Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.     

Inhibition of natural killer cells protects the liver against acute injury in the absence of glycine N-methyltransferase

Glycine N-methyltransferase (GNMT) catabolizes S-adenosylmethionine (SAMe), the main methyl donor of the body. Patients with cirrhosis show attenuated GNMT expression, which is absent in hepatocellular carcinoma (HCC) samples. GNMT(-/-) mice develop spontaneous steatosis that progresses to steatohepatitis, cirrhosis, and HCC. The liver is highly enriched with innate immune cells and plays a key role in the body's host defense and in the regulation of inflammation. Chronic inflammation is the major hallmark of nonalcoholic steatohepatitis (NASH) progression. The aim of our study was to uncover the molecular mechanisms leading to liver chronic inflammation in the absence of GNMT, focusing on the implication of natural killer (NK) / natural killer T (NKT) cells. We found increased expression of T helper (Th)1- over Th2-related cytokines, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-R2/DR5, and several ligands of NK cells in GNMT(-/-) livers. Interestingly, NK cells from GNMT(-/-) mice were spontaneously activated, expressed more TRAIL, and had strong cytotoxic activity, suggesting their contribution to the proinflammatory environment in the liver. Accordingly, NK cells mediated hypersensitivity to concanavalin A (ConA)-mediated hepatitis in GNMT(-/-) mice. Moreover, GNMT(-/-) mice were hypersensitive to endotoxin-mediated liver injury. NK cell depletion and adoptive transfer of TRAIL(-/-) liver-NK cells protected the liver against lipopolysaccharide (LPS) liver damage. CONCLUSION: Our data allow us to conclude that TRAIL-producing NK cells actively contribute to promote a proinflammatory environment at early stages of fatty liver disease, suggesting that this cell compartment may contribute to the progression of NASH.     

Large platelet aggregates in endoscopic ultrasound‐guided fine‐needle aspiration of the pancreas and peripancreatic region: A clue for the diagnosis of intrapancreatic or accessory spleen

Intrapancreatic and intraabdominal accessory spleens (IPIASs) are rarely encountered in endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) biopsies. However, as incidentally discovered IPIAS can mimic a benign or malignant pancreatic neoplasm on imaging studies, a definitive diagnosis made by EUS‐FNA can avert an unnecessary surgical intervention or additional radiologic follow‐up. We report five cases of intrapancreatic splenules and one case of accessory spleen (AS) in which a definitive diagnosis was made on EUS‐FNA. Previously recognized FNA cytomorphologic features of splenic tissue, including ASs and splenosis, are endothelial cells and polymorphous lymphocytes admixed with neutrophils, eosinophils, plasma cells, histiocytes, and lymphoglandular bodies. We describe the additional finding of abundant large platelet aggregates as another distinguishing feature of splenic tissue on FNA. In all six cases, large platelet aggregates were identified along with polymorphous lymphoid cells, lymphoglandular bodies, loose aggregates of endothelial cells and scattered or aggregated bland spindle cells. A review of 10 consecutive cases of EUS‐FNA‐sampled benign intraabdominal lymph nodes showed that the presence of large platelet aggregates, three‐dimensional aggregates of lymphoid cells and of bland slender spindle cells and the absence of follicular germinal cell components (tingible body macrophages and lymphohistiocytic aggregates) are useful in differentiating IPIASs from reactive lymph nodes. Immunoperoxidase stains were useful to confirm a suspected IPIASs by showing CD31‐positive acellular flocculent material, consistent with large platelet aggregates and a rich CD8‐positive endothelial cell network between CD45‐positive lymphoid cells and CD68‐positive histiocytes in all six cases. Diagn. Cytopathol. 2013;41:661–672. © 2013 Wiley Periodicals, Inc.     

The role of atypical pathogens in community-acquired pneumonia

The term atypical pneumonia was first used in 1938, and by the 1970s it was widely used to refer to pneumonia due to Mycoplasma pneumoniae, Legionella pneumophila (or other Legionella species), and Chlamydophila pneumoniae. However, in the purest sense all pneumonias other than the classic bacterial pneumonias are atypical. Currently many favor abolition of the term atypical pneumonia.This review categorizes atypical pneumonia pathogens as conventional ones; viral agents and emerging atypical pneumonia pathogens. We emphasize viral pneumonia because with the increasing availability of multiplex polymerase chain reaction we can identify the agent(s) responsible for viral pneumonia. By using a sensitive assay for procalcitonin one can distinguish between viral and bacterial pneumonia. This allows pneumonia to be categorized as bacterial or viral at the time of admission to hospital or at discharge from the emergency department and soon thereafter further classified as to the etiology, which should be stated as definite or probable.     

Pediatric dentoalveolar surgery

Dentoalveolar surgery in children presents general dentists with unique challenges not encountered in adults. The long-term effects that treatments have on these children must always be taken into consideration. A clear understanding of the growth and development of pediatric patients is necessary to correctly identify dental abnormalities.     

“The Shoop Shoop Song”

In this paper I describe how I integrate the interpersonal psychoanalytic idea of transference–countertransference with the systems idea of couple's fit. I define the two constructs as I use them, including a redefinition of couple's fit. The redefinition includes both the similarity of a couple's fears and the complementarity of the partners' styles of coping with those fears. I also contrast this integrative approach with that of projective identification. Finally, I describe a countertransference enactment with a couple to show that discussing such enactments can offer great therapeutic leverage. After the discussion, the therapist may find the connections between how the two people in the couple relate to each other and how the therapist and couple related. Clinical vignettes illustrate these ideas.