Metachronous metastasis confined to isolated lymph node after curative treatment of colorectal cancer.

BACKGROUND: The incidence of lymph node metastasis (LNM) in colorectal cancer is known to be 2-6%, but little data are available regarding metachronous metastasis confined to isolated LN. The aim of this study is to determine the distribution of isolated LNM and the risk factors for survival of isolated LNM in colorectal cancer. METHODS: We retrospectively reviewed consecutive patients with colorectal adenocarcinoma between January 2008 and December 2015 at a tertiary referral center. A total of 5902 patients with biopsy-proven colorectal adenocarcinoma treated via surgery were included. Multivariate Cox proportional hazards analysis was used to identify prognostic factors for overall survival. RESULTS: Of the 5902 patients, recurrent cases were 1326. Among the relapsed patients, 301 patients had isolated LNM (22.69%). Para-aortic (48.8%), pelvic (29.9%), and Lung hilum (10.0%) were the most common sites of isolated LNM; there were statistically significant differences in the distribution of isolated LNM between the colon and rectal cancer (p = 0.02). Approximately 80% of isolated LNM were diagnosed within 3 years. Multidisciplinary therapy for LNM, diagnosis time to LNM, the T-stage, and histological type of primary cancer were identified as independent prognostic factors for overall survival. CONCLUSION: This study suggests that multidisciplinary management is a potentially effective treatment strategy for isolated LNM. Since time to LNM, the T-stage, and histological type are prognostic factors, an active follow-up program for colorectal cancer is required.

Activation of the Basal Plane in Two Dimensional Transition Metal Chalcogenide Nanostructures.

Achieving a molecular level understanding of chemical reactions on the surface of solid-state nanomaterials is important, but challenging. For example, the fully saturated basal plane is believed to be practically inert and its surface chemistry has been poorly explored, while two-dimensional (2D) layered transition-metal chalcogenides (TMCs) display unique reactivities due to their unusual anisotropic nature, where the edges consisting of unsaturated metals and chalcogens are sites for key chemical reactions. Herein, we report the use of Lewis acids/bases to elucidate the chemical reactivity of the basal plane in 2D layered TMCs. Electrophilic addition by Lewis acids (i.e., AlCl3) selectively onto sulfides in the basal plane followed by transmetalation and subsequent etching affords nanopores where such chemical activations are initiated and propagated from the localized positions of the basal plane. This new method of surface modification is generally applicable not only to various chemical compositions of TMCs, but also in crystal geometries such as 1T and 2H. Nanoporous NbS2 obtained by this method was found to have an enhanced electrochemical energy storage capacity, offering this chemical strategy to obtain functional 2D layered nanostructures.

Predictive Factors for Lymph Node Metastasis in Submucosal Invasive Colorectal Carcinoma: A New Proposal of Depth of Invasion for Radical Surgery.

BACKGROUND: Patients with lymph node metastasis (LNM) in submucosal invasive colorectal carcinoma (SM cancer) require additional surgical treatment after endoscopic dissection. However, because additional radical resection after endoscopic local resection may be unnecessary for cases without LNM, more specific criteria are required in order to diminish the incidence of further radical resection after endoscopic dissection. METHODS: A total of 492 patients with biopsy-proven SM cancer who underwent curative surgery between January 2008 and December 2012 were collected and were divided into LNM group and no LNM group. The cutoff value for the depth of submucosal invasion was analyzed by a receiver operating characteristic (ROC) curve. In this retrospective study, the association between LNM and clinicopathologic factors was analyzed by logistic regression analysis. RESULTS: The depth of submucosal invasion of 1900 µm was determined as the cutoff value by ROC curve. Significant, independent predictive factors for LNM included the depth of submucosal invasion >1900 µm (odds ratio [OR] 7.5; 95% confidence interval [CI] 3.1-18.3; p < 0.001), venous invasion (OR 2.4; 95% CI 1.1-5.5; p = 0.03), and poorly differentiated/mucinous adenocarcinoma (OR 6.3; 95% CI 1.3-30.8; p = 0.02). CONCLUSIONS: Our study demonstrates that the depth of submucosal invasion (>1900 µm), vascular invasion and poorly differentiated/mucinous carcinoma were predictive factors of LNM in patients with SM cancer. These predictors may help to reduce the incidence of unnecessary surgery after endoscopic resection.

