Ninjurin 2 Modulates Tumorigenesis, Inflammation, and Metabolism via Pyroptosis.

The nerve injury-induced protein 2 (NINJ2) belongs to a family of homophilic adhesion molecules and was initially found to be involved in nerve regeneration. However, the role of NINJ2 in other cellular processes is not well studied. The Ninj2-deficient mice generated in the current study had a short lifespan and were prone to spontaneous tumors, systemic inflammation, and metabolic defects. Comprehensive carbohydrate and lipid metabolic analyses were performed to better understand the metabolic traits that contribute to these phenotypes. Carbohydrate metabolic analyses showed that NINJ2 deficiency led to defects in monosaccharide metabolism along with accumulation of multiple disaccharides and sugar alcohols. Lipidomic analyses showed that Ninj2 deficiency altered patterns of several lipids, including triglycerides, phospholipids, and ceramides. To identify a cellular process that associated with these metabolic defects, the role of NINJ2 in pyroptosis, a programmed cell death that links cancer, inflammation, and metabolic disorders, was examined. Loss of NINJ2 promoted pyroptosis by activating the NOD-like receptor protein 3 (NLRP3) inflammasome. Taken together, these data reveal a critical role of NINJ2 in tumorigenesis, inflammatory response, and metabolism via pyroptosis.

Mutant p53 antagonizes p63/p73-mediated tumor suppression via Notch1.

p53 is the most frequently mutated gene in human cancers and mutant p53 has a gain of function (GOF) that promotes tumor progression and therapeutic resistance. One of the major GOF activities of mutant p53 is to suppress 2 other p53 family proteins, p63 and p73. However, the molecular basis is not fully understood. Here, we examined whether mutant p53 antagonizes p63/p73-mediated tumor suppression in vivo by using mutant p53-R270H knockin and TAp63/p73-deficient mouse models. We found that knockin mutant p53-R270H shortened the life span of p73+/- mice and subjected TAp63+/- or p73+/- mice to T lymphoblastic lymphomas (TLBLs). To unravel the underlying mechanism, we showed that mutant p53 formed a complex with Notch1 intracellular domain (NICD) and antagonized p63/p73-mediated repression of HES1 and ECM1. As a result, HES1 and ECM1 were overexpressed in TAp63+/- ;p53R270H/- and p73+/- ;p53R270H/- TLBLs, suggesting that normal function of HES1 and ECM1 in T cell activation is hyperactivated, leading to lymphomagenesis. Together, our data reveal a previously unappreciated mechanism by which GOF mutant p53 hijacks the p63/p73-regulated transcriptional program via the Notch1 pathway.

Partial oxidation of methane to methanol by isolated Pt catalyst supported on a CeO2 nanoparticle.

Catalytic transformation of methane (CH4) into methanol in a single step is a challenging issue for the utilization of CH4. We present a direct method for converting CH4 into methanol with high selectivity over a Pt/CeO2 catalyst which contains ionic Pt2+ species supported on a CeO2 nanoparticle. The Pt/CeO2 catalyst reproducibly yielded 6.27 mmol/g of Pt with a selectivity of over 95% at 300 °C when CH4 and CO are used as reactants, while the catalyst had a lower activity when using only CH4 without CO. Active lattice oxygen created on the Pt and CeO2 interface provides selective reaction pathways for the conversion of CH4 to methanol. Based on high-angle annular dark-field scanning transmission electron microscopy, x-ray photoelectron spectroscopy, x-ray absorption near-edge structure, extended x-ray absorption fine structure, catalytic studies, and density functional theory calculations, we propose a mechanistic pathway involving CH4 activation at the active site in the vicinity of Pt2+ species.

Effects of radiation therapy on the meibomian glands and dry eye in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma.

