Deletion of monoamine oxidase A in a prostate cancer model enhances anti-tumor immunity through reduced immune suppression.

We have previously shown that monoamine oxidase A (MAO A) mediates prostate cancer growth and metastasis. Further, MAO A/Pten double knockout (DKO) mice were generated and demonstrated that the deletion of MAO A delayed prostate tumor development in the Pten knockout mouse model of prostate adenocarcinoma. Here, we investigated its effect on immune cells in the tumor microenvironment in MAO A/Pten DKO mouse model. Our results shows that Paraffin embedded prostate tissues from MAO A/Pten DKO mice had elevated markers of immune stimulation (CD8+ cytotoxic T cells, granzyme B, and IFNγ) and decreased expression of markers of immune suppression (FoxP3, CD11b, HIF-1-alpha, and arginase 1) compared to parental Pten knockouts (MAO A wildtype). CD11b+ myeloid derived suppressor cells (MDSC) were the primary immunosuppressive cell types in these tumors. The data suggest that deletion of MAO A reduces immune suppression in prostate tumors to enhance antitumor immunity in prostate cancer. Thus, MAO A inhibitor may alleviate immune suppression, increase the antitumor immune response and be used for cancer immunotherapy.

Tumor specifically internalizing peptide 'HN-1': Targeting the putative receptor retinoblastoma-regulated discoidin domain receptor 1 involved in metastasis.

BACKGROUND: Less than 0.5% of intravenously injected drugs reach tumors, contributing to side effects. To limit damage to healthy cells, various delivery vectors have been formulated; yet, previously developed vectors suffer from poor penetration into solid tumors. This issue was resolved by the discovery of HN-1 peptide isolated via biopanning a phage-display library. HN-1 targets human head and neck squamous cell carcinoma (HNSCC) (breast, thyroid; potentially lung, cervix, uterine, colon cancer), translocates across the cell membrane, and efficiently infiltrates solid tumors. HN-1 peptide has been conjugated to various anticancer drugs and imaging agents though the identity of its receptor remained enigmatic. AIM: To decipher the clues that pointed to retinoblastoma (Rb)-regulated discoidin-domain receptor 1 as the putative receptor for HN-1 is described. METHODS: HN-1 peptide was synthesized and purified using reverse-phase high-performance liquid chromatography and gel electrophoresis. The predicted mass was confirmed by mass spectroscopy. To image the 3-dimensional structure of HN-1 peptide, PyMOL was used. Molecular modeling was also performed with PEP-FOLD3 software via RPBS bioinformatics web portal (INSERM, France). The immunohistochemistry results of discoidin domain receptor 1 (DDR1) protein were obtained from the publicly accessible database in the Human Protein Atlas portal, which contained the images of immunohistochemically labeled human cancers and the corresponding normal tissues. RESULTS: The clues that led to DDR1 involved in metastasis as the putative receptor mediating HN-1 endocytosis are the following: (1) HN-1 is internalized in phosphate-buffered saline and its uptake is competitively inhibited; (2) HN-1 (TSPLNIHNGQKL) exhibits similarity with a stretch of amino acids in alpha5 beta3 integrin (KLLITIHDRKEF). Aside from two identical residues (Ile-His) in the middle, the overall distribution of polar and nonpolar residues throughout the sequences is nearly identical. As HN-1 sequence lacks the Arg-Gly-Asp motif recognized by integrins, HN-1 may interact with an "integrin-like" molecule. The tertiary structure of both peptides showed similarity at the 3-dimensional level; (3) HN-1 is internalized by attached cells but not by suspended cells. As culture plates are typically coated with collagen, collagen-binding receptor (expressed by adherent but not suspended cells) may represent the receptor for HN-1; (4) DDR1 is highly expressed in head and neck cancer (or breast cancer) targeted by HN-1; (5) Upon activation by collagen, DDR1 becomes internalized and compartmentalized in endosomes consistent with the determination of 'energy-dependent clathrin-mediated endocytosis' as the HN-1 entry route and the identification of HN-1 entrapped vesicles as endosomes; and (6) DDR1 is essential for the development of mammary glands consistent with the common embryonic lineage rationale used to identify breast cancer as an additional target of HN-1. In summary, collagen-activated tyrosine kinase receptor DDR1 overexpressed in HNSCC assumes a critical role in metastasis. Further studies are warranted to assess HN-1 peptide's interaction with DDR1 and the therapeutic potential of treating metastatic cancer. Additionally, advances in delivery (conformation, endocytic mechanism, repertoire of targeted cancers of HN-1 peptide), tracking (HN-1 conjugated imaging agents), and activity (HN-1 conjugated therapeutic agents) are described. CONCLUSION: The discovery of DDR1 as HN-1 peptide's putative receptor represents a significant advance as it enables identification of metastatic cancers or clinical application of previously developed therapeutics to block metastasis.

Tumor-specific lytic path "hyperploid progression mediated death": Resolving side effects through targeting retinoblastoma or p53 mutant.

