Achaete-scute family bHLH transcription factor 2 activation promotes hepatoblastoma progression.

Achaete-scute family bHLH transcription factor 2 (ASCL2) is highly expressed in hepatoblastoma (HB) tissues, but its role remains unclear. Thus, biological changes in the HB cell line HepG2 in response to induced ASCL2 expression were assessed. ASCL2 expression was induced in HepG2 cells using the Tet-On 3G system, which includes doxycycline. Cell viability, proliferation activity, mobility, and stemness were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, colony-formation, migration, invasion, and sphere-formation assays. Quantitative reverse-transcription polymerase chain reaction was used to assess the expression of markers for proliferation (CCND1 and MYC), epithelial-mesenchymal transition (EMT; SNAI1, TWIST1, and ZEB1), mesenchymal-epithelial transition (CDH1), and stemness (KLF4, POU5F1, and SOX9). Compared with the non-induced HepG2 cells, cells with induced ASCL2 expression showed significant increases in viability, colony number, migration area (%), and sphere number on days 7, 14, 8, and 7, respectively, and invasion area (%) after 90 h. Furthermore, induction of ASCL2 expression significantly upregulated CCND1, MYC, POU5F1, SOX9, and KLF4 expression on days 2, 2, 3, 3, and 5, respectively, and increased the ratios of SNAI1, TWIST1, and ZEB1 to CDH1 on day 5. ASCL2 promoted the formation of malignant phenotypes in HepG2 cells, which may be correlated with the upregulation of the Wnt signaling pathway-, EMT-, and stemness-related genes. ASCL2 activation may therefore be involved in the progression of HB.

GLIS1, a novel hypoxia-inducible transcription factor, promotes breast cancer cell motility via activation of WNT5A.

We previously demonstrated that expression of a Krüppel-like zinc finger transcription factor, GLIS1, dramatically increases under hypoxic conditions via a transcriptional mechanism induced by HIF-2α cooperating with AP-1 members. In this study, we focused on the functional roles of GLIS1 in breast cancer. To uncover its biological function, the effects of altered levels of GLIS1 in breast cancer cell lines on cellular growth, wound-healing and invasion capacities were assessed. Knockdown of GLIS1 using siRNA in BT-474 cells resulted in significant growth stimulation under normoxia, while attenuation was found in the cell invasion assay under hypoxic conditions. In MDA-MB-231 cells expressing exogenous 3xFLAG-tagged GLIS1, GLIS1 attenuated cell proliferation and enhanced cell mobility and invasion capacities under normoxia. In addition, breast cancer cells expressing GLIS1 acquired resistance to irradiation. Whole transcriptome analysis clearly demonstrated that downstream signals of GLIS1 are related to various cellular functions. Among the genes with increased expression, we focused on WNT5A. Knockdown of WNT5A indicated that enhancement of acquired cell motility in the MDA-MB-231 cells expressing GLIS1 was mediated, at least in part, by WNT5A. In an analysis of publicly available data, patients with estrogen receptor-negative breast cancer showing high levels of GLIS1 expression showed much worse prognosis than those with low levels. In summary, hypoxia-induced GLIS1 plays significant roles in breast cancer cells via regulation of gene expression related to cell migration and invasion capacities, resulting in poorer prognosis in patients with advanced breast cancer.

Sera from Septic Patients Contain the Inhibiting Activity of the Extracellular ATP-Dependent Inflammasome Pathway.