BACKGROUND: Radiation therapy (RT) is the treatment of choice in patients with low-grade ocular adenexal mucosa-associated lymphoid tissue lymphoma (OAML) and many of them experience post-RT dry eye with varying severity. The purpose of the present study was to investigate ocular effects of RT on meibomian glands and dry eye by directly visualizing structural changes. Secondly, we focused on the comparison of two groups of patients according to tumor location and radiation technique. METHODS: Sixty-four eyes with OAML of conjunctiva, orbit, lacrimal gland, or lacrimal sac were grouped into conjunctival lymphoma and "orbital-type" lymphoma (i.e., orbit, lacrimal gland, and lacrimal sac). Subjects were investigated for morphological changes in meibomian glands by meiboscore grading system. Radiation technique was examined and Ocular Surface Disease Index (OSDI) questionnaire, Schirmer's test, tear film break-up time (TBUT), slit lamp examination of corneal surface and lid margin abnormality were conducted before and after RT. RESULTS: The increase in meiboscore was statistically significant over time after RT in both groups (P < 0.001). The extent of increase in meiboscore was significantly greater in the "orbital-type" lymphoma group than in the conjunctival lymphoma group (P < 0.001). The changes in OSDI, TBUT, corneal fluorescein staining score and lid margin abnormality score after RT were significantly different across two groups (P = 0.042, 0.001, 0.035 and 0.001, respectively). Schirmer's value decreased after RT in both groups. Dry eye symptoms were most severe right after RT in both groups, but a gradual resolution was noted in most patients with conjunctival lymphoma, whereas symptoms persisted in "orbital-type" lymphoma patients. The OSDI score and corneal fluorescein staining score were positively correlated with meiboscore in "orbital-type" patients at post-RT 6 months (r = 0.43, P = 0.04; r = 0.39, P = 0.03, respectively). CONCLUSIONS: Patients with OAML had different degrees of morphological changes in meibomian glands according to tumor location and radiation technique. "Orbital-type" lymphoma patients are more likely to experience severe injury to meibomian glands, which eventually leads to persistent dry eye. Patients with "orbital-type" lymphoma should be well informed of post-RT damage on meibomian glands and persistent dry eye.

Ninjurin 1 has two opposing functions in tumorigenesis in a p53-dependent manner.

WT p53 is critical for tumor suppression, whereas mutant p53 promotes tumor progression. Nerve injury-induced protein 1 (Ninj1) is a target of p53 and forms a feedback loop with p53 by repressing p53 mRNA translation. Here, we show that loss of Ninj1 increased mutant p53 expression and, subsequently, enhanced cell growth and migration in cells carrying a mutant p53. In contrast, loss of Ninj1 inhibited cell growth and migration in cells carrying a WT p53. To explore the biological significance of Ninj1, we generated a cohort of Ninj1-deficient mice and found that Ninj1+/- mice were prone to systemic inflammation and insulitis, but not to spontaneous tumors. We also found that loss of Ninj1 altered the tumor susceptibility in both mutant p53 and p53-null background. Specifically, in a mutant p53(R270H) background, Ninj1 deficiency shortened the lifespan, altered the tumor spectrum, and increased tumor burden, likely via enhanced expression of mutant p53. In a p53-null background, Ninj1 deficiency significantly increased the incidence of T-lymphoblastic lymphoma. Taken together, our data suggest that depending on p53 genetic status, Ninj1 has two opposing functions in tumorigenesis and that the Ninj1-p53 loop may be targeted to manage inflammatory diseases and cancer.

The Clinical Differences between Urgent Visits and Non-Urgent Visits in Emergency Department During the Neonatal Period.

As neonates are brought to the emergency department (ED) for various complaints, it is challenging for emergency physicians to clinically determine the urgency of the visit. We sought to explore clinical characteristics associated with urgent visits to the ED. We conducted a retrospective study by reviewing medical records of neonatal visits to a tertiary pediatric regional emergency center for 5 years. Cases of patients who were discharged after checking only chest or abdominal X-ray or discharged without workup, were classified as non-urgent visits. Cases where more examinations were performed, or when the patient was hospitalized, were classified as urgent visits. Various clinical features and process in the ED were compared between the groups. Of the 1,008 cases enrolled in this study, 856 (84.9%) were urgent and 152 (15.1%) were non-urgent visits. After adjustment by multiple logistic regression analysis, non-urgent visits were associated with self-referrals rather than physician-referrals (odds ratio [OR], 5.96), visits in the evening rather than at night or daytime (OR, 2.51), patient visits from home rather than from medical facilities (OR, 2.19; 95). Fever and jaundice were the most common complaints (25.7% and 24.5%, respectively), and their OR of non-urgent visit was relatively low (adjusted OR 0.03 and 0.03, respectively). However, other common complaints, such as vomiting and cough (7.4% and 7.1%, respectively), were more likely to be non-urgent visits (adjusted OR 2.96 and 9.83, respectively). For suspected non-urgent visits, emergency physicians need to try to reduce unnecessary workup and shorten length of stay in ED.

Inhibition of hedgehog signalling attenuates UVB-induced skin photoageing.

