Apoptotic signaling pathway activated by Helicobacter pylori infection and increase of apoptosis-inducing activity under serum-starved conditions

The enhanced gastric epithelial cell apoptosis observed during infection with Helicobacter pylori has been suggested to be of significance in the etiology of gastritis, peptic ulcers, and neoplasia. To investigate the cell death signaling induced by H. pylori infection, human gastric epithelial cells were incubated with H. pylori for up to 72 h. H. pylori infection induced the activation of caspase -8, -9, and -3 and the expression of the proapoptotic Bcl-2 family proteins Bad and Bid. The peak of the activity of the caspases occurred at 24 h. At this time, the inhibition of caspase-8 or -9 almost completely suppressed H. pylori-induced apoptosis. Inhibition of caspase-8 suppressed the expression of Bad and Bid and the subsequent activation of caspase-9 and -3. These observations indicate that H. pylori induces apoptosis through a pathway involving the sequential induction of apical caspase-8 activity, the proapoptotic proteins Bad and Bid, caspase-9 activity, and effector caspase-3 activity. Activation of the pathway was independent of CagA or vacuolating toxin. A membrane fraction of H. pylori was sufficient to activate this pathway, and treatment with proteinase K eliminated the activity. Apoptotic activity of the membrane fraction was significantly increased by incubating the bacteria under serum-starved conditions for 24 h. These observations suggest that environmental conditions in the human stomach could induce H. pylori-mediated pathogenesis, leading to a variety of clinical outcomes.     

Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study)

We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th-75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th-75th percentiles -0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.     

Limited value of the international staging system for predicting long-term outcome of transplant-ineligible,newly diagnosed,symptomatic multiple myeloma in the era of novel agents

We retrospectively investigated clinical outcomes and prognostic factors of 131 patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM) who received melphalan and prednisolone (MP) as first-line therapy from 2006 to 2013. Eighty-one patients received salvage therapies incorporating bortezomib, lenalidomide, and/or thalidomide. The overall response rate to MP was 54.2 %, including 9.2 % of better than very good partial response. With a median follow-up period of 30.2 months, median overall survival (OS) and median time to next treatment (TNT) were 54.4 and 19.0 months, respectively. Univariate analysis revealed that performance status and serum calcium level significantly associated with both OS and TNT, and multivariate analysis revealed that the higher serum calcium level had a significantly unfavorable impact on OS and TNT. Importantly, staging informed by the international staging system (ISS) was not predictive for OS or TNT in the analyzed cohort. Our study revealed that, in the context of first-line MP therapy for NDMM, the salvage therapy incorporating novel agents produced a survival period of >30 months after the initiation of second-line therapy, suggesting that the predictive value of ISS for OS and TNT may be limited in the era of novel agents.     

HMGA2 as a potential molecular target in KMT2A‐AFF1‐positive infant acute lymphoblastic leukaemia

Acute lymphoblastic leukaemia (ALL) in infants is an intractable cancer in childhood. Although recent intensive chemotherapy progress has considerably improved ALL treatment outcome, disease cure is often accompanied by undesirable long‐term side effects, and efficient, less toxic molecular targeting therapies have been anticipated. In infant ALL cells with KMT2A (MLL) fusion, the microRNA let‐7b (MIRLET7B) is significantly downregulated by DNA hypermethylation of its promoter region. We show here that the expression of HMGA2, one of the oncogenes repressed by MIRLET7B, is reversely upregulated in infant ALL leukaemic cells, particularly in KMT2A‐AFF1 (MLL‐AF4) positive ALL. In addition to the suppression of MIRLET7B, KMT2A fusion proteins positively regulate the expression of HMGA2. HMGA2 is one of the negative regulators of CDKN2A gene, which encodes the cyclin‐dependent kinase inhibitor p16^INK4A. The HMGA2 inhibitor netropsin, when combined with demethylating agent 5‐azacytidine, upregulated and sustained the expression of CDKN2A, which resulted in growth suppression of KMT2A‐AFF1‐expressing cell lines. This effect was more apparent compared to treatment with 5‐azacytidine alone. These results indicate that the MIRLET7B‐HMGA2‐CDKN2A axis plays an important role in cell proliferation of leukaemic cells and could be a possible molecular target for the therapy of infant ALL with KMT2A‐AFF1.     

