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Schematic representation of multiple ROS-generation-based tumor-therapy approach of AgNP. [Display omitted] • A simple mixing procedure has been utilized to synthesize bimetallic silver nitroprusside (AgNP) as CDT agent together with peroxynitrite generator. • AgNP decomposes more endogenous H 2 O 2 to produce highly toxic radicals. • AgNP are involved in the inhibition of AKT pathway, which is involved in cell survival, angiogenesis, proliferation, and apoptosis. • AgNP showed biocompatible nature towards normal mouse liver and ovarian organoids while are toxic on PDTO through altering the redox homeostasis. Chemodynamic therapy (CDT) holds great promise in achieving cancer therapy through Fenton and Fenton-like reactions, which generate highly toxic reactive species. However, CDT is limited by the lower amount of catalyst ions that can decompose already existing intracellular H 2 O 2 and produce reactive oxygen species (ROS) to attain a therapeutic outcome. To overcome these limitations, a tailored approach, which utilizes dual metals cations (Ag+, Fe2+) based silver pentacyanonitrosylferrate or silver nitroprusside (AgNP) were developed for Fenton like reactions that can specifically kill cancer cells by taking advantage of tumor acidic environment without used of any external stimuli. A simple solution mixing procedure was used to synthesize AgNP as CDT agent. AgNP were structurally and morphologically characterized, and it was observed that a minimal dose of AgNP is required to destroy cancer cells with limited effects on normal cells. Moreover, comprehensive in vitro studies were conducted to evaluate antitumoral mechanism. AgNP have an effective ability to decompose endogenous H 2 O 2 in cells. The decomposed endogenous H 2 O 2 generates several different types of reactive species (•OH, O 2 •−) including peroxynitrite (ONOO−) species as apoptotic inducers that kill cancer cells, specifically. Cellular internalization data demonstrated that in short time, AgNP enters in lysosomes, avoid degradation and due to the acidic pH of lysosomes significantly generate high ROS levels. These data are further confirmed by the activation of different oxidative genes. Additionally, we demonstrated the biocompatibility of AgNP on mouse liver and ovarian organoids as an ex vivo model while AgNP showed the therapeutic efficacy on patient derived tumor organoids (PDTO). This work demonstrates the therapeutic application of silver nitroprusside as a multiple ROS generator utilizing Fenton like reaction. Thereby, our study exhibits a potential application of CDT against HGSOC (High Grade Serous Ovarian Cancer), a deadly cancer through altering the redox homeostasis. [ABSTRACT FROM AUTHOR]

After an initial benefit from tyrosine kinase inhibitors (TKI), most gastrointestinal stromal tumors (GISTs) eventually develop disease progression or secondary resistance. An altered tumor (immune)phenotype with anaplasia and morphological changes secondary to therapy have occasionally been described in the literature. We present a 52-year old patient, diagnosed with high risk, spindle-cell, GIST (CD117 positive, Pankeratin negative) in 2003, showing a c-Kit exon 11 mutation. After TKI therapy, he developed drug resistance and disease progression. Pathological assessment of the last surgical specimen showed a pure epithelioid/clear cell histology, without evidence of cellular anaplasia. Tumor cells were CD117 positive, DOG1 positive but also E-cadherin positive and Pankeratin positive, whereas molecular analysis confirmed the presence of the c-Kit exon 11 mutation, with no additional mutations. We describe an unusual case of GIST showing peculiar (immuno)phenotypic changes under therapy, different from the vast majority of therapy-driven changes, which include marked cellular pleomorphisms and KIT immunonegativity. Possible molecular explanations to understand these phenomena and a brief review of the literature are also addressed. [ABSTRACT FROM AUTHOR]

Abstract: This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms. [Copyright &y& Elsevier]

