Effective use of the hybrid emergency Department system in the treatment of non-traumatic critical care diseases.

BACKGROUND: The hybrid emergency room (ER) system can provide resuscitation, computed tomography imaging, endovascular treatment, and emergency surgery, without transferring the patient. However, although several reports have demonstrated the effectiveness of the hybrid ER for trauma conditions, only a few case reports have demonstrated its usefulness for non-traumatic critical diseases. In this observational cohort study, we aimed to identify endogenous diseases that may benefit from treatment in the hybrid ER. METHODS: We retrospectively reviewed the clinical characteristics of patients with non-traumatic conditions treated in a hybrid ER between August 2017 and July 2022 at our institution. Patients who underwent surgery, endoscopy, or interventional radiology (IR) in the hybrid ER were selected and pathophysiologically divided into a bleeding and non-bleeding group. The rate of shock or cardiac arrest, blood transfusion, and death within 24 h of admission or in-hospital death were compared among the groups using Fisher's exact test. Multivariable logistic regression analysis was performed to confirm the relationships among in-hospital mortality, transfusion, and hemorrhagic conditions in patients who underwent endoscopy and IR. RESULTS: Among the 726 patients with non-traumatic conditions treated in a hybrid ER system, 50 (6.9%) experienced cardiac arrest at or before admission to the hybrid ER, 301 (41.5%) were in shock, 126 (17.4%) received blood transfusions, 42 (5.8%) died within 24 h of admission to the hybrid ER, and 141 (19.4%) died in the hospital. Emergency surgery was performed in 39 patients (7 in the bleeding group and 32 in the non-bleeding group). Significantly more blood transfusions were administered in the bleeding group (71.4% vs. 18.8%, P = 0.01); there were no significant differences in the rate of shock or cardiac arrest, death within 24 h, or in-hospital death between groups. Endoscopy was performed in 122 patients (80 in the bleeding group and 42 in the non-bleeding group). The bleeding group had a significantly higher rate of shock or cardiac arrest (87.5% vs. 66.7%, P = 0.008) and rate of blood transfusion (62.5% vs. 4.8%, P < 0.0001); there was no significant difference in death within 24 h and in-hospital death between groups. IR was performed in 100 patients (68 in the bleeding group and 32 in the non-bleeding group). Significantly more blood transfusions were administered in the hemorrhage group (67.7% vs. 12.5%, P < 0.0001); there was no difference in the rate of shock or cardiac arrest, death within 24 h, or in-hospital death between groups. Multivariable analysis in patients who underwent endoscopy showed a trend toward more in-hospital deaths in non-hemorrhagic conditions than in hemorrhagic conditions (odds ratio = 3.8, 95% confidence interval: 0.88-17, P = 0.073); however, no significant relationship with in-hospital death was observed for any of the adjusted variables. CONCLUSION: Among endogenous diseases treated in the hybrid ER, there is a possible association between in-hospital mortality and hemorrhagic conditions. Future studies are needed to focus on diseases to demonstrate the effectiveness of the hybrid ER.

Hybrid emergency rooms reduce the requirement of blood transfusion in patients with severe trauma.

BACKGROUND: A hybrid emergency room (ER) is defined as an emergency unit with four functions-performing resuscitation, computed tomography (CT), surgery, and angiography. However, the safety and efficacy of performing CT in a hybrid ER are unclear in primary surveys. Therefore, this study aimed to evaluate the safety and clinical effects of hybrid ERs. METHODS: This retrospective observational study used data from the Shimane University Hospital Trauma Database from January 2016 to February 2019. Hospitalized patients with severe trauma and an injury severity score of ≥ 16 were divided into the non-hybrid ER group (n = 134) and the hybrid ER group (n = 145). The time from arrival to CT and interventions and the number of in-hospital survivors, preventable trauma deaths (PTD), and unexpected survivors (US) were assessed in both groups. Further, the amount of blood transfused was compared between the groups using propensity score matching. RESULTS: The time from arrival to CT and interventions was significantly reduced in the hybrid ER group compared to that in the non-hybrid ER group (25 vs. 6 min; p < 0.0001 and 101 vs. 41 min; p = 0.0007, respectively). There was no significant difference in the rate of in-hospital survivors (96.9% vs. 96.3%; p = 0.770), PTD (0% vs. 0%), and US (9.0 vs. 6.2%; p = 0.497) between the groups. The amount of blood transfused was significantly lower in the hybrid ER group than in the non-hybrid ER group (whole blood 14 vs. 8, p = 0.004; red blood cell 6 vs. 2, p = 0.012; fresh frozen plasma 9 vs. 6, p = 0.021). This difference was maintained after propensity score matching (whole blood 28 [10-54] vs. 6 [4-16.5], p = 0.015; RBC 8 [2.75-26.5] vs. 2 [0-8.5], p = 0.020, 18 [5.5-27] vs. 6 [3.5-7.5], p = 0.057). CONCLUSIONS: The study results suggest that trauma treatment in a hybrid ER is as safe as conventional treatment performed in a non-hybrid ER. Further, hybrid ERs, which can reduce the time for trauma surveys and treatment, do not require patient transfer and can reduce the amount of blood transfused during resuscitation.

