Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

Cocoa by-product inclusion in dairy sheep diet: effect on sensory, volatile and antioxidant properties of cheese.

The possibility of inclusion of agro-industrial by-products in the diet of small ruminants represents both an economical and an environmental strategy for reducing waste management by industries and the cost of feeding as well as the impact of livestock farming. Large amounts of wastes from the cocoa industry are annually produced with a considerable part represented by cocoa bean shells, considered a suitable ingredient to be included in the diet of ruminants within the limits established by European legislation. The aim of this study was to assess the effect of including cocoa bean shells in the diet of dairy sheep on the sensory, volatile, and antioxidant properties of cheese. To this purpose, 20 Comisana lactating ewes were randomly assigned to 2 experimental groups: control (CTRL) and cocoa bean shells (CBS), and received alfalfa hay ad libitum and 800g of conventional (CTRL) or experimental (CBS) concentrate containing 11.7% CBS to partially replace corn and barley of the CTRL concentrate. Bulk milk collected from each group was used to produce a total of 15 cheeses per group, obtained in 5 different days of cheese-making (3 cheeses a day per group). After 60 d of aging, each cheese of each experimental group was sampled for the analyses. The results on chemical composition revealed a greater monounsaturated fatty acids content and an increase in the nutritional indices suggesting a favorable role of cocoa bean shells dietary inclusion on the nutritive value of the cheese. The cheese sensory profile was affected by the cocoa bean shells inclusion, with more pronounced appearance, odor, aroma, and taste attributes in the product. The volatile profile showed only a few significant differences, mainly related to the cheese ripening process, and no differences were found in α-tocopherol contents in cheese fat between the 2 groups. Therefore, the coca bean shells inclusion in the diet of dairy sheep allowed to obtain a good quality cheese, without altering the characteristics associated with the typical profiles of sheep cheese. Furthermore, the use of this by-product could contribute to decrease feed costs and waste management, representing a good practice for increasing the sustainability of dairy products.

First Simultaneous Determination of Inclusive and Exclusive |V_{ub}|.

The first simultaneous determination of the absolute value of the Cabibbo-Kobayashi-Maskawa matrix element V_{ub} using inclusive and exclusive decays is performed with the full Belle data set at the ϒ(4S) resonance, corresponding to an integrated luminosity of 711 fb^{-1}. We analyze collision events in which one B meson is fully reconstructed in hadronic modes. This allows for the reconstruction of the hadronic X_{u} system of the semileptonic b→uℓν[over ¯]_{ℓ} decay. We separate exclusive B→πℓν[over ¯]_{ℓ} decays from other inclusive B→X_{u}ℓν[over ¯]_{ℓ} and backgrounds with a two-dimensional fit that utilizes the number of charged pions in the X_{u} system and the four-momentum transfer q^{2} between the B and X_{u} systems. Combining our measurement with information from lattice QCD and QCD calculations of the inclusive partial rate as well as external experimental information on the shape of the B→πℓν[over ¯]_{ℓ} form factor, we determine |V_{ub}^{excl}|=(3.78±0.23±0.16±0.14)×10^{-3} and |V_{ub}^{incl}|=(3.88±0.20±0.31±0.09)×10^{-3}, respectively, with the uncertainties being the statistical error, systematic errors, and theory errors. The ratio of |V_{ub}^{excl}|/|V_{ub}^{incl}|=0.97±0.12 is compatible with unity.

Search for the Lepton Flavor Violating Decays B

We present a search for the lepton flavor violating decays B^{+}→K^{+}τ^{±}ℓ^{∓}, with ℓ=(e,µ), using the full data sample of 772×10^{6} BB[over ¯] pairs recorded by the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. We use events in which one B meson is fully reconstructed in a hadronic decay mode. We find no evidence for B^{±}→K^{±}τℓ decays and set upper limits on their branching fractions at the 90% confidence level in the (1-3)×10^{-5} range. The obtained limits are the world's best results.

Hematocolpos due to imperforate hymen: a case report and literature systematic review.