Immunoparalysis is a common cause of death for critical care patients with sepsis, during which comprehensive suppression of innate and adaptive immunity plays a significant pathophysiological role. Although the underlying mechanisms are unknown, damage-associated molecular patterns (DAMPs) from septic tissues might be involved. Therefore, we surveyed sera from septic patients for factors that suppress the innate immune response to DAMPs, including adenosine triphosphate (ATP), monosodium urate, and high mobility group box-1. Macrophages, derived from THP-1 human acute monocytic leukemia cells, were incubated with each DAMP, in the presence or absence of sera that were collected from critically ill patients. Secreted cytokines were then quantified, and cell lysates were assayed for relevant intracellular signaling mediators. Sera from septic patients who ultimately did not survive significantly suppressed IL-1ß production only in response to extracellular ATP. This effect was most pronounced with sera collected on day 3, and persisted with sera collected on day 7. However, this effect was not observed when THP-1 cells were treated with sera from survivors of sepsis. Septic sera collected at the time of admission (day 1) also diminished intracellular levels of inositol 1,4,5-triphosphate and cytosolic calcium (P < 0.01), both of which are essential for ATP signaling. Finally, activated caspase-1 was significantly diminished in cells exposed to sera collected on day 7 (P < 0.05). In conclusion, the sera of septic patients contain certain factors that persistently suppress the immune response to extracellular ATP, thereby leading to adverse clinical outcomes.

Health effects of radiation and other health problems in the aftermath of nuclear accidents, with an emphasis on Fukushima.

437 nuclear power plants are in operation at present around the world to meet increasing energy demands. Unfortunately, five major nuclear accidents have occurred in the past--ie, at Kyshtym (Russia [then USSR], 1957), Windscale Piles (UK, 1957), Three Mile Island (USA, 1979), Chernobyl (Ukraine [then USSR], 1986), and Fukushima (Japan, 2011). The effects of these accidents on individuals and societies are diverse and enduring. Accumulated evidence about radiation health effects on atomic bomb survivors and other radiation-exposed people has formed the basis for national and international regulations about radiation protection. However, past experiences suggest that common issues were not necessarily physical health problems directly attributable to radiation exposure, but rather psychological and social effects. Additionally, evacuation and long-term displacement created severe health-care problems for the most vulnerable people, such as hospital inpatients and elderly people.

Pediatric cardiorespiratory failure successfully managed with venoarterial-venous extracorporeal membrane oxygenation: a case report.

BACKGROUND: Venoarterial-venous extracorporeal membrane oxygenation (VAV ECMO) configuration is a combined procedure of extracorporeal membrane oxygenation (ECMO). The proportion of cardiac and respiratory support can be controlled by adjusting arterial and venous return. Therefore, VAV ECMO can be applicable as a bridging therapy in the transition from venoarterial (VA) to venovenous (VV) ECMO. CASE PRESENTATION: We present an 11-year-old girl with chemotherapy-induced myocarditis requiring extracorporeal cardiorespiratory support. She showed progressive hypotension, tachycardia, hyperlactemia, and tachypnea under support of catecholamines. Echocardiography showed severe left ventricular hypokinesis with an ejection fraction of 30 %. She was placed on VA ECMO with a drainage catheter from the right femoral vein (19.5 Fr) and a return catheter to the right femoral artery (16.5 Fr). Extracorporeal circulation was initiated at a blood flow of 2.0 L/min (59 mL/kg/min). On day 31, although cardiac function had improved, persistent pulmonary failure made weaning from VA ECMO difficult. We planned transition from VA ECMO to VAV ECMO to ensure gradual tapering of extracorporeal cardiac support while evaluating cardiopulmonary function. An additional return cannula (13.5 Fr) was inserted from the right internal jugular vein, which was connected to the circuit branch from the original returning cannula. We then gradually shifted the blood from the femoral artery to the right internal jugular vein over 24 h. She was successfully switched from VA to VV ECMO via VAV ECMO. CONCLUSIONS: VAV ECMO might be an option in ensuring oxygenation to the coronary circulation and allowing time to adequately evaluate cardiac function during transition from VA to VV ECMO. Further investigations using larger cohorts are necessary to validate the efficacy of VAV ECMO as a bridging therapy in the transition from VA to VV ECMO.

Influence of clinical experience of the Macintosh laryngoscope on performance with the Pentax-AWS Airway Scope(®), a rigid video-laryngoscope, by paramedics in Japan.

