Testing the Short-Term Efficacy of a Lipid-Lowering Nutraceutical in the Setting of Clinical Practice: A Multicenter Study

The main guidelines for cardiovascular disease prevention suggest that nutraceuticals could be an efficacious tool to improve lipid pattern. Our aim was to carry out a clinical trial comparing the metabolic effects of a combined nutraceutical containing both red yeast rice and polyunsaturated fatty acids (PUFAs) and a phytosterol-based approach in a setting of clinical practice. This was a multicenter open study with parallel control. We consecutively enrolled 107 pharmacologically untreated subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome, assigned to 8-week treatment with a combined treatment with red yeast rice (Dif1Stat\uc2\uae, including 5mg monacolin K) and 610mg PUFAs. A parallel group of 30 subjects with similar characteristics was treated with phytosterols 1600mg/die. In the combined nutraceutical group, compared with the baseline level, we observed a significant decrease in total cholesterol (TC; -42.50\uc2\ub118.1mg/dL), low-density lipoprotein cholesterol (LDL-C; -37.6\uc2\ub113.6mg/dL), triglycerides (TG; -19.8\uc2\ub125.1mg/dL), and non-HDL-C (-43.1\uc2\ub117.7mg/dL) (all P<.001). In the phytosterol-treated group, compared to the baseline level, we observed a significant decrease in TC (-13.7\uc2\ub14.3mg/dL), LDL-C (-17.6\uc2\ub18.5mg/dL), and non-HDL-C (-14.1\uc2\ub15.6mg/dL) (all P<.001). When comparing the combined nutraceutical effect with that of phytosterols, we observed that the combined nutraceutical intake was associated with a significantly higher decrease in TC, LDL-C, TG, and non-HDL-C (all P<.001). In the short term, a combined nutraceutical containing red yeast rice and PUFAs is well tolerated and efficacious in reducing plasma lipid levels in subjects affected by primary polygenic hypercholesterolemia and metabolic syndrome

Evaluation of Proton-Induced Biomolecular Changes in MCF-10A Breast Cells by Means of FT-IR Microspectroscopy

Radiotherapy (RT) with accelerated beams of charged particles (protons and carbon ions), also known as hadrontherapy, is a treatment modality that is increasingly being adopted thanks to the several benefits that it grants compared to conventional radiotherapy (CRT) treatments performed by means of high-energy photons/electrons. Hence, information about the biomolecular effects in exposed cells caused by such particles is needed to better realize the underlying radiobiological mechanisms and to improve this therapeutic strategy. To this end, Fourier transform infrared microspectroscopy (-FT-IR) can be usefully employed, in addition to long-established radiobiological techniques, since it is currently considered a helpful tool for examining radiation-induced cellular changes. In the present study, MCF-10A breast cells were chosen to evaluate the effects of proton exposure using -FT-IR. They were exposed to different proton doses and fixed at various times after exposure to evaluate direct effects due to proton exposure and the kinetics of DNA damage repair. Irradiated and control cells were examined in transflection mode using low-e substrates that have been recently demonstrated to offer a fast and direct way to examine proton-exposed cells. The acquired spectra were analyzed using a deconvolution procedure and a ratiometric approach, both of which showed the different contributions of DNA, protein, lipid, and carbohydrate cell components. These changes were particularly significant for cells fixed 48 and 72 h after exposure. Lipid changes were related to variations in membrane fluidity, and evidence of DNA damage was highlighted. The analysis of the Amide III band also indicated changes that could be related to different enzyme contributions in DNA repair

FT-IR Transflection Micro-Spectroscopy Study on Normal Human Breast Cells after Exposure to a Proton Beam

