A peptide derived from the N-terminal region of HIV-1 Vpr promotes nuclear import in permeabilized cells: elucidation of the NLS region of the Vpr

AbstractViral protein r (Vpr), a HIV-1 auxiliary protein which mediates nuclear import of the viral preintegration complex (PIC), contains two regions, N- and C-terminal, which have been proposed to function as a nuclear localization signal (NLS). We have synthesized peptides corresponding to both regions (designated as VprN and VprC), conjugated them to bovine serum albumin (BSA), and tested their ability to mediate nuclear import in permeabilized cells. Only VprN, and not VprC, functioned as an active NLS and promoted translocation of the conjugate into nuclei. Nuclear import of the conjugate was found to be energy and temperature dependent and was inhibited by wheat germ agglutinin (WGA). However, it did not require the addition of cytosolic factors and was not inhibited by the prototypic SV40 large T-antigen NLS peptide. Our results show that Vpr harbours a non-conventional negatively charged NLS and therefore suggest that Vpr may use a distinct nuclear import pathway

Brain Metastasis of Nasopharyngeal Carcinoma: A Case Report and Literature Review

Central nervous system metastases from nasopharyngeal carcinoma (NPC) are uncommon. The patient presented was diagnosed with aggressive advanced NPC resistant to treatment and complicated by a solitary brain metastasis. A PubMed database search was conducted to review the existing literature regarding brain metastases of NPC, using the search terms “nasopharyngeal neoplasia,” “nasopharyngeal carcinoma,” “nasopharynx,” “radiotherapy,” “central nervous system,” and “brain” in section of “Title/Abstract.” The articles were first evaluated by title and then by abstract, and thereafter appropriate manuscripts were evaluated by full text. References of the published papers were also reviewed

18 kDa Translocator Protein in Mitochondria-Related Pathology: The Case of Traumatic Brain Injury

Translocator protein (TSPO) takes part in mitochondrial adenine triphosphate (ATP) production and transport. Mitochondrial TSPO is a part of the apoptotic and cell necrotic mechanism. Ligands to TSPO, endogenous and synthetic, have different effects on metabolism and protein expression in human well-differentiated metabolically active cells. In general, most of the TSPO ligands affect the cellular function or metabolism in the same general direction, but different specific TSPO ligands have their own unique effects in human cells. Regulation of gene expression via the actions of TSPO ligands on the mitochondrial TSPO may form an essential mechanism for the regulation of cellular functions, especially during acute organ injury, such as acute brain damage. The exact mode of action of the specific TSPO ligands is not clear enough and should be further investigated. TSPO is a potential target for therapeutic efforts to mitigate secondary tissue injury caused by programmed cell death

Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02). Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.Supported by CERCA Programme/Generalitat de Catalunya, Health Department PERIS #SLT/002/16/00374, AGAUR-project #2017SGR1080; MCI/AEI/ERDF project #RTI2018-094049-B-I00; ERC EPIPHARM; Cellex Foundation; “la Caixa” Foundation (LCF/PR/GN18/51140001 and LCF/PR/GN18/50310007), RF-2016–02364388, Accelerator Award—Cancer Research UK/AIRC—INCAR Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC) Project 5 × 1000 no. 9962, AIRC IG 2018 id. 21724, AIRC MFAG id. 21769 and id. 20450; MIUR (Grant PRIN 2017); and RCR-2019–23669115

“At ‘Amen Meals’ It’s Me and God” Religion and Gender: A New Jewish Women’s Ritual

New ritual practices performed by Jewish women can serve as test cases for an examination of the phenomenon of the creation of religious rituals by women. These food-related rituals, which have been termed ‘‘amen meals’’ were developed in Israel beginning in the year 2000 and subsequently spread to Jewish women in Europe and the United States. This study employs a qualitative-ethnographic methodology grounded in participant-observation and in-depth interviews to describe these nonobligatory, extra-halakhic rituals. What makes these rituals stand out is the women’s sense that through these rituals they experience a direct con- nection to God and, thus, can change reality, i.e., bring about jobs, marriages, children, health, and salvation for friends and loved ones. The ‘‘amen’’ rituals also create an open, inclusive woman’s space imbued with strong spiritual–emotional energies that counter the women’s religious marginality. Finally, the purposes and functions of these rituals, including identity building and displays of cultural capital, are considered within a theoretical framework that views ‘‘doing gender’’ and ‘‘doing religion’’ as an integrated experience

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

Lymphoepithelioma-Like Carcinoma of the Salivary Gland: Is Radiotherapy Alone Adequate?

Introduction. Lymphoepithelioma-like carcinoma (LELC) of the salivary gland is a rare tumor. Currently, surgery with or without radiotherapy is the recommended treatment for all salivary gland carcinomas. However, in contrast to other high-grade salivary gland carcinomas, LELCs are considered radiosensitive. There are only a few published reports of radiotherapy alone for the treatment of salivary gland LELC. Case. We present two cases of LELC of the salivary gland. One was treated with surgery and postoperative radiotherapy, and the other was given a single cycle of chemotherapy and then radiotherapy. Currently, both patients have no evidence of disease. Conclusion. Radiotherapy as a single modality should be reevaluated. The role of systemic chemotherapy to gain systemic control should be addressed due to noteworthy metastatic disease