PURPOSE: We sought to establish the clinical utility of the Pentax-AWS Airway Scope(®) (AWS) when used by paramedics to intubate the trachea, and to evaluate whether their performance was influenced by previous clinical experience with the Macintosh laryngoscope (ML). METHODS: Twenty paramedics attempted tracheal intubation using the AWS in five patients each in the operating room. We recorded the success rate, the number of intubation attempts, and the time for intubation and adverse events, and compared these based on the paramedics' previous clinical experience with the ML. Ten paramedics had no prior clinical experience of the ML (group A) and 10 had used it on more than 30 occasions (group B). RESULTS: The intubation success rate was 99 % (99/100). Notably, 96 % (47/49) of intubations were achieved on the first attempt by the inexperienced paramedics in group A, compared with 64 % (32/50) by the experienced paramedics in group B (p = 0.0001). The time to intubation (mean ± SD) was significantly shorter in group A than in group B (37 ± 24 vs. 48 ± 21 s, p = 0.002). There were marked variations in the times taken to intubate, but no apparent improvement as the intubators gained experience between their first and fifth cases. No complications were encountered in either group. CONCLUSION: We found that paramedics could achieve a high tracheal intubation success rate using the AWS independent of previous airway management experience. Better intubation performance with the AWS was observed in paramedics without clinical experience with the ML.

p53 status modifies cytotoxic activity of lactoferrin under hypoxic conditions.

Lactoferrin (LF) is an iron binding glycoprotein of the transferrin family with a wide spectrum of biological effects, including anti-cancer activity. However, the detailed molecular mechanisms of anti-cancer activity of LF have not been fully determined. In this study, we tried to clarify cytotoxic functions of LF on various cell lines under hypoxic conditions and elucidate those molecular mechanisms. Cytotoxic activity of LF on cell lines was found to have a range of sensitivities. Hypoxia decreased sensitivity to LF in KD (lip fibroblast) but increased that in HSC2 (oral squamous cell carcinoma). Expression analyses further revealed that LF treatments increased hypoxic HIF-1α, -2α and p53 proteins in KD but attenuated them in HSC2 cells, and decreased HIF-1 target gene, DEC2, in KD but increased it in HSC2, suggesting a possible relationship between LF-modified DEC2 expression and HIF-α protein. MTT assay strikingly demonstrated that cells expressing mutant-type p53 (MT5) were more sensitive to LF than control HepG2 (hepatoma), suggesting an important role of the p53 signal. Knock-down of TP53 (p53 gene) interestingly reduced sensitivity to LF in HepG2, suggesting that p53 may be a target of LF cytotoxic activity. Further analyses with a ferroptosis promoter or inhibitor demonstrated that LF increased ACSL4 in hypoxic MT5, suggesting LF-induced ferroptosis in cells expressing mutant-type p53. In conclusion, hypoxia was found to regulate cytotoxic activities of LF differently among various cell lines, possibly through the p53 signaling pathway. LF further appeared to regulate ferroptosis through a modification of ACSL4 expression.

Low-Dose-Rate Irradiation Suppresses the Expression of Cell Cycle-Related Genes, Resulting in Modification of Sensitivity to Anti-Cancer Drugs.