INTRODUCTION AND HYPOTHESIS: Hematocolpos is a rare condition, where menstrual blood fills the vagina, instead of being expelled, due to a series of uterovaginal pathologies, the most frequent of which is the imperforate hymen. To date, few cases of hematocolpos have been reported in the literature. METHODS: We report a case of hematometrocolpos due to imperforate hymen initially misdiagnosed as constipation and subsequently as ovarian mass; moreover, the present study undertakes a systematic review of studies on hematometrocolpos due to imperforate hymen to synthesize available knowledge on epidemiology, diagnosis, and management about this rare condition. RESULTS: A total of 35 studies, describing 61 patients, were identified. The presence of hematocolpos should be suspected in premenarchal patients complaining of low abdominal pain, abdominal swelling, and urinary retention. Genital examination disclosing a tender, pale hymen and ultrasound represent a useful tool for diagnosis. The goal of the management is to timely perform hymenotomy to drain the hematocolpos, followed by hymenectomy to prevent recurrence. Follow-up is needed to diagnose possible recurrences. CONCLUSIONS: In the case of an adolescent girl complaining of genital pain associated with primary amenorrhea, hematocolpos due to imperforate hymen should be suspected.

Striatal glutamatergic hyperactivity in Parkinson's disease.

Glutamatergic hyperactivity in the nucleus striatum, the main basal ganglia input, has been involved in the progression of Parkinson's disease (PD) and the onset of L-Dopa-induced dyskinesias (LIDs). Abnormalities in the spiny projection neurons excitability and firing, and in the overactivity of glutamate transmission found in animal models of PD, pointed to the synaptic dysfunctions as a primary target to counteract alterations before overt neurodegeneration, conferring a key role to striatal glutamatergic transmission in the early phases of the disease. The present paper provides an overview of the evidence that glutamatergic overactivity is a critical mechanism underlying different PD-associated striatal alterations in early and advanced symptomatic stages of the disease. These aberrant changes, under L-Dopa therapy, lead to a more complex synaptopathy that involves other neurotransmitter systems and persistent modifications to generate LIDs. The review discusses the main changes in glutamatergic functions found in PD preclinical models and clinical studies and an update of the current pharmacological strategies to modulate the glutamatergic systems at the pre- and postsynaptic levels will be provided.

Comparison of BICAMS and ARCS for assessment of cognition in multiple sclerosis and predictive value of employment status.

BACKGROUND: Cognitive impairment is common in multiple sclerosis (MS) but not adequately monitored by Expanded Disability Status Scale assessment. The Audio Recorded Cognitive Screen (ARCS) and Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) are easy-to-use tools to assess cognitive function in clinical practice. OBJECTIVE: To compare the sensitivity of ARCS to BICAMS and their relative predictive value for employment status. METHODS: MS patients and healthy controls were assessed using the ARCS and the BICAMS consecutively. Receiver Operating Characteristic (ROC) curve analyses were used to compare the two tests. A step-wise, logistic regression analysis was used to identify the cognitive test(s) that best predicted employment status and quality of life. RESULTS: Total ARCS, memory and attention domain scores were moderately correlated with all BICAMS tests (r = 0.3-0.5; P ≤ 0.05). Total ARCS predicts cognitive impairment with good sensitivity and specificity relative to the BICAMS tests (AUC = 0.8; P = 0.00045). Total ARCS detects higher levels of impairment than BICAMS in MS patients (44% versus 21%). The memory domain of the ARCS and the BVMT-R were the best predictors of employment status (OR = 1.12 and 1.14, P < 0.05). CONCLUSION: BICAMS and ARCS have comparable sensitivity for cognitive impairment in MS. Memory assessment from either tests is the best predictor of employment status; however, the BICAMS is a better predictor of work productivity.

Constant rate infusion of tramadol in isoflurane-anesthetized pigs undergoing experimental surgery.

The purpose of this study was to investigate the effect of tramadol (TM) (2 mg/kg) administered intramuscularly (IM) followed by a constant rate infusion (CRI) of TM (2 mg/kg/h) in pigs. Sixteen pigs undergoing experimental surgery were premedicated IM with a combination of alfaxalone (5 mg/kg) and midazolam (0.5 mg/kg). Anaesthesia was induced with propofol (2 mg/kg) intravenously (IV) and maintained with isoflurane. Pigs were randomly assigned to one of the two following groups: Group 1 (n=8): received a loading dose of TM (2 mg/kg) followed by a CRI of TM (2 mg/kg/h); Group 2 (n=8): a loading dose of TM (2 mg/kg) followed by a CRI of lactated Ringer's solution (2 ml/kg/h). Heart rate (HR), respiratory rate (RR), rectal temperature (RT), haemoglobin oxygen saturation (SpO2), fraction of inspired oxygen (FIO2), end-tidal concentration of isoflurane (FEISO), end-tidal carbon dioxide concentration (FECO2), pH, arterial oxygen partial pressure (PaO2), arterial carbon dioxide partial pressure (PaCO2) and bicarbonate concentration (HCO3-) were recorded immediately after loss of righting reflex (T=0 min) and at 15-min intervals over a period of 60 min. Continuous data were analysed using a repeated- -measure analysis of variance (ANOVA) and a p-value ⟨0.05 was considered significant. HR, RR and FEISO were significantly lower (p⟨0.05) in Group 1 at T30 and T45, which corresponded to the time of the most intense surgical stimulation. The results suggest that the TM infusion minimizes the HR and RR response, slightly reducing isoflurane requirements and determining a superior perioperative analgesia.

