Clinical characteristics of local allergic rhinitis sensitized to house dust mites in Asia.

PURPOSE: Local allergic rhinitis (LAR) is characterized by a localized nasal allergic response without evidence of systemic atopy. LAR is an underdiagnosed entity and is a diagnostic and therapeutic challenge for clinicians. This study aimed to investigate the prevalence and clinical characteristics of patients with LAR to house dust mites (LAR-HDM) in Korea. METHODS: We performed a retrospective chart review of 336 adult patients with rhinitis symptoms who visited the Rhinologic Clinic at Korea University Guro Hospital from October 2019 to April 2021. Using results of the skin prick test, serologic test, and nasal provocation test, patients were classified as allergic rhinitis (AR) to HDM (AR-HDM), AR to other allergens, non-allergic rhinitis (NAR), or LAR-HDM. We excluded patients with AR to other allergens and compared the clinical characteristics of the remaining three groups. Patient demographic data were reviewed, and patients' nasal symptoms, olfactory function, serum total IgE, and severity of accompanying rhinosinusitis were evaluated. RESULTS: In total, 336 patients were examined. AR-HDM was diagnosed in 138 (41.1%) patients, AR to other allergens in 36 (10.7%) patients, NAR in 21 (42.0%) patients, and LAR-HDM in 21 (6.3%) patients. The mean age of patients with LAR-HDM was significantly higher than that of patients with AR-HDM. There were no significant differences in sex, smoking history, asthma, and family history of allergic diseases between the groups. Compared to NAR patients, there were significantly more patients with LAR-HDM who had persistent nasal symptoms. The frequency of nasal itching and sneezing was significantly higher in the LAR-HDM group than in the NAR group. The olfactory function score in the LAR-HDM group was significantly worse than that in the AR-HDM group, and the Lund-Mackay score was significantly higher in the LAR-HDM group than in the other groups. CONCLUSION: Clinical history and nasal symptoms are very similar in LAR-HDM and AR-HDM. Clinicians should take more care to differentiate them. LAR-HDM should also be considered in patients with persistent and severe nasal symptoms without systemic atopy.

Wedge resection combined with 3D-printed polycaprolactone mesh for caudal septal deviation.

BACKGROUND: Biocompatibility and stability of three-dimensional printed polycaprolactone mesh grafts for nasal surgery are proven in both animal and human models. However, their safety and durability as batten grafts for caudal septal deviation has not been documented. This study was designed to investigate the efficacy and safety of three-dimensional printed polycaprolactone mesh batten graft in septoplasty using the wedge resection technique for the correction of caudal septal deviation. METHODS: This retrospective study reviewed the medical records of 20 patients aged ≥ 18 years with caudal septal deviation who underwent septoplasty with wedge resection and three-dimensional printed polycaprolactone mesh graft from a tertiary medical center in South Korea, between December 1, 2019 and May 31, 2021. Those without nasal obstruction before surgery or with a short follow-up period (< 28 days) were excluded from the survey analysis. RESULTS: Of the 20 patients (mean age, 48.0 [range, 19-65] years), 17 (85.0%) were male, and three (15.0%) were female. A significant change was noted in the mean nasal obstruction symptom evaluation score (68.2 vs. 15.0, P < .001) in the 17 patients included in the analysis. Postoperative endoscopic evaluation revealed a straight septum in 19/20 (95.0%) patients, and no complications were noted in the postoperative follow-up period of up to 364 days. CONCLUSIONS: The three-dimensional printed polycaprolactone nasal mesh is safe and provides adequate support to resist the intrinsic memory of the cartilage of the caudal septum. In addition to nasal surgeries, it has great potential as a graft in other reconstructive surgeries. Trial registration Retrospectively registered.

Clinical and imaging features of ethmomaxillary sinus compared to Haller's cell.

