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The valorization of coffee cherry waste through hydrothermal carbonization (HTC) was investigated using various organic and inorganic acid catalysts to produce platform chemicals. This study aimed to evaluate the effectiveness of these catalysts for enhancing reaction rates, improving yields, and promoting selectivity. The results showed that sulfuric acid and adipic acid were the most effective, each resulting in a 20% increase in the total yield, demonstrating the potential of organic acids as efficient catalysts in HTC. Other catalysts, such as benzoic acid and phenylacetic acid, also showed promising results, while butyric acid significantly decreased the total yield. The most abundantly produced platform chemicals were sugars, followed by formic acid, levulinic acid, HMF, and furfural. These findings highlight the potential of coffee cherry waste as a valuable resource for producing key chemicals, and the feasibility of hydrothermal carbonization as a sustainable approach for biomass valorization. This study emphasizes the importance of selecting the appropriate catalysts to optimize the conversion process and maximize the extraction of valuable chemicals. The environmental and economic implications of these findings are significant, as they can contribute to the development of sustainable and efficient biomass utilization technologies that could transform agricultural waste into high-value products while reducing waste and promoting a circular economy.

In this article we can observe the scanning by the literature for the pretreatment of steam explosion applied to lignocellulose biomass. A comparison of the chemical and physical characterization of potato peel as a lignocellulose biomass. Besides, the innovative design of a continuous reactor for the potato peel steam explosion process is shown, with specific temperature and pressure conditions on a pilot scale, detailing its parts. Finally, a finite element analysis was performed where stress results were obtained from the reactor material, severity factor, structural analysis and thermal analysis, providing a panorama of the reactor's behavior with the conditions specific., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Carlos Guerrero reports financial support was provided by Colombia Ministry of Science Technology and Innovation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Colombia is one of the world's leading exporters of coal and coke, with significant reserves of high-quality coal. Most of the coal exported from Colombia is used for power generation, but there is also a class of coal that is suitable for making coke. Coke is a raw material required for making steel, and it is produced by heating coal to high temperatures in the absence of air. Colombia is the third-largest global exporter of coke, with a significant portion of its exports going to the steel industry in countries such as Brazil, Mexico, and the United States. The country's high-quality coal reserves and proximity to major markets make it an important player in the global coal and coke trade. On the other hand, graphene and its derivative Graphene Oxide (GO) have unique properties that make them suitable for a wide range of commercial applications. Graphene has exceptional mechanical strength and high electrical conductivity, which make it an attractive material for a variety of electronic and structural applications. For example, graphene-based materials are being developed for use in flexible electronic devices, sensors, and high-strength composites. GO, on the other hand, is highly resistive but still retains exceptional mechanical strength. This makes it useful in applications where electrical conductivity is not necessary but mechanical strength and durability are important. Graphene production using current techniques can be expensive and inefficient, which limits its widespread adoption for commercial applications. However, new production methods, such as Liquid Phase Exfoliation (LPE), are being developed to address these challenges. LPE is a method for producing graphene and graphene oxide that involves using a liquid solvent to break apart graphite into individual graphene sheets. This method is more efficient and cost-effective than traditional methods such as mechanical exfoliation and chemical vapor deposition. In recent years, there has been increasing interest in using high-rank coal from Colombia as a raw material for graphene production using LPE. This is because high-rank coal from Colombia is known to have a high carbon content and low impurity levels, which makes it an ideal raw material for graphene production. Researchers have successfully produced GO using the LPE method and high-rank coal from Boavita, Colombia. This has the potential to significantly increase the supply of graphene and graphene oxide, making it more accessible for commercial applications. Additionally, using coal as a raw material for graphene production has the potential to create a new market for coal, which could benefit the Colombian economy. In order to synthesize GO, it is important to establish a suitable protocol for the grinding procedure and particle size selection. (i. more than 0.15 mm, ii. 0.15 mm to 0.05 mm, and iii. less than 0.05 mm) were defined. To compare the yield, the mineral matter removal procedure was carried out with a basic leaching bath. Coal oxidation was performed using the modified Hummers process, and GO was then obtained using LPE. This method has the following advantages:•It is feasible to produce GO from high-rank coal with acceptable quality and particulate size smaller than 0.15 mm, yields that are close to 5%, and flakes with fewer than 15 layers.•This approach also could eliminate dependence on graphite as the carbon feedstock for graphene production.•It is an alternative to manufacture GO from coal dust collected from mines., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

Transition metal oxides (TMO) have been successfully used as electrocatalytically active materials for CO 2 reduction in some studies. Because of the lack of understanding of the catalytic behavior of TMOs, electrochemical methods are used to investigate the CO 2 reduction in thin-film nanostructured electrodes. In this context, nanostructured thin films of Fe 2 O 3 and MoO 3 in an aprotic medium of acetonitrile have been used to study the CO 2 reduction reaction. In addition, a synergistic effect between CO 2 and the TMO surface is observed. Faradic cathodic processes not only start at lower potentials than those reported with metal electrodes, but also an increase in capacitive currents is observed, which is directly related to an increase in oxygen vacancies. Finally, the results obtained show CO as a product of the reduction.

