Purpose
Chimeric antigen receptor (CAR) engineered T-cells occupy an increasing niche in cancer immunotherapy. In this context, CAR-mediated CD3ζ signaling is sufficient to elicit cytotoxicity and ...interferon-γ production while the additional provision of CD28-mediated signal 2 promotes T-cell proliferation and interleukin (IL)-2 production. This compartmentalisation of signaling opens the possibility that complementary CARs could be used to focus T-cell activation within the tumor microenvironment.
Methods
Here, we have tested this principle by co-expressing an ErbB2- and MUC1-specific CAR that signal using CD3ζ and CD28 respectively. Stoichiometric co-expression of transgenes was achieved using the SFG retroviral vector containing an intervening
Thosea asigna
peptide.
Results
We found that “dual-targeted” T-cells kill ErbB2
+
tumor cells efficiently and proliferate in a manner that requires co-expression of MUC1 and ErbB2 by target cells. Notably, however, IL-2 production was modest when compared to control CAR-engineered T-cells in which signaling is delivered by a fused CD28 + CD3ζ endodomain.
Conclusions
These findings demonstrate the principle that dual targeting may be achieved using genetically targeted T-cells and pave the way for testing of this strategy in vivo.
The vascular endothelium is a multifunctional organ and is critically involved in modulating vascular tone and structure. Endothelial cells produce a wide range of factors that also regulate cellular ...adhesion, thromboresistance, smooth muscle cell proliferation, and vessel wall inflammation. Thus, endothelial function is important for the homeostasis of the body and its dysfunction is associated with several pathophysiological conditions, including atherosclerosis, hypertension and diabetes. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus. The mechanisms of endothelial dysfunction in diabetes may point to new management strategies for the prevention of cardiovascular disease in diabetes. This review will focus on the mechanisms and therapeutics that specifically target endothelial dysfunction in the context of a diabetic setting. Mechanisms including altered glucose metabolism, impaired insulin signaling, low-grade inflammatory state, and increased reactive oxygen species generation will be discussed. The importance of developing new pharmacological approaches that upregulate endothelium-derived nitric oxide synthesis and target key vascular ROS-producing enzymes will be highlighted and new strategies that might prove clinically relevant in preventing the development and/or retarding the progression of diabetes associated vascular complications.
•Overview of the multiple functions of endothelium•Mechanisms underlying diabetes-related endothelial dysfunction•Endothelial dysfunction a main therapeutic target for cardiovascular disease•Potential therapeutics for vascular endothelial dysfunction•Potential NO-based therapeutic approaches for endothelial dysfunction
This study optimized the conditions of Lactobacillus casei NRRL B-442 cultivation in cashew apple juice, as well as, determined the proper inoculum amount and fermentation time. Moreover, it was ...investigated the survivability ability of L. casei in cashew apple juice during refrigerated storage (4°C) for 42days. The optimum conditions for probiotic cashew apple juice production were initial pH 6.4, fermentation temperature of 30°C, inoculation level of 7.48 Log CFU/mL (L. casei) and 16h of fermentation process. It was observed that the L. casei grew during the refrigerated storage. Viable cell counts were higher than 8.00 Log CFU/mL throughout the storage period (42days). The values of lightness, yellowness and total color change increased and the values of redness reduced along the fermentation and refrigerated storage periods. The fermented juice with L. casei is a good and healthy alternative functional food containing probiotics. Cashew apple juice showed to be as efficient as dairy products for L. casei growth.
To evaluate the incidence and risk factors of lymphedema 10 years after surgical treatment for breast cancer.
Prospective observational hospital-based cohort of women undergoing axillary lymph node ...dissection. Lymphedema was assessed by indirect volume, measured by circumference, and diagnosed if there was a difference of 200 mL between the arms or if the patient was treated for it. Independent variables were patient, tumour and treatment characteristics. Descriptive statistics were conducted as survival analysis using the Kaplan-Meier estimate. Cox regression was performed, considering a 95% confidence interval (95%CI).