PURPOSE: Understanding the anatomy of the paranasal sinuses and their variations is essential to achieving safe and effective endoscopic sinus surgery. The ethmomaxillary sinus (EMS) is a relatively under-researched anatomical variation. This study investigated the prevalence, clinical features, and effect of EMS on the maxillary sinus in comparison with Haller's cells. METHODS: Patients who visited the Rhinology Clinic at our hospital for rhinologic symptoms between January 2020 and December 2020. Computed tomography (CT) scans of paranasal sinuses were obtained at 1 mm-section thickness. Using CT scans, we investigated the clinical features of EMS, measured maxillary sinus volume, and analyzed the presence of maxillary sinusitis. RESULTS: EMS was observed in 26 of the 250 patients (10.4%). The male-to-female ratio was equal. The age ranged from 18 to 83 years (mean age, 56.3). Of the patients with EMS, 65.4% were unilateral and 34.6% were bilateral. The prevalence of Haller's cells was similar to that in EMS (10.8%). In the analysis of patients with unilateral EMS, the EMS side was found to have a significantly reduced maxillary sinus volume compared to the opposite side, whereas the difference was not significant in Haller's cells. There was no significant relationship between EMS or Haller's cells and maxillary sinusitis. CONCLUSIONS: EMS can significantly affect maxillary sinus volume. Therefore, surgeons should thoroughly review PNS CT scans before paranasal sinus surgery to determine the presence and features of EMS.

Huge Nasopalatine Duct Cyst Treated by Transnasal Endoscopic Marsupialization: A Case Report and Literature Review.

Nasopalatine duct cyst (NPDC) is the most common nonodontogenic cyst originating from the epithelial remnants of the incisive canal in the maxilla. NPDC is treated with complete enucleation via a sublabial or transpalatal approach, and recently tranasnasal endoscopic marsupialization has been gradually used. However, in large and extensive cases, it is difficult to remove the cyst completely, and there is a high risk of postoperative complications, including oronasal fistula. Therefore, tranasnasal endoscopic marsupialization is recommended as an effective treatment modality. Herein, we report a case of a 49-year-old man with a very large NPDC with a maximum diameter of 58 mm. NPDC was successfully managed by transnasal endoscopic marsupialization under general anesthesia without any major problems. No postoperative complications or recurrence occurred until 12 months postoperatively. Transnasal endoscopic marsupialization for large NPDC is minimally invasive and useful.

Changing Trends in the Clinical Characteristics and Treatment Strategies for Odontogenic Sinusitis Over the Past 10 Years.

OBJECTIVES: The incidence of odontogenic sinusitis has been gradually increasing due to the recent increases in invasive dental procedures. This study aimed to describe the clinical features of present patients with odontogenic sinusitis compared to the past, confirm the importance of endoscopic sinus surgery (ESS), and analyze the predictive factors for ESS. METHODS: This retrospective review included all patients diagnosed with odontogenic sinusitis between January 2010 and December 2011 and between January 2019 and December 2020. The patients were classified into 2 groups (past and present) depending on the time of the first visit. The clinical characteristics and treatment modalities were compared between the two groups. In addition, among patients in the present group, we analyzed variables to identify factors contributing to the risk of undergoing ESS. RESULTS: This study included 56 patients (23 in the past group and 33 in the present group). Compared to the past group, the present group had an older mean age (P = .001) and significantly increased iatrogenic etiologies (52.1% vs 90.9%; P = .002). The proportion of patients treated with ESS also increased in the present group compared to that in the past group (39.1% vs 66.7%; P = .041). In the present group, 11 patients (33.3%) were cured with conservative treatment, while 22 patients (66.7%) underwent additional ESS. Multivariate analysis revealed that the Lund-Mackay score was the only significant predictor of ESS (odds ratio [OR]: 14.901, P = .035). CONCLUSION: The incidence of odontogenic sinusitis with iatrogenic etiologies has increased compared to the past. In addition, two-thirds of the patients in the present study underwent ESS, a significantly higher proportion than in the past. Therefore, ESS is one of the most important treatment modalities for odontogenic sinusitis, especially iatrogenic, in recent years. A severe Lund-Mackay score was associated with a significantly increased risk of ESS.

Amelioration of alcohol­induced gastric mucosa damage by oral administration of food­polydeoxyribonucleotides.

