Microarrays and NGS for Drug Discovery

Novel technologies and state of the art platforms developed and launched over the last two decades such as microarrays, next-generation sequencing, and droplet PCR have provided the medical field many opportunities to generate and analyze big data from the human genome, particularly of genomes altered by different diseases like cancer, cardiovascular, diabetes and obesity. This knowledge further serves for either new drug discovery or drug repositioning. Designing drugs for specific mutations and genotypes will dramatically modify a patient’s response to treatment. Among other altered mechanisms, drug resistance is of concern, particularly when there is no response to cancer therapy. Once these new platforms for omics data are in place, available information will be used to pursue precision medicine and to establish new therapeutic guidelines. Target identification for new drugs is necessary, and it is of great benefit for critical cases where no alternatives are available. While mutational status is of highest importance as some mutations can be pathogenic, screening of known compounds in different preclinical models offer new and quick strategies to find alternative frameworks for treating more diseases with limited therapeutic options

New methodological aspects in rehabilitation after proximal humerus fracture

Proximal humerus fracture ranks third in the elderly after femoral neck fractures and distal radius fractures, and seventh in adults, and the risk of occurrence is related to advancing age. In this study we aimed to analyze the efficacy of a 24-weeks physical therapy programme based on a particular methodology consisting of the reprogramming of the specific proprioceptive neuromuscular facil-itation techniques added to the classical physical therapy and by introducing modern interactive therapies and technologies: Capacitive Resistive Electric Transference, Instrument Assisted Soft Tissue Mobilization, kinesiological tapes and PRAMA system, compared with classical physical therapy. Our study included 26 patients, aged between 18 and 55 years, with proximal humerus fracture, who complete the 24-weeks rehabilitation programme. We assessed pain, shoulder range of motion, muscle strength and the ability to perform activities of daily living. The statistical analysis was performed using IBM SPSS and Excel 2021. The results showed statistically significant im-provement in all shoulder motion, increased muscle strength, decreased pain, and a better ability to perform daily activities. The physical therapy programme based on the proposed particular methodology has proven to be more effective than classical physical therapy, both regarding the improvement of the movement parameters compared to the physiological values, as well as the symmetry of both shoulders

Comparative study on metal versus zirconium dioxide infrastructure manufacturing in prosthetic rehabilitation in the maxillary frontal zone

Prosthetic rehabilitation of the maxillary front teeth is an extremely laborious problem for the dental team, consisting of the dentist and the dental technician. If for the physiognomic component the most recommended materials are the ceramic masses, for the resistance substrate there are several variants. Conventional technologies using dental alloys and modern ones involving the use of zirconium dioxide can be used successfully in performing fixed prosthetic restorations in the maxillary frontal area, both options having both advantages and disadvantages, as we will describe in this material

Dentists, members of the French Resistance movement during the World War II

The Resistance was a reaffirmation of France's independence and individuality, as well as a struggle to regain freedom and, above all, national integrity. In fact, many historians appreciate that the French Resistance could have achieved more if it had been more effectively integrated into Allied plans and strategies. Thus, in this material we tried to present some short biographies of dentists who worked in the French Resistance against the German occupation troops, some of them even paying with their lives for the courage they showed

17β-estradiol promotes extracellular vesicle release and selective miRNA loading in ERα-positive breast cancer

The causes and consequences of abnormal biogenesis of extracellular vesicles (EVs) are not yet well understood in malignancies, including in breast cancers (BCs). Given the hormonal signaling dependence of estrogen receptor–positive (ER+) BC, we hypothesized that 17β-estradiol (estrogen) might influence EV production and microRNA (miRNA) loading. We report that physiological doses of 17β-estradiol promote EV secretion specifically from ER+ BC cells via inhibition of miR-149-5p, hindering its regulatory activity on SP1, a transcription factor that regulates the EV biogenesis factor nSMase2. Additionally, miR-149-5p downregulation promotes hnRNPA1 expression, responsible for the loading of let-7’s miRNAs into EVs. In multiple patient cohorts, we observed increased levels of let-7a-5p and let-7d-5p in EVs derived from the blood of premenopausal ER+ BC patients, and elevated EV levels in patients with high BMI, both conditions associated with higher levels of 17β-estradiol. In brief, we identified a unique estrogen-driven mechanism by which ER+ BC cells eliminate tumor suppressor miRNAs in EVs, with effects on modulating tumor-associated macrophages in the microenvironment

CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer

The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk

Inflamma-miRs in aging and breast cancer: Are they reliable players?

Human aging is characterized by chronic low-grade inflammation known as inflammaging. Persistent low-level inflammation also plays a key role in all stages of breast cancer since inflammaging is the potential link between cancer and aging through NF-kB pathways highly influenced by specific miRs. Micro-RNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at a post-transcriptional level. Inflamma-miRs have been implicated in the regulation of immune and inflammatory responses. Their abnormal expression contributes to the chronic pro-inflammatory status documented in normal aging and major age-related diseases (ARDs), inflammaging being a significant mortality risk factor in both cases. Nevertheless, the correct diagnosis of inflammaging is difficult to make and its hidden contribution to negative health outcomes remains unknown. This methodological work flow was aimed at defining crucial unanswered questions about inflammaging that can be used to clarify aging-related miRNAs in serum and cell lines as well as their targets, thus confirming their role in aging and breast cancer tumorigenesis.Moreover, we aim to highlight the links between the pro-inflammatory mechanism underlying the cancer and aging processes and the precise function of certain miRNAs in cellular senescence (CS). In addition, miRNAs and cancer genes represent the basis for new therapeutic findings indicating that both cancer and ARDs genes are possible candidates involved in CS and vice versa. Our goal is to obtain a focused review which could facilitate future approaches in the investigation of the mechanisms by which miRNAs control the aging process by acting as efficient ARDs inflammatory biomarkers. An understanding of the sources and modulation of inflamma-miRs, along with the identification of their specific target genes could enhance their therapeutic potential

Genome Editing Approaches with CRISPR/Cas9 for Cancer Treatment: Critical Appraisal of Preclinical and Clinical Utility, Challenges, and Future Research

The increasing burden on human malignant diseases became a major concern for healthcare practitioners, that must deal with tumor relapse and the inability to efficiently treat metastasis, in addition to side effects. Throughout the decades, many therapeutic strategies have been employed to improve the clinical outcomes of cancer patients and great efforts have been made to develop more efficient and targeted medicines. The malignant cell is characterized by genetic and epigenetic modifications, therefore targeting those specific drivers of carcinogenesis is highly desirable. Among the genome editing technologies, CRISPR/Cas9 stood as a promising candidate for cancer treatment alternatives, due to its low complexity design. First described as a defense mechanism of bacteria against invading foreign DNA, later it was shown that CRISPR components can be engineered to target specific DNA sequences in a test tube, a discovery that was awarded later with the Nobel Prize in chemistry for its rapid expansion as a reliable genome editing tool in many fields of research, including medicine. The present paper aims of describing CRISPR/Cas9 potential targets for malignant disorders, and the approaches used for achieving this goal. Aside from preclinical studies, we also present the clinical trials that use CRISPR-based technology for therapeutic purposes of cancer. Finally, a summary of the presented studies adds a more focused view of the therapeutic value CRISPR/Cas9 holds and the associated shortcomings