Immune profile of cancer patients to improve selection and efficacy of immunotherapeutic strategies

Over the years, the clinical outcome of cancer patients has remarkably improved with the introduction of immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs), that by targeting immune system restore an efficient anti-tumor immune response. Despite the potential of immunotherapy as cancer leading treatment, initial response rates with ICIs are however limited and depend on the host pre-existing anti-cancer immunity and the degree of immunosuppression present in the patient. Most of patients fail to respond and to increase the number of responder patients is necessary a more in-depth understanding of the underlying immunity and the identification of biomarkers. In this research project we investigate and characterize the immune system of cancer patients (mRCC, NSCLC, HNSCC, UM) before and during treatment with TKIs or ICIs, in order to investigate the relation between circulating immune profile, tumor microenvironment (TME), the gut microbiome and clinical outcome. The aim was the identification of possible biomarkers/immune profile able to select patients and improve clinical outcome. We assessed immunological analysis to evaluate exhausted/activated circulating T cells by cytofluorimetric assay, 14 immune checkpoint-related proteins and 20 inflammation cytokines/chemokines using Luminex assay. The immunological profile was correlated with survival (PFS and OS), clinical parameters and response to treatment. Gut microbiota composition was evaluated through metagenomic analysis and immunohistochemistry was used to characterize tumor microenvironment. Our results demonstrated that TKIs and ICIs modulate immune system. We observed a decrease of soluble immune checkpoint molecules in serum of mRCC (sPDL2, sHVEM, sPD1, sGITR) and NSCLC patients (sPD1, sPDL2) during treatment (p<0.05). In particular, the decrease of sPD1 and sPDL2 resulted associated with response to treatments (p=0.03 and p=0.01, respectively). Moreover, the immune profile of responder (R) patients was characterized by low levels of soluble protein (sCTLA4, sPD-L1 in mRCC vs sCD137, sTIM3, sPDL1, sPDL2 in NSCLC) (p<0.05) and by a high proportion of eubiosis-associated gut metabolites. These data resulted also associated with better clinical status, PS=0 (performance status). Profiling circulating immune cells in patients undergoing ICI treatment (anti-PD1) we identified CD3+CD137+ and CD3+CD8+CD137+ T cells that correlate with improved response to therapy. The percentage of both CD3+CD137+ and CD3+CD8+CD137+ T population was higher in R patients (p=0.03 and p=0.02) and correlated to a better survival in terms of PFS and OS (p<0.05). Moreover, R patients had higher levels of CD3+CD137+PD1+ and of CD8+CD137+PD1+ lymphocytes (p=0.02 and p=0.01), but only CD3+CD137+PD1+ resulted associated with a low number of metastasis (p=0.01) and longer survival (OS)(p=0.015). Instead, the high concentration of the immunosuppressive sCD137 in the serum was associated with a lower PFS (p=0.038) and OS (p=0.012). In tumor microenvironment, patients with a complete pathological response showed a high percentage of CD137+ and CD8+ T cells. Results were validated in an independent cohort of metastatic cancer patients. These results identified immunological parameters that, independently from tumor setting and administered therapy, predict clinical outcome of cancer patients, monitor immune response and help clinicians in the decision-making

Screening for Tuberculosis in Health Care Workers. Experience in an Italian Teaching Hospital

Health care workers (HCW) are particularly at risk of acquiring tuberculosis (TB), even in countries with low TB incidence. Therefore, TB screening in HCW is a useful prevention strategy in countries with both low and high TB incidence. Tuberculin skin test (TST) is widely used although it suffers of low specificity; on the contrary, the in vitro enzyme immunoassay tests (IGRA) show superior specificity and sensitivity but are more expensive. The present study reports the results of a three-year TB surveillance among HCW in a large teaching hospital in Rome, using TST (by standard Mantoux technique) and IGRA (by QuantiFERON-TB) as first- and second-level screening tests, respectively. Out of 2290 HCW enrolled, 141 (6.1%) had a positive TST; among them, 99 (70.2%) underwent the IGRA and 16 tested positive (16.1%). The frequency of HCW tested positive for TB seems not far from other experiences in low incidence countries. Our results confirm the higher specificity of IGRA, but, due to its higher cost, TST can be considered a good first level screening test, whose positive results should be further confirmed by IGRA before the patients undergo X-ray diagnosis and/or chemotherapy