Gastritis refers to inflammation caused by injury to the gastric epithelium, which is usually due to excessive alcohol consumption and prolonged use of nonsteroidal anti­inflammatory drugs. Millions of individuals worldwide suffer from this disease. However, the lack of safe and promising treatments makes it urgent to explore and develop leads from natural resources. Therefore, food as medicine may be the best approach for the treatment of these disorders. The present study described the protective effects of food­polydeoxyribonucleotides (f­PDRNs) in a rat model of gastric mucosal injury induced by HCl­EtOH. Administration of f­PDRN was performed with low­PRF002 (26 mg/kg/day), medium­PRF002 (52 mg/kg/day) and high­PRF002 (78 mg/kg/day) on the day of autopsy. The site of damage to the mucous membrane was also analysed. In addition, an increase in gastric juice pH, total acidity of gastric juice and decrease in gastric juice secretion were confirmed, and gastric juice secretion­related factors corresponding to the administration of f­PDRN were analysed. Administration of f­PDRN reduced the mRNA expression of histamine H2 receptor, muscarinic acetylcholine receptor M3, cholecystokinin 2 receptor and H+/K+ ATPase related to gastric acid secretion and downregulation of histamine, myeloperoxidase and cyclic adenosine monophosphate. In addition, it was histologically confirmed that the loss of epithelial cells and the distortion of the mucosa were recovered in the group in which f­PDRN was administered compared to the model group with gastric mucosa damage. In summary, the present study suggested that f­PDRN has therapeutic potential and may have beneficial effects if taken regularly as a food supplement.

Phase I clinical trial of KML001 monotherapy in patients with advanced solid tumors.

BACKGROUND: We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors. RESEARCH DESIGN AND METHODS: With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1. RESULTS: A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease. CONCLUSIONS: Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

All-trans retinoic acid regulates TGF-ß1-induced extracellular matrix production via p38, JNK, and NF-κB-signaling pathways in nasal polyp-derived fibroblasts.

BACKGROUND: All-trans retinoic acid (ATRA), a derivative of vitamin A, is known to have anti-fibrogenic effects and regulates cell proliferation and differentiation. Therefore, these abilities of ATRA may influence tissue remodeling in the upper airway. The aims of the present study were to investigate the effects of ATRA on the myofibroblast differentiation, extracellular matrix (ECM) production, cell migration, and collagen gel contraction and to determine the molecular mechanisms of ATRA in TGF-ß1-induced nasal polyp-derived fibroblasts (NPDFs). METHODS: NPDFs were isolated from nasal polyp. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide assay. TGF-ß1-induced fibroblasts were pretreated with ATRA. The expression levels of alpha-smooth muscle actin (α-SMA), collagen type 1, fibronectin, phospho-mitogen-activated protein kinase, and p-p50 (nuclear factor-kappaB [NF-κB]) were measured by Western blot analysis, real-time polymerase chain reaction, and/or immunofluorescence staining. Cell migration was analyzed with cell migration scratch assay and Transwell migration assay. Collagen contractile activity was measured using a collagen gel contraction assay. RESULTS: ATRA had no significant cytotoxic effect in NPDFs. Expression levels of α-SMA, collagen type 1, and fibronectin stimulated by TGF-ß1 were significantly downregulated in the ATRA-pretreated fibroblasts. TGF-ß1-induced cell migration and collagen gel contraction were significantly inhibited by ATRA pretreatment. ATRA also significantly inhibited phosphorylation of c-Jun N-terminal kinase (JNK), p38, and p50 in TGF-ß1-induced NPDFs, but did not inhibit phosphorylation of extracellular signal-related kinase (ERK). CONCLUSION: ATRA downregulated myofibroblast differentiation, ECM production, cell migration, and collagen gel contraction via p38, JNK-dependent NF-κB-signaling pathways in TGF-ß1-induced NPDFs. The findings suggest that ATRA could serve as a novel therapeutic agent to ameliorate nasal polyp development.

Antitumoral effect of arsenic compound, sodium metaarsenite (KML001), on multiple myeloma cells.

KML001 (sodium metaarsenite;NaAs2O3) is known to have antitumor activity against a variety of cancers. In this study, we examined its effect on multiple myeloma (MM). KML001 reduced the growth of all MM cell lines examined with an IC50 of 5x10­8 M. Exposure to KML001 (5x10­8 M) decreased levels of cyclins A/B1/D1/E1, CDK2/4/6 in U266 cells and increased the p21 and p27 levels. Furthermore, p21 became bound to CDK2/4/6, resulting in a reduction of CDK2/4/6 kinase activity. The cleaved forms of Bcl-2, and caspases­3, ­8 and ­9 were detected, and the anti-apoptotic molecule, Bax, also increased. Activation of STAT1/3, NF-κB (p65 and p50 subunits), pAKT and pERK decreased, and p­PTEN increased. There was also a significant reduction of hTERT at 12 h and upregulation of γ-H2AX and CHK1/2 molecules at 24 h. Thus, KML001 appears to have antitumor activity against MM by inhibiting various oncogenic signaling pathways. It may be useful for treating MM.

