A Case of Edwardsiella tarda Infection With Iliopsoas Abscess Following Acute Pyelonephritis.

Edwardsiella tarda (E. tarda) is a gram-negative bacillus commonly isolated from aquatic environments and various aquatic animals. It rarely causes infections in humans, but rare human infections occur primarily through ingestion of infected seafood or aquatic animals. Symptoms include fever, gastroenteritis, and diarrhea, but severe extraintestinal infections have also been reported. This report describes a 76-year-old female developing E. tarda infection with iliopsoas abscess following acute pyelonephritis. Her chief complaint was fatigue and difficulty moving. Blood tests showed an increased inflammatory response, but the cause could not be identified from the patient's medical history, physical findings, and imaging findings. We diagnosed it as a urinary tract infection from the results of gram staining and started treatment, but the fever persisted thereafter, and a contrast-enhanced CT scan performed for re-evaluation revealed an iliopsoas abscess. After CT-guided abscess drainage, the patient made good progress and was transferred to a rehabilitation hospital on day 48 of the presentation. To the best of our knowledge, this is the first report of a case of E. tarda infection with iliopsoas abscess following acute pyelonephritis. Iliopsoas abscess is often difficult to diagnose. In this case report, we also present how we diagnosed and treated iliopsoas abscesses.

Short- and Long-Term Outcomes of Neoadjuvant Chemoradiotherapy Followed by Pancreatoduodenectomy in Elderly Patients with Resectable and Borderline Resectable Pancreatic Cancer: A Retrospective Study.

Background: The efficacy of neoadjuvant chemoradiotherapy (NACRT) followed by pancreatoduodenectomy (PD) in elderly patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. Methods: This retrospective analysis of prospectively collected data examined the effect of NACRT followed by PD in elderly patients with PDAC. A total of 112 patients with resectable (R-) and borderline resectable (BR-) PDAC, who were planned for PD and received NACRT between 2009 and 2022, were assessed. Changes induced by NACRT, surgical outcomes, nutritional status, renal and endocrine functions, and prognosis were compared between elderly (≥75 years, n = 43) and non-elderly (<75 years, n = 69) patients over two years following PD. Results: Completion and adverse event rates during NACRT, nutritional status, renal function, endocrine function over two years postoperatively, and prognosis did not significantly differ between the two groups. Low prognostic index after NACRT and the absence of postoperative adjuvant chemotherapy may be adverse prognostic indicators for elderly patients undergoing NACRT for R- and BR-PDAC. Conclusions: Despite a higher incidence of postoperative complications, NACRT followed by PD can be safely performed in elderly patients, resulting in a prognosis similar to that in non-elderly patients.

Predictive role of the prognostic nutritional index in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant chemoradiotherapy followed by curative pancreatic resection: A retrospective study using prospectively collected data.

BACKGROUND: Despite a strong association between nutritional indices and disease prognosis, evidence regarding the evaluation of nutritional indices after preoperative treatment for pancreatic ductal adenocarcinoma (PDAC) is insufficient. We evaluated the clinical significance of the prognostic nutritional index (PNI) in patients with resectable (R-) and borderline resectable (BR-) PDAC who received neoadjuvant chemoradiotherapy (NACRT) followed by pancreatic resection. METHODS: We assessed 153 patients with R- and BR-PDAC who underwent NACRT followed by curative resection between 2009 and 2022. We evaluated the association between preoperative PNI after NACRT and short- and long-term outcomes. RESULTS: The median preoperative PNI value after NACRT was 42.1, and the optimal cutoff value from the time-dependent receiver operating characteristic curve was 38.6. The low PNI group (PNI < 38.6, n = 44) exhibited significantly worse inflammatory parameters, surgical outcomes, and prognoses than the high PNI group (PNI ≥ 38.6, n = 109). Multivariate analysis identified preoperative PNI ≤ 38.6 (hazard ratio [HR]: 2.32, 95% confidence interval [CI]: 1.00-5.38, p = .049), blood loss ≥1642 mL (HR: 3.05, 95% CI: 1.65-5.64, p < .001), node positive pathology (HR: 2.10, 95% CI: 1.32-3.34, p = .002), and lack of postoperative adjuvant chemotherapy (HR: 3.55, 95% CI: 2.05-6.15, p < .001) as significant predictors of overall survival. CONCLUSIONS: For patients with R- and BR-PDAC receiving preoperative treatment, it is imperative to closely monitor their nutritional status when determining the optimal surgical procedure timing.

