Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates

An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.     

Podoplanin is a highly sensitive and specific marker to distinguish primary skin adnexal carcinomas from adenocarcinomas metastatic to skin

Distinction of primary skin adnexal carcinomas from cutaneous metastasis of adenocarcinomas is challenging. In this study, we evaluated podoplanin immunoreactivity in a series of primary skin adnexal tumors and adenocarcinomas metastatic to skin using a D2-40 antibody. The initial test series were composed of a total of 93 cases including 32 primary skin adnexal carcinomas, 46 benign primary adnexal tumors, and 15 cutaneous metastatic adenocarcinomas. We found that variable D2-40 reactivity was seen in all of the primary cutaneous carcinomas including sebaceous carcinomas (10/10), squamous cell carcinomas (10/10), porocarcinomas (4/4), trichilemmal carcinomas (4/4), skin adnexal carcinomas not otherwise specified (4/4), and in the majority of benign skin adnexal tumors. In contrast, no podoplanin immunoreactivity was seen in any of the 15 (0/15) cutaneous metastases. To confirm the initial findings and to further explore the utility of podoplanin reactivity in the distinction of these tumors, we also examined a test set of 35 unknown cases, including 21 adenocarcinomas metastatic to skin and 14 primary adnexal tumors, in a blinded fashion. In this test set of cases, podoplanin was negative in 22 cases and positive in 13 cases. Of the 22 podoplanin negative cases, 20 were proven to be metastatic adenocarcinoma. Of the 13 D2-40 positive cases, 12 were proven to be primary adnexal tumors. Our results suggest that podoplanin can be a useful tool to distinguish primary skin adnexal carcinomas form adenocarcinomas metastatic to skin with high sensitivity (94.5%) and specificity (97.2%).     

Cognitive distortions in child sex offenders: an overview of theory, research & practice

A great deal of clinical and research attention has been paid to understanding and explaining child sex offenders' social cognition. Cognitive distortions have been implicated as a core feature of child sex offenders' offense supportive cognition. The primary aim of this paper is to critically evaluate the phenomenon of cognitive distortions as currently understood with respect to child sex offenders: it reviews the theoretical and research literature and highlights the implications for clinical practice.     

Systematic review of the incidence of discitis after cervical discography

Background contextCervical discography is not uniformly used in part because of the fear of discitis. Studies report widely varying rates of this life-threatening infection.PurposeThe aim of this study was to estimate the incidence of discitis after cervical discography, delineate the consequences of discitis, and identify factors that may influence this complication.Study designMeta-analysis.MethodsStudies pertaining to cervical discography were identified by a literature review and bibliographic search. These were screened for inclusion into the meta-analysis by two reviewers. Data were collected on a wide range of clinical and demographic variables including age, gender, morbidities, number of patients, number of discograms, use of prophylactic antibiotics, type of surgical prep, number of needles used, and the number of patients and discs infected. Primary data were used to calculate the incidence of discitis per patient and per disc.ResultsFourteen studies were included in the analysis. Both procedural details and demographic information on patients were missing from eight studies. The mean age of patients ranged from 41 to 47 years, and gender distribution varied greatly. Antibiotics use was reported in three studies. Cervical discography was complicated by postprocedural discitis in 22 of 14,133 disc injections (0.15%) and 21 of 4,804 patients (0.44%). Only one patient suffered from an infection at more than one spinal level.ConclusionsThe rate of discitis after cervical discography is relatively low. This can perhaps be further decreased by the use of prophylactic intradiscal antibiotics. Should the ability of cervical discography to improve surgical outcomes be proven, the fear of discitis should not preclude performance of disc provocation.     

Plasmonic nanobubble-enhanced endosomal escape processes for selective and guided intracellular delivery of chemotherapy to drug-resistant cancer cells

Cancer chemotherapies suffer from multi drug resistance, high non-specific toxicity and heterogeneity of tumors. We report a method of plasmonic nanobubble-enhanced endosomal escape (PNBEE) for the selective, fast and guided intracellular delivery of drugs through a self-assembly by cancer cells of separately targeted gold nanoparticles and encapsulated drug (Doxil). The co-localized with Doxil plasmonic nanobubbles optically generated in cancer cells released the drug into the cytoplasm thus increasing the therapeutic efficacy against these drug-resistant cells by 31-fold, reducing drug dose by 20-fold, the treatment time by 3-fold and the non-specific toxicity by 10-fold compared to standard treatment. Thus the PNBEE mechanism provided selective, safe and efficient intracellular drug delivery in heterogeneous environment opening new opportunities for drug therapies.     

APOBEC3B deletion impacts on susceptibility to acquire HIV‐1 and its advancement among individuals in western India

APOBEC3B deletion polymorphism has been associated with risk of HIV‐1 acquisition and its progression. Therefore, we aimed to investigate the association of APOBEC3B ins/del polymorphism with risk of acquisition of HIV‐1 and its progression. In the present case–control study, we enrolled a total of 150 HIV‐infected individuals and 150 healthy controls. Polymorphism for APOBEC3B gene was genotyped by PCR. APOBEC3B ID, DD genotypes, and D allele were associated with higher risk of acquisition of HIV‐1 (p = 0.004, OR = 4.96; p = 0.03, OR = 3.55; and p = 0.004; OR = 1.60). The individuals with ID genotypes and combined genotype ID+DD of APOBEC3B in the presence of tobacco and alcohol showed the higher risk of advancement of HIV disease; however, risk could not reach statistical significance (OR = 1.14, 95% CI: 0.59–2.18; OR = 1.33, 95% CI: 0.83–2.15 and OR = 1.44, 95% CI: 0.77–2.69; OR = 1.50, 95% CI: 0.94–2.40). Individuals in advanced HIV disease stage and ID genotype and combined genotype ID + DD of APOBEC3B were more likely to be associated with advanced HIV disease stage but risk could not reach significant (OR = 1.50, 95% CI: 0.94–2.40; OR = 1.27, 95% CI: 0.88–1.84). Individuals with ID and DD genotype of APOBEC3B had influence on susceptibility to acquisition of HIV‐1. This suggests that APOBEC3B deletion may attenuate innate cellular immunity against HIV‐1 and thus confer the host persistence for HIV infection.