Background: Identification of the clinical behavior of atypical Spitzoid tumors with conflicting histopathologic features remains controversial. Objective: We sought to assess whether molecular findings may be helpful in the diagnostic and prognostic assessment of atypical Spitzoid tumors. Methods: A total of 38 controversial, atypical Spitzoid lesions (≥1 mm in thickness) were analyzed for clinicopathological features, chromosomal alterations by fluorescence in situ hybridization (FISH) analysis (RREB1/MYB/CCND1/CEP6), BRAF V600E mutation by allele-specific real-time polymerase chain reaction confirmed by sequencing, and H-RAS gene mutation by direct sequencing. Results: Atypical Spitzoid lesions developed in 21 female and 17 male patients (mean age 22 years). Nine patients underwent sentinel lymph node biopsy and a sentinel lymph node micrometastasis was detected in 4 of these 9 cases. Four additional patients, who did not receive a sentinel lymph node biopsy, experienced bulky lymph node metastases and one experienced visceral metastases and death. Lesions from patients with lymph node involvement showed more deep mitoses (P < .01), less inflammation (P = .05), and more plasma cells (P = .04). FISH analysis demonstrated the presence of chromosomal alterations in 6 of 25 cases. Correlation with follow-up data showed that the only case with fatal outcome showed multiple chromosomal alterations by FISH analysis. BRAFV600E mutation was detected in 12 of 16 cases (75%) and H-RAS mutation on exon 3 was found in 3 of 11 cases (27%). Limitations: Our results require validation in a larger series with longer follow-up information. Conclusions: FISH assay may be of help in the prognostic evaluation of atypical Spitzoid tumors. Diagnostic significance of BRAFV600E and H-RAS mutations in this setting remains unclear. [Copyright &y& Elsevier]

Summary: We describe a case of human immunodeficiency virus–associated T-lymphoblastic leukemia/lymphoblastic lymphoma in a 43-year-old Italian man with a history of human immunodeficiency virus infection lasting 9 years. Immunoperoxidase stains showed that neoplastic cells were positive for CD3, TdT, CD45, CD10, CD1a, CD2, CD7, CD5, and CD43 (focal). The proliferation rate was approximately 70%, assessed by Ki-67/MIB-1 staining. Flow cytometry of the marrow aspirate revealed an intermediate/cortical T-lymphoblastic phenotype: negative for surface CD3 and positive for cytoplasmic CD3, CD1a, TdT, CD2, CD7, CD5, and CD8, with partial coexpression of dimCD4. Analysis of T-cell receptor γ polymerase chain reaction products showed clonality. T-lymphoblastic leukemia/lymphoblastic lymphoma is a very rare occurrence in the clinical setting of human immunodeficiency virus infection. It is not listed in the World Health Organization classification of lymphomas associated with human immunodeficiency virus infection. Only 4 cases of human immunodeficiency virus–associated T-lymphoblastic leukemia/lymphoblastic lymphoma are reported in the current medical literature. [Copyright &y& Elsevier]

High grade serous ovarian carcinoma (HGSOC) is recognized as the most frequent type of ovarian cancer and the main cause of ovarian cancer related deaths worldwide. Although homologous recombination deficiency testing has been adopted in the clinical workflow, morphological analysis remains the main diagnostic tool. In this study Atomic Force Microscopy (AFM) was tested in standard hematoxylin and eosin (H&E) stained sections to investigate the biomechanical properties of different architectural growing patterns of HGSOC. Our results showed that AFM was able to discriminate HGSOC morphological growing patterns as well as patients' stage. Micropapillary pattern, which has been associated to poor outcome, had lower Young's moduli. In addition stage IV HGSOC was significantly softer than stage III cancers. Based on our results, AFM analysis could represent an additional tool in HGSOC morphological diagnosis as the biomechanical proprieties of HGSOC were quantitatively associated to tumor staging and architectural pattern. Conventional morphological analysis is integrated with atomic force microscopy-based tissue biomechanics in standard hematoxylin and eosin histological sections to provide a better prognostication of high grade serous ovarian cancers [Display omitted] [ABSTRACT FROM AUTHOR]

Summary: We investigated the feasibility and diagnostic agreement of a virtual slide system (VSS) in teledermatopathology. Forty-six biopsy specimens from inflammatory skin diseases were selected and scanned with a VSS at the Research Unit of Teledermatology, Medical University of Graz, Graz, Austria. Images were stored on a virtual slide server on which a specific Web application suited for telepathology (http://telederm.org/research/dermatopath/) runs. Twelve teleconsultants from 6 different countries reviewed the 46 cases, working directly on the Web application. Telediagnoses agreed with gold standard and conventional diagnosis with an average of 73% and 74%, respectively. Complete concordance among all teleconsultants with gold standard and conventional diagnosis was found in 20% of the cases. In 10 cases in which complete clinical data were missing, the average agreement of telediagnosis with gold standard diagnosis and conventional diagnosis decreased to 65% and 66%, respectively. Only 3 of 4 cases of inflammatory skin diseases were correctly diagnosed remotely with VSS. The system that we have used, despite its usability, is not completely feasible for teledermatopathology of inflammatory skin disease. Moreover, the performance seems to have been influenced by the availability of complete clinical data and by the intrinsic difficulty of the pathology of inflammatory skin diseases. [Copyright &y& Elsevier]

