Germinal ovarian tumors in reproductive age women: Fertility-sparing and outcome

MOGCTs (malignant ovarian germ cell tumors) are rare tumors that mainly affect patients of reproductive age. The aim of this study was to evaluate the fertility and survival outcomes in young women with MOCGTs treated with fertility-sparing surgery (FSS).From 2000 to 2018, data from 28 patients of reproductive age with a diagnosis of MOGCT at the University of Bari were collected. Most received FSS, and in patients treated conservatively, the reproductive outcome and survival were investigated. Data of patient demographics, clinical presentation, oncology marker dosage, staging, type of surgery, histological examination, survival, and reproductive outcome were collected from hospital and office charts. All informed consent was obtained from all patients. The median age was 24 (range: 9-45 years). The majority of the patients had stage IIIC. Twenty-four woman received FSS consisting of unilateral ovariectomy and omentectomy, whereas only 4 women, based on their stage (IIIC), received a radical surgery (hysterectomy with bilateral adnexectomy, lymphadenectomy, and omentectomy). Our study shows that FSS in MOGCTs can produce good results both on reproductive outcomes and on survival. Indeed, in our group, there was only 1 case of exitus as result of recurrence. Furthermore, patients after FSS maintained normal ovarian function and 5 of 5 women who tried to get pregnant succeeded spontaneously. The median follow-up was 90 months (range 3-159).Conservative surgery for MOGCTs should be considered for women of reproductive age who wish to preserve fertility

Neural responses to facial and vocal expressions of fear and disgust

Neuropsychological studies report more impaired responses to facial expressions of fear than disgust in people with amygdala lesions, and vice versa in people with Huntington's disease. Experiments using functional magnetic resonance imaging (fMRI) have confirmed the role of the amygdala in the response to fearful faces and have implicated the anterior insula in the response to facial expressions of disgust. We used fMRI to extend these studies to the perception of fear and disgust from both facial and vocal expressions. Consistent with neuropsychological findings, both types of fearful stimuli activated the amygdala. Facial expressions of disgust activated the anterior insula and the caudate-putamen; vocal expressions of disgust did not significantly activate either of these regions. All four types of stimuli activated the superior temporal gyrus. Our findings therefore (i) support the differential localization of the neural substrates of fear and disgust; (ii) confirm the involvement of the amygdala in the emotion of fear, whether evoked by facial or vocal expressions; (iii) confirm the involvement of the anterior insula and the striatum in reactions to facial expressions of disgust; and (iv) suggest a possible general role for the perception of emotional expressions for the superior temporal gyrus

Somatic BRCA Mutation in a Cholangiocarcinoma Patient for HBOC Syndrome Detection

BRCA-associated hereditary breast and ovarian cancer syndrome (HBOC) is characterized by an increased risk of developing other malignancies including cholangiocarcinoma (CCA). Somatic BRCA mutations have been reported in CCA, but they have yet to be utilized in a proband case to identify HBOC in families. Two healthy daughters of a deceased female patient who had had metachronous breast cancer and CCA received genetic counseling to assess their cancer risk. Somatic BRCA1/2 mutation analysis was performed by next-generation sequencing on the DNA extracted from a formalin-fixed, paraffin-embedded CCA biopsy specimen of their mother. A pathogenic variant was identified (c.6468_6469delTC in a BRCA2 gene mutation). Germline BRCA mutation analysis of the two daughters detected the same pathogenic variant in one of them. For the first time, a CCA somatic BRCA mutation has been used to identify a family with HBOC

Prediction of Friction Stir Welding effects on AA2024-T3 plates and stiffened panels using a shell-based finite element model

Manufacturing-induced effects significantly affect in-service behaviour of welded structures, such as integrally stiffened panels for aeronautic applications. Being a complex phenomenon with several variables involved, the assessment of the effects coming from welding usually relies on numerical simulations. Here, a novel shell-based finite element model is proposed to accurately simulate the transient thermal fields and stress-strain distributions resulting from friction stir welding (FSW) processes. The capability of the model to predict (i) residual stresses, (ii) material softening and (iii) geometric distortion of the welded parts is assessed by the modelling and simulation of FSW applied on aluminium integrally stiffened panels

Pharmacokinetic and metabolism determinants of fluoropyrimidines and oxaliplatin activity in treatment of colorectal patients

Fluoropyrimidines and oxaliplatin continued to be the mainstay of therapeutic regimens in the treatment of colorectal cancer (CRC). For this reason, pharmacokinetic and metabolism of these drugs were analyzed and the identification of accurate and validated predictive, prognostic and toxicity markers became necessary to develop an effective therapy adapted to the patient's molecular profile, while minimizing life-threatening toxicities. In this review, we discuss literature data, defining predictive and prognostic markers actually identified in the treatment of CRC. We analyzed predictive markers of fluoropyrimidines effectiveness, principally for 5-Fluorouracil (5-FU) and also for oral fluoropyrimidines, as thymidylate Synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), methylenetetrahydrofolate reductase (MTHFR), deoxyuridine triphosphate nucleotidohydrolase (dUTPase), micro-satellite instability. DPD represent the more studied 5-FU toxicity marker, followed by TS and OPRT. Oxaliplatin effectiveness is principally regulated by nucleotide excision repair (NER) pathway, including excision repair cross-complementation group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1) and xeroderma pigmentosum group D (XDP). The major oxaliplatin toxicity marker is represented by glutathione S-transferase (GST). All these results are based principally on retrospective studies. The future challenge became to validate molecular markers and their association with clinical outcomes in prospective trials, refining technologic platforms and bioin-formatics to accommodate the complexity of the multifaceted molecular map that may determine outcome, and determining CRC patients most likely to benefit from therapeutic interventions tailored specifically for them