Fourier transform infrared micro-spectroscopy (mu-FT-IR) is nowadays considered a valuable tool for investigating the changes occurring in human cells after exposure to ionizing radiation. Recently, considerable attention has been devoted to the use of this optical technique in the study of cells exposed to proton beams, that are being increasingly adopted in cancer therapy. Different experimental configurations are used for proton irradiation and subsequent spectra acquisition. To facilitate the use of mu-FT-IR, it may be useful to investigate new experimental approaches capable of speeding up and simplifying the irradiation and measurements phases. Here, we propose the use of low-e-substrates slides for cell culture, allowing the irradiation and spectra acquisition in transflection mode in a fast and direct way. In recent years, there has been a wide debate about the validity of these supports, but many researchers agree that the artifacts due to the presence of the electromagnetic standing wave effects are negligible in many practical cases. We investigated human normal breast cells (MCF-10 cell line) fixed immediately after the irradiation with graded proton radiation doses (0, 0.5, 2, and 4 Gy). The spectra obtained in transflection geometry showed characteristics very similar to those present in the spectra acquired in transmission geometry and confirm the validity of the chosen approach. The analysis of spectra indicates the occurrence of significant changes in DNA and lipids components of cells. Modifications in protein secondary structure are also evidenced

MALIGNANT TUMOR-LIKE GAASTRIC LESION DUE TO CANDIDA ALBICANS IN A DIABETIC PATIENT TREATED WITH CYCLOSPORIN: A CASE REPORT AND REVIEW OF THE LITERATURE

The gastrointestinal tract of healthy individuals is colonized by hundreds of saprophytes and mycetes, especially in the candida species, are habitual ones. Under certain conditions, the fungal flora may overgrow, resulting in lesion of the digestive mucosa which rarely, can have a local diffusion and/or spread to the lympho-hematogenous system. Mycotic infections of the stomach can sometimes look like benign gastric ulcers. here, we present the case report of a woman, aged 64, who presented with type II diabetes mellitus and psoriasis, on chronic treatment with cyclosporin A and with endoscopic evidence of an ulcerated, vegetating gastric lesion secondary to Candida Albicans infection. Although strongly sugestive of malignancy, it completely healed after cyclosporin withdrawal and the administration of oral antifungal drugs

Molecular Investigation on a Triple Negative Breast Cancer Xenograft Model Exposed to Proton Beams

Specific breast cancer (BC) subtypes are associated with bad prognoses due to the absence of successful treatment plans. The triple-negative breast cancer (TNBC) subtype, with estrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) negative receptor status, is a clinical challenge for oncologists, because of its aggressiveness and the absence of effective therapies. In addition, proton therapy (PT) represents an effective treatment against both inaccessible area located or conventional radiotherapy (RT)-resistant cancers, becoming a promising therapeutic choice for TNBC. Our study aimed to analyze the in vivo molecular response to PT and its efficacy in a MDA-MB-231 TNBC xenograft model. TNBC xenograft models were irradiated with 2, 6 and 9 Gy of PT. Gene expression profile (GEP) analyses and immunohistochemical assay (IHC) were performed to highlight specific pathways and key molecules involved in cell response to the radiation. GEP analysis revealed in depth the molecular response to PT, showing a considerable immune response, cell cycle and stem cell process regulation. Only the dose of 9 Gy shifted the balance toward pro-death signaling as a dose escalation which can be easily performed using proton beams, which permit targeting tumors while avoiding damage to the surrounding healthy tissue

Charcot-Marie-Tooth Type 2B: A New Phenotype Associated with a Novel RAB7A Mutation and Inhibited EGFR Degradation

