Mechanisms Controlling PD-L1 Expression in Cancer.

The engagement of programmed cell death protein 1 (PD-1; encoded by the PDCD1 gene) receptor expressed on activated T cells and its ligand, programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), is a major co-inhibitory checkpoint signaling that controls T cell activities. Various types of cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T cell immunity. Blocking the PD-L1/PD-1 pathway has consistently shown remarkable anti-tumor effects in patients with advanced cancers and is recognized as the gold standard for developing new immune checkpoint blockade (ICB) and combination therapies. However, the response rates of anti-PD-L1 have been limited in several solid tumors. Therefore, furthering our understanding of the regulatory mechanisms of PD-L1 can bring substantial benefits to patients with cancer by improving the efficacy of current PD-L1/PD-1 blockade or other ICBs. In this review, we provide current knowledge of PD-L1 regulatory mechanisms at the transcriptional, posttranscriptional, post-translational, and extracellular levels, and discuss the implications of these findings in cancer diagnosis and immunotherapy.

Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer.

Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell-mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor-T cell therapy may represent a promising strategy for patients with EphA10-positive tumors.

A Unique Case of Community Acquired Proteus mirabilis Meningitis.

Proteus mirabilis, a gram-negative bacterium commonly known for causing urinary tract infections (UTI) can rarely present with central nervous system (CNS) infections. Proteus mirabilis CNS infections are usually encountered in the neonatal and infantile period and occasionally cause brain abscesses. It is an uncommon cause of adult CNS infection. We report the first case of a community-acquired Proteus mirabilis meningitis (PMM) in a patient with Proteus mirabilis UTI, urolithiasis, and bacteremia. Risk factors for gram-negative bacillary meningitis (GNBM) include extremes of age, cancer history, diabetes mellitus, UTI, and nosocomial exposure, with the latter being a more prominent cause of PMM. Compromise of the anatomical defense against CNS infections whether accidental or neurosurgical is another important cause, and approximately two-thirds of reported cases of PMM have occurred after neurosurgical procedures. PMM patients develop fever, altered consciousness, and have an acute clinical course. Antimicrobials that can be used for treatment include third-generation cephalosporins, ciprofloxacin, imipenem/ cilastatin, aztreonam, and intraventricular aminoglycosides. Despite appropriate antibiotic therapy outcomes are poor with severe neurological deficit and death commonly resulting. Nosocomial infections can be drug-resistant and multiple antibiotics should be started while awaiting culture results. Literature review reveals that treatment with intraventricular aminoglycosides when attempted has shown bacteriological cure indicating this can be an important treatment approach. Due to the acute clinical course and high morbidity and mortality, we recommend starting multiple antibiotics with different mechanisms of action as soon as the disease is suspected. Our patient was initially started on ceftriaxone, vancomycin, acyclovir, and ampicillin for UTI and meningoencephalitis. The antibiotics were later consolidated to cefepime based on blood, urine and, cerebrospinal fluid cultures growing pan-sensitive Proteus mirabilis. Her clinical condition continued to worsen and ciprofloxacin was added. However, due to the progressive decline in her condition, the family elected for inpatient hospice care and intraventricular aminoglycosides were not attempted.

Ribonuclease 7-driven activation of ROS1 is a potential therapeutic target in hepatocellular carcinoma.