The biological effects of low-dose-rate (LDR) radiation exposure in nuclear power plant accidents and medical uses of ionizing radiation (IR), although being a social concern, remain unclear. In this study, we evaluated the effects of LDR-IR on global gene expression in human cells and aimed to clarify the mechanisms. RNA-seq analyses demonstrated that relatively low dose rates of IR modify gene expression levels in TIG-3 cells under normoxic conditions, but those effects were attenuated under hypoxia-mimicking conditions. Gene set enrichment analysis demonstrated that LDR-IR significantly decreased gene expression related to cell division, cell cycle, mitosis, and the Aurora kinase B and FOXM1 pathways. Quantitative RT-PCR confirmed the down-regulation of AURKB and FOXM1 genes in TIG-3 cells with LDR-IR or hypoxia-mimicking treatments without any dose-rate effect. Knock-down experiments suggested that HIF-1α and HIF-2α, as well as DEC1, participated in down-regulation of AURKB and FOXM1 under DFOM treatments, but to a lesser extent under LDR-IR treatment. FACS and microscopic analyses demonstrated that LDR-IR induced G0/G1 arrest and increased micronucleus or chromosome condensation. Finally, MTT assays demonstrated that LDR-IR decreased sensitivity to paclitaxel or barasertib in TIG-3 cells but not in A549 cells. In conclusion, LDR-IR modifies global gene expression and cell cycle control, resulting in a reduction of sensitivity to anti-cancer chemotherapy in non-cancer cells and thus a reduction in untoward effects (GA).

Oncogenic Role of ADAM32 in Hepatoblastoma: A Potential Molecular Target for Therapy.

Outcomes of pediatric hepatoblastoma (HBL) have improved, but refractory cases still occur. More effective and safer drugs are needed that are based on molecular mechanisms. A disintegrin and metalloproteases (ADAMs) are expressed with high frequency in various human carcinomas and play an important role in cancer progression. In this study, we analyzed expression of ADAMs in HBL with a cDNA microarray dataset and found that the expression level of ADAM32 is particularly high. To investigate the role of ADAM32 in cancer, forced expression or knockdown experiments were conducted with HepG2 and HBL primary cells. Colony formation, cell migration and invasion, and cell viability were increased in HepG2 expressing ADAM32, whereas knockdown of ADAM32 induced a decrease in these cellular functions. Quantitative RT-PCR demonstrated an association between ADAM32 expression and the expression of genes related to cancer stem cells and epithelial-mesenchymal transition (EMT), suggesting a role of ADAM32 in cancer stemness and EMT. Furthermore, knockdown of ADAM32 increased cisplatin-induced apoptosis, and this effect was attenuated by a caspase-8 inhibitor, suggesting that ADAM32 plays a role in extrinsic apoptosis signaling. We conclude that ADAM32 plays a crucial role in progression of HBL, so it might be a promising molecular target in anticancer therapy.

Radiation Emergency Medical Preparedness in Japan: A Survey of Nuclear Emergency Core Hospitals.

OBJECTIVE: Based on experiences following the Great East Japan Earthquake and nuclear power plant accident in 2011, Nuclear Emergency Core Hospitals (NECHs) were designated as centers for radiation disaster management in Japan. This study aimed to investigate their current status and identify areas for improvement. METHODS: This cross-sectional study was conducted in October 2018. Demographic data were collected by a questionnaire with free text responses about attitudes toward NECHs. Considerations regarding risk communications during a radiation disaster were analyzed using qualitative text mining analysis. RESULTS: A total of 36 hospitals participated in this study. Only 31% of NECHs anticipated a radiation disaster. The importance of business continuity plans and risk communications was shown. Text analysis identified 7 important categories for health care workers during a radiation disaster, including media response, communications to hospital staff, risk communications, radiation effects on children, planning for a radiation disaster in the region, rumors, and the role in the region. CONCLUSION: The radiation disaster medical system and NECHs in Japan were surveyed. The importance of risk communications, planning for a radiation disaster in each region, and the role in the region are identified as issues that need to be addressed.

Results of the 2018 Japan Society for Blood Purification in Critical Care survey: current status and outcomes.