The scientific community, recently, has focused notable attention on the chemopreventive and therapeutic effects of dietary polyphenols for human health. Emerging evidence demonstrates that polyphenols, flavonoids and vitamins counteract and neutralize genetic and environmental stressors, particularly oxidative stress and inflammatory process closely connected to cancer initiation, promotion and progression. Interestingly, polyphenols can exert antioxidant or pro-oxidant cytotoxic effects depending on their endogenous concentration. Notably, polyphenols at high dose act as pro-oxidants in a wide type of cancer cells by inhibiting Nrf2 pathway and the expression of antioxidant vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), GPx, heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system which play an essential role in the metabolism of reactive oxygen species (ROS), detoxification of xenobiotics and inhibition of cancer progression, by inducing apoptosis and cell cycle arrest according to the hormesis approach. Importantly, mutagenesis of Nrf2 pathway can exacerbate its "dark side" role, representing a crucial event in the initiation stage of carcinogenesis. Herein, we review the hormetic effects of polyphenols and nanoincapsulated-polyphenols in chemoprevention and treatment of brain tumors via activation or inhibition of Nrf2/vitagenes to suppress carcinogenesis in the early stages, and thus inhibit its progression. Lastly, we discuss innovative preclinical approaches through mini-brain tumor organoids to study human carcinogenesis, from basic cancer research to clinical practice, as promising tools to recapitulate the arrangement of structural neuronal tissues and biological functions of the human brain, as well as test drug toxicity and drive personalized and precision medicine in brain cancer. [Display omitted] • Low dose polyphenols are chemoprotective through the activation of Nrf2 pathway and vitagenes according to the hormesis concept. • Constitutive upregulation of Nrf2, as the "dark side" , leads to brain cancer growth and chemoresistance to therapy. • Combined nano-polyphenols and chemotherapeutics are cytotoxic to cancer cells inhibiting tumor proliferation. • Mini-brain cancer organoids are an innovative tool to develop precision medicine in clinical management of brain cancer. [ABSTRACT FROM AUTHOR]

The clinical application of nanomaterials for chemodynamic therapy (CDT), which generate multiple reactive oxygen species (ROS), presents significant challenges. These challenges arise due to insufficient levels of endogenous hydrogen peroxide and catalytic ions necessary to initiate Fenton reactions. As a result, sophisticated additional delivery systems are required. In this study, a novel bimetallic copper (II) pentacyanonitrosylferrate (Cu(II)NP, Cu[Fe(CN) 5 NO]) material was developed to address these limitations. This material functions as a multiple ROS generator at tumoral sites by self-inducing hydrogen peroxide and producing peroxynitrite (ONOO-) species. The research findings demonstrate that this material exhibits low toxicity towards normal liver organoids, yet shows potent antitumoral effects on High Grade Serous Ovarian Cancer (HGSOC) organoid patients, regardless of platinum resistance. Significantly, this research introduces a promising therapeutic opportunity by proposing a single system capable of replacing the need for H 2 O 2 , additional catalysts, and NO-based delivery systems. This innovative system exhibits remarkable multiple therapeutic mechanisms, paving the way for potential advancements in clinical treatments. [Display omitted] • CuNP overcome the low endogenous H 2 O 2 level issue, due to which CDT is severely restricted by increasing the H 2 O 2 level. • CuNP provides (Fe+2, Cu+2) dual metal cations in a single system to improve the catalytic activity of Fenton reaction. • CuNP also produced ONOO− as apoptosis inducer specifically at tumoral sites. • This single system also inhibits the expression of multiple cancerous genes e.g., CuNP inhibits (SOD1, c-myc, NF-κB). [ABSTRACT FROM AUTHOR]