BACKGROUND & AIMS: There are currently limited therapeutic options for hepatocellular carcinoma (HCC), particularly when it is diagnosed at advanced stages. Herein, we examined the pathophysiological role of ROS1 and assessed the utility of ROS1-targeted therapy for the treatment of HCC. METHODS: Recombinant ribonucleases (RNases) were purified, and the ligand-receptor relationship between RNase7 and ROS1 was validated in HCC cell lines by Duolink, immunofluorescence, and immunoprecipitation assays. Potential interacting residues between ROS1 and RNase7 were predicted using a protein-protein docking approach. The oncogenic function of RNase7 was analyzed by cell proliferation, migration and invasion assays, and a xenograft mouse model. The efficacy of anti-ROS1 inhibitor treatment was evaluated in patient-derived xenograft (PDX) and orthotopic models. Two independent patient cohorts were analyzed to evaluate the pathological relevance of RNase7/ROS1. RESULTS: RNase7 associated with ROS1's N3-P2 domain and promoted ROS1-mediated oncogenic transformation. Patients with HCC exhibited elevated plasma RNase7 levels compared with healthy individuals. High ROS1 and RNase7 expression were strongly associated with poor prognosis in patients with HCC. In both HCC PDX and orthotopic mouse models, ROS1 inhibitor treatment markedly suppressed RNase7-induced tumorigenesis, leading to decreased plasma RNase7 levels and tumor shrinkage in mice. CONCLUSIONS: RNase7 serves as a high-affinity ligand for ROS1. Plasma RNase7 could be used as a biomarker to identify patients with HCC who may benefit from anti-ROS1 treatment. LAY SUMMARY: Receptor tyrosine kinases are known to be involved in tumorigenesis and have been targeted therapeutically for a number of cancers, including hepatocellular carcinoma. ROS1 is the only such receptor with kinase activity whose ligand has not been identified. Herein, we show that RNase7 acts as a ligand to activate ROS1 signaling. This has important pathophysiological and therapeutic implications. Anti-ROS1 inhibitors could be used to treatment patients with hepatocellular carcinoma and high RNase7 levels.

H2O2 induces nuclear transport of the receptor tyrosine kinase c-MET in breast cancer cells via a membrane-bound retrograde trafficking mechanism.

Reactive oxygen species (ROS) are cellular by-products produced from metabolism and also anticancer agents, such as ionizing irradiation and chemotherapy drugs. The ROS H2O2 has high rates of production in cancer cells because of their rapid proliferation. ROS oxidize DNA, protein, and lipids, causing oxidative stress in cancer cells and making them vulnerable to other stresses. Therefore, cancer cell survival relies on maintaining ROS-induced stress at tolerable levels. Hepatocyte growth factor receptor (c-MET) is a receptor tyrosine kinase overexpressed in malignant cancer types, including breast cancer. Full-length c-MET triggers a signal transduction cascade from the plasma membrane that, through downstream signaling proteins, up-regulates cell proliferation and migration. Recently, c-MET was shown to interact and phosphorylate poly(ADP-ribose) polymerase 1 in the nucleus and to induce poly(ADP-ribose) polymerase inhibitor resistance. However, it remains unclear how c-MET moves from the cell membrane to the nucleus. Here, we demonstrate that H2O2 induces retrograde transport of membrane-associated full-length c-MET into the nucleus of human MCF10A and MCF12A or primary breast cancer cells. We further show that knocking down either coatomer protein complex subunit γ1 (COPG1) or Sec61 translocon ß subunit (SEC61ß) attenuates the accumulation of full-length nuclear c-MET. However, a c-MET kinase inhibitor did not block nuclear c-MET transport. Moreover, nuclear c-MET interacted with KU proteins in breast cancer cells, suggesting a role of full-length nuclear c-MET in ROS-induced DNA damage repair. We conclude that a membrane-bound retrograde vesicle transport mechanism facilitates membrane-to-nucleus transport of c-MET in breast cancer cells.

MET Inhibitors Promote Liver Tumor Evasion of the Immune Response by Stabilizing PDL1.

