication in vitro and the reduction in the viral load in the lungs of infected hamsters treated with Larifan alongside the improved lung histopathology suggests a potential use of Larifan in also controlling the COVID-19 disease in humans.


Role of the Circadian Clock “Death-Loop” in the DNA Damage Response Underpinning Cancer Treatment Resistance
Ninel Miriam Vainshelbaum, Kristine Salmina, Bogdan I. Gerashchenko, Marija Lazovska, Pawel Zayakin, Mark Steven Cragg, Dace Pjanova, and Jekaterina Erenpreisa
MDPI AG
Here, we review the role of the circadian clock (CC) in the resistance of cancer cells to genotoxic treatments in relation to whole-genome duplication (WGD) and telomere-length regulation. The CC drives the normal cell cycle, tissue differentiation, and reciprocally regulates telomere elongation. However, it is deregulated in embryonic stem cells (ESCs), the early embryo, and cancer. Here, we review the DNA damage response of cancer cells and a similar impact on the cell cycle to that found in ESCs—overcoming G1/S, adapting DNA damage checkpoints, tolerating DNA damage, coupling telomere erosion to accelerated cell senescence, and favouring transition by mitotic slippage into the ploidy cycle (reversible polyploidy). Polyploidy decelerates the CC. We report an intriguing positive correlation between cancer WGD and the deregulation of the CC assessed by bioinformatics on 11 primary cancer datasets (rho = 0.83; p &lt; 0.01). As previously shown, the cancer cells undergoing mitotic slippage cast off telomere fragments with TERT, restore the telomeres by ALT-recombination, and return their depolyploidised offspring to telomerase-dependent regulation. By reversing this polyploidy and the CC “death loop”, the mitotic cycle and Hayflick limit count are thus again renewed. Our review and proposed mechanism support a life-cycle concept of cancer and highlight the perspective of cancer treatment by differentiation.


Addressing the importance of melanoma tumor-infiltrating lymphocytes in disease progression and clinicopathological characteristics
Tatjana Zablocka, Anna Nikolajeva, Madara Kreismane, Dace Pjanova, and Sergejs Isajevs
Spandidos Publications
Tumor-infiltrating lymphocytes (TILs) in primary cutaneous melanoma are considered to represent the host's antitumor immunological response; however, whether there are associations between TIL grade and histopathological characteristics and disease survival remains controversial. BRAF mutational status has been established as a routine screening method in advanced malignant melanoma, and worse prognosis rates have been demonstrated in patients harboring BRAF mutations. However, the general impact of BRAF mutational status on survival and histopathological characteristics is still debated. The aim of the present study was to compare the value of the assessment of TIL grade in stages I-II nodular and superficial spreading melanoma and BRAF mutational status, and its influence on clinicopathological characteristics. Altogether, 85 patients at stage IA-IIC who underwent melanoma surgical treatment at the Riga East University Hospital between 2012 and 2017 were retrospectively enrolled in the study. The histopathological characteristics were assessed according to the current World Health Organization and The American Joint Committee on Cancer 8th edition guidelines. The current study showed that patients with melanoma with high TIL grade had significantly better progression-free survival than patients with low TIL grade (hazard ratio, 4.9; 95% CI, 2.3-11.2; P<0.0001). BRAF mutations were observed in 52 patients (61.2%). BRAF mutational status in melanoma was associated with Clark invasion level (P=0.045), patient age (P=0.02) and TIL (P=0.04). The assessment of TIL grade in stage I-II melanoma demonstrated prognostic significance value and may help improve risk assessment in the future.


Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
John Charles A. Lacson, , Shawn A. Zamani, Luis Alberto Ribeiro Froes, Nandita Mitra, Lu Qian, Scarlet H. Doyle, Esther Azizi, Claudia Balestrini, D. Timothy Bishop,et al.
BMC Public Health Springer Science and Business Media LLC
Abstract Background Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. Methods Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. Results A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. Conclusions Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.