Damage control surgery for spontaneous perforation of pyometra with septic shock: a case report.

BACKGROUND: Although spontaneous perforation of pyometra is very rare, it sometimes causes severe peritonitis, leading to lethal conditions. Damage control surgery reportedly improves the survival of critically ill patients; however, there has been no report describing damage control surgery for ruptured pyometra. CASE PRESENTATION: An 83-year-old postmenopausal woman with generalized peritonitis and septic shock was admitted and underwent emergency laparotomy. Abbreviated surgery was carried out because of progressing septic shock, and planned reoperation was carried out 2 days after the initial surgery. Histopathological examination revealed the perforation of pyometra with no evidence of malignancy. The patient was discharged on the 32nd postoperative day in stable condition. CONCLUSION: We report a case of spontaneous perforation of pyometra with severe septic shock successfully treated by damage control surgery. Damage control surgery is a useful treatment option for hemodynamically unstable patients with diseases in the field of obstetrics and gynecology.

Delayed massive hemothorax due to diaphragm injury with rib fracture: A case report.

INTRODUCTION: Delayed massive hemothorax after blunt trauma is rare, although associated with significant morbidity and mortality. In most cases, the intercostal artery is the main bleeding source. We report a rare case of delayed massive hemothorax due to a diaphragm injury with a lower rib fractures. PRESENTATION OF CASE: A 58-year-old man, transported to our hospital four hours after a 2-meter fall from a ladder, had left-sided fractures to ribs 11 and 12, thoracic and lumbar vertebral fractures, and traumatic subarachnoid hemorrhage. On admission, no left hemothorax was documented; however, 17 h post-injury he developed hypovolemic shock. Plain chest radiographs showed a massive left hemothorax with a mediastinal shift. Chest contrast-enhanced computed tomography revealed extravasation of the contrast agent in the chest cavity. No intercostal arterial bleeding was evident on emergency angiography. A left anterolateral thoracotomy through the 6th intercostal space revealed rib fractures and active bleeding from the dorsal side of the left hemidiaphragm. Suture hemostasis was performed for the diaphragm injury and the disrupted ribs were repaired. DISCUSSION: Embolization of diaphragm-feeding arteries is not a simple or fast procedure. Clinically, predicting delayed hemothorax is challenging, and careful observation of trauma patients with lower rib fractures is needed. Thoracotomy should be considered for immediate hemostasis in patients with sudden shock, with complete hematoma drainage and repair of the disrupted rib. CONCLUSION: Diaphragmatic injury with lower rib fractures can result in delayed hemothorax, requiring thoracotomy.

Damage control surgery for unstable thoracic wall injury.

Damage control surgery (DCS) consists of three steps: an abbreviated initial operation, resuscitation in the ICU, and a planned reoperation. Although DCS for lung and heart injury have been established, there is no concept of DCS for the chest wall. We experienced a successful case, in which a DCS of chest wall lifting procedure and internal pneumatic stabilization were performed on the flail chest accompanied by a remarkable destruction of chest wall. As a result, the patient's abnormal breathing improved. Surgical fixations using KANI plate were performed at a later date. We suggest that the chest wall lifting procedure may be suitable as a DCS for thoracic cage destruction from severe chest wall injury.