Polarization dependence of second harmonic generation from plasmonic nanoprism arrays.

The second order nonlinear optical response of gold nanoprisms arrays is investigated by means of second harmonic generation (SHG) experiments and simulations. The polarization dependence of the nonlinear response exhibits a 6-fold symmetry, attributed to the local field enhancement through the excitation of the surface plasmon resonances in bow-tie nanoantennas forming the arrays. Experiments show that for polarization of the input light producing excitation of the plasmonic resonances in the bow-tie nanoantennas, the SHG signal is enhanced; this despite the fact that the linear absorption spectrum is not dependent on polarization. The results are confirmed by electrodynamic simulations which demonstrate that SHG is also determined by the local field distribution in the nanoarrays. Moreover, the maximum of SHG intensity is observed at slightly off-resonance excitation, as implemented in the experiments, showing a close relation between the polarization dependence and the structure of the material, additionally revealing the importance of the presence of non-normal electric field components as under focused beam and oblique illumination.

The causal role of the left parietal lobe in facilitation and inhibition of return.

Following non-informative peripheral cues, responses are facilitated at the cued compared to the uncued location at short cue-target intervals. This effect reverses at longer intervals, giving rise to Inhibition of Return (IOR). The integration-segregation hypothesis (Lupiáñez, 2010) suggests that peripheral cues always produce an onset-detection cost regardless the behavioral cueing effect that is measured - either facilitation or IOR. In the present study, we used transcranial magnetic stimulation (TMS) to investigate the causal contribution of this detection cost to performance. We used a cueing paradigm with a target discrimination task that was preceded by a non-informative peripheral cue. The presence-absence of a central intervening event was manipulated. Online TMS to the left superior parietal lobe (compared to an active vertex stimulation) lead to an overall more positive effect (faster responses for cued as compared to uncued trials), by putatively impairing the detection cost contribution to performance. The data revealed a strong association between overall RT and the TMS effect, and also between overall RT and the integrity of the first branch of the left superior longitudinal fascicule. These results have critical implications not only for the open debate about the mechanism/s underlying spatial orienting effects, but also for the growing literature demonstrating that white matter connectivity is crucial for explaining inter-individual behavioral variability.

Nutraceutical Properties of Herbal Infusions from Six Native Plants of Argentine Patagonia.

Six native plants of South America traditionally consumed in the Patagonian region (southern Argentina and Chile), namely: Adesmia boronioides Hook. f., Apium australe Thouars, Buddleja globosa Hope, Drimys andina (Reiche) R. Rodr. & Quezada, Dysphania multifida L. and Solidago chilensis Meyen were investigated to determine the nutraceutical properties of infusions of their aerial parts. The infusions were characterized in terms of their antioxidant activity, phenolic and flavonoid content, profile of phenolic compounds, general toxicity and cytotoxicity on two different human cell lines: T84 (derived from colon cancer) and HTR8/SVneo (not derived from cancer). Twenty-nine compounds, mainly phenolic acids and flavonoids, were identified. This is the first analysis of phenolic compounds in infusions from native plants of Patagonia. D. andina, B. globosa and S. chilensis showed high levels of antioxidants, even higher than those of Green Tea. The content of phenolic compounds correlated significantly with the antioxidant activity of the samples analyzed. The toxicity test indicated that the use of A. australe, B. globosa and D. multifida seems safe, but a moderate consumption is suggested for A. boronioides, D. andina and S. chilensis until more exhaustive and long-term results are available. Moreover, A. boronioides and S. chilensis showed anticancer potential due to their antiproliferative activity on human cancer cell lines.

Skin complications of insulin injections: A case presentation and a possible explanation of hypoglycaemia.