A combined score for predicting clinically relevant postoperative pancreatic fistula based on inflammatory parameters and drainage fluid culture results on postoperative day 3.

BACKGROUND: Clinically relevant postoperative pancreatic fistula (CR-POPF) after pancreatic resection can lead to severe postoperative complications. POPF is defined based on postoperative day (POD) 3 drainage fluid amylase level. POPF correlates with inflammatory parameters as well as drainage fluid bacterial infection. However, a standardized model based on these factors for predicting CR-POPF remains elusive. We aimed to identify inflammatory parameter- and drainage fluid culture-related risk factors for CR-POPF on POD 3 after pancreatoduodenectomy (PD) and distal pancreatectomy (DP). METHODS: Data from 351 patients who underwent PD or DP between 2013 and 2022 at a single institution were retrospectively analyzed. Risk factors for CR-POPF were investigated using multivariate analyses, and a prediction model combining the risk factors for CR-POPF was developed. RESULTS: Of the 351 patients, 254 and 97 underwent PD and DP, respectively. Multivariate analyses revealed that drainage fluid amylase level ≥722 IU/L, culture positivity, as well as neutrophil count ≥5473/mm3 on POD 3 were independent risk factors for CR-POPF in PD group. Similarly, drainage fluid, amylase level ≥500 IU/L, and culture positivity on POD 3 as well as pancreatic thickness ≥11.1 mm were independent risk factors in the DP group. The model for predicting CR-POPF achieved the maximum overall accuracy rate when the number of risk factors was ≥2 in both the PD and DP groups. CONCLUSIONS: Inflammatory parameters on POD 3 significantly influence the risk of CR-POPF onset after pancreatectomy. The combined models based on these values can accurately predict the risk of CR-POPF after pancreatectomy.

Serum Carbohydrate Antigen 19-9 and Metabolite Hypotaurine Are Predictive Markers for Early Recurrence of Pancreatic Ductal Adenocarcinoma.

OBJECTIVE: A significant number of patients experience early recurrence after surgical resection for pancreatic ductal adenocarcinoma (PDAC), negating the benefit of surgery. The present study conducted clinicopathologic and metabolomic analyses to explore the factors associated with the early recurrence of PDAC. MATERIALS AND METHODS: Patients who underwent pancreatectomy for PDAC at Kagawa University Hospital between 2011 and 2020 were enrolled. Tissue samples of PDAC and nonneoplastic pancreas were collected and frozen immediately after resection. Charged metabolites were quantified by capillary electrophoresis-mass spectrometry. Patients who relapsed within 1 year were defined as the early recurrence group. RESULTS: Frozen tumor tissue and nonneoplastic pancreas were collected from 79 patients. The clinicopathologic analysis identified 11 predictive factors, including preoperative carbohydrate antigen 19-9 levels. The metabolomic analysis revealed that only hypotaurine was a significant risk factor for early recurrence. A multivariate analysis, including clinical and metabolic factors, showed that carbohydrate antigen 19-9 and hypotaurine were independent risk factors for early recurrence ( P = 0.045 and P = 0.049, respectively). The recurrence-free survival rate 1 year after surgery with both risk factors was only 25%. CONCLUSIONS: Our results suggested that tumor hypotaurine is a potential metabolite associated with early recurrence. Carbohydrate antigen 19-9 and hypotaurine showed a vital utility for predicting early recurrence.

Tumor location, clinicopathological features, and perioperative and prognostic outcomes in patients who underwent pancreatic resection following neoadjuvant chemoradiotherapy for resectable pancreatic cancer: A retrospective study.