Background: The Japan Society for Blood Purification in Critical Care (JSBPCC) has reported survey results on blood purification therapy (BPT) for critically ill patients in 2005, 2009, and 2013. To clarify the current clinical status, including details of the modes used, treated diseases, and survival rate, we conducted this cohort study using data from the nationwide JSBPCC registry in 2018. Methods: We analyzed data of 2371 patients who underwent BPT in the intensive care units of 43 facilities to investigate patient characteristics, disease severity, modes of BPTs, including the dose of continuous renal replacement therapy (CRRT) and hemofilters, treated diseases, and the survival rate for each disease. Disease severity was assessed using Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores. Results: BPT was performed 2867 times in the 2371 patients. Mean APACHE II and SOFA scores were 23.5 ± 9.4 and 10.0 ± 4.4, respectively. The most frequently used mode of BPT was CRRT (67.4%), followed by intermittent renal replacement therapy (19.1%) and direct hemoperfusion with the polymyxin B-immobilized fiber column (7.3%). The most commonly used anticoagulant was nafamostat mesilate (78.6%). Among all patients, the 28-day survival rate was 61.7%. CRRT was the most commonly used mode for many diseases, including acute kidney injury (AKI), multiple organ failure (MOF), and sepsis. The survival rate decreased according to the severity of AKI (P = 0.001). The survival rate was significantly lower in patients with multiple organ failure (MOF) (34.6%) compared with acute lung injury (ALI) (48.0%) and sepsis (58.0%). Multivariate logistic regression analysis revealed that sepsis, ALI, acute liver failure, cardiovascular hypotension, central nervous system disorders, and higher APACHE II scores were significant predictors of higher 28-day mortality. Conclusion: This large-scale cohort study revealed the current status of BPT in Japan. It was found that CRRT was the most frequently used mode for critically ill patients in Japan and that 28-day survival was lower in those with MOF or sepsis. Further investigations are required to clarify the efficacy of BPT for critically ill patients.Trial Registration : UMIN000027678. Supplementary Information: The online version contains supplementary material available at 10.1186/s41100-022-00445-0.

KL-6 concentration in pulmonary epithelial lining fluid is a useful prognostic indicator in patients with acute respiratory distress syndrome.

BACKGROUND: KL-6 is a mucin-like glycoprotein expressed on the surface of alveolar type II cells. Elevated concentrations of KL-6 in serum and epithelial lining fluid (ELF) in patients with acute respiratory distress syndrome (ARDS) have been previously reported; however, kinetics and prognostic significance of KL-6 have not been extensively studied. This study was conducted to clarify these points in ARDS patients. METHODS: Thirty-two patients with ARDS who received mechanical ventilation under intubation were studied for 28 days. ELF and blood were obtained from each patient at multiple time points after the diagnosis of ARDS. ELF was collected using a bronchoscopic microsampling procedure, and ELF and serum KL-6 concentrations were measured. RESULTS: KL-6 levels in ELF on days 0 to 3 after ARDS diagnosis were significantly higher in nonsurvivors than in survivors, and thereafter, there was no difference in concentrations between the two groups. Serum KL-6 levels did not show statistically significant differences between nonsurvivors and survivors at any time point. When the highest KL-6 levels in ELF and serum sample from each patient were examined, KL-6 levels in both ELF and serum were significantly higher in nonsurvivors than in survivors. The optimal cut-off values were set at 3453 U/mL for ELF and 530 U/mL for serum by receiver operating characteristic (ROC) curve analyses. Patients with KL-6 concentrations in ELF higher than 3453 U/mL or serum concentrations higher than 530 U/mL had significantly lower survival rates up to 90 days after ARDS diagnosis. CONCLUSIONS: ELF and serum KL-6 concentrations were found to be good indicators of clinical outcome in ARDS patients. Particularly, KL-6 levels in ELF measured during the early period after the diagnosis were useful for predicting prognosis in ARDS patients.

Inhibiting SARS-CoV-2 infection in vitro by suppressing its receptor, angiotensin-converting enzyme 2, via aryl-hydrocarbon receptor signal.

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.

Tracheal intubation of a difficult airway using Airway Scope, Airtraq, and Macintosh laryngoscope: a comparative manikin study of inexperienced personnel.