Mediastinal, retroperitoneal, and subcutaneous emphysema due to sigmoid colon penetration: A case report and literature review.

INTRODUCTION: Mediastinal and subcutaneous emphysema usually result from spontaneous rupture of the alveolar wall. We present an extremely rare case of massive mediastinal, retroperitoneal, and subcutaneous emphysema due to the penetration of the colon into the mesentery. PRESENTATION OF CASE: A 57-year-old man presented to our institution with a history of chest pain. The patient's medical history included malignant rheumatoid arthritis during the use of steroids and an immunosuppressive agent. The patient had no signs of peritoneal irritation or abdominal pain. A chest radiography revealed subcutaneous emphysema of the neck, mediastinal emphysema, as well as subdiaphragmatic free air. Computed tomography showed extensive retroperitoneal, mediastinal, and mesenteric emphysema of the sigmoid colon without pneumothorax. Diagnostic laparoscopy was performed and revealed perforation into the sigmoid mesentery. Segmental resection of the sigmoid colon and end-colostomy were performed. The diverticulum was communicating with the outside of the mesentery via the mesentery. The mediastinal emphysema disappeared a few days after the surgery. DISCUSSION: Colonic perforation generally results in free perforation. Colonic gas may spread via various anatomical pathways when perforation of the colon occurs in the retroperitoneum; thus, diverse atypical clinical symptoms may be present. Signs of peritoneal irritation can be hidden in cases of retroperitoneal colonic perforation. The atypical manifestation of a retroperitoneal colonic perforation can cause difficulties in making a diagnosis. CONCLUSIONS: Massive mediastinal and retroperitoneum emphysema are rare signs of colonic perforation. Emergency laparotomy should be considered in colonic penetration of the diverticulitis where the emphysema expands to the mediastinum extensively.

First establishment of a new table-rotated-type hybrid emergency room system.

The hybrid emergency room (hybrid ER) system was first established in 2011 in Japan. It is defined as an integrated system including an ER, emergency computed tomography (CT) and interventional radiology (IVR) rooms, and operating rooms. Severe trauma patients can undergo emergency CT examinations and therapies (surgeries) without being transferred. The hybrid ER system is attracting attention because trauma resuscitation using this system has been reported to potentially improve the mortality rate in severe trauma patients. In August 2017, we established a new table-rotated-type hybrid ER to facilitate surgical functions. Herein, we introduce a new table-rotated-type hybrid ER consisting of an IVR-CT-operating room system and discuss its efficiency and feasibility for trauma resuscitation, including surgery and IVR. This system includes four new concepts: (1) to secure a wide working space during trauma resuscitation by reconsidering the arrangement of the C-arm, (2) ensure an air-conditioned operating room in the hybrid ER, (3) adopt an operating table but not interventional radiology table, and (4) prepare a trauma bay with three additional beds for multiple victims. This hybrid ER system also adopted the rotated-type table to secure a wide working space during the resuscitation phase. The C-arm was located away from the patients and placed on the wall opposite to the CT gantry, in contrast to that in previous systems. If patients needed an emergency IVR, the table was just rotated, and the IVR could be conducted immediately. This improvement can secure a wide working space in the hybrid ER. Moreover, the patient table was also a surgical operating table, and the hybrid ER system had an air-conditioned operating room (class 10,000). In the anticipation of many trauma patients being transported to the ER, a new trauma bay with three additional beds next to the hybrid ER was established, which also had an air-conditioned operating room. This new rotated-type hybrid ER system facilitates efficient surgical functions during trauma resuscitation and can secure a wide working space for the medical team to immediately perform resuscitative procedures and IVRs without delay.

A Novel Prognostic Scoring System Using Inflammatory Response Biomarkers for Esophageal Squamous Cell Carcinoma.

