Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF and MEK inhibition-induced selection of cancer stem cells in BRAF-mutated melanoma

Combination therapy with BRAF and MEK inhibitors significantly improves survival in BRAF mutated melanoma patients but is unable to prevent disease recurrence due to the emergence of drug resistance. Cancer stem cells (CSCs) have been involved in these long-term treatment failures. We previously reported in lung cancer that CSCs maintenance is due to altered lipid metabolism and dependent upon Stearoyl-CoA-desaturase (SCD1)-mediated upregulation of YAP and TAZ. On this ground, we investigated the role of SCD1 in melanoma CSCs

A Straightforward Method to Produce Multi-Nanodrug Delivery Systems for Transdermal/Tympanic Patches Using Electrospinning and Electrospray

The delivery of drugs through the skin barrier at a predetermined rate is the aim of transdermal drug delivery systems (TDDSs). However, so far, TDDS has not fully attained its potential as an alternative to hypodermic injections and oral delivery. In this study, we presented a proof of concept of a dual drug-loaded patch made of nanoparticles (NPs) and ultrafine fibers fabricated by using one equipment, i.e., the electrospinning apparatus. Such NP/fiber systems can be useful to release drugs locally through the skin and the tympanic membrane. Briefly, dexamethasone (DEX)-loaded poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) fiber meshes were decorated with rhodamine (RHO)-loaded poly(lactic-co-glycolic acid) (PLGA) NPs, with RHO representing as a second drug model. By properly tuning the working parameters of electrospinning, DEX-loaded PHBHV fibers (i.e., by electrospinning mode) and RHO-loaded PLGA NPs (i.e., by electrospray mode) were successfully prepared and straightforwardly assembled to form a TDDS patch, which was characterized via Fourier transform infrared spectroscopy and dynamometry. The patch was then tested in vitro using human dermal fibroblasts (HDFs). The incorporation of DEX significantly reduced the fiber mesh stiffness. In vitro tests with showed that HDFs were viable for 8 days in contact with drug-loaded samples, and significant signs of cytotoxicity were not highlighted. Finally, thanks to a beaded structure of the fibers, a controlled release of DEX from the electrospun patch was obtained over 4 weeks, which may accomplish the therapeutic objective of a local, sustained and prolonged anti-inflammatory action of a TDDS, as is requested in chronic inflammatory conditions, and other pathological conditions, such as in sudden sensorineural hearing loss treatment

Compartmental tongue surgery for intermediate-advanced squamous cell carcinoma: A multicentric study

Background: A multicentric study was conducted on technical reproducibility of compartmental tongue surgery (CTS) in advanced tongue cancers (OTSCC) and comparison to standard wide margin surgery (SWMS). Methods: We studied 551 patients with OTSCC treated by CTS and 50 by SWMS. Oncological outcomes were analyzed. A propensity score was performed to compare survival endpoints for the two cohorts. Results: In the CTS group, survival and prognosis were significantly associated with positive lymph-nodes, extranodal extension, depth of invasion and involvement of the soft tissue connecting the tongue primary tumor to neck lymph nodes (T-N tract), independently from the center performing the surgery. SWMS versus CTS showed a HR Cause-Specific Survival (CSS) of 3.24 (95% CI: 1.71-6.11; p < 0.001); HR Loco-Regional Recurrence Free Survival (LRRFS) of 2.54 (95% CI: 1.47-4.40; p < 0.001); HR Overall Survival (OS) of 0.11 (95% CI: 0.01-0.77; p = 0.03). Conclusion: Performing the CTS could provide better CSS and LRRFS than SWMS regardless of the center performing the surgery, in advanced OTSSC

Tree Resin Composition, Collection Behavior and Selective Filters Shape Chemical Profiles of Tropical Bees (Apidae: Meliponini)