Tissue Fluid Enzyme-Linked Immunosorbant Assay for Piglets Experimentally Infected with Toxoplasma gondii and Survey on Local and Imported Pork in Korean Retail Meat Markets.

To investigate the prevalence of Toxoplasma gondii in pork on the market in Korea, an in-house enzyme-linked immunosorbent assay for tissue fluid (CAU-tf-ELISA) was developed using a soluble extract of T. gondii RH strain tachyzoites. As the standard positive controls, the piglets were experimentally infected with T. gondii: Group A (1,000 cysts-containing bradyzoites), Group B (500 cysts-containing bradyzoites) and Group C (1.0×103 or 1.0×104 tachyzoites). The CAU-tf-ELISA demonstrated infection intensity-dependent positivity toward tissue fluids with average cut-off value 0.15: 100% for Group A, 93.8% for Group B and 40.6% for Group C. When tissue-specific cut-off values 0.066-0.199 were applied, CAU-tf-ELISA showed 96.7% sensitivity, 100% specificity, 100% positive and 90.0% negative predictive values. When compared with the same tissue fluids, performance of CAU-tf-ELISA was better than that of a commercial ELISA kit. Of the 583 Korea domestic pork samples tested, anti-T. gondii antibodies were detected from 9.1% of whole samples and 37.9% from skirt meat highest among pork parts. In the 386 imported frozen pork samples, 1.8% (skirt meat and shoulder blade) were positive for anti-T. gondii antibodies. In Korea, prevalence of anti-T. gondii antibodies in the pork on retail markets appeared high, suggesting that regulations on pig farming and facilities are necessary to supply safe pork on the tables.

Intraoperative colonoscopy for the assessment and prevention of anastomotic leakage in low anterior resection for rectal cancer.

PURPOSE: Anastomotic leakage (AL) after stapled anastomosis in rectal cancer surgery is a major concern. Various types of intraoperative anastomotic air leakage tests (ALTs) have been proposed to reduce AL. This study aimed to evaluate the impact of intraoperative colonoscopy (IOC) as an intraoperative ALT in low anterior resection for rectal cancer. METHODS: A total of 1266 patients were retrospectively reviewed. Among them, 215 patients who underwent IOC as an ALT in rectal cancer surgery were identified. IOC was performed after anastomosis to visualize the anastomosis line and to perform an ALT by insufflating the neorectum. Propensity score matching was used to match this group at a 1:1 ratio with 215 patients who underwent ALT with a 250-mL bulb irrigation syringe. Anastomotic defects that were found intraoperatively were resolved either by means of primary repair of the anastomotic defect, if possible, or by performing a preventive diverting ileostomy. RESULTS: The patient characteristics, pathologic outcomes, and operation details showed no significant difference between the two groups. Comparison of the AL rate showed a significant difference between the groups (IOC group without intraoperative leaks vs. non-IOC group without intraoperative leaks 4.3 vs. 11.7%, P = 0.007). The incidence of preventive diverting ileostomy because of a positive ALT was significantly higher in the IOC group than in the non-IOC group (10 vs. 2 cases, P = 0.036). CONCLUSION: IOC can be a valuable method for the assessment of stapled anastomosis and has the additional benefit of directly visualizing the anastomosis line.

Transanal Endoscopic Operation Versus Conventional Transanal Excision for Rectal Tumors: Case-Matched Study with Propensity Score Matching.