• Patients immunogenetics can impact tumor response to radiotherapy. • Unmet need of prognostic markers in locally advanced rectal cancer. • Two immunogenetic prognostic markers in IL17F were identified. • Tumor Regression Grade prognostic value is integrated by IL17F -rs641701 and IL17F- rs9463772. • Additional stratification criteria for the selection of an organ sparing strategy. The role of the immune system in tumor response to chemo-radiotherapy (CRT) is an emerging issue. This work aimed at identifying predictive and prognostic immunogenetic variants in LARC patients after preoperative (po)-CRT and surgery. A set of 192 polymorphisms in 34 candidate genes involved in the regulation of the immune response signalling network, was selected and analyzed in 370 LARC patients treated with po-CRT and surgery, split into a Test Set (n = 233) and a Validation Set (n = 137). Immunogenetic markers were selected based on a concordant significant effect on 2-year relapse-free survival (2-yrRFS) (bootstrapped P < 0.05) in both patients Sets. The effect of the selected immunogenetic variants on 5-year metastases-free (5yrMFS), 5-year disease-free (5yrDFS), and 10-year overall (10yrOS) survival was tested in the entire Set of 370 patients. Two immunogenetic IL17F (IL17F -rs641701 and IL17F -rs9463772) markers predictive of 2yrRFS, 5yrDFS, 5yrMFS, and 10yrOS were identified. The combination of tumor regression grade (TRG) and patients genotype for IL17F -rs641701 and IL17F -rs9463772 allowed the identification of subgroups of patients with differential prognosis in term of both 5yrDFS (HR 11.29, P -value <0.001, and HR 5.86, P-value = 0.001, respectively) and 10yrOS (HR 7.07, P -value = 0.005, and HR 6.05, P -value = 0.002, respectively). IL17F -rs641701 and IL17F -rs9463772 were highlighted as promising immunogenetic markers significantly associated with the prognosis of LARC patients. After a prospective validation of the herein reported findings, the combination of TRG and patients genotype should be considered to provide additional stratification criteria for the selection of a personalized multimodality treatment. [ABSTRACT FROM AUTHOR]

Background: Risk of relapse or progression remains high in the treatment of most patients with epithelial ovarian cancer, and development of a molecular predictor could be a valuable tool for stratification of patients by risk. We aimed to develop a microRNA (miRNA)-based molecular classifier that can predict risk of progression or relapse in patients with epithelial ovarian cancer.Methods: We analysed miRNA expression profiles in three cohorts of samples collected at diagnosis. We used 179 samples from a Multicenter Italian Trial in Ovarian cancer trial (cohort OC179) to develop the model and 263 samples from two cancer centres (cohort OC263) and 452 samples from The Cancer Genome Atlas epithelial ovarian cancer series (cohort OC452) to validate the model. The primary clinical endpoint was progression-free survival, and we adapted a semi-supervised prediction method to the miRNA expression profile of OC179 to identify miRNAs that predict risk of progression. We assessed the independent prognostic role of the model using multivariable analysis with a Cox regression model.Findings: We identified 35 miRNAs that predicted risk of progression or relapse and used them to create a prognostic model, the 35-miRNA-based predictor of Risk of Ovarian Cancer Relapse or progression (MiROvaR). MiROvaR was able to classify patients in OC179 into a high-risk group (89 patients; median progression-free survival 18 months [95% CI 15-22]) and a low-risk group (90 patients; median progression-free survival 38 months [24-not estimable]; hazard ratio [HR] 1·85 [1·29-2·64], p=0·00082). MiROvaR was a significant predictor of progression in the two validation sets (OC263 HR 3·16, 95% CI 2·33-4·29, p<0·0001; OC452 HR 1·39, 95% CI 1·11-1·74, p=0·0047) and maintained its independent prognostic effect when adjusted for relevant clinical covariates using multivariable analyses (OC179: adjusted HR 1·48, 95% CI 1·03-2·13, p=0·036; OC263: adjusted HR 3·09 [2·24-4·28], p<0·0001; and OC452: HR 1·41 [1·11-1·79], p=0·0047).Interpretation: MiROvaR is a potential predictor of epithelial ovarian cancer progression and has prognostic value independent of relevant clinical covariates. MiROvaR warrants further investigation for the development of a clinical-grade prognostic assay.Funding: AIRC and CARIPLO Foundation. [ABSTRACT FROM AUTHOR]