Objective: To examine the association between probiotic use and antimicrobial utilization., Study Design: We retrospectively evaluated very-low-birth-weight (VLBW) infants admitted to tertiary neonatal intensive care units in Canada between 2014 and 2019. Our outcome was antimicrobial utilization rate (AUR) defined as number of days of antimicrobial exposure per 1000 patient-days., Result: Of 16,223 eligible infants, 7279 (45%) received probiotics. Probiotic use rate increased from 10% in 2014 to 68% in 2019. The AUR was significantly lower in infants who received probiotics vs those who did not (107 vs 129 per 1000 patient-days, aRR = 0.89, 95% CI [0.81, 0.98]). Among 13,305 infants without culture-proven sepsis or necrotizing enterocolitis ≥Stage 2, 5931 (45%) received probiotics. Median AUR was significantly lower in the probiotic vs the no-probiotic group (78 vs 97 per 1000 patient-days, aRR = 0.85, 95% CI [0.74, 0.97])., Conclusion: Probiotic use was associated with a significant reduction in AUR among VLBW infants., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: Neonatal exposure to episodic hypoxemia and hyperoxemia is highly relevant to outcomes. Our goal was to investigate the differences in the frequency and duration of extreme low and high SpO 2 episodes between automated and manual inspired oxygen control., Design: Post-hoc analysis of a cohort from prospective randomized cross-over studies., Setting: Seven tertiary care neonatal intensive care units., Patients: Fifty-eight very preterm neonates (32 or less weeks PMA) receiving respiratory support and supplemental oxygen participating in an automated versus manual oxygen control cross-over trial., Main Measures: Extreme hypoxemia was defined as a SpO 2  < 80%, extreme hyperoxemia as a SpO 2  > 98%. Episode duration was categorized as < 5 seconds, between 5 to < 30 seconds, 30 to < 60 seconds, 60 to < 120 seconds, and 120 seconds or longer., Results: The infants were of a median postmenstrual age of 29 (28-31) weeks, receiving a median FiO 2 of 0.28 (0.25-0.32) with mostly receiving non-invasive respiratory support (83%). While most of the episodes were less than 30 seconds, longer episodes had a marked effect on total time exposure to extremes. The time differences in each of the three longest durations episodes (30, 60, and 120 seconds) were significantly less during automated than during manual control (p < 0.001). Nearly two-third of the reduction of total time spent at the extremes between automated and manual control (3.8 to 2.1% for < 80% SpO 2 and 3.0 to 1.6% for > 98% SpO 2 ) was seen in the episodes of at least 60 seconds., Conclusions: This study shows that the majority of episodes preterm infants spent in SpO 2 extremes are of short duration regardless of manual or automated control. However, the infrequent longer episodes not only contribute the most to the total exposure, but also their reduction in frequency to the improvement associated with automated control., (© 2022. The Author(s).)

Immunotherapy has raised high expectations in the treatment of virtually every cancer. Many current efforts are focused on ensuring the efficient delivery of active cytotoxic cells to tumors. It is assumed that, once these active cytotoxic cells are correctly engaged to cancer cells, they will unfailingly eliminate the latter, provided that inhibitory factors are in check. T cell bispecific antibodies (TCBs) and chimeric antigen receptors (CARs) offer an opportunity to test this assumption. Using TCB and CARs directed against HER2, here we show that disruption of interferon-gamma signaling confers resistance to killing by active T lymphocytes. The kinase JAK2, which transduces the signal initiated by interferon-gamma, is a component repeatedly disrupted in several independently generated resistant models. Our results unveil a seemingly widespread strategy used by cancer cells to resist clearance by redirected lymphocytes. In addition, they open the possibility that long-term inhibition of interferon-gamma signaling may impair the elimination phase of immunoediting and, thus, promote tumor progression.

In this work, the textural parameters of graphene oxide (GO) and graphite (Gr) samples were determined. The non-local density functional theory (NLDFT) and quenched solid density functional theory (QSDFT) kernels were used to evaluate the pore size distribution (PSD) by modeling the pores as slit, cylinder and slit-cylinder. The PSD results were compared with the immersion enthalpies obtained using molecules with different kinetic diameter (between 0.272 nm and 1.50 nm). Determination of immersion enthalpy showed to track PSD for GO and graphite (Gr), which was used as a comparison solid. Additionally, the functional groups of Gr and GO were determined by the Boehm method. Donor number (DN) Gutmann was used as criteria to establish the relationship between the immersion enthalpy and the parameter of the probe molecules. It was found that according to the Gutmann DN the immersion enthalpy presented different values that were a function of the chemical groups of the materials. Finally, the experimental and modeling results were critically discussed.