Prognostic significance of circadian variability of RR and QT intervals and QT dynamicity in patients with chronic heart failure

BACKGROUND: In patients with chronic heart failure (CHF), circadian variability of RR and QT intervals may be altered because of neurohumoral activation and functional and structural remodeling of the heart. OBJECTIVE: The aim of this study was to evaluate the prognostic significance of circadian variability of the RR and QT intervals and QT dynamicity (QT/RR slope) in CHF patients. METHODS: We prospectively enrolled 121 patients with stable CHF in sinus rhythm (age 67 +/- 14 years, mean +/- SD; range 34 to 87 years). The RR, QT, and rate-corrected QT (QTc) intervals and the QT/RR slope measured from 24-hour Holter electrocardiogram were fitted by cosine curves. RESULTS: During the follow-up period of 34 +/- 17 months, 40 (33%) patients died of cardiac causes, 10 of which were sudden. All patients showed significant circadian rhythms in the RR, QT, and QTc intervals and the QT/RR slope by cosine-curve fitting. In addition to the expected higher heart rate, longer QT interval, and steeper QT/RR slope, we found that patient who died of cardiac causes had reduced circadian variability of QT interval (10 +/- 10 ms vs 21 +/- 13 ms) and a later maximum RR interval (4.1 +/- 0.9 AM vs 2.3 +/- 2.1 AM) compared with survivors, among many other statistically significant circadian parameter differences. These 2 parameters were independent predictors of cardiac death in multivariate Cox proportional hazards regression analysis. CONCLUSION: Circadian variability analyses of Holter-derived RR and QT intervals may provide prognostic information beyond that provided by 24-hour averages of these parameters.     

Immunohistochemical analysis of TrkA neurotrophin receptor expression in human non-neuronal carcinomas

The Trk family of tyrosine protein kinase receptors plays a significant role in the development and maintenance of neural tissues. It has been recently shown that Trk receptors are also expressed by a wide range of normal non-neuronal tissues in humans in a cell type-specific manner. In the present study, the expression patterns of TrkA in 337 non-neuronal invasive carcinomas of 15 different human tissues were investigated immunohistochemically. Overall, 133 (39%), 101 (30%) and 103 (31%) tumors exhibited strong, moderate and no TrkA Immunoreactivity, respectively. Esophageal and thyroid carcinomas expressed high levels of TrkA, whereas the levels in gastric and colon cancers were low. TrkA expression was detected not only in carcinomas originating from TrkA-positive normal counterpart tissues, Including the esophagus, breast, lung and uterus, but also in those from TrkA-negative tissues/cells of the thyroid, liver and ovary. Immunostaining for nerve growth factor-β, the specific ligand for TrkA, in esophageal and breast carcinomas demonstrated its immunoreactivity in stromal fibroblasts and some TrkA-expressing tumor cells. These results suggest that paracrine/autocrine regulation via stromal/tumoral NGF-tumoral TrkA interaction may be involved In the growth of certain non-neuronal carcinomas.     

Recent Advances and Future Directions of Hypothermia Therapy for Traumatic Brain Injury

For severe traumatic brain injury (TBI) patients, no effective treatment method replacing hypothermia therapy has emerged, and hypothermia therapy still plays the major role. To increase its efficacy, first, early introduction is important. Since there are diverse pathologies of severe TBI, it is necessary to appropriately control the temperature in the hypothermia maintenance and rewarming phases by monitoring relative to the pathology. Currently, hypothermia is considered appropriate for severe TBI patients requiring craniotomy for removal of hematoma, while induced normothermia is appropriate for severe TBI patients with diffuse brain injury. Induced normothermia is expected to exhibit a cerebroprotective effect equivalent to hypothermia, as well as reduce the complexity of whole-body management and systemic complications. According to the Japan Neurotrauma Data Bank of the Japan Society of Neurotraumatology, the brain temperature was controlled in 43.9% of severe TBI patients (induced normothermia: 32.2%, hypothermia: 11.7%) in Japan. Brain temperature management was performed mainly in young patients, and the outcome on discharge was favorable in patients who received brain temperature management. Particularly, patients who need craniotomy for removal of hematoma were a good indication of therapeutic hypothermia. Improvement of therapeutic outcomes with widespread temperature management in TBI patients is expected.