Implications of the microbiome and metabolic intermediaries produced by bacteria in breast cancer.

The breast microbiome presents a diverse microbial community that could affects health and disease states, in the context of breast cancer. Sequencing technologies have allowed describing the diversity and abundance of microbial communities among individuals. The complex tumoral microenvironment that includes the microbial composition could influence tumor growth. The imbalance of diversity and abundance inside the microbial community, known as dysbiosis plays a crucial role in this context. One the most prevalent bacterial genera described in breast invasive carcinoma are Bacillus, Pseudomonas, Brevibacillus, Mycobacterium, Thermoviga, Acinetobacter, Corynebacterium, Paenibacillus, Ensifer, and Bacteroides. Paenibacills genus shows a relation with patient survival. When the Paenibacills genus increases its abundance in patients with breast cancer, the survival probability decreases. Within this dysbiotic environment, various bacterial metabolites could play a pivotal role in the progression and modulation of breast cancer. Key bacterial metabolites, such as cadaverine, lipopolysaccharides (LPS), and trimethylamine N-oxide (TMAO), have been found to exhibit potential interactions within breast tissue microenvironments. Understanding the intricate relationships between dysbiosis and these metabolites in breast cancer may open new avenues for diagnostic biomarkers and therapeutic targets. Further research is essential to unravel the specific roles and mechanisms of these microbial metabolites in breast cancer progression.

A Computational Approach to Predict the Role of Genetic Alterations in Methyltransferase Histones Genes With Implications in Liver Cancer.

Histone methyltransferases (HMTs) comprise a subclass of epigenetic regulators. Dysregulation of these enzymes results in aberrant epigenetic regulation, commonly observed in various tumor types, including hepatocellular adenocarcinoma (HCC). Probably, these epigenetic changes could lead to tumorigenesis processes. To predict how histone methyltransferase genes and their genetic alterations (somatic mutations, somatic copy number alterations, and gene expression changes) are involved in hepatocellular adenocarcinoma processes, we performed an integrated computational analysis of genetic alterations in 50 HMT genes present in hepatocellular adenocarcinoma. Biological data were obtained through the public repository with 360 samples from patients with hepatocellular carcinoma. Through these biological data, we identified 10 HMT genes (SETDB1, ASH1L, SMYD2, SMYD3, EHMT2, SETD3, PRDM14, PRDM16, KMT2C, and NSD3) with a significant genetic alteration rate (14%) within 360 samples. Of these 10 HMT genes, KMT2C and ASH1L have the highest mutation rate in HCC samples, 5.6% and 2.8%, respectively. Regarding somatic copy number alteration, ASH1L and SETDB1 are amplified in several samples, while SETD3, PRDM14, and NSD3 showed a high rate of large deletion. Finally, SETDB1, SETD3, PRDM14, and NSD3 could play an important role in the progression of hepatocellular adenocarcinoma since alterations in these genes lead to a decrease in patient survival, unlike patients who present these genes without genetic alterations. Our computational analysis provides new insights that help to understand how HMTs are associated with hepatocellular carcinoma, as well as provide a basis for future experimental investigations using HMTs as genetic targets against hepatocellular carcinoma.

Simulation Model for Hashimoto Autoimmune Thyroiditis Disease.

Hashimoto thyroiditis (HT) is a pathology that often causes a gradual thyroid insufficiency in affected patients due to the autoimmune destruction of this gland. The cellular immune response mediated by T helper lymphocytes TH1 and TH17 can induce the HT disease. In this pathologic condition, there is an imbalance between the TH17 and Treg lymphocytes as well as a gut microbiota dysfunction. The objective of this work was to describe the interactions of the cell subpopulations that participate in HT. To achieve this goal, we generated a mathematical model that allowed the simulation of different scenarios for the dynamic interaction between thyroid cells, the immune system, and the gut microbiota. We used a hypothetical-deductive design of mathematical modeling based on a system of ordinary differential equations, where the state variables are the TH1, TH17, and Treg lymphocytes, the thyrocytes, and the bacteria from gut microbiota. This work generated a compartmental model of the cellular immune response occurring in the thyroid gland. It was observed that TH1 and TH17 lymphocytes could increase the immune cells' activity, as well as activate effector cells directly and trigger the apoptosis and inflammation processes of healthy thyrocytes indirectly. Likewise, the model showed that a reduction in Treg lymphocytes could increase the activity of TH17 lymphocytes when an imbalance of the gut microbiota composition occurred. The numerical results highlight the TH1, TH17, and bacterial balance of the gut microbiota activities as important factors for the development of HT disease.