The rare autosomal dominant Charcot-Marie-Tooth type 2B (CMT2B) is associated with mutations in the RAB7A gene, involved in the late endocytic pathway. CMT2B is characterized by predominant sensory loss, ulceromutilating features, with lesser-to-absent motor deficits. We characterized clinically and genetically a family harboring a novel pathogenic RAB7A variant and performed structural and functional analysis of the mutant protein. A 39-year-old woman presented with early-onset walking diculties, progressive distal muscle wasting and weakness in lower limbs and only mild sensory signs. Electrophysiology demonstrated an axonal sensorimotor neuropathy. Nerve biopsy showed a chronic axonal neuropathy with moderate loss of all caliber myelinated fibers. Next-generation sequencing (NGS) technology revealed in the proband and in her similarly affected father the novel c.377A&gt;G (p.K126R) heterozygous variant predicted to be deleterious. The mutation affects the biochemical properties of RAB7 GTPase, causes altered interaction with peripherin, and inhibition of neurite outgrowth, as for previously reported CMT2B mutants. However, it also shows differences, particularly in the epidermal growth factor receptor degradation process. Altogether, our findings indicate that this RAB7A variant is pathogenic and widens the phenotypic spectrum of CMT2B to include predominantly motor CMT2. Alteration of the receptor degradation process might explain the different clinical presentations in this family

Proton-irradiated breast cells: molecular points of view

Breast cancer (BC) is the most common cancer in women, highly heterogeneous at both the clinical and molecular level. Radiation therapy (RT) represents an efficient modality to treat localized tumor in BC care, although the choice of a unique treatment plan for all BC patients, including RT, may not be the best option. Technological advances in RT are evolving with the use of charged particle beams (i.e. protons) which, due to a more localized delivery of the radiation dose, reduce the dose administered to the heart compared with conventional RT. However, few data regarding proton-induced molecular changes are currently available. The aim of this study was to investigate and describe the production of immunological molecules and gene expression profiles induced by proton irradiation. We performed Luminex assay and cDNA microarray analyses to study the biological processes activated following irradiation with proton beams, both in the non-tumorigenic MCF10A cell line and in two tumorigenic BC cell lines, MCF7 and MDA-MB-231. The immunological signatures were dose dependent in MCF10A and MCF7 cell lines, whereas MDA-MB-231 cells show a strong pro-inflammatory profile regardless of the dose delivered. Clonogenic assay revealed different surviving fractions according to the breast cell lines analyzed. We found the involvement of genes related to cell response to proton irradiation and reported specific cell line- and dose-dependent gene signatures, able to drive cell fate after radiation exposure. Our data could represent a useful tool to better understand the molecular mechanisms elicited by proton irradiation and to predict treatment outcome

Genetically Determined Measures of Striatal D2 Signaling Predict Prefrontal Activity during Working Memory Performance

Background: Variation of the gene coding for D2 receptors (DRD2) has been associated with risk for schizophrenia and with working memory deficits. A functional intronic SNP (rs1076560) predicts relative expression of the two D2 receptors isoforms, D2S (mainly pre-synaptic) and D2L (mainly post-synaptic). However, the effect of functional genetic variation of DRD2 on striatal dopamine D2 signaling and on its correlation with prefrontal activity during working memory in humans is not known. Methods: Thirty-seven healthy subjects were genotyped for rs1076560 (G>T) and underwent SPECT with [123I]IBZM (which binds primarily to post-synaptic D2 receptors) and with [123I]FP-CIT (which binds to pre-synaptic dopamine transporters, whose activity and density is also regulated by pre-synaptic D2 receptors), as well as BOLD fMRI during N-Back working memory. Results: Subjects carrying the T allele (previously associated with reduced D2S expression) had striatal reductions of [ 123I]IBZM and of [123I]FP-CIT binding. DRD2 genotype also differentially predicted the correlation between striatal dopamine D2 signaling (as identified with factor analysis of the two radiotracers) and activity of the prefrontal cortex during working memory as measured with BOLD fMRI, which was positive in GG subjects and negative in GT. Conclusions: Our results demonstrate that this functional SNP within DRD2 predicts striatal binding of the two radiotracers to dopamine transporters and D2 receptors as well as the correlation between striatal D2 signaling with prefrontal cortex activity during performance of a working memory task. These data are consistent with the possibility that the balance of excitatory/inhibitory modulation of striatal neurons may also affect striatal outputs in relationship with prefrontal activity during working memory performance within the cortico-striatal-thalamic- cortical pathwa