Combined anti-PD-1 and anti-CTLA-4 checkpoint blockade: Treatment of melanoma and immune mechanisms of action

Cytotoxic T-lymphocyte associated protein-4 (CTLA-4) and the Programmed Death Receptor 1 (PD-1) are immune checkpoint molecules that are well-established targets of antibody immunotherapies for the management of malignant melanoma. The monoclonal antibodies, Ipilimumab, Pembrolizumab, and Nivolumab, designed to interfere with T cell inhibitory signals to activate immune responses against tumors, were originally approved as monotherapy. Treatment with a combination of immune checkpoint inhibitors may improve outcomes compared to monotherapy in certain patient groups and these clinical benefits may be derived from unique immune mechanisms of action. However, treatment with checkpoint inhibitor combinations also present significant clinical challenges and increased rates of immune-related adverse events. In this review, we discuss the potential mechanisms attributed to single and combined checkpoint inhibitor immunotherapies and clinical experience with their use.     

Oligo-glycerol based non-ionic amphiphilic nanocarriers for lipase mediated controlled drug release

A new class of non-ionic amphiphiles is synthesized using a diaryl derivative of diglycerol as a central core and functionalizing it with long alkyl chains (C-12/C-15) and monomethoxy PEG moiety (M_n: 350/550) by following a chemo-enzymatic approach. The aggregation behavior of the amphiphiles in aqueous medium is studied by using dynamic light scattering (DLS) and fluorescence spectroscopy, whereas the size and morphology of the aggregates are studied by transmission electron microscopy (TEM). A hydrophobic dye, Nile red and a hydrophobic drug, nimodipine, are used to demonstrate the nano-carrier capability of these non-ionic amphiphilic systems and the results are compared with amphiphilic analogues obtained from the triaryl derivatives of triglycerol. The in vitro controlled release of the encapsulated dye is successfully carried out in the presence of immobilized Candida antarctica lipase (Novozym 435). Furthermore, cytotoxicity data is also collected which suggests that the amphiphiles are suitable for biomedical applications.

A new series of oligo-glycerol based amphiphiles have been synthesized for drug delivery.     

Evaluation of an ASFV RNA Helicase Gene A859L for Virus Replication and Swine Virulence

African swine fever virus (ASFV) is producing a devastating pandemic that, since 2007, has spread to a contiguous geographical area from central Europe to Asia. In July 2021, ASFV was detected in the Dominican Republic, the first report of the disease in the Americas in more than 40 years. ASFV is a large, highly complex virus harboring a large dsDNA genome that encodes for more than 150 genes. The majority of these genes have not been functionally characterized. Bioinformatics analysis predicts that ASFV gene A859L encodes for an RNA helicase, although its function has not yet been experimentally assessed. Here, we evaluated the role of the A859L gene during virus replication in cell cultures and during infection in swine. For that purpose, a recombinant virus (ASFV-G-∆A859L) harboring a deletion of the A859L gene was developed using the highly virulent ASFV Georgia (ASFV-G) isolate as a template. Recombinant ASFV-G-∆A859L replicates in swine macrophage cultures as efficiently as the parental virus ASFV-G, demonstrating that the A859L gene is non-essential for ASFV replication. Experimental infection of domestic pigs demonstrated that ASFV-G-∆A859L replicates as efficiently and induces a clinical disease indistinguishable from that caused by the parental ASFV-G. These studies conclude that the predicted RNA helicase gene A859L is not involved in the processes of virus replication or disease production in swine.     

