Use of Micropipette-Guided Drug Administration as an Alternative Method to Oral Gavage in Rodent Models.

Oral gavage (OG) with the use of a cannula attached to a syringe is one of the most common methods used to deliver precise dosing of compounds to the stomach of research animals. Unfortunately, this method comes with difficulties for both the operator and the research animal. Studies have shown that OG may lead to complications, including esophagitis, perforation of the esophagus, and inadvertent tracheal drug administration.

FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer.

Unlabelled: Fatty acid synthase (FASN) catalyzes the synthesis of long-chain saturated fatty acids and is overexpressed during prostatic tumorigenesis, where it is the therapeutic target in several ongoing trials. However, the mechanism of FASN upregulation in prostate cancer remains unclear. Here, we examine FASN gene CpG methylation pattern by InfiniumEPIC profiling and whole-genome bisulfite sequencing across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing with FASN protein expression as measured by digitally quantified IHC assay and reverse phase protein array analysis or FASN gene expression.

Intratumoral Bacteria as Mediators of Cancer Immunotherapy Response.

Multiple lines of evidence spanning from animal models to human clinical trials indicate that the microbiome influences cancer immunotherapy response. Whereas initial studies focused exclusively on the gastrointestinal (gut) microbiota-tumor axis, more recent studies have examined the possibility that bacteria located within tumor cells or within the tumor microenvironment mediate cancer treatment response. Strikingly, this phenomenon has been demonstrated in cancers that arise in anatomic locations that are traditionally thought to be devoid of resident microbiota.

Club-like cells in proliferative inflammatory atrophy of the prostate.

Club cells are a type of bronchiolar epithelial cell that serve a protective role in the lung and regenerate damaged lung epithelium. Single-cell RNA sequencing (scRNA-seq) of young adult human prostate and urethra identified cell populations in the prostatic urethra and collecting ducts similar in morphology and transcriptomic profile to lung club cells. We further identified club cell-like epithelial cells by scRNA-seq of prostate peripheral zone tissues.

Association of self-identified race and genetic ancestry with the immunogenomic landscape of primary prostate cancer.

The genomic and immune landscapes of prostate cancer differ by self-identified race. However, few studies have examined the genome-wide copy number landscape and immune content of matched cohorts with genetic ancestry data and clinical outcomes. Here, we assessed prostate cancer somatic copy number alterations (sCNA) and tumor immune content of a grade-matched, surgically treated cohort of 145 self-identified Black (BL) and 145 self-identified White (WH) patients with genetic ancestry estimation.

Localization of macrophage subtypes and neutrophils in the prostate tumor microenvironment and their association with prostate cancer racial disparities.

Background: Black men are two to three times more likely to die from prostate cancer (PCa) than White men. This disparity is due in part to discrepancies in socioeconomic status and access to quality care. Studies also suggest that differences in the prevalence of innate immune cells and heightened function in the tumor microenvironment of Black men may promote PCa aggressiveness.

Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab).

Recent studies in cancer patients and animal models demonstrate that intestinal microbiota influence the therapeutic efficacy of cancer treatments, including immune checkpoint inhibition. However, no studies to-date have investigated relationships between gastrointestinal microbiota composition and response to checkpoint inhibition in advanced metastatic castrate resistant prostate cancer (mCRPC). We performed 16S rRNA gene sequencing of fecal DNA from 23 individuals with mCRPC progressing on enzalutamide and just prior to treatment with anti-PD-1 (pembrolizumab) to determine whether certain features of the microbiome are associated with treatment response (defined as serum PSA decrease >50% at any time on treatment or radiographic response per RECIST V.

P2 purinergic receptor dysregulation in urologic disease.

P2 purinergic receptors are involved in the normal function of the kidney, bladder, and prostate via signaling that occurs in response to extracellular nucleotides. Dysregulation of these receptors is common in pathological states and often associated with disease initiation, progression, or aggressiveness. Indeed, P2 purinergic receptor expression is altered across multiple urologic disorders including chronic kidney disease, polycystic kidney disease, interstitial cystitis, urinary incontinence, overactive bladder syndrome, prostatitis, and benign prostatic hyperplasia.

Modeling Human Prostate Cancer Metastasis in Mice Resection of Subcutaneous Allografts.

The 5-year survival rate for patients diagnosed with distant metastatic prostate cancer in the United States is 30.6%. Therefore, there is a great need to develop model systems to study prostate cancer metastasis and to test potential therapeutics.

Identification of novel biomarkers differentially expressed between African-American and Caucasian-American prostate cancer patients.

Prostate cancer (PCa) incidence and mortality rate vary among racial and ethnic groups with the highest occurrence in African American (AA) men who have mortality rates twice that of Caucasians (CA). In this study, we focused on differential expression of proteins in AA prostate cancer compared to CA using Protein Pathway Array Analysis (PPAA), in order to identify protein biomarkers associated with PCa racial disparity. Fresh frozen prostate samples (n=90) obtained from radical prostatectomy specimens with PCa, including 25 AA tumor, 21 AA benign, 23 CA tumor, 21 CA benign samples were analyzed.