BACKGROUND: We describe a novel scoring system, namely the inflammatory response biomarker (IRB) score. The aim of this study is to evaluate the clinical value of IRB score in patients undergoing curative resection for esophageal squamous cell carcinoma (SCC). METHODS: We retrospectively reviewed patients who underwent curative esophagectomy. We evaluated IRB score in both non-elderly (<70 years) and elderly (≥70 years) SCC patients. The IRB score was determined as follows: a high lymphocyte-to-monocyte ratio (LMR) (>4), a high neutrophil-to-lymphocyte ratio (NLR) (>1.6), and a low platelet-to-lymphocyte ratio (PLR) (<147) were each scored as 1, and the remaining values were scored as 0; the individual scores were then summed to produce the IRB score (range 0-3). RESULTS: Univariate analyses demonstrated that the TNM pStage (p < 0.0001), tumor size (p = 0.002), LMR (p = 0.0057), PLR (p = 0.0328) and IRB score (p = 0.0003) were significant risk factors for a worse prognosis. On multivariate analysis, the TNM pStage (p < 0.0001) and IRB score (p = 0.0227) were independently associated with worse prognosis in overall patients. Among non-elderly patients, multivariate analyses demonstrated that the pStage (p = 0.0015) and IRB score (p = 0.0356) were independent risk factors for a worse prognosis. Among elderly patients, multivariate analysis demonstrated that the pStage (p = 0.0016), and IRB score (p = 0.0102) were independent risk factors for a worse prognosis. CONCLUSION: The present study provides evidence that the preoperative IRB score can be considered a promising independent prognostic factor of cancer-specific survival in patients undergoing curative resection for SCC, and that its predictive ability is useful in both non-elderly and elderly patients.

Prognostic Value of Excision Repair Cross-Complementing Gene 1, Dihydropyrimidine Dehydrogenase, and Human Equilibrative Nucleotide Transporter 1 Expression and Their Implications for Adjuvant Treatment in Patients With Ampullary Carcinoma.

OBJECTIVES: The purpose of this study was to characterize the intratumoral expression profiles of excision repair cross-complementing gene 1 (ERCC1), dihydropyrimidine dehydrogenase (DPD), and human equilibrative nucleotide transporter 1 (hENT1) in ampullary carcinomas (ACs) to evaluate their prognostic values and better tailor adjuvant chemotherapy for individual patients with AC after surgery. METHODS: This study included 49 patients with AC who underwent a curative pancreaticoduodenectomy. Various clinicopathological factors, including ERCC1, DPD, and hENT1, were analyzed in relation to postoperative disease recurrence and the patients' survival. RESULTS: The median recurrence-free survival and overall survival were 24.5 months and 32.4 months, respectively. Multivariate Cox regression analysis of recurrence-free survival identified a DPD expression (hazard ratio [HR], 8.18; 95% confidence interval [CI], 2.00-34.8; P = 0.003) and combined ERCC1/DPD expression (HR, 134.8; 95% CI, 11.8-1920; P < 0.001) as independent predictors of disease recurrence. Multivariate Cox regression analysis of overall survival also identified a DPD expression (HR, 8.48; 95% CI, 1.71-46.3; P = 0.008) and combined ERCC1/ DPD expression (HR, 135.6; 95% CI, 11.8-1940; P < 0.001) as independent predictors of survival. CONCLUSIONS: The DPD and ERCC1 expression profile could potentially serve as a useful prognostic biomarker and therapeutic target for surgically resected patients with AC.

A novel technique to minimize deformation of the stomach in laparoscopic partial gastrectomy for intraluminal gastric GISTs.

BACKGROUND: The laparoscopic approach would be difficult to perform without causing deformation of the stomach in managing gastrointestinal stromal tumors (GISTs) of the intraluminal type, especially in those that are located in the posterior gastric wall or around the gastroesophageal junction and the pylorus, because intraluminal GISTs usually require an excessive resection of the gastric wall for cure. We present a novel surgical technique for successful management of intraluminal gastric GISTs that minimizes deformation of the stomach regardless of tumor location. MATERIALS AND METHODS: The operating surgeon handles the tumor by holding tissue surrounding the tumor and performs seromyotomy using an ultrasonically activated device along the outer edge of the tumor. The tumor gradually protrudes like an extraluminal tumor as the seromyotomy proceeds. When seromyotomy along the tumor comes up to the point where the tumor sufficiently turns over the gastric serosa, the tumor looks like a pedunculated extraluminal GIST. Two seromuscular sutures are applied to close the exfoliated seromuscular layer. The tips of two seromuscular sutures are held and then pulled up toward the ventral side so that the staple line is aligned in line with the minor axis of the stomach. Finally, complete tumor removal with minimal seromuscular resection is accomplished by applying a linear stapler. RESULTS: All patients resumed oral ingestion on the day after surgery and showed no signs of anastomotic constriction or obstruction. CONCLUSIONS: Our laparoscopic procedure for gastric GISTs is simple and allows us easy and precise removal of the tumor and closure of the gastric wall with minimum necessary resection, regardless of the location and growth form of the tumors.