We are willing to report the case of a woman with type 2 diabetes treated with insulin, 4 shots a day, referring to us for 2 very large pigmented abdominal lipo-hypertrophy (LH) areas due to incorrect injection technique. The ultrasound examination showed the presence offluidwithin both LH lesions. Fluid examination showed insulin concentrations 13 times higher thancirculating ones. A12-month longstructured training on correct injection techniques normalized metabolic control and took rid of all sudden severe hypoglycemic episodes and the wide glycemic variability. In fact, both LH areas disappeared became softer and slightly smaller and got fluid-free. This is the first case documenting the presence of sort of an insulin reservoir within LH lesions and fluid reabsorption can explain the disappearance of hypoglycemic episodes and the improvement of glycemic control.

The Human Odontoblast Cell Layer and Dental Pulp Proteomes and N-Terminomes.

The proteome and N-terminome of the human odontoblast cell layer were identified for the first time by shotgun proteomic and terminal amine isotopic labeling of substrates (TAILS) N-terminomic analyses, respectively, and compared with that of human dental pulp stroma from 26 third molar teeth. After reverse-phase liquid chromatography-tandem mass spectrometry, >170,000 spectra from the shotgun and TAILS analyses were matched by 4 search engines to 4,888 and 12,063 peptides in the odontoblast cell layer and pulp stroma, respectively. Within these peptide groups, 1,543 and 5,841 protein N-termini, as well as 895 and 2,423 unique proteins, were identified with a false discovery rate of ≤1%. Thus, the human dental pulp proteome was expanded by 974 proteins not previously identified among the 4,123 proteins in our 2015 dental pulp study. Further, 222 proteins of the odontoblast cell layer were not found in the pulp stroma, suggesting many of these proteins are synthesized only by odontoblasts. When comparing the proteomes of older and younger donors, differences were more apparent in the odontoblast cell layer than in the dental pulp stroma. In the odontoblast cell layer proteome, we found proteomic evidence for dentin sialophosphoprotein, which is cleaved into dentin sialoprotein and dentin phosphoprotein. By exploring the proteome of the odontoblast cell layer and expanding the known dental pulp proteome, we found distinct proteome differences compared with each other and with dentin. Moreover, between 61% and 66% of proteins also occurred as proteoforms commencing with a neo-N-terminus not annotated in UniProt. Hence, TAILS increased proteome coverage and revealed considerable proteolytic processing, by identifying stable proteoforms in these dynamic dental tissues. All mass spectrometry raw data have been deposited to ProteomeXchange with the identifier , with the accompanying metadata at Mendeley Data ( https://data.mendeley.com/datasets/b57zfh6wmy/1 ).

Penultimate deglacial warming across the Mediterranean Sea revealed by clumped isotopes in foraminifera.

The variability of seawater temperature through time is a critical measure of climate change, yet its reconstruction remains problematic in many regions. Mg/Ca and oxygen isotope (δ 18OC) measurements in foraminiferal carbonate shells can be combined to reconstruct seawater temperature and δ 18O (δ 18OSW). The latter is a measure of changes in local hydrology (e.g., precipitation/evaporation, freshwater inputs) and global ice volume. But diagenetic processes may affect foraminiferal Mg/Ca. This restricts its potential in many places, including the Mediterranean Sea, a strategic region for deciphering global climate and sea-level changes. High alkalinity/salinity conditions especially bias Mg/Ca temperatures in the eastern Mediterranean (eMed). Here we advance the understanding of both western Mediterranean (wMed) and eMed hydrographic variability through the penultimate glacial termination (TII) and last interglacial, by applying the clumped isotope (Δ 47) paleothermometer to planktic foraminifera with a novel data-processing approach. Results suggest that North Atlantic cooling during Heinrich stadial 11 (HS11) affected surface-water temperatures much more in the wMed (during winter/spring) than in the eMed (during summer). The method's paired Δ 47 and δ 18OC data also portray δ 18OSW. These records reveal a clear HS11 freshwater signal, which attenuated toward the eMed, and also that last interglacial surface warming in the eMed was strongly amplified by water-column stratification during the deposition of the organic-rich (sapropel) interval known as S5.

Bioimpedance analysis, metabolic effects and safety of the association Berberis aristata/Bilybum marianum: a 52-week double-blind, placebo-controlled study in obese patients with type 2 diabetes.