BACKGROUNDS: Although transanal endoscopic surgery is practiced worldwide, there is no consensus on comparative outcomes between transanal endoscopic operation (TEO) and transanal excision (TAE). In this study, we reviewed our experiences with these techniques and compared patients who underwent TEO and TAE using propensity score matching (PSM). METHODS: A total of 207 patients underwent local rectal tumor excision between January 2008 and November 2015. To overcome selection bias, we used PSM to achieve a one-to-one TEO: TAE ratio. We included baseline characteristics, age, sex, surgeon, American Society of Anesthesiologists score, tumor location (clockwise direction), involved circumference quadrants, tumor size, and pathology. RESULTS: After PSM, 72 patients were included in each group. The tumor distance from the anal verge was higher in the TEO group (8.0 [5-10] vs. TAE: 4.0 [3-5], p < 0.001). Complication rates did not differ between the groups (TEO: 8.3% vs. TAE: 11.1%, p = 0.39). TEO was associated with a shorter hospital stay (3.01 vs. 4.68 days, p = 0.001), higher negative margin rate (95.8 vs. 86.1%, p = 0.039), and non-fragmented specimen rate vs. TAE (98.6 vs. 90.3%, p = 0.029). CONCLUSIONS: TEO was more beneficial for patients with higher rectal tumors. Regardless of tumor location, involved circumference quadrants, and tumor size, TEO may more effectively achieve negative resection margins and non-fragmented specimens. Consequently, although local excision method according to tumor distance may be important, TEO will become the standard for rectal tumors.

Chemical synthetic strategy for single-layer transition-metal chalcogenides.

A solution-phase synthetic protocol to form two-dimensional (2D) single-layer transition-metal chalcogenides (TMCs) has long been sought; however, such efforts have been plagued with the spontaneous formation of multilayer sheets. In this study, we discovered a solution-phase synthetic protocol, called "diluted chalcogen continuous influx (DCCI)", where controlling the chalcogen source influx (e.g., H2S) during its reaction with the transition-metal halide precursor is the critical parameter for the formation of single-layer sheets as examined for the cases of group IV TMCs. The continuous influx of dilute H2S throughout the entire growth period is necessary for large sheet formation through the exclusive a- and b-axial growth processes. By contrast, the burst influx of highly concentrated H2S in the early stages of the growth process forms multilayer TMC nanodiscs. Our DCCI protocol is a new synthetic concept for single-layer TMCs and, in principle, can be operative for wide range of TMC nanosheets.

Impact of Long-Term Supplementation with Probiotics on Gut Microbiota and Growth Performance in Post-Weaned Piglets.

This study aimed to investigate effects of long-term probiotic supplementation on gut microbiota and growth performance in health weaned piglets. The non-probiotic group (N-PrB) was fed only a basal diet, while the probiotic group (PrB) was fed a basal diet + probiotic combination (E. faecium 1.6 × 108 CFU/g, B. subtilis 2.0 × 108 CFU/g, S. cerevisiae 3.0 × 108 CFU/g). The probiotics combination was provided to the PrB, mixing with the basal diet in 5 kg/ton. As a result, the PrB exhibited significantly improved weight gain compared to the N-PrB (p = 0.00991). In the gut microbiome analysis, the PrB exhibited a significant increasing tendency of α-diversity compared to those of the N-PrB (p < 0.01). In the bacterial relative abundance changes in bacteria comprising the gut microbiota, Ruminococcaceae (p = 0.00281) and Prevotella (p = 0.00687) tended to significantly increase in the PrB, but decreased in the N-PrB. The Eubaterium coprostanoligenes group exhibited an increasing tendency in both groups, but tended to increase more significantly in the PrB compared to the N-PrB (p = 0.00681). Muribaculaceae tended to significantly increase in the N-PrB, but decreased in the PrB (p = 0.002779). In this study, significant differences on the gut microbiome were found according to the probiotics supplementation in the weaned piglets and these gut microbiome changes appeared to improve the growth performance.

Safety and Effectiveness of Dulaglutide in the Treatment of Type 2 Diabetes Mellitus: A Korean Real-World Post-Marketing Study.