Safe and simple gastric conduit pull-through procedure through the posterior mediastinal route using echo probe cover in thoracoscopic subtotal esophagectomy.

A gastric conduit is commonly used to reconstruct the alimentary tract after esophagectomy. When the posterior mediastinum is applied to a reconstruction route, the gastric conduit created has been protected by an echo probe cover and, then blindly elevated to the neck. However, using this elevation method, the gastric conduit has the potential to catch on the vessels and nerves, posing a risk of major bleeding. We report a safe method of gastric conduit pull-through procedure to avoid unexpected technical complications. Two approximately 60-cm-long polyester tapes are prepared and ligated at both ends forming a loop. A 50-cm-long echo probe cover of 10 cm in diameter is prepared, and the closed end of the echo probe cover is cut to make an open-ended echo probe cover. A line parallel to the long axis of the echo probe cover is drawn across the echo probe cover with a sterile surgical marking pen. The looped polyester tape is inserted into the echo probe cover. The looped polyester tape and echo probe cover are ligated with 2-0 silk, approximately 5 cm in front of the knots on both sides. After dissection is carried out according to practice, the previously crafted polyester tape is inserted into the chest cavity. The echo probe cover is placed to connect the distal and proximal ends of the esophagus, and its torsion is corrected using the line marked with the pen and a crease, both of which are parallel to the long axis of the echo probe cover. One end of polyester tape is fixed to the distal esophageal stump by using the clips, with the opposite end fixed to the proximal esophageal stump. Either one of the 2 lengths of polyester tape is connected to the gastric conduit. By pulling up this length of polyester tape from the neck, the gastric conduit can pass through the echo probe cover and be elevated to the neck.

Enhanced expression of nuclear factor I/B in oxaliplatin-resistant human cancer cell lines.

Oxaliplatin is a third-generation platinum drug that has favorable activity in cisplatin-resistant cells. However, the molecular mechanisms underlying oxaliplatin resistance are not well understood. To investigate the molecular mechanisms involved, resistant cell lines were independently derived from colon cancer (DLD1) and bladder cancer (T24) cells. Oxaliplatin-resistant DLD1 OX1 and DLD1 OX2 cell lines were approximately 16.3-fold and 17.8-fold more resistant to oxaliplatin than the parent cell lines, respectively, and had 1.7- and 2.2-fold higher cross-resistance to cisplatin, respectively. Oxaliplatin-resistant T24 OX2 and T24 OX3 cell lines were approximately 5.0-fold more resistant to oxaliplatin than the parent cell line and had 1.9-fold higher cross-resistance to cisplatin. One hundred and fifty-eight genes commonly upregulated in both DLD1 OX1 and DLD1 OX2 were identified by microarray analysis. These genes were mainly involved in the function of transcriptional regulators (14.6%), metabolic molecules (14.6%), and transporters (9.5%). Of these, nuclear factor I/B (NFIB) was upregulated in all oxaliplatin-resistant cells. Downregulation of NFIB rendered cells sensitive to oxaliplatin, but not to cisplatin. Forced expression of NFIB induced resistance to oxaliplatin, but not to cisplatin. Taken together, these results suggest that NFIB is a novel and specific biomarker for oxaliplatin resistance in human cancers.

Enhanced expression of PCAF endows apoptosis resistance in cisplatin-resistant cells.

Histone acetyltransferase (HAT) regulates transcription. We have previously shown that two HAT genes, Clock and Tip60, are overexpressed, and upregulate glutathione biosynthesis and the expression of DNA repair genes in cisplatin-resistant cells. To better understand the mechanism of HAT-related drug resistance, we investigated the role of another HAT gene, p300/CBP-associated factor (PCAF), and found that PCAF was also overexpressed in cisplatin-resistant cells and endowed an antiapoptotic phenotype through enhanced E2F1 expression. PCAF-overexpressing cells showed enhanced expression of E2F1 and conferred cell resistance to chemotherapeutic agents. Downregulation of PCAF decreased E2F1 expression and sensitized cells to chemotherapeutic agents. Moreover, knockdown of PCAF induced G(1) arrest and apoptosis. These results suggest that PCAF is one of pleiotropic factors for drug resistance and seems to be critical for cancer cell growth.

