Over‐expression of BACH2 is related to ongoing somatic hypermutation of the immunoglobulin heavy chain gene variable region of de novo diffuse large B‐cell lymphoma

The basic region–leucine zipper (bZip) factor BTB, CNC homology 2 (BACH2) is known to have important roles in class switch recombination and somatic hypermutation (SHM) of the immunoglobulin (Ig) gene. In this study, we investigated the relationship between the expression of BACH2 and the status of SHM of the Ig heavy chain gene variable region (IgHV) for SHM in diffuse large B‐cell lymphoma (DLBCL). We examined 20 cases of DLBCL, 13 of which were germinal center B‐cell (GCB) DLBCL and 7 were non‐GCB DLBCL. Seven cases were negative, 6 were positive (cytoplasmic expression) and 7 were strongly positive (both nuclear and cytoplasmic expression) for BACH2. Confirmed mutation (CM) was identified in 8 cases and the CM index (number of confirmed mutations per 10 subclones) was distributed from 0 to 5. A CM index of 7 strongly positive (over‐expression) cases with BACH2 were distributed from 0 to 5, and that of 7 negative and 6 positive cases were distributed from 0 to 1. Over‐expression of BACH2 was statistically related to CM index (P = 0.008). In conclusion, over‐expression of BACH2 is critical for ongoing SHM of IgHV in DLBCL, and our data suggest that BACH2 may play an essential role for SHM of the Ig gene in B‐cell lymphoma.     

Successful preoperative chemotherapy with S-1 plus low-dose cisplatin for advanced gastric cancer with synchronous liver metastases: report of 2 cases

We report 2 cases of advanced gastric cancer with synchronous liver metastases who were successfully downstaged using S-1 plus low-dose cisplatin chemotherapy followed by surgical resection. S-1 was administered orally (80 mg/m(2)/day) twice daily for 14 consecutive days, and cisplatin (15 mg/m(2)) was infused over 1 h on days 1 and 8. Successful downstaging of the hepatic metastases was confirmed by imaging analyses; however, neither patient showed a complete response of the primary lesion in the stomach. Toxicities, according to the WHO criteria, were mild. The patients underwent surgical resection within 4 weeks after the last chemotherapy. Postoperatively, they were discharged without complications and received adjuvant chemotherapy. Both patients remained alive and well at 17 and 12 months after surgery, respectively, without recurrence. These cases provide further evidence that S-1 plus low-dose cisplatin chemotherapy enables downstaging of advanced gastric cancer and a subsequent potentially curative resection without serious complications.     

Lipopolysaccharide interaction with cell surface Toll-like receptor 4-MD-2: higher affinity than that with MD-2 or CD14

Toll-like receptors (TLRs) are innate recognition molecules for microbial products, but their direct interactions with corresponding ligands remain unclarified. LPS, a membrane constituent of gram-negative bacteria, is the best-studied TLR ligand and is recognized by TLR4 and MD-2, a molecule associated with the extracellular domain of TLR4. Although TLR4-MD-2 recognizes LPS, little is known about the physical interaction between LPS and TLR4-MD-2. Here, we demonstrate cell surface LPS-TLR4-MD-2 complexes. CD14 greatly enhances the formation of LPS-TLR4-MD-2 complexes, but is not coprecipitated with LPS-TLR4-MD-2 complexes, suggesting a role for CD14 in LPS loading onto TLR4-MD-2 but not in the interaction itself between LPS and TLR4-MD-2. A tentative dissociation constant (Kd) for LPS-TLR4-MD-2 complexes was approximately 3 nM, which is approximately 10-20 times lower than the reported Kd for LPS-MD-2 or LPS-CD14. The presence of detergent disrupts LPS interaction with CD14 but not with TLR4-MD-2. E5531, a lipid A antagonist developed for therapeutic intervention of endotoxin shock, blocks LPS interaction with TLR4-MD-2 at a concentration 100 times lower than that required for blocking LPS interaction with CD14. These results reveal direct LPS interaction with cell surface TLR4-MD-2 that is distinct from that with MD-2 or CD14.     

