Association of prolactin receptor (PRLR) variants with prolactinomas

Prolactinomas are the most frequent type of pituitary tumors, which represent 10–20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P 1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Coinfections as an aetiology of acute undifferentiated febrile illness among adult patients in the sub-Himalayan region of north India

Background & objectives: In India, certain geographic regions witness simultaneous outbreaks of two or more diseases like scrub typhus, dengue fever, malaria, leptospirosis and chikungunya during monsoon and post-monsoon period, sharing common indication of acute febrile illness. The objective of the present study was to assess the prevalence of coinfections among patients with acute undifferentiated fevers (AUF) admitted in a tertiary care hospital in the northern hilly state of Himachal Pradesh, India. Methods: This was a hospital based open cohort study conducted over a period of two months (September and October) in 2016. All the patients above the age of 18 yr admitted in medical wards and fulfilling the definition of AUF were included. The patients diagnosed with dual infections were the subjects of the study. Standard guidelines were used for case definitions of scrub typhus, dengue, chikungunya, malaria and leptospirosis. Results: Dual infections were noted in 16 patients admitted with AUF. The most common coinfection was scrub typhus and dengue, reported in 10 patients. Scrub typhus and leptospirosis coinfection was observed in three patients. Dengue and chikungunya was observed in one patient. Scrub typhus, dengue and vivax malaria was detected in one patient. Scrub typhus and vivax malaria was detected in one patient. Out of the 10 cases positive for both scrub and dengue, four had no history of travel outside Himachal Pradesh. All three cases positive for both scrub and leptospirosis were indigenous without any history of travel outside Kangra, Himachal Pradesh. The outcome of all the patients was with full recovery. Interpretation & conclusion: The study established the presence of coinfections (mainly dengue fever and leptospirosis) as a cause of AUF in the study area, which is a nonendemic region. The role of easily available and widely performed serological tests in the aetiological diagnosis of AUF is significant. Studies are required to determine the normal titres in the local population before using the imported commercially available serological tests in the diagnosis of AUF

An insight into the redox activity of Ru and Os complexes of the N,N′-bis(2-pyridyl)benzene-1,2-diamine ligand: structural, electrochemical and electronic structure analysis by density functional theory calculations

The synthesis of Ru and Os complexes of the ligand, N,N′-bis(2-pyridyl)benzene-1,2-diamine namely, [Ru-¹¹¹(acac)₂(Py-bqdi)], (9), (Ru-¹¹(Ph-trpy)(Py-bqdi)Cl], (10) and (Os-¹¹(bpy)₂(Py-bqdi)](ClO₄), ([11]ClO₄) [where Py-bqdi = N,N′-dipyridyl-o-benzoquinonediimine, acac = 2,4-pentanedionate, Ph-trpy = 4'-phenyl-2,2′:6′,2″ -terpyridine, bpy = 2,2′-bipyridine] is reported. The molecular structures of complexes 9-[11]ClO₄ are authenticated by single crystal X-ray diffraction studies. The electronic structural properties of the complexes, in particular, the accessible oxidized/reduced forms of the complexes, are examined by using an array of analytical techniques (magnetic resonance, UV-Vis-NIR spectroscopy and electrochemistry). Comprehensive Density Functional Theory (DFT) calculations have also been carried out to provide additional support to the experimental work