Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1−CD8+ Tumor-Infiltrating T Cells

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A randomized controlled trial of a protocol of interviews designed to improve adherence to antiretroviral medications in southern Brazil

The aim of this study was to evaluate the efficacy of the Portuguese version of the Medication Adherence Training Instrument (MATI) for improving adherence to antiretroviral therapy (ART) in southern Brazil. Two different follow-up modalities were compared in this 225 days randomized controlled study: one based on the MATI protocol and a conventional (non-MATI) clinical follow-up. There were no differences between the groups with the exception of socioeconomic class (P < 0.005). The mean length of continuance in treatment was 111.4 (SD = 13.9) and 137.6 (SD = 17.3) days in the MATI and non-MATI groups, respectively. A Mantel-Cox log-rank test revealed no significant difference between the two interventions (P = 0.34). Despite the sample size limitation, the results from this study indicate that the Portuguese version of the MATI was not more efficacious than the regular follow-up intervention for improving adherence of outpatients to ART.     

Increasing frequency of hospital admissions for retinal detachment and vitreo-retinal surgery in England 2000–2018

ObjectivesTo analyse the changes in reported frequency of retinal detachment admissions and vitreo-retinal surgery procedures performed between 2000 and 2018 in England. To obtain information useful to contribute towards the planning of service delivery.MethodsAnalysis of England’s Hospital Episode Statistics from the Health and Social Care Information Centre and population data from the United Kingdom’s Office for National Statistics.ResultsEpisodes of ‘retinal detachments with breaks’ increased year on year from 3447 (7.0/100 M) in 2000 to 10,971 (19.7/100 M) in 2018 (p < 0.001), whereas records of ‘tractional retinal detachment’ increased from 290 (0.6/100 M) to 910 (1.6/100 M) in the same period (p < 0.0001). The number of reported pars plana vitrectomies irrespective of indication increased over fourfold from 5761 to 26,900 (p < 0.0001), while the number of scleral buckling records decreased by two thirds from 2897 to 780 (p < 0.0001). During the same period, the population of England increased from 49.2 to 55.6 million, proportionally at a slower rate than that for recorded hospital episodes.ConclusionsThe frequency of admissions to hospital for surgically treated retinal detachment seems to have been increasing significantly since 2000. This effect is more marked in cases of rhegmatogenous retinal detachment. This may be explained by increased incidence of disease (due to increased rates of cataract surgery, increasing longevity and increasing rates of myopia) as well as repeat surgery in cases of recurrent retinal detachment. Other factors which may play a role include improvements in patient access, increased public awareness and improved local coding and reporting practice.Subject terms: Retinal diseases, Epidemiology     

A3 adenosine receptor as a target for cancer therapy

Targeting the A3 adenosine receptor (A3AR) by adenosine or a synthetic agonist to this receptor (IB-MECA and Cl-IB-MECA) results in a differential effect on tumor and on normal cells. Both the adenosine and the agonists inhibit the growth of various tumor cell types such as melanoma, colon or prostate carcinoma and lymphoma. This effect is specific and is exerted on tumor cells only. Moreover, exposure of peripheral blood mononuclear cells to adenosine or the agonists leads to the induction of granulocyte colony stimulating factor (G-CSF) production. When given orally to mice, the agonists suppress the growth of melanoma, colon and prostate carcinoma in these animals, while inducing a myeloprotective effect via the induction of G-CSF production. The de-regulation of the Wnt signaling pathway was found to be involved in the anticancer effect. Receptor activation induces inhibition of adenylyl cyclase with a subsequent decrease in the level of protein kinase A and protein kinase B/Akt leading to activation of glycogen synthase kinase-3beta, a key element in the Wnt pathway. The oral bioavailability of the synthetic A3AR agonists, and their induced systemic anticancer and myeloprotective effect, renders them potentially useful in three different modes of treatment: as a stand-alone anticancer treatment, in combination with chemotherapy to enhance its therapeutic index and myelprotection. It is evident that use of the A3AR agonist for increasing the therapeutic index of chemotherapy may also invariably give rise to myeloprotection and vice versa. The A3AR agonists are thus a promising new class of agents for cancer therapy.     

Inhibition of primary colon carcinoma growth and liver metastasis by the A3 adenosine receptor agonist CF101

Adenosine is a purine nucleoside that acts as a regulatory molecule by binding to specific G-protein-coupled A1, A(2A), A(2B), and A3 cell surface receptors. We have recently demonstrated that adenosine inhibits tumour cell growth and concomitantly stimulates bone marrow cell proliferation via activation of the A3 adenosine receptor (A3AR). In the present study, we show that a synthetic agonist to the A3AR, CF101, at the low nanomolar concentration range, inhibits HCT-116 human colon carcinoma cell growth. This effect was reversed by the selective A3AR antagonist MRS1523, demonstrating the specificity of the response. CF101 (given orally) was efficacious in inhibiting the development of primary tumours in xenograft and syngeneic models in which mice were inoculated subcutaneously with human HCT-116 or murine CT-26 colon carcinoma cells, respectively. Moreover, CF101 suppressed (50%, P<0.01) colon cancer liver metastases in syngeneic mice inoculated to the spleen with CT-26 cells. The mechanism of action entailed upregulation of interleukin-12 production in the CF101-treated groups and potentiation of NK cell activity. In the HCT-116 xenograft model in which a combined therapy of CF101 and 5-fluorouracyl (5-FU) was examined, an additive antitumour effect was demonstrated. Moreover, CF101 prevented the 5-FU-induced myelotoxicity, resulting in normal values of white blood cell and neutrophil counts. We conclude that the A3AR agonist CF101, a small orally bioavailable molecule, exerts systemic anticancer, antimetastatic, and myeloprotective effects in colon carcinoma-bearing mice, and may serve as an adjuvant treatment to enhance the chemotherapeutic index and prevent myelotoxicity.