Background Three primary synchronous cancers in the female genital tract are extremely rare. In the literature, only four studies have described three different invasive gynecologic cancers of epithelial origin identified simultaneously in the same patient. Case presentation This is the first case in the literature that reports on triple primary ovarian, endometrial and endocervical cancers in a 38-year-old woman with a history of previously treated malignant disease (acute lymphatic leukemia). With a preoperative diagnosis of endocervical adenocarcinoma stage Ib1 (according to International Federation of Gynecology and Obstetrics—FIGO), as well as an adnexal mass, she underwent radical hysterectomy with bilateral adnexectomy. Pathologic examination of the surgical specimen revealed a mucinous adenocarcinoma of the cervix, an endometrioid adenocarcinoma of the uterine corpus, and a mucinous adenocarcinoma of the left ovary. Eighteen months after appropriate treatment, the patient is free of disease. Conclusion The incidental diagnosis of more than one tumor is often a post-operative finding, usually with the detection of low-stage neoplasms. Multiple synchronous gynecologic cancers have a better prognosis than metastatic or advanced primitive disease. In a patient with multiple neoplasms, the prognosis is determined by the tumor with the worst prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Proteolysis of the extracellular matrix (ECM) is a key event in tumor growth and progression. The breakdown of ECM can lead to the generation of bioactive fragments that promote cell growth and spread. EMILIN1, a multidomain glycoprotein expressed in several tissues, exerts a crucial regulatory function through the engagement of α4/α9 integrins. Unlike the majority of ECM molecules that elicit a proliferative program, the signals emitting from EMILIN1 engaged by α4/α9β1 integrins are antiproliferative. In this study, aimed to demonstrate if the suppressor role of EMILIN1 was related to its structural integrity, we tested the possibility that EMILIN1 could be specifically cleaved. Among the proteolytic enzymes released in the tumor microenvironment we showed that neutrophil elastase cleaved EMILIN1 in three/four major fragments. The consequence of this proteolytic process was the impairment of its anti-proliferative role. Accordingly, EMILIN1 was digested in sarcomas and ovarian cancers. Sarcoma specimens were infiltrated by neutrophils (PMNs) and stained positively for elastase. The present findings highlight the peculiar activity of PMN elastase in disabling EMILIN1 suppressor function. [Copyright &y& Elsevier]

[Display omitted] Monoacylglycerol lipase (MAGL) is an emerging therapeutic target for cancer. It is involved in lipid metabolism and its inhibition impairs many hallmarks of cancer including cell proliferation, migration/invasion and tumor growth. For these reasons, our group has recently developed a potent reversible MAGL inhibitor (MAGL23), which showed promising anticancer activities. Here in, to improve its pharmacological properties, a nanoformulation based on nanocrystals coated with albumin was prepared for therapeutic applications. MAGL23 was solubilized by a nanocrystallization method with Pluronic F-127 as surfactant into an organic solvent and was recovered as nanocrystals in water after solvent evaporation. Finally, the solubilized nanocrystals were stabilized by human serum albumin to create a smart delivery carrier. An in-silico prediction (lipophilicity, structure at different pH and solubility in water), as well as experimental studies (solubility), have been performed to check the chemical properties of the inhibitor and nanocrystals. The solubility in water increases from less than 0.01 mg/mL (0.0008 mg/mL, predicted) up to 0.82 mg/mL in water. The formulated inhibitor maintained its potency in ovarian and colon cancer cell lines as the free drug. Furthermore, the system was thoroughly observed at each step of the solubilization process till the final formulation stage by different spectroscopic techniques and a comparative study was performed to check the effects of Pluronic F-127 and CTAB as surfactants. The formulated system is favorable to release the drug at physiological pH conditions (at pH 7.4, after 24 h, less than 20% of compound is released). In vivo studies have shown that albumin-complexed nanocrystals increase the therapeutic window of MAGL23 along with a favorable biodistribution. As per our knowledge, we are reporting the first ever nanoformulation of a MAGL inhibitor, which is promising as a therapeutic system where the MAGL enzyme is involved, especially for cancer therapeutic applications. [ABSTRACT FROM AUTHOR]