Effect of tetracaine on DMPC and DMPC + cholesterol biomembrane models: Liposomes and monolayers

“NOTICE: this is the author’s version of a work that was accepted for publication in Colloids and Surfaces B: Biointerfaces. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Colloids and Surfaces B: Biointerfaces, [Vol. 16, (April 2014)] DOI 10.1016/j.colsurfb.2013.12.042 ""Different types of lipid bilayers/monolayers have been used to simulate the cellular membranes in the investigation of the interactions between drugs and cells. However, to our knowledge, very few studies focused on the influence of the chosen membrane model upon the obtained results. The main objective of this work is to understand how do the nature and immobilization state of the biomembrane models influence the effect of the local anaesthetic tetracaine (TTC) upon the lipid membranes. The interaction of TTC with different biomembrane models of dimyristoylphosphatidylcholine (DMPC) with and without cholesterol (CHOL) was investigated through several techniques. A quartz crystal microbalance with dissipation (QCM-D) was used to study the effect on immobilized liposomes, while phosphorus nuclear magnetic resonance (31P-NMR) and differential scanning calorimetry (DSC) were applied to liposomes in suspension. The effect of TTC on Langmuir monolayers of lipids was also investigated through surface pressure-area measurements at the air-water interface. The general conclusion was that TTC has a fluidizing effect on the lipid membranes and, above certain concentrations, induced membrane swelling or even solubilization. However, different models led to variable responses to the TTC action. The intensity of the disordering effect caused by TTC increased in the following order: supported liposomes < liposomes in solution < Langmuir monolayers. This means that extrapolation of the results obtain in in vitro studies of the lipid/anaesthetic interactions to in vivo conditions should be done carefully.

Identification of key receptor residues discriminating human chorionic gonadotropin (Hcg)-and luteinizing hormone (lh)-specific signaling

(1) The human luteinizing hormone (LH)/chorionic gonadotropin (hCG) receptor (LHCGR) discriminates its two hormone ligands and differs from the murine receptor (Lhr) in amino acid residues potentially involved in qualitative discerning of LH and hCG. The latter gon-adotropin is absent in rodents. The aim of the study is to identify LHCGR residues involved in hCG/LH discrimination. (2) Eight LHCGR cDNAs were developed, carrying “murinizing” mutations on aminoacidic residues assumed to interact specifically with LH, hCG, or both. HEK293 cells expressing a mutant or the wild type receptor were treated with LH or hCG and the kinetics of cyclic adenosine monophosphate (cAMP) and phosphorylated extracellular signal-regulated ki-nases 1/2 (pERK1/2) activation was analyzed by bioluminescence resonance energy transfer (BRET). (3) Mutations falling within the receptor leucine reach repeat 9 and 10 (LRR9 and LRR10; K225S +T226I and R247T), of the large extracellular binding domain, are linked to loss of hormone-specific induced cAMP increase, as well as hCG-specific pERK1/2 activation, leading to a Lhr-like modulation of the LHCGR-mediated intracellular signaling pattern. These results support the hypothesis that LHCGR LRR domain is the interaction site of the hormone β-L2 loop, which differs between LH and hCG, and might be fundamental for inducing gonadotropin-specific signals. (4) Taken to-gether, these data identify LHCGR key residues likely evolved in the human to discriminate LH/hCG specific binding

Expression and characterization of a novel recombinant cytotoxin II from Naja naja oxiana venom: A potential treatment for breast cancer

Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 μg mL−1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs

Higher Muscle Mass Implies Increased Free-Thyroxine to Free-Triiodothyronine Ratio in Subjects With Overweight and Obesity

Thyroid hormones control both metabolic pathways and body composition, whereas little knowledge is available about the possible influence of skeletal muscle mass (MM) on thyroid hormone metabolism and circulating levels. This was a cross-sectional study conducted at the Population Health Unit of the National Institute of Gastroenterology IRCCS “S. de Bellis” (Italy) and investigating the extent to which skeletal MM affects thyroid function in obesity. Two hundred twenty-seven consecutive healthy volunteers (155 women and 72 men) with overweight and obesity (BMI ≥ 25 kg/m2) and taking no medication or supplement were assessed for hormone, metabolic and routine laboratory parameters. Body composition parameters were collected by using bioelectrical impedance analysis (BIA). MM was directly related to the body mass index (BMI), waist circumference (WC), insulin, triglycerides, uric acid and free-triiodothyronine (FT3) serum levels, FT3 to the free-thyroxine (FT4) ratio, and insulin-resistance (HOMA-IR), and inversely related to age, total, and HDL-cholesterol serum levels. Multiple regression models confirmed the relationship between MM and the FT3 to FT4 ratio, independently of age, BMI, TSH, triglycerides, and insulin serum levels. The same analyses run by gender showed that this relationship maintained significance only in men. Increased skeletal MM in obesity results in improved thyroid activity mediated by increased T4 conversion to T3, and higher FT3 circulating levels, particularly in men. In conclusion, preserving a greater skeletal MM in obesity helps to enhance thyroid activity. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04327375