The diversity of species is striking, but can be far exceeded by the chemical diversity of compounds collected, produced or used by them. Here, we relate the specificity of plant-consumer interactions to chemical diversity applying a comparative network analysis to both levels. Chemical diversity was explored for interactions between tropical stingless bees and plant resins, which bees collect for nest construction and to deter predators and microbes. Resins also function as an environmental source for terpenes that serve as appeasement allomones and protection against predators when accumulated on the bees' body surfaces. To unravel the origin of the bees' complex chemical profiles, we investigated resin collection and the processing of resin-derived terpenes. We therefore analyzed chemical networks of tree resins, foraging networks of resin collecting bees, and their acquired chemical networks. We revealed that 113 terpenes in nests of six bee species and 83 on their body surfaces comprised a subset of the 1,117 compounds found in resins from seven tree species. Sesquiterpenes were the most variable class of terpenes. Albeit widely present in tree resins, they were only found on the body surface of some species, but entirely lacking in others. Moreover, whereas the nest profile of Tetragonula melanocephala contained sesquiterpenes, its surface profile did not. Stingless bees showed a generalized collecting behavior among resin sources, and only a hitherto undescribed species-specific “filtering” of resin-derived terpenes can explain the variation in chemical profiles of nests and body surfaces from different species. The tight relationship between bees and tree resins of a large variety of species elucidates why the bees' surfaces contain a much higher chemodiversity than other hymenopterans

3D fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging at different stages of otosclerosis

The aim of this work is to study otosclerotic patients by 3D-FLAIR (fluid attenuated inversion recovery) sequence magnetic resonance imaging (MRI) with and without Gadolinium administration (-/+ Gd), to understand whether there is a direct relationship between radiological findings at 3D FLAIR MRI sequences and some clinical features of otosclerosis, such as the presence and entity of sensorineural involvement, duration of disease, patient gender, and other factors

Can Magnetic Resonance Radiomics Analysis Discriminate Parotid Gland Tumors? A Pilot Study

Our purpose is to evaluate the performance of magnetic resonance (MR) radiomics analysis for differentiating between malignant and benign parotid neoplasms and, among the latter, between pleomorphic adenomas and Warthin tumors. We retrospectively evaluated 75 T2-weighted images of parotid gland lesions, of which 61 were benign tumors (32 pleomorphic adenomas, 23 Warthin tumors and 6 oncocytomas) and 14 were malignant tumors. A receiver operating characteristics (ROC) curve analysis was performed to find the threshold values for the most discriminative features and determine their sensitivity, specificity and area under the ROC curve (AUROC). The most discriminative features were used to train a support vector machine classifier. The best classification performance was obtained by comparing a pleomorphic adenoma with a Warthin tumor (yielding sensitivity, specificity and a diagnostic accuracy as high as 0.8695, 0.9062 and 0.8909, respectively) and a pleomorphic adenoma with malignant tumors (sensitivity, specificity and a diagnostic accuracy of 0.6666, 0.8709 and 0.8043, respectively). Radiomics analysis of parotid tumors on conventional T2-weighted MR images allows the discrimination of pleomorphic adenomas from Warthin tumors and malignant tumors with a high sensitivity, specificity and diagnostic accuracy

Pulmonary artery resections for lung cancer. When and how?

Resection and reconstruction of the pulmonary artery (PA), whether associated or not to a sleeve resection of the bronchus, allows complete resection of centrally located lung cancer, thus avoiding pneumonectomy. Despite initial concern related to technical difficulties, perioperative management and long term survival, recent studies showed continuous enhancement of the surgical technique and reconstruction materials, reduction of the complication rate and improvement in the survival. This allowed this procedure to gain widespread acceptance in the treatment of lung cancer