The hedgehog (Hh) signalling pathway regulates normal development and cell proliferation in metazoan organisms, but its aberrant activation can promote tumorigenesis and progression of a variety of aggressive human cancers including skin cancer. Despite its importance, little is known about its role in photoageing, a type of UV-induced skin lesions. In this study, we investigated the involvement of Hh signalling in the photoageing process as well as the use of an Hh-regulating alkaloid compound as a novel therapeutic drug to regulate photoageing in keratinocytes. We found that UVB induced Hh signalling by the expression of Hh ligands and Hh-mediated transcription factors, respectively. Moreover, UVB-induced Hh activation relied on mitogen-activated protein kinase (p38, ERK and JNK) activity and inflammatory responses (upregulation of COX-2, IL-1ß, IL-6 and TNF-α), resulting in premature senescence and photoageing in vitro and in vivo. Notably, a selected Hh inhibitor, evodiamine, mediated photoageing blockade in a mouse skin model. Taken together, our findings demonstrated that Hh signalling is associated with UVB-induced photoageing, while pharmacological inhibition of Hh signalling significantly reduced experimental photoageing, indicating its potential for use as a therapeutic target for this disease.

Phosphorylation of ribosomal protein S3 and antiapoptotic TRAF2 protein mediates radioresistance in non-small cell lung cancer cells.

Radioresistance is considered as a main factor restricting efficacy of radiotherapy. However, the exact molecular mechanism of radioresistance has not been explained yet. In this study, to elucidate radioresistance mechanism in lung cancer, we compared radiation responses in two types of non-small cell lung cancer (NSCLC) cells with different radiosensitivity and identified key molecules conferring radioresistance. In radioresistant NSCLC cells, ionizing radiation (IR) led to casein kinase 2α (CK2α)- and PKC-mediated phosphorylation of rpS3 and TRAF2, respectively, which induced dissociation of rpS3-TRAF2 complex and NF-κB activation, resulting in significant up-regulation of prosurvival genes (cIAP1, cIAP2, and survivin). Also, dissociated phospho-rpS3 translocated into nucleus and bound with NF-κB complex (p65 and p50), contributing to p65 DNA binding property and specificity. However, in radiosensitive NSCLC cells, IR-mediated rpS3 phosphorylation was not detected due to the absence of CK2α overexpression. Consequently, IR-induced rpS3-TRAF2 complex dissociation, NF-κB activation, and prosurvival gene expression were not presented. Taken together, our findings revealed a novel radioresistance mechanism through functional orchestration of rpS3, TRAF2, and NF-κB in NSCLC cells. Moreover, we provided the first evidence for the function of rpS3 as a new TRAF2-binding protein and demonstrated that phosphorylation of both rpS3 and TRAF2 is a key control point of radioresistance in NSCLC cells. These results suggest that regulation of rpS3 and TRAF2 in combination with radiotherapy could have high pharmacological therapeutic potency for radioresistance of NSCLC.

Gaba transporter SLC6A11 gene polymorphism associated with tardive dyskinesia.

BACKGROUND: Gamma-aminobutyric acid (GABA) insufficiency has been reported to be related to the tardive dyskinesia (TD) susceptibility. Inada et al. (Pharmacogenet Genomics 2008;18:317-23) identified eight genes belonging to GABA receptor signaling pathway that may be involved in TD susceptibility by genome-wide screening and they replicated associations in an independent sample for polymorphisms in SLC6A11 (GABA transporter 3), GABRG3 (c-3 subunit of GABA-A receptor) and GABRB2 (ß-2 subunit of GABA-A receptor). In this study, we tried to replicate their finding in a larger Korean sample and find if any of the genes was associated with the susceptibility to TD. METHODS: We selected three polymorphisms in SLC6A11 (rs4684742), GABRG3 (rs2061051) and GABRB2 (rs918528) from the previous study. We carried out a case-control study (105 TD and 175 non-TD schizophrenic patients) to identify the association between the three candidate polymorphisms and susceptibility to TD and their epistatic interactions by using the multifactor dimensionality reduction (MDR) algorithm. RESULTS: Among the three variants, SCL6A11 genotypes distribution showed a significant difference between the TD and non-TD patients (P = 0.049). However, GABRG3 and GABRB2 genotype distributions were not associated with TD (P = 0.268 and P = 0.976, respectively). Further, our analyses provided significant evidence for gene-gene interactions (SCL6A11, GABRG3 and GABRB2) in the development of TD. The odds ratio increased to 2.53 (CI = 1.515-4.217, P = 0.0003) when the genetic susceptibility to TD was analyzed with the three genes considered altogether through MDR approach. CONCLUSION: These results suggest that GABA receptor signaling pathway was associated with the increased susceptibility to TD in Korean schizophrenic patients.

