Radiotherapy plus pembrolizumab for advanced urothelial carcinoma: results from the ARON-2 real-world study

\ua9 The Author(s) 2024.The addition of metastasis-directed radiotherapy (MDRT) to immunotherapy in patients with advanced urothelial carcinoma (aUC) has shown promising results. We report the real-world data from the ARON-2 study (NCT05290038) on the impact of conventional (CRT) or stereotactic body radiotherapy (SBRT) on the outcome of aUC patients receiving pembrolizumab after platinum-based-chemotherapy. Medical records of 837 patients were reviewed from 60 institutions in 20 countries. Two hundred and sixty-two patients (31%) received radiotherapy (cohort A), of whom 193 (23%) received CRT and 69 (8%) received SBRT. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. With a median follow-up of 22.7 months, the median OS was 10.2 months, 6.8 months and 16.0 months in no RT, CRT and SBRT subgroups (p = 0.005), with an 1y-OS rates of 47%, 34% and 61%, respectively (p < 0.001). The 1y-OS rate in the SBRT subgroup were significantly higher for both lower (63%) and upper tract UC (68%), for pure urothelial histology (63%) and variant histologies (58%), and for patients with bone (40%) and lymph-node metastases (61%). Median PFS was 4.8 months, 9.6 months and 5.8 months in the CRT, SBRT and no RT subgroups, respectively (p = 0.060). The 1y-PFS rate was significantly higher (48%) in the SBRT population and was confirmed in all patient subsets. The difference in terms of ORR was in favour of SBRT. Our real-world analysis showed that the use of SBRT/pembrolizumab combination may play a role in a subset of aUC patients to increase disease control and possibly overall survival

The Role of Superior Temporal Cortex in Auditory Timing

Recently, there has been upsurge of interest in the neural mechanisms of time perception. A central question is whether the representation of time is distributed over brain regions as a function of stimulus modality, task and length of the duration used or whether it is centralized in a single specific and supramodal network. The answers seem to be converging on the former, and many areas not primarily considered as temporal processing areas remain to be investigated in the temporal domain. Here we asked whether the superior temporal gyrus, an auditory modality specific area, is involved in processing of auditory timing. Repetitive transcranial magnetic stimulation was applied over left and right superior temporal gyri while participants performed either a temporal or a frequency discrimination task of single tones. A significant decrease in performance accuracy was observed after stimulation of the right superior temporal gyrus, in addition to an increase in response uncertainty as measured by the Just Noticeable Difference. The results are specific to auditory temporal processing and performance on the frequency task was not affected. Our results further support the idea of distributed temporal processing and speak in favor of the existence of modality specific temporal regions in the human brain

Motif co-regulation and co-operativity are common mechanisms in transcriptional, post-transcriptional and post-translational regulation

A substantial portion of the regulatory interactions in the higher eukaryotic cell are mediated by simple sequence motifs in the regulatory segments of genes and (pre-)mRNAs, and in the intrinsically disordered regions of proteins. Although these regulatory modules are physicochemically distinct, they share an evolutionary plasticity that has facilitated a rapid growth of their use and resulted in their ubiquity in complex organisms. The ease of motif acquisition simplifies access to basal housekeeping functions, facilitates the co-regulation of multiple biomolecules allowing them to respond in a coordinated manner to changes in the cell state, and supports the integration of multiple signals for combinatorial decision-making. Consequently, motifs are indispensable for temporal, spatial, conditional and basal regulation at the transcriptional, post-transcriptional and post-translational level. In this review, we highlight that many of the key regulatory pathways of the cell are recruited by motifs and that the ease of motif acquisition has resulted in large networks of co-regulated biomolecules. We discuss how co-operativity allows simple static motifs to perform the conditional regulation that underlies decision-making in higher eukaryotic biological systems. We observe that each gene and its products have a unique set of DNA, RNA or protein motifs that encode a regulatory program to define the logical circuitry that guides the life cycle of these biomolecules, from transcription to degradation. Finally, we contrast the regulatory properties of protein motifs and the regulatory elements of DNA and (pre-)mRNAs, advocating that co-regulation, co-operativity, and motif-driven regulatory programs are common mechanisms that emerge from the use of simple, evolutionarily plastic regulatory modules

Xanthine Oxidoreductase In Atherosclerosis Pathogenesis: Not Only Oxidative Stress.

Endothelial xanthine oxidoreductase (XOR) together with NAD(P)H oxidase and nitric oxide (NO) synthase plays a physiologic role in inflammatory signalling, the regulation of NO production and vascular function. The oxidative stress generated by these enzymes may induce endothelial dysfunction, leading to atherosclerosis, cardiovascular diseases and metabolic syndrome. XOR activity creates both oxidant and anti-oxidant products that are implicated in the development of hypertension, smoking vascular injury, dyslipidemia and diabetes, which are the main risk factors of atherosclerosis. In particular, uric acid may have a protective as well as a detrimental role in vascular alterations, thus justifying the multi-directional effects of XOR inhibition. Moreover, XOR products are associated with cell differentiation, leading to adipogenesis and foam cell formation, as well as to the production of monocyte chemoattractant protein-1 from arterial smooth muscle cells, after proliferation and migration. The role of XOR in adipogenesis is also connected with insulin resistance and obesity, two main features of type 2 diabetes

Xanthine Oxidoreductase-Derived Reactive Species: Physiological and Pathological Effects

