Decline in the Conception Rate of Wild Japanese Monkeys after the Fukushima Daiichi Nuclear Power Plant Accident.

We examined the conception rate of wild Japanese monkeys (Macaca fuscata) in Fukushima City that were exposed to radiation as a result of the Fukushima Daiichi Nuclear Power Plant accident in March 2011. The conception rate in the year of delivery from 2009 to 2022 was estimated by dissecting individuals that were euthanized by the government for population control as a countermeasure against crop damage. To evaluate the effects of exposure, the cumulative exposure dose for each individual was calculated using the concentration of radiocesium deposited in the soil at the capture site and the concentration of radiocesium in muscle estimated from the aggregated transfer factor. There were no significant differences in conception rates across all age classes over time. In terms of conception rates by age class, there was a significant decrease post-exposure compared with pre-exposure in the age class ≥ 8 years, but no significant differences in the age class 5-7 years. The non-ovulation rate did not significantly differ between the pre- and post-exposure periods for any age class. Body fat index, which can affect fertility, was compared between the pre- and post-exposure periods, and no significant differences were found in either age class. In contrast, the median total cumulative exposure (cumulative internal exposure + cumulative external exposure) was significantly higher in the age class ≥ 8 years compared with the age class 5-7 years. These results suggest that the total cumulative exposure dose may be one of the reasons for the lower conception rate in the post-exposure period among the age class ≥ 8 years.

Non-Invasive Myocardial Work Indices in Infants Born to Mothers With Diabetes in Pregnancy.

BACKGROUND: This study used echocardiography to investigate non-invasive myocardial work (MCW) indices in infants born to mothers with diabetes mellitus (DM) in pregnancy (gestational DM: GDM), including those diagnosed under novel classification criteria and those with pre-existing DM.Methods and Results: This single-centered, retrospective study included 25 infants born to mothers with GDM (termed "infant with GDM"), which was diagnosed by oral glucose tolerance test results during pregnancy or the presence of diabetes before the current pregnancy. We evaluated the relationship between the infant's MCW, such as global constructive work (GCW), global work index (GWI), global work efficiency (GWE), and global wasted work (GWW), and the mother's GDM maximal HbA1c during pregnancy. HbA1c level in GDM significantly negatively correlated with GWI* (r=-0.565) and GCW* (r=-0.641). In infants with GDM, GWI and GCW were significantly higher with <6.5% HbA1c than in those with >6.5% HbA1c GDM; however, the specific-layer global longitudinal strain analyses did not show any significant differences between the groups. The pressure-strain loop in infants with >6.5% HbA1c in GDM tended to be smaller than in those infants with <6.5% HbA1c GDM. CONCLUSIONS: The hyperglycemic environment of GDM leads to impaired MCW in the infants. MCW is useful for screening for cardiac illnesses among infants with GDM. Appropriate maternal blood glucose management while maintaining HbA1c <6.5% might be beneficial for the cardiac performance of infants with GDM.

Clinical, cytological, and pathological characteristics of metastatic renal cell carcinoma to the thyroid: A study of 14 cases at a Japanese single institution.

A preoperative diagnosis of metastatic renal cell carcinoma to the thyroid (MRCCT) is important for determining clinical management but is challenging even in cases with a clinical history of renal cell carcinoma (RCC). This study aimed to elucidate the clinical, cytological, and pathological characteristics of MRCCT. Fourteen MRCCT cases extracted from 18 320 malignant thyroid tumors were included in this study. Twelve MRCCT (85.7%) occurred as solitary lesions and the most frequently suspected lesions on ultrasonography were follicular tumors. On cytology, 46.2% of cases were reported as RCC or suspected RCC; a medical history of RCC and immunocytochemistry were helpful in interpretation. RCC metastasized to a follicular adenoma in 50.0% of the solitary lesions. MRCCTs with a long interval from the initial presentation, solitary lesion, and Ki-67 labeling index <10% showed significantly longer disease-free survival. MRCCT is characterized by a long interval from the initial presentation of RCC, appearance as a solitary nodule, ultrasonographic similarity to follicular tumors, sharing cytological findings with primary thyroid tumors, and high frequency of metastasis within follicular adenoma. A long interval from the initial presentation, occurrence as a solitary lesion, and low Ki-67 labeling index may be favorable prognostic factors.