Ninjurin 2, a Cell Adhesion Molecule and a Target of p53, Modulates Wild-Type p53 in Growth Suppression and Mutant p53 in Growth Promotion.

The nerve injury-induced protein 1 (NINJ1) and NINJ2 constitute a family of homophilic adhesion molecules and are involved in nerve regeneration. Previously, we showed that NINJ1 and p53 are mutually regulated and the NINJ1-p53 loop plays a critical role in p53-dependent tumor suppression. However, the biology of NINJ2 has not been well-explored. By using multiple in vitro cell lines and genetically engineered mouse embryo fibroblasts (MEFs), we showed that NINJ2 is induced by DNA damage in a p53-dependent manner. Moreover, we found that the loss of NINJ2 promotes p53 expression via mRNA translation and leads to growth suppression in wild-type p53-expressing MCF7 and Molt4 cells and premature senescence in MEFs in a wild-type p53-dependent manner. Interestingly, NINJ2 also regulates mutant p53 expression, and the loss of NINJ2 promotes cell growth and migration in mutant p53-expressing MIA-PaCa2 cells. Together, these data indicate that the mutual regulation between NINJ2 and p53 represents a negative feedback loop, and the NINJ2-p53 loop has opposing functions in wild-type p53-dependent growth suppression and mutant p53-dependent growth promotion.

PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells.

Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance.

The BTBD9 gene may be associated with antipsychotic-induced restless legs syndrome in schizophrenia.

OBJECTIVE: A genome-wide association study and several replication studies have shown significant association between BTBD9 gene single nucleotide polymorphisms and restless legs syndrome (RLS). The aim of this study is to investigate the association between the BTBD9 gene polymorphisms and antipsychotic-induced RLS in schizophrenic patients. METHODS: Restless legs syndrome symptoms were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group in 190 Korean schizophrenic patients. We genotyped the rs9357271 and rs3923809 polymorphisms of the BTBD9 gene in schizophrenic patients with (n = 96) and without (n = 94) RLS symptoms. RESULTS: There was a significant difference in the allele frequency (χ(2) = 8.14, p = 0.004) of the rs9357271 polymorphism between schizophrenic patients with and without RLS symptoms. Significant genotypic association of this single nucleotide polymorphisms with RLS symptoms was also observed for the dominant model (χ(2) = 10.32, p = 0.001) and heterozygous model (χ(2) = 10.9, p = 0.001). When we compared the frequencies of the rs3923809-rs9357271 haplotypes between the two groups, the overall haplotype frequencies were significantly different (permuted p = 0.037), and the A-T haplotype was significantly more frequent in the RLS symptom group than in the no RLS symptom group (0.112 vs. 0.041, permuted p = 0.007). CONCLUSIONS: These data suggest that the BTBD9 gene is associated with antipsychotic-induced RLS symptoms in schizophrenic patients.

Effect of pre-fragmentation on efficacy and safety for phacoemulsification in femtosecond laser-assisted cataract surgery: a non-randomized clinical trial.

Background: Ultrasound energy during phacoemulsification results in the endothelial cell loss of cornea. Crystallin lens fragmentation with softening before phacoemulsification can be used with femtosecond laser-assisted cataract surgery (FLACS) device. Methods: This non-randomized clinical trial included patients who underwent cataract surgery and not had corneal opacity. Patients who were not possible to apply the interface on the ocular surface, were excluded. Each subject was allowed to decide the surgical method by himself/herself. Cataract surgery was performed with FLACS (groups I and II) or conventional surgical technique (group III). The FLACS group was further subdivided into two groups according to whether a lens softening procedure was performed (group I) or not (group II). The nuclear density of cataract was objectively classified by Pentacam nuclear staging (PNS), preoperatively. Surgical parameters including total phacoemulsification time (TPT), cumulative dissipated energy (CDE), and the balanced salt solution (BSS) volume consumed, were measured during the surgery. Postoperative visual outcomes were evaluated at three months after the surgery, and corneal endothelial cell count (ECC) loss were calculated based on ECC measured before the surgery and two months after the surgery. Results: Eighty-nine eyes from 89 patients were enrolled. Fifty-three were treated using FLACS (groups I; quadrant pattern with softening of pre-fragmentation, n=31 and II; sextant pattern without softening of pre-fragmentation, n=22) and 36 (group III) with the conventional manual technique. The FLACS groups (groups I and II) had statistically significant lower TPT (P<0.001), CDE (P<0.001), and BSS volumes (P<0.001) used in the nucleus removal step compared to group III. Furthermore, ECC loss in groups I (4.59%±2.57%) and II (6.10%±3.30%) were also statistically lower compared to group III (13.49%±10.55%, P<0.001). From subgroup analysis with the PNS 2, group I showed lower pre-fragmentation time, lower CDE, lower BSS volume used during nucleus removal, and lower ECC loss compared to group II (all P<0.001). Conclusions: Pre-fragmentation using FLACS may reduce intraoperative ultrasound energy and intraocular manipulations compared to conventional cataract surgery.