Efficacy of topical cyclosporine 0.05% and osmoprotective lubricating eye drops in treating dry eye disease and inflammation

Purpose:To evaluate the effect of topical cyclosporine 0.05% and osmoprotective lubricating eye drops on patients with dry eye disease (DED) with inflammation as measured by raised tear matrix metalloproteinases (MMP-9).Methods:This prospective study included 106 eyes of 53 patients diagnosed with DED based on any of the following DED criteria (Ocular Surface Disease Index [OSDI] score >12, tear film breakup time [TBUT] <10 s, Schirmer’s I test result <10 mm/5 min, ocular surface staining). Ocular surface inflammation was assessed by assessing MMP-9 positivity from tears of the patients in the study (Inflammadry kit Quidel corporation). Patients were prescribed osmoprotective lubricating eye drops (Osmodrops, Cipla Ltd) four times a day and cyclosporine A 0.05% eye drops (Imudrops, Cipla Ltd) twice a day for 6 months. Efficacy of the formulations was evaluated by OSDI scores, Schirmer’s test, TBUT change, reduction in ocular surface staining, and reduction in MMP-9 levels after 6 months of usage. Check P value and add from resultsResults:After 6 months of topical therapy, improvement was observed in OSDI scores (mean pretreatment: 25.7 ± 12.8, and mean posttreatment: 15.2 ± 8.4), P < 0.001. There was also reduction number of patients who were MMP-9 positive. Out of 75 eyes that tested MMP-9 positive, 70.66% showed reduction in MMP-9 levels P < 0.0001). Ocular surface staining also improved.Conclusion:Topical osmoprotective lubricating eye drops and cyclosporine A 0.05% reduce inflammation in cases of DED, which correlates with improvement in OSDI scores, ocular surface staining, and reduction in inflammation as measured by levels of tear MMP-9.     

Extent of re-excision,sequence/timing of salvage re-irradiation,and disease-free interval impact upon clinical outcomes in recurrent/progressive ependymoma

Journal of Neuro-Oncology - To report clinical outcomes of salvage re-irradiation (re-RT) in recurrent/progressive ependymoma. Medical records of patients treated with curative-intent re-RT as...     

Ovarian clear cell carcinoma with papillary features: a potential mimic of serous tumor of low malignant potential

The differential diagnostic problems usually associated with clear cell carcinoma (CCC) of the ovary have been well characterized and include primitive germ cell tumor, sex cord stromal tumor, and metastasis. Distinction from other types of surface epithelial carcinoma may also pose a diagnostic challenge, but the potential for misdiagnosis of serous tumor of low malignant potential (S-LMP) is not well recognized. We report 13 cases of ovarian CCC with prominent papillary architecture that were initially misdiagnosed as S-LMP or low-grade serous carcinoma either on frozen section or at final diagnosis. The ages of the patients ranged from 39 to 65 years (mean, 52.2 y). All patients presented with a pelvic mass; 1 was undergoing evaluation for infertility. Macroscopically, most were described as unilateral, multilocular cysts with internal papillary structures. On microscopic examination, each tumor had a papillary architecture that accounted for 30% to 95% of the tumor; in 6 cases, the cores of the papillae were hyalinized. The neoplastic cells covering the papillae had clear to granular and eosinophilic cytoplasm. Hobnail cells were focal and often subtle. Most had a low mitotic index (9/13) and/or deceptively bland cytology (8/13); only careful attention to the cytologic features and/or mitotic index allowed correct identification of the tumor type in 5 cases. Six were associated with pelvic/ovarian endometriosis. Ten were Federation of Gynecology and Obstetrics stage I (8 IA, 2 IC), 2 were stage II (1 IIB, 1 IIC), and 1 stage IIIC. CCC with prominent papillary architecture is uncommon, but may pose a challenging differential diagnosis with S-LMP, resulting in inadequate staging and delayed treatment. Features most helpful in distinguishing papillary CCC are unilaterality, nonhierarchical branching, monomorphous cell population, and the presence of more typical CCC patterns elsewhere in the tumor. The presence of endometriosis, although not specific, should also prompt consideration for papillary CCC. Increased numbers of mitotic figures may not be present and high-grade cytologic atypia may be focal, requiring careful examination of multiple tumor sections for detection. As CCC and S-LMP exhibit significantly different immunoreactivity for Wilms' Tumor 1 and estrogen receptor, these markers may also be useful adjunctive tests in problematic cases.