A Submarine Journey: The Pyrrole-Imidazole Alkaloids †

In his most celebrated tale “The Picture of Dorian Gray”, Oscar Wilde stated that “those who go beneath the surface do so at their peril”. This sentence could be a prophetical warning for the practitioner who voluntarily challenges himself with trying to synthesize marine sponge-deriving pyrrole-imidazole alkaloids. This now nearly triple-digit membered community has been growing exponentially in the last 20 years, both in terms of new representatives and topological complexity – from simple, achiral oroidin to the breathtaking 12-ring stylissadines A and B, each possessing 16 stereocenters. While the biosynthesis and the role in the sponge economy of most of these alkaloids still lies in the realm of speculations, significant biological activities for some of them have clearly emerged. This review will account for the progress in achieving the total synthesis of the more biologically enticing members of this class of natural products

Malignancies and Biosensors: A Focus on Oral Cancer Detection through Salivary Biomarkers

Oral cancer is among the deadliest types of malignancy due to the late stage at which it is usually diagnosed, leaving the patient with an average five-year survival rate of less than 50%. The booming field of biosensing and point of care diagnostics can, in this regard, play a major role in the early detection of oral cancer. Saliva is gaining interest as an alternative biofluid for non-invasive diagnostics, and many salivary biomarkers of oral cancer have been proposed. While these findings are promising for the application of salivaomics tools in routine practice, studies on larger cohorts are still needed for clinical validation. This review aims to summarize the most recent development in the field of biosensing related to the detection of salivary biomarkers commonly associated with oral cancer. An introduction to oral cancer diagnosis, prognosis and treatment is given to define the clinical problem clearly, then saliva as an alternative biofluid is presented, along with its advantages, disadvantages, and collection procedures. Finally, a brief paragraph on the most promising salivary biomarkers introduces the sensing technologies commonly exploited to detect oral cancer markers in saliva. Hence this review provides a comprehensive overview of both the clinical and technological advantages and challenges associated with oral cancer detection through salivary biomarkers

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Novel Polymeric Composite TPPS/s-PEEK Membranes for Low Relative Humidity PEFC

Composite membranes based on different wt percentages of meso-tetrakis-(4-sulfonatophenyl)porphyrin (TPPS) embedded in a medium sulfonation degree (50%) sulfonated poly(etheretherketone) (s-PEEK) were investigated. The successful introduction of porphyrin into the membranes and the characterization of its different species into the membrane ionic domains were carried out by spectroscopic techniques. Moreover, the effect of TPPS arrangement was investigated in terms of water retention, proton conductivity and fuel cell performance at low relative humidity (RH). It was found that the introduction of this porphyrin induces a variation of the chemical-physical parameters, such as ion exchange capacity (IEC), water up-take (Wup %) λ and proton concentration ([H+]), attributable to the interactions that occur between the sulfonic groups of the polymer and the nitrogen sites of TPPS. The TPPS, in its J-aggregated form, actively participates in the proton conduction mechanism, also maintaining the adequate water content in more drastic conditions (80 °C and 50% RH). A maximum power density value of 462 mW cm−2 was obtained for the s-PEEK membrane, with a 0.77 wt % content of TPPS. This evidence suggests that the presence of J-aggregates in the proton conduction channels maintains a good hydration, even if a drastic reduction of the RH of the reactant gases occurs, preventing the membrane from a dry-out effect