BACKGROUND: /Objective: Preoperative treatment of resectable pancreatic ductal adenocarcinoma (PDAC) is gaining popularity worldwide. However, the characteristics of tumors located in the pancreatic head (Ph), or those in the body or tail (Pbt), after surgery following neoadjuvant chemoradiotherapy (NACRT) remain unclear. This study aimed to evaluate and compare the clinicopathological features, perioperative outcomes, and prognosis of patients with resectable PDAC who underwent NACRT followed by curative pancreatic resection, focusing on distinguishing between Ph and Pbt PDACs. METHODS: We included 107 patients with resectable PDAC who underwent curative resection following NACRT between 2009 and 2023. Clinicopathological features, perioperative and prognostic outcomes, recurrence patterns, and prognoses were compared between Ph and Pbt PDAC groups. RESULTS: Tumors were found in the Ph and Pbt in 64 and 43 patients, respectively. Albumin levels and lymphocyte-to-monocyte ratios after NACRT were significantly lower in the Ph group than in the Pbt group. The Pbt group showed significantly higher rates of positive peritoneal lavage cytology and serosal, arterial, and portal vein invasion than the Ph group did. Overall and recurrence-free survival were similar between the two groups. The most common site of initial postoperative recurrence was the lung only in both groups; however, the rate of peritoneal dissemination only was significantly higher in the Pbt group than in the Ph group. CONCLUSIONS: The prognoses based on tumor locations in the Ph and Pbt after surgery following NACRT are similar. Following the resection of resectable Pbt PDAC, the possibility of peritoneal dissemination recurrence should be considered.

Tumor-to-blood pool ratio of 18F-fluorodeoxyglucose-positron emission tomography's standardized uptake value as a useful parameter indicating malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasm compared to the international Fukuoka guidelines: a retrospective cohort study from surgical resections.

BACKGROUND: Identifying malignant transformation in pancreatic branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) remains challenging, but the standardized uptake value (SUV) obtained from 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT has the potential to become a valuable parameter for differentiation. This study aimed to assess the effectiveness of SUV of FDG-PET/CT in distinguishing low-grade dysplasia (LGD), high-grade dysplasia (HGD), and intraductal papillary mucinous carcinoma (IPMC) within BD-IPMNs. METHODS: We assessed 58 patients with confirmed BD-IPMN undergoing surgery between 2008 and 2022. Receiver operating characteristic curves were plotted using the tumor-to-blood pool ratio (TBR) of FDG-PET/CT in two scenarios: one considering HGD + IPMC as positive and the other considering only IPMC as positive. RESULTS: In the cohort of 58 cases, there were 39 females, and the median age was 71 years. The median TBR value was 1.45 (range, 0.35-25.44). The TBRs exhibited a significant correlation with each histopathology (p < 0.001). Furthermore, in the multivariate analysis, TBR was independently significant in both scenarios, with HGD + IPMC defined as malignant (p = 0.001) and with only IPMC defined as malignant (p = 0.024). CONCLUSIONS: TBR might have the potential to serve as a valuable parameter for indicating malignant transformation in pancreatic BD-IPMNs.

Internal hernia after laparoscopic sigmoidectomy with splenic flexural mobilization and high ligation of the inferior mesenteric vein: A case report.

Several studies have recently reported the rare occurrence of internal herniation of the small bowel after laparoscopic colorectal surgery. Most cases of internal herniation after laparoscopic colorectal surgery occur due to a mesenteric defect. However, there have been no reports on the indications for closing mesenteric defects to prevent the development of an internal hernia. This study reports a case of an internal hernia of the proximal jejunum near the ligament of Treitz in a patient who underwent laparoscopic sigmoidectomy with splenic flexural mobilization and high ligation of the inferior mesenteric vein. Assessing the risk for internal herniation before completing the initial surgery is crucial. Additionally, mesenteric defect closure should be performed to prevent the development of internal hernias among patients with a potential risk.