Efficacy of hyaluronic acid and hydroxyethyl starch in preventing adhesion following endoscopic sinus surgery.

Adhesion is a major complication of endoscopic sinus surgery that may lead to recurrence of chronic rhinosinusitis, necessitating revision surgery. The purpose of this study was to evaluate the effect of hyaluronic acid and hydroxyethyl starch (HA-HES) relative to hyaluronic acid and carboxymethylcellulose (HA-CMC) with regard to anti-adhesion effect. In this multi-center, prospective, single-blind, randomized controlled study, 77 consecutive patients who underwent bilateral endoscopic sinus surgery were enrolled between March 2014 and March 2015. HA-HES and HA-CMC were applied to randomly assigned ethmoidectomized cavities after the removal of middle meatal packing. At the 1st, 2nd and 4th weeks after surgery, the presence and grades of adhesion, edema, and infection were, respectively, examined via endoscopy by a blinded assessor. The incidence and grades of adhesion at the 2-week follow-up were significantly less in the HA-CMC group than in the HA-HES group (p < 0.05). However, with the exception of week 2, there were no significant differences in the incidence or grades of adhesion, edema, and infection between the two groups. When the primary endpoint-the presence of adhesion at the 4-week follow-up-was compared between two groups, the incidence of adhesion in HA-HES group at the 4-week follow-up was 32% and in HA-CMC was 41.3%, indicating that HA-HES was not inferior to HA-CMC in terms of anti-adhesive effect. No severe adverse reactions were noted during the study period. In conclusion, HA-HES is a safe substitutional anti-adhesion agent that has equivalent effect as HA-CMC after endoscopic sinus surgery.

KML001 and doxercalciferol induce synergistic antileukemic effect in acute lymphoid leukemia cells.

KML001 (NaAsO2, sodium metaarsenite, KOMINOX), a kind of arsenic compound, that has shown promising efficacy in non-Hodgkin's lymphoma (NHL) both in vitro and in vivo. In our study, the antileukemic effect of KML001 on acute lymphoid leukemia (ALL) and its mechanism of action were investigated. The results showed that KML001 inhibited cell proliferation in two types of ALL cell lines, CCRF-CEM and Molt-4. Exposure of ALL cells to KML001 induced apoptosis in a time-dependent manner. KML001 caused cell cycle arrest at G2/M phase instead of G0/G1 phase shown in other leukemia cells. In addition, we also tested the possibility of synergy of KML001 with doxercalciferol, a vitamin D2 derivative. Also, we found that a combination of KML001 with doxercalciferol showed a synergistic effect on ALL cell lines and this could be due to its different mechanism of action. Overall, our findings demonstrated KML001 could be a promising antileukemic agent especially when it is combined with doxercalciferol in ALL treatment.

Downregulation of androgen receptors by NaAsO2 via inhibition of AKT-NF-κB and HSP90 in castration resistant prostate cancer.

BACKGROUND: Androgen and androgen receptor (AR) play essential roles in the development and maintenance of prostate cancer. The recently identified AR splice variants (AR-Vs) have been considered as a plausible mechanism for the primary resistance against androgen deprivation therapy (ADT) in castration-resistant prostate cancer (CRPC). Sodium meta-arsenite (NaAsO2 ; KML001; Kominox), a trivalent arsenical, is an orally bioavailable and water soluble, which is currently in phase I/II clinical trials for the treatment of prostate cancer. It has a potent anti-cancer effect on prostate cancer cells and xenografts. The aim of this study was to examine the effect of NaAsO2 on AR signaling in LNCaP and 22Rv1 CRPC cells. METHODS: We used hormone-sensitive LNCaP cells, hormone-insensitive 22Rv1 cells, and CRPC patient-derived primary cells. We analyzed anti-cancer effect of NaAsO2 using real-time quantitative reverse transcription-PCR, Western blotting, immunofluorescence staining and CellTiter Glo® luminescent assay. Statistical evaluation of the results was performed by one-way ANOVA. RESULTS: NaAsO2 significantly reduced the translocation of AR and AR-Vs to the nucleus as well as their level in LNCaP and 22Rv1 cells. Besides, the level of the prostate-specific antigen (PSA), downstream target gene of AR, was also decreased. This compound was also an effective modulator of AKT-dependent NF-κB activation which regulates AR. NaAsO2 significantly inhibited phosphorylation of AKT and expression and nuclear translocation of NF-κB. We then investigated the effect of NaAsO2 on AR stabilization. NaAsO2 promoted HSP90 acetylation by down-regulating HDAC6, which reduces the stability of AR in prostate cancer cells. CONCLUSIONS: Here, we show that NaAsO2 disrupts AR signaling at multiple levels by affecting AR expression, stability, and degradation in primary tumor cell cultures from prostate cancer patients as well as CRPC cell lines. These results suggest that NaAsO2 could be a novel therapeutics for prostate cancer.