BACKGROUND: The Airway Scope (AWS) (Pentax-AWS, Hoya Corp., Tokyo, Japan) and the Airtraq (ATQ) (Prodol, Vizcaya, Spain) have similarities in the novel structures of their blades. In this study, we evaluated the ease of use of the AWS and ATQ compared with the Macintosh laryngoscope (ML) by inexperienced personnel in a simulated manikin difficult airway. METHODS: Twenty-four fifth-year medical students with no previous experience in tracheal intubation participated in this study. We used an advanced patient simulator (SimMan(R), Laerdal Medical, Stavanger, Norway) to simulate difficult airway scenarios including cervical spine rigidity, limited mouth opening, and pharyngeal obstruction. The sequences in selecting devices and scenarios were randomized. Success rates for tracheal intubation, and the time required for visualization of the glottis, tracheal intubation, and inflation of the lungs, and the number of optimization maneuvers and dental click sounds were analyzed. The 3 different intubation devices were tested in 4 different scenarios by 24 students. RESULTS: Both the AWS and ATQ had very high success rates of tracheal intubation compared with the ML (AWS 100%*; ATQ 98%*; and ML 89%; *P < 0.05 AWS, ATQ versus ML). The time to intubation with the AWS was significantly shorter than with the ATQ and ML (AWS 11 +/- 6 seconds; ATQ 16 +/- 12 seconds; and ML 16 +/- 11 seconds; *P < 0.05 AWS versus ATQ, ML). The number of optimization maneuvers with the AWS was significantly lower than with the ATQ and ML. There were significantly more audible dental click sounds with the ML than with the AWS and ATQ. CONCLUSION: Both the AWS and ATQ may be suitable devices for difficult intubation by inexperienced personnel in this manikin simulated scenario. Further studies in a clinical setting are necessary to confirm these findings.

Practical use of airway pressure release ventilation for severe ARDS--a preliminary report in comparison with a conventional ventilatory support.

Airway pressure release ventilation (APRV) is a ventilatory mode that allows unsupported spontaneous breathing at any phase of the ventilatory cycle with high mean airway pressures. We hypothesized that use of APRV might produce potential beneficial effects on oxygenation, reducing mortality in patients with severe acute respiratory distress syndrome (ARDS) in comparison with synchronized intermittent mandatory ventilation (SIMV) as a conventional mode of ventilation. We retrospectively reviewed data of 58 patients with severe ARDS (the ratios of partial arterial oxygen tension to fraction of inspired oxygen, PaO2/F(I)O2 ratio <150). The patients' data were divided into two groups: SIMV-group and APRV-group. Patients' backgrounds, oxygenation on day 0, 1, 3, 5 and 7 following initiation of each mode, vasopressor dependence, duration of ventilation, duration of ICU stay, and mortality in ICU were analyzed. PaO2/F(I)O2 ratios were statistically higher in the APRV-group (APRV vs. SIMV on day 1, 3, 5, 7: 201.6 +/- 76 vs.150 +/- 59.1, 256.7 +/- 71.5 vs.182.1 +/- 65.4, 268.8 +/- 73.3 vs. 204.6 +/- 72.8, and 263 +/- 74.5 vs. 204.1 +/- 67.1, respectively, p<0.05). Vasopressors were less used (p=0.018), and mortality in ICU tended to be lower in the APRV group (31%) than in the SIMV group (59%) (p=0.050). Use of APRV in patients with severe ARDS appears to be associated with improvements in oxygenation, and a trend toward lower mortality in ICU. No significant adverse effects were observed. Prospective controlled studies are required to confirm the benefits of this ventilatory mode in comparison with conventional methods for severe ARDS.

Simulated microgravity enhances CDDP-induced apoptosis signal via p53-independent mechanisms in cancer cells.