Isoform-specific disruption of the TP73 gene reveals a critical role for TAp73γ in tumorigenesis via leptin.

TP73, a member of the p53 family, is expressed as TAp73 and ΔNp73 along with multiple C-terminal isoforms (α-η). ΔNp73 is primarily expressed in neuronal cells and necessary for neuronal development. Interestingly, while TAp73α is a tumor suppressor and predominantly expressed in normal cells, TAp73 is found to be frequently altered in human cancers, suggesting a role of TAp73 C-terminal isoforms in tumorigenesis. To test this, the TCGA SpliceSeq database was searched and showed that exon 11 (E11) exclusion occurs frequently in several human cancers. We also found that p73α to p73γ isoform switch resulting from E11 skipping occurs frequently in human prostate cancers and dog lymphomas. To determine whether p73α to p73γ isoform switch plays a role in tumorigenesis, CRISPR technology was used to generate multiple cancer cell lines and a mouse model in that Trp73 E11 is deleted. Surprisingly, we found that in E11-deificient cells, p73γ becomes the predominant isoform and exerts oncogenic activities by promoting cell proliferation and migration. In line with this, E11-deficient mice were more prone to obesity and B-cell lymphomas, indicating a unique role of p73γ in lipid metabolism and tumorigenesis. Additionally, we found that E11-deficient mice phenocopies Trp73-deficient mice with short lifespan, infertility, and chronic inflammation. Mechanistically, we showed that Leptin, a pleiotropic adipocytokine involved in energy metabolism and oncogenesis, was highly induced by p73γ,necessary for p73γ-mediated oncogenic activity, and associated with p73α to γ isoform switch in human prostate cancer and dog lymphoma. Finally, we showed that E11-knockout promoted, whereas knockdown of p73γ or Leptin suppressed, xenograft growth in mice. Our study indicates that the p73γ-Leptin pathway promotes tumorigenesis and alters lipid metabolism, which may be targeted for cancer management.

Gene engineering, purification, crystallization and preliminary X-ray diffraction of cytochrome P450 p-coumarate-3-hydroxylase (C3H), the Arabidopsis membrane protein.

Cytochrome P450s (P450s) are the most versatile biological catalysts in plants; however, because the structure of the P450s has not been fully established, their broad substrate specificity has been limitedly discussed. p-coumarate-3-hydroxylase (C3H) is an essential enzyme for the biosynthesis of phenolic natural products in plants, but all attempts to express and purify C3H, have failed. In this research, we developed a bacterial expression of Arabidopsis C3H by combinational mutagenesis and purified C3H as a catalytically active form. The modified C3H could be purified in the absence of detergent, and crystallized in two forms (orthorhombic and trigonal space group) under different conditions. X-ray diffraction was processed to a 4.0 Å resolution (first type crystal) and a 3.8 Å resolution (second type crystal). Although the diffraction results of C3H(mod) crystals are not enough to determine crystallographic structure due to low resolution, the simplicity and rapidity of this technology are competitive advantages in comparison with other methods, and may contribute to structural analyses of other membrane proteins including P450s family.

Changes in the levels of depressive symptoms and anxiety in Ansan city after the 2014 Sewol ferry disaster.