Functional Information, Biomolecular Messages and Complexity of BioSequences and Structures

In the quest for a mathematical measure able to capture and shed light on the dual notions of information and complexity in biosequences, Hazen et al. have introduced the notion of Functional Information (FI for short). It is also the result of earlier considerations and findings by Szostak and Carothers et al. Based on the experiments by Charoters et al., regarding FI in RNA binding activities, we decided to study the relation existing between FI and classic measures of complexity applied on protein-DNA interactions on a genome-wide scale. Using classic complexity measures, i.e, Shannon entropy and Kolmogorov Complexity as both estimated by data compression, we found that FI applied to protein-DNA interactions is genuinely different from them. Such a fact, together with the non-triviality of the biological function considered, contributes to the establishment of FI as a novel and useful measure of biocomplexity. Remarkably, we also found a relationship, on a genome-wide scale, between the redundancy of a genomic region and its ability to interact with a protein. This latter finding justifies even more some principles for the design of motif discovery algorithms. Finally, our experiments bring to light methodological limitations of Linguistic Complexity measures, i.e., a class of measures that is a function of the vocabulary richness of a sequence. Indeed, due to the technology and associated statistical preprocessing procedures used to conduct our studies, i.e., genome-wide ChIP-chip experiments, that class of measures cannot give any statistically significant indication about complexity and function. A serious limitation due to the widespread use of the technology. References J.M. Carothers, S.C. Oestreich, J.H. Davis, and J.W. Szostack. Informational complexity and functional activity of RNA structures. J. AM. CHEM. SOC., 126 (2004), pp. 5130-5137. R.M. Hazen, P.L. Griffin, J.M. Carothers, and J.W. Szostak. Functional Information and the emergence of biocomplexity. Proc. of Nat. Acad. Sci, 104 (2007), pp. 8574-8581. J.W. Szostak. Functional Information: molecular messages, Nature, 423 (2003)

Wearable sensors for human–robot walking together

Thanks to recent technological improvements that enable novel applications beyond the industrial context, there is growing interest in the use of robots in everyday life situations. To improve the acceptability of personal service robots, they should seamlessly interact with the users, understand their social signals and cues and respond appropriately. In this context, a few proposals were presented to make robots and humans navigate together naturally without explicit user control, but no final solution has been achieved yet. To make an advance toward this end, this paper proposes the use of wearable Inertial Measurement Units to improve the interaction between human and robot while walking together without physical links and with no restriction on the relative position between the human and the robot. We built a prototype system, experimented with 19 human participants in two different tasks, to provide real-time evaluation of gait parameters for a mobile robot moving together with a human, and studied the feasibility and the perceived usability by the participants. The results show the feasibility of the system, which obtained positive feedback from the users, giving valuable information for the development of a natural interaction system where the robot perceives human movements by means of wearable sensors

Healthcare Associated Infections. educational intervention by "Adult Learning" in an Italian teaching hospital

An educational intervention for HAI prevention based on a combination of training, motivation and subsequent application in the current clinical practice in an Italian teaching hospital

INDICADORES BIOQUÍMICOS SÉRICOS E DO LÍQUIDO PERITONEAL DE EQUINOS SUBMETIDOS À OBSTRUÇÃO INTESTINAL

Twenty-four horses were distributed into four different groups, instrumented control (GI), duodenum obstruction (GII), ileum obstruction (GIII) and large colon obstruction (GIV). Serum and peritoneal fluid analysis of aspartate aminotransferase, creatine kinase, lactate dehydrogenase, alkaline phosphatase, inorganic phosphorus and lactate were measured. Samples were collected one hour before the surgical procedure (T0); 3 hours after the obstruction (T3ob), 1, 3, 12, 24, 120 and 168 hours after the beginning of reperfusion/deobstruction. Duodenal (GII) and ileum (GIII) obstructions changed serum and peritoneal fluid biochemical analysis. However, only lactate, lactate dehydrogenase, creatine kinase and inorganic phosphorus concentrations were abnormal in peritoneal fluid three hours after the obstruction. The biochemical analysis of peritoneal fluid allowed a faster diagnostic of intestinal alterations than the serum analysis; hence it should be prioritized when pre-operatory colic assessment is carried out