Anti-tumoral effect of arsenic compound, sodium metaarsenite (KML001), in non-Hodgkin's lymphoma: an in vitro and in vivo study.

Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients.

Anti-leukemic effect of sodium metaarsenite (KML001) in acute myeloid leukemia with breaking-down the resistance of cytosine arabinoside.

Sodium metaarsenite (NaAs2O3: code name KML001) is an orally bioavailable arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in acute myeloid leukemia (AML). We investigated the anti-leukemic effect of KML001 in AML, and determined the mode of action of KML001. KML001 inhibited the cellular proliferation in all AML cell lines and primary AML blasts as well as HL-60R (cytosine arabinoside-resistant HL-60) cells, while As2O3 was not effective in primary AML blasts and AML cell lines including HL-60R cells. KML001 induced G1 arrest and apoptosis in HL-60 and HL-60R cells. KML001 inhibited the activation of STAT (signal transducer and activator of transcription) 1, 3, 5, NF-κB, AKT and PI3K, while phosphorylated PTEN was upregulated. In addition, activation of ERK, p38 and JNK was observed in KML001-induced growth inhibition of HL-60 and HL-60R cells. Furthermore, KML001 induced telomeric terminal restriction fragment (TRF) length shortening in a time-dependent manner in HL-60 and HL-60R cells. Real­time PCR with RNA extracted from KML001-treated HL-60 and HL-60R cells showed a significant reduction of catalytic subunit of telomerase, hTERT, in a time-dependent manner. Additionally, γ-H2AX, a sensitive molecular marker of DNA damage, in HL-60 and HL-60R cells was induced by KML001. These results suggest that KML001 inhibits the proliferation of AML cells including cytosine arabinoside-resistant AML cells via various mechanisms such as cell cycle arrest, induction of apoptosis, inhibition of JAK/STAT and PI3K pathways, activation of MAPK pathway and telomere targeting.

KML001, a telomere-targeting drug, sensitizes glioblastoma cells to temozolomide chemotherapy and radiotherapy through DNA damage and apoptosis.

Standard treatment for glioblastoma comprises surgical resection, chemotherapy with temozolomide, and radiotherapy. Nevertheless, majority of glioblastoma patients have recurrence from resistance to the cytotoxic conventional therapies. We examined combinational effects of KML001, an arsenic compound targeting telomeres of chromosomes with temozolomide or irradiation, in glioblastoma cell lines and xenograft models, to overcome the therapeutic limitation of chemoradiation therapy for glioblastoma. Although KML001 alone showed little effects on in vitro survival of glioblastoma cells, cell death by in vitro temozolomide treatment or irradiation was synergistically potentiated by combination with KML001. Since phosphorylated γ-H2AX, cleaved casepase-3, and cleaved PARP were dramatically increased by KML001, the synergistic effects would be mediated by increased DNA damage and subsequent tumor cell apoptosis. Combinatorial effects of KML001 were observed not only in chemo- and radiosensitive glioblastoma cell line, U87MG, but also in the resistant cell line, U251MG. In the U87MG glioblastoma xenograft models, KML001 did not have systemic toxicity but showed synergistic therapeutic effects in combination with temozolomide or irradiation to reduce tumor volumes significantly. These data indicated that KML001 could be a candidate sensitizer to potentiate therapeutic effects of conventional cytotoxic treatment for glioblastoma.

Sodium meta-arsenite induces reactive oxygen species-dependent apoptosis, necrosis, and autophagy in both androgen-sensitive and androgen-insensitive prostate cancer cells.

