Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides.

Circular RNAs (circRNAs) are covalently closed non-coding RNAs lacking the 5' cap and the poly-A tail. Nevertheless, it has been demonstrated that certain circRNAs can undergo active translation. Therefore, aberrantly expressed circRNAs in human cancers could be an unexplored source of tumor-specific antigens, potentially mediating anti-tumor T cell responses.

Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD.

Adequacy of Severe Malaria Markers and Prognostic Scores in an Intensive Care Unit in Luanda, Angola: A Clinical Study.

Severe malaria remains the primary cause of mortality in several African countries, including Angola, where severe malaria patient admission into intensive care units (ICU) is mandatory. The present observational and prospective study enrolled 101 consecutive severe malaria patients admitted at the ICU of Américo Boavida University Hospital (Luanda, Angola). Malaria was confirmed by microscopy and RDT, and WHO criteria were used to define severe malaria.

Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer.

Background: Acquired resistance to trastuzumab is a major clinical problem in the treatment of HER2-positive (HER2+) breast cancer patients. The selection of trastuzumab-resistant patients is a great challenge of precision oncology. The aim of this study was to identify novel epigenetic biomarkers associated to trastuzumab resistance in HER2+ BC patients.

Epigenetic loss of the endoplasmic reticulum-associated degradation inhibitor SVIP induces cancer cell metabolic reprogramming.

The endoplasmic reticulum (ER) of cancer cells needs to adapt to the enhanced proteotoxic stress associated with the accumulation of unfolded, misfolded and transformation-associated proteins. One way by which tumors thrive in the context of ER stress is by promoting ER-Associated Degradation (ERAD), although the mechanisms are poorly understood. Here, we show that the Small p97/VCP Interacting Protein (SVIP), an endogenous inhibitor of ERAD, undergoes DNA hypermethylation-associated silencing in tumorigenesis to achieve this goal.

Discovery of a Potent, Long-Acting, and CNS-Active Inhibitor (BIA 10-2474) of Fatty Acid Amide Hydrolase.

Fatty acid amide hydrolase (FAAH) can be targeted for the treatment of pain associated with various medical conditions. Herein we report the design and synthesis of a novel series of heterocyclic-N-carboxamide FAAH inhibitors that have a good alignment of potency, metabolic stability and selectivity for FAAH over monoacylglycerol lipase (MAGL) and carboxylesterases (CEs). Lead optimization efforts carried out with benzotriazolyl- and imidazolyl-N-carboxamide series led to the discovery of clinical candidate 8 l (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide; BIA 10-2474) as a potent and long-acting inhibitor of FAAH.

Circular RNA CpG island hypermethylation-associated silencing in human cancer.

Noncoding RNAs (ncRNAs), such as microRNAs and long noncoding RNAs (lncRNAs), participate in cellular transformation. Work done in the last decade has also demonstrated that ncRNAs with growth-inhibitory functions can undergo promoter CpG island hypermethylation-associated silencing in tumorigenesis. Herein, we wondered whether circular RNAs (circRNAs), a type of RNA transcripts lacking 5'-3' ends and forming closed loops that are gaining relevance in cancer biology, are also a target of epigenetic inactivation in tumors.

CpG Islands in Cancer: Heads, Tails, and Sides.

DNA methylation is a dynamic epigenetic mark that characterizes different cellular developmental stages, including tissue-specific profiles. This CpG dinucleotide modification cooperates in the regulation of the output of the cellular genetic content, in both healthy and pathological conditions. According to endogenous and exogenous stimuli, DNA methylation is involved in gene transcription, alternative splicing, imprinting, X-chromosome inactivation, and control of transposable elements.

Non-coding RNAs, epigenetics, and cancer: tying it all together.

While only a small part of the human genome encodes for proteins, biological functions for the so-called junk genome are increasingly being recognized through high-throughput technologies and mechanistic experimental studies. Indeed, novel mechanisms of gene regulation are being discovered that require coordinated interaction between DNA, RNA, and proteins. Therefore, interdisciplinary efforts are still needed to decipher these complex transcriptional networks.

Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.

Background: One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized.

BMP Inhibition in Seminomas Initiates Acquisition of Pluripotency via NODAL Signaling Resulting in Reprogramming to an Embryonal Carcinoma.

Type II germ cell cancers (GCC) can be subdivided into seminomas and non-seminomas. Seminomas are similar to carcinoma in situ (CIS) cells, the common precursor of type II GCCs, with regard to epigenetics and expression, while embryonal carcinomas (EC) are totipotent and differentiate into teratomas, yolk-sac tumors and choriocarcinomas. GCCs can present as seminomas with a non-seminoma component, raising the question if a CIS gives rise to seminomas and ECs at the same time or whether seminomas can be reprogrammed to ECs.

Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR.

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade.

A comprehensive DNA methylation profile of epithelial-to-mesenchymal transition.

Epithelial-to-mesenchymal transition (EMT) is a plastic process in which fully differentiated epithelial cells are converted into poorly differentiated, migratory and invasive mesenchymal cells, and it has been related to the metastasis potential of tumors. This is a reversible process and cells can also eventually undergo mesenchymal-to-epithelial transition. The existence of a dynamic EMT process suggests the involvement of epigenetic shifts in the phenotype.

Epigenetic loss of the PIWI/piRNA machinery in human testicular tumorigenesis.

Although most cancer research has focused in mRNA, non-coding RNAs are also an essential player in tumorigenesis. In addition to the well-recognized microRNAs, recent studies have also shown that epigenetic silencing by CpG island hypermethylation of other classes of non-coding RNAs, such as transcribed ultraconserved regions (T-UCRs) or small nucleolar RNAs (snoRNAs), also occur in human neoplasia. Herein we have studied the putative existence of epigenetic aberrations in the activity of PIWI proteins, an Argonaute family protein subclass, and the small regulatory PIWI-interacting RNAs (piRNAs) in testicular cancer, as the PIWI/piRNA pathway plays a critical role in male germline development.