Effect of Bacteriophage-Derived Double Stranded RNA on Rat Peritoneal Macrophages and Microglia in Normoxia and Hypoxia
Dace Pjanova, Yevheniia Hurmach, Mariia Rudyk, Natalia Khranovska, Oksana Skachkova, Irina Verhovcova, and Larysa Skivka
Walter de Gruyter GmbH
Abstract The involvement of tissue-resident macrophages (TRMs) in health and diseases makes them unique therapeutic targets. TRMs are activated through their surface pattern recognition receptors, such as Toll-like receptors (TLRs) that are essential sensors of danger signals. Here, we determine the activation status of rat peritoneal macrophages (PMs) and microglia (MG) cells under normal and hypoxic conditions and investigate the effect of TLR3 agonist bacteriophage-derived dsRNA (Larifan) on the metabolic profile of TRMs in vitro. We implemented the phenotypic markers CD14 and CD206, arginine metabolism, phagocytic activity and reactive oxygen species generation as metabolic characteristics to evaluate TRMs activation. We showed that normoxic TRMs from different tissue niches responded to Larifan exposure in different ways. PM exhibited signs towards M1 polarisation. In contrast, the MG activation pattern could be considered as neither pro-inflammatory nor anti-inflammatory. We also showed that TRMs, regardless of the tissue niche, responded to hypoxia with a phenotypic shift towards an anti-inflammatory (M2) state. Larifan could attenuate hypoxia-induced TRMs metabolic programming. However, hypoxic conditions could negatively affect the interaction of TRMs with danger signals.


Association of HERV-K and LINE-1 hypomethylation with reduced disease-free survival in melanoma patients
Maurizio Cardelli, Remco van Doorn, Lares Larcher, Michela Di Donato, Francesco Piacenza, Elisa Pierpaoli, Robertina Giacconi, Marco Malavolta, Sivaramakrishna Rachakonda, Nelleke A Gruis,et al.
Future Medicine Ltd
Aim: To evaluate CpG methylation of long interspersed nuclear elements 1 (LINE-1) and human endogenous retrovirus K (HERV-K) retroelements as potential prognostic biomarkers in cutaneous melanoma. Materials &amp; methods: Methylation of HERV-K and LINE-1 retroelements was assessed in resected melanoma tissues from 82 patients ranging in age from 14 to 88 years. In addition, nevi from eight patients were included for comparison with nonmalignant melanocytic lesions. Results: Methylation levels were lower in melanomas than in nevi. HERV-K and LINE-1 methylation were decreased in melanoma patients with clinical parameters associated with adverse prognosis, while they were independent of age and gender. Hypomethylation of HERV-K (but not LINE-1) was an independent predictor of reduced disease-free survival. Conclusion: HERV-K hypomethylation can be a potential independent biomarker of melanoma recurrence.


Features associated with melanoma metastasis in Latvia
Dace Pjanova, Dace Ruklisa, Elza Kregere, Kristine Azarjana, Aija Ozola, and Ingrida Cema
Spandidos Publications
Cutaneous melanoma (CM) is the most aggressive form of skin cancer, exhibits an increasing incidence worldwide and has a high potential to develop metastasis. The current study aimed to identify a set of parameters that may aid in predicting the probability and timing of the onset of CM metastasis. A retrospective analysis was performed using the archive data of 2,026 patients with CM that were treated at the Riga East University Hospital Latvian Oncology Centre, which is the largest oncological hospital in the country, between 1998 and 2015. A case-control study design was employed, where patients with metastasis (n=278) were used as the cases and patients without metastasis were used as the controls. The present study examined the associations between metastasis and potential risk factors and constructed multivariate models of features that predicted metastasis using stepwise regression. Time until metastasis was analyzed using negative binomial regression models. The results of the present study indicated an increase in the number of melanomas that developed metastases during 1998–2015. Tumor Breslow thickness was demonstrated to be significantly larger in patients with metastasis compared with those without (P=0.012). The presence of ulceration significantly increased the risk of metastases [odds ratio (OR), 1.66; 95% CI, 1.07-2.59; P=0.033]. The absence of pigment in melanoma tissues was indicated to lead to a greater likelihood of metastasis (OR, 2.14; 95% CI, 1.10-4.19; P=0.035). Shorter times from diagnosis until the onset of metastases were observed in older patients (incident rate ratio (IRR), 6.85; 95% CI, 2.43-19.30; P=2.78×10−4), and a borderline significant association was observed in those with ulcerated tumors (IRR, 1.33; 95% CI, 0.98-1.80; P=0.064). Therefore, the main features associated with the development of melanoma metastasis in Latvia were indicated to be tumor ulceration, absence of pigment and Breslow thickness.


