Boosting the MHC class II-restricted tumor antigen presentation to CD4+ T helper cells: A critical issue for triggering protective immunity and re-orienting the tumor microenvironment toward an anti-tumor state

6noopenAlthough the existence of an immune response against tumor cells is well documented, the fact that tumors take off in cancer patients indicates that neoplastic cells can circumvent this response. Over the years many investigators have described strategies to rescue the anti-tumor immune response with the aim of creating specific and long-lasting protection against the disease. When exported to human clinical settings, these strategies have revealed in most cases a very limited, if any, positive outcome. We believe that the failure is mostly due to the inadequate triggering of the CD4+ T helper (TH) cell arm of the adaptive immunity, as TH cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells. In this review, we focus on novel strategies that by stimulating MHC class II-restricted activation of TH cells generate a specific and persistent adaptive immunity against the tumor. This point is of critical importance for both preventive and therapeutic anti-tumor vaccination protocols, because adaptive immunity with its capacity to produce specific, long-lasting protection and memory responses is indeed the final goal of vaccination. We will discuss data from our as well as other laboratories which strongly suggest that triggering a specific and persistent anti-tumor CD4+ TH cell response stably modify not only the tumor microenvironment but also tumor-dependent extratumor microenvironments by eliminating and/or reducing the blood-derived tumor infiltrating cells that may have a pro-tumor growth function such as regulatory CD4+/CD25+ T cells and myeloid-derived-suppressor cells. Within this frame, therefore, we believe that the establishment of a pro-tumor environment is not the cause but simply the consequence of the tumor strategy to primarily counteract components of the adaptive cellular immunity, particularly TH lymphocytes.openAccolla, R.S.; Lombardo, L.; Abdallah, R.; Raval, G.; Forlani, G.; Tosi, G.Accolla, Roberto; Lombardo, L.; Abdallah, R.; Raval, G.; Forlani, Greta; Tosi, Giovann

Genus Salsola : chemistry, biological activities and future prospective-a review

The genus Salsola L. (Russian thistle, Saltwort) includes halophyte plants and is considered one of the largest genera in the family Amaranthaceae. The genus involves annual semi-dwarf to dwarf shrubs and woody tree. The genus Salsola is frequently overlooked, and few people are aware of its significance. The majority of studies focus on pollen morphology and species identification. Salsola has had little research on its phytochemical makeup or biological effects. Therefore, we present this review to cover all aspects of genus Salsola, including taxonomy, distribution, differences in the chemical constituents and representative examples of isolated compounds produced by various species of genus Salsola and in relation to their several reported biological activities for use in folk medicine worldwide

A mathematical modeling of the mitochondrial proton leak via quantum tunneling

The mitochondrion is a vital intracellular organelle that is responsible for ATP production. It utilizes both the concentration gradient and the electrical potential of the inner mitochondrial membrane to drive the flow of protons from the intermembrane space to the matrix to generate ATP via ATP-synthase. However, the proton leak flow, which is mediated via the inner mitochondrial membrane and uncoupling proteins, can reduce the efficiency of ATP production. Protons can exhibit a quantum behavior within biological systems. However, the investigation of the quantum behavior of protons within the mitochondria is lacking particularly in the contribution to the proton leak. In the present study, we proposed a mathematical model of protons tunneling through the inner mitochondrial membrane and the mitochondrial carrier superfamily MCF including uncoupling proteins UCPs and the adenine nucleotide translocases ANTs. According to the model and its assumptions, the quantum tunneling of protons may contribute significantly to the proton leak if it is compared with the classical flow of protons. The quantum tunneling proton leak may depolarize the membrane potential, hence it may contribute to the physiological regulation of ATP synthesis and reactive oxygen species ROS production. In addition to that, the mathematical model of proton tunneling suggested that the proton-tunneling leak may depolarize the membrane potential to values beyond the physiological needs which in turn can harm the mitochondria and the cells. Moreover, we argued that the quantum proton leak might be more energetically favorable if it is compared with the classical proton leak. This may give the advantage for quantum tunneling of protons to occur since less energy is required to contribute significantly to the proton leak compared with the classical proton flow

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways

Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications.Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment.Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group.Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Human tumor retrovirus-host-interaction: role of CIITA in the functional inhibition of HTLV-1 Tax-1 oncogenic protein.