Histone Methyltransferases Useful in Gastric Cancer Research.

Gastric cancer (GC) is one of the most frequent tumors in the world. Stomach adenocarcinoma is a heterogeneous tumor, turning the prognosis prediction and patients' clinical management difficult. Some diagnosis tests for GC are been development using knowledge based in polymorphisms, somatic copy number alteration (SCNA) and aberrant histone methylation. This last event, a posttranslational modification that occurs at the chromatin level, is an important epigenetic alteration seen in several tumors including stomach adenocarcinoma. Histone methyltransferases (HMT) are the proteins responsible for the methylation in specific amino acids residues of histones tails. Here, were presented several HMTs that could be relating to GC process. We use public data from 440 patients with stomach adenocarcinoma. We evaluated the alterations as SCNAs, mutations, and genes expression level of HMTs in these aforementioned samples. As results, it was identified the 10 HMTs most altered (up to 30%) in stomach adenocarcinoma samples, which are the PRDM14, PRDM9, SUV39H2, NSD2, SMYD5, SETDB1, PRDM12, SUV39H1, NSD3, and EHMT2 genes. The PRDM9 gene is among most mutated and amplified HMTs within the data set studied. PRDM14 is downregulated in 79% of the samples and the SUV39H2 gene is down expressed in patients with recurred/progressed disease. Several HMTs are altered in many cancers. It is important to generate a genetic atlas of alterations of cancer-related genes to improve the understanding of tumorigenesis events and to propose novel tools of diagnosis and prognosis for the cancer control.

Xeloda Oral, Trastuzumab, and Pertuzumab Combined Drug Therapy Reduced Cervical Lymphadenopathy and Dermal Involvement in Patient With Recurrent Breast Cancer: Case Report.

We report the case of a 42-year-old woman who was diagnosed with breast cancer that recurred 3 years later, with supraclavicular lymphadenopathy and dermal involvement. The main drug used in the therapy was trastuzumab; however, the association of this drug with docetaxel was not able to decrease or cease the effect of the inflammatory BCA component with erythema and thickening of the skin as well as the supraclavicular lymphadenopathy previously diagnosed. Thus, a combined therapy was required. The patient was started on 6 cycles (1 per month) of trastuzumab subcutaneous 600 mg, pertuzumab intravenous 840 mg (as an attack dose, later on 420 mg), and xeloda oral 1000 mg. As a result, the patient showed a significant improvement in erythema and thickening of the skin in the neck and the right part of her trunk, besides decrease in supraclavicular lymphadenopathy. After 6 cycles, her skin was almost restored. Intravenous trastuzumab can be an effective single agent; however, its association with other chemotherapies-such as pertuzumab-can present a synergic effect, which can increase the survival expectations of metastatic HER2+ patients. Additionally, as reported in the literature, the use of xeloda plays a key role in restoring the skin health of patients with breast cancer presenting with skin metastasis. Our findings suggest that trastuzumab, pertuzumab, and xeloda combined therapy, following the schedule and posology handled in this study, can be a good treatment for recurrent HER2+ breast cancer with signs of supraclavicular lymphadenopathy and severe inflammatory BCA component with erythema and thickening of the skin.

Identification of Altered Genes in Gallbladder Cancer as Potential Driver Mutations for Diagnostic and Prognostic Purposes: A Computational Approach.