A thermodynamic and kinetic study of the adsorption process of Zn (II) and Pb (II) ions from aqueous solution on the surface of graphene oxide (GO) to establish the mechanisms of adsorbate-adsorbent interaction on this surface. The effect of pH on the retention capacity was studied and adsorption isotherms were determined from aqueous solution of the ions; once the experimental data was obtained, the kinetic and thermodynamic study of the sorption process was carried out. The data were fitted to the Langmuir, Freundlich, Dubinin-Raduskevich and Temkin isotherm models. The results showed that Zn(II) and Pb(II) on the GO adsorbing surface fitted the Langmuir model with correlation coefficients (R 2 ) of 0.996. Kinetic models studied showed that a pseudo-second-order model was followed and thermodynamically, the process was spontaneous according to the values of Gibbs free energy (ΔG°). N 2 adsorption isotherms were determined and modeled with the NLDFT (nonlocal density functional theory) and QSDFT (quenched solid density functional theory) kernels., Competing Interests: The authors declare no conflict interest.

Poor tumor targeting of oncolytic adenoviruses (OAdv) after systemic administration is considered a major limitation for virotherapy of disseminated cancers. The benefit of using mesenchymal stem cells as cell carriers for OAdv tumor targeting is currently evaluated not only in preclinical models but also in clinical trials. In this context, we have previously demonstrated the enhanced antitumor efficacy of OAdv-loaded menstrual blood-derived mesenchymal stem cells (MenSCs). However, although significant, the antitumor efficacy obtained was modest, and we hypothesized that a greater antitumor efficacy could be obtained arming the OAdv with a therapeutic transgene. Here we show that combining MenSCs with ICOVIR15-cBiTE, an OAdv expressing an epidermal growth factor receptor (EGFR)-targeting bispecific T-cell engager (cBiTE), enhances the antitumor efficacy compared to MenSCs loaded with the unarmed virus ICOVIR15. We found that MenSCs properly produce cBiTE after viral infection leading to a greater antitumor potency both in vitro and in vivo. These findings indicate the mutual benefit of combining MenSCs and armed OAdv and support the combination of ICOVIR15-cBiTE and MenSCs as a cancer treatment.

Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify CD8+ or CD4+ lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the CD8+PD-1+/hi or CD4+PD-1+/hi subsets, but not in the corresponding bulk or PD-1- fractions. In 6 of 7 individuals analyzed we identified circulating CD8+ and CD4+ lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the CD8+PD-1+ subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer.

All tumors accumulate genetic alterations, some of which can give rise to mutated, non-self peptides presented by human leukocyte antigen (HLA) molecules and elicit T-cell responses. These immunogenic mutated peptides, or neoantigens, are foreign in nature and display exquisite tumor specificity. The correlative evidence suggesting they play an important role in the effectiveness of various cancer immunotherapies has triggered the development of vaccines and adoptive T-cell therapies targeting them. However, the systematic identification of personalized neoantigens in cancer patients, a critical requisite for the success of these therapies, remains challenging. A growing amount of evidence supports that only a small fraction of all tumor somatic non-synonymous mutations (NSM) identified represent bona fide neoantigens; mutated peptides that are processed, presented on the cell surface HLA molecules of cancer cells and are capable of triggering immune responses in patients. Here, we provide an overview of the existing strategies to identify candidate neoantigens and to evaluate their immunogenicity, two factors that impact on neoantigen identification. We will focus on their strengths and limitations to allow readers to rationally select and apply the most suitable method for their specific laboratory setting.

Background: Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor-associated stroma limits the efficacy of oncolytic viruses by forming a barrier that blocks efficient viral penetration and spread. The stroma also plays a critical role in progression, immunosuppression and invasiveness of cancer. Fibroblast activation protein-α (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs), the main cellular component of tumor stroma, and in this study we assessed whether arming oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) could retarget infiltrated lymphocytes towards CAFs, enhancing viral spread and T cell-mediated cytotoxicity against the tumor stroma to improve therapeutic activity., Methods: The bispecific T-cell Engager against FAP was constructed using an anti-human CD3 single-chain variable fragment (scFv) linked to an anti-murine and human FAP scFv. This FBiTE was inserted in the oncolytic adenovirus ICOVIR15K under the control of the major late promoter, generating the ICO15K-FBiTE. ICO15K-FBiTE replication and potency were assessed in HT1080 and A549 tumor cell lines. The expression of the FBiTE and the activation and proliferation of T cells that induced along with the T cell-mediated cytotoxicity of CAFs were evaluated by flow cytometry in vitro. In vivo, T-cell biodistribution and antitumor efficacy studies were conducted in NOD/scid/IL2rg - / - (NSG) mice., Results: FBiTE expression did not decrease the infectivity and replication potency of the armed virus. FBiTE-mediated binding of CD3 + effector T cells and FAP + target cells led to T-cell activation, proliferation, and cytotoxicity of FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. The antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus., Conclusions: Combination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP-expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development.