Efficacy of neoadjuvant chemoradiotherapy followed by pancreatic resection for older patients with resectable and borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: The benefit of preoperative treatment followed by pancreatic resection in older patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. In this retrospective analysis of prospectively collected data, we evaluated the significance and safety of preoperative treatment followed by curative resection for older PDAC patients. METHODS: We evaluated 122 patients with resectable and borderline resectable PDAC who received neoadjuvant chemoradiotherapy (NACRT) followed by curative resection between 2009 and 2019. Changes in the prognostic nutritional indices during NACRT, surgical outcomes, and prognosis were compared between older (≥75 years, n = 44) and younger patients (<75 years, n = 78). RESULTS: The completion rate, adverse event rate, changes in prognostic nutritional indices during NACRT, and prognosis were similar between the groups. In multivariate analysis, an elevated C-reactive protein/albumin ratio (CRP/Alb) ≥ 33.1% during NACRT (p = 0.035) and no postoperative adjuvant chemotherapy (p = 0.041) were identified as significant predictors of overall survival. CONCLUSIONS: NACRT followed by pancreatic resection could be safely performed in older patients, with a similar prognosis as that of younger patients, despite an increased frequency of postoperative complications. Elevated CRP/Alb during NACRT and no postoperative adjuvant chemotherapy were poor prognostic factors for older patients.

Constrictive pericarditis caused by pericardial metastasis from esophageal squamous cell carcinoma: a case report.

Constrictive pericarditis is a rare condition characterized by clinical signs of right heart failure subsequent to the loss of pericardial compliance. We report a case of constrictive pericarditis due to pericardial metastasis in a patient with a history of esophageal squamous cell carcinoma that had a pathological complete response (pCR) to preoperative chemoradiotherapy. A 66-year-old woman was referred to our division for the treatment of advanced esophageal cancer. Video-assisted thoracoscopic surgery esophagectomy (VATSE) with 3-field lymphadenectomy was performed after neoadjuvant chemoradiotherapy (NAC-CRT). Pathological examination revealed no residual tumor, lymph node metastasis, lymphatic invasion, or vessel invasion. The histological treatment effect of the chemoradiotherapy was pathological complete response (pCR). Five months after surgery, the patient was admitted to a nearby hospital for the treatment of acute pericarditis. However, a month after admission, acute pericarditis progressed to constrictive pericarditis, and she was referred to our hospital for further management. Subsequently, urgent pericardiectomy was performed through a lower half sternotomy incision. After surgery, heart failure improved for a while but worsened again. The patient died 7 days after the surgery. Pathological examination of the resected pericardium revealed evidence of metastasis from squamous cell carcinoma of the esophagus. An autopsy revealed the spread of esophageal cancer to the bilateral pleura, right lung, pericardium, diaphragm, soft tissue surrounding the tracheal bifurcation, and bilateral hilar lymph nodes. Similarly, tumor cells were found in the lymphatic vessels of the pericardium and pleura. Even if pCR is achieved with NAC-CRT, as in our case, esophageal cancer may metastasize and present as constrictive pericarditis within a short period; therefore, careful patient follow-up is essential.

Efficacy and Safety of Neoadjuvant Chemoradiation Therapy Administered for 5 Versus 2 Weeks for Resectable and Borderline Resectable Pancreatic Cancer.

OBJECTIVES: Indications of preoperative treatment for resectable (R-) or borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC) are unclear, and the protocol remains to be standardized. METHODS: Included 65 patients with R- and BR-PDAC with venous involvement (V-) received neoadjuvant chemoradiotherapy with S-1 and 50 Gy of radiation as the 5-week regimen. The outcomes of this group were compared with those of 52 patients who underwent S-1 and 30 Gy of radiation as the 2-week regimen, previously collected as our prospective phase II study. RESULTS: Compared with the 2-week regimen, there were no significant differences in the rate of protocol completion, adverse events, mortality and morbidity, or R0 resection in the 5-week regimen. In subgroup analyses of R-PDAC, there were no significant differences in overall survival and recurrence-free survival between the groups. In contrast, the 5-week regimen had significantly better overall survival and recurrence-free survival than the 2-week regimen for BRV-PDAC. Similar results were observed after propensity score matching analysis. CONCLUSIONS: The 5-week regimen of neoadjuvant chemoradiotherapy has good clinical efficacy and safety for R- and BRV-PDAC. The 5-week regimen could achieve better outcomes than the 2-week regimen for BRV-PDAC. In contrast, both regimens achieved similar outcomes for R-PDAC.