Berberine, a quaternary isoquinoline alkaloid present in Berberis aristata, is well known in terms of cholesterol-lowering, hypoglycemic, and insulin sensitizing effects. Because of its low oral bioavailability, to improve intestinal absorption it has been recently combined with silymarin (Silybum marianum). The aim of our placebo controlled study was to evaluate the effects of its association with silymarin on abdominal fat in overweight/obese patients with type 2 diabetes mellitus (T2DM). To do so, 136 obese subjects with T2DM and metabolic syndrome were analyzed for fasting blood glucose and insulin, Insulin Resistance index according to the Homeostatic Model Assessment (HOMA-R), total, HDL and LDL cholesterol, triglycerides, uric acid, BMI, waist circumference, waist to hip ratio and underwent bioelectrical impedance to assess % of abdominal fat. All the above-mentioned parameters, as recorded at enrollment, after 6 months and at the end of the study, had significantly improved in the BBR-treated group in respect to baseline and to the control group. A validated national cardiovascular risk score also improved significantly after BBR treatment in respect to placebo. Our results point to a clinically significant effect in obese people with T2DM and metabolic syndrome. Moreover, for the first time, they provide evidence of a significant uric acid lowering activity as an additive beneficial effect of the association BBR + silymarin.

Long-term outcomes in ypT0 rectal cancers: An international multi-centric investigation on behalf of Italian Society of Surgical Oncology Young Board (YSICO).

AIM: To investigate the outcome and pattern of survivals of rectal cancer patients presenting a complete or nearly complete tumor response after neo-adjuvant treatment. METHODS: Young surgeons <40 years old affiliated to the Italian Society of Surgical Oncology (YSICO) from 13 referral centers for colorectal cancer treatment, were invited to participate a retrospective study. Records from patients treated from 2005 to 2015 with a pathological diagnosis of ypT0/ypTis were retrieved and pooled in a common data-base for statistical purposes. All clinical and pathological variables were reviewed. Univariate and multivariate analyses were conducted with the end-point of survivals. RESULTS: Two hundreds and sixty-one patients were analyzed including 237 ypT0 and 24 ypTis. Nodal positive patients were 8.7%. More than sixty-six percent of the patients did not perform adjuvant chemotherapy, with a statistical difference comparing N0 versus N+ patients (66.8% vs 40.9%, p 0.02). Mean follow-up was of 47.6 months. Twenty-two relapses were observed, 91.6% at a distant site. The mean time to recurrence was of 35.3 months. On univariate analysis, the use of adjuvant chemotherapy correlated with better OS exclusively in ypT0N + patients and not in ypT0N0. Univariate and multivariate analyses documented nodal positivity as the only prognostic factor correlated with a worse OS. CONCLUSION: Recurrences were mostly diagnosed at a distant site and within the third year of follow-up. Nodal positivity was the only variable independently correlated with a worse OS. Univariate analysis documented a benefit for the use of adjuvant chemotherapy treatment exclusively in ypT0N + rectal cancers.

Tagged ATG8-Coding Constructs for the In Vitro and In Vivo Assessment of ATG4 Activity.

Autophagy is a catabolic pathway, which mediates the degradation of cytoplasmic components and sustains many essential cellular functions. More than 30 genes have been involved in different aspects of this essential process in simple eukaryotes as yeast. Among these genes, those coding for members of the Atg4-Atg8 proteolytic system have acquired a high degree of complexity throughout evolution. Contrasting with the situation in unicellular eukaryotes, in which the system is composed by just a single protease (Atg4) and a single substrate (Atg8), evolution has led to the presence of several members for both Atg4 and Atg8 families in multicellular organisms. In human cells, there are four Atg4 proteases and six Atg8 substrates, which have probably evolved to cope with specific requirements for autophagic pathway in more complex scenarios. Despite these considerations, the reasons for the evolutionarily acquired complexity of this proteolytic system are still not completely understood. In this work, we describe two different applications of a relatively simple but useful technique to analyze protease-substrate specificity of this system in mammalian cells. By using the described technique, it is possible to determine the cellular efficiency in the initial cleavage for each of the Atg8 family members in diverse experimental settings both in cultured cells and live laboratory mice.

Controlling second-harmonic generation at the nanoscale with monolithic AlGaAs-on-AlOx antennas.

We review recent achievements in the field of nanoscale nonlinear AlGaAs photonics based on all-dielectric optical antennas. After discussing the motivation and main technological challenges for the development of an AlGaAs monolithic platform for χ (2) nonlinear nanophotonics, we present numerical and experimental investigations of the second-order nonlinear response and physical reasons for high efficiency of second-order nonlinear interactions in the AlGaAs nano-antennas. In particular, we emphasize the role of the dipolar resonances at the fundamental frequency and the multipolar resonances at the second harmonic wavelength. We also discuss second-harmonic generation directionality and show possible strategies to engineer the radiation pattern of nonlinear antennas.