The synthesis of twelve new palladium allyl complexes bearing benzimidazole-based NHC (NHC = N -heterocyclic carbene) ligands is reported. Comparing the IC 50 values of mixed NHC/PTA complexes reported in this work and their trifluoromethyl congeners recently published by our group, it appears evident that they have very similar antiproliferative activity against cancer cells but the absence of the CF 3 significantly decreases the selectivity toward them. [Display omitted] The synthesis of twelve new palladium allyl complexes bearing benzimidazole-based NHC (NHC = N -heterocyclic carbene) ligands is reported. All the complexes were characterized by NMR and elemental analysis and, in the case of complex 5c , it was possible to confirm the connectivity by single crystal X-ray diffraction. The cationic palladium allyl complexes were tested toward 5 different cancer lines, with IC 50 values generally lower than cisplatin and similar antiproliferative activity in the two ovarian cancer cell lines (A2780 and A2780 cis), suggesting a different mechanism of action from classical platinum-based anticancer drugs. Compounds equipped with a pyridine arm or with the NHC/PTA combination (PTA = 1,3,5-triaza-7-phosphaadamantane) showed a lower cytotoxicity on normal cells with respect to cancer ones. By comparing the IC 50 values of mixed NHC/PTA complexes reported in this work and their trifluoromethyl congeners recently published by our group, it appears evident that they have very similar antiproliferative activity against cancer cells but the absence of the CF 3 group significantly decreases the selectivity toward them. [ABSTRACT FROM AUTHOR]

Abstract: We analysed 21 samples of malignant fibrous histiocytoma (MFH) distinguished into the two principal morphological categories (‘spindle cell’ and the ‘pleomorphic’ subtypes). The aim of our study was to verify if a distinction between the two subclasses of MFH in terms of expression/activation of protein profiles could support and extend the morphological criteria. For this purpose, we carried out an immunohistochemical and immunoblotting analysis of proteins that could be relevant in sarcoma biology and potential diagnostic and therapeutical targets such as matrix metalloproteinases (MMPs) and molecules related to adhesive and proliferative properties. Our analysis revealed that MMP-1, MMP-9 expression and p27(kip1) cytoplasmic localisation can be considered valid parameters in the classification and potential explanation of the aggressive behaviour of this non-homogeneous group of MFH. [Copyright &y& Elsevier]

Abstract: Cell adhesion and motility are central aspects in the pathophysiology of B cell chronic lymphocytic leukemia (B-CLL), but the role of specific extracellular matrix proteins is still to be completely unveiled. Purified peripheral blood neoplastic cells of B-CLL patients migrated poorly on laminins-111,-411,-511, but showed pronounced motility on laminin (LM)-332 in a high percentage of cases. B-CLL cell motility on LM-332 was mediated by the α3β1 integrin and was preferentially observed in cells carrying a mutated IgVH gene profile. Within normal lymph nodes, LM-332 was circumscribed around blood vessels and to areas corresponding to marginal zones, where it was deposited in a pattern reminiscent of reticular fibers. Conversely, in B-CLL involved lymph nodes, a positive LM-332 reticular mesh was diffusely evident, throughout the disrupted nodal architecture. In the present study we identified LM-332 as a crucial motility-promoting factor for B-CLL lymphocytes and as a potential constituent favoring the dissemination of B-CLL lymphocytes through vascular basement membranes and possibly lymph node compartments. [Copyright &y& Elsevier]

Abstract: To analyse the risk factors for different histologic types of ovarian cancer, we conducted a case-control study. The cases included 750 women with incident, histologically confirmed invasive epithelial ovarian cancer subdivided into: 493 serous, 81 mucinous, 78 endometrioid, and 98 other histologies. The controls included 2411 women admitted to the same hospitals as cases. The odds ratios for women with three or more births, in comparison with nulliparae, were 0.6 for serous, 0.4 for endometrioid, 1.0 for mucinous and 0.7 for other histological types of ovarian cancer. Family history of ovarian/breast cancer was associated to the risk of all ovarian cancer types, except mucinous ones. Selected dietary factors were less strongly directly (meat and starch), or inversely (fish and vitamin E) related to mucinous than to other histological types of ovarian cancer. High occupational physical activity was inversely related to the risk of ovarian cancer, with no heterogeneity across histologies. In conclusion, the association of reproductive factors and of selected dietary habits was weaker for mucinous ovarian cancer than for other histologic types. [Copyright &y& Elsevier]

Emerging evidences suggest that cyclin-dependent kinase inhibitors (CKIs) can regulate cellular functions other than cell cycle progression, such as differentiation and migration. Here, we report that cytoplasmic expression of p27kip1 affects microtubule (MT) stability following cell adhesion on extracellular matrix (ECM) constituents. This p27kip1 activity is due to its ability to bind and impair the function of the MT-destabilizing protein stathmin. Accordingly, upregulation of p27kip1 or downregulation of stathmin expression results in the inhibition of mesenchymal cell motility. Moreover, high stathmin and low cytoplasmic p27kip1 expression correlate with the metastatic phenotype of human sarcomas in vivo. This study provides a functional link between proliferation and invasion of tumor cells based on diverse activities of p27kip1 in different subcellular compartments. [Copyright &y& Elsevier]

