PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients : Dramatic improvement of prognosis and overall survival after decades of hopelessness in patients with metastatic urothelial cancer

Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control. Five immune CPI have recently been approved for aUC/mUC by the US Food and Drug Administration (FDA) including atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab. All five CPI are FDA-approved as second-line therapy with atezolizumab and pembrolizumab also being approved for first-line therapy in cisplatin-ineligible patients. The rapid acceptance in the treatment algorithm of UC is based on the impressive clinical efficacy of these agents in some patients, combined with their excellent safety profile. These new agents are indeed the most important advancement in UC care. However, the challenge in the age of precision medicine is to identify the patients who are most likely to benefit from CPIs, as the majority of patients do not respond to CPI. Toward this goal, validation of clinical, molecular and imaging biomarkers that serve for prediction and monitoring of treatment response are of central necessity.(VLID)357544

Mitochondrial Complex I Activity is Conditioned by Supercomplex I–III2–IV Assembly in Brain Cells: Relevance for Parkinson’s Disease

The assembly of complex I (CI) with complexes III (CIII) and IV (CIV) of the mitochondrial respiratory chain (MRC) to configure I–III- or I–III–IV-containing supercomplexes (SCs) regulates mitochondrial energy efficiency and reactive oxygen species (mROS) production. However, whether the occurrence of SCs impacts on CI specific activity remains unknown to our knowledge. To investigate this issue, here we determined CI activity in primary neurons and astrocytes, cultured under identical antioxidants-free medium, from two mouse strains (C57Bl/6 and CBA) and Wistar rat, i.e. three rodent species with or without the ability to assemble CIV into SCs. We found that CI activity was 6- or 1.8-fold higher in astrocytes than in neurons, respectively, from rat or CBA mouse, which can form I–III2–IV SC; however, CI activity was similar in the cells from C57Bl/6 mouse, which does not form I–III2–IV SC. Interestingly, CII–III activity, which was comparable in neurons and astrocytes from mice, was about 50% lower in astrocytes when compared with neurons from rat, a difference that was abolished by antioxidants- or serum-containing media. CIV and citrate synthase activities were similar under all conditions studied. Interestingly, in rat astrocytes, CI abundance in I–III2–IV SC was negligible when compared with its abundance in I–III-containing SCs. Thus, CIV-containing SCs formation may determine CI specific activity in astrocytes, which is important to understand the mechanism for CI deficiency observed in Parkinson’s disease.J.P.B. is funded by MINECO (SAF2013-41177-R, SAF2016-78114-R), CIBER on Frailty and Aging from the Instituto de Salud Carlos III (CB16/10/00282), E.U. SP3-People-MC-ITN programme (608381), EU BATCure Grant (666918) and FEDER (European regional development fund). A.A.P. is funded by the Instituto de Salud Carlos III (RD12/0014/0007).Peer reviewe

World Journal of Urology / Pseudoprogression and hyperprogression during immune checkpoint inhibitor therapy for urothelial and kidney cancer

Objectives A small subset of patients treated with immune checkpoint inhibitors manifest atypical patterns of response, the so-called pseudoprogression (PP) and hyperprogression (HP). Their prevalence in urothelial (UC) and renal cancer (RCC) remains, to date, mostly uninvestigated. Therefore, we aimed to provide a summary of the current knowledge about PP and HP during immune checkpoint inhibitor therapy in UC and RCC patients. Methods and materials A systematic medline/pubmed© literature search was performed. The atypical patterns of response to systemic immunotherapy were reviewed. Endpoints were PP and HP in UC and RCC. Results Tumors respond differently to immunotherapy compared to systemic chemotherapy. To evaluate response to immunotherapy, new guidelines (iRECIST) have been developed. To date, no studies focused on PP in UC and RCC, and the only way to evaluate its role is to take patients who respond to treatment beyond progression as surrogate for pseudoprogressors. PP seems to occur in a non-negligible rate of UC and RCC (from 1.5 to 17% and from 5 to 15%, respectively). The concept of HP, defined as a rapid progression after treatment, just took the first steps, and therefore, data from ongoing trials are awaited to elucidate its impact in genitourinary cancers. Conclusions PP and HP are not uncommon entities in UC and RCC patients, treated with PD-1/PD-L1 inhibitors. Further investigation is warranted to define which patients are likely to experience PP and could benefit from treatment beyond progression and which ones will instead rapidly experience progression despite treatment and should, therefore, avoid systemic immunotherapy.(VLID)360161