B-cell to T-cell ratio as a novel indicator in flow cytometry in the diagnosis of thyroid lymphoma.

Preoperative flow cytometry is recommended to prove the monoclonality and confirm the diagnosis of thyroid lymphoma. However, lymphoma cases without light chain restriction may also have monoclonality. The aim of our study was to identify a novel marker for thyroid lymphomas using aspirated materials for flow cytometry. We retrospectively analyzed 26 patients with primary thyroid lymphomas and 16 patients with benign lymphoproliferative lesions. The materials for flow cytometry were obtained by fine-needle aspiration cytology using a 22-gauge needle under ultrasound guidance. Light chain restriction was defined as a κ to λ ratio of less than 0.5 or more than 3.0. According to the light chain-positive rate, 25% or less and more than 25% were classified as the low and high light chain-positive rate groups, respectively. B-cell predominance was defined as a CD19 to CD4 ratio (B- to T-cell ratio) of more than 2.0. B-cell predominance was more frequently observed in lymphomas (88.5%) than in benign lymphoproliferative lesions (25.0%; p < 0.001). Light chain restriction based on the κ/λ ratio was detected in 69.2% of lymphomas, but not in benign lymphoproliferative lesions. Among lymphomas belonging to the low light chain-positive rate group, 88.9% did not exhibit light chain restriction and B-cell predominance was present. In contrast, benign lymphoproliferative lesions with B-cell predominance were not detected in the low light chain-positive rate group. B-cell predominance was a useful indicator for diagnosing thyroid lymphoma in the low light chain-positive rate group without light chain restriction.

Evaluation of E-Cadherin and ß-Catenin Immunoreactivity for Determining Undifferentiated Cells in Anaplastic Thyroid Carcinoma.

INTRODUCTION: An immunohistochemical study has occasionally been performed to diagnose anaplastic thyroid carcinoma (ATC). However, antibodies to confirm the undifferentiated nature of ATC have not yet been evaluated. The aim of this study was to evaluate E-cadherin and ß-catenin expressions in immunoreactivity to determine undifferentiated carcinoma cells in the diagnosis of ATC. METHODS: We immunohistochemically examined 29 ATCs, 30 poorly differentiated thyroid carcinomas (PDTCs), 22 well-differentiated thyroid carcinomas (WDTCs), and 3 squamous cell carcinomas. Antibodies for thyroid transcription factor-1 (TTF-1), paired-box gene 8 (PAX8), ß-catenin, and E-cadherin were used. RESULTS: All WDTCs tested positive for TTF-1, PAX8, and E-cadherin. The positive rates of TTF-1, PAX8, and E-cadherin were 93.3, 93.3, and 100%, respectively, in PDTCs and 17.2, 51.7, and 10.3%, respectively, in ATCs. WDTC expressed the lateral cell membrane staining for ß-catenin and E-cadherin, whereas PDTC showed circumferential cell membranous expression (fishnet pattern). ß-catenin cell membrane expression in ATCs is lost or discontinuous. Carcinoma cells with ß-catenin nuclear expression without cell membranous expression were scattered in 72.4% of ATCs but were not observed in the other carcinomas. CONCLUSION: We propose 3 immunohistochemical findings to determine undifferentiated carcinoma cells in the diagnosis of ATC: (1) ß-catenin nuclear expression with no or reduced cell membranous expression, (2) the loss or discontinuous pattern of E-cadherin expression, and (3) the loss of PAX8 nuclear expression.