BACKGROUND: In April 2014, a ferry carrying 476 passengers sunk on the coast of Korea, resulting in 304 deaths. Of these, 250 were local high school students, and the disaster significantly affected their community. This study aimed to examine the prevalence of depressive symptoms and anxiety among Ansan city residents to understand their recovery process after the accident. METHODS: Two cross-sectional surveys (survey 1, after 4-6 months and survey 2, after 16-18 months of disaster) were used to compare prevalence among residents of Ansan city and adjacent cities. Symptoms were determined by the Center for Epidemiologic Studies-Depression Scale and the Generalized Anxiety Disorder 7-item Scale. RESULTS: A total of 1,773 and 1,748 participants were included in Survey 1 and Survey 2, respectively. Survey 1 showed a significantly higher prevalence of depressive symptoms (19.0%; 95% confidence interval [CI], 16.9-21.1) and anxiety (6.1%; 95% CI, 5.0-7.5) among Ansan city, compared to participants from adjacent cities (depressive symptoms: 14.3%; 95% CI, 12.7-16.1; anxiety: 3.6%; 95% CI, 2.9-4.5). Survey 2 showed a decreased prevalence of depression (15.8%; 95% CI, 14.0-17.9) and anxiety (5.0%; 95% CI, 4.0-6.4) among Ansan city residents. Depressive symptoms and anxiety adjusted odds ratio in survey 2 compared with survey 1 were 0.74 (95% CI 0.62-0.89) and 0.81 (0.60-1.08) among Ansan city, respectively. LIMITATIONS: Cross-sectional study design and lack of pre-disaster baseline data for comparison are limitations of this study. CONCLUSIONS: Psychological distress occurred at a population level, not only among survivors and their families, but also among Ansan city residents indirectly impacted by the traumatic event. Although populations indirectly affected by a disaster show a natural recovery process, timely population-based interventions may be helpful.

Comparison of Selection and Long-term Clinical Outcomes Between Chemotherapy and Radiotherapy as Primary Therapeutic Modality for Ocular Adnexal MALT Lymphoma.

BACKGROUND: The choice of a primary treatment for ocular adnexal mucosa-associated lymphoid tissue lymphoma (OAML) depends on the extent of tumor spread. However, radiotherapy is commonly used as a first-line therapy despite ophthalmic complications, because most OAMLs are in a limited stage of progression. However, the initial therapeutic modality, including chemotherapy and treatment of the advanced stage, has not been fully established for OAML. Therefore, we evaluated the optimal therapeutic options and survival outcome-related parameters for patients with primary OAML. METHODS: We evaluated 208 consecutive patients with primary OAML who were diagnosed at the Catholic University Lymphoma Group between January 2004 and April 2015. FINDINGS: During a median follow-up of 70.0 months (range, 3.2-182.0 months) in 208 patients with primary OAML, most patients were female and the median age was 46 years old. Overall survival (OS) and progression-free survival (PFS) at 13 years were excellent (92.7% and 69.7%, respectively). Of the 117 patients who received the first-line radiotherapy, 92% achieved complete remission (CR), usually by being treated with less than 30 Gy. Radiation-related ophthalmic complications including dry eye syndrome (59%) and cataract (22%) caused a decline in the quality of life (QoL). Chemotherapy alone was used to treat 86 OAML patients, with 84.9% achieving CR and 12.8% achieving partial remission with tolerable toxicities. There were no differences in survival outcomes between patients treated with radiotherapy versus those treated with rituximab-containing chemotherapy, although the latter group had more advanced stages of OAML (OS, p = 0.057; PFS, p = 0.075). INTERPRETATION: OAML patients were predominantly female and relatively young, and radiotherapy as a primary therapeutic option was more likely to lead to radiation-related complications, resulting in lower QoL. On the other hand, frontline chemotherapy showed consistent therapeutic outcomes with tolerable toxicities compared to radiotherapy, and there were no long-term or delayed adverse events. Therefore, when considering therapeutic efficacy and therapy-related QoL, chemotherapy is recommended for younger patients, and radiotherapy is recommended for older and chemotherapy-ineligible patients. FUNDING: A National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (No. NRF-2016R1A2B4007282).

Genetic Ablation of Rbm38 Promotes Lymphomagenesis in the Context of Mutant p53 by Downregulating PTEN.