Mitochondrial respiratory chain disorganization in Parkinson's disease-relevant PINK1 and DJ1 mutants

Brain mitochondrial complex I (CI) damage is associated with the loss of the dopaminergic neurons of the Substantia Nigra in Parkinson's Disease (PD) patients. However, whether CI inhibition is associated with any alteration of the mitochondrial respiratory chain (MRC) organization in PD patients is unknown. To address this issue, here we analyzed the MRC by blue native gel electrophoresis (BNGE) followed by western blotting, in mitochondria purified from fibroblasts of patients harboring PD-relevant Pink1 mutations. We found a decrease in free CI, and in free versus supercomplexes (SCs)-assembled CI in PD; however, free complex III (CIII) was only modestly affected, whereas its free versus SCs-assembled forms decreased. Interestingly, complex IV (CIV) was considerably lost in the PD samples. These results were largely confirmed in mitochondria isolated from cultured neurons from Pink1-/- mice, and in cultured neurons and forebrain samples from the PD-related Dj1-/- mice. Thus, besides CI damage, the MRC undergoes a profound structural remodeling in PD likely responsible for the energetic inefficiency and mitochondrial reactive oxygen species (mROS) over-production observed in this disease.J.P.B. is funded by MINECO (SAF2016-78114-R; RTC-2015-3237-1), CIBERFES (CB16/10/00282), E.U. SP3-People-MC-ITN programme (608381), EU BATCure grant (666918) and FEDER (European regional development fund). R.S.P. is funded by the Joint Program in Neurodegenerative Diseases (DAMNDPATHS).Peer reviewe

Anxiety and depression analyses of patients undergoing diagnostic cystoscopy

Purpose To prospectively assess anxiety and depression in patients undergoing diagnostic cystoscopy. Methods Patients presenting for outpatient diagnostic cystoscopy were recruited from four European urological departments. Anxiety and depression were assessed with the 'Hospital Anxiety and Depression Scale' (HADS) before cystoscopy and after 1 week. Statistical analyses, including the Chi-square test, univariate, and multivariate logistic regression analyses, were carried out with SPSS v. 21 (IBM Corp., Armonk, NY). Results Prior to cystoscopy, 30.2 % of patients were anxious and 24.8 % depressive (n = 442). In the post-examination period, anxiety declined to 24.5 %, while depression was unchanged (24.4 %). Pre-cystoscopy anxiety was significantly more common in women (41.8 vs. 24.5 %, p < 0.0001), patients aged < 65 years (34.9 vs. 25.9 %, p = 0.04), and in those being examined with rigid cystoscopes (35.7 vs. 23.9 %, p = 0.007). In multivariate regression analyses, female gender (OR 2.6, p < 0.0001), <65 years of age (OR 1.7, p = 0.03), and coexistence of depression (OR 7.8, p < 0.0001) were independently associated with elevated pre-cystoscopy anxiety. Anxious (OR 2.1, p = 0.03) and depressive (OR 2.1, p = 0.01) patients had higher odds of experiencing moderate or severe pain during cystoscopy. Bladder cancer diagnosis did not significantly change patient's anxiety (p = 0.23) or depression (p = 0.7) during the 1 week of follow-up. Conclusions Women, patients aged < 65 years, depressive patients and those being examined with rigid devices had higher rates of anxiety prior to cystoscopy. Anxious and depressive patients experienced more pain during cystoscopy. Bladder cancer diagnosis seems to have a minor effect on anxiety and depression during the first week after diagnosis

Clinical & Experimental Allergy / Tropomyosins in mosquito and house dust mite crossreact at the humoral and cellular level