“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres
Kristine Salmina, Agnieszka Bojko, Inna Inashkina, Karolina Staniak, Magdalena Dudkowska, Petar Podlesniy, Felikss Rumnieks, Ninel M Vainshelbaum, Dace Pjanova, Ewa Sikora,et al.
MDPI AG
Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.


Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
Nicholas J. Taylor, Nandita Mitra, Lu Qian, Marie-Françoise Avril, D. Timothy Bishop, Brigitte Bressac-de Paillerets, William Bruno, Donato Calista, Francisco Cuellar, Anne E. Cust,et al.
Elsevier BV
BACKGROUND Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of melanoma families and whether performance improvements can be achieved. METHODS 2,116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CI) along with net reclassification indices (NRI) as performance metrics. RESULTS MELPREDICT performed well (AUC=0.752; 95%CI: 0.730, 0.775), and GenoMELPREDICT performance was similar (AUC=0.748; 95% CI: 0.726, 0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (p<0.0001) in GenoMELPREDICT (AUC=0.772; 95%CI: 0.750, 0.793; NRI=0.40). Including phenotypic risk factors did not improve performance. CONCLUSION The MELPREDICT model functioned well in a global dataset of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in counselling these patients towards genetic testing or cancer risk counselling.


Comparison of the effects of bacteriophage-derived dsRNA and poly(I:C) on ex vivo cultivated peripheral blood mononuclear cells
Dace Pjanova, Laima Mandrika, Ramona Petrovska, Kristine Vaivode, and Simona Donina
Elsevier BV
Double-stranded RNA (dsRNA), regardless of the origin and nucleotide sequence, exhibits multiple biological activities, including the establishment of an antiviral state and modulation of the immune response. Both involve the stimulation of innate immunity primarily via the release of pro-inflammatory cytokines, which in turn shapes the adaptive immune response. In this study, we compared the immune response triggered by two different dsRNAs: 1) a well-known synthetic dsRNA-poly (I:C); and 2) bacteriophage-derived dsRNA (bf-dsRNA) that is a replicative form of ssRNA bacteriophage f2. Human peripheral blood mononuclear cells (PBMCs) from 61 heathy volunteers were stimulated ex vivo with both dsRNAs. Subsequently, activation markers on the main lymphocyte subpopulations were analysed by flow cytometry and the production of 29 different cytokines and chemokines was measured by Luminex xMAP technology. The effect of bf-dsRNA on ex vivo cultivated PBMCs is similar to that induced by poly(I:C), albeit with subtle dissimilarities. Both treatments increased expression of the lymphocyte CD38 marker and intracellular IFN-γ in CD8+ T and natural killer (NK) cells, as well as the CD95 marker on the main lymphocyte subpopulations. Poly(I:C) was a stronger inducer of IL-6, IL-1β, and CCL4, whereas bf-dsRNA induced higher levels of IFN-α2, CXCL10, and CCL17. These differences might contribute to a distinct clinical manifestation when used as vaccine adjuvants, and bf-dsRNA may have more profound activity against several types of bacteria.


The complementary effect of rs1042522 in TP53 and rs1805007 in MC1R is associated with an elevated risk of cutaneous melanoma in Latvian population
Aija Ozola, Dace Ruklisa, and Dace Pjanova
Spandidos Publications
Genetic factors serve important roles in melanoma susceptibility. Although much genetic variation has been associated with cutaneous melanoma (CM), little is known about the interactions between genetic variants. The current study investigated the joint effect of rs1042522 in the tumour protein 53 (TP53) gene, rs2279744 in the murine double minute-2 (MDM2) gene and several single nucleotide polymorphisms (SNPs) in the melanocortin 1 receptor (MC1R) gene. All of these genes are interconnected in a single signalling pathway that regulates pigmentation. The current study included 479 individuals, of which, 255 were patients with CM and 224 were controls from the Latvian population. Multifaceted analyses of potential interactions between SNPs were performed, whilst taking into account the pigmentation phenotypes of individuals and tumour characteristics (Breslow thickness and ulceration). Univariate analyses revealed a borderline significant association between rs1042522 in the TP53 gene and CM risk. The results also confirmed a known association with rs1805007 in the MC1R gene. The rs1042522 was also selected as a CM risk factor in multivariate models, suggesting an effect that is independent from and complementary to that of rs1805007. The results indicated that these SNPs need to be taken into account when determining melanoma risk. A strong association between CM and red hair was identified for rs1805007, and rs1805008 in the MC1R gene was mainly associated with red hair. An association was also determined between rs2279744 in the MDM2 gene and brown eye colour. No convincing associations were identified between the analysed SNPs and Breslow thickness of tumours or ulcerations.