Human T-cell Lymphotropic Virus type-1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Many evidences have shown that constitutive activation of NF-\u3baB pathway by Tax-1 is crucial for T-cell transformation. Previous results demonstrated that CIITA, the master regulator of MHC class II gene transcription, inhibits HTLV-1 replication by blocking the transcription function of the viral transactivator Tax-1. Here we show that CIITA suppresses also Tax-1-mediated activation of the NF-\u3baB pathway. CIITA interacts with and retains Tax-1 in the detergent unsoluble cell fraction (cytoplasmic debris) and inhibits Tax-1-dependent nuclear translocation of RelA. Moreover, the overexpression of CIITA does not affect Tax-1 interaction with both RelA and IKK\u3b3. Nevertheless, the enzymatic activity of IKK kinase promoted by Tax-1 is impaired in the presence of CIITA. CIITA acts by suppressing at least the canonical NF-\u3baB pathway, in that it also inhibits the activation of NF-\u3baB by Tax-2, which is known to activate NF-\u3baB through the canonical but not the non-canonical pathway. Overall, our results indicate that CIITA, beside acting as viral restriction factor against HTLV-1 infection, might counteract Tax-1 transforming activity. Thus, assessing the molecular basis of CIITA-mediated Tax-1 inhibition may be important in defining new strategies to control HTLV-1 spreading and oncogenic potential

The constitutive activation of NF-kB by HTLV-1 Tax-1 oncoprotein is inhibited by the MHC class II transactivator CIITA

The constitutive activation of NF-kB by HTLV-1 Tax-1 oncoprotein is inhibited by the MHC class II transactivator CIITA Greta Forlani, PhD, University of Insubria; Rawan Abdallah, PhD, University of Insubria; Roberto Accolla, MD, PhD, University of Insubria; Giovanna Tosi, PhD, University of Insubria Human T cell lymphotropic virus type 1 (HTLV-1) Tax-1, induces T cell transformation deregulating diverse cell signaling pathways. Tax-1 activates the NF-kB pathway through binding to NF-kB proteins and activation of the IkB kinase (IKK). Upon IKK-mediated phosphorylation of IkB and consequent IkB degradation, NF-kB migrates into the nucleus mediating Tax-1-stimulated gene expression. We show that the transcriptional regulator of major histocompatibility complex class II genes CIITA endogenously or ectopically expressed in different cells, inhibits the activation of the canonical NF-kB pathway by Tax-1 and we mapped the CIITA region that mediates this effect. CIITA affects the subcellular localization of Tax-1, which is mostly retained in the cytoplasm, and this correlates with the impaired migration of the NF-kB RelA subunit into the nucleus. Cytoplasmic and nuclear mutant forms of CIITA reveal that CIITA exploits different strategies to suppress Tax-1-mediated NF-kB activation in both sub-cellular compartments. CIITA interacts with Tax-1 without preventing Tax-1 binding to both IKKg and RelA. Nevertheless, CIITA affects Tax-1-induced IKK activity, causing the retention of the inactive p50/RelA/IkB complex in the cytoplasm. Nuclear CIITA associates with Tax-1/RelA in nuclear bodies, blocking Tax-1-dependent activation of NFkB-responsive genes. Thus, CIITA inhibits both cytoplasmic and nuclear steps of Tax-1-mediated NF-kB activation. These results, indicate that CIITA is a versatile molecule that might also counteract Tax-1 transforming activity. Unveiling the molecular basis of CIITA-mediated inhibition of Tax-1 functions may be important in defining new strategies to control HTLV-

Eco-Efficiency Analysis of Integrated Waste Management Strategies Based on Gasification and Mechanical Biological Treatment

Integrated solid waste management (ISWM) strategies are developed towards promoting sustainable approaches for handling waste. Recently, gasification and mechanical biological treatment (MBT) technologies were recognized as effective processes for treating municipal solid waste. This study investigates the feasibility of integrating gasification and MBT technologies in multiple ISWM strategies, compared to incineration- and anaerobic digestion (AD)-based strategies. A comprehensive techno-economic and environmental assessment was carried out to evaluate the performance of the examined ISWM strategies. The evaluation was based on the energy generation potential, carbon footprint, and life cycle costing (LCC). An eco-efficiency analysis was conducted to quantify the environmental costs by incorporating the carbon footprint and LCC results. The proposed strategies were applied for the city of Abu Dhabi, United Arab Emirates, based on local bylaws and guidelines. The analysis revealed that the gasification-based strategy had the highest energy production of 47.0 million MWh, followed by the incineration- (34.2 million MWh), AD- (17.2 million MWh), and MBT-based (14.9 million MWh) strategies. Results of the environmental analysis indicated that the MBT- and AD-based strategies contributed the least to global warming with greenhouse gas emissions of 4442 and 4539 GgCO2-eq, respectively, compared to the gasification- (9922 GgCO2-eq) and incineration-based (15,700 GgCO2-eq) strategies. Furthermore, over a 25-year assessment period, the LCC findings demonstrated that the gasification- and MBT-based strategies were the most financially feasible with a positive net present value (NPV) of USD 364 and USD 284 million, respectively. The eco-efficiency analysis indicated that the MBT and gasification strategies are the most sustainable among the examined strategies. The sustainability of the assessed systems was improved by implementing policy and legal reforms, including incentive programs, less stringent bylaws on digestate, and encouraging source separation of wastes. Overall, this research emphasized the potential environmental and financial benefits of incorporating MBT and gasification technologies into ISWM strategies