Although the biological systems in the human body are affected by the earth's gravity, information about the underlying molecular mechanisms is limited. For example, apoptotic signaling is enhanced in cancer cells subjected to microgravity. We reasoned that signaling regulated by p53 may be involved because of its role in apoptosis. Therefore, we aimed to clarify the molecular mechanisms of modified cis-diamminedichloroplatinum (CDDP)-sensitivity under simulated microgravity by focusing on p53-related cell death mechanisms. Immunoblotting analyses indicated that, under microgravity, CDDP-induced ATM/p53 signaling increased and caspase-3 was cleaved earlier. However, microgravity decreased the levels of expression of p53 targets BAX and CDKN1A. Interestingly, microgravity increased the PTEN, DRAM1, and PRKAA1 mRNA levels. However, microgravity decreased the levels of mTOR and increased the LC3-II/I ratio, suggesting the activation of autophagy. The CDDP-induced cleavage of caspase-3 was increased during the early phase in Group MG (+), and cleaved caspase-3 was detected even in Group MG (+) with constitutive expression of a mutant type of p53 (hereafter, "+" indicates CDDP treatment). These results interestingly indicate that microgravity altered CDDP sensitivity through activation of caspase-3 by p53-independent mechanism.

Airway Scope for emergency intubations: usefulness of a new video-laryngoscope.

The Airway Scope (AWS-S100, Pentax, Tokyo, Japan) is a new video-laryngoscope, which has a specially designed blade and a portable, battery-powered, 2.4-inch built-in liquid crystal device (LCD) full-color video screen at the top of the handle. In this study, we tested the usefulness of the AWS for tracheal intubation in acute, urgent situations. Patients admitted to the Advanced Emergency and Critical Care Center at Hiroshima University Hospital and who required orotracheal intubations were prospectively enrolled. Tracheal intubations were performed using the AWS by residents (the novice group) or staff physicians (the experienced group), who received a brief instruction in the AWS. We enrolled 38 patients (23 males, 15 females; age, 60 +/- 19 years). Intubations were attempted by 22 intubators (11 residents and 11 experienced personnel). The durations from inserting the blade via the oral cavity until observing the glottis (T1), inserting the tube into the trachea (T2), and confirming the chest rise (T3) were 22 +/- 15, 34 +/- 21 and 49 +/- 27 sec, respectively. When the results were classified into t experienced and novice groups, T1, T2 and T3 were 17 +/- 10 vs. 26 +/- 17, 32 +/- 23 vs. 36 +/- 20, and 45 +/- 25 vs. 53 +/- 27 sec, respectively (the experienced vs. the novice group, n.s.). These results suggested that the AWS may be a suitable device particularly for less experienced personnel, such as novice Advanced Life Support providers.

Differentiated embryo chondrocyte plays a crucial role in DNA damage response via transcriptional regulation under hypoxic conditions.

Tumor hypoxia contributes to a biologically aggressive phenotype and therapeutic resistance. Recent studies have revealed that hypoxia reduces expression of several DNA damage recognition and repair (DRR) genes via both hypoxia-inducible factor (HIF)-independent and -dependent pathways, and this induced genomic instability in cancer cells. We show here that one of the HIF-target genes-differentiated embryo chondrocyte (DEC)-plays a role in DNA damage response via transcriptional repression. Comprehensive gene expression and database analyses have revealed systemic repression of DNA-DRR genes in cancer and non-cancer cells under hypoxic conditions. Hypoxic repression in typical cases was confirmed by quantitative RT-PCR and promoter reporter experiments, and knockdown experiments indicated the critical role of DEC2 in such repression. Assessment of histone H2AX phosphorylation revealed that recognition and repair of DNA double-strand breaks (DSBs) induced by bleomycin or γ-ray irradiation were attenuated; moreover, Cleaved Caspase-3 levels were decreased with pre-conditioning under hypoxia: opposing phenomena were ascertained by knockdown of DEC2. Finally, pre-conditioning under hypoxia decreased the sensitivity of cancer cells to DSBs, and knockdown of DEC2 increased γ-ray sensitivity. These data imply that a critical reduction of DNA-DRR occurs via DEC-dependent transcriptional repression and suggest that DEC is a potential molecular target for anti-cancer strategies.