Prognostic markers for cancer can assist in the evaluation of survival probability of patients and help clinicians to assess the available treatment modalities. Gallbladder cancer (GBC) is a rare tumor that causes 165 087 deaths in the world annually. It is the most common cancer of the biliary tract and has a particularly high incidence in Chile, Japan, and northern India. Currently, there is no accurate diagnosis test or effective molecular markers for GBC identification. Several studies have focused on the discovery of genetic alterations in important genes associated with GBC to propose novel diagnosis pathways and to create prognostic profiles. To achieve this, we performed data-mining of GBC in public repositories, harboring 133 samples of GBC, allowing us to describe relevant somatic mutations in important genes and to propose a genetic alteration atlas for GBC. In our results, we reported the 14 most altered genes in GBC: arid1a, arid2, atm, ctnnb1, erbb2, erbb3, kmt2c, kmt2d, kras, pik3ca, smad4, tert, tp53, and znf521 in samples from Japan, the United States, Chile, and China. Missense mutations are common among these genes. The annotations of many mutations revealed their importance in cancer development. The observed annotations mentioned that several mutations found in this repository are probably oncogenic, with a putative loss-of-function. In addition, they are hotspot mutations and are probably linked to poor prognosis in other cancers. We identified another 11 genes, which presented a copy number alteration in gallbladder database samples, which are ccnd1, ccnd3, ccne1, cdk12, cdkn2a, cdkn2b, erbb2, erbb3, kras, mdm2, and myc. The findings reported here can help to detect GBC cancer through the development of systems based on genetic alterations, for example, the development of a mutation panel specifically for GBC diagnosis, as well as the creation of prognostic profiles to accomplish the development of GBC and its prevalence.

Computational analyses on genetic alterations in the NSD genes family and the implications for colorectal cancer development.

Colorectal cancer (CRC) is a prevalent tumour throughout the world. CRC symptoms appear only in advanced stages causing decrease in survival of patients. Therefore, it is necessary to establish new strategies to detect CRC through subclinical screening. Genetic alterations and differential expression of genes that codify histone methyltransferases (HMTs) are linked to tumourigenesis of CRC. One important group of genes that codify HMTs are the NSD family composed of NSD1, NSD2 and NSD3 genes. This family participates in several cancer processes as oncogenes, harbouring several genetic alterations and presenting differential expression in tumour cells. To investigate the implications of NSD genes in CRC cancer, we described the genomic landscape of all NSD family members in a cohort of CRC patients from publicly available cancer datasets. We identified associations among recurrent copy number alterations (CNAs), mutations and differential gene expression concerning clinical outcome. We found in CRC repositories that NSD1 harbours a missense mutation in SET domain-the catalytic region-that probably could decrease its activity. In addition, we found an association between the low expressions of NSD1 and NSD2 and decrease of survival probability in CRC patients. Finally, we reported that NSD3 showed the highest rate of gene amplification, which was highly correlated to its mRNA expression, a common feature of many cancer drivers. Our results highlight the potential use of the NSD1 and NSD2 gene as prognostic markers of poor prognosis in CRC patients. Additionally, we appointed the use of the NSD3 gene as a putative cancer driver gene in CRC given that this gene harbours the highest rate of genetic amplification. All our findings are leading to novel strategies to predict and control CRC, however, some studies need to be conducted to validate these findings.

Learning from transgenics: advanced gene editing technologies should also bridge the gap with traditional genetic selection

We highlight the importance of the mixed genetic approaches (classical and currents) to improve the social perception related to the GMOs acceptance. We pointed out that CRISPR/Cas9 events could carry DNA variability/rearrangements related to somaclonal variations or epigenetic changes that are independent from the editing per se. The transformation of single cells, followed by plant regeneration, is used to generate modified plants, transgenic or genome editing (CRISPR/Cas9). The incidence of undesirable somaclonal variations and/or epigenetic changes that might have occurred during in vitro multiplication and regeneration processes, must be carefully analyzed in replicates in field trials. One remarkable challenge is related to the time lapse that selects the modified elite genotypes, because these strategies may spend a variable amount of time before the results are commercialized, where in all the cases it should be take into account the genotype × environment interactions. Furthermore, this combination of techniques can create an encouraging bridge between the public opinion and the community of geneticists who are concerned with plant genetic improvement. In this context, either transgenesis or genomic editing strategies become complementary modern tools to facing the challenges of plant genetic improvement. Their applications will depend on case-by-case analysis, and when possible will necessary associate them to the schemes and bases of classic plant genetic improvement.