Functional Expression of Programmed Death-Ligand 1 (B7-H1) by Immune Cells and Tumor Cells

The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8+ T cells, leading to enhanced antitumor CD8+ T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8+ T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8+ T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8+ T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8+ T cell responses

Expression and localization of nerve growth factor (NGF) in the testis of alpaca (llama pacos)

During alpaca testis development and spermatogenesis, nerve growth factor (NGF) may play an important role. The main aim of this study was to determine the expression and localization of NGF in the alpaca testis, and to discuss the important role of NGF in alpaca reproductive characteristics. Immunohistochemical staining technique and real-time PCR were used. The expression of NGF in the same cells one-month old (newborn) alpacas 12-month, and 24-month old alpacas showed significant differences (p < 0.05); 12- and 24-month old alpacas showed no significant differences (p > 0.05); NGF at different cell stages showed no significant differences (p > 0.05). It suggests that NGF may be involved in the regulation of spermatogenesis, which provides direct evidence for NGF action in the alpaca testis during postnatal development and spermatogenesis. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 1, pp. 55&#8211;61

PKCθ Synergizes with TLR-Dependent TRAF6 Signaling Pathway to Upregulate MUC5AC Mucin via CARMA1

CARD-containing MAGUK protein 1 (CARMA1) plays a crucial role in regulating adaptive immune responses upon T-cell receptor (TCR) activation in T cells. Its role in regulating host mucosal innate immune response such as upregulation of mucin remains unknown. Here we show that CARMA1 acts as a key signaling mediator for synergistic upregulation of MUC5AC mucin by bacterium nontypeable Haemophilus influenzae (NTHi) and phorbol ester PMA in respiratory epithelial cells. NTHi-induced TLR-dependent TRAF6-MKK3-p38 MAPK signaling pathway synergizes with PKCθ-MEK-ERK signaling pathway. CARMA1 plays a crucial role in mediating this synergistic effect via TRAF6, thereby resulting in synergistic upregulation of MUC5AC mucin. Thus our study unveils a novel role for CARMA1 in mediating host mucosal innate immune response

Combining Immune Checkpoint Inhibitors With Conventional Cancer Therapy

Immune checkpoint inhibitors (ICIs) have recently revolutionized cancer treatment, providing unprecedented clinical benefits. However, primary or acquired therapy resistance can affect up to two-thirds of patients receiving ICIs, underscoring the urgency to elucidate the mechanisms of treatment resistance and to design more effective therapeutic strategies. Conventional cancer treatments, including cytotoxic chemotherapy, radiation therapy, and targeted therapy, have immunomodulatory effects in addition to direct cancer cell-killing activities. Their clinical utilities in combination with ICIs have been explored, aiming to achieve synergetic effects with improved and durable clinical response. Here, we will review the immunomodulatory effects of chemotherapy, targeted therapy, and radiation therapy, in the setting of ICI, and their clinical implications in reshaping modern cancer immunotherapy

Molecular Analysis of Evolution and Origins of Cultivated Hawthorn (Crataegus spp.) and Related Species in China

Hawthorn is of high economic value owing to its medicinal properties and health benefits. Crataegus is a member of the Rosaceae family; the genus has a complicated taxonomic history, and several theories on its origin have been proposed. In this study, 53 accessions from seven Crataegus taxa native to China and accessions of exotic Crataegus species (two from Europe and one from North America) were analyzed by specific locus amplified fragment sequencing (SLAF-seq). In total, 933,450 single-nucleotide polymorphisms were identified after filtering and used to investigate the species’ genomic evolution. Phylogenetic trees derived from nuclear simple sequence repeats (SSRs) and SLAF-seq data showed the same topology, in which Crataegus maximowiczii and Crataegus sanguineae formed a closely related cluster that was clearly separated from the cluster composed of Crataegus hupehensis, Crataegus pinnatifida, Crataegus pinnatifida var. major, Crataegus bretschneideri and Crataegus scabrifolia. Phylogenetic and structure analysis indicated that the seven Chinese Crataegus taxa had two separate speciation events. Plants that evolved the southwestern route shared the genepool with the European species, whereas plants along the northeastern route shared the genepool with the North American species. TreeMix genetic analysis revealed that C. bretschneideri may have a hybrid origin. This study provides valuable information on the origins of Chinese Crataegus and suggests an evolutionary model for the main Crataegus species that native to China

Differential Impact of Stress Reduction Programs upon Ambulatory Blood Pressure among African American Adolescents: Influences of Endothelin-1 Gene and Chronic Stress Exposure

Stress-activated gene × environment interactions may contribute to individual variability in blood pressure reductions from behavioral interventions. We investigated effects of endothelin-1 (ET-1) LYS198ASN SNP and discriminatory stress exposure upon impact of 12-week behavioral interventions upon ambulatory BP (ABP) among 162 prehypertensive African American adolescents. Following genotyping, completion of questionnaire battery, and 24-hour ABP monitoring, participants were randomized to health education control (HEC), life skills training (LST), or breathing awareness meditation (BAM). Postintervention ABP was obtained. Significant three-way interactions on ABP changes indicated that among ET-1 SNP carriers, the only group to show reductions was BAM from low chronic stress environments. Among ET-1 SNP noncarriers, under low chronic stress exposure, all approaches worked, especially BAM. Among high stress exposure noncarriers, only BAM resulted in reductions. If these preliminary findings are replicated via ancillary analyses of archival databases and then via efficacy trials, selection of behavioral prescriptions for prehypertensives will be edging closer to being guided by individual's underlying genetic and environmental factors incorporating the healthcare model of personalized preventive medicine

FTO variant rs9939609 is associated with body mass index and waist circumference, but not with energy intake or physical activity in European- and African-American youth

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies found common variants in the fat mass and obesity-associated (<it>FTO</it>) gene associated with adiposity in Caucasians and Asians but the association was not confirmed in African populations. Association of <it>FTO </it>variants with insulin resistance and energy intake showed inconsistent results in previous studies. This study aimed to assess the influence of <it>FTO </it>variant rs9939609 on adiposity, insulin resistance, energy intake and physical activity in European - (EA) and African-American (AA) youth.</p> <p>Methods</p> <p>We conducted a cross-sectional study in EA and AA youths. One thousand, nine hundred and seventy-eight youths (48.2% EAs, 47.1% male, mean age 16.5 years) had measures of anthropometry. Percent body fat (%BF) was measured by dual-energy X-ray absorptiometry, visceral adipose tissue (VAT) and subcutaneous abdominal adipose tissue (SAAT) by magnetic resonance imaging. Energy intake and physical activity were based on self report from up to 7 24-hour recalls. Physical activity was also measured by accelerometry.</p> <p>Results</p> <p><it>FTO </it>rs9939609 was significantly associated with body mass index (BMI) (<it>P </it>= 0.01), weight (<it>P </it>= 0.03) and waist circumference (<it>P </it>= 0.04), with per-allele effects of 0.4 kg/m², 1.3 kg and 0.8 cm, respectively. No significant association was found between rs9939609 and %BF, VAT, SAAT or insulin resistance (<it>P </it>> 0.05), or between rs9939609 and energy intake or vigorous physical activity (<it>P </it>> 0.05). No significant interactions of rs9939609 with ethnicity, gender, energy intake or physical activity were observed (<it>P </it>> 0.05).</p> <p>Conclusions</p> <p>The <it>FTO </it>variant rs9939609 is modestly associated with BMI and waist circumference, but not with energy intake or physical activity. Moreover, these effects were similar for EAs and AAs. Improved understanding of the effect of the <it>FTO </it>variant will offer new insights into the etiology of excess adiposity.</p