Several studies have evaluated the efficacy of using human oncolytic adenovirus (OAdv)-loaded mesenchymal stem cells (MSC) for cancer treatment. For example, we have described the antitumor efficacy of CELYVIR, autologous bone marrow-mesenchymal stem cells infected with the OAdv ICOVIR-5, for treatment of patients with neuroblastoma. Results from this clinical trial point out the role of the immune system in the clinical outcome. In this context, a better understanding of the immunophenotypic changes of human MSCs upon adenoviral infection and how these changes affect human autologous or allogeneic peripheral blood mononuclear cells (PBMC) could guide strategies to improve the antitumor efficacy of infected MSCs. In this work, we show how infection by an OAdv induces toll-like receptor 9 overexpression and activation of the NFĸB pathway in menstrual blood-derived MSCs, leading to a specific cytokine secretion profile. Moreover, a proinflammatory environment, mainly mediated by monocyte activation that leads to the activation of both T cells and natural killer cells (NK cell), is generated when OAdv-loaded MSCs are cocultured with allogeneic PBMCs. This combination of allogeneic PBMCs and OAdv-loaded MSCs enhances antitumor efficacy both in vitro and in vivo, an effect partially mediated by monocytes and NK cells. Altogether our results demonstrate not only the importance of the immune system for the OAdv-loaded MSCs antitumor efficacy, but in particular the benefits of using allogeneic MSCs for this therapy., (©2018 American Association for Cancer Research.)

T cells expressing chimeric antigen receptors (CART) have shown significant promise in clinical trials to treat hematologic malignancies, but their efficacy in solid tumors has been limited. Oncolytic viruses have the potential to act in synergy with immunotherapies due to their immunogenic oncolytic properties and the opportunity of incorporating therapeutic transgenes in their genomes. Here, we hypothesized that an oncolytic adenovirus armed with an EGFR-targeting, bispecific T-cell engager (OAd-BiTE) would improve the outcome of CART-cell therapy in solid tumors. We report that CART cells targeting the folate receptor alpha (FR-α) successfully infiltrated preestablished xenograft tumors but failed to induce complete responses, presumably due to the presence of antigen-negative cancer cells. We demonstrated that OAd-BiTE-mediated oncolysis significantly improved CART-cell activation and proliferation, while increasing cytokine production and cytotoxicity, and showed an in vitro favorable safety profile compared with EGFR-targeting CARTs. BiTEs secreted from infected cells redirected CART cells toward EGFR in the absence of FR-α, thereby addressing tumor heterogeneity. BiTE secretion also redirected CAR-negative, nonspecific T cells found in CART-cell preparations toward tumor cells. The combinatorial approach improved antitumor efficacy and prolonged survival in mouse models of cancer when compared with the monotherapies, and this was the result of an increased BiTE-mediated T-cell activation in tumors. Overall, these results demonstrated that the combination of a BiTE-expressing oncolytic virus with adoptive CART-cell therapy overcomes key limitations of CART cells and BiTEs as monotherapies in solid tumors and encourage its further evaluation in human trials. Cancer Immunol Res; 6(5); 605-16. ©2018 AACR ., (©2018 American Association for Cancer Research.)

To enhance adenovirus-mediated oncolysis, different approaches that tackle the selectivity, tumor penetration, and spreading potential of oncolytic adenoviruses have been reported. We have previously demonstrated that insertion of the internalizing Arginine-Glycine-Aspartic (iRGD) tumor-penetrating peptide at the C terminus of the fiber or transgenic expression of a secreted hyaluronidase can improve virus tumor targeting and spreading. Here we report a new oncolytic adenovirus ICOVIR17K-iRGD in which both modifications have been incorporated. In xenografted A549 tumors in nude mice, ICOVIR17K-iRGD shows higher efficacy than the non-iRGD counterpart. To gain insights into the role of the immune system in oncolysis, we have studied ICOVIR17K-iRGD in the tumor isograft mouse model CMT64.6, partially permissive to human adenovirus 5 replication, in immunodeficient or immunocompetent mice. Whereas no efficacy was observed in the immunodeficient setting due to insufficient viral replication, partial efficacy and a polymorphonuclear and CD8+ T cell infiltrate were observed in the immunocompetent mice. The results indicate that the elicitation of a virus-induced anti-tumoral immune response is responsible for the observed partial anti-tumoral effect.

