This review analyzes the potential impact of milk-induced signal transduction on the pathogenesis of prostate cancer (PCa). Articles in PubMed until November 2021 reporting on milk intake and PCa were reviewed. Epidemiological studies identified commercial cow milk consumption as a potential risk factor of PCa. The potential impact of cow milk consumption on the pathogenesis of PCa may already begin during fetal and pubertal prostate growth, critical windows with increased vulnerability. Milk is a promotor of growth and anabolism via activating insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3 kinase (PI3K)/AKT/mechanistic target of rapamycin complex 1 (mTORC1) signaling. Estrogens, major steroid hormone components of commercial milk of persistently pregnant dairy cows, activate IGF-1 and mTORC1. Milk-derived signaling synergizes with common driver mutations of the PI3K/AKT/mTORC1 signaling pathway that intersect with androgen receptor, MFG-E8, MAPK, RUNX2, MDM4, TP53, and WNT signaling, respectively. Potential exogenously induced drivers of PCa are milk-induced elevations of growth hormone, IGF-1, MFG-E8, estrogens, phytanic acid, and aflatoxins, as well as milk exosome-derived oncogenic microRNAs including miR-148a, miR-21, and miR-29b. Commercial cow milk intake, especially the consumption of pasteurized milk, which represents the closest replica of native milk, activates PI3K-AKT-mTORC1 signaling via cow milk’s endocrine and epigenetic modes of action. Vulnerable periods for adverse nutrigenomic impacts on prostate health appear to be the fetal and pubertal growth periods, potentially priming the initiation of PCa. Cow milk-mediated overactivation of PI3K-AKT-mTORC1 signaling synergizes with the most common genetic deviations in PCa, promoting PCa initiation, progression, and early recurrence.

Aim: To model a complex retinal disease such as age-related macular degeneration (AMD) in vitro, we aimed to combine genetic and environmental risk factors in a retinal pigment epithelium (RPE) cell culture model generated via induced pluripotent stem cells (iPSCs) from subjects with an extremely high and an extremely low genetic disease risk. As an external stimulus, we chose defined oxidative stress conditions.

Methods: Patients were genotyped for known AMD-associated genetic variants and their individual genetic risk score (GRS) was calculated defining individual iPSC-RPE cell lines which reflect the extreme ends of the genetic risk for AMD. Sodium iodate (NaIO₃, SI) was used to induce oxidative stress and cellular responses were followed by analyzing nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation by mRNA and protein expression.

Results: We present a collection of eight iPSC-RPE cell lines, with four each harboring an extreme low or an extreme high GRS for AMD. RPE identity was verified structurally and functionally. We found that 24 and 72 h of SI treatment induced a significant upregulation of NRF2 response genes HMOX1 and NQO1, without showing cytotoxic effects or negatively influencing RPE cell integrity. High- vs. low-risk cell lines revealed similar first line defenses in oxidative stress response mediated through the NRF2 pathway.

Conclusion: Delineating the NRF2-mediated oxidative stress response was sought in iPSC-RPE cell lines with maximally divergent genetic AMD risk profiles. Under the specific stress conditions chosen, our data indicate that genetic predisposition to AMD may not exert a major influence on the NRF2 signaling pathway.

Genomic aberrations comprise hallmarks of multiple myeloma (MM), a plasma cell malignancy with an overall poor prognosis. MM is heterogeneous and has different molecularly-defined subtypes according to varying clinical and pathological features. Hyperdiploidy or non-hyperdiploidy has usually been identified as early initiating genetic events that can be followed by secondary aberrations, including copy number changes, secondary translocations, and different epigenetic modifications, which cause immortalization of plasma cell and disease progression. Even though recent advances in drug discovery have offered new perspectives of treatment, MM remains incurable. However, understanding the molecular complexity of MM would allow patients to get precision treatment. Our review focuses on current evidence in myeloma biology with special attention to genomic and molecular variations.

Aim: Currently, the obesity epidemic is one of the biggest problems for human health. Obesity is impacted on survival in patients with breast cancer. However, key biomarkers of obesity-related breast cancer risk are still not well known. Thus, using machine learning to identify the most appropriate features in obesity-associated breast cancer patients may improve the predictive accuracy and interpretability of regression models.

Methods: In the present study, we identified 23 differentially expressed genes (DEGs) from the GSE24185 transcriptome dataset. Seed genes were identified from DEGs, the co-expression network genes and hub genes of the protein-protein interaction network. Pathway enrichment analysis was performed for DEGs. The Ridge penalty regression model was executed by using P-values of enriched pathways and seed gene pathway association score to obtain the most relevant molecular signatures. The model was performed using 10-fold cross-validation to fit the penalized models.