Potential role of mobile rapid on-site evaluation® in thyroid fine-needle aspiration cytology to reduce delayed repeated aspiration.

Rapid on-site evaluation of fine-needle aspiration cytology is time-consuming and requires specialized cytopathology staff. Mobile Rose® is a newly developed device for rapid on-site evaluation of fine-needle aspiration cytology. This study aimed to investigate the potential role of Mobile Rose® in reducing delayed repeated aspiration of the thyroid. A total of 120 cytological samples were collected and observed using Mobile Rose® after fine-needle aspiration cytology between September and October 2020, with immediate assessment of minimal or no cell clusters after conventional smear preparation. After qualifying and scoring, needle washout materials were prepared using the BD CytoRichTM method and correlated with cytology results. The average turn-around time of Mobile Rose® was found to be 1.5 minutes. Sensitivity, specificity, positive predictive value, and negative predictive value were 94.4%, 100%, 100%, and 57.1%, respectively. False-negative results were attributed to small aggregates of cells that were difficult to distinguish from the background and artifacts. Mobile Rose® may represent an important innovation for rapid on-site evaluation that is fast, has high diagnostic performance, does not require the presence of specialized cytology staff, and can reduce delayed repeated aspiration of the thyroid gland. However, further minor improvements and confirmation are required.

Optimal needle size for thyroid fine needle aspiration cytology.

Concerning the needle size for thyroid fine needle aspiration cytology (FNAC), 25-27-gauge needles are generally used in Western countries. However, in Japan, the use of larger needles (21-22-gauge needles) is common. The aim of our study was to determine the optimal needle size for thyroid FNAC. We performed ultrasound-guided FNAC for 200 thyroid nodules in 200 patients using two different-sized needles (22 and 25 gauge). For each nodule, two passes with the different-sized needles were performed. The order of needle sizes was reversed for the second group of 100 nodules. The second aspiration was more painful than the first, regardless of the needle size. An association with more severe blood contamination was more frequently observed with the use of 22-gauge needles (32.0%) than with the use of 25-gauge needles (17.5%) and in the second aspiration (37.5%) than in the initial aspiration (12.0%). The initial aspiration samples were more cellular than the second aspiration samples. Regarding the unsatisfactory and malignancy detection rates, there was no statistical difference between the needles. In three of seven markedly calcified nodules, it was difficult to insert 25-gauge needles into the nodules. In terms of the diagnostic accuracy and pain, either needle size can be used. We recommend using 22-gauge needles for markedly calcified nodules because 25-gauge needles bend more easily in such cases. We demonstrated that the initial aspiration tended to obtain more cellular samples and to be less contaminated. Thus, the initial aspiration is more important and should be closely attended.

Mediator cyclin-dependent kinases upregulate transcription of inflammatory genes in cooperation with NF-κB and C/EBPß on stimulation of Toll-like receptor 9.

In eukaryotes, the Mediator complex has important roles in regulation of transcription by RNA polymerase II. Mediator is a large complex with more than 20 subunits that form head, middle, tail and CDK/cyclin modules. Among them, CDK8 and/or CDK19 (CDK8/19), and their counterpart cyclin C, form the CDK/cyclin module together with Mediator subunits MED12 and MED13. Despite evidences of both activation and repression, the precise functional roles of CDK8/19 in transcription are still elusive. Our previous results indicate that CDK8/19 recruits epigenetic regulators to repress immunoresponse genes. Here, this study focused on Toll-like receptors (TLRs), which exert innate immune responses through recognition of pathogen-associated molecular patterns and examined the functional roles of CDK8/19. As a result, CDK8/19 regulated transcription of inflammatory genes on stimulation of TLR9 in myeloma-derived RPMI8226 cells, which led to expression of inflammation-associated genes such as IL8, IL10, PTX3 and CCL2. Mediator subunits CDK8/19 and MED1, inflammation-related transcriptional activator NF-κB and C/EBPß, and general transcription factors TFIIE and TFIIB colocalized at the promoter regions of these genes under this condition. Our results show that CDK8/19 positively regulates inflammatory gene transcription in cooperation with NF-κB and C/EBPß on stimulation of TLR9.