Antiviral immune responses present a major hurdle to the efficacious use of oncolytic adenoviruses as cancer treatments. Despite the existence of a highly immunosuppressive tumor environment, adenovirus-infected cells can nonetheless be efficiently cleared by infiltrating cytotoxic T lymphocytes (CTL) without compromising tumor burden. In this study, we tested the hypothesis that tumor-infiltrating T cells could be more effectively activated and redirected by oncolytic adenoviruses that were armed with bispecific T-cell-engager (BiTE) antibodies. The oncolytic adenovirus ICOVIR-15K was engineered to express an EGFR-targeting BiTE (cBiTE) antibody under the control of the major late promoter, leading to generation of ICOVIR-15K-cBiTE, which retained its oncolytic properties in vitro cBiTE expression and secretion was detected in supernatants from ICOVIR-15K-cBiTE-infected cells, and the secreted BiTEs bound specifically to both CD3 + and EGFR + cells. In cell coculture assays, ICOVIR-15K-cBiTE-mediated oncolysis resulted in robust T-cell activation, proliferation, and bystander cell-mediated cytotoxicity. Notably, intratumoral injection of this cBiTE-expressing adenovirus increased the persistence and accumulation of tumor-infiltrating T cells in vivo , compared with the parental virus lacking such effects. Moreover, in two distinct tumor xenograft models, combined delivery of ICOVIR-15K-cBiTE with peripheral blood mononuclear cells or T cells enhanced the antitumor efficacy achieved by the parental counterpart. Overall, our results show how arming oncolytic adenoviruses with BiTE can overcome key limitations in oncolytic virotherapy. Cancer Res; 77(8); 2052-63. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Antitumor efficacy of systemically administered oncolytic adenoviruses (OAdv) is limited due to diverse factors such as liver sequestration, neutralizing interactions in blood, elimination by the immune system, and physical barriers in tumors. It is therefore of clinical relevance to improve OAdv bioavailability and tumor delivery. Among the variety of tumor-targeting strategies, the use of stem cells and specifically bone marrow-derived mesenchymal stem cells (BM-MSCs) is of particular interest due to their tumor tropism and immunomodulatory properties. Nonetheless, the invasive methods to obtain these cells, the low number of MSCs present in the bone marrow, and their restricted in vitro expansion represent major obstacles for their use in cancer treatments, pointing out the necessity to identify an alternative source of MSCs. Here, we have evaluated the use of menstrual blood-derived mesenchymal stem cells (MenSCs) as cell carriers for regional delivery of an OAdv in the tumor. Our results indicate that MenSCs can be isolated without invasive methods, they have an increased proliferation rate compared to BM-MSCs, and they can be efficiently infected with different serotype 5-based capsid-modified adenoviruses, leading to viral replication and release. In addition, our in vivo studies confirmed the tumor-homing properties of MenSCs after regional administration.

Recombinant adenoviruses are used as vaccines, gene therapy vectors, and oncolytic viruses. However, the efficacy of such therapies is limited by pre-existing neutralizing antibodies (NAbs), especially when the virus is administered systemically for a wider biodistribution or to reach multiple metastases. To protect adenovirus against NAbs we inserted an albumin-binding domain (ABD) in the main adenovirus capsid protein, the hexon. This domain binds serum albumin to shield the virus upon systemic administration. The ABD-modified adenoviruses bind human and mouse albumin and maintain the infectivity and replication capacity in presence of NAbs. In pre-immunized mice non-modified viruses are completely neutralized, whereas ABD-modified viruses preserve the ability to transduce target organs, induce oncolysis, or generate immune responses to expressed proteins. Our results indicate that albumin coating of the virus capsid represents an effective approach to evade pre-existing NAbs. This strategy has translational relevance in the use of adenovirus for gene therapy, cancer virotherapy, and vaccination., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: To determine the efficacy and safety of automated adjustment of the fraction of inspired oxygen (FiO2) in maintaining arterial oxygen saturation (SpO2) within a higher (91%-95%) and a lower (89%-93%) target range in preterm infants., Study Design: Eighty preterm infants (gestational age [median]: 26 weeks, age [median] 18 days) on noninvasive (n = 50) and invasive (n = 30) respiratory support with supplemental oxygen, were first randomized to one of the SpO2 target ranges and then treated with automated FiO2 (A-FiO2) and manual FiO2 (M-FiO2) oxygen control for 24 hours each, in random sequence., Results: The percent time within the target range was higher during A-FiO2 compared with M-FiO2 control. This effect was more pronounced in the lower SpO2 target range (62 ± 17% vs 54 ± 16%, P < .001) than in the higher SpO2 target range (62 ± 17% vs 58 ± 15%, P < .001). The percent time spent below the target or in hypoxemia (SpO2 <80%) was consistently reduced during A-FiO2, independent of the target range. The time spent above the target range or at extreme hyperoxemia (SpO2 >98%) was only reduced during A-FiO2 when targeting the lower SpO2 range (89%-93%). These outcomes did not differ between infants on noninvasive and invasive respiratory support. Manual adjustments were significantly reduced during A-FiO2 control., Conclusions: A-FiO2 control improved SpO2 targeting across different SpO2 ranges and reduced hypoxemia in preterm infants on noninvasive and invasive respiratory support., Trial Registration: ISRCTN 56626482., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Oncolytic adenoviruses can promote immune responses against tumors by expressing and/or displaying tumor-associated antigens. However, the strong immunodominance of viral antigens mask responses against tumor epitopes. In addition, defects in major histocompatibility complex class I antigen presentation pathway such as the downregulation of the transporter-associated with antigen processing (TAP) are frequently associated with immune evasion of tumor cells. To promote the immunogenicity of exogenous epitopes in the context of an oncolytic adenovirus, we have taken advantage of the ER localization of the viral protein E3-19K. We have inserted tumor-associated epitopes after the N-terminal signal sequence for membrane insertion of this protein and flanked them with linkers cleavable by the protease furin to facilitate their TAP-independent presentation. This strategy allowed an enhanced presentation of the exogenous epitopes in TAP-deficient tumor cells in vitro and the generation of higher specific immune responses in vivo that were able to significantly control tumor growth.

