Distribution of novel immune-checkpoint targets in ovarian cancer tumor microenvironment: A dynamic landscape.

BackgroundThe disappointing activity of single agent immune-checkpoint inhibitors in epitherlial ovarian cancer (EOC) has been attributed in part to its unique tumor microenvironment (TME). IDO, PDL1, LAG3 and TIM3 have been implicated in the immunotolerance of EOC. We investigated the expression of these co-regulators, their change with neoadjuvant chemotherapy (NACT), and their association with outcome.MethodWe identified 98 patients with EOC treated with NACT and performed IDO, PDL1, LAG3 and TIM3 immunohistochemistry on samples obtained before and after NACT. The cut-off threshold to consider a positive sample was set at 5%.ResultsIn our cohort, TIM3 was the most prevalent co-regulator, with more than 75% of the samples being TIM3 positive. In comparison, only 22%, 28% and 17% of the samples were considered IDO, PDL1 and LAG3 positive. More than half of ovarian tumors expressed 2, 3 or even all 4 co-inhibitory molecules. However, biomarkers were not correlated with each other. NACT had a marked impact on immune co-regulator expression with over 70% of patients showing a change in biomarker status from negative to positive or vice versa. There was no significant difference in the pattern of co-regulator expression between platinum-sensitive and resistant patients. Co-expression of multiple inhibitory molecules did not appear to affect overall and progression-free survival.ConclusionTIM3 is the most abundant co-inhibitory molecule in OC and may represent an attractive target. In addition, OC frequently co-expressed 2 or more markers supporting ICI combinatorial approaches. Finally, NACT significantly altered the expression of immunosuppressive molecules suggesting that the choice of ICI combinations should be adapted to the composition of the post-NACT immune TME.     

Reevaluating brain networks activated during mental imagery of finger movements using probabilistic Tensorial Independent Component Analysis (TICA)

The cerebral and cerebellar networks involved in execution and mental imagery of the same sequential finger movements performed with the non-dominant hand were assessed by 3T functional magnetic resonance imaging using multivariate model-free analysis. Eight right-handed healthy volunteers successively performed execution and mental imagery tasks (sequential thumb to fingers opposition). The same data were analyzed by using (1) the linear General Model (p < 0.05 corrected), and (2) probabilistic tensorial independent component analysis (TICA). TICA confirmed that overt movement execution and motor imagery share a common network mainly including: premotor, parietal, insular, temporal, cerebellar cortices and putamen. Motor imagery specifically and bilaterally recruited frontopolar, prefrontal, cingulate, medial insula, neocerebellar cortices and precuneus. Non-dominant hand movements induced bilateral brain and cerebellar activation. In comparison with GLM, TICA identified a more widespread and bilateral network especially during motor imagery. TICA revealed that motor imagery also recruits frontopolar precuneal and occipital cortices, rostral M1/S1 corresponding to the hand somatotopic representation, thalamus and cerebellar lobule VIII. TICA also showed concomitant activation of (1) a cerebello-thalamo-cortical network during motor execution, and (2) a control executive network during imagination. TICA therefore allows precise identification of the brain networks collaborating in the same performance. TICA constitutes a valuable tool to assess and improve detection of brain networks engaged in mental imagery in comparison with GLM.     

Eosin B as a novel antimalarial agent for drug-resistant Plasmodium falciparum

4',5'-Dibromo-2',7'-dinitrofluorescein, a red dye commonly referred to as eosin B, inhibits Toxoplasma gondii in both enzymatic and cell culture studies with a 50% inhibitory concentration (IC(50)) of 180 microM. As a non-active-site inhibitor of the bifunctional T. gondii dihydrofolate reductase-thymidylate synthase (DHFR-TS), eosin B offers a novel mechanism for inhibition of the parasitic folate biosynthesis pathway. In the present study, eosin B was further evaluated as a potential antiparasitic compound through in vitro and cell culture testing of its effects on Plasmodium falciparum. Our data revealed that eosin B is a highly selective, potent inhibitor of a variety of drug-resistant malarial strains, with an average IC(50) of 124 nM. Furthermore, there is no indication of cross-resistance with other clinically utilized compounds, suggesting that eosin B is acting via a novel mechanism. The antimalarial mode of action appears to be multifaceted and includes extensive damage to membranes, the alteration of intracellular organelles, and enzymatic inhibition not only of DHFR-TS but also of glutathione reductase and thioredoxin reductase. In addition, preliminary studies suggest that eosin B is also acting as a redox cycling compound. Overall, our data suggest that eosin B is an effective lead compound for the development of new, more effective antimalarial drugs.     

Prevalence and impact of pain on the quality of life of lung transplant recipients: a prospective observational study

STUDY OBJECTIVE: To study the prevalence and impact of pain on the quality of life (QOL) of lung transplant recipients. Design and patients: Prospective, observational, cross-sectional study. Ninety-six lung transplant recipients (> 3 months after transplantation) completed questionnaires measuring the severity and impact of pain (Brief Pain Inventory), anxiety (State Trait Anxiety Inventory), QOL (Short Form-36 version 2 [SF-36v2]), and depression (Beck Depression Inventory [BDI]). SETTING: University medical center lung transplant outpatient clinic. RESULTS: The prevalence of pain in lung transplant recipients was 49%. Patients with pain were older, more likely to have undergone unilateral lung transplantation (64% vs 40%, p = 0.03), and were more likely to have lung emphysema (55% vs 38%, p = 0.004). Only a pulmonary diagnosis of lung emphysema remained an independent predictor for postoperative pain in a logistic regression model. Average (+/- SD) score of the BDI was 9.6 +/- 7.8 and 5.8 +/- 5.8 (p = 0.005) for patients with and without pain, respectively. Patients with and without pain did not significantly differ in terms of anxiety. Pain-free patients had a significantly higher physical component score than patients with pain in the SF-36v2 (mean, 48.7 +/- 8.6 vs 38.6 +/- 9.8, p < 0.0001, respectively), while the mental component scores were not statistically different between the two groups. CONCLUSIONS: Lung transplant recipients have a high prevalence of pain. Patients with lung emphysema as their preoperative diagnosis are more likely to have pain. The occurrence of pain is associated with a decreased QOL in lung transplant recipients.     

Tonotopic control of auditory thalamus frequency tuning by reticular thalamic neurons

GABAergic cells of the thalamic reticular nucleus (TRN) can potentially exert strong control over transmission of information through thalamus to the cerebral cortex. Anatomical studies have shown that the reticulo-thalamic connections are spatially organized in the visual, somatosensory, and auditory systems. However, the issue of how inhibitory input from TRN controls the functional properties of thalamic relay cells and whether this control follows topographic rules remains largely unknown. Here we assessed the consequences of increasing or decreasing the activity of small ensembles of TRN neurons on the receptive field properties of medial geniculate (MG) neurons. For each MG cell, the frequency tuning curve and the rate-level function were tested before, during, and after microiontophoretic applications of GABA, or of glutamate, in the auditory sector of the TRN. For 66 MG cells tested during potent pharmacological control of TRN activity, group data did not reveal any significant effects. However, for a population of 20/66 cells (all but 1 recorded in the ventral, tonotopic, division), the breadth of tuning, the frequency selectivity and the acoustic threshold were significantly modified in the directions expected from removing, or reinforcing, a dominant inhibitory input onto MG cells. Such effects occurred only when the distance between the characteristic frequency of the recorded ventral MG cell and that of the TRN cells at the ejection site was <0.25 octaves; they never occurred for larger distances. This relationship indicates that the functional interactions between TRN cells and ventral MG cells rely on precise topographic connections.