The study evaluated 964 women. The cumulative incidence of lymphedema observed was 13.5% at two years of follow-up, 30.2% at five years and 41.1% at 10 years. Final model showed an increased risk for lymphedema among women that underwent radiotherapy (HR = 2.19; 95%CI 1.63–2.94), were obese (HR = 1.52; 95%CI 1.20–1.92), had seroma formation after surgery (HR = 1.46; 95%CI 1.14–1.87), underwent chemotherapy infusion in the affected limb (HR = 1.45; 95%CI 1.12–1.87) or advanced disease staging (HR = 1.41; 95%CI 1.11–1.80).
Cumulative incidence of lymphedema was 41.1%. Women undergoing axillary radiotherapy, obese, who developed seroma, underwent chemotherapy infusion in the affected limb and with advanced disease had a higher risk of lymphedema.
•We followed a cohort of women surgically treated for breast cancer for 10 years.•Incidence of lymphedema increases from 13.5% in two years to 41.1% in ten years.•Radiotherapy, obesity, seroma, chemotherapy and stage were associated variables.
(Rubiaceae) has a recognized therapeutic potential against various diseases associated with oxidative stress. The aim of this research was to evaluate the antioxidant potential of an aqueous leaf ...extract (ALE) from
, and its major alkaloids mitraphylline and isomitraphylline. The antioxidant activity of ALE was investigated in vitro using standard assays (DPPH, ABTS and FRAP), while the in vivo activity and mode of action were studied using
as a model organism. The purified alkaloids did not exhibit antioxidant effects in vivo. ALE reduced the accumulation of reactive oxygen species (ROS) in wild-type worms, and was able to rescue the worms from a lethal dose of the pro-oxidant juglone. The ALE treatment led to a decreased expression of the oxidative stress response related genes
,
and
. The treatment of mutant worms lacking the DAF-16 transcription factor with ALE resulted in a significant reduction of ROS levels. Contrarily, the extract had a pro-oxidant effect in the worms lacking the SKN-1 transcription factor. Our results suggest that the antioxidant activity of ALE in
is independent of its alkaloid content, and that SKN-1 is required for ALE-mediated stress resistance.
We conducted a prospective cohort study in a population with diverse ethnic backgrounds from Brazil to assess clinically meaningful symptoms after surviving coronavirus disease. For most of the 175 ...patients in the study, clinically meaningful symptoms, including fatigue, dyspnea, cough, headache, and muscle weakness, persisted for >120 days after disease onset.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
L. (lupine) is a legume whose grain/seed has gained increasing interest. Its recognized nutritional properties, namely a high content of protein, dietary fiber and its low fat content, make lupine a ...suitable alternative not only for animal protein, but also as a substitute for more processed and less balanced flours from a nutritional point of view, used in the preparation of bread, cakes and cookies, among others. In addition, its nutritional and bioactive compounds have potential benefits for human health in the prevention and treatment of some diseases. However, the existence of some anti-nutritional compounds and contaminants reveal some concern, requiring effective methods for their detection and eventual removal. This review intends to address the potential of lupine (
) in food and human health and to balance the pros and cons. Nutritional and anti-nutritional components of
seeds and possible contaminants of lupine seeds are examined. The potential health benefits of lupine (seeds), including energy metabolism, cardiovascular diseases, hypertension, glucose and insulin metabolism, bower function and anticonvulsant action, are discussed based on scientific evidence (both clinical trials and studies performed with animal models).
Polyclonal T-cells can be directed against cancer using transmembrane fusion molecules known as chimeric antigen receptors (CARs). Although preclinical studies have provided encouragement, pioneering ...clinical trials using CAR-based immunotherapy have been disappointing. Key obstacles are the need for robust expansion ex vivo followed by sustained survival of infused T-cells in patients. To address this, we have developed a system to achieve selective proliferation of CAR+ T-cells using IL-4, a cytokine with several pathophysiologic and therapeutic links to cancer. A chimeric cytokine receptor (4αβ) was engineered by fusion of the IL-4 receptor α (IL-4Rα) ectodomain to the βc subunit, used by IL-2 and IL-15. Addition of IL-4 to T-cells that express 4αβ resulted in STAT3/STAT5/ERK phosphorylation and exponential proliferation, mimicking the actions of IL-2. Using receptor-selective IL-4 muteins, partnering of 4αβ with γc was implicated in signal delivery. Next, human T-cells were engineered to co-express 4αβ with a CAR specific for tumor-associated MUC1. These T-cells exhibited an unprecedented capacity to elicit repeated destruction of MUC1-expressing tumor cultures and expanded through several logs in vitro. Despite prolonged culture in IL-4, T-cells retained specificity for target antigen, type 1 polarity, and cytokine dependence. Similar findings were observed using CARs directed against two additional tumor-associated targets, demonstrating generality of application. Furthermore, this system allows rapid ex vivo expansion and enrichment of engineered T-cells from small blood volumes, under GMP-compliant conditions. Together, these findings provide proof of principle for the development of IL-4-enhanced T-cell immunotherapy of cancer.