Objective: To compare the incidence of oxygen dependency in SIBEN neonatal units while adjusting for altitude., Study Design: We reviewed the charts of infants who were ⩽ 1500 g at birth, admitted to six neonatal intensive care units (NICUs) near sea level and in seven NICUs at varying altitudes above sea level from the SIBEN network between 2008 and 2010. We defined bronchopulmonary dysplasia (BPD) as oxygen dependency at 28 days of life and at 36 weeks postmenstrual age., Result: There were 767 babies in the first group and 318 in the second group. BPD incidence was greater in hospitals at higher altitudes when it was not corrected for barometric pressure. After correction, there was a decrease in the incidence of oxygen dependency at 28 days of life (P<0.0002) and at 36 weeks corrected age. (P<0.0001) CONCLUSION: After correction for higher altitudes, the decrease in oxygen dependency as equivalent to BPD was significant. A proper classification of BPD for higher altitudes is urgently needed.

The field of adenovirology is undergoing rapid change in response to increasing appreciation of the potential advantages of adenoviruses as the basis for new vaccines and as vectors for gene and cancer therapy. Substantial knowledge and understanding of adenoviruses at a molecular level has made their manipulation for use as vaccines and therapeutics relatively straightforward in comparison with other viral vectors. In this review we summarize the structure and life cycle of the adenovirus and focus on the use of adenovirus-based vectors in vaccines against infectious diseases and cancers. Strategies to overcome the problem of preexisting antiadenovirus immunity, which can hamper the immunogenicity of adenovirus-based vaccines, are discussed. When armed with tumor-associated antigens, replication-deficient and oncolytic adenoviruses can efficiently activate an antitumor immune response. We present concepts on how to use adenoviruses as therapeutic cancer vaccines and consider some of the strategies used to further improve antitumor immune responses. Studies that explore the prospect of adenoviruses as vaccines against infectious diseases and cancer are underway, and here we give an overview of the latest developments.

Aim: To investigate the influence of the CagA diversity in Helicobacter pylori (H. pylori) strains from Colombia on the host cell biology., Methods: Eighty-four H. pylori-cagA positive strains with different Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs patterns, isolated from patients with gastritis (n = 17), atrophic gastritis (n = 17), duodenal ulcer (n = 16), intestinal metaplasia (n = 16) and gastric cancer (n = 18), were included. To determine the integrity of the cag pathogenicity island (cagPAI) we evaluated the presence of cagA, cagT, cagE, and cag10 genes by polymerase chain reaction. AGS gastric epithelial cells were infected with each strain and assayed for translocation and tyrosine phosphorylation of CagA by western blot, secretion of interleukin-8 (IL-8) by enzyme-linked immuno sorbent assay after taking supernatants from cocultures and cell elongation induction. For cell elongation quantification, coculture photographs were taken and the proportion of "hummingbird" cells (> 15 μm) was determined., Results: Overall 72% (60/84) of the strains were found to harbor a functional cagPAI. Levels of phosphorylated CagA were significantly higher for isolates from duodenal ulcer than the ones in strains from gastritis, atrophic gastritis, intestinal metaplasia and gastric cancer (49.1% ± 23.1% vs 21.1% ± 19.5%, P < 0.02; 49.1% ± 23.1% vs 26.2% ± 14.8%, P < 0.045; 49.1% ± 23.1% vs 21.5% ± 19.5%, P < 0.043 and 49.1% ± 23.1% vs 29.5% ± 27.1%, P < 0.047 respectively). We observed variable IL-8 expression levels ranging from 0 to 810 pg/mL and from 8.8 to 1442 pg/mL at 6 h and 30 h post-infection, respectively. cagPAI-defective strains did not induce detectable levels of IL-8 at 6 h post-infection. At 30 h post-infection all strains induced IL-8 expression in AGS cells, although cagPAI-defective strains induced significantly lower levels of IL-8 than strains with a functional cagPAI (57.1 ± 56.6 pg/mL vs 513.6 ± 338.6 pg/mL, P < 0.0001). We did not observe differences in the extent of cell elongation induction between strains with a functional or a defective cagPAI in 6 h cocultures. At 24 h post infection strains with functional cagPAI showed high diversity in the extent of hummingbird phenotype induction ranging from 7% to 34%. cagPAI defective strains induced significantly lower levels of elongation than strains with functional cagPAI with one or more than one EPIYA-C motif (15.1% ± 5.2% vs 18.9% ± 4.7%, P < 0.03; and 15.1% ± 5.2% vs 20.0% ± 5.1%, P < 0.003 respectively). No differences were observed in cellular elongation induction or IL-8 expression among H. pylori strains bearing one and more than one EPIYA-C motifs, neither at 6 h nor at 24 h of coculture. There were no associations between the levels of induction of cell elongation or IL-8 expression and number of EPIYA motifs or pathology., Conclusion: The present work describes a lack of association between H. pylori CagA protein EPIYA motifs variations from Colombian isolates and disease-associated cellular responses.

