SINTESI DI INIBITORI DELLA LATTATO DEIDROGENASI 5 UMANA A STRUTTURA N-IDROSSIINDOL-2-CARBOSSILICA

Many studies have demonstrated the presence of regions at very low oxygen concentration (hypoxia) in solid tumors; so during the tumoural progression only cells that change their metabolism and switch to glycolytic phenotype survive. As a consequence, the development of hypoxic areas is very closely linked to the development of a malignant and metastatic phenotype. The molecular mechanisms that underlie metabolic reprogramming of cancer cells are complex, but the activation of hypoxia-inducible factor (HIF) represents one of the principal causes of the metabolic switch. HIF-1 is a transcription factor that is activated by hypoxic stress, causing a up-regulation of lactate dehydrogenase A (LDH-A). In my thesis work I tried to synthesize molecules able to inhibit LDH-A, in fact, by inhibiting the lactic fermentation, the lack of NAD+ cofactors causes the block of glycolysis and, consequently, the interruption of energy production

Historical mystery solved: A multi-analytical approach to the identification of a key marker for the historical use of brazilwood (Caesalpinia spp.) in paintings and textiles

Brazilwood-derived pigments and dyes are found in many historical objects, from European paintings to North American First Nations textiles.</p

Acute alcohol intoxication: a clinical overview

Alcohol is a legal and yet detrimental psychoactive substance, capable of establishing addiction and impacting the physical, mental, social, and economic health of people. Alcohol intake causes a large variety of tissue damages severely impacting the nervous system, digestive and cardiovascular systems and causing oral cavity, oropharyngeal, hypopharyngeal, esophageal, colon-rectal, laryngeal, liver and intrahepatic bile duct, and breast cancers. Alcohol can also play a role in the pathogenesis of diabetes mellitus, cardiomyopathy and hemorrhagic strokes. When drunk during pregnancy it is proved to be responsible for serious damage to fetuses causing a wide range of pathological conditions from miscarriage to Fetal Alcoholic Spectrum Disorder (FASD). Acute ethanol intoxication happens when the amount of alcohol consumed is greater than the disposal capacity of the liver, causing an accumulation of its metabolites displayed by initial dysphoria and disinhibition. Nausea, vomiting, memory loss could happen. Although, it can lead to more serious conditions like impaired speaking, impaired coordination, unstable gait, nystagmus, stupor, or coma. Respiratory depression and death could also happen in such cases. Unfortunately, diagnosis of acute alcohol intoxication is difficult because most of the drinkers deny or minimize their assumption. It is dramatically important to assess when the last intake happened to avoid withdrawal syndrome. Alcohol acute intoxication can be considered a serious harm to health and a relevant issue for healthcare provid-ers working in emergency rooms. Differential diagnosis is crucial to avoid serious outcomes. There is no consensus about therapies for acute intoxication, but supportive and symptomatic treatments were proved effective. The repercussions of alcohol misuse over drinkers' social, familiar, economical and working life enhance the importance of a multidisciplinary approach in such cases

Carbonic anhydrase VII is S-glutathionylated without loss of catalytic activity and affinity for sulfonamide inhibitors

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Phenotype Screening of an Azole-bisindole Chemical Library Identifies URB1483 as a New Antileishmanial Agent Devoid of Toxicity on Human Cells

none11sìWe report the evaluation of a small library of azole-bisindoles for their antileishmanial potential, in terms of efficacy on Leishmania infantum promastigotes and intracellular amastigotes. Nine compounds showed good activity on L. infantum MHOM/TN/80/IPT1 promastigotes with IC50 values ranging from 4 to 10 μM. These active compounds were also tested on human (THP-1, HEPG2, HaCaT, and human primary fibroblasts) and canine (DH82) cell lines. URB1483 was selected as the best compound, with no quantifiable cytotoxicity in mammalian cells, to test the efficacy on intracellular amastigotes. URB1483 significantly reduced the infection index of both human and canine macrophages with an effect comparable to the clinically used drug pentamidine. URB1483 emerges as a new anti-infective agent with remarkable antileishmanial activity and no cytotoxic effects on human and canine cells.openDiotallevi, Aurora; Scalvini, Laura; Buffi, Gloria; Pérez-Pertejo, Yolanda; De Santi, Mauro; Verboni, Michele; Favi, Gianfranco; Magnani, Mauro; Lodola, Alessio; Lucarini, Simone; Galluzzi, LucaDiotallevi, Aurora; Scalvini, Laura; Buffi, Gloria; Pérez-Pertejo, Yolanda; De Santi, Mauro; Verboni, Michele; Favi, Gianfranco; Magnani, Mauro; Lodola, Alessio; Lucarini, Simone; Galluzzi, Luc

Carbonic anhydrase inhibitors targeting metabolism and tumor microenvironment

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed

Detection of Alkaline Sphingomyelinase Activity in Human Stool: Proposed Role as a New Diagnostic and Prognostic Marker of Colorectal Cancer

Abstract Objectives: Intestinal alkaline sphingomyelinase, by exerting a major role in dietary sphingomyelin digestion, is responsible for the generation of messengers able to trigger the rapid turnover and apoptosis in intestinal epithelial cells. Markedly reduced mucosal alkaline sphingomyelinase activity has been associated with human colorectal neoplasms. The aim of this study was to analyze the alkaline sphingomyelinase activity in feces from healthy subjects and colorectal adenocarcinoma patients and to correlate it with the enzyme activity in intestinal tissues. Materials and Methods: The enzyme activity was measured both in the intestinal samples from 12 healthy controls and 51 patients with colorectal adenocarcinoma (tumoral and paratumoral tissue) and in the fecal samples of 34 healthy subjects and 29 patients with adenocarcinoma. The relation between sphingomyelinase activity and Dukes' stage, cell differentiation degree, age, and gender was also analyzed. Results: Alkaline sphingomyelinase was significantly decreased (P &lt; 0.001; mean reduction &gt;90%) in tumoral intestinal mucosa of patients compared with controls independently of Dukes' stage and tumor differentiation grade. Interestingly, the enzyme activity in histologically normal paratumoral tissues was statistically lower than control samples (P &lt; 0.001). As occurs in neoplastic tissues, a relevant mean reduction (P &lt; 0.0001; almost 90%) of alkaline sphingomyelinase was revealed in stool samples from tumor patients when compared with controls. Conclusion: These findings may have implications for cancer biology and perhaps also for the design of clinical test, thus suggesting that the fecal sphingomyelinase activity could really reflect the human intestinal mucosa enzyme level and could represent a new marker for human colorectal adenocarcinoma, mainly taking into account its early appearance in intestinal neoplasms

Performance of the LHCb muon system

The performance of the LHCb Muon system and its stability across the full 2010 data taking with LHC running at ps = 7 TeV energy is studied. The optimization of the detector setting and the time calibration performed with the first collisions delivered by LHC is described. Particle rates, measured for the wide range of luminosities and beam operation conditions experienced during the run, are compared with the values expected from simulation. The space and time alignment of the detectors, chamber efficiency, time resolution and cluster size are evaluated. The detector performance is found to be as expected from specifications or better. Notably the overall efficiency is well above the design requirementsComment: JINST_015P_1112 201

The role of opioids in cancer response to immunotherapy

BACKGROUND: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities.METHODS: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival.RESULTS: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3months vs. 19months, HR 1.70, 95% CI 1.37-2.09, p&lt;0.0001; median OS, 4months vs. 35months, HR 1.60, 95% CI 1.26-2.02, p&lt;0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS≥1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden.DISCUSSION: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well.CONCLUSIONS: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes