The FABP12/PPARγ pathway promotes metastatic transformation by inducing epithelial‐to‐mesenchymal transition and lipid‐derived energy production in prostate cancer cells

Early stage localized prostate cancer (PCa) has an excellent prognosis; however, patient survival drops dramatically when PCa metastasizes. The molecular mechanisms underlying PCa metastasis are complex and remain unclear. Here, we examine the role of a new member of the fatty acid‐binding protein (FABP) family, FABP12, in PCa progression. FABP12 is preferentially amplified and/or overexpressed in metastatic compared to primary tumors from both PCa patients and xenograft animal models. We show that FABP12 concurrently triggers metastatic phenotypes (induced epithelial‐to‐mesenchymal transition (EMT) leading to increased cell motility and invasion) and lipid bioenergetics (increased fatty acid uptake and accumulation, increased ATP production from fatty acid β‐oxidation) in PCa cells, supporting increased reliance on fatty acids for energy production. Mechanistically, we show that FABP12 is a driver of PPARγ activation which, in turn, regulates FABP12''s role in lipid metabolism and PCa progression. Our results point to a novel role for a FABP‐PPAR pathway in promoting PCa metastasis through induction of EMT and lipid bioenergetics.

Abbreviations

AR

androgen receptor

ATP

adenosine triphosphate

CN

copy number

CPT1

carnitine palmitoyltransferase I

CS

citrate synthase

EMT

epithelial–mesenchymal transition

ET

electron transfer‐state

FABP

fatty acid‐binding protein

LD

lipid droplet

OA

oleic acid

PCa

prostate cancer

PPAR

peroxisome proliferator‐activated receptor

PPRE

peroxisome proliferator‐activated receptor response element

TZD

thiazolidinediones

     

Ostium primum atrial septal defect with persistent left superior vena cava opening into unroofed coronary sinus—A rare entity

Raghib syndrome is a rare developmental complex consisting of termination of the left superior vena cava in the left atrium, absence of the coronary sinus, and an atrial septal defect commonly located at the posterior‐inferior angle of the atrial septum. This complex was considered unique to Raghib syndrome; however, cases with a normal atrial septum have been reported where the orifice of the unroofed coronary sinus functions as the inter‐atrial communication. Our patient demonstrated an isolated persistent left superior vena cava draining into the left atrium through unroofed coronary sinus and presence of ostium primum atrial septal defect.     

Effect of Different Rituximab Doses on B Cell Count,Anti-A/B Antibody Titer,Graft Function,and Infectious Complications in ABO-Incompatible Renal Transplantation: A Prospective Study

BackgroundABO-incompatible kidney transplantation (ABOiKT) has been accepted as a viable and cost-effective modality with outcomes comparable to ABO-compatible transplants, but there is a concern regarding higher infectious complications in ABOiKT because of the heightened immunosuppression.The desensitization protocol normally includes antibody removal, B cell depletion by rituximab (RTX), and immunomodulation with intravenous immunoglobulin. Efforts have been made over the years to decrease the dose of RTX in an effort to decrease the infective complications. There is limited literature about the minimum effective dose of RTX, which can cause an effective B cell depletion. This prospective study was designed to correlate the RTX dose with peripheral absolute B cell count, graft function, graft and patient survival, and infective complications.MethodsThis study included 52 adult ABOiKT recipients with anti-A/B antibody titer up to a maximum of 1:512. The participants were divided into 2 groups of 26 each according to the RTX dosage used: Group A received 100 mg/patient, and Group B received 200 mg/patient. RTX was given 14 days prior to transplant after B cell measurement by flow cytometry. The outcomes were compared after 1 year of follow-up.ResultsBoth the dosages effectively depleted the absolute B cell count. Although patient survivals, graft survival, graft function, acute rejection episodes, and post-transplant hospital stay were similar in both groups, infective complications were significantly higher in group B.ConclusionA low dose (100 mg/patient) of RTX produces effective depletion of B cells while lowering the infective complications in ABOiKT.     

Total Hip Arthroplasty in Ankylosing Spondylitis With Extension Contracture of Hips

Background

Despite significant pain relief following total hip arthroplasty (THA) in patients with ankylosing spondylitis, a small subset of patients presenting with extra-articular extension contracture of hips remains unsatisfied.

Super selective intra-arterial cerebral infusion of modern chemotherapeutics after blood–brain barrier disruption: where are we now,and where we are going

Journal of Neuro-Oncology - Intra-arterial (IA) delivery of therapeutic agents across the blood-brain barrier (BBB) is an evolving strategy which enables the distribution of high concentration...     

Therapeutic cooperation between auranofin,a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8^+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.