Incorporation of Data From Multiple Hypervariable Regions when Analyzing Bacterial 16S rRNA Gene Sequencing Data.

Short read 16 S rRNA amplicon sequencing is a common technique used in microbiome research. However, inaccuracies in estimated bacterial community composition can occur due to amplification bias of the targeted hypervariable region. A potential solution is to sequence and assess multiple hypervariable regions in tandem, yet there is currently no consensus as to the appropriate method for analyzing this data.

Association of B7-H3 expression with racial ancestry, immune cell density, and androgen receptor activation in prostate cancer.

Background: B7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa.

Multiplex immunohistochemical phenotyping of T cells in primary prostate cancer.

Background: Most prostate cancers are "immune cold" and poorly responsive to immune checkpoint inhibitors. However, the mechanisms responsible for the lack of a robust antitumor adaptive immune response in the prostate are poorly understood, which hinders the development of novel immunotherapeutic approaches.

Aims: Most inflammatory infiltrates in the prostate are centered around benign glands and stroma, which can confound the molecular characterization of the antitumor immune response.

Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression.

Unlike several other tumor types, prostate cancer rarely responds to immune checkpoint blockade (ICB). To define tumor cell intrinsic factors that contribute to prostate cancer progression and resistance to ICB, we analyzed prostate cancer epithelial cells from castration-sensitive and -resistant samples using implanted tumors, cell lines, transgenic models and human tissue. We found that castration resulted in increased expression of interleukin-8 (IL-8) and its probable murine homolog Cxcl15 in prostate epithelial cells.

Health inequity drives disease biology to create disparities in prostate cancer outcomes.

Prostate cancer exerts a greater toll on African American men than on White men of European descent (hereafter referred to as European American men): the disparity in incidence and mortality is greater than that of any other common cancer. The disproportionate impact of prostate cancer on Black men has been attributed to the genetics of African ancestry, to diet and lifestyle risk factors, and to unequal access to quality health care. In this Review, all of these influences are considered in the context of the evolving understanding that chronic or recurrent inflammatory processes drive prostatic carcinogenesis.

Examining the Effects of 4He Exposure on the Gut-Brain Axis.

Beyond low-Earth orbit, space radiation poses significant risks to astronaut health. Previous studies have shown that the microbial composition of the gastrointestinal (GI) microbiome changes upon exposure to high-linear energy transfer radiation. Interestingly, radiation-induced shifts in GI microbiota composition are linked to various neuropsychological disorders.

Immune cell infiltrates and prognosis in localized prostate cancer.

Multiple lines of evidence indicate that quantification of immune cell infiltrates in primary prostate cancer can predict outcomes after radical prostatectomy, including biochemical recurrence, metastasis, and death from prostate cancer. In a recent issue of The Journal of Pathology, Andersen et al explored the predictive value of cancer tissue infiltration of seven immune cell types (mast cells, M1 macrophages, M2 macrophages, B cells, T helper cells, cytotoxic T cells, and regulatory T cells) in association with biochemical recurrence after radical prostatectomy. In addition to reporting a potential association between cancer-infiltrating regulatory T cells and M1 and M2 macrophages and biochemical recurrence, the study also highlighted the use of multiplex digital pathology analyses to assess adverse predictors of prostate cancer outcomes.

P2X4 purinergic receptors offer a therapeutic target for aggressive prostate cancer.

Prostate cancer (PCa) remains a leading cause of cancer-related deaths in American men and treatment options for metastatic PCa are limited. There is a critical need to identify new mechanisms that contribute to PCa progression, that distinguish benign from lethal disease, and that have potential for therapeutic targeting. P2X4 belongs to the P2 purinergic receptor family that is commonly upregulated in cancer and is associated with poorer outcomes.

Pathology Residency Program Special Expertise Tracks Meet the Needs of an Evolving Field.

Pathologists who enter the workforce must have a diverse skill set beyond that of clinical diagnostics alone. Anticipating this need, the Johns Hopkins Pathology Residency Program developed Special Expertise Tracks to enhance training in relevant subspecialty domains. Using a combination of discussions and surveys, we assessed: (1) our current resident curriculum; (2) perceived curricular strengths and needs; (3) resident career preferences and ultimate career paths; (4) perceived barriers to implementing an advanced elective curriculum; and (5) available departmental/institutional resources.

Oncogenic gene fusions in nonneoplastic precursors as evidence that bacterial infection can initiate prostate cancer.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development.

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States.

GSTP1 is a member of the Glutathione-S-transferase (GST) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on tissue microarrays (TMAs) with redundant sampling from the index tumor from prostatectomies.

Why Do Epidemiologic Studies Find an Inverse Association Between Intraprostatic Inflammation and Prostate Cancer: A Possible Role for Colliding Bias?

Inflammation is an emerging risk factor for prostate cancer based largely on evidence from animal models and histopathologic observations. However, findings from patho-epidemiologic studies of intraprostatic inflammation and prostate cancer have been less supportive, with inverse associations observed in many studies of intraprostatic inflammation and prostate cancer diagnosis. Here, we propose collider stratification bias as a potential methodologic explanation for these inverse findings and provide strategies for conducting future etiologic studies of intraprostatic inflammation and prostate cancer.