BACKGRUOUND: To investigate the real-world safety and effectiveness of dulaglutide in Korean adults with type 2 diabetes mellitus (T2DM). METHODS: This was a real-world, prospective, non-interventional post-marketing safety study conducted from May 26, 2015 to May 25, 2021 at 85 Korean healthcare centers using electronic case data. Data on patients using dulaglutide 0.75 mg/0.5 mL or the dulaglutide 1.5 mg/0.5 mL single-use pens were collected and pooled. The primary objective was to report the frequency and proportion of adverse and serious adverse events that occurred. The secondary objective was to monitor the effectiveness of dulaglutide at 12 and 24 weeks by evaluating changes in glycosylated hemoglobin (HbA1c ), fasting plasma glucose, and body weight. RESULTS: Data were collected from 3,067 subjects, and 3,022 subjects who received ≥1 dose (of any strength) of dulaglutide were included in the safety analysis set (53% female, mean age 56 years; diabetes duration 11.2 years, mean HbA1c 8.8%). The number of adverse events reported was 819; of these, 68 (8.3%) were serious adverse events. One death was reported. Adverse events were mostly mild in severity; 60.81% of adverse events were considered related to dulaglutide. This study was completed by 72.73% (2,198/3,022) of subjects. At 12/24 weeks there were significant (P<0.0001) reductions from baseline in least-squares mean HbA1c (0.96%/0.95%), fasting blood glucose (26.24/24.43 mg/dL), and body weight (0.75/1.21 kg). CONCLUSION: Dulaglutide was generally well tolerated and effective in real-world Korean individuals with T2DM. The results from this study contribute to the body of evidence for dulaglutide use in this population.

Occurrence of mycotoxins in swine feed from South Korea.

Objectives: To update recent information on contamination levels of mycotoxins in South Korea. Materials and methods: A total of 208 samples sourced from the feeds of swine farms were collected. The contamination levels of mycotoxins, which are aflatoxin (Afla), ochratoxin A (OTA), deoxynivalenol (DON), zearalenone (ZEN), fumonisin (FUM), and T-2 toxin, were investigated by enzyme-linked immunosorbent assays (ELISAs). Results: The detection levels of the total samples were 78.91% for DON, 75.24% for Afla, 47.02% for ZEN, 68.31% for FUM, and 5.94% for OTA and T-2, which were not detected at all. Most of the analyzed mycotoxins showed significant high occurrences in 47.02%-78.91% of the swine feed samples. 11 of the 152 alfa-positive samples exceeded the maximum residue limit (MRL) of Afla proposed by the Korean regulation. In the analysis of mycotoxin detection levels by growth stage, ZEN was found in the nursery stage at a remarkably high concentration level (126.46 ± 63.76 ppb), exceeding the MRL of ZEN for piglets proposed by the European Commission. This mycotoxin was also found in the samples from the gestation barn (89.04 ± 46.05 ppb) and the farrowing house (105.58 ± 94.12) at a high concentration level. Afla was found in the nursery stage at a high concentration (8.00 ± 2.22 ppb), approaching the MRL (10 ppb) of Afla proposed by the Korean regulation. Conclusion: These results indicate that many swine farms in South Korea are still exposed to mycotoxin risk, and special attention and surveillance are necessary for these mycotoxin risks in swine farms.

Platelet to lymphocyte ratio is a risk factor for failure of non-operative treatment of colonic diverticulitis.

Non-operative treatment is the mainstay of colonic diverticulitis, but some patients require surgery due to non-operative treatment failure. This study aims to identify risk factors for the failure of non-operative treatment of colonic diverticulitis. From January 2011 to December 2020, we retrospectively reviewed 2362 patients with non-operative treatment for first-attack acute diverticulitis. Patients were categorized into non-operative treatment success or failure groups. Clinical characteristics and serum inflammatory markers were analyzed by multivariable logistic regression to determine risk factors for non-operative treatment failure of colonic diverticulitis. Overall, 2.2% (n = 50) of patients underwent delayed surgery within 30 days (median 4.0 [3.0; 8.0]) due to non-operative treatment failure. Multivariable logistic regression identified that platelet to lymphocyte ratio (odds ratio [OR], 4.2; 95% confidence interval [CI], 0.05-0.13; p < 0.001), diabetes mellitus (OR, 2.2; 95% CI, 0.01-0.09; p = 0.025), left-sided colonic diverticulitis (OR, 4.1; 95% CI, 0.04-0.13; p < 0.001), and modified Hinchey classification (OR, 6.2; 95% CI, 0.09-0.17; p < 0.001) were risk factors for non-operative treatment failure. Platelet to lymphocyte ratio (PLR) is a potential risk factor for the non-operative treatment failure of acute first-attack colonic diverticulitis. Therefore, patients with higher PLR during non-operative treatment should be monitored with special caution.

Hybrid Appendectomy in Pediatric Appendicitis: A Comparative Analysis of Single-Port and Multiport Laparoscopic Appendectomy.

