Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the ...biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of diagnosis at late stage and inherent/acquired chemoresistance. Recent advances in genomic profiling and biology of ...this disease have not yet been translated to a relevant improvement in terms of disease management and patient's survival. However, new possibilities for treatment may emerge from studies on key epigenetic factors. Deregulation of microRNA (miRNA) dependent gene expression and mRNA splicing are epigenetic processes that modulate the protein repertoire at the transcriptional level. These processes affect all aspects of PDAC pathogenesis and have great potential to unravel new therapeutic targets and/or biomarkers. Remarkably, several studies showed that they actually interact with each other in influencing PDAC progression. Some splicing factors directly interact with specific miRNAs and either facilitate or inhibit their expression, such as Rbfox2, which cleaves the well-known oncogenic miRNA miR-21. Conversely, miR-15a-5p and miR-25-3p significantly downregulate the splicing factor hnRNPA1 which acts also as a tumour suppressor gene and is involved in processing of miR-18a, which in turn, is a negative regulator of KRAS expression. Therefore, this review describes the interaction between splicing and miRNA, as well as bioinformatic tools to explore the effect of splicing modulation towards miRNA profiles, in order to exploit this interplay for the development of innovative treatments. Targeting aberrant splicing and deregulated miRNA, alone or in combination, may hopefully provide novel therapeutic approaches to fight the complex biology and the common treatment recalcitrance of PDAC.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive tumor characterized by early invasiveness, rapid progression and resistance to treatment. For more than twenty years, gemcitabine ...has been the main therapy for PDAC both in the palliative and adjuvant setting. After the introduction of FOLFIRINOX as an upfront treatment for metastatic disease, gemcitabine is still commonly used in combination with nab-paclitaxel as an alternative first-line regimen, as well as a monotherapy in elderly patients unfit for combination chemotherapy. As a hydrophilic nucleoside analogue, gemcitabine requires nucleoside transporters to permeate the plasma membrane, and a major role in the uptake of this drug is played by human equilibrative nucleoside transporter 1 (hENT-1). Several studies have proposed hENT-1 as a biomarker for gemcitabine efficacy in PDAC. A recent comprehensive multimodal analysis of hENT-1 status evaluated its predictive role by both immunohistochemistry (with five different antibodies), and quantitative-PCR, supporting the use of the 10D7G2 antibody. High hENT-1 levels observed with this antibody were associated with prolonged disease-free status and overall-survival in patients receiving gemcitabine adjuvant chemotherapy. This commentary aims to critically discuss this analysis and lists molecular factors influencing hENT-1 expression. Improved knowledge on these factors should help the identification of subgroups of patients who may benefit from specific therapies and overcome the limitations of traditional biomarker studies.
Because mutations of splicing factor 3B subunit-1 (SF3B1) have been identified in 4% of pancreatic ductal adenocarcinoma (PDAC) patients, we investigated the activity of new potential inhibitors of ...SF3B1 in combination with gemcitabine, one of the standard drugs, in PDAC cell lines.
One imidazo2,1-
1,3,4thiadiazole derivative (IS1) and three indole derivatives (IS2, IS3 and IS4), selected by virtual screening from an in-house library, were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2, Hs766t and Panc05.04, the latter harbouring the SF3B1 mutations. The effects on the splicing pattern of proto-oncogene recepteur d'origine nantais (RON) and the gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT1) were assessed by PCR, while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.
The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death. All compounds showed an interesting anti-migratory ability, associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure. Moreover, IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in hENT1 expression (
< 0.05
. untreated control cells), potentially reversing PDAC chemoresistance.
These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. ...Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.
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•Exosome-derived miRNAs showed interesting clinical implications in OC patients.•Exo-miRNAs may be potential biomarkers for prognosis and therapy response in OC.•Exo-miRNAs could provide a non-invasive approach for future therapeutic strategies.
Sublay mesh repair seems to be the most effective method for treating incisional hernias (IHs). The aim of this study was to report our experience with retromuscular repair and self-gripping mesh for ...the treatment of midline IHs. In addition, we provided a systematic review of the literature regarding the use of this novel combination. All patients undergoing elective IH repair from June 2016 to November 2018 were included. The self-gripping mesh was placed in the sublay position. Demographic data, defect sizes, postoperative complications and follow-up durations were collected. A systematic review of the available literature was conducted in January 2020 using main databases. A total of 37 patients (20/17M/F) were included in this study, and the mean age and body mass index (BMI) were 58 years and 27 kg/m
2
, respectively. Minor complications occurred in six patients. Long-term follow-up demonstrated recurrence in three patients. Regarding the review, five publications were considered relevant. The highest complication rate was 28.6%, and the recurrence rate varied from 0 to 5.1%. This is the first review of the literature regarding sublay IH repair using a self-gripping mesh. The low rates of postoperative complications and recurrence in our experience and those reported by most of the reviewed articles demonstrate that this is a safe and effective method for repairing IHs.
Evidence-based preventive interventions for adolescent substance use, violence, and mental health issues are increasingly being adapted and disseminated internationally. In the present paper, we ...report the results of an effectiveness study that was part of a comprehensive initiative by a coalition of health promotion organizations in the Lombardy region of Italy to select, culturally adapt, implement, evaluate, and sustain an evidence-based drug abuse prevention program developed in the USA. Findings are presented from a large-scale effectiveness study of the Life Skills Training prevention program among over 3000 students attending 55 middle schools in Italy. The prevention program taught drug refusal skills, antidrug norms, personal self-management skills, and general social skills. Relative to comparison group students, students who received the prevention program were less likely to initiate smoking at the post-test and 2-year follow-up, and less likely to initiate weekly drunkenness at the 1-year follow-up. The program had direct positive effects on several cognitive, attitudinal, and skill variables believed to play a protective role in adolescent substance use. The findings from this study show that a drug abuse prevention program originally designed for adolescents in the USA is effective in a sample of Italian youth when a rigorous and systematic approach to cultural adaptation is followed that incorporates the input of multiple stakeholders.
Purpose. Angelman syndrome (AS) accounts for upto 6% of all cases with severe mental retardation and epilepsy. Clinical findings include developmental delay, severely impaired expressive language, ...ataxic gait, tremulousness of limbs and a typical behavioral profile including a happy demeanour, hyperactive behavior and low attention span. Seizures, abnormal electroencephalogram, microcephaly and scoliosis are observed in >80% of patients. Cognitive, language and orthopedic problems must be addressed with vigorous rehabilitation programs. Classification of functioning disability and health, children and youth adaptation (ICF-CY) can provide the most adequate framework to describe the condition of the persons towards whom rehabilitative efforts are concentrated. The aim of the study is to test whether the ICF-CY framework is effectively able to capture the various dimensions of health in AS.
Methods. We applied the ICF-CY, to the detail of second level codes, to a cohort of 11 patients with AS of various ages. The coding was obtained by the multi-professional team following these children for the rehabilitation program.
Results. The functional profile obtained applying the ICF-CY is complete and comparable with the characteristics of the syndrome described in literature. The possibility of highlighting not only the problems but also the points of strength appears as very helpful. The second level codes may be too broad to provide insight in the clinical and rehabilitative peculiarities, and the use of the full power of the classification may be more advisable for clinical use.
Conclusions. This prelimiary study shows that ICF-CY is a valid tool to frame the clinical characteristics of a complex syndrome as AS, and may give a strong foundation for the rehabilitation programming.
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