Sodium meta-arsenite (NaAsO2), a novel compound synthesized by Komipham International Co. Ltd, is an orally bioavailable, water-soluble trivalent arsenical that has shown potent cytotoxic activity in human solid cancer cells in vitro and in vivo, and is currently undergoing phase I/II clinical trials for the treatment of prostate cancer. In this study, mechanisms of cell death induced by sodium meta-arsenite were investigated. Sodium meta-arsenite reduced cell viability and increased the sub-G1 population in cell cycle analysis in both androgen-sensitive LNCaP and androgen-insensitive CWR22RV1 cells. The apoptosis induced by sodium meta-arsenite was associated with cleavage of caspases 3, 8, and 9, and poly (ADP-ribose) polymerase (PARP) and increased annexin V-positive cells, and was inhibited by the pan-caspase inhibitor Z-VAD-fmk. Sodium meta-arsenite also increased the level of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and the number of autophagic vacuoles as shown by electron microscopy. Both the autophagy inhibitor 3-methyladenine and the necrosis inhibitor necrostatin-1 blocked cell death induced by sodium meta-arsenite. Moreover, sodium meta-arsenite led to the accumulation of intracellular reactive oxygen species (ROS) and N-acetyl-L-cysteine (NAC), a ROS scavenger, decreased sodium meta-arsenite-induced levels of cleaved PARP and LC3-II. Propidium iodide (PI) staining also showed that NAC restored membrane integrity, damaged by sodium meta-arsenite. Therefore, these results suggest that sodium meta-arsenite induces apoptotic, necrotic, and autophagic cell death through intracellular ROS accumulation in both androgen-sensitive and androgen-insensitive prostate cancer cells and may be used as a new anticancer drug for the treatment of prostate cancer.

Sodium meta-arsenite ameliorates hyperglycemia in obese diabetic db/db mice by inhibition of hepatic gluconeogenesis.

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg(-1) body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1.

The role of nkx2.5 in keratinocyte differentiation.

BACKGROUND: Nkx2.5 is a homeodomain-containing nuclear transcription protein that has been associated with acute T-lymphoblastic leukemia. In addition, Nkx2.5 has an essential role in cardiomyogenesis. However, the expression of Nkx2.5 in the skin has not been investigated. OBJECTIVE: In an attempt to screen the differentially regulated genes involved in keratinocyte differentiation, using a cDNA microarray, we identified Nkx2.5 as one of the transcription factors controlling the expression of proteins associated with keratinocyte differentiation. METHODS: To investigate the expression of Nkx2.5 during keratinocyte differentiation, we used a calcium-induced keratinocyte differentiation model. RESULTS: RT-PCR and Western blot analysis revealed that the expression of Nkx2.5, in cultured human epidermal keratinocytes, increased with calcium treatment in a time-dependent manner. In normal skin tissue, the expression of Nkx2.5 was detected in the nuclei of the keratinocytes in all layers of the epidermis except the basal layer by immunohistochemistry. In addition, the expression of Nkx2.5 was significantly increased in psoriasis and squamous cell carcinoma, but was barely detected in atopic dermatitis and basal cell carcinoma. CONCLUSION: These results suggest that Nkx2.5 may play a role in the change from proliferation to differentiation of keratinocytes and in the pathogenesis of skin disease with aberrant keratinocyte differentiation.

Structured polychotomous machine diagnosis of multiple cancer types using gene expression.

MOTIVATION: The problem of class prediction has received a tremendous amount of attention in the literature recently. In the context of DNA microarrays, where the task is to classify and predict the diagnostic category of a sample on the basis of its gene expression profile, a problem of particular importance is the diagnosis of cancer type based on microarray data. One method of classification which has been very successful in cancer diagnosis is the support vector machine (SVM). The latter has been shown (through simulations) to be superior in comparison with other methods, such as classical discriminant analysis, however, SVM suffers from the drawback that the solution is implicit and therefore is difficult to interpret. In order to remedy this difficulty, an analysis of variance decomposition using structured kernels is proposed and is referred to as the structured polychotomous machine. This technique utilizes Newton-Raphson to find estimates of coefficients followed by the Rao and Wald tests, respectively, for addition and deletion of import vectors. RESULTS: The proposed method is applied to microarray data and simulation data. The major breakthrough of our method is efficiency in that only a minimal number of genes that accurately predict the classes are selected. It has been verified that the selected genes serve as legitimate markers for cancer classification from a biological point of view. AVAILABILITY: All source codes used are available on request from the authors.