BACKGROUND & AIMS: Inhibitors of MET have not produced satisfactory outcomes in trials of patients with liver cancer. We investigated the mechanisms of liver tumor resistance to MET inhibitors in mice. METHODS: We tested the effects of MET inhibitors tivantinib and capmatinib in the mouse hepatocellular carcinoma (HCC) cell line HCA-1 and in immune-competent and immunodeficient mice with subcutaneous tumors grown from this cell line. Tumors were collected from mice and tumor cells were analyzed by time-of-flight mass cytometry. We used short hairpin RNAs to weaken expression of MET in Hep3B, SK-HEP-1, HA59T, and HA22T liver cancer cell lines and analyzed cells by immunoblot, immunofluorescence, and immunoprecipitation assays. Mass spectrometry was used to assess interactions between MET and glycogen synthase kinase 3ß (GSK3B), and GSK3B phosphorylation, in liver cancer cell lines. C57/BL6 mice with orthotopic tumors grown from Hep1-6 cells were given combinations of capmatinib or tivantinib and antibodies against programmed cell death 1 (PDCD1; also called PD1); tumors were collected and analyzed by immunofluorescence. We analyzed 268 HCCsamples in a tissue microarray by immunohistochemistry. RESULTS: Exposure of liver cancer cell lines to MET inhibitors increased their expression of PD ligand 1 (PDL1) and inactivated cocultured T cells. MET phosphorylated and activated GSK3B at tyrosine 56, which decreased the expression of PDL1 by liver cancer cells. In orthotopic tumors grown in immune-competent mice, MET inhibitors decreased the antitumor activity of T cells. However, addition of anti-PD1 decreased orthotopic tumor growth and prolonged survival of mice compared with anti-PD1 or MET inhibitors alone. Tissue microarray analysis of HCC samples showed an inverse correlation between levels of MET and PDL1 and a positive correlation between levels of MET and phosphorylated GSK3B. CONCLUSIONS: In studies of liver cancer cell lines and mice with orthotopic tumors, MET mediated phosphorylation and activated GSK3B, leading to decreased expression of PDL1. Combined with a MET inhibitor, anti-PD1 and anti-PDL1 produced additive effect to slow growth of HCCs in mice.

The impact of PD-L1 N-linked glycosylation on cancer therapy and clinical diagnosis.

N-linked glycosylation is one of the most abundant posttranslational modifications of membrane-bound proteins in eukaryotes and affects a number of biological activities, including protein biosynthesis, protein stability, intracellular trafficking, subcellular localization, and ligand-receptor interaction. Accumulating evidence indicates that cell membrane immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), are glycosylated with heavy N-linked glycan moieties in human cancers. N-linked glycosylation of PD-L1 maintains its protein stability and interaction with its cognate receptor, programmed cell death protein 1 (PD-1), and this in turn promotes evasion of T-cell immunity. Studies have suggested targeting PD-L1 glycosylation as a therapeutic option by rational combination of cancer immunotherapies. Interestingly, structural hindrance by N-glycan on PD-L1 in fixed samples impedes its recognition by PD-L1 diagnostic antibodies. Notably, the removal of N-linked glycosylation enhances PD-L1 detection in a variety of bioassays and more accurately predicts the therapeutic efficacy of PD-1/PD-L1 inhibitors, suggesting an important clinical implication of PD-L1 N-linked glycosylation. A detailed understanding of the regulatory mechanisms, cellular functions, and diagnostic limits underlying PD-L1 N-linked glycosylation could shed new light on the clinical development of immune checkpoint inhibitors for cancer treatment and deepen our knowledge of biomarkers to identify patients who would benefit the most from immunotherapy. In this review, we highlight the effects of protein glycosylation on cancer immunotherapy using N-linked glycosylation of PD-L1 as an example. In addition, we consider the potential impacts of PD-L1 N-linked glycosylation on clinical diagnosis. The notion of utilizing the deglycosylated form of PD-L1 as a predictive biomarker to guide anti-PD-1/PD-L1 immunotherapy is also discussed.

Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade.

OBJECTIVE: In the tumour microenvironment, critical drivers of immune escape include the oncogenic activity of the tumour cell-intrinsic osteopontin (OPN), the expression of programmed death ligand 1 (PD-L1) and the expansion of tumour-associated macrophages (TAMs). We investigated the feasibility of targeting these pathways as a therapeutic option in hepatocellular carcinoma (HCC) mouse models. DESIGN: We analysed the number of tumour-infiltrating immune cells and the inflammatory immune profiles in chemically induced liver tumour isolated from wild-type and OPNknockout (KO) mice. In vitro cell cocultures were further conducted to investigate the crosstalk between TAMs and HCC cells mediated by OPN, colony stimulating factor-1 (CSF1) and CSF1 receptor (CSF1R). The in vivo efficacy of anti-PD-L1 and CSF1/CSF1R inhibition was evaluated in OPN overexpressing subcutaneous or orthotopic mouse model of HCC. RESULTS: The numbers of TAMs, as well as the expression levels of M2 macrophage markers and PD-L1 were significantly decreased, but the levels of cytokines produced by T-helper 1 (Th1) cells were upregulated in tumour tissues from OPN KO mice compared with that from the controls. In addition, we observed a positive association between the OPN and PD-L1 expression, and OPN expression and TAM infiltration in tumour tissues from patients with HCC. We further demonstrated that OPN facilitates chemotactic migration, and alternative activation of macrophages, and promotes the PD-L1 expression in HCC via activation of the CSF1-CSF1R pathway in macrophages. Combining anti-PD-L1 and CSF1R inhibition elicited potent antitumour activity and prolonged survival of OPNhigh tumour-bearing mice. Histological, flow cytometric and ELISA revealed increased CD8+ T cell infiltration, reduced TAMs and enhanced Th1/Th2 cytokine balance in multiple mouse models of HCC. CONCLUSIONS: OPN/CSF1/CSF1R axis plays a critical role in the immunosuppressive nature of the HCC microenvironment. Blocking CSF1/CSF1R prevents TAM trafficking and thereby enhances the efficacy of immune checkpoint inhibitors for the treatment of HCC.

EGFR modulates microRNA maturation in response to hypoxia through phosphorylation of AGO2.

MicroRNAs (miRNAs) are generated by two-step processing to yield small RNAs that negatively regulate target gene expression at the post-transcriptional level. Deregulation of miRNAs has been linked to diverse pathological processes, including cancer. Recent studies have also implicated miRNAs in the regulation of cellular response to a spectrum of stresses, such as hypoxia, which is frequently encountered in the poorly angiogenic core of a solid tumour. However, the upstream regulators of miRNA biogenesis machineries remain obscure, raising the question of how tumour cells efficiently coordinate and impose specificity on miRNA expression and function in response to stresses. Here we show that epidermal growth factor receptor (EGFR), which is the product of a well-characterized oncogene in human cancers, suppresses the maturation of specific tumour-suppressor-like miRNAs in response to hypoxic stress through phosphorylation of argonaute 2 (AGO2) at Tyr 393. The association between EGFR and AGO2 is enhanced by hypoxia, leading to elevated AGO2-Y393 phosphorylation, which in turn reduces the binding of Dicer to AGO2 and inhibits miRNA processing from precursor miRNAs to mature miRNAs. We also identify a long-loop structure in precursor miRNAs as a critical regulatory element in phospho-Y393-AGO2-mediated miRNA maturation. Furthermore, AGO2-Y393 phosphorylation mediates EGFR-enhanced cell survival and invasiveness under hypoxia, and correlates with poorer overall survival in breast cancer patients. Our study reveals a previously unrecognized function of EGFR in miRNA maturation and demonstrates how EGFR is likely to function as a regulator of AGO2 through novel post-translational modification. These findings suggest that modulation of miRNA biogenesis is important for stress response in tumour cells and has potential clinical implications.

CD83 is a new potential biomarker and therapeutic target for Hodgkin lymphoma.