Light chain cardiac amyloidosis in a nonagenarian

Cardiac amyloidosis is an infiltrative and restrictive cardiomyopathy caused by the extracellular deposition of amyloid fib-rils within the heart as systemic amyloidosis,lead-ing to heart failure,reduced quality of life,and death.[1]There are two major amyloid fibril proteins that af-fect the heart:amyloid immunoglobulin light chain(AL)and amyloid transthyretin(ATTR).The latter is further subdivided into wild-type ATTR and variant types based on the presence of a mutation in the transthyretin gene.     

Comparison of Kidney Disease: Improving Global Outcomes and Acute Kidney Injury Network criteria for assessing patients in intensive care units

Background

The Kidney Disease: Improving Global Outcomes (KDIGO) group proposed to adopt the 48-h time window for the 0.3  mg/dL rise in serum creatinine (sCr) proposed by the Acute Kidney Injury Network (AKIN) group as a modification to the original risk, injury, failure, loss, and end-stage renal disease criteria, keeping the 7-day window for the 50 % increase in sCr from baseline. The present study evaluates the prevalence of acute kidney injury (AKI) and the accuracy of predicting mortality based on the KDIGO and AKIN criteria.

Patients and methods

We retrospectively studied a cohort of 2579 patients admitted to the intensive care unit of Nagoya University Hospital between 2005 and 2009.

Results

The total AKI prevalence was higher according to the KDIGO than to the AKIN criteria (38.4 versus 29.5 %). In-hospital mortality rates were higher among 238 patients classified as non-AKI by the AKIN but AKI by the KDIGO criteria than among those classified as non-AKI by both criteria (7.1 versus 2.7 %). Survival curves generated using KDIGO significantly differed among all stages, but not between AKIN stages I and II. Multivariate analysis showed that KDIGO criteria were better in a statistical model than the AKIN criteria according to the Akaike information criterion. Harrell’s C statistic was greater for the KDIGO than for the AKIN criteria.

Conclusions

The KDIGO criteria have improved sensitivity without compromising specificity for AKI and might predict mortality at least as well as the AKIN criteria.     

Osteoclasts and the immune system

Investigation into arthritis as well as the numerous bone phenotypes found in mice lacking immune-related genes has highlighted the importance of the dynamic interplay between the bone and immune systems. It has recently led to both the emergence and subsequent rapid evolution of the field of osteoimmunology. Receptor activator of nuclear factor-κB ligand (RANKL) stimulates osteoclastogenesis through the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is well known as a crucial regulator of immunity. Studies on RANKL signaling revealed various immune-related genes which are involved in the regulation of osteoclastogenesis. Bone destruction in rheumatoid arthritis is caused by the enhanced activity of osteoclasts resulting from the activation of T cells. Here we describe our efforts to address the challenging question as to how abnormal T-cell activation mechanistically induces bone destruction. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to both the bone and immune systems.     

Endothelial dysfunction as a potential contributor in diabetic nephropathy

The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30-40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin-angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy.     

Risk factors and prediction of bleeding after gastric endoscopic submucosal dissection in patients on antithrombotic therapy: newly developed bleeding prediction application software,SAMURAI model

Bleeding after gastric endoscopic submucosal dissection (ESD) remains problematic, especially in patients receiving antithrombotic therapy. Therefore, this study aimed to identify the risk factors. In this retrospective study, patients (n = 1,207) who underwent gastric ESD while receiving antithrombotic therapy were enrolled at Osaka Medical and Pharmaceutical University Hospital and 18 other referral hospitals in Japan. Risks of post-ESD bleeding were calculated using multivariable logistic regression. The dataset was divided into a derivation cohort and a validation cohort. We created a prediction model using the derivation cohort. The accuracy of the model was evaluated using the validation cohort. Post-ESD bleeding occurred in 142 (11.8%) participants. Multivariable analysis yielded an odds ratio of 2.33 for aspirin, 4.90 for P2Y12 receptor antagonist, 1.79 for cilostazol, 0.95 for other antithrombotic agents, 6.53 for warfarin, 5.65 for dabigatran, 7.84 for apixaban, 10.45 for edoxaban, 6.02 for rivaroxaban, and 1.46 for heparin bridging. The created prediction model was called safe ESD management using the risk analysis of post-bleeding in patients with antithrombotic therapy (SAMURAI). This model had good predictability, with a C-statistic of 0.77. In conclusion, use of the SAMURAI model will allow proactive management of post-ESD bleeding risk in patients receiving antithrombotic therapy.