Circadian disruption accelerates tumor growth and angio/stromagenesis through a Wnt signaling pathway.

Epidemiologic studies show a high incidence of cancer in shift workers, suggesting a possible relationship between circadian rhythms and tumorigenesis. However, the precise molecular mechanism played by circadian rhythms in tumor progression is not known. To identify the possible mechanisms underlying tumor progression related to circadian rhythms, we set up nude mouse xenograft models. HeLa cells were injected in nude mice and nude mice were moved to two different cases, one case is exposed to a 24-hour light cycle (L/L), the other is a more "normal" 12-hour light/dark cycle (L/D). We found a significant increase in tumor volume in the L/L group compared with the L/D group. In addition, tumor microvessels and stroma were strongly increased in L/L mice. Although there was a hypervascularization in L/L tumors, there was no associated increase in the production of vascular endothelial cell growth factor (VEGF). DNA microarray analysis showed enhanced expression of WNT10A, and our subsequent study revealed that WNT10A stimulates the growth of both microvascular endothelial cells and fibroblasts in tumors from light-stressed mice, along with marked increases in angio/stromagenesis. Only the tumor stroma stained positive for WNT10A and WNT10A is also highly expressed in keloid dermal fibroblasts but not in normal dermal fibroblasts indicated that WNT10A may be a novel angio/stromagenic growth factor. These findings suggest that circadian disruption induces the progression of malignant tumors via a Wnt signaling pathway.

Thioredoxin2 enhances the damaged DNA binding activity of mtTFA through direct interaction.

Mitochondrial transcription factor A (mtTFA) is a member of the HMG (high mobility group)-box protein family. We previously showed that mtTFA preferentially binds to both cisplatin-damaged and oxidatively damaged DNA. In this study, we found that expression levels of both mtTFA and the mitochondrial antioxidant protein thioredoxin2 (TRX2) are upregulated in cisplatin-resistant cell lines. In addition, TRX2 directly interacts with mtTFA and enhances its damaged DNA binding activity. The interaction between mtTFA and TRX2 requires the HMG box 1 motif of mtTFA. Furthermore, when amino acid substitutions were introduced at either C49G or C246stop, TRX2 interacted with mtTFA. However, the interaction of TRX2 with mtTFA was enhanced when both mutations (C49G and C246stop) were introduced. Binding to cisplatin-damaged DNA was similar among mutant mtTFA proteins. By contrast, binding to oxidized DNA was significantly enhanced when double mutations were introduced. These results suggest that TRX2 not only functions as an antioxidant, but also supports mtTFA functions.

Multicenter safety study of mFOLFOX6 for unresectable advanced/recurrent colorectal cancer in elderly patients.

BACKGROUND: Combination chemotherapy with oxaliplatin plus 5-fluorouracil/leucovorin (FOLFOX) has become a standard regimen for colorectal cancer. An increase of adverse events with combination chemotherapy is predicted in elderly patients, and it remains controversial whether they should receive the same chemotherapy as younger patients. Accordingly, this study of modified FOLFOX6 (mFOLFOX6) therapy was performed to compare its safety between elderly and non-elderly patients. METHODS: We prospectively studies 14 non-elderly patients aged <70 years old and 8 elderly patients aged >or= 70 years with unresectable advanced/recurrent colorectal cancer who received mFOLFOX6 therapy during the period from March 2006 to March 2007. Adverse events and the response to treatment were compared between the elderly and non-elderly groups. RESULTS: The main adverse events were neutropenia and peripheral neuropathy, which occurred in 62.5% (>or= grade 3) and 87.5% (>or= grade 1) of elderly patients. The grade and frequency of adverse events were similar in the elderly and non-elderly groups. In some patients with neutropenia, treatment could be continued without reducing the dose of oxaliplatin by deleting bolus 5-fluorouracil. A correlation was found between the cumulative dose of oxaliplatin and the severity of neuropathy, and there were 2 elderly and 3 younger patients in whom discontinuation of treatment was necessary due to peripheral neuropathy. The median number of treatment cycles was 10.0 and 9.5 in the non-elderly and elderly groups, respectively. The response rate was 60.0% in the non-elderly and 50.0% in the elderly group, while the disease control rate was 100% and 83.3% respectively, showing no age-related difference. CONCLUSION: mFOLFOX6 therapy was well-tolerated and effective in both non-elderly and elderly patients. However, discontinuation of treatment was sometimes necessary due to peripheral neuropathy, which is dose-limiting toxicity of this therapy.

