B lymphopoiesis declines with age, and in rabbit this occurs by 8 weeks of age. We found that colony-forming units fibroblasts (CFU-F) in the bone marrow (BM) decrease 10-fold by a few weeks of age, and that the CFU-Fs preferentially differentiate into adipocytes instead of osteoblasts. BM becomes filled with fat spaces during this time, making rabbit a unique model to study the effects of accelerated fat accumulation on B lymphopoiesis. We show that adipocytes of both rabbit and human secrete a soluble factor(s) that inhibits B lymphopoiesis and we tested if this inhibition was due to effects on the BM stroma or hematopoietic progenitors. Pre-treatment of BM mononuclear cells (MNCs) with adipocyte conditioned medium (CM) dramatically inhibited their differentiation into proB cells in co-cultures with OP9 stromal cells. In contrast, pre-treatment of OP9 stromal cells with adipocyte CM had no effect on B lymphopoiesis. Using human HSCs we show that inhibition by the adipocyte-derived factor occurred at the common lymphoid progenitor (CLP) to pre-proB cell stage. We propose that the age-related decline in B lymphopoiesis is due to a decrease in CFU-F, an increase in adipocytes, and an adipocyte-derived factor that blocks B lymphopoiesis at the CLP to pre-proB cell stage.

Prostate cancer is one of the most common cancers in men. Recent estimates suggest that over a million men are diagnosed with the disease annually. Prostate cancer pathogenesis involves both heritable and environmental factors. The molecular events involved in the development or progression of prostate cancer are still unclear. Recent body of literature highlights the role of viral infections in initiation or progression of prostate cancer. In this regard, certain viruses have been reported to interact with host proteins and bring about changes in genetic, immunological and inflammatory events that lead to initiation or progression of prostate cancer. We conducted a comprehensive PubMed database search to identify publications relevant to viruses associated with prostate cancer. In this review, we discuss the possible viral etiology of prostate cancer and evidence of viral-mediated genetic changes, and immune dysregulation involved in initiation or progression of prostate cancer.

Aim Variations of dopamine receptor type 2 (DRD2) are among the key factors involved in the pathology of schizophrenia. Presence of certain SNPs in DRD2 gene also amend patients’ response to antipsychotics. Keeping in view the genetic diversity among populations and important role of DRD2 polymorphisms in schizophrenia, we aimed to study two of its SNPs rs1801028 and rs6277 in patients with schizophrenia from Pakistan. Methods A total of 100 schizophrenia cases and 100 healthy controls were recruited. DNA was extracted from whole blood followed by PCR, Sanger sequencing and genotyping of two SNPs, that is, rs1801028 and rs6277. Results No association of rs1801028 and rs6277 was found with schizophrenia in Pakistani population (P > .05). Highlight of our study is the association of polymorphism rs201256011 with schizophrenia (P = .001), which is being reported for the first time. Significant association of rs201256011 was also found with Positive and Negative Syndrome Scale negative, cognitive and total score (P < .05). Conclusion In conclusion, genetic variants rs1801028 and rs6277 of DRD2 are not associated with schizophrenia in Pakistani population. While, previously unreported polymorphism rs201256011 have shown significant association with schizophrenia and its severity. A large scale multicentre replication study is required to confirm the association of this SNP with schizophrenia.

No abstract

No abstract

B lymphopoiesis arrests in rabbits by 16 weeks of age, and data suggest that the bone marrow (BM) environment is responsible for this. We hypothesize that this arrest is due to differences in the BM stroma of young and adult rabbits. Using limiting dilution analysis to quantify the number of CFU in BM of 2 to 6 wk-old rabbits, we found an 8-10 fold decrease in the number of stromal progenitors by 6 wk-of-age. This decrease in stromal progenitors is reflective of the age-related decline in progenitor B cells in BM. Histology of BM sections reveals trabecular bone formation in young rabbits but not in adults; in contrast, BM from adults shows large amounts of adipose tissue. We tested the capability of stromal progenitors to differentiate into adipocytes or osteoblasts in vitro , and found that stromal progenitors from BM of young rabbits displayed a higher propensity to form oseoblastic colonies than do stromal progenitors from BM of adults, which more readily formed adipocytic colonies. We conclude that with aging, the number of BM stromal progenitors decreases dramatically, and further, that these progenitors from adults more readily differentiate into adipocytes than into osteoblasts. We suggest that these changes in BM are responsible for the arrest of B lymphopoiesis.

No abstract

Introduction: The immune system plays a pivotal role in identification and clearance of tumor cells, but can also be counterproductive and enhance tumor progression. Presence of neutrophils in solid tumors, including the sixth most common cancer globally - head and neck squamous cell carcinomas (HNSCC), is associated with poor prognosis. IL-8 and GM-CSF, whose secretion is regulated by NF-κB, are pro-inflammatory cytokines that promote extravasation of neutrophils into tissue and play an important role in the proliferation, invasion, and metastasis of HNSCC. The onset and progression of HNSCC is also associated with genetic alterations that affect several cellular signaling pathways such as transforming growth factor-β (TGFβ) pathway. TGF-β is responsible for polarization of neutrophils towards anti-tumor (N1) versus pro-tumor (N2) phenotype. Objective: The role of neutrophils in HNSCC and the possible molecular mechanisms of pro-tumor neutrophil recruitment is being investigated. Methods and Results: IL-8 and GM-CSF released at various time points by FaDu (ATCC® HTB-43™), SCC-9 (ATCC® CRL-1629™) and Cal-27 (ATCC® CRL-2095™) was measured by ELISA. Conditioned media from FaDu and Cal-27 cells exhibited consistent expression of IL-8 (115 - 117pg/mL and 103 - 110pg/ml, respectively) at 6 - 72 hours. SCC-9 conditioned media exhibited sustained levels of IL-8 expression (103 - 110pg/ml) at 6 - 24 hours that then declined at 48 - 72 hours. GM-CSF was not significantly expressed in the FaDu conditioned media; even with increasing cell density, the mean expression remained 0.142pg/ml. SCC-9 and Cal-27 expressed GM-CSF at 6 - 72 hours (16 - 20pg/mL and ~15pg/ml, respectively). In all cell lines, IL-8 expression decreased in a dose and time dependent manner after treatment with the NF-κB inhibitor, BAY 11-7082, while effect on GM-CSF expression was negligible. Expression of phosphorylated IκBα in FaDu and SCC-9 cell lysates decreased in a time and dose dependent manner, indicating inhibition of the NF-κB pathway by BAY11-7082. Expression of phosphorylated NF-κB also decreased as compared to control in these cells. In nuclear extracts, BAY 11-7082 dose-dependent alteration in NF-κB expression was observed in FaDu and Cal-27 cells at earlier time points. Conditioned media from SCC-9 and Cal-27 cells also exhibited sustained baseline expression of TGF- β (~30pg/ml) over 6 - 72 hours. Conclusion: HNSCC cells derived from tongue and hypopharyngeal squamous cell carcinoma release pro-inflammatory cytokines. The NF-κB signaling pathway appears to be involved in the release of IL-8, a cytokine that is in turn likely to be involved in recruitment of neutrophils to the cancer site that may be polarized towards the N2 pro-tumor phenotype by TGF-β secreted by HNSCC cells. Citation Format: Hina Shakeel, Fareena Bilwani, Kiran Iqbal, Kulsoom Ghias. NF-κB-mediated pro-inflammatory cytokine release and neutrophil recruitment in head and neck squamous cell carcinoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3152.