Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-ß pathway.

Background: Dormant cancer cells are commonly known to play a pivotal role in cancer recurrence and metastasis. However, the mechanism of tumor dormancy and recurrence remains largely unknown. This study aimed to investigate the mechanism by which exosomes derived from dormant lung adenocarcinoma (LUAD) cells activate cancer-associated fibroblasts (CAFs) to reconstruct the extracellular matrix (ECM), providing a novel idea for decoding the mechanism of tumor dormancy. Methods: In this study, high-dose cisplatin was used to induce the dormant LUAD cells. Exosomes were extracted from the culture supernatant of normal and dormant cancer cells. The effects of selected exosomal proteins on the fibroblasts were evaluated. RNA-seq for fibroblasts and exosomal proteomics for normal and dormant cancer cells were used to identify and verify the mechanism of activating fibroblasts. Results: We demonstrated that exosomes derived from dormant A549 cells could be taken by fibroblasts. Exosomal ITGB6 transferred into fibroblasts induced the activation of CAFs by activating the KLF10 positive feedback loop and transforming growth factor ß (TGF-ß) pathway. High ITGB6 expression was associated with activation of the TGF-ß pathway and ECM remodeling. Conclusions: In all, we demonstrated that CAFs were activated by exosomes from dormant lung cancer cells and reconstruct ECM. ITGB6 may be a critical molecule for activating the TGF-ß pathway and remodeling ECM.

Nomogram for prediction of diabetic retinopathy in patients with type 2 diabetes mellitus: A retrospective study.

OBJECTIVE: To develop a nomogram for the risk of diabetic retinopathy (DR) among type 2 diabetes mellitus (T2DM). METHODS: Questionnaires, physical examinations and biochemical tests were performed on 5900 T2DM patients in the Second Hospital of Shijiazhuang. The least absolute shrinkage and selection operator regression was used to optimize feature selection, and the importance of selected features was analyzed by random forest. Logistic regression was performed with selected features, and the nomogram was established based on the results. The Harrell's C-statistic, bootstrap-corrected C-statistic, area under curve (AUC), calibration curve, decision curve analysis (DCA) and clinical impact curve (CIC) were used to validate the discrimination, calibration and clinical usefulness of the nomogram, and further assessment was running by external validation. RESULTS: Predictors included duration of diabetes, diabetic neuropathy, diabetic kidney disease, diabetic foot, hyperlipidemia, hypoglycemic drugs, glycated albumin, Lactate dehydrogenase. The model displayed medium predictive power with a Harrell's C-statistic of 0.820, bootstrap-corrected C-statistic of 0.813 and AUC of 0.820 in the training set, and which was respectively 0.842, 0.835 and 0.842 in the validation set. The calibration curve displayed good agreement (P > 0.05). The DCA and CIC showed that the nomogram could be applied clinically if the risk threshold is between 2 % and 75 % and 2 %-88 % in validation set. CONCLUSIONS: This nomogram incorporating 8 features is useful to predict the risk of DR in T2DM patients.

Auto-Administered Photobiomodulation on Diabetic Leg Ulcers Treatment: A New Way to Manage It?

BACKGROUND: Peripheral arterial disease is a dramatic consequence of an uncontrolled diabetic condition causing an increase of morbidity and mortality and its treatment is currently medical or surgical, finally requiring, in the 7-20% of cases, major or minor amputation. Photobiomodulation therapy (PBM) is a laser treatment used in medicine, thanks to its ability to stimulate the wound healing, the acceleration of inflammatory process, and the modulation of pain. Recently, the self-administration of the treatment has been suggested for different purposes in medicine and dentistry with a great number of advantages and no side effects. METHODS: A 84-year-old woman affected by diabetes type 2 and positive for diabetes complications had diagnosis for an ulcerative lesion of 1 cm diameter on her right leg and started a treatment of the lesion applying the B-Cure Laser Pro (Erika Carmel, Haifa, Israel) on her own with a fluence per minute of 3.2 J/cm2 for 2 sessions of 15 minutes by cutaneous application. RESULTS: After a week of treatment, the ulcer dried and crusted, finally providing complete healing after 30 days of treatment. CONCLUSION: With this short case report, we think to add a further contribution by suggesting this kind of treatment for successful management of the leg ulcers in diabetic patients.

Identification of Maturity-Onset Diabetes of the Young Caused by Mutation in FOXM1 via Whole-Exome Sequencing in Northern China.

Diabetes mellitus is a highly heterogeneous disorder encompassing different types with particular clinical manifestations, while maturity-onset diabetes of the young (MODY) is an early-onset monogenenic diabetes. Most genetic predisposition of MODY has been identified in European and American populations. A large number of Chinese individuals are misdiagnosed due to defects of unknown genes. In this study, we analyzed the genetic and clinical characteristics of the Northern China. A total of 200 diabetic patients, including 10 suspected MODY subjects, were enrolled, and the mutational analysis of monogenic genes was performed by whole-exome sequencing and confirmed by familial information and Sanger sequencing. We found that clinical features and genetic characteristics have varied widely between MODY and other diabetic subjects in Northern China. FOXM1, a key molecule in the proliferation of pancreatic ß-cells, has a rare mutation rs535471991, which leads to instability within the phosphorylated domain that impairs its function. Our findings indicate that FOXM1 may play a critical role in MODY, which could reduce the misdiagnose rate and provide promising therapy for MODY patients.

GPER stabilizes F-actin cytoskeleton and activates TAZ via PLCß-PKC and Rho/ROCK-LIMK-Cofilin pathway.