Tumor metabolic alterations after neoadjuvant chemoradiotherapy predict postoperative recurrence in patients with pancreatic cancer.

OBJECTIVE: We investigated the metabolic changes in pancreatic ductal adenocarcinoma to identify the mechanisms of treatment response of neoadjuvant chemoradiation therapy. METHODS: Frozen tumor and non-neoplastic pancreas tissues were prospectively obtained from 88 patients with pancreatic ductal adenocarcinoma who underwent curative-intent surgery. Sixty-two patients received neoadjuvant chemoradiation therapy and 26 patients did not receive neoadjuvant therapy (control group). Comprehensive analysis of metabolites in tumor and non-neoplastic pancreatic tissue was performed by capillary electrophoresis-mass spectrometry. RESULTS: Capillary electrophoresis-mass spectrometry detected 90 metabolites for analysis among more than 500 ionic metabolites quantified. There were significant differences in 27 tumor metabolites between the neoadjuvant chemoradiation therapy and control groups. There were significant differences in eight metabolites [1-MethylnNicotinamide, Carnitine, Glucose, Glutathione (red), N-acetylglucosamine 6-phosphate, N-acetylglucosamine 1-phosphate, UMP, Phosphocholine] between good responder and poor responder for neoadjuvant chemoradiation therapy. Among these metabolites, phosphocholine, Carnitine and Glutathione were associated with recurrence-free survival only in the neoadjuvant chemoradiation therapy group. Microarray confirmed marked gene suppression of choline transporters [CTL1-4 (SLC44A1-44A4)] in pancreatic ductal adenocarcinoma tissue of neoadjuvant chemoradiation therapy group. CONCLUSION: The present study identifies several important metabolic consequences and potential neoadjuvant chemoradiation therapy targets in pancreatic ductal adenocarcinoma. Choline metabolism is one of the key pathways involved in recurrence of the patients with pancreatic ductal adenocarcinoma who received neoadjuvant chemoradiation therapy.

Prediction of local tumor control and recurrence-free survival in patients with pancreatic cancer undergoing curative resection after neoadjuvant chemoradiotherapy.

BACKGROUND AND OBJECTIVES: There is little data on the correlation between the reduction in fluorodeoxyglucose positron emission tomography (FDG-PET) radioactive accumulation and carbohydrate antigen 19-9 (CA19-9) levels with pathological tumor responses (PTRs) and prognosis after neoadjuvant chemoradiotherapy (NACRT) for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: This study was a retrospective analysis of prospectively collected data from 102 patients with resectable (R-) and borderline resectable (BR-) PDAC who received NACRT, followed by curative resection. Data were prospectively collected and compared between the responders and nonresponders to NACRT. RESULTS: Patients with 60% or more reduction in maximum standardized uptake value (SUVmax) on FDG-PET, with 75% or more reduction in CA19-9 levels, or with 50%-100% of tumor cells destroyed due to NACRT had significantly better recurrence-free survival (RFS) than each of the nonresponders (p = 0.028, <0.001, and 0.022, respectively). The reduction rates of SUVmax and CA19-9 levels were correlated with PTR. The combined evaluation of these biomarkers reflected RFS. CONCLUSIONS: Reduction rates of FDG uptake and CA19-9 levels were preoperative predictors of pathological response to NACRT. These biomarkers of local response had prognostic value in R-PDAC and BR-PDAC. The combined evaluation of these biomarkers allowed for reliable prediction of RFS after surgery.

Role of Short-Term Neoadjuvant Chemoradiotherapy for Potentially Resectable Pancreatic Cancer.

Although the efficacy of neoadjuvant therapies for pancreatic cancer (PDAC) is reported in recent years, ideal neoadjuvant treatment for patients with potentially resectable (R) PDAC remains uncertain. We conducted the retrospective study about the effect of short-term neoadjuvant chemoradiotherapy (sNACRT) on R PDAC. The 94 patients received curative intent pancreatectomy for R PDAC between 2000 and 2016. Among them, 31 patients received sNACRT (S1 60 mg/m2/day for 2w and RTx 30 Gy/2w). Clinical outcomes of the 31 patients with sNACRT were analyzed in comparison with 63 patients without sNACRT. The 1-, 3-, and 5-year overall survival (OS) rates were 93, 71, and 62% in the patients with sNACRT and 78, 35, and 26% in the patients without sNACRT (P = .0007), respectively. Lymph node metastasis was found in 41.9% of patients with sNACRT and 56.5% of patients without sNACRT (P = .09). Microscopic tumor infiltration at resection margins (R1) was found in no patient with sNACRT and 5 patients (7.9%) without sNACRT (P=.042). Retropancreatic infiltration (P = .04), lymphatic invasion (P = .002), plexus invasion (P = .042), and main pancreatic duct extension (P = .004) were significantly fewer in patients with sNACRT than the patients without sNACRT. The recurrences were found in 64% of patients with sNACRT (39% distant, 16% local, and 10% mix pattern) and 68% in patients without sNACRT (28% distant, 21% local, and 19% mix pattern). The recurrence patterns were significantly different (P = .008) between the groups. Short-term neoadjuvant chemoradiotherapy decreased R1 resection rate and improved OS. Short-term neoadjuvant chemoradiotherapy may provide ideal local control during the short term and improve clinical outcome of R PDAC.

Low prevalence of biliary tract cancer with defective mismatch repair genes in a Japanese hospital-based population.

Recent studies have reported that immune checkpoint inhibitors are effective against various defective mismatch repair (dMMR)/microsatellite instability-high (MSI-H) cancers. A limited number of reports are available on the frequency of dMMR/MSI-H carcinoma in biliary tract cancer (BTC), describing its clinicopathological characteristics and prognosis. The latter carcinoma is also associated with Lynch syndrome (LS). The present study was performed to investigate the frequency of patients with dMMR/MSI-H in BTC and the clinical characteristics of BTC with dMMR/MSI-H in a single institution in Japan. A total of 116 patients with BTC who underwent curative surgical resection at Kagawa University Hospital between January 2008 and December 2017 were included. The protein expression levels of the mismatch repair (MMR) genes [mutL homolog 1 (MLH1), mismatch repair endonuclease PMS2 (PMS2), MutS homolog (MSH)2 and MSH6] were assessed by immunohistochemistry (IHC) using formalin-fixed paraffin-embedded tissue specimens. Subsequently, MSI testing was performed on patients who exhibited loss of MMR protein expression. Loss of expression of one or more proteins was detected in five cases (4.3%). Loss of MLH1/PMS2 expression was observed in one case of intrahepatic cholangiocarcinoma, whereas loss of PMS2 expression was noted in one case of perihilar cholangiocarcinoma. Loss of MSH2/MSH6 and MSH6 expression was noted in two cases of distal cholangiocarcinoma and loss of PMS2 expression in one case of ampullary carcinoma. Out of the five patients, two demonstrated MSI-H. Microsatellite stability was observed in two cases and for one case, no data were available. Two MSI-H cases were patients with loss of expression of MLH1/PMS2 and MSH2/MSH6. None of the five patients exhibited a past medical history or family history of suspected LS. The frequency of dMMR in BTC was ~5%, which was similar to that reported by similar studies performed in other countries. In the present study, IHC appeared to be more useful than MSI testing for detecting MMR abnormalities with regards to the detection rate. Furthermore, there may only be a limited number of patients with BTCs who are likely to benefit from the therapeutic effects of treatment with immune checkpoint inhibitors.

Aberrant E2F activation by polyglutamine expansion of androgen receptor in SBMA neurotoxicity.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by a polyglutamine repeat (polyQ) expansion within the human androgen receptor (AR). Unlike other neurodegenerative diseases caused by abnormal polyQ expansion, the onset of SBMA depends on androgen binding to mutant human polyQ-AR proteins. This is also observed in Drosophila eyes ectopically expressing the polyQ-AR mutants. We have genetically screened mediators of androgen-induced neurodegeneration caused by polyQ-AR mutants in Drosophila eyes. We identified Rbf (Retinoblastoma-family protein), the Drosophila homologue of human Rb (Retinoblastoma protein), as a neuroprotective factor. Androgen-dependent association of Rbf or Rb with AR was remarkably potentiated by aberrant polyQ expansion. Such potentiated Rb association appeared to attenuate recruitment of histone deacetyltransferase 1 (HDAC1), a corepressor of E2F function. Either overexpression of Rbf or E2F deficiency in fly eyes reduced the neurotoxicity of the polyQ-AR mutants. Induction of E2F function by polyQ-AR-bound androgen was suppressed by Rb in human neuroblastoma cells. We conclude that abnormal expansion of polyQ may potentiate innate androgen-dependent association of AR with Rb. This appears to lead to androgen-dependent onset of SBMA through aberrant E2F transactivation caused by suppressed histone deacetylation.

Corepressive action of CBP on androgen receptor transactivation in pericentric heterochromatin in a Drosophila experimental model system.

Ligand-bound nuclear receptors (NR) activate transcription of the target genes. This activation is coupled with histone modifications and chromatin remodeling through the function of various coregulators. However, the nature of the dependence of a NR coregulator action on the presence of the chromatin environment at the target genes is unclear. To address this issue, we have developed a modified position effect variegation experimental model system that includes an androgen-dependent reporter transgene inserted into either a pericentric heterochromatin region or a euchromatic region of Drosophila chromosome. Human androgen receptor (AR) and its constitutively active truncation mutant (AR AF-1) were transcriptionally functional in both chromosomal regions. Predictably, the level of AR-induced transactivation was lower in the pericentric heterochromatin. In genetic screening for AR AF-1 coregulators, Drosophila CREB binding protein (dCBP) was found to corepress AR transactivation at the pericentric region whereas it led to coactivation in the euchromatic area. Mutations of Sir2 acetylation sites or deletion of the CBP acetyltransferase domain abrogated dCBP corepressive action for AR at heterochromatic areas in vivo. Such a CBP corepressor function for AR was observed in the transcriptionally silent promoter of an AR target gene in cultured mammalian cells. Thus, our findings suggest that the action of NR coregulators may depend on the state of chromatin at the target loci.

Activation of facultatively silenced Drosophila loci associates with increased acetylation of histone H2AvD.

H2A.Z is an evolutionarily highly conserved non-allelic variant of histone H2A. H2A.Z and its homologues have been shown to involve in both chromatin silencing and activation. Although much of our knowledge of H2A.Z biological activity has come from studies on its yeast homologue Htz1, H2A.Z appears to have more complex and diverse functions in higher eukaryotes. To investigate the involvement of H2AvD, a Drosophila homologue of mammalian H2A.Z, in mechanisms of conditional activation of facultatively silenced genes, we generated transgenic Drosophila lines expressing H2AvD fused at the C- or N-terminus with the green fluorescent protein (GFP). Using heat shock-induced gene activation and polytene chromosome puff formation as an in vivo model system, we analyzed effects of H2AvD termini modifications on transcription. We found that N-terminally fused GFP inhibited H2AvD acetylation and impaired heat shock-induced puff formation and hsp70 gene activation. Our data suggest that the N-terminal region of H2AvD plays a pivotal role in transcriptional activation and that induction of transiently silenced Drosophila loci associates with increased acetylation of H2AvD.

RNA-binding protein hoip accelerates polyQ-induced neurodegeneration in Drosophila.

Abnormal polyglutamine (polyQ) expansion in the N-terminal domain of the human androgen receptor (hAR) is known to cause spinobulbar muscular atrophy (SBMA), a hereditary human neurodegenerative disorder. To explore the molecular mechanisms of neurodegeneration in SBMA, we genetically screened modulators of neurodegeneration in a Drosophila SBMA experimental model system. We identified hoip as an accelerator of polyQ-induced neurodegeneration. We found that hoip forms a complex with 18s rRNA together nop56 and nop5 proteins, whose human homologs are known to form a snoRNP complex involved in ribosomal RNA processing. Significantly, the levels of mutant polyQ-hAR were up-regulated in a mutant line overexpressing hoip. Consistently, severe neurodegeneration phenotype (rough eye) was also observed in both nop56 and nop5 overexpression mutant lines. These findings suggest that the process of neurodegeneration induced by abnormal polyQ expansion in the hAR may be regulated by the activity of snoRNP complex.