The Metabolic Signature of Macrophage Responses

Macrophages are a heterogeneous population of immune cells playing several and diverse functions in homeostatic and immune responses. The broad spectrum of macrophage functions depends on both heterogeneity and plasticity of these cells, which are highly specialized in sensing the microenvironment and modify their properties accordingly. Although it is clear that macrophage phenotypes are difficult to categorize and should be seen as plastic and adaptable, they can be simplified into two extremes: a pro-inflammatory (M1) and an anti-inflammatory/pro-resolving (M2) profile. Based on this definition, M1 macrophages are able to start and sustain inflammatory responses, secreting pro-inflammatory cytokines, activating endothelial cells, and inducing the recruitment of other immune cells into the inflamed tissue; on the other hand, M2 macrophages promote the resolution of inflammation, phagocytose apoptotic cells, drive collagen deposition, coordinate tissue integrity, and release anti-inflammatory mediators. Dramatic switches in cell metabolism accompany these phenotypic and functional changes of macrophages. In particular, M1 macrophages rely mainly on glycolysis and present two breaks on the TCA cycle that result in accumulation of itaconate (a microbicide compound) and succinate. Excess of succinate leads to Hypoxia Inducible Factor 1α (HIF1α) stabilization that, in turn, activates the transcription of glycolytic genes, thus sustaining the glycolytic metabolism of M1 macrophages. On the contrary, M2 cells are more dependent on oxidative phosphorylation (OXPHOS), their TCA cycle is intact and provides the substrates for the complexes of the electron transport chain (ETC). Moreover, pro- and anti-inflammatory macrophages are characterized by specific pathways that regulate the metabolism of lipids and amino acids and affect their responses. All these metabolic adaptations are functional to support macrophage activities as well as to sustain their polarization in specific contexts. The aim of this review is to discuss recent findings linking macrophage functions and metabolis

Poly(ADP-ribose) polymerase inhibition in cancer therapy:Are we close to maturity?

Background: During the last few years an increasing number of poly(ADP-ribose) polymerase (PARP) inhibitors have been appearing in the context of cancer therapy. This is mainly due to a better knowledge of the best-characterized member of the PARP family of enzymes, PARP-1, further reinforced by the recognition of the clinical benefits arising from its inhibition. Objective/method: The aim of this review is to give the reader an update on PARP inhibition in cancer therapy, by covering both the scientific (SciFinder® search) and the patent literature (Chemical Abstract®/ Derwent® search) published recently (2005 - 2008). Conclusions: More patient-compliant orally available PARP-1 inhibitor clinical candidates, along with their possible use as single agents in specific, molecularly defined cancer indications, increase the expectations for this therapeutic approach. The growing understanding of the biological role of other PARPs, such as Tankyrase 1, may be of interest as new potential targets. Besides the classical NAD-mimicking pharmacophore, additional compounds, which either do not resemble nicotinamide or exploit different binding sites, are emerging.</p

Effect of a new oral contraceptive with estradiol valerate/dienogest on carbohydrate metabolism

Background: Insulin resistance may be induced by both the estrogen and progestin component in hormonal contraception. When estrogen dose is reduced from 50 to 20 mcg, the extent of hyperinsulinemia decreases. Recently, the oral combination contraceptive (COC) containing estradiol valerate (E2V) in combination with dienogest (DNG) was developed in a new estrogen step-down, progesterone step-up dosing strategy (Qlaira, Bayer Healthcare Pharmaceuticals). This study was conducted to evaluate of the effect of a 3-month treatment with E2V/DNG on carbohydrate metabolism in women with polycystic ovarian syndrome (PCOS) and insulin resistance. Study Design: Study consisted of subjects attending the gynecological clinic of Siena or Pisa, with PCOS and insulin resistance, and without contraindications for the use of COCs. PCOS females (n=20) aged 18 to 33 years were treated with a contraceptive formulation containing E2V/DNG for 3 months. Before treatment and during the third month of therapy, body mass index (BMI) measurement and an oral glucose tolerance test (OGTT) were performed. Results: Median values of insulin after treatment were lower than median values before treatment. In particular, the median value of insulin at To was reduced by 54.6% (p&lt;.001), and the mean difference between time 0 and 30 min was significantly reduced [42.96 (9.99) mU/mL vs 38.00 (15.10) mU/mL; p&lt;.05]. Homeostasis model assessment of insulin resistance levels were significantly decreased following treatment. OGTT after treatment revealed median fasting glucose levels to be stable (p=.895) at T-0. At T-30, T-60, T-120 and T-180 min, glucose median values were moderately reduced in comparison to median values before treatment. No significant difference was observed between median BMI values before [26 (4.8) kg/m(2)] and after treatment [26 (3.7) kg/m(2)]. Conclusions: Median insulin levels at T-0 and the mean difference between time 0 and 30 of insulin following OGTT were significantly reduced than values before treatment with E2V/DNG for 3 months. Median BMI and glucose levels were not significantly modified. Natural estradiol and nonandrogenic progestogen in the Qlaira formulation could be recommended as an oral contraceptive in women with PCOS who are insulin resistant or who are overweigh