Actin is a highly abundant cytoskeletal protein that is essential for all eukaryotic cells and participates in many structural and functional roles. It has long been noted that estrogen affects cellular morphology. However, recent studies observed that both estrogen and tamoxifen induce a remarkable cytoskeletal remodeling independent of ER. In addition to ER, G protein-coupled estrogen receptor 1 (GPER, also known as GPR30) also binds to estrogen with high affinity and mediates intracellular estrogenic signaling. Here, we show that activation of GPER by its specific agonist G-1 induces re-organization of F-actin cytoskeleton. We further demonstrate that GPER acts through PLCß-PKC and Rho/ROCK-LIMK-Cofilin pathway, which are upstream regulators of F-actin cytoskeleton assembly, thereby enhancing TAZ nuclear localization and activation. Furthermore, we find that LIMK1/2 is critical for GPER activation-induced breast cancer cell migration. Together, our results suggest that GPER mediates G-1-induced cytoskeleton assembly and GPER promotes breast cancer cell migration via PLCß-PKC and Rho/ROCK-LIMK-Cofilin pathway.

Effect of laser irradiation on aphthae pain management: A four different wavelengths comparison.

Recurrent Aphthous Stomatitis (RAS) is an oral condition characterized by painful ulcerations of the mucosa, healing spontaneously in 10-14 days but sometimes, due to their number, size and frequency of recurrence, lesions may be the cause of a severe disconfort with an impact on the quality of life of the patients due to the increased difficulty to eat, swallow and speak. For RAS, different protocols and treatments have been proposed as standard topical treatment to provide symptomatic relief, immunomodulating drugs as thalidomide, colchicine and steroids have been also proposed with the outcome to relief the pain, accelerating the healing process and increase the duration of ulcer-free period but without definitive results and without side effects. In this study we analysed the effect of laser treatment of aphthous lesions with four devices available on the market, two with wavelength in the infra-red region (2940 nm 808 nm) and two with a wavelength in the visible region (450 nm and 635 nm). Diode lasers 808 nm and 450 nm defined almost the same results with an improvement starting already after the application and gradually improving until 7 days after treatment without any statistically significant difference between them. Diode 635 nm was the device gaining the earliest effect reducing the pain already during the treatment and maintaining it at low level immediately after the laser application and after 3 and 7 days with levels of pain comparable with them obtained with 808 nm and 450 nm lasers. Er:YAG laser with the used parameters obtained a pain relief only during the treatment. The originality of this study was to compare different laser wavelengths, some of them never used for this purpose, and to compare also the two different ways to use lasers, the photobiomodulation (LLLT) and the high-power irradiation.

Erbium-Doped, Yttrium-Aluminum-Garnet Laser Debonding of Porcelain Laminate Veneers: An Ex vivo Study.

BACKGROUND: The use of ceramic laminate veneer has considerably and successfully grown to improve anterior tooth esthetics in recent years. The removal of ceramic laminate veneers with laser is reported only in a scanty number of publications and for this reason the importance and the aim of this ex vivo study consist to verify the ability of Er: YAG laser for laminate veneers debonding with the preserving of the tooth structures (scanning electron microscopy [SEM] observations). AIM: The purpose of this study consists to verify if erbium-doped, yttrium-aluminum-garnet (Er:YAG) laser, at low fluences, is able to debond porcelain veneers, successfully used to improve anterior tooth esthetics, without damaging the tooth structures. SETTINGS AND DESIGN: A total of 12 freshly extracted teeth were used, and samples were decontaminated, stored, and bonded to obtain veneers adhesion. One week after, Er:YAG laser with a non-contact sapphire tip with air-water spray was used for veneer debonding at 100 mJ of energy and 30 Hz of frequency (Fluence 19.94 J/cm2). RESULTS: Results demonstrated that veneer debonding is possible with an Er:YAG laser and the total number of pulses seems not related to its efficiency. SEM observation confirms that residual tooth structure is not altered when using these low fluences. CONCLUSIONS: Low fluences with Er:YAG laser are able to debond veneers while preserving the tooth structures and SEM observation confirmed that residual tooth structure is not altered with low fluences.

Hippocampal deep brain stimulation in nonlesional refractory mesial temporal lobe epilepsy.

PURPOSE: To evaluate the efficacy of chronic continuous hippocampal deep brain stimulation (DBS) in nonlesional refractory mesial temporal lobe epilepsy. METHODS: Three adult patients with medically intractable epilepsy treated with hippocampal DBS were studied. Two patients underwent invasive recordings with depth stereo-electroencephalography (SEEG) electrodes to localize ictal onset zone prior to implantation of DBS electrodes. All the patients with no lesion in brain magnetic resonance imaging (MRI) scan received bilateral implantation of DBS electrodes. Chronic continuous high-frequency hippocampal stimulation was applied during treatment. The number of seizures in each patient before and after stimulation was compared. RESULTS: Long-term hippocampal stimulation produced a median reduction in seizure frequency of 93%. Two out of these patients received unilateral activation of the electrodes and experienced a 95% and 92% reduction in seizure frequency after hippocampal DBS respectively. The last patient had bilateral electrode activation and had a seizure-frequency reduction of 91%. None of the patients had neuropsychological deterioration and showed side effects. Generalized tonic-clonic seizures disappeared completely after hippocampal DBS. CONCLUSIONS: Chronic continuous hippocampal DBS demonstrated a potential efficiency and safety in nonlesional refractory mesial temporal lobe epilepsy and might represent an effective therapeutic option for these patients.