The cancer aneuploidy paradox: In the light of evolution
Kristine Salmina, Anda Huna, Martins Kalejs, Dace Pjanova, Harry Scherthan, Mark S. Cragg, and Jekaterina Erenpreisa
MDPI AG
Aneuploidy should compromise cellular proliferation but paradoxically favours tumour progression and poor prognosis. Here, we consider this paradox in terms of our most recent observations of chemo/radio-resistant cells undergoing reversible polyploidy. The latter perform the segregation of two parental groups of end-to-end linked dyads by pseudo-mitosis creating tetraploid cells through a dysfunctional spindle. This is followed by autokaryogamy and a homologous pairing preceding a bi-looped endo-prophase. The associated RAD51 and DMC1/γ-H2AX double-strand break repair foci are tandemly situated on the AURKB/REC8/kinetochore doublets along replicated chromosome loops, indicative of recombination events. MOS-associated REC8-positive peri-nucleolar centromere cluster organises a monopolar spindle. The process is completed by reduction divisions (bi-polar or by radial cytotomy including pedogamic exchanges) and by the release of secondary cells and/or the formation of an embryoid. Together this process preserves genomic integrity and chromosome pairing, while tolerating aneuploidy by by-passing the mitotic spindle checkpoint. Concurrently, it reduces the chromosome number and facilitates recombination that decreases the mutation load of aneuploidy and lethality in the chemo-resistant tumour cells. This cancer life-cycle has parallels both within the cycling polyploidy of the asexual life cycles of ancient unicellular protists and cleavage embryos of early multicellulars, supporting the atavistic theory of cancer.


Erratum to: Telomere length and survival in primary cutaneous melanoma patients (Scientific Reports, (2018), 8, 1, (10947), 10.1038/s41598-018-29322-9)
Sivaramakrishna Rachakonda, Nalini Srinivas, Seyed Hamidreza Mahmoudpour, Zaida Garcia-Casado, Celia Requena, Victor Traves, Virtudes Soriano, Maurizio Cardelli, Dace Pjanova, Anders Molven,et al.
Springer Science and Business Media LLC
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.


Association of the 16q24.3 region gene variants rs1805007 and rs4785763 with heightened risk of melanoma in Latvian population
Aija Ozola, Dace Ruklisa, and Dace Pjanova
Elsevier BV
Abstract Chromosome region 16q24.3 has been shown to modify the risk for developing melanoma in genome-wide association studies (GWAS). This region includes at least three SNPs for which significant independent effects on melanoma risk have been demonstrated: rs258322 (CDK10 intron), rs4785763 (pseudogene AFG3L1P), and rs8059973 (flanking 5′UTR of DBNDD1). Also variants within the MC1R gene, located in the same region, are known to be associated with an increased melanoma risk. However, the exact risk these variants convey has never been estimated in the population of Latvia. Also the haplotypes of the 16q24.3 region and their relationship with melanoma have not been studied in this population before. To elucidate the associations of the variants from the 16q24.3 region with melanoma alongside their mutual interactions, we performed direct sequencing of the MC1R gene and genotyped the rs258322, rs4785763, and rs8059973 SNPs. In total, the study subjects included 479 individuals, comprising 255 melanoma patients and 224 controls. Univariate analyses of genotypes showed that only rs1805007 variant from MC1R gene, and two chromosome 16 SNPs, rs258322 and rs4785763, were nominally associated with an increased risk of melanoma. Multivariate models built by stepwise regression revealed that the contributions of rs1805007 and rs4785763 to melanoma risk are independent. Haplotype analyses demonstrated that rs1805007 and rs4785763 are independently associated with melanoma, whereas the impact of rs258322 to melanoma risk is related to rs1805007.


Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells
Tiphaine Delaunay, Mathilde Violland, Nicolas Boisgerault, Soizic Dutoit, Virginie Vignard, Christian Münz, Monique Gannage, Brigitte Dréno, Kristine Vaivode, Dace Pjanova,et al.
Informa UK Limited
ABSTRACT Oncolytic immunotherapy using oncolytic viruses (OV) has been shown to stimulate the antitumor immune response by inducing the release of tumor-associated antigens (TAA) and danger signals from the dying infected tumor cells. In this study, we sought to determine if the lysis of tumor cells induced by different OV: measles virus, vaccinia virus, vesicular stomatitis virus, herpes simplex type I virus, adenovirus or enterovirus, has consequences on the capacity of tumor cells to present TAA, such as NY-ESO-1. We show that the co-culture of NY-ESO-1neg/HLA-DP4pos melanoma cells with NY-ESO-1pos/HLA-DP4neg melanoma cells infected and killed by different OV induces an intercellular transfer of NY-ESO-1 that allows the recognition of NY-ESO-1neg/HLA-DP4pos tumor cells by an HLA-DP4/NY-ESO-1(157–170)-specific CD4+ cytotoxic T cell clone, NY67. We then confirmed this result in a second model with an HLA-DP4+ melanoma cell line that expresses a low amount of NY-ESO-1. Recognition of this cell line by the NY67 clone is largely increased in the presence of OV productive infection. Altogether, our results show for the first time another mechanism of stimulation of the anti-tumor immune response by OV, via the loading of tumor cells with TAA that sensitizes them for direct recognition by specific effector CD4+ T cells, supporting the use of OV for cancer immunotherapy.


The effect of intranasally administered tlr3 agonist larifan on metabolic profile of microglial cells in rat with c6 glioma
Y. Hurmach, , M. Rudyk, V. Svyatetska, N. Senchylo, O. Skachkova, D. Pjanova, K. Vaivode, L. Skivka, ,et al.
National Academy of Sciences of Ukraine (Co. LTD Ukrinformnauka)
Glioma-associated microglia/macrophages (Gam) represent an attractive therapeutic target for the development of the alternative methodology in the treatment of gliomas. this study was aimed to investigate the effect of intranasally administered TLR3 agonist Larifan on microglial cell metabolic profile in rats with c6 glioma. our results demonstrate progressive generation microglial cell population with immunosuppressive and pro-inflammatory properties in C6 glioma-bearing brain. Intranasally delivered TLR3 agonist is capable to abrogate the creation of this pro-tumoral immune infiltrates, probably, through the effect on myeloid-derived suppressor cells, and can be considered as a promising agent for glioma therapy aimed the Gam re-education.


Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families
Nicholas J. Taylor, Nandita Mitra, Alisa M. Goldstein, Margaret A. Tucker, Marie-Françoise Avril, Esther Azizi, Wilma Bergman, D. Timothy Bishop, Brigitte Bressac-de Paillerets, William Bruno,et al.
Elsevier BV
Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

RECENT SCHOLAR PUBLICATIONS

Bacteriophage derived dsRNA induces polarized activation of alveolar macrophages from Balb/c and C57Bl/6 mice in vitro in sex-and age-dependent manner
R Dovhyi, A Dvukhriadkina, K Ostrovska, M Rudyk, I Verhovcova, ...
Cellular Immunology 408, 104916 2025



IgA class-switched CD27⁻CD21⁺ B cells in IgA nephropathy
A Popova, B Slisere, K Racenis, V Kuzema, R Karklins, M Saulite, J Seilis, ...
Nephrology Dialysis Transplantation, gfae173 2024



Enhanced differentiation of IgA⁺ class-switched CD27^-CD21⁺ B cells in patients with IgA nephropathy
A Popova, B Slisere, K Racenis, V Kuzema, R Karklins, M Saulite, J Seilis, ...
medRxiv, 2024.04. 29.24306572 2024



Liver regeneration by oval cells employing bistability of stemness-senescence, Hippo signaling, EMT-MET, and polyploidy circuit
M Lazovska, K Salmina, D Pjanova, BI Gerashchenko, J Erenpreisa
bioRxiv, 2024.03. 26.586724 2024



Immunomodulatory properties of bacteriophage derived dsRNA of different size and their use as anticancer vaccine adjuvants
N Dobrovolskienė, R Balevičius, A Mlynska, K Žilionytė, JA Krasko, ...
Vaccine 42 (3), 512-521 2024



Repair and misrepair of telomeric DNA in dynamic interactions with PML nuclear bodies and lamin B1. A gear-wheel nuclear traffic-[v1]
K Salmina
Preprints 2024