Mutant p53 exerts gain-of-function effects that drive metastatic progression and therapeutic resistance, but the basis for these effects remain obscure. The RNA binding protein RBM38 limits translation of mutant p53 and is often altered in tumors harboring it. Here we show how loss of Rbm38 significantly alters cancer susceptibility in mutant p53 knock-in mice by shortening lifespan, altering tumor incidence, and promoting T-cell lymphomagenesis. Loss of Rbm38 enhanced mutant p53 expression and decreased expression of the tumor suppressor Pten, a key regulator of T-cell development. Furthermore, Rbm38 was required for Pten expression via stabilization of Pten mRNA through an AU-rich element in its 3'UTR. Our results suggest that Rbm38 controls T-cell lymphomagenesis by jointly modulating mutant p53 and Pten, with possible therapeutic implications for treating T-cell malignancies.Significance: An RNA-binding protein controls T-cell lymphomagenesis by jointly modulating mutant p53 and PTEN, with possible therapeutic implications for treating T-cell malignancies. Cancer Res; 78(6); 1511-21. ©2018 AACR.

Characteristics of corneal biomechanical responses detected by a non-contact scheimpflug-based tonometer in eyes with glaucoma.

PURPOSE: To determine the corneal biomechanical properties in eyes with glaucoma using a non-contact Scheimpflug-based tonometer. METHODS: Corneal biomechanical responses were examined using a non-contact Scheimpflug-based tonometer. The tonometer parameters of the normal control group (n = 75) were compared with those of the glaucoma group (n = 136), including an analysis of glaucoma subgroups categorized by visual field loss. RESULTS: After adjusting for potential confounding factors, including the intraocular pressure (IOP), central corneal thickness (CCT), age and axial length, the deformation amplitude was smaller in the glaucoma group (1.09 ± 0.02 mm) than in the normal control group (1.12 ± 0.02 mm; p value = 0.031). The deformation amplitude and the deflection amplitude of the severe glaucoma group (1.12 ± 0.02 mm and 0.92 ± 0.01 mm) were significantly greater than that of the early glaucoma group (1.07 ± 0.01  mm and 0.88 ± 0.11 mm, p = 0.006 and p = 0.031), whereas that of the moderate glaucoma group (1.09 ± 0.02 mm and 0.90 ± 0.02 mm) was greater than that of the early glaucoma group, but this difference was not statistically significant. The deformation amplitude showed a negative correlation with the CCT in the normal control group (r = -0.235), with a weaker negative relationship observed in the early glaucoma group (r = -0.099). However, in the moderate and severe glaucoma groups, the deformation amplitude showed a positive relationship with the CCT, showing an inverse relationship. The duration and number of antiglaucomatous eyedrops used had negative correlations with the CCT in eyes with moderate and severe glaucoma. CONCLUSION: Overall, the glaucoma group showed significantly less deformable corneas than did the normal controls, even after adjusting for the IOP, CCT, age and axial length. However, there were also differences according to the severity of glaucoma, where the corneal deformation amplitude was greater in the severe glaucoma group compared to the early glaucoma group. The combined effects of stiffening due to glaucoma and increased viscoelastic properties caused by the chronic use of antiglaucomatous eyedrops may have resulted in the present findings.

TRAF4 promotes lung cancer aggressiveness by modulating tumor microenvironment in normal fibroblasts.

Normal fibroblasts surrounding tumor cells play a crucial role in cancer progression through formation of the tumor microenvironment. Because factors secreted from normal fibroblasts can modulate the tumor microenvironment, it is necessary to identify key factors associated with regulation of secreted factors and to investigate the molecular mechanisms contributing to the tumor microenvironment formation process. In this study, we found that radiation induced the expression and K63-linkage poly-ubiquitination of TRAF4 in normal lung fibroblasts. The K63-linkage poly-ubiquitinated TRAF4 formed complexes with NOX2 or NOX4 by mediating phosphorylated p47-phox in normal lung fibroblasts. Moreover, we showed that TRAF4 stabilized NOX complexes by decreasing lysosomal degradation of NOX2 and NOX4 after irradiation. NOX complexes increased endosomal ROS levels that were permeable into cytoplasm, leading to NF-κB-mediated ICAM1 up-regulation. Soluble ICAM1 was subsequently secreted into conditioned media of radiation-activated normal lung fibroblasts. The conditioned media from irradiated normal fibroblasts enhanced proliferation and epithelial-mesenchymal transition of non-small cell lung cancer cells both in vitro and in vivo. These results demonstrate that TRAF4 in irradiated fibroblasts is positively associated with aggressiveness of adjacent cancer cells by altering the tumor microenvironment. Thus, we suggest that regulation of TRAF4 might be a promising strategy for cancer therapy.