Background: Hybrid appendectomy (HA) has the technical advantages of the excellent visual field provided by laparoscopic surgery and is fast and easy similar to open surgery. We aimed to compare the safety and effectiveness of HA with single- and multiport laparoscopic appendectomy (SPLA and MPLA) in pediatric patients with acute appendicitis. Materials and Methods: This retrospective study compared the short-term operative outcomes between HA, SPLA, and MPLA groups. From January, 2010 to December, 2019, 239 patients aged <12 years who underwent laparoscopic appendectomy for acute appendicitis were included. The primary outcome was the 30-day postoperative complication rate, stratified according to the modified Clavien-Dindo classification. Results: In 239 patients, HA was more frequently performed in patients with a low body mass index (17.42 versus 18.97 kg/m2 in the SPLA group versus 18.44 kg/m2 in the MPLA group, P = .029) and tended to be more frequently adopted in uncomplicated appendicitis. In uncomplicated appendicitis, the HA group had a significantly shorter operation time than the MPLA group (31.77 versus 40.09 min, P < .001), but had a comparable operation duration with the SPLA group. The rate of 30-day postoperative complications was not significantly different between the groups (HA 7.6% versus SPLA 7.8% versus MPLA 5.4%, P = .841). The postoperative time to resume water intake was significantly longer in the SPLA group than in the HA and MPLA groups (P = .008). Conclusions: HA showed a short operation time, fast functional recovery, and acceptable postoperative complication rate in patients with uncomplicated appendicitis and can be safely and effectively performed in these patients.

Neoadjuvant therapy of metformin is associated with good tumor response after preoperative concurrent chemoradiotherapy for rectal cancer.

Metformin is associated with good tumor response in preoperative concurrent chemoradiotherapy (CCRT) for rectal cancer. This study aims to demonstrate that the timing of metformin is related to the tumor response on preoperative CCRT for rectal cancer. From January 2010 to December 2017, 232 patients who underwent curative resection after preoperative CCRT were reviewed. Patients were divided into groups with or without diabetes or metformin. The timing of metformin administration was divided based on before and from initiation of CCRT. Multivariate logistic regression analysis was used to identify predictors for tumor response. Tumor downstaging (p = 0.02) and good response rates of tumor regression grade (TRG) (p = 0.008) were significantly higher in the group administered metformin before CCRT than other groups. In the multivariate analysis, metformin administration before CCRT was a significant factor in predicting tumor downstaging [odds ratio (OR) 10.31, 95% confidence interval (CI) 1.76-102.08, p = 0.02] and good TRG (OR 12.55, 95% CI 2.38-80.24, p = 0.004). In patients with rectal cancer who underwent preoperative CCRT, neoadjuvant therapy of metformin before CCRT was significantly associated with good tumor response.

A COVID-19 Vaccine for Dogs Prevents Reverse Zoonosis.

COVID-19 is caused by severe acute respiratory syndrome virus type 2 (SARS-CoV-2), which can infect both humans and animals. SARS-CoV-2 originated from bats and can affect various species capable of crossing the species barrier due to active mutation. Although reports on reverse zoonosis (human-to-animal transmission) of SARS-CoV-2 remain limited, reverse zoonosis has been reported in many species such as cats, tigers, minks, etc. Therefore, transmission to more animals cannot be ruled out. Moreover, the wide distribution of SARS-CoV-2 in the human population could result in an increased risk of reverse zoonosis. To counteract reverse zoonosis, we developed the first COVID-19 subunit vaccines for dogs, which are representative companion animals, and the vaccine includes the SARS-CoV-2 recombinant protein of whole S1 protein and the receptor-binding domain (RBD). A subunit vaccine is a vaccine developed by purifying only the protein region that induces an immune response instead of the whole pathogen. This type of vaccine is safer than the whole virus vaccine because there is no risk of infection and proliferation through back-mutation of the virus. Vaccines were administered to beagles twice at an interval of 3 weeks subcutaneously and antibody formation rates were assessed in serum. We identified a titer, comparable to that of vaccinated people, shown to be sufficient to protect against SARS-CoV-2. Therefore, the vaccination of companion animals, such as dogs, may prevent reverse zoonosis by protecting animals from SARS-CoV-2; thus, reverse zoonosis of COVID-19 is preventable.