A new series of Zn(
ii
) and Cu(
ii
)-based porphyrin complexes
5a
and
5b
doubly functionalised with carbazole units were developed to be used as hole-transporting materials (HTMs) in perovskite ...solar cells (PSCs). These complexes were obtained
via
a nucleophilic substitution reaction mediated by PhI(OAc)
2
/NaAuCl
4
·2H
2
O, or using C-N transition metal-assisted coupling. The hole extraction capability of
5a
and
5b
was assessed using cyclic voltammetry; this study confirmed the better alignment of the Zn(
ii
) complex
5a
with the perovskite valence band level, compared to the Cu(
ii
) complex
5b
. The optimised geometry and molecular orbitals of both complexes also corroborate the higher potential of
5a
as a HTM. Photoluminescence characterisation showed that the presence of
5a
and
5b
as HTMs on the perovskite surface resulted in the quenching of the emission, matching the hole transfer phenomenon. The photovoltaic performance was evaluated and compared with those of reference cells made with the standard HTM spiro-OMeTAD. The optimised
5
-based devices showed improvements in all photovoltaic characteristics; their open circuit voltage (
V
oc
) reached close to 1 V and short-circuit current density (
J
sc
) values were 13.79 and 9.14 mA cm
−2
for
5a
and
5b
, respectively, disclosing the effect of the metallic centre. A maximum power conversion efficiency (PCE) of 10.01% was attained for
5a
, which is 65% of the PCE generated by using the spiro-OMeTAD reference. This study demonstrates that C-N linked donor-type porphyrin derivatives are promising novel HTMs for developing efficient and reproducible PSCs.
A novel series of Zn(
ii
) and Cu(
ii
)-based porphyrin complexes doubly functionalised with carbazole units pave the way for efficient hole-transporting materials for perovskite solar cells.
•Biogas production and electric generation by individual assessment of landfills.•Electric capacity estimated by simplified technical and economic optimization.•Electric potential out of landfill ...biogas 4 times as high as the explored.•Consortiums can improve the economic feasibility of landfill biogas power plants.
Due to the relatively low investment, operation costs, and technical requirements, landfills are still the most widespread alternative for final disposal of municipal solid waste (MSW). The biogas produced in the landfill, a renewable energy source, may be an important alternative for electric power generation. Brazil has a significant number of operating landfills, which receive the most part of the collected MSW. However, the country has only 17 landfill biogas power plants (LBPPs), resulting in about 122 MW of capacity. The United Kingdom, for instance, which is about 3 times smaller than Brazil in population, has 442 LBPPs (corresponding to 1051 MW of capacity). This fact highlights a considerable unexplored potential of landfill biogas in Brazil. It is also important to estimate this potential throughout the country to provide information for the government, researchers and companies in decision making, planning and formulation of public policies regarding this use of landfill biogas. Therefore, this study aims at estimating the spatially distributed potential of landfill biogas production that can be used for electric power generation in Brazil from 2015 to 2045, considering two scenarios: (i) operating sanitary landfills and (ii) hypothetical scenario of Territorial Arrangements (TA) comprising every Brazilian city, considering one landfill per TA. The total installed capacity estimated in 2018 for scenario 1 is about 523 MW and 87% of this number are related to LBPPs bigger than 1 MW. In this same year, the total installed capacity estimated for scenario 2 is 768 MW and 95% of this number are related to LBPPs bigger than 1 MW. These results emphasize that Brazil has a considerable unexplored potential of landfill biogas and the importance of municipal consortiums for MSW management.
PDF
