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Article ; Online: Pdx1 expression in hematopoietic cells activates

Walcheck, Morgan T / Nukaya, Manabu / Ranheim, Erik A / Matkowskyj, Kristina A / Ronnekleiv-Kelly, Sean

2023 Volume 64, Issue 6, Page(s) 1112–1122

Abstract: The highly utilized KC model has a reported lethality rate of about 30%, which has been attributed to pancreas cancer. However, a competing cause of lethality in KC mice is due to the activation of mutant- ...

Abstract	The highly utilized KC model has a reported lethality rate of about 30%, which has been attributed to pancreas cancer. However, a competing cause of lethality in KC mice is due to the activation of mutant-
MeSH term(s)	Animals ; Mice ; Mice, Transgenic ; Mutation ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism
Chemical Substances	Cre recombinase (EC 2.7.7.-) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; pancreatic and duodenal homeobox 1 protein ; Hras protein, mouse (EC 3.6.5.2)
Language	English
Publishing date	2023-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1042374-6
ISSN	1029-2403 ; 1042-8194
ISSN (online)	1029-2403
ISSN	1042-8194
DOI	10.1080/10428194.2023.2202788
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Article: Aryl hydrocarbon receptor knockout accelerates PanIN formation and fibro-inflammation in a mutant

Walcheck, Morgan T / Schwartz, Patrick B / Carrillo, Noah D / Matkowsky, Kristina A / Nukaya, Manabu / Bradfield, Christopher A / Ronnekleiv-Kelly, Sean M

bioRxiv : the preprint server for biology

2023

Abstract: Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of ... ...

Abstract	Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear. Therefore, we evaluated the role of AHR in the development of PDAC Methods: We created a global AHR-null, mutant Results: We found a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A Conclusion: These findings show the loss of AHR results in heightened
Language	English
Publishing date	2023-02-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.02.01.526625
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Article ; Online: Chronic jetlag accelerates pancreatic neoplasia in conditional

Schwartz, Patrick B / Walcheck, Morgan T / Nukaya, Manabu / Pavelec, Derek M / Matkowskyj, Kristina A / Ronnekleiv-Kelly, Sean M

Chronobiology international

2023 Volume 40, Issue 4, Page(s) 417–437

Abstract: Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ...

Abstract	Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma - a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated
MeSH term(s)	Animals ; Humans ; Mice ; Carcinoma, Pancreatic Ductal/genetics ; Carcinoma, Pancreatic Ductal/metabolism ; Carcinoma, Pancreatic Ductal/pathology ; Circadian Rhythm/genetics ; Obesity ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism
Chemical Substances	Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Hras protein, mouse (EC 3.6.5.2)
Language	English
Publishing date	2023-03-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	998996-1
ISSN	1525-6073 ; 0742-0528
ISSN (online)	1525-6073
ISSN	0742-0528
DOI	10.1080/07420528.2023.2186122
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Article ; Online: Robot-assisted radical nephrectomy with inferior vena cava thrombectomy: a case report.

Takahara, Kiyoshi / Takenaka, Masashi / Zennami, Kenji / Nukaya, Takuhisa / Ichino, Manabu / Sasaki, Hitomi / Sumitomo, Makoto / Shiroki, Ryoichi

Translational cancer research

2023 Volume 12, Issue 12, Page(s) 3792–3798

Abstract: Background: Recently, robot-assisted surgery has been widely used to treat several urological cancers. Robot-assisted radical nephrectomy (RARN) was approved by the health insurance system in April 2022; however, RARN with inferior vena cava tumor ... ...

