Decreased Expression of Insulin-like Growth Factor Binding Protein-related Protein-1 (IGFBP-rP1) in Radiation-induced Mouse Hepatocellular Carcinoma

Insulin-like growth factor binding protein related protein-1(以下IGFBP-rP1)は, IGFBPファミリーに属する遺伝子で, IGFとの結合を介したIGF依存性の作用の他に, IGF非依存性の多岐にわたる作用経路の存在が示唆されている。IGFBP-rP1は乳癌や前立腺癌などの悪性腫瘍において発現の低下が認められており, 前立腺癌や骨肉腫の細胞株に導入することにより増殖抑制効果がみられることからtumor suppressor geneの可能性が示唆されている。本研究では, 肝癌の発生, 増殖におけるIGFBP-rP1の役割を明らかにするため, 放射線誘発マウス肝癌とその培養系細胞株を用いてIGFBP-rP1の発現とその機能について解析した。まずB6C3F1マウスの正常肝組織と肝癌組織におけるIGFBP-rP1の発現をノーザンブロット法で比較したところ, 肝癌組織では正常肝に比しIGFBP-rP1の発現の低下がみられた。また, 培養系細胞株では足場非依存性増殖能の強い細胞株においてIGFBP-rP1の発現低下が著明であった。そこでマウス正常肝より作製したcDNA libraryからIGFBP-rP1遺伝子をクローニングし, 発現ベクターを用いて肝癌細胞株へ導入し, その増殖能への影響について検討した。その結果, IGFBP-rP1を導入した細胞株では倍加時間の延長と細胞増殖能の低下が観察され, 同時に足場非依存性増殖能の著明な低下を認めた。さらにこの導入細胞を同系マウスに移植しその増殖能を検討したところ, 導入細胞の腫瘍形成能の低下を認めた。またヒト肝癌についてもノーザンブロット解析において, IGFBP-rP1の発現低下を認めた。これらの結果より, IGFBP-rP1の発現低下が肝癌の発生, 増殖に関与している可能性が示唆された。Insulin-like growth factor binding protein-related protein-1 (IGFBP-rP1) is a member of the IGFBP family, which was called IGFBP-7 or mac25 previously. Decreased expression of IGFBP-rP1 has been shown in breast cancer and prostatic cancer, and tumor suppressive effects of IGFBP-rP1 have been reported in prostatic cancer and osteosarcoma cell lines. In the present study, we investigated whether expression levels of IGFBP-rP1 were related to the development and the growth of radiation-induced hepatomas of B6C3F1 mice. In northern blot analysis, decreased expressions of IGFBP-rP1 gene were shown in radiation-induced mouse hepatomas compared to normal livers. In hepatoma cell lines established from these hepatomas, decreased expressions of IGFBP-rP1 were strongly related to the grade of anchorage-independent growth. In cell lines which were transfected with IGFBP-rP1cDNA, the doubling time of cell growth was increased, and the number and the size of colony formation in soft agar culture were decreased. In tumor formation assay by injecting these cells to B6C3F1 mice subcutaneously, the volume of tumors were decreased. Furthermore, the decreased expression of IGFBP-rP1 gene was observed in human hepatomas by northern blot analysis. These results may suggest that the suppression of IGFBP-rP1 is related to development and progression of mouse and human hepatomas

Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC

Purpose: The present study compared the efficacy of sunitinib and sorafenib as first-line treatment of metastatic clear cell renal cell carcinoma (mCC-RCC) with favorable or intermediate Memorial Sloan Kettering Cancer Center (MSKCC) risk. Patients and methods: Treatment-naive patients with mCC-RCC were randomized to receive open-label sunitinib followed by sorafenib (SU/SO) or sorafenib followed by sunitinib (SO/SU). The primary endpoint was first-line progression-free survival (PFS). The secondary endpoints were total PFS and overall survival (OS). Results: Of the 124 patients enrolled at 39 institutions from February 2010 to July 2012, 120 were evaluated. The median first-line PFS duration was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.42-1.08). The total PFS and OS were not significantly different between the SU/SO and SO/SU groups (27.8 and 22.6 months; HR, 0.73; 95% CI, 0.428-1.246; and 38.4 and 30.9 months; HR, 0.934; 95% CI, 0.588-1.485, respectively). The subgroup analysis revealed that the total PFS with SU/SO was superior to the total PFS with SO/SU in the patients with favorable MSKCC risk and those with Conclusions: No statistically significant differences were found in first-line PFS, total PFS, or OS between the 2 treatment arms (ClinicalTrials.gov identifier, NCT01481870)

A Clinical Trial Evaluating the Usefulness of Tailored Antimicrobial Prophylaxis Using Rectal-culture Screening Media Prior to Transrectal Prostate Biopsy: A Multicenter, Randomized Controlled Trial