To examine the influence of sleep state, respiratory pattern, and ventilation on cyclical fluctuations (CF) in cerebral blood flow (CBF) velocity (CBFV), we studied 21 'healthy' preterm infants: birth weight 1,790 +/- 162 g (SEM), study weight 1,960 +/- 165 g, gestational age 32 +/- 1 weeks, postnatal age 20 +/- 4 (range 8-57) days. The CBFV was measured using on-line pulsed Doppler ultrasound by insonating the middle cerebral artery. Breathing was measured using a flow through system. The sleep state was monitored according to conventional criteria. Three hundred and seventy-five epochs of 1 min each were analyzed; 207 during quiet sleep (QS) and 168 during rapid eye movement (REM) sleep. CFs in CBFV were detected in all babies. The frequency of CF ranged from 0.5 to 6 cycles/min. The proportion of epochs showing CF was similar during both sleep states (56% QS vs. 59% REM; p = NS). Although the mean CBFV (cm/s) was similar in these two sleep states, the mean coefficient of variation, a measure of CF amplitude, was significantly higher during REM as compared with QS (6 +/- 0.5 vs. 4.3 +/- 0.2%; p < 0.05). Similarly, the mean CBFVs were similar with various respiratory patterns, but the coefficient of variation was significantly higher in periodic and apneic patterns as compared with regular and irregular respiratory patterns (5.6 +/- 0.6% periodic, 5.6 +/- 0.3% apneic, 3.6 +/- 0.3% regular, and 4.1 +/- 0.5% irregular, p < 0.05). The amplitude of CF was associated with the variability of the heart rate (p < 0.05), but not with the variability of the respiratory measurements. These findings suggest: (1) REM sleep is associated with a greater CBF variability than QS, and (2) periodic and apneic breathing are associated with a greater CBF variability than regular or irregular breathing. We speculate that sleep state and respiratory pattern do not determine but modulate the CBF. Our data suggest that in studies involving interpretation of CBFV data using the Doppler technique, breathing patterns should be taken into account in addition to sleep state.

We evaluated a new method of monitoring cerebral blood flow velocity (CBFV) and described changes in CBFV in relation to central apnea in 17 healthy term infants. The area under the velocity curve during apnea did not change, whereas area under the velocity curve per the waveform showed a significant difference, suggesting that stability is maintained through an increase in CBFV with each heartbeat. The maintenance of cerebral hemodynamics during isolated central apnea supports the assumption that these episodes are benign.