Electrophilic reactivity of tetrabromorhodamine 123 is bromine induced: convergent interpretation through complementary molecular descriptors.

Nucleophilic addition of water and of methanol to 3,6-diamino-2,4,5,7-tetrabromo-9-[2-(methoxycarbonyl) phenyl]-9H-xanthen-9-ylium, 4BrR123, yields respectively 2-(3,6-diamino-2,4,5,7-tetrabromo-9-hydroxy-9H-xanthen-9-yl)xanthyl benzoate, HO4BrR123 and 2-(3,6-diamino-2,4,5,7-tetrabromo-9-methoxy-9H-xanthen-9-yl)xanthyl benzoate, MeO4BrR123. The novel experimental results are addressed theoretically. The linear free energy relationship, LFER, second-order perturbation theory analysis of the natural bond orbital, NBO, and quantum theory of atoms in molecules, QTAIM, lead to the same conclusion: the electron-withdrawing effect of bonded Br atoms in 4BrR123 extremely enhances the molecular electrophilicity, as compared to 3,6-diamino-9-[2-(methoxycarbonyl) phenyl]-9H-xanthen-9-ylium, R123.

Epigenetic disruption of the PIWI pathway in human spermatogenic disorders.

Epigenetic changes are involved in a wide range of common human diseases. Although DNA methylation defects are known to be associated with male infertility in mice, their impact on human deficiency of sperm production has yet to be determined. We have assessed the global genomic DNA methylation profiles in human infertile male patients with spermatogenic disorders by using the Infinium Human Methylation27 BeadChip.

DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker.

Using whole blood from 15 twin pairs discordant for breast cancer and high-resolution (450K) DNA methylation analysis, we identified 403 differentially methylated CpG sites including known and novel potential breast cancer genes. Confirming the results in an independent validation cohort of 21 twin pairs determined the docking protein DOK7 as a candidate for blood-based cancer diagnosis. DNA hypermethylation of the promoter region was also seen in primary breast cancer tissues and cancer cell lines.

Distinct DNA methylomes of newborns and centenarians.

Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes.

CpG island hypermethylation-associated silencing of small nucleolar RNAs in human cancer.

Much effort in cancer research has focused on the tiny part of our genome that codes for mRNA. However, it has recently been recognized that microRNAs also contribute decisively to tumorigenesis. Studies have also shown that epigenetic silencing by CpG island hypermethylation of microRNAs with tumor suppressor activities is a common feature of human cancer.

Discovery of a long-acting, peripherally selective inhibitor of catechol-O-methyltransferase.

Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone.

Clenbuterol storage stability in the bovine urine and liver samples used for European official control in the azores islands (portugal).

Clenbuterol is a well-known growth promoter, illegally used in farm animals, especially in cattle. Samples collected for the screening of beta(2)-agonist residues in Portuguese Azores Islands must travel through all the nine islands until they reach Azores Central Laboratory. If any suspicious sample is detected, it must be further transported to the National Reference Laboratory in Lisbon for confirmation.

Squalenoyl nanomedicine of gemcitabine is more potent after oral administration in leukemia-bearing rats: study of mechanisms.

In an earlier report, we demonstrated the superior anticancer efficacy of orally administered squalenoyl gemcitabine (SQdFdC) nanomedicine over its parent drug gemcitabine on rats bearing RNK-16 large granular lymphocytic (LGL) leukemia. In the present communication, we investigated the mechanisms behind this observation both at the cell and tissue level. The mechanisms were investigated by performing cytotoxicity, cell uptake, and biodistribution experiments.

Human endogenous retrovirus family HERV-K(HML-2) RNA transcripts are selectively packaged into retroviral particles produced by the human germ cell tumor line Tera-1 and originate mainly from a provirus on chromosome 22q11.21.

The human germ cell tumor line Tera-1 produces retroviral particles which are encoded by the human endogenous retrovirus family HERV-K(HML-2). We show here, by quantitative reverse transcriptase PCR, that HML-2 gag and env RNA transcripts are selectively packaged into Tera-1 retroviral particles, whereas RNAs from cellular housekeeping genes and from other HERV families (HERV-H and HERV-W) are nonselectively copackaged. Assignment of cloned HML-2 gag and env cDNAs from Tera-1 retroviral particles to individual HML-2 loci in the human genome demonstrated that HML-2 RNA transcripts packaged into Tera-1 retroviral particles originate almost exclusively from an HML-2 provirus on chromosome 22q11.

Squalenoylation favorably modifies the in vivo pharmacokinetics and biodistribution of gemcitabine in mice.

Gemcitabine (2',2'-difluorodeoxyribofuranosylcytosine; dFdC) is an anticancer nucleoside analog active against wide variety of solid tumors. However, this compound is rapidly inactivated by enzymatic deamination and can also induce drug resistance. To overcome the above drawbacks, we recently designed a new squalenoyl nanomedicine of dFdC [4-N-trisnorsqualenoyl-gemcitabine (SQdFdC)] by covalently coupling gemcitabine with the 1,1',2-trisnorsqualenic acid; the resultant nanomedicine displayed impressively greater anticancer activity compared with the parent drug in an experimental murine model.

Efficient synthesis of 2-(trifluoromethyl)nicotinic acid derivatives from simple fluorinated precursors.

Novel routes to 2-trifluoromethyl-nicotinic acid derivatives have been developed involving synthesis of the pyridine ring. These pyridyl compounds serve as key intermediates in the manufacture of the recently discovered COMT inhibitor, 3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-2-(trifluoromethyl)pyridine 1-oxide.