An interesting enzyme of the endocannabinoid system is monoacylglycerol lipase (MAGL). This enzyme, which metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG), has attracted great interest due to its involvement in several physiological and pathological processes, such as cancer progression. Experimental evidences highlighted some drawbacks associated with the use of irreversible MAGL inhibitors in vivo , therefore the research field concerning reversible inhibitors is rapidly growing. In the present manuscript, the class of benzoylpiperidine-based MAGL inhibitors was further expanded and optimized. Enzymatic assays identified some compounds in the low nanomolar range and steered molecular dynamics simulations predicted the dissociation itinerary of one of the best compounds from the enzyme, confirming the observed structure-activity relationship. Biological evaluation, including assays in intact U937 cells and competitive activity-based protein profiling experiments in mouse brain membranes, confirmed the selectivity of the selected compounds for MAGL versus other components of the endocannabinoid system. An antiproliferative ability in a panel of cancer cell lines highlighted their potential as potential anticancer agents. Future studies on the potential use of these compounds in the clinical setting are also supported by the inhibition of cell growth observed both in cancer organoids derived from high grade serous ovarian cancer patients and in pancreatic ductal adenocarcinoma primary cells, which showed genetic and histological features very similar to the primary tumors. Image 1 • 24 novel benzoylpiperidine derivatives were synthesized and tested for their MAGL inhibition activity. • Compounds 21a,b and 22a,b are potent and selective reversible MAGL inhibitors. • Compounds 21a,b and 22a,b reduced the proliferation of a series of cancer cell lines. [ABSTRACT FROM AUTHOR]

Diabetes is a pathological condition that requires the continuous monitoring of glucose level in the blood. Its control has been tremendously improved by the application of point-of-care devices. Conventional enzyme-based sensors with electrochemical and optical transduction systems can successfully measure the glucose concentration in human blood, but they suffer from the low stability of the enzyme. Non-enzymatic wearable electrochemical and optical sensors, with low-cost, high stability, point-of-care testing and online monitoring of glucose levels in biological fluids, have recently been developed and can help to manage and control diabetes worldwide. Advances in nanoscience and nanotechnology have enabled the development of novel nanomaterials that can be implemented for the use in enzyme-free systems to detect glucose. This review summarizes recent developments of enzyme-free electrochemical and optical glucose sensors, as well as their respective wearable and commercially available devices, capable of detecting glucose at physiological pH conditions without the need to pretreat the biological fluids. Additionally, the evolution of electrochemical glucose sensor technology and a couple of widely used optical detection systems along with the glucose detection mechanism is also discussed. Finally, this review addresses limitations and challenges of current non-enzymatic electrochemical, optical, and wearable glucose sensor technologies and highlights opportunities for future research directions. • Recent advances of enzyme-less glucose sensors at physiological pH are reviewed. • Fundamentals of electrochemical and optical glucose sensors are described. • Advances in the development of nanomaterials and molecular recognition elements are discussed. • Wearable glucose sensors for continuous glucose monitoring are reviewed. • The perspective of electrochemical, optical, and wearable glucose sensors is envisioned. [ABSTRACT FROM AUTHOR]

Abstract: We report a case of left atrial cardiac myxoma harbouring an incidental atypical B-cell lymphoid proliferation. Histology disclosed classic myxoma cells embedded in a mucopolysaccharide-rich matrix and a micronodular atypical lymphoid proliferation under the surface of the mass. Myxoma cells were immunoreactive for calretinin, while lymphoid cells expressed B lineage markers (CD 20+, CD79a), without evidence of clonality. Moreover, they were LMP1 positive; EBNA2 negative; KSHV/HHV8 negative; and, by in situ hybridization, EBER/Epstein–Barr virus (EBV) positive and Kappa and Lambda negative. According to the 2008 WHO schemes, the present case shares close similarities either with diffuse large B-cell lymphomas growing in the context of long-standing chronic inflammation or with primary effusion lymphomas, solid variant, both associated with EBV infection. This is the sixth case of incidental atypical lymphoid proliferation discovered in a cardiac myxoma reported so far. The optimal treatment of such lesions remains undefined, but their clinical course is indolent. After an accurate staging workup, without any postsurgical treatment, the patient we observed has been well with no recurrence of the disease at 6 years of follow-up. [Copyright &y& Elsevier]