Anxiolytic Effects in Mice of a Dual Blocker of Fatty Acid Amide Hydrolase and Transient Receptor Potential Vanilloid Type-1 Channels

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Tumor derived Microvesicles enhance cross-processing ability of clinical grade Dendritic Cells

Tumor cells release extracellular microvesicles (MVs) in the microenvironment to deliver biological signals to neighbouring cells as well as to cells in distant tissues. Tumor-derived MVs appear to play contradictory role promoting both immunosuppression and tumor growth and both evoking tumor specific immune response. Recent evidences indicate that tumor-derived MVs can positively impact Dendritic Cells (DCs) immunogenicity by reprogramming DC antigen processing machinery and intracellular signaling pathways, thus promoting anti-tumor response. DCs are considered pivot cells of the immune system due to their exclusive ability to coordinate the innate and acquired immune responses, cross-present exogenous antigens and prime naïve T cells. DCs are required for the induction and maintenance of long-lasting anti-tumor immunity and their exploitation has been extensively investigated for the design of anti-tumor vaccines. However, the clinical grade culture conditions that are required to generate DCs for therapeutic use can strongly affect their functions. Here, we investigated the immunomodulatory impact of MVs carrying the MUC1 tumor glycoantigen (MVsMUC1) as immunogen formulation on clinical grade DCs grown in X-VIVO 15 (X-DCs). Results indicated that X-DCs displayed reduced performance of the antigen processing machinery in term of diminished phagocytosis and acidification of the phagosomal compartment suggesting an altered immunogenicity of clinical grade DCs. Pulsing DCs with MVsMUC1 restored phagosomal alkalinization, triggering ROS increase. This was not observed when a soluble MUC1 protein was employed (rMUC1). Concurrently, MVsMUC1 internalization by X-DCs allowed MUC1 cross-processing. Most importantly, MVsMUC1 pulsed DCs activated IFNγ response mediated by MUC1 specific CD8+ T cells. These results strongly support the employment of tumor-derived MVs as immunogen platforms for the implementation of DC-based vaccine

AVALIAÇÃO CLÍNICA E ERITROLEUCOGRAMA DE EQÜINOS COM CÓLICA SUBMETIDOS À LAPAROTOMIA, SOBREVIVENTES E NÃO SOBREVIVENTES

Utilizaram-se setenta equinos, vinte sadios (GI) e cinquenta com cólica, submetidos à laparotomia, sobreviventes (GII, n=25) e não sobreviventes (GIII, n=25). O exame clínico e a colheita das amostras de sangue foram realizados antes da laparotomia (T0) e diariamente, a partir da cirurgia, até o décimo dia após a intervenção (T24h - T10o dia). No T0, observou-se aumento dos valores da frequência cardíaca e respiratória, do tempo de perfusão tecidual, do número de hemácias, do volume globular e do número de leucócitos nos equinos dos grupos GII e GIII, que ainda se mantiveram até o décimo dia pós-operatório nos animais do grupo GIII. Nesses mesmos momentos e animais verificou-se diminuição na concentração das proteínas plasmáticas totais. A intensidade e a persistência das alterações relacionaram-se negativamente com a recuperação dos animais e foram atribuídas ao tempo, à localização e à gravidade do processo obstrutivo. A avaliação seriada dos parâmetros clinicolaboratoriais analisados pode ser útil na definição do prognóstico dos animais com cólica submetidos à laparotomia.  PALAVRAS-CHAVES: Abdômen agudo, equinos, hemograma

Epiphora as a sign of unexpected underlying squamous cell carcinoma within sinonasal inverted papilloma

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