IgA class-switched CD27− CD21 B cells in IgA nephropathy
J Seilis, AJ Saulite, A Vasilvolfa, K Vaivode, D Pjanova, J Kroica, ...
2024



The price of human evolution: Cancer-testis antigens, the decline in male fertility and the increase in cancer
J Erenpreisa, NM Vainshelbaum, M Lazovska, R Karklins, K Salmina, ...
International Journal of Molecular Sciences 24 (14), 11660 2023



The role of mitotic slippage in creating a “Female Pregnancy-like System” in a single polyploid giant cancer cell
K Salmina, NM Vainshelbaum, M Kreishmane, I Inashkina, MS Cragg, ...
International journal of molecular sciences 24 (4), 3237 2023



Polarized activation of human peripheral blood phagocytes by bacteriophage-derived double-stranded RNA (Larifan) in vitro
R Dovhyi, M Rudy, Y Hurmac, T Serhiichuk, Y Yumyna, A Dvukhriadkina, ...
Biotechnologia Acta, 69-75 2023



The transcriptome and proteome networks of malignant tumours reveal atavistic attractors of polyploidy-related asexual reproduction
NM Vainshelbaum, A Giuliani, K Salmina, D Pjanova, J Erenpreisa
International Journal of Molecular Sciences 23 (23), 14930 2022



Effects of BRAF V600E and NRAS mutational status on the progression-free survival and clinicopathological characteristics of patients with melanoma
T Zablocka, M Kreismane, D Pjanova, S Isajevs
Oncology Letters 25 (1), 27 2022



The value of peritumoral lymphocyte infiltration in progression free survival in BRAF and NRAS mutant stage I and II melanoma: a retrospective cohort study
T Zablocka, V Kregere, S Savcenko, L Sulca, M Kreismane, D Pjanova, ...
VIRCHOWS ARCHIV 481 (SUPPL 1), S130-S130 2022



Bacteriophage-derived double-stranded RNA exerts anti-SARS-CoV-2 activity in vitro and in golden Syrian hamsters in vivo
K Vaivode, I Verhovcova, D Skrastina, R Petrovska, M Kreismane, ...
Pharmaceuticals 15 (9), 1053 2022



Role of the circadian clock “death-loop” in the DNA damage response underpinning cancer treatment resistance
NM Vainshelbaum, K Salmina, BI Gerashchenko, M Lazovska, P Zayakin, ...
Cells 11 (5), 880 2022



Addressing the importance of melanoma tumor-infiltrating lymphocytes in disease progression and clinicopathological characteristics
T Zablocka, A Nikolajeva, M Kreismane, D Pjanova, S Isajevs
Molecular and clinical oncology 15 (6), 255 2021



Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families
JCA Lacson, SA Zamani, LAR Froes, N Mitra, L Qian, SH Doyle, E Azizi, ...
BMC Public Health 21, 1-16 2021



Component in Reproduction of
D Pjanova, NM Vainshelbaum, K Salmina, J Erenpreisa
Melanoma, 91 2021



Role of Mitotic slippage in cancer resistance and DNA damage response in the MDA-MB-231-DOX-Treated Cells
K Salmina, F Rumnieks, NM Vainshelbaum, D Pjanova, J Erenpreisa
MDPI 2021



The evaluation of immunogenic and tolerogenic gene expression with different length Larifan fractions matured dendritic cell
N Dobrovolskienė, A Mlynska, K Žilionytė, V Pašukonienė, R Balevičius, ...
Wiley-VCH Verlag GmbH & Co 2021

MOST CITED SCHOLAR PUBLICATIONS

Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants
HE Puntervoll, XR Yang, HH Vetti, IM Bachmann, MF Avril, M Benfodda, ...
Journal of medical genetics 50 (4), 264-270 2013
Citations: 185



Predictors of sun protection behaviors and severe sunburn in an international online study
R Brnstrm, NA Kasparian, Y Chang, P Affleck, A Tibben, LG Aspinwall, ...
Cancer Epidemiology, Biomarkers & Prevention 19 (9), 2199-2210 2010
Citations: 151



Toluidine blue test for sperm DNA integrity and elaboration of image cytometry algorithm
J Erenpreisa, J Erenpreiss, T Freivalds, M Slaidina, R Krampe, J Butikova, ...
Cytometry Part A: The Journal of the International Society for Analytical 2003
Citations: 140



Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study
JR Davies, J Randerson‐Moor, K Kukalizch, M Harland, R Kumar, ...
Pigment cell & melanoma research 25 (3), 384-394 2012
Citations: 91



Melanoma risk factors, perceived threat and intentional tanning: an international online survey
R Brnstrm, YM Chang, N Kasparian, P Affleck, A Tibben, LG Aspinwall, ...
European Journal of Cancer Prevention 19 (3), 216-226 2010
Citations: 75



The cancer aneuploidy paradox: In the light of evolution
K Salmina, A Huna, M Kalejs, D Pjanova, H Scherthan, MS Cragg, ...
Genes 10 (2), 83 2019
Citations: 69



“Mitotic slippage” and extranuclear DNA in cancer chemoresistance: A focus on telomeres
K Salmina, A Bojko, I Inashkina, K Staniak, M Dudkowska, P Podlesniy, ...
International journal of molecular sciences 21 (8), 2779 2020
Citations: 49



CDKN2A and CDK4 variants in Latvian melanoma patients: analysis of a clinic-based population
D Pjanova, L Engele, JA Randerson-Moor, M Harland, DT Bishop, ...
Melanoma research 17 (3), 185-191 2007
Citations: 48



Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination
NA Kasparian, R Brnstrm, Y Chang, P Affleck, LG Aspinwall, A Tibben, ...
Archives of dermatology 148 (10), 1142-1151 2012
Citations: 44



An inherited variant in the gene coding for vitamin D‐binding protein and survival from cutaneous melanoma: a B io G eno MEL study
JR Davies, S Field, J Randerson‐Moor, M Harland, R Kumar, GM Anic, ...
Pigment cell & melanoma research 27 (2), 234-243 2014
Citations: 34



Inherited variation in the PARP1 gene and survival from melanoma
JR Davies, R Jewell, P Affleck, GM Anic, J Randerson‐Moor, A Ozola, ...
International journal of cancer 135 (7), 1625-1633 2014
Citations: 30



Telomere length and survival in primary cutaneous melanoma patients
S Rachakonda, N Srinivas, SH Mahmoudpour, Z Garcia-Casado, ...
Scientific reports 8 (1), 10947 2018
Citations: 29



Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells.
T Delaunay, M Violland, N Boisgerault, S Dutoit, V Vignard, C Mnz, ...
Oncoimmunology 7 (3), e1407897 2018
Citations: 29



Somatic BRAF and NRAS mutations in familial melanomas with known germline CDKN2A status: a GenoMEL study.
A Zebary, K Omholt, R Van Doorn, P Ghiorzo, K Harbst, V Hiom, ...
The Journal of investigative dermatology 134 (1), 287-290 2013
Citations: 26



Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
NJ Taylor, N Mitra, L Qian, MF Avril, DT Bishop, B Bressac-de Paillerets, ...
Journal of the American Academy of Dermatology 81 (2), 386-394 2019
Citations: 24



Germline variation at CDKN2A and associations with nevus phenotypes among members of melanoma families
NJ Taylor, N Mitra, AM Goldstein, MA Tucker, MF Avril, E Azizi, ...
Journal of Investigative Dermatology 137 (12), 2606-2612 2017
Citations: 23



Melanoma epidemiology, prognosis and trends in Latvia
K Azarjana, A Ozola, D Ruklisa, I Cema, A Rivosh, A Azaryan, D Pjanova
Journal of the European Academy of Dermatology and Venereology 27 (11), 1352 2013
Citations: 22



Effects of BRAF V600E and NRAS mutational status on the progression-free survival and clinicopathological characteristics of patients with melanoma
T Zablocka, M Kreismane, D Pjanova, S Isajevs
Oncology Letters 25 (1), 27 2022
Citations: 21



Analysis of Latvian familial melanoma patients shows novel variants in the noncoding regions of CDKN2A and that the CDK4 mutation R24H is a founder mutation
R Veinalde, A Ozola, K Azarjana, A Molven, LA Akslen, S Donina, ...
Melanoma Research 23 (3), 221-226 2013
Citations: 21



Phenotypic and histopathological tumor characteristics according to CDKN2A mutation status among affected members of melanoma families
NJ Taylor, EA Handorf, N Mitra, MF Avril, E Azizi, W Bergman, ...
Journal of Investigative Dermatology 136 (5), 1066-1069 2016
Citations: 19