Impact of the modification of the diagnostic criteria in the 2017 Bethesda System for Reporting Thyroid Cytopathology: a report of a single institution in Japan.

The Bethesda System for Reporting Thyroid Cytopathology has recently been revised in 2017 (TBSRTC 2017). This study aimed to evaluate the impact of modifying the diagnostic criteria in TBSRTC 2017 at a single institute. We retrospectively reviewed cytological specimens of 10,399 thyroid nodules submitted for thyroid fine-needle aspiration cytology. Among them, 56 atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) nodules, 16 suspicious for malignancy (SFM) nodules, and 8 malignant nodules were re-categorized into follicular neoplasm or suspicious for a follicular neoplasm (FN/SFN). The incidence of FN/SFN was increased by 0.8%, while that of AUS/FLUS, SFM, and malignant nodule was decreased by 0.5%, 0.2%, and 0.1%, respectively. In nine (60%) of the 15 nodules that were re-classified from AUS/FLUS to FN/SFN nodules and re-aspiration was performed, it was possible to judge whether they were benign or malignant. Of the 24 patients with FN/SFN nodules originally diagnosed with SFM or malignant, 16 were followed up without surgical resection. In conclusion, TBSRTC 2017 only caused minor changes in the incidence of each diagnostic category. TBSRTC 2017 was revised to avoid false positives owing to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) that account for >10% of papillary thyroid carcinomas; however, it is not necessary in low frequency NIFTP institutes or countries. In Japan, we propose active surveillance as an accepted option for clinically managing AUS/FLUS, FN/SFN, SFM, or malignant nodules having favorable benign clinical findings or being part of the low-risk group.

Utility of monoclonal PAX8 antibody for distinguishing intrathyroid thymic carcinoma from follicular cell-derived thyroid carcinoma.

Follicular cell-derived thyroid carcinomas, including thyroid squamous cell carcinomas (SCCs) and anaplastic carcinomas, are immunoreactive for paired-box gene 8 (PAX8), while non-follicular cell-derived thyroid carcinomas stain negative for the PAX8 antibody. Intrathyroid thymic carcinoma (ITTC) arising from the intrathyroidal ectopic thymus exhibits moderate-to-strong nuclear reactivity for polyclonal PAX8. This is difficult to understand given that PAX8 is not associated with embryonic thymic development. We aimed to determine the diagnostic significance of monoclonal PAX8 antibody in distinguishing ITTCs from follicular cell-derived thyroid carcinomas. Ten ITTCs, 14 poorly differentiated thyroid carcinomas (PDTCs), 14 thyroid SCCs, 7 thymic tissue specimens, 7 thymomas, and 1 thymic carcinoma were analyzed using antibodies against polyclonal and monoclonal PAX8, thyroid transcription factor-1, p63, and CD5. Four ITTCs (40.0%) stained positive for polyclonal PAX8; none stained positive for monoclonal PAX8. All PDTCs and 92.9% of SCCs were immunoreactive for both polyclonal and monoclonal PAX8. All PDTCs, 46.2% of SCCs, and none of the ITTCs were immunoreactive for thyroid transcription factor-1. Eight ITTCs (80.0%), but none of the PDTCs and SCCs, were immunoreactive for CD5. We are the first to show that ITTCs stain negative for monoclonal PAX8. Monoclonal PAX8 is a more reliable marker than polyclonal PAX8 for determining follicular cell origin. We conclude that monoclonal PAX8 is a useful marker for distinguishing ITTCs from PDTCs and SCCs. Monoclonal PAX8 negativity is additional evidence in support of ITTCs not being follicular cell-derived thyroid carcinomas, but having a thymic origin.