Uniportal thoracoscopy for pneumothorax

Introduction: Videothoracoscopy (VATS) is the gold standard for pneumothorax (PNX). However, in the last years, the surgical technique has been progressively modified towards less invasiveness to reduce postoperative pain and hospitalization. We present our experience with uniportal VATS to treat PNX. Methods: Seventy-six patients (mean age 19 ±14 years) with PNX underwent surgery with an uniportal approach. In fifty-eight patients (76.3%) the indication was a recurrence of previous spontaneous PNX, in 14 (18.4%) prolonged air leakage after chest tube placement for the first episode of PNX and in 4 (5.3%) redo surgery after no resolution of air leakage. One patient with bilateral PNX was simultaneously treated on both sides. All patients had a chest drainage before the surgery and VATS has been performed through a single port of 2.5 cm corresponding to the chest tube insertion. All patients have received blebs or bullae resection and partial parietal pleurectomy. Results: One postoperative bleeding required reoperation through the same approach. One recurrence on the operated side occurred after 2 years and it was successfully treated with uniportal VATS through the previous incision. Comparing this series with an historical population of patients treated with three-port VATS, we observed a significant decrease of postoperative pain measured with Visual Analog Scale (VAS) at 1st postoperative day, at discharge and at one month (2.92 vs 4.03 p=0.04; 1.2 vs 2.6 p=0.04; 0.58 vs 1.34 p=0.03). Furthermore, Uniportal group has been discharged earlier (3.67 vs 6.3 days; p=0.003). Conclusions: Uniportal VATS is a safe and effective approach to treat PNX also in difficult situations

B4GALT1 is a new candidate to maintain the stemness of lung cancer stem cells

Background: According to the cancer stem cells (CSCs) hypothesis, a population of cancer cells with stem cell properties is responsible for tumor propagation, drug resistance, and disease recurrence. Study of the mechanisms responsible for lung CSCs propagation is expected to provide better understanding of cancer biology and new opportunities for therapy. Methods: The Lung Adenocarcinoma (LUAD) NCI-H460 cell line was grown either as 2D or as 3D cultures. Transcriptomic and genome-wide chromatin accessibility studies of 2D vs. 3D cultures were carried out using RNA-sequencing and Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq), respectively. Reverse transcription polymerase chain reaction (RT-PCR) was also carried out on RNA extracted from primary cultures derived from malignant pleural eusions to validate RNA-seq results. Results: RNA-seq and ATAC-seq data disentangled transcriptional and genome accessibility variability of 3D vs. 2D cultures in NCI-H460 cells. The examination of genomic landscape of genes upregulated in 3D vs. 2D cultures led to the identification of 2D cultures led to the identification of Beta-1,4-galactosyltranferase 1 (B4GALT1) as the top candidate. B4GALT1 as the top candidate. B4GALT1 was validated as a stemness factor, since its silencing caused strong inhibition of 3D spheroid formation. Conclusion: Combined transcriptomic and chromatin accessibility study of 3D vs. 2D LUAD cultures led to the identification of B4GALT1 as a new factor involved in the propagation and maintenance of LUAD CSCs

CytoMatrix for a reliable and simple characterization of lung cancer stem cells from malignant pleural effusions

Cancer stem cells (CSCs) are a subpopulation with the properties of extensive self-renewal, capability to generate differentiated cancer cells and resistance to therapies. We have previously shown that malignant pleural effusions (MPEs) from patients with non-small-cell lung cancer (NSCLC) represent a valuable source of cancer cells that can be grown as three-dimensional (3D) spheroids enriched for stem-like features, which depend on the activation of the Yes-associated protein-transcriptional coactivator with PDZ-binding motif (YAP-TAZ)/Wnt-βcatenin/stearoyl-CoA desaturase 1 (SCD1) axis. Here, we describe a novel support, called CytoMatrix, for the characterization of limited amounts of cancer cells isolated from MPEs of patients with NSCLC. Our results show that this synthetic matrix allows an easy and fast characterization of several epithelial cellular markers. The use of CytoMatrix to study CSCs subpopulation confirms that SCD1 protein expression is enhanced in 3D spheroids when compared with 2D adherent cell cultures. YAP/TAZ nuclear-cytoplasmic distribution analysed by CytoMatrix in 3D spheroids is highly heterogeneous and faithfully reproduces what is observed in tumour biopsies. Our results confirm and extend the robustness of our workflow for the isolation and phenotypic characterization of primary cancer cells derived from the lung MPEs and underscore the role of SCD1