To characterise the genetics of splenic marginal zone lymphoma (SMZL), we performed whole exome sequencing of 16 cases and identified novel recurrent inactivating mutations in Kruppel-like factor 2 (KLF2), a gene whose deficiency was previously shown to cause splenic marginal zone hyperplasia in mice. KLF2 mutation was found in 40 (42%) of 96 SMZLs, but rarely in other B-cell lymphomas. The majority of KLF2 mutations were frameshift indels or nonsense changes, with missense mutations clustered in the C-terminal zinc finger domains. Functional assays showed that these mutations inactivated the ability of KLF2 to suppress NF-κB activation by TLR, BCR, BAFFR and TNFR signalling. Further extensive investigations revealed common and distinct genetic changes between SMZL with and without KLF2 mutation. IGHV1-2 rearrangement and 7q deletion were primarily seen in SMZL with KLF2 mutation, while MYD88 and TP53 mutations were nearly exclusively found in those without KLF2 mutation. NOTCH2, TRAF3, TNFAIP3 and CARD11 mutations were observed in SMZL both with and without KLF2 mutation. Taken together, KLF2 mutation is the most common genetic change in SMZL and identifies a subset with a distinct genotype characterised by multi-genetic changes. These different genetic changes may deregulate various signalling pathways and generate cooperative oncogenic properties, thereby contributing to lymphomagenesis.
Background and AimsHereditary diffuse gastric cancer (HDGC) accounts for 1% of gastric cancer cases. For patients with a germline CDH1 mutation, risk-reducing gastrectomy is recommended. However, for those delaying surgery or for families with no causative mutation identified, regular endoscopy is advised. This study aimed to determine the yield of signet ring cell carcinoma (SRCC) foci in individuals with a CDH1 pathogenic variant compared with those without and how this varies with successive endoscopies.MethodsPatients fulfilling HDGC criteria were recruited to a prospective longitudinal cohort study. Endoscopy was performed according to a strict protocol with visual inspection followed by focal lesion and random biopsy sampling to detect foci of SRCC. Survival analysis determined progression to finding of SRCC according to CDH1 mutation status. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and 36-item Short Form Health Survey questionnaires assessed quality of life before surveillance and each endoscopy.ResultsEighty-five individuals fulfilling HDGC criteria underwent 201 endoscopies; 54 (63.5%) tested positive for CDH1 mutation. SRCC yield was 61.1% in CDH1 mutation carriers compared with 9.7% in noncarriers, and mutation-positive patients had a 10-fold risk of SRCC on endoscopy compared with those with no mutation detected (P < .0005). Yield of SRCC decreased substantially with subsequent endoscopies. Surveillance was associated with improved psychological health.ConclusionsSRCC foci are prevalent in CDH1 mutation carriers and can be detected at endoscopy using a standardized, multiple biopsy sampling protocol. Decreasing yield over time suggests that the frequency of endoscopy might be reduced. For patients with no CDH1 pathogenic variant detected, the cost-to-benefit ratio needs to be assessed in view of the low yield.
Povidone-iodine (PVI) is principally used as an antimicrobial agent. It has been found that 0.5% PVI can attenuate congestion, edema and pain induced by pressure sores. Thus this study aimed to assess the effects of 0.5% PVI on acute skin wounds. Four full-thickness excisional wounds were generated on the dorsal skin of male Sprague-Dawley rats with a 10-mm sterile punch. Two wounds were left untreated and the other two were dressed with gauze with 0.5% PVI for 1 hour per day for the first 5 days after injury. 10-mm full-thickness excisional wounds were also generated on the dorsal skin of rats treated with 10 mg/kg SB431542 and all wounds were treated with 0.5% PVI for 5 days. PVI treatment enhanced wound healing via promotion of expression of α SMA and TGF β, neovascularization and re-epithelialization. Interleukin 6 was reduced following PVI treatment. Inhibition of TGF β abolished the effect of PVI treatment on wound closure. These data show that topical application of 0.5% PVI could promote acute skin wound healing though increased expression of TGF β leading to enhanced formation of granulation tissue, even in the absence of obvious infection.
Sevoflurane promotes the metastatic potential of renal carcinoma, but not of non-small cell lung cancer. This may be associated with its differential effect on cellular signalling including TGF-β. Our findings indicate that sevoflurane may have different effects on the metastatic potential and chemosensitivity of different tumour types.
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