The aim of this report is to introduce an on-going, multicenter, randomized controlled trial to evaluate whether tailored antimicrobial prophylaxis guided by rectal culture screening prevents acute bacterial prostatitis following transrectal prostate biopsy (TRPB). Patients will be randomized into an intervention or non-intervention group; tazobactam-piperacillin or levofloxacin will be prophylactically administered according to the results of rectal culture prior to TRPB in the intervention group whereas levofloxacin will be routinely given in the non-intervention group. The primary endpoint is the occurrence rate of acute bacterial prostatitis after TRPB. Recruitment begins in April, 2021 and the target total sample size is 5,100 participants

GNL3L stabilizes the TRF1 complex and promotes mitotic transition

Telomeric repeat binding factor 1 (TRF1) is a component of the multiprotein complex “shelterin,” which organizes the telomere into a high-order structure. TRF1 knockout embryos suffer from severe growth defects without apparent telomere dysfunction, suggesting an obligatory role for TRF1 in cell cycle control. To date, the mechanism regulating the mitotic increase in TRF1 protein expression and its function in mitosis remains unclear. Here, we identify guanine nucleotide-binding protein-like 3 (GNL3L), a GTP-binding protein most similar to nucleostemin, as a novel TRF1-interacting protein in vivo. GNL3L binds TRF1 in the nucleoplasm and is capable of promoting the homodimerization and telomeric association of TRF1, preventing promyelocytic leukemia body recruitment of telomere-bound TRF1, and stabilizing TRF1 protein by inhibiting its ubiquitylation and binding to FBX4, an E3 ubiquitin ligase for TRF1. Most importantly, the TRF1 protein-stabilizing activity of GNL3L mediates the mitotic increase of TRF1 protein and promotes the metaphase-to-anaphase transition. This work reveals novel aspects of TRF1 modulation by GNL3L

Molecular mechanisms of docetaxel resistance in prostate cancer

Docetaxel (DTX) chemotherapy offers excellent initial response and confers significant survival benefit in patients with castration-resistant prostate cancer (CRPC). However, the clinical utility of DTX is compromised when primary and acquired resistance are encountered. Therefore, a more thorough understanding of DTX resistance mechanisms may potentially improve survival in patients with CRPC. This review focuses on DTX and discusses its mechanisms of resistance. We outline the involvement of tubulin alterations, androgen receptor (AR) signaling/AR variants, ERG rearrangements, drug efflux/influx, cancer stem cells, centrosome clustering, and phosphoinositide 3-kinase/AKT signaling in mediating DTX resistance. Furthermore, potential biomarkers for DTX treatment and therapeutic strategies to circumvent DTX resistance are reviewed

Needlescopic-assisted laparoendoscopic single-site adrenalectomy

Our objective was to compare the perioperative parameters of needle-assisted and conventional laparoendoscopic single-site adrenalectomy (LESS-A). We compared 23 patients undergoing needle-assisted LESS-A with 29 patients undergoing conventional LESS-A at Hiroshima University Hospital between November 2009 and February 2014. Needle-assisted LESS-A was performed using a MiniLap instrument (Stryker, San Jose, CA, USA). We used this instrument to protectively retract the liver at the right side of the tumor and the spleen at the left side by grasping with a Securea endoscopic surgical spacer (Hogy Medical Co., Ltd., Tokyo, Japan). Various parameters including insufflation time, estimated blood loss, pain scale, resumption of oral intake, transfusion rate, and complications were analyzed using the Mann–Whitney U test. In all cases, LESS-A was completed successfully with no major intraoperative complications. Patients in both treatment groups had similar age, body mass index, sex, and laterality. Significantly, needle-assisted LESS-A was performed using the transumbilical approach rather than the subcostal approach. The insufflation time of the needle-assisted LESS-A was shorter than that of the conventional LESS-A (p = 0.0335). No patients required intraoperative or postoperative blood transfusions. Retrospective design and the small sample size are main limitations of this study. Needle-assisted LESS-A was performed safely and in a manner that mitigated many of the difficulties of LESS surgery