The protective effect of dietary supplementation of Salmonella-specific bacteriophages in post-weaning piglets challenged with Salmonella typhimurium.

OBJECTIVE: The efficacy of Salmonella typhimurium-specific bacteriophage STP-1 on S. typhimurium infection in weaning piglets was evaluated in this study. MATERIAL AND METHODS: Twenty-eight weaning piglets were randomly allocated to four groups (Group A: non-challenged/basal; Group B: non-challenged/+phage; Group C: challenged/basal; Group D: challenged/+phage) according to S. typhimurium infection or bacteriophage administration. The total experimental period (14 days) was subdivided in to non-challenged periods (phase I; day 1-7) and challenged periods (phase II; day 7-14) based on the challenging date (day 7). Each group was fed with basal feed or feed supplemented with bacteriophage STP-1 [1.0 × 109 plaque-forming unit (PFU)/kg] during the whole period (day 1-14). Body weights (BW) were measured to evaluate growth performance. Clinical symptoms (rectal temperatures and fecal consistency) induced by S. typhimurium were regularly checked. Bacteria colonization levels in feces and intestinal tissue samples were measured using real-time polymerase chain reaction (PCR). After necropsy, small intestine samples (jejunum) were collected. Villus height and crypt depth (CD) were measured through histological examination with H&E staining. RESULTS: The supplementation of bacteriophage significantly reduced bacterial colonization and intestine damage in the piglets infected with S. typhimurium. In the antigen concentrations of the feces and jejunum, Group C showed 5.8 ± 0.6, 5.7 ± 0.6, and 1.2 ± 2.0 log colony-forming unit (CFU)/ml on 1, 3, and 7 days post-inoculation (DPI) and 2.8 ± 1.3 log CFU/ml, whereas Group D showed 3.5 ± 1.7, 2.2 ± 2.1, and 0.3 ± 0.9 log CFU/ml on 1, 3, and 7 DPI and 5.1 ± 0.9 log CFU/ml. In the villous height, Groups C and D showed 266.3 ± 24.1 and 324.6 ± 18.0 µm, respectively. In the goblet cell density of villi and crypts, Group C showed 10.0 ± 1.8 and 16.0 ± 3.7, while Group D showed 15.0 ± 4.8 and 21.1 ± 5.4. Also, the supplementation of bacteriophage significantly improved the growth performance in the infected piglets. The average daily gains of Groups C and D were 91 ± 24 and 143 ± 23, respectively, during the period after inoculation with S. typhimurium. CONCLUSION: The dietary supplementation of the phage was effective for alleviating S. typhimurium infection in post-weaning piglets.

The impact of early adjuvant chemotherapy in rectal cancer.

PURPOSES: Although adjuvant chemotherapy (AC) has been established as a standard of treatment for advanced rectal cancer, there is no guideline regarding the timing of AC initiation. In this study, we aimed to evaluate the oncologic outcome of early AC initiation and clarify the ideal time to AC among rectal cancer patients receiving preoperative chemo-radiotherapy (preCRT). METHODS: The medical records of 719 patients who underwent curative resection followed by AC for rectal cancer were analyzed retrospectively. Data distributions were compared according to the calculated cut-off for AC initiation, survival results, and chemotherapy-induced toxicity. Additionally, patients were divided into two groups according to preCRT status and compared with respect to differences in the optimal time to AC. RESULTS: Overall, a cut-off time point of 20 days after surgery for AC initiation was identified as the optimal interval; this yielded a significant difference in disease-free survival but no significant difference in AC toxicity. In the cut-off analysis of patients treated without preCRT, 19 days was identified as the optimal time to AC. However, for patients treated with preCRT, no significant value affected the survival outcome. CONCLUSIONS: Earlier initiation of AC (within approximately 3 weeks) was associated with better oncological outcomes among patients with rectal cancer. Additionally, the optimal timing of AC was unclear among patients who received preCRT; this might be attributable to an undetermined role of AC after preCRT or the effects of complications such as anastomotic leakage.

Evaluation of 1-Propanol Toxicity in B6C3F1 Mice via Repeated Inhalation over 28 and 90 Days.

We evaluated the toxicity of 1-propanol exposure following repeated inhalation over 28- and 90-day periods in male and female B6C3F1 mice to confirm the potential target organs and to determine the no-observable-adverse-effect levels (NOAELs). Five mice of each sex were exposed to 1-propanol at concentrations of 0, 100, 400, or 1600 ppm for 28 days and showed no consequent toxicity. Following this, ten mice of each sex were exposed at concentrations of 0, 500, 1600, or 5200 ppm for 90 days. We observed no effects on food consumption, body weight, organ weight, clinical signs, hematology and biochemistry parameters, or gross or histological features even at the maximum concentration. Therefore, the NOAEL of inhaled 1-propanol was defined as 5200 ppm (12.8 mg/L) for male and female mice under study conditions.

Benzene activates caspase-4 and -12 at the transcription level, without an association with apoptosis, in mouse bone marrow cells lacking the p53 gene.

Benzene is a well-known environmental pollutant that can induce hematotoxicity, aplastic anemia, acute myelogenous leukemia, and lymphoma. However, although benzene metabolites are known to induce oxidative stress and disrupt the cell cycle, the mechanism underlying lympho/leukemogenicity is not fully understood. Caspase-4 (alias caspase-11) and -12 are inflammatory caspases implicated in inflammation and endoplasmic reticulum stress-induced apoptosis. The objectives of this study were to investigate the altered expression of caspase-4 and -12 in mouse bone marrow after benzene exposure and to determine whether their alterations are associated with benzene-induced bone marrow toxicity, especially cellular apoptosis. In addition, we evaluated whether the p53 gene is involved in regulating the mechanism, using both wild-type (WT) mice and mice lacking the p53 gene. For this study, 8-week-old C57BL/6 mice [WT and p53 knockout (KO)] were administered a benzene solution (150 mg/kg diluted in corn oil) via oral gavage once daily, 5 days/week, for 1 or 2 weeks. Blood and bone marrow cells were collected and cell counts were measured using a Coulter counter. Total mRNA and protein extracts were prepared from the harvested bone marrow cells. Then qRT-PCR and Western blotting were performed to detect changes in the caspases at the mRNA and protein level, respectively. A DNA fragmentation assay and Annexin-V staining were carried out on the bone marrow cells to detect apoptosis. Results indicated that when compared to the control, leukocyte number and bone marrow cellularity decreased significantly in WT mice. The expression of caspase-4 and -12 mRNA increased significantly after 12 days of benzene treatment in the bone marrow cells of benzene-exposed p53KO mice. However, apoptosis detection assays indicated no evidence of apoptosis in p53KO or WT mice. In addition, no changes of other apoptosis-related caspases, such as caspase-3 and -9, were found in WT or p53KO mice at the level of mRNA and proteins. These results indicated that upregulation of caspase-4 and -12 in mice lacking the p53 gene is not associated with cellular apoptosis. In conclusion, caspase-4 and -12 can be activated by benzene treatment without inducing cell apoptosis in mouse bone marrow, which are partly under the regulation of the p53 gene.

miR-1307-3p Stimulates Breast Cancer Development and Progression by Targeting SMYD4.

Recent studies show that dysregulated miRNAs play an important role in breast cancer initiation and progression. Here, we identified upregulated expression of miR-1307-3p in breast cancer tissues and that increased level of miR-1307-3p was closely correlated with lower survival rate in breast cancer patients. Consistent with clinical data, our in vitro data show that expression level of miR-1307-3p was significantly increased in breast cancer cell lines compared to human mammary epithelial cell line MCF10A. Overexpression of miR-1307-3p in MCF10A stimulated cell proliferation and caused their growth in soft agar and tumor formation in nude mice. In contrast, inhibition of miR-1307-3p suppressed breast cancer cell proliferation and their growth in soft agar and inhibited tumor formation in nude mice. Further, we identified that miR-1307-3p plays its oncogenic role through targeting SET and MYND domain-containing 4 (SMYD4) expression in breast cancer. Taken together, our findings suggest that miR-1307-3p is a oncogenic miRNA that significantly contributes to breast cancer development and progression, and inhibition of miR-1307-3p may be a novel strategy for inhibits breast cancer initiation and progression.