Programmed cell death protein 4 down-regulates Y-box binding protein-1 expression via a direct interaction with Twist1 to suppress cancer cell growth.

Programmed cell death protein 4 (PDCD4) has recently been shown to be involved in both transcription and translation, and to regulate cell growth. However, the mechanisms underlying PDCD4 function are not well understood. In this study, we show that PDCD4 interacts directly with the transcription factor Twist1 and leads to reduced cell growth through the down-regulation of the Twist1 target gene Y-box binding protein-1 (YB-1). PDCD4 interacts with the DNA binding domain of Twist1, inhibiting its DNA binding ability and YB-1 expression. Immunohistochemical analysis showed that an inverse correlation between nuclear PDCD4 and YB-1 expression levels was observed in 37 clinical prostate cancer specimens. Growth suppression by PDCD4 expression was completely recovered by either Twist1 or YB-1 expression. Moreover, PDCD4-overexpressing cells are sensitive to cisplatin and paclitaxel but not to etoposide or 5-fluorouracil. In summary, PDCD4 negatively regulates YB-1 expression via its interaction with Twist1 and is involved in cancer cell growth and chemoresistance.

Ets regulates peroxiredoxin1 and 5 expressions through their interaction with the high-mobility group protein B1.

Peroxiredoxins (Prdxs) are thiol-specific antioxidant proteins that are highly expressed in human cancer cells. Prdxs have been shown to be involved in tumor cell proliferation under conditions of microenvironmental stress such as hypoxia. We hypothesized that Prdxs could be categorized into two groups, stress-inducible and non-inducible ones. In this study, we analyzed the promoter activity and expression levels of five Prdx family members in human cancer cells. We found that both Prdx1 and Prdx5 are inducible after treatment with hydrogen peroxide or hypoxia, but that Prdx2, Prdx3, and Prdx4 are not or are only marginally inducible. We also found that Ets transcription factors are the key activators for stress-inducible expression. High-mobility group protein HMGB1 was shown to function as a coactivator through direct interactions with Ets transcription factors. The DNA binding of Ets transcription factors was significantly enhanced by HMGB1. Silencing of Ets1, Ets2, Prdx1, and Prdx5 expression sensitized cells to oxidative stress. These data indicate that transcription of Prdx genes mediated by Ets/HMG proteins might protect cells from oxidative stress.

Tip60 is regulated by circadian transcription factor clock and is involved in cisplatin resistance.

Histone modification is important for maintaining chromatin structure and function. Recently, histone acetylation has been shown to have a critical regulatory role in both transcription and DNA repair. We report here that expression of histone acetyltransferase (HAT) genes is associated with cisplatin resistance. We found that Tip60 is overexpressed in cisplatin-resistant cells. The expression of two other HAT genes, HAT1 and MYST1, did not differ between drug-sensitive and -resistant cells. Knockdown of Tip60 expression rendered cells sensitive to cisplatin but not to oxaliplatin, vincristine, and etoposide. Tip60 expression is significantly correlated with cisplatin sensitivity in human lung cancer cell lines. Interestingly, the promoter region of the Tip60 gene contains several E boxes, and its expression was regulated by the E-box binding circadian transcription factor Clock but not by other E-box binding transcription factors such as c-Myc, Twist, and USF1. Hyperacetylation of H3K14 and H4K16 was found in cisplatin-resistant cells. The microarray study reveals that several genes for DNA repair are down-regulated by the knockdown of Tip60 expression. Our data show that HAT gene expression is required for cisplatin resistance and suggest that Clock and Tip60 regulate not only transcription, but also DNA repair, through periodic histone acetylation.