Needlescopic-assisted laparoendoscopic single-site adrenalectomy

Objective: Our objective was to compare the perioperative parameters of needle-assisted and conventional laparoendoscopic single-site adrenalectomy (LESS-A). Methods: We compared 23 patients undergoing needle-assisted LESS-A with 29 patients undergoing conventional LESS-A at Hiroshima University Hospital between November 2009 and February 2014. Needle-assisted LESS-A was performed using a MiniLap instrument (Stryker, San Jose, CA, USA). We used this instrument to protectively retract the liver at the right side of the tumor and the spleen at the left side by grasping with a Securea endoscopic surgical spacer (Hogy Medical Co., Ltd., Tokyo, Japan). Various parameters including insufflation time, estimated blood loss, pain scale, resumption of oral intake, transfusion rate, and complications were analyzed using the Mann–Whitney U test. Results: In all cases, LESS-A was completed successfully with no major intraoperative complications. Patients in both treatment groups had similar age, body mass index, sex, and laterality. Significantly, needle-assisted LESS-A was performed using the transumbilical approach rather than the subcostal approach. The insufflation time of the needle-assisted LESS-A was shorter than that of the conventional LESS-A (p = 0.0335). No patients required intraoperative or postoperative blood transfusions. Retrospective design and the small sample size are main limitations of this study. Conclusion: Needle-assisted LESS-A was performed safely and in a manner that mitigated many of the difficulties of LESS surgery

Longitudinal analysis of laparoendoscopic single-site adrenalectomy and conventional laparoscopic adrenalectomy regarding patient-reported satisfaction and cosmesis outcomes

Summary: Background/Objective: To compare longitudinal patient-reported cosmesis of laparoendoscopic single-site adrenalectomy (LESS-A) to that of conventional laparoscopic adrenalectomy (CLA). Methods: A total of 23, 15, and 9 patients underwent transumbilical LESS-A (TU-LESS), subcostal LESS-A (SC-LESS), and CLA, respectively. A questionnaire was administered asking the patient to assess wound pain (0: not painful to 10: very painful), satisfaction (0: not satisfied to 10: very satisfied), and cosmesis (0: very ugly to 10: very beautiful) on the basis of a visual analogue scale. We mailed questionnaires to all patients who received LESS-A and CLA at postoperative 1, 3, 6, 9, and 12 months. Results: No significant differences were observed in the pain scores between TU-LESS, SC-LESS, and CLA at every time point. In the CLA group, the cosmesis and satisfaction scores were significantly lower at postoperative 3 months (p = 0.0033, 0.0130). There were no significant inter-group differences in the cosmesis score between the three groups after postoperative 6 months. However, the satisfaction score of SC-LESS decreased after postoperative 3 months and was significantly lower at postoperative 9 and 12 months (p = 0.0333, 0.0160). The difference between the satisfaction scores of each procedure gradually increased after postoperative 6 months. Conclusion: This study is the first comprehensive longitudinal analysis of patient-reported satisfaction and cosmesis outcomes between LESS-A and CLA. The resulting data provide important insights into the improvement in satisfaction in patients who underwent TU-LESS. These findings can facilitate the treatment decision-making process for patients who are considering laparoscopic adrenalectomy. Keywords: Cosmesis, Laparoendoscopic single-site surgery, Adrenalectomy, Longitudinal stud

Endoscopic repair of the urinary bladder with magnetically labeled mesenchymal stem cells: Preliminary report

Introduction: Transurethral resection of a bladder tumor (TURBT) using a resectoscope has been standard treatment for bladder cancer. However, no treatment method promotes the repair of resected bladder tissue. The aim of this study was to examine the healing process of damaged bladder tissue after a transurethral injection of bone marrow mesenchymal stem cells (MSCs) into the bladder. An injection of magnetic MSCs meant that they accumulated in the damaged area of the bladder. Another aim of this study was to compare the acceleration effect of MSC magnetic delivery on the repair of bladder tissue with that of non-magnetic MSC injection. Methods: Using the transurethral approach to avoid opening the abdomen, electrofulguration was carried out on the anterior wall of the urinary bladder of white Japanese rabbits to mimic tumor resection. An external magnetic field directed at the injured site was then applied using a 1-tesla (T) permanent magnet. Twelve rabbits were divided into three groups. The 1 × 106 of magnetically labeled MSCs were injected into the urinary bladder with or without the magnetic field (MSC M+ and MSC M-groups, respectively), and phosphate-buffered saline was injected as the control. The effects of the injections in the three groups at 14 days were examined using 4.7-T magnetic resonance imaging (MRI) then macroscopically and histologically. The mRNA expressions of several cytokines in the repair tissues were assessed using real-time polymerase chain reaction. Results: The macroscopic findings showed the area of repair tissue in the MSC M+ group to be larger than that in either the MSC M-group or control group. MRI clearly depicted the macroscopic findings. The histological study showed that repair of the cauterized area with myofibrous tissue was significantly better in the MSC M+ group than that in either the MSC M-group or control group, although there was no significant difference in several mRNA cytokines among the three groups at 14 days after surgery. Conclusions: The magnetic delivery of MSCs shows promise as an effective, minimally invasive method of enhancing tissue regeneration after TURBT. Keywords: Urinary bladder, Cancer, Bone marrow, Mesenchymal stem cell, Transurethral resection, Regeneratio