Unlabelled: Recently, inhaled nitric oxide (NO) became clinically available for the treatment of persistent pulmonary hypertension of the newborn. Such use requires administration and continuous monitoring of a very low concentration of NO to prevent potential toxicity. Since limited data on the reliability of NO monitoring devices are available, we evaluated the performance of a chemiluminescent and electrochemical sensor NO analyzer in a patient ventilator circuit., Results: The chemiluminescence analyzer readings were significantly altered by the oxygen concentration in the ventilator circuit. When the FiO2 was increased from 0.21 to 1, a 4.5% +/- 0.3 decrease in the NO readings was found (p < 0.01). Similarly, adding humidity to the circuit, reduced the NO readings by 4.8% +/- 0.9 (p < 0.01). The effect of gas pressure was proportional to its magnitude but independent of whether a pulsatile or continuous gas flow was provided. At a mean airway pressure of 15 cm H2O, the NO readings increased by 3.94% +/- 0.05 (NO = 10 parts per million) and 3.97% +/- 0.02 (40 parts per million) (p < 0.01). The electrochemical sensor NO readings were directly proportional to the ventilator circuit pressure but independent of whether a pulsatile or continuous gas flow was provided. At a mean airway pressure of 15 cm H2O, the NO reading was increased by 25.39% +/- 0.04 (NO = 40 parts per million) (p < 0.01) and 1.07% +/- 0.16 (NO = 10 parts per million) (p NS). The greatest difference with NO = 10 parts per million from baseline was found at a mean airway pressure of 6 cm H2O (6.67% +/- 0.23; p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypothesis that sighs are mechanistically important in triggering apnea, we studied 10 preterm infants, group 1: body weight 1.8 +/- 0.1 kg, gestational age 33 +/- 1 weeks, postnatal age 21 +/- 4 days, and 10 term infants, group 2: body weight 3.9 +/- 0.15 kg, gestational age 40 +/- 0.4 weeks, postnatal age 1.4 +/- 0.2 days. Instantaneous ventilatory changes associated with a sigh were studied in another 10 preterm infants, group 3: body weight 1.6 +/- 0.11 kg, gestational age 32 +/- 0.4 weeks, postnatal age 25 +/- 4 days. Ventilation was measured using a nosepiece and a flow-through system. Sleep states were recorded. Sighs were more frequent in preterm than in term infants (0.4 +/- 0.04 vs. 0.18 +/- 0.03 sighs/min; p = 0.03) and in rapid eye movement than in quiet sleep (0.5 +/- 0.05 vs. 0.3 +/- 0.05 sighs/min; p = 0.05). Of 722 apneas, 235 (33%) were associated with a sigh; of these, 113 (48%) preceded and 122 (52%) followed a sigh. Sighs induced with airway occlusion (groups 1 and 2) were more frequent after occlusion on 21 than on 35% O2, particularly when O2 saturation was low and negative airway pressure high. Instantaneous ventilation measured over 10 breaths preceding a sigh did not show any trend indicating the possible appearance of a sigh. Tidal volume increased from 7.5 +/- 0.7 before the sigh to 18.9 +/- 0.7 ml/kg (p < 0.01) during a sigh, with a significant increase in inspiratory drive. Ventilation increased from 0.327 +/- 0.041 to 0.660 +/- 0.073 l/min/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

To test the hypotheses that administering dopamine before and concurrently with indomethacin therapy would (1) increase successful ductal closure rate, (2) act by maintaining a diuresis, and (3) prevent oliguria or high serum creatinine concentrations, we conducted a randomized, controlled trial in infants whose gestational age was <36 weeks and who had hemodynamically significant ductus arteriosus. Thirty-six infants were selected to receive a continuous infusion of either placebo or dopamine at either a low dosage of 2 micrograms/kg per minute or a higher dosage of 5 micrograms/kg per minute, beginning 6 hours before the use of indomethacin and continuing until 12 hours after the third dose of indomethacin. A total of 12 patients were selected to receive placebo, 14 were selected to receive "low dopamine," and 10 were selected to receive "high dopamine." The three groups were similar in their initial characteristics. Serum creatinine concentrations, urine output, and fractional excretion of sodium were not different in the three groups after indomethacin treatment. Two patients receiving placebo required a second course of indomethacin compared with four patients in the low-dopamine group and one in the high-dopamine group. The proportion of failures of medical treatment was not statistically different among the three groups. We conclude that concomitant dopamine therapy neither decreases the failure rate in indomethacin-treated infants nor reduces the magnitude of the indomethacin-induced oliguria.

A term female infant was admitted to the intensive care unit with the diagnosis of tetralogy of Fallot with critical pulmonary stenosis. On the seventh day of life a long saphenous line was inserted that remained without complications until seven days later when the infant appeared septic. A lumbar puncture demonstrated the presence of intra-lipid in the cerebrospinal fluid that we interpreted as due to migration of the saphenous catheter. The child had an uneventful recovery.

Although the administration of 100% O2 alone or combined with umbilical cord occlusion induces continuous breathing and arousal in the fetal sheep (Baier, Hasan, Cates, Hooper, Nowaczyk & Rigatto, 1990a), the individual contribution of O2 and cord occlusion to the response have not been determined. We hypothesized that if O2 is an important factor in the induction of continuous breathing, administration of O2 low enough (10%) to bring fetal arterial PO2 to about 20 torr while the fetus is breathing continuously should reverse these changes. Thus we subjected 12 chronically instrumented fetal sheep to 10% O2 for 10 minutes after the establishment of continuous breathing by O2 (4 fetuses; 137 +/- 1 days) or by O2 plus umbilical cord occlusion (8 fetuses; 134 +/- 1 days). Arterial PO2 decreased from about 250 torr to 20 torr during 10% O2. This induced a significant decrease in breathing output (EMGdi x f) related primarily to a decrease in frequency (f). In 3/5 experiments in 4 fetuses, with O2 alone, apnoea developed within 4 +/- 0.6 min; in 12/13 experiments in 8 fetuses, with added cord occlusion it developed at 5 +/- 0.6 min. With the decrease in PaO2, electrocortical activity (ECoG) switched from low to high-voltage within 6 minutes in 5/5 experiments (O2 alone) and in 11/13 (O2 plus cord occlusion). The findings suggest that umbilical cord occlusion alone is not sufficient to maintain breathing continuously and an increased PaO2 is needed. We speculate that in the fetus there is a vital link between PaO2, breathing and ECoG with low PaO2 inhibiting and high PaO2 favouring breathing and arousal.