Phase 1 study of veliparib with carboplatin and weekly paclitaxel in Japanese patients with newly diagnosed ovarian cancer.

This phase 1, open-label, dose-escalation study was conducted to determine the safety, tolerability, pharmacokinetics and preliminary efficacy of veliparib with carboplatin and weekly paclitaxel in Japanese women with newly diagnosed, advanced ovarian cancer. Patients received veliparib at 100 or 150 mg b.i.d. on days 1-21 with carboplatin (area under the concentration-time curve 6 mg/mL•min) on day 1 and paclitaxel 80 mg/m2 on days 1, 8 and 15 every 3 weeks for up to 6 21-day cycles. Dose escalation followed a 3 + 3 design to determine dose-limiting toxicities, maximum tolerated dose and the recommended phase 2 dose. Nine patients (median age 62 [range 27-72] years) received a median of 5 (range 3-6) cycles of treatment (3 at 100 mg, 6 at 150 mg). There were no dose-limiting toxicities. The most common adverse events of any grade were neutropenia (100%), alopecia (89%), peripheral sensory neuropathy (78%), and anemia, nausea and malaise (67% each). Grade 3 or 4 adverse events were associated with myelosuppression. Pharmacokinetics of carboplatin/paclitaxel were similar at both veliparib doses. Response, assessed in five patients, was partial in four and complete in one (objective response rate 100%). The response could not be assessed in four patients who had no measurable disease at baseline. The recommended phase 2 dose of veliparib, when combined with carboplatin/paclitaxel, is 150 mg b.i.d. Findings from this phase 1 trial demonstrate the tolerability and safety of veliparib with carboplatin/paclitaxel, a regimen with potential clinical benefit in Japanese women with ovarian cancer.

The issues regarding postoperative adjuvant therapy and prognostic risk factors for patients with stage I-II cervical cancer: A review.

The treatment for most patients with early-stage cervical cancer involves radical hysterectomy and pelvic lymph node dissection, and indications for postoperative adjuvant therapy have been determined by evaluating the prognostic risk factors for recurrence in each case. The aim of this review is to raise and discuss the various issues that have not yet been resolved regarding the prognostic risk factors and postoperative adjuvant therapy. Several clinicopathological factors, such as tumor size, lymphovascular space involvement, deep stromal invasion, parametrial involvement and lymph node metastasis, have been identified to have prognostic significance in early-stage cervical cancer. However, this remains controversial because there is suggested to be substantial heterogeneity among patients after radical hysterectomy and lymphadenectomy and it would be difficult to define the risk groups clearly. This indicates the need to develop more convenient and accurate criteria to define risk groups. According to the currently available evidence, patients in the high-risk group should receive adjuvant concurrent chemoradiotherapy (CCRT) with cisplatin (CDDP) and fluolouracil. However, CCRT with CDDP administered weekly (CCRT-P) has instead been applied in a clinical context worldwide. Whether CCRT-P has a survival benefit compared with radiotherapy (RT) alone is unknown because no randomized phase III trials have been performed for patients in the high-risk group after radical surgery. Patients with high-risk factors have a high incidence of distant metastasis, for whom systemic chemotherapy might be a key to improving overall survival. The pivotal study that investigated the role of RT alone for patients with intermediate-risk factors after hysterectomy is the GOG092 trial. This trial showed a 47% reduction in the risk of recurrence after RT compared with no further treatment (NFT). However, the improvement in overall survival with RT did not reach statistical significance, while patients allocated to the RT group did experience an increase in severe toxicities compared with the NFT group. This could be why many physicians are reluctant to treat patients with this approach, although guidelines recommend RT for patients with intermediate-risk factors. With regard to toxicities, postoperative RT would be problematic because the organs in the pelvis targeted by RT have already been damaged by radical surgery. To reduce the toxicities, intensity-modulated radiotherapy would best be used worldwide. Further improvement in adjuvant therapy will come from enhanced definition of prognostic risk factors, better patient selection, and refinements in both local and systematic therapies.