Background Aedes aegypti and Dermatophagoides pteronyssinus contain important allergens including crossreactive tropomyosins. However, the functional and clinical relevance of their crossreactivity is still debated. Objective To analyse the humoral and cellular crossreactivity of recombinant Aed a 10.01, Aed a 10.02 and Der p 10. Methods Sera from 15 Austrian house dust miteallergic, Der p 10sensitized individuals were tested for IgE reactivity to recombinant tropomyosins in ELISA, inhibition ELISA and basophil activation tests. BALB/c mice were immunized with Aed a 10.01 or Aed a 10.02, and their sera were assessed for reactivity to all tropomyosins. Splenocytes were stimulated with all tropomyosins and synthetic peptides representing the amino acid sequence of Aed a 10.01. Results IgE antibodies of Der p 10sensitized patients crossreacted with both tropomyosins from A. aegypti. Aed a 10.01 was a more potent inhibitor of IgE binding to Der p 10 and a stronger activator of basophils sensitized with Der p 10specific IgE than Aed a 10.02. Murine antibodies raised against Aed a 10.01 and Aed a 10.02 crossreacted with Der p 10. Aed a 10.01specific antibody showed stronger crossreactivity with Der p 10 than Aed a 10.02specific antibody. Splenocytes from both groups of mice proliferated similarly to all tropomyosins. Five crossreactive T cellactivating regions were identified. Conclusion and Clinical relevance Tropomyosins from D. pteronyssinus and A. aegypti show humoral and cellular crossreactivity, involving 5 potential T cellactivating regions. The more pronounced crossreactivity of Aed a 10.01 and Der p 10 matched the higher sequence similarity of both proteins.(VLID)339840

Functional Near-Infrared Spectrometry as a Useful Diagnostic Tool for Understanding the Visual System: A Review

This comprehensive review explores the role of Functional Near-Infrared Spectroscopy (fNIRS) in advancing our understanding of the visual system. Beginning with an introduction to fNIRS, we delve into its historical development, highlighting how this technology has evolved over time. The core of the review critically examines the advantages and disadvantages of fNIRS, offering a balanced view of its capabilities and limitations in research and clinical settings. We extend our discussion to the diverse applications of fNIRS beyond its traditional use, emphasizing its versatility across various fields. In the context of the visual system, this review provides an in-depth analysis of how fNIRS contributes to our understanding of eye function, including eye diseases. We discuss the intricacies of the visual cortex, how it responds to visual stimuli and the implications of these findings in both health and disease. A unique aspect of this review is the exploration of the intersection between fNIRS, virtual reality (VR), augmented reality (AR) and artificial intelligence (AI). We discuss how these cutting-edge technologies are synergizing with fNIRS to open new frontiers in visual system research. The review concludes with a forward-looking perspective, envisioning the future of fNIRS in a rapidly evolving technological landscape and its potential to revolutionize our approach to studying and understanding the visual system

Microbiological and Geochemical Heterogeneity in an in Situ Uranium Bioremediation Field Site

The geochemistry and microbiology of a uranium-contaminated subsurface environment that had undergone two seasons of acetate addition to stimulate microbial U(VI) reduction was examined. There were distinct horizontal and vertical geochemical gradients that could be attributed in large part to the manner in which acetate was distributed in the aquifer, with more reduction of Fe(III) and sulfate occurring at greater depths and closer to the point of acetate injection. Clone libraries of 16S rRNA genes derived from sediments and groundwater indicated an enrichment of sulfate-reducing bacteria in the order Desulfobacterales in sediment and groundwater samples. These samples were collected nearest the injection gallery where microbially reducible Fe(III) oxides were highly depleted, groundwater sulfate concentrations were low, and increases in acid volatile sulfide were observed in the sediment. Further down-gradient, metal-reducing conditions were present as indicated by intermediate Fe(II)/Fe(total) ratios, lower acid volatile sulfide values, and increased abundance of 16S rRNA gene sequences belonging to the dissimilatory Fe(III)- and U(VI)-reducing family Geobacteraceae. Maximal Fe(III) and U(VI) reduction correlated with maximal recovery of Geobacteraceae 16S rRNA gene sequences in both groundwater and sediment; however, the sites at which these maxima occurred were spatially separated within the aquifer. The substantial microbial and geochemical heterogeneity at this site demonstrates that attempts should be made to deliver acetate in a more uniform manner and that closely spaced sampling intervals, horizontally and vertically, in both sediment and groundwater are necessary in order to obtain a more in-depth understanding of microbial processes and the relative contribution of attached and planktonic populations to in situ uranium bioremediation