Abstract	Background: Recently, robot-assisted surgery has been widely used to treat several urological cancers. Robot-assisted radical nephrectomy (RARN) was approved by the health insurance system in April 2022; however, RARN with inferior vena cava tumor thrombectomy (IVCTT) is still challenging. Also, its safety and feasibility have not yet been established owing to lack of literature, especially in Japan. Case description: We performed RARN with IVCTT in four patients between April 2022 and March 2023 at Fujita Health University Hospital. To reduce the risk of tumor embolism and major hemorrhage, an "IVC-first, kidney-last" robotic technique was developed. The safety and feasibility of RARN with IVCTT were evaluated by assessing the perioperative outcomes. Three women and one man were enrolled in this study. The median age was 72 years, and the tumor was on the right side in all cases. According to the Mayo Clinic thrombus classification, two patients were classified as level I, and the others were classified as level II. The two patients at level I did not undergo presurgical treatments, whereas the others at level II underwent presurgical treatments, which were combinations of tyrosine kinase inhibitors and immune-checkpoint inhibitors. The median operation and console times were 341 and 247 min, respectively. The median bleeding volume was 577 mL, and no complications beyond grade III of the Clavien-Dindo classification were observed. The median length of postoperative hospital stay was 10 days. Conclusions: Although the sample size was relatively small, we demonstrated the safety and feasibility of RARN with IVCTT in the Japanese population.
Language	English
Publishing date	2023-12-06
Publishing country	China
Document type	Case Reports
ZDB-ID	2901601-0
ISSN	2219-6803 ; 2218-676X
ISSN (online)	2219-6803
ISSN	2218-676X
DOI	10.21037/tcr-23-855
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Article ; Online: The circadian clock is disrupted in pancreatic cancer.

Schwartz, Patrick B / Nukaya, Manabu / Berres, Mark E / Rubinstein, Clifford D / Wu, Gang / Hogenesch, John B / Bradfield, Christopher A / Ronnekleiv-Kelly, Sean M

PLoS genetics

2023 Volume 19, Issue 6, Page(s) e1010770

Abstract: Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, ... ...

Abstract	Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.
MeSH term(s)	Animals ; Mice ; Humans ; Circadian Clocks/genetics ; Circadian Rhythm/genetics ; Minocycline ; Pancreatic Neoplasms/genetics ; ARNTL Transcription Factors/genetics ; ARNTL Transcription Factors/metabolism ; Pancreatic Neoplasms
Chemical Substances	Minocycline (FYY3R43WGO) ; ARNTL Transcription Factors
Language	English
Publishing date	2023-06-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010770
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Article ; Online: The Role of Lymph Node Dissection in Patients With Muscle-Invasive Bladder Cancer Who Underwent Radical Cystectomy Following Neoadjuvant Chemotherapy.

Zennami, Kenji / Takahara, Kiyoshi / Nukaya, Takuhisa / Takenaka, Masashi / Ichino, Manabu / Sasaki, Hitomi / Kusaka, Mamoru / Sumitomo, Makoto / Shiroki, Ryoichi

Clinical genitourinary cancer

2023 Volume 22, Issue 2, Page(s) 1–9

Abstract: Background: The interaction between lymph node dissection (LND) during radical cystectomy (RC) and neoadjuvant chemotherapy (NAC) remains unclear. This study aimed to evaluate the role of LND in patients undergoing RC after NAC.: Patients and methods!# ...

Abstract	Background: The interaction between lymph node dissection (LND) during radical cystectomy (RC) and neoadjuvant chemotherapy (NAC) remains unclear. This study aimed to evaluate the role of LND in patients undergoing RC after NAC. Patients and methods: We retrospectively analyzed 259 patients with muscle-invasive bladder cancer (MIBC) who underwent RC following NAC at Fujita Health University Hospital and Fujita Health University Okazaki Medical Center between 2010 and 2022. Baseline characteristics, pathological outcomes, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were compared between propensity score (PS)-matched cohorts. Results: PS matching analysis resulted in 94 matched pairs from the adequate (standard or extended template) and inadequate (limited template or unilateral- or no-LND) LND groups. The median number of dissected nodes was significantly higher in the adequate LND group than in the inadequate LND group (19 vs. 5, P < .001). Similarly, a higher pathological node-positive rate (ypN+) was observed in the adequate group than in the inadequate group (18.1% vs. 7.4%, P = .03). The adequate LND group identified more ypN+ with ≤ ypT1 cases than the inadequate group (4 vs. 1). There were no statistically significant differences between the adequate and inadequate groups in RFS (P = .94), CSS (P = .54), and OS (P = .65). Subgroup analysis also showed comparable survival rates, even in patients with ≥ pT3 or cN+ disease. ypN+ was an independent predictor of OS in the Cox regression analysis, while adequate LND and the number of lymph nodes removed (≥10 or ≥15) were not associated with survival. Conclusions: Although adequate LND did not show a significant therapeutic effect in RC after NAC, adequate LND may have an important diagnostic role in detecting ypN+, which is a robust predictor, and is a useful biomarker to perform appropriate adjuvant immunotherapy especially in ≤ ypT1 cases.
MeSH term(s)	Humans ; Cystectomy/methods ; Neoadjuvant Therapy ; Retrospective Studies ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/surgery ; Lymph Node Excision/methods ; Lymph Nodes/surgery ; Lymph Nodes/pathology ; Muscles/pathology
Language	English
Publishing date	2023-06-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2225121-2
ISSN	1938-0682 ; 1558-7673
ISSN (online)	1938-0682
ISSN	1558-7673
DOI	10.1016/j.clgc.2023.06.016
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Zs.A 6168: Show issues