[AN ADULT CASE OF EGG ALLERGY TREATED WITH RUSH ORAL IMMUNOTHERAPY].

A 26-year-old female patient exhibited symptoms associated with egg allergy, which had been present since early childhood. The patient requested the treatment of egg allergy and was admitted to our hospital for rush oral immunotherapy. The threshold was determined by an oral food challenge test, after positive results on a double-blind food challenge test. The patient ingested dry powder of raw egg-white 5 times per day starting with a tenth of the threshold dose (3.0mg), followed by a 1.2-times increase every time. When the amount of powder reached 1g, it was replaced with 8g of scrambled egg, after then subsequent doses were increased 1.5 times every time. The target of one chicken egg (60g) was reached on the 18th day. During treatment, minor allergic symptoms of urticarial and dyspnea were observed on two occasions, but they disappeared after oral administration of antihistamines. The result of an exercise challenge test after ingestion of egg was negative, and no allergic symptoms were observed by the ingestion of processed foods that contained egg. The patient currently receives ongoing maintenance treatment, consisting of the ingestion of one chicken egg per day; no allergic symptoms have been observed during a period of 2 year while receiving this treatment. Rush oral immunotherapy is a treatment option to be considered for adults with food allergy who were not able to acquire immune tolerance during childhood.

Association of the winged helix motif of the TFIIEα subunit of TFIIE with either the TFIIEß subunit or TFIIB distinguishes its functions in transcription.

In eukaryotes, the general transcription factor TFIIE consists of two subunits, α and ß, and plays essential roles in transcription. Structure-function studies indicate that TFIIE has three-winged helix (WH) motifs, with one in TFIIEα and two in TFIIEß. Recent studies suggested that, by binding to the clamp region of RNA polymerase II, TFIIEα-WH promotes the conformational change that transforms the promoter-bound inactive preinitiation complex to the active complex. Here, to elucidate its roles in transcription, functional analyses of point-mutated human TFIIEα-WH proteins were carried out. In vitro transcription analyses identified two classes of mutants. One class was defective in transcription initiation, and the other was defective in the transition from initiation to elongation. Analyses of the binding of this motif to other general transcription factors showed that the former class was defective in binding to the basic helix-loop-helix motif of TFIIEß and the latter class was defective in binding to the N-terminal cyclin homology region of TFIIB. Furthermore, TFIIEα-WH bound to the TFIIH XPB subunit at a third distinct region. Therefore, these results provide further insights into the mechanisms underlying RNA polymerase II activation at the initial stages of transcription.

Human mediator MED17 subunit plays essential roles in gene regulation by associating with the transcription and DNA repair machineries.

In eukaryotes, holo-Mediator consists of four modules: head, middle, tail, and CDK/Cyclin. The head module performs an essential function involved in regulation of RNA polymerase II (Pol II). We studied the human head module subunit MED17 (hMED17). Recent structural studies showed that yeast MED17 may function as a hinge connecting the neck and movable jaw regions of the head module to the fixed jaw region. Luciferase assays in hMED17-knockdown cells showed that hMED17 supports transcriptional activation, and pulldown assays showed that hMED17 interacted with Pol II and the general transcription factors TFIIB, TBP, TFIIE, and TFIIH. In addition, hMED17 bound to a DNA helicase subunit of TFIIH, XPB, which is essential for both transcription and nucleotide excision repair (NER). Because hMED17 associates with p53 upon UV-C irradiation, we treated human MCF-7 cells with either UV-C or the MDM2 inhibitor Nutlin-3. Both treatments resulted in accumulation of p53 in the nucleus, but hMED17 remained concentrated in the nucleus in response to UV-C. hMED17 colocalized with the NER factors XPB and XPG following UV-C irradiation, and XPG and XPB bound to hMED17 in vitro. These findings suggest that hMED17 may play essential roles in switching between transcription and NER.