Xanthine oxidoreductase (XOR) is the enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is widely distributed among species. In addition to this housekeeping function, mammalian XOR is a physiological source of superoxide ion, hydrogen peroxide, and nitric oxide,which can function as second messengers in the activation of various pathways. This review intends to address the physiological and pathological roles of XOR-derived oxidant molecules.The cytocidal action of XOR products has been claimed in relation to tissue damage, in particular damage induced by hypoxia and ischemia. Attempts to exploit this activity to eliminate unwanted cells via the construction of conjugates have also been reported. Moreover, different aspects of XOR activity related to phlogosis, endothelial activation, leukocyte activation, and vascular tone regulation, have been taken into consideration. Finally, the positive and negative outcomes concerning cancer pathology have been analyzed because XOR products may induce mutagenesis, cell proliferation, and tumor progression, but they are also associated with apoptosis and cell differentiation. In conclusion, XOR activity generates free radicals and other oxidant reactive species that may result in either harmful or beneficial outcomes

Saporin-S6: a useful tool in cancer therapy.

Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials

Xanthine oxidoreductase activity in human liver disease

OBJECTIVES: The aim of this study was to investigate the level and the form of xanthine oxidoreductase (XOR) in severely diseased human livers, to ascertain whether the modifications of the enzyme activity reported in experimental pathology also occur in human liver disease. METHODS: Total, dehydrogenase, and oxidase activities of XOR were measured in samples of human liver removed for transplantation or partial hepatectomy. Samples included four groups: 1) histologically normal liver tissue, adjacent to metastases from extrahepatic tumors (controls), 2) liver with virus-related cirrhosis; 3) liver with virus-negative cirrhosis, and 4) hepatocellular carcinoma tissue (HCC). RESULTS: The level of total XOR was significantly higher in liver with virus-related cirrhosis, but not in virus-negative cirrhosis, than in controls. In virus-positive cirrhosis, the total XOR activity correlated positively with the level of ALT. The percentage of XOR oxidase activity in cirrhotic liver, regardless of virus infection, correlated positively with aspartate amino-transferase, bilirubin concentration, and partial thromboplastin time, and negatively with prothrombin time. The activity of XOR was significantly lower in HCC than in control tissue or in a nonneoplastic area of the same liver. CONCLUSIONS: Consistent with previous reports in experimental pathology, the level of XOR was increased in cirrhotic liver, in association with viral infection. This increment correlated with ALT, suggesting a relationship between XOR activity and the extent of liver injury caused by viral replication. The percentage of oxidase activity seems to be correlated with tissue damage and consequent liver impairment. The low XOR activity observed in HCC is consistent with reported experimental pathology. © 2002 by Am. Coll. of Gastroenterology

Rituximab and other new anti-CD20 mAbs for non-Hodgkin\u2019s lymphoma treatment.

Non-Hodgkin\u2019s lymphomas (NHLs) are a heterogeneous group of different haematological cancers with a wide range of aggressiveness. NHLs represent >80% of lymphomas and the majority of NHLs involve B cells. CD20 represents a good target for NHL immunotherapy because it is largely expressed on B cell NHL and not on B cell precursors and plasma cells. The anti-CD20 monoclonal antibody (mAb) rituximab (RTX) was the first antibody approved by the FDA for lymphoma therapy and has revolutionised B cell lymphoma treatment. Several clinical trials have demonstrated the high efficacy of RTX, resulting in a significant improvement in overall response rates and in NHL patient survival. However, RTX, both as a single agent and in combination with chemotherapy, induces several side-effects and resistance mechanisms. Remarkable efforts have been made to improve RTX efficacy, including conjugation to an active moiety (radionuclide, toxin, enzyme, or drug) and the development of new anti-CD20 mAbs. This review summarises the characteristics of RTX and other anti-CD20 mAbs for NHL treatment; the results of the main clinical trials are reported

Sindrome di Seckel: un caso riabilitato con protesi mobile

Lo scopo del seguente lavoro \ue8 documentare il piano di trattamento di un paziente affetto da sindrome di Seckel. La sindrome di Seckel \ue8 un disordine autosomico recessivo caratterizzato da importante ritardo di crescita intrauterina e post-natale, ritardo mentale e facies peculiare con microcefalia, fronte sfuggente, prominenza della regione mediana del volto con radice nasale prominente, orecchie spesso maformate a impianto basso, occhi grandi e micrognazia, caratteristiche che hanno dato origine all\u2019appellativo di \u201cfaccia da uccello\u201d. Il paziente, di anni 6, si \ue8 presentato alla nostra osservazione nel gennaio del 2005. All\u2019esame obiettivo si riscontrava la presenza in arcata dei soli elementi decidui 5.4 e 6.4; l\u2019esame radiologico evidenziava la ritenzione di tutti gli altri elementi dentali decidui e la presenza di dei germi dei primi molari e canini permanenti. Il bambino \ue8 syto riabilitato con due protesi mobili al fine da un lato di rpristinare la funzione e l\u2019estetica dell\u2019apparato stomatognatico, dall\u2019altro di favorire l\u2019eruzione dei denti ritenuti Dopo un mese dalla consegna delle protesi la fonetica e la masticazione non possono essere considerati ottimali nonostante il buon adattamento del bambino alle protesi. L\u2019eruzione in arcata dell\u2019elemento 7.1 ci motiva a proseguire con questo piano terapeutic