Effects of oral contraceptives on markers of hyperandrogenism and SHBG in women with polycistic ovary sindrome

Background: This randomized study's aim was to compare the effect of four oral contraceptives (OCs) containing 30 mcg of ethinylestradiol (EE) and different progestogens [drospirenone, (DRSP), chlormadinone acetate (CMA), desogestrel (DSG), gestodene (GSD)] on biochemical and hormonal parameters of hyperandrogenism and sex hormone-binding globulin (SHBG) in women with polycystic ovary syndrome (PCOS). Study Design: Forty women with PCOS (age 16–35 years) were recruited and randomly assigned to one of four treatment groups of 10 women each, treated, respectively, with 3 mg DRSP/30 mcg EE (Yasmin, Bayer Shering), 2 mg CMA/30 mcg EE (Belara, Grunenthal), 75 mcg GSD/30 mcg EE (Minulet, Wyeth Lederle) and 150 mcg DSG/30 mcg EE (Practil 21, Organon Italia). Blood samples were obtained on day 6-8 of the control cycle and day 6-8 of the third treatment cycle for assay of the following hormones: androsteredione (A), total testosterone (T), free T, SHBG, dehydroepiandrosterone sulphate (DHEAS). Results: In all groups, mean concentrations of free T, total T and A dropped by 40-60%, and concentrations of DHEAS dropped by 20–50%. Formulations with DRSP and CMA caused a greater reduction of androgens and a progressive increase in serum concentrations of SHBG than those with DSG and GSD. Conclusions: Clinical studies need to be performed to determine effects of these OCs upon clinical signs of hyperandrogenism

Efficacy of Kinematic Parameters for Assessment of Temporomandibular Joint Function and Disfunction: A Systematic Review and Meta-Analysis

The aim of this review was to answer the following PICO question: &ldquo;Do TMJ kinematic parameters (intervention and comparison) show efficacy for assessment of mandibular function (Outcome) both in asymptomatic and TMD subjects? (Population)&rdquo;. PubMed, Scopus, Web of Science, Embase, Central databases were searched. The inclusion criteria were (1) performed on human, (2) English only, (3) on healthy, symptomatic or surgically altered TMJ, (4) measured dynamic kinematics of mandible or TMJ (5) with six degrees of freedom. To assess the Risk of Bias, the Joanna Briggs Institute tool for non-randomised clinical studies was employed. A pairwise meta-analysis was carried out using STATA v.17.0 (Stata). The heterogeneity was estimated using the Q value and the inconsistency index. Ninety-two articles were included in qualitative synthesis, nine studies in quantitative synthesis. The condylar inclination was significantly increased in female (effect size 0.03&deg;, 95% CI: &minus;0.06, 0.12, p = 0.00). Maximum mouth opening (MMO) was increased significantly in female population in comparison with males (effect size 0.65 millimetres (0.36, 1.66). Incisor displacement at MMO showed higher values for control groups compared with TMD subjects (overall effect size 0.16 millimetres (&minus;0.37, 0.69). Evidence is still needed, considering the great variety of devices and parameters used for arthrokinematics. The present study suggests standardising outcomes, design, and population of the future studies in order to obtain more reliable and repeatable values