Efficacy and safety of olanzapine combined with aprepitant, palonosetron, and dexamethasone for preventing nausea and vomiting induced by cisplatin-based chemotherapy in gynecological cancer: KCOG-G1301 phase II trial.

PURPOSE: Olanzapine is effective in chemotherapy-induced nausea and vomiting (CINV). In patients receiving highly emetogenic chemotherapy (HEC), its efficacy was reported as rescue therapy for breakthrough emesis refractory to triplet therapy (palonosetron, aprepitant, and dexamethasone). However, its preventive effects with triplet therapy for CINV are unknown. This study aimed to investigate efficacy and safety of preventive use of olanzapine with triplet therapy for CINV of HEC. METHODS: This study is a prospective multicenter study conducted by Kansai Clinical Oncology Group. Forty chemo-naïve gynecological cancer patients receiving HEC with cisplatin (≥50 mg/m(2)) were enrolled. Oral olanzapine (5 mg) was administered with triplet therapy a day prior to cisplatin administration and on days 1-5. The primary endpoint was complete response (no vomiting and no rescue) rate for the overall phase (0-120 h post-chemotherapy). Secondary endpoints were complete response rate for acute phase (0-24 h post-chemotherapy) and delayed phase (24-120 h post-chemotherapy) and complete control (no vomiting, no rescue, and no significant nausea) rate and total control (no vomiting, no rescue, and no nausea) rate for each phase. These endpoints were evaluated during the first cycle of chemotherapy. RESULTS: Complete response rates for acute, delayed, and overall phases were 97.5, 95.0, and 92.5 %, respectively. Complete control rates were 92.5, 87.5, and 82.5 %, respectively. Total control rates were 87.5, 67.5, and 67.5 %, respectively. There were no grade 3 or 4 adverse events. CONCLUSIONS: Preventive use of olanzapine combined with triplet therapy gives better results than those from previously reported studies of triplet therapy.

Adjuvant chemotherapy versus concurrent chemoradiotherapy for high-risk cervical cancer after radical hysterectomy and systematic lymphadenectomy.

BACKGROUND: The aims of this study were to evaluate the efficacy and toxicity of chemotherapy (CT) compared with concurrent chemoradiotherapy (CCRT) after radical hysterectomy and lymphadenectomy in high-risk patients with early-stage cervical cancer and to evaluate whether the radicality of the lymphadenectomy would affect the outcome and toxicity of postoperative adjuvant therapy. METHODS: The cases of all patients (n = 393) with FIGO IB1-IIB cervical cancer who were treated by radical surgery at Shizuoka Cancer Center between January 2002 and December 2013 were reviewed. Of these, 111 patients met the inclusion criteria for this retrospective study: (1) high risk for occurrence due to pathologically confirmed parametrial invasion and/or pelvic lymph node metastasis; (2) postoperative treatment with adjuvant CT or CCRT. The clinical data of these patients were reviewed. RESULTS: Of the 111 patients, 37 and 74 patients underwent CT and CCRT, respectively. The 4-year progression-free survival rate [PFS; 71.7 (CT) vs. 68.3 % (CCRT)] and overall survival rate [76.0 (CT) vs. 82.7 % (CCRT)] did not differ significantly between the two groups. The CT group contained significantly more patients with severe neutropenia than the CCRT group (66.7 vs. 23.0 %, respectively; p < 0.001), and the CCRT group contained significantly more patients with diarrhea than the CT group (10.8 vs. 0 %, respectively; p = 0.04). The patients who had ≥40 lymph nodes dissected (≥40 group) had higher PFS than the patients who had <40 lymph nodes dissected (<40 group) (73.2 vs. 64.2 %, respectively), although the difference was not significant. In the CT group, there was no significant association between the number of dissected lymph nodes and severe toxicities. However, in the CCRT