A major advance was made to reduce the side effects of cancer therapy via the elucidation of the tumor-specific lytic path "hyperploid progression-mediated death" targeting retinoblastoma (Rb) or p53-mutants defective in G1 DNA damage checkpoint. The genetic basis of human cancers was uncovered through the cloning of the tumor suppressor Rb gene. It encodes a nuclear DNA-binding protein whose self-interaction is regulated by cyclin-dependent kinases. A 3D-structure of Rb dimer is shown, confirming its multimeric status. Rb assumes a central role in cell cycle regulation and the "Rb pathway" is universally inactivated in human cancers. Hyperploidy refers to a state in which cells contain one or more extra chromosomes. Hyperploid progression occurs due to continued cell-cycling without cytokinesis in G1 checkpoint-defective cancer cells. The evidence for the triggering of hyperploid progression-mediated death in RB-mutant human retinoblastoma cells is shown. Hence, the very genetic mutation that predisposes to cancer can be exploited to induce lethality. The discovery helped to establish the principle of targeted cytotoxic cancer therapy at the mechanistic level. By triggering the lytic path, targeted therapy with tumor specificity at the genetic level can be developed. It sets the stage for systematically eliminating side effects for cytotoxic cancer therapy.

Vascular safety of erenumab for migraine prevention.

OBJECTIVE: To examine the cardiovascular, cerebrovascular, and peripheral vascular safety of erenumab across migraine prevention studies. METHODS: Vascular adverse events (AEs) and blood pressure data were integrated across 4 double-blind, placebo-controlled studies of erenumab and their open-label extensions in patients with chronic or episodic migraine. Subgroup analyses were conducted by acute migraine-specific medication use and number of vascular risk factors at baseline. Standardized search terms were used to identify vascular AEs (cardiovascular, cerebrovascular, or peripheral). An independent committee adjudicated whether targeted events were vascular in origin. RESULTS: In placebo-controlled studies, 2,443 patients received placebo (n = 1,043), erenumab 70 mg (n = 893), or erenumab 140 mg (n = 507) subcutaneously once monthly. Regardless of acute migraine-specific medication use or vascular risk factors at baseline, AE incidence was similar across the placebo and erenumab treatment groups. Hypertension AEs were reported for 0.9% (placebo), 0.8% (erenumab 70 mg), and 0.2% (erenumab 140 mg) of patients. Vascular AEs, which were similar across double-blind and open-label treatment, generally were confounded, with plausible alternative etiologies. In 18 patients with events reviewed by the independent committee, 4 events were positively adjudicated as cardiovascular in origin: 2 deaths and 2 vascular events. All 4 positively adjudicated cardiovascular events occurred during open-label erenumab treatment. CONCLUSION: Selective blockade of the canonical calcitonin gene-related peptide receptor with erenumab for migraine prevention had a vascular safety profile comparable to that of placebo over 12 weeks, with no increased emergence of events over time. Further study of long-term safety of erenumab in patients with migraine is needed. CLINICALTRIALSGOV IDENTIFIERS: NCT02066415, NCT02456740, NCT01952574, NCT02483585, NCT02174861, and NCT01723514. CLASSIFICATION OF EVIDENCE: This analysis provides Class II evidence that for patients with migraine, erenumab does not increase the risk of vascular AEs.

Revisiting acquired aplastic anaemia: current concepts in diagnosis and management.

Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

BACKGROUND: Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease. AIM: To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB. METHODS: Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded. RESULTS: Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients. CONCLUSION: Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.

Prevalence and causes of preoperative anaemia in elective major surgery patients.

BACKGROUND: Preoperative anaemia is associated with increased morbidity and mortality in surgical patients. Recent national patient blood management guideline recommended screening surgical patients for anaemia, particularly iron deficiency anaemia, without reference to the prevalence of anaemia or iron deficiency anaemia in this patient population. AIMS: To establish the prevalence and cause of preoperative anaemia in elective major surgery patients. METHODS: Patients attending the anaesthetic pre-admission clinics from 1 July 2013 to 30 June 2014 prior to their major elective surgery in our institution were screened for anaemia and iron deficiency by measuring full blood count, iron studies and C-reactive protein. Patients who were anaemic were either further assessed in the haematology clinic or had their medical records reviewed to ascertain the cause of the anaemia. RESULTS: Of 1494 patients, 208 (13.9%) were anaemic, with a male predominance (70.7%); 57 (27.4%) of them had iron deficiency anaemia. Other common causes of anaemia include underlying malignancy (18.3%), end-stage renal failure (11.5%) and other chronic diseases (7.2%). In 53 patients (25.5%), the cause was unknown. Anaemia was most commonly found in patients scheduled for gastrointestinal surgery. CONCLUSION: Preoperative anaemia affects 13.9% of patients undergoing elective major surgery. The most common causes are iron deficiency and chronic diseases. The cause was unexplained in 25.5% of patients with anaemia. The prevalence of anaemia in different surgical specialties may have implications on the approach to screening, particularly in resource-limited areas.