Results: Angiotensin II receptor type 1 (AGTR1), cyclin D1 (CCND1), glutamate ionotropic receptor AMPA type subunit 2 (GRIA2), interleukin-6 cytokine family signal transducer (IL6ST), matrix metallopeptidase 9 (MMP9), and protein kinase CAMP-dependent type II regulatory subunit beta (PRKAR2B) were considered as candidate molecular signatures of obese patients with breast cancer. In addition, RAF-independent MAPK1/3 activation, collagen degradation, bladder cancer, drug metabolism-cytochrome P450, and signaling by Hedgehog pathways in cancer were primarily associated with obesity-associated breast cancer.

Conclusion: These genes may be used for risk analysis of the disease progression of obese patients with breast cancer. Corresponding genes and pathways should be validated via experimental studies.

Inherited retinal degenerations (IRDs) cause permanent vision impairment or vision loss due to the death of rod and cone photoreceptors. Animal models of IRDs have been instrumental in providing knowledge of the pathological mechanisms that cause photoreceptor death and in developing successful approaches that could slow or prevent vision loss. Zebrafish models of IRDs represent an ideal model system to study IRDs in a cone-rich retina and to test strategies that exploit the natural ability to regenerate damaged neurons. This review highlights those zebrafish mutants and transgenic lines that exhibit adult-onset retinal degeneration and serve as models of retinitis pigmentosa, cone-rod dystrophy, and ciliopathies.

Aim: To examine the utility of gene editing therapies for retinitis pigmentosa using Xenopus laevis carrying a mutation in Rhodopsin.

Methods: Xenopus laevis were genetically modified using CRISPR-Cas9 based methods and characterized by Sanger sequencing, dot blot, electroretinography, and confocal microscopy.

Results: We identified genetically modified Xenopus laevis carrying a net 12 base pair deletion in the Rho.L gene. These animals have a retinal degeneration that is apparent by 14 days, with abnormal or missing rod outer segments, and a reduced electroretinogram signal. We prevented the majority of this retinal degeneration via a treatment strategy using a single sgRNA to neutralize the mutant allele via non-homologous end joining, yielding long-term improvements in histology and the electroretinogram. A second strategy using two sgRNAs to generate large deletions in the mutant allele was also successful, but did not significantly improve outcomes relative to the single-guide strategy as it was less efficient. We found limited evidence of success with a third strategy dependent on homology-directed repair; this treatment was also too inefficient to generate an outcome superior to the single-guide strategy.

Conclusion: Our results demonstrate the utility of this new Xenopus laevis model for rapidly assessing and comparing multiple gene-editing based treatment strategies. We conclude that it would be technically difficult to improve on the simple single-guide based strategy, as strategies requiring multiple successive events (such as cleavage followed by homology-directed repair) are likely to be less efficient.

RNA polymerase III (pol III) synthesizes short noncoding RNA (ncRNA) exclusively and is unique in having alternative paralogues of one of its subunits, POLR3G and POLR3GL. Although most pol III target loci can be transcribed by either isoform, exceptions have been found. For example, depletion of POLR3G curtails the production of BC200 and snaR ncRNAs that are implicated in cancer progression. Furthermore, POLR3G may protect pol III against repression by MAF1, a key physiological regulator. Expression of POLR3G is promoted selectively by MYC, NANOG and OCT4A, master regulators of stem cell pluripotency, resulting in its preferential accumulation in undifferentiated cells. Indeed, differentiation of prostate cancer cells is suppressed by a positive feedback mechanism between POLR3G and NANOG, involving the control of NANOG mRNA degradation by ncRNAs. Specific knockdown of POLR3G inhibits proliferation and induces differentiation of prostate cancer cells, but this response is not seen following comparable depletion of its POLR3GL paralogue. ML-60218 is a cell-permeable small molecule pol III inhibitor that triggers the replacement of POLR3G with POLR3GL. Proliferation and viability of primary prostate cancer cells are suppressed by ML-60218, whereas differentiation is induced, effects that mimic POLR3G depletion. Transient exposure to ML-60218 reduced tumour initiating activity in a xenograft model. Untransformed prostate cells are much less sensitive to these treatments, raising the possibility of therapeutic benefit.

In this review we present contemporary understanding of aetiological heterogeneity in Hodgkin lymphoma, discuss how this may influence tumour phenotype and whether it does or may impact treatment outcomes. Many new treatments are being tested in this era. We especially discuss T-cell therapy and immune checkpoint blockade, because these two modern treatments are expected to have differential efficacy by the presence/absence of Epstein-Barr virus in the malignant Hodgkin-Reed-Sternberg cells. Survival after Hodgkin lymphoma is excellent in many patient strata with first-line treatment, but less so for patients with refractory or relapsing disease. On the other hand, this good prognosis also means that very large trials are needed to demonstrate superior efficacy of new treatment regimes. And our understanding of aetiological heterogeneity in Hodgkin lymphoma and how it affects prognosis is hampered for the same reason. We discuss the potential for fine-tuning risk stratification and treatment based on information that is little used today.