Chemotherapy and hematopoietic stem cell transplantation are effective treatments for most Hodgkin lymphoma patients, however there remains a need for better tumor-specific target therapy in Hodgkin lymphoma patients with refractory or relapsed disease. Herein, we demonstrate that membrane CD83 is a diagnostic and therapeutic target, highly expressed in Hodgkin lymphoma cell lines and Hodgkin and Reed-Sternberg cells in 29/35 (82.9%) Hodgkin lymphoma patient lymph node biopsies. CD83 from Hodgkin lymphoma tumor cells was able to trogocytose to surrounding T cells and, interestingly, the trogocytosing CD83+T cells expressed significantly more programmed death-1 compared to CD83-T cells. Hodgkin lymphoma tumor cells secreted soluble CD83 that inhibited T-cell proliferation, and anti-CD83 antibody partially reversed the inhibitory effect. High levels of soluble CD83 were detected in Hodgkin lymphoma patient sera, which returned to normal in patients who had good clinical responses to chemotherapy confirmed by positron emission tomography scans. We generated a human anti-human CD83 antibody, 3C12C, and its toxin monomethyl auristatin E conjugate, that killed CD83 positive Hodgkin lymphoma cells but not CD83 negative cells. The 3C12C antibody was tested in dose escalation studies in non-human primates. No toxicity was observed, but there was evidence of CD83 positive target cell depletion. These data establish CD83 as a potential biomarker and therapeutic target in Hodgkin lymphoma.

The Analysis of CD83 Expression on Human Immune Cells Identifies a Unique CD83+-Activated T Cell Population.

CD83 is a member of the Ig gene superfamily, first identified in activated lymphocytes. Since then, CD83 has become an important marker for defining activated human dendritic cells (DC). Several potential CD83 mRNA isoforms have been described, including a soluble form detected in human serum, which may have an immunosuppressive function. To further understand the biology of CD83, we examined its expression in different human immune cell types before and after activation using a panel of mouse and human anti-human CD83 mAb. The mouse anti-human CD83 mAbs, HB15a and HB15e, and the human anti-human CD83 mAb, 3C12C, were selected to examine cytoplasmic and surface CD83 expression, based on their different binding characteristics. Glycosylation of CD83, the CD83 mRNA isoforms, and soluble CD83 released differed among blood DC, monocytes, and monocyte-derived DC, and other immune cell types. A small T cell population expressing surface CD83 was identified upon T cell stimulation and during allogeneic MLR. This subpopulation appeared specifically during viral Ag challenge. We did not observe human CD83 on unstimulated human natural regulatory T cells (Treg), in contrast to reports describing expression of CD83 on mouse Treg. CD83 expression was increased on CD4+, CD8+ T, and Treg cells in association with clinical acute graft-versus-host disease in allogeneic hematopoietic cell transplant recipients. The differential expression and function of CD83 on human immune cells reveal potential new roles for this molecule as a target of therapeutic manipulation in transplantation, inflammation, and autoimmune diseases.

Collaborating to Enhance Faculty Development through Structured Funding.

PROBLEM: Faculty development is critical to individual career growth and success in academic medicine and it enhances the overall academic climate of an institution. Despite these well-recognized benefits, time and financial constraints often limit participation of faculty members. To address this issue, the University of South Dakota Sanford School of Medicine (SSOM) developed a novel policy and process to support participation in faculty development programs. APPROACH: In 2014, the SSOM Office of Continuing Professional Development (OCPD) implemented a process for funding faculty members' participation in external career and educational development programs. A subcommittee of the Faculty Development Committee reviewed and selected applications based on the benefit to the applicant's career and the SSOM as whole. Selected applicants were required to disseminate new knowledge from the external programs to other SSOM faculty, staff, and trainees. OUTCOMES: With the implementation of this program, 17 faculty members received funding. The race/ethnicities of the selected applicants reflected the overall demographics of the larger SSOM community. The majority of the selected applicants were female (n=12, 70 percent), assistant professors (n=9, 53 percent), and members of clinical departments (n=12, 70 percent). Upon completion of the program, five participants achieved academic promotion. This novel funding mechanism greatly increased faculty participation in external programs and participants reported enhanced networking opportunities, leadership experience, and career opportunities. NEXT STEPS: Challenges observed with implementation of the program have led to revision of the application process, tracking of participant demographic data, and confirmation of knowledge dissemination.

M. chimaera: A Multi-Headed Pathogen.

We present the case of a 64-year-old man with Mycobacterium chimaera prosthetic aortic valve endocarditis likely acquired through exposure to a contaminated heater-cooler device used for cardiopulmonary bypass during valve replacement. This case demonstrates multi-system involvement with a non-tuberculous mycobacterial species that was previously not considered a significant human pathogen. We review the key features of the case and review published literature regarding an international outbreak of M. chimaera arising from point-source contamination during the manufacturing process. This report highlights the importance of clinician awareness of this international outbreak.

Catch Me If You Can.

Nocardia is a genus of anaerobic gram-positive bacteria that most commonly infect persons with compromised immunity. Pneumonia and soft tissue infections are seen most frequently; osteomyelitis is an uncommonly reported manifestation of nocardiosis. We report a case of pelvic osteomyelitis due to Nocardia asteroides in a patient with unrecognized acquired immune deficiency syndrome (AIDS) without evidence of concomitant pulmonary or skin infection.

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer.

Breast cancer affects approximately 1 in 8 women, and it is estimated that over 246,660 women in the USA will be diagnosed with breast cancer in 2016. Breast cancer mortality has decline over the last two decades due to early detection and improved treatment. Over the last few years, there is mounting evidence to demonstrate the prominent role of receptor tyrosine kinases (RTKs) in tumor initiation and progression, and targeted therapies against the RTKs have been developed, evaluated in clinical trials, and approved for many cancer types, including breast cancer. However, not all breast cancers are the same as evidenced by the multiple subtypes of the disease, with some more aggressive than others, showing differential treatment response to different types of drugs. Moreover, in addition to canonical signaling from the cell surface, many RTKs can be trafficked to various subcellular compartments, e.g., the multivesicular body and nucleus, where they carry out critical cellular functions, such as cell proliferation, DNA replication and repair, and therapeutic resistance. In this review, we provide a brief summary on the role of a selected number of RTKs in breast cancer and describe some mechanisms of resistance to targeted therapies.

Enhancer of Zeste Homolog 2 and Histone Deacetylase 9c Regulate Age-Dependent Mesenchymal Stem Cell Differentiation into Osteoblasts and Adipocytes.

Mesenchymal stem cells (MSCs) are multipotent precursors that can undergo multilineage differentiation, including osteogenesis and adipogenesis, which are two mutually exclusive events. Previously, we demonstrated that enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, mediates epigenetic silencing of histone deacetylase 9c (HDAC9c) in adipocytes but not in osteoblasts and that HDAC9c accelerates osteogenesis while attenuating adipogenesis of MSCs through inactivation of peroxisome proliferator-activated receptor gamma 2 activity. Importantly, disrupting the balance between adipogenesis and osteogenesis can lead to age-associated bone loss (osteoporosis) and obesity. Here, we investigated the relationship between age, and osteogenic and adipogenic differentiation potential of MSCs by comparing EZH2 and HDAC9c expression in osteoblasts and adipocytes of both human and mice origins to determine whether the EZH2-HDAC9c axis regulates age-associated osteoporosis and obesity. Our findings indicated that a decline in HDAC9c expression over time was accompanied by increased EZH2 expression and suggested that a therapeutic intervention for age-associated osteoporosis and obesity may be feasible by targeting the EZH2-HDAC9c axis. Stem Cells 2016;34:2183-2193.

Disseminated Blastomycosis Mimicking Malignancy.

Blastomycosis is an endemic fungal infection commonly found within the Mississippi and Ohio River basins and Great Lakes region. While patients typically present with acute pneumonia, Blastomyces dermatitidis has the potential to spread hematogenously, resulting in disseminated infection of multiple organs. In this report, we describe a 57-year-old male with disseminated blastomycosis acquired in South Dakota. The diagnostic evaluation was confounded by concern for malignancy given the involvement of multiple locations, including brain, lungs, adrenal glands, and testes. Despite aggressive therapy with amphotericin B, the patient succumbed to this infection.