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Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.

DNA repair pathways are disrupted in PALB2-deficient cells, thereby accounting for the tumor suppressor gene properties of I PALB2 i .[1],[2] Durable benefit from olaparib in a patient with metastatic prostate cancer and heterozygous I PALB2 i gene deletion[30] and a case of PALB2-mutant pancreatic cancer treated with mitomycin C have been reported.[31] Because it is not yet known, further study is warranted to determine how closely the PALB2 alterations described thus far share traits with cancers defined by BRCAness. Pseudopapillary neoplasm of the pancreas is a rare epithelial tumor comprising 1% to 2% of exocrine pancreatic neoplasms.[32] These tumors generally present as large encapsulated masses, although metastatic disease has been reported. Although several local therapies (eg, surgical resection, tumor embolization, and radiotherapy) have been described, no standard of care exists.[33]-[35] Our patient highlights the potential of CGP in identifying tumor-specific and actionable drug targets for uncommon neoplasms. [Extracted from the article]

Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.