[Persistent hiccups after perforated cholecystitis]. / Vedvarende hikke etter perforert kolecystitt.

BACKGROUND: Persistent hiccups lasting more than 48 hours are rare and have numerous possible causes that require further investigation. CASE PRESENTATION: We present a man in his seventies who was admitted to hospital after 11 days of hiccups. The hiccups were preceded by abdominal pain that spontaneously receded after a few hours. At admission he had no abdominal pain during examination, but a CT scan later suggested that the cause was a perforated cholecystitis with an intra-abdominal abscess. The abscess was drained percutaneously and treated with antibiotics, and the hiccups stopped. INTERPRETATION: Persistent hiccups warrant thorough examination, and it is recommended to consider CT scans of the head and truncus, cerebral MRI scan and an upper GI endoscopy. Treating the underlying cause of hiccups is the ultimate target, while symptomatic treatment simultaneously is preferred.

PRL-3 induces a positive signaling circuit between glycolysis and activation of STAT1/2.

Multiple myeloma (MM) is an incurable hematologic malignancy resulting from the clonal expansion of plasma cells. MM cells are interacting with components of the bone marrow microenvironment such as cytokines to survive and proliferate. Phosphatase of regenerating liver (PRL)-3, a cytokine-induced oncogenic phosphatase, is highly expressed in myeloma patients and is a mediator of metabolic reprogramming of cancer cells. To find novel pathways and genes regulated by PRL-3, we characterized the global transcriptional response to PRL-3 overexpression in two MM cell lines. We used pathway enrichment analysis to identify pathways regulated by PRL-3. We further confirmed the hits from the enrichment analysis with in vitro experiments and investigated their function. We found that PRL-3 induced expression of genes belonging to the type 1 interferon (IFN-I) signaling pathway due to activation of signal transducer and activator of transcription (STAT) 1 and STAT2. This activation was independent of autocrine IFN-I secretion. The increase in STAT1 and STAT2 did not result in any of the common consequences of increased IFN-I or STAT1 signaling in cancer. Knockdown of STAT1/2 did not affect the viability of the cells, but decreased PRL-3-induced glycolysis. Interestingly, glucose metabolism contributed to the activation of STAT1 and STAT2 and expression of IFN-I-stimulated genes in PRL-3-overexpressing cells. In summary, we describe a novel signaling circuit where the key IFN-I-activated transcription factors STAT1 and STAT2 are important drivers of the increase in glycolysis induced by PRL-3. Subsequently, increased glycolysis regulates the IFN-I-stimulated genes by augmenting the activation of STAT1/2.

Conversion of ATP to adenosine by CD39 and CD73 in multiple myeloma can be successfully targeted together with adenosine receptor A2A blockade.

BACKGROUND: PD1/PDL1-directed therapies have been unsuccessful for multiple myeloma (MM), an incurable cancer of plasma cells in the bone marrow (BM). Therefore, other immune checkpoints such as extracellular adenosine and its immunosuppressive receptor should be considered. CD39 and CD73 convert extracellular ATP to adenosine, which inhibits T-cell effector functions via the adenosine receptor A2A (A2AR). We set out to investigate whether blocking the adenosine pathway could be a therapy for MM. METHODS: Expression of CD39 and CD73 on BM cells from patients and T-cell proliferation were determined by flow cytometry and adenosine production by Liquid chromatograpy-mass spectrometry (HPCL/MS). ENTPD1 (CD39) mRNA expression was determined on myeloma cells from patients enrolled in the publicly available CoMMpass study. Transplantable 5T33MM myeloma cells were used to determine the effect of inhibiting CD39, CD73 and A2AR in mice in vivo. RESULTS: Elevated level of adenosine was found in BM plasma of MM patients. Myeloma cells from patients expressed CD39, and high gene expression indicated reduced survival. CD73 was found on leukocytes and stromal cells in the BM. A CD39 inhibitor, POM-1, and an anti-CD73 antibody inhibited adenosine production and reduced T-cell suppression in vitro in coculture of myeloma and stromal cells. Blocking the adenosine pathway in vivo with a combination of Sodium polyoxotungstate (POM-1), anti-CD73, and the A2AR antagonist AZD4635 activated immune cells, increased interferon gamma production, and reduced the tumor load in a murine model of MM. CONCLUSIONS: Our data suggest that the adenosine pathway can be successfully targeted in MM and blocking this pathway could be an alternative to PD1/PDL1 inhibition for MM and other hematological cancers. Inhibitors of the adenosine pathway are available. Some are in clinical trials and they could thus reach MM patients fairly rapidly.

Phosphatase of regenerating liver-3 (PRL-3) is overexpressed in classical Hodgkin lymphoma and promotes survival and migration.

BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3) is implicated in oncogenesis of hematological and solid cancers. PRL-3 expression increases metastatic potential, invasiveness and is associated with poor prognosis. With this study, we aimed to show a possible oncogenic role of PRL-3 in classical Hodgkin lymphoma (cHL). METHODS: PRL-3 expression was measured in 25 cHL patients by immunohistochemistry and gene expression was analyzed from microdissected malignant cells. We knocked down PRL-3 in the cHL cell lines L1236 and HDLM2 and used small molecular inhibitors against PRL-3 to investigate proliferation, migration and cytokine production. RESULTS: PRL-3 protein was expressed in 16% of patient samples. In three different gene expression datasets, PRL-3 was significantly overexpressed compared to normal controls. PRL-3 knockdown reduced proliferation, viability and Mcl-1 expression in L1236, but not in HDLM2 cells. Thienopyridone, a small molecule inhibitor of PRL-3, reduced proliferation of both L1236 and HDLM2. PRL-3 affected IL-13 secretion and enhanced STAT6 signaling. IL-13 stimulation partially rescued proliferation in L1236 cells after knockdown of PRL-3. PRL-3 knockdown reduced migration in both L1236 and HDLM2 cells. CONCLUSION: PRL-3 was overexpressed in a subset of cHL patients. Inhibition of PRL-3 increased IL-13 cytokine production and reduced migration, proliferation and viability. The effects could be mediated through regulation of the anti-apoptotic molecule Mcl-1 and a feedback loop of IL-13 mediated activation of STAT6. This point to a role for PRL-3 in the pathogenesis of Hodgkin lymphoma, and PRL-3 could be a possible new drug target.