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Article ; Online: DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

Ma, Rosanna K / Tsai, Pei-Yin / Farghli, Alaa R / Shumway, Alexandria / Kanke, Matt / Gordan, John D / Gujral, Taranjit S / Vakili, Khashayar / Nukaya, Manabu / Noetzli, Leila / Ronnekleiv-Kelly, Sean / Broom, Wendy / Barrow, Joeva / Sethupathy, Praveen

PLoS genetics

2024 Volume 20, Issue 3, Page(s) e1011216

Abstract: Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene ... ...

Abstract	Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.
MeSH term(s)	Adolescent ; Humans ; Young Adult ; Carcinoma, Hepatocellular/genetics ; Carcinoma, Hepatocellular/pathology ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/genetics ; HSP40 Heat-Shock Proteins/genetics ; HSP40 Heat-Shock Proteins/metabolism ; Liver Neoplasms/metabolism ; RNA, Long Noncoding/genetics ; RNA, Long Noncoding/metabolism
Chemical Substances	Cyclic AMP-Dependent Protein Kinase Catalytic Subunits (EC 2.7.11.11) ; DNAJB1 protein, human ; HSP40 Heat-Shock Proteins ; PRKACA protein, human (EC 2.7.11.11) ; RNA, Long Noncoding ; LINC00473 RNA, human
Language	English
Publishing date	2024-03-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1011216
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Article ; Online: Older versus younger patients in robot-assisted radical cystectomy with intracorporeal ileal conduit comparing safety and clinical outcomes.

Sowanthip, Dutsadee / Zennami, Kenji / Bejrananda, Tanan / Nukaya, Takuhisa / Takenaka, Masashi / Ichino, Manabu / Takahara, Kiyoshi / Sasaki, Hitomi / Kusaka, Mamoru / Sumitomo, Makoto / Shiroki, Ryoichi

International journal of urology : official journal of the Japanese Urological Association

2024 Volume 31, Issue 4, Page(s) 370–378

Abstract: Objective: To evaluate the safety and efficacy of robot-assisted radical cystectomy using an intracorporeal ileal conduit in older compared to younger patients.: Methods: We retrospectively analyzed 122 patients who underwent robot-assisted radical ... ...

Abstract	Objective: To evaluate the safety and efficacy of robot-assisted radical cystectomy using an intracorporeal ileal conduit in older compared to younger patients. Methods: We retrospectively analyzed 122 patients who underwent robot-assisted radical cystectomy with an intracorporeal ileal conduit at Fujita Health University Hospital and Fujita Health University Okazaki Medical Center between 2012 and 2022. Patients were categorized into two groups: older (age ≥ 75 years; n = 53) and younger (age < 75 years; n = 69). Perioperative outcomes, complications, recurrence-free survival, cancer-specific survival, and overall survival were compared between the cohorts. Results: The groups had no significant differences in perioperative outcomes, such as estimated blood loss, operative time, and blood transfusion rate. However, hospital stay was longer in the older patients than in the younger group (19 vs. 16 days; p < 0.001). The 30-day minor and major complication rates were 33.3% and 13.0%, respectively, for the younger group and 50.9% and 9.4% for the older group (p = 0.11). Urinary tract infection and bowel ileus were the most common complications in both groups. No significant differences were observed in recurrence-free survival, cancer-specific survival, and overall survival between the groups (p = 0.58, p = 0.75, and p = 0.78), and subgroup analysis in ≥cT3 revealed the older group tended to have poorer cancer-specific survival and overall survival (p = 0.07 and p = 0.01). Multivariate analysis indicated that older age was not associated with high-grade complications and cancer-specific survival. Conclusions: Robot-assisted radical cystectomy with an intracorporeal ileal conduit is a safe and effective treatment option for older patients.
MeSH term(s)	Humans ; Aged ; Cystectomy/adverse effects ; Robotics ; Retrospective Studies ; Urinary Bladder Neoplasms ; Robotic Surgical Procedures/adverse effects ; Postoperative Complications/epidemiology ; Postoperative Complications/etiology ; Postoperative Complications/surgery ; Urinary Diversion/adverse effects ; Treatment Outcome
Language	English
Publishing date	2024-01-05
Publishing country	Australia
Document type	Journal Article
ZDB-ID	1328401-0
ISSN	1442-2042 ; 0919-8172
ISSN (online)	1442-2042
ISSN	0919-8172
DOI	10.1111/iju.15377
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Zs.A 4460: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Functional Outcomes after Selective Clamping in Robot-Assisted Partial Nephrectomy.

Takahara, Kiyoshi / Kusaka, Mamoru / Nukaya, Takuhisa / Takenaka, Masashi / Zennami, Kenji / Ichino, Manabu / Sasaki, Hitomi / Sumitomo, Makoto / Shiroki, Ryoichi

Journal of clinical medicine

2022 Volume 11, Issue 19

Abstract: This study aimed to assess the risks and benefits of selective clamping in robot-assisted partial nephrectomy (RAPN). We retrospectively analyzed 372 patients who had undergone RAPN at our hospital between July 2010 and March 2021. After propensity score ...

Abstract	This study aimed to assess the risks and benefits of selective clamping in robot-assisted partial nephrectomy (RAPN). We retrospectively analyzed 372 patients who had undergone RAPN at our hospital between July 2010 and March 2021. After propensity score matching between the full and selective clamping groups, perioperative outcomes and postoperative preservation ratio of the estimated glomerular filtration rate (eGFR) were compared at 6 and 12 months of follow-up. After propensity score matching, we evaluated 47 patients from each group. While no significant differences were observed in surgical time, warm ischemia time, or incidence rates of all grades of complications between the two cohorts, the estimated blood loss (EBL) was significantly lower in the full clamping group than in the selective clamping group (30 vs. 60,
Language	English
Publishing date	2022-09-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm11195648
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Article: Perioperative and long-term functional outcomes of robot-assisted versus open partial nephrectomy: A single-center retrospective study of a Japanese cohort.

Takahara, Kiyoshi / Fukaya, Kosuke / Nukaya, Takuhisa / Takenaka, Masashi / Zennami, Kenji / Ichino, Manabu / Sasaki, Hitomi / Sumitomo, Makoto / Shiroki, Ryoichi

Annals of medicine and surgery (2012)

2022 Volume 75, Page(s) 103482

Abstract: Objective: This study aimed to compare the perioperative and long-term functional outcomes between robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) in Japanese patients.: Methods: We retrospectively analyzed 242 patients ... ...

Abstract	Objective: This study aimed to compare the perioperative and long-term functional outcomes between robot-assisted partial nephrectomy (RAPN) and open partial nephrectomy (OPN) in Japanese patients. Methods: We retrospectively analyzed 242 patients who underwent either RAPN or OPN between 2007 and 2017 at our hospital. Propensity score matching was carried out between the two groups at a ratio of 1:1. Perioperative outcomes and postoperative estimated glomerular filtration rates (eGFR) were compared at one and three years of follow-up. Results: After propensity score matching, we evaluated 39 patients from each group. The ischemia duration of the RAPN group was significantly shorter than that of the OPN group (18 vs. 24, Conclusion: RAPN resulted in shorter ischemia durations and lower rates of EBL than did OPN; however, no differences in long-term renal function were observed between RAPN and OPN in our propensity-score matched Japanese cohort.
Language	English
Publishing date	2022-03-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2745440-X
ISSN	2049-0801
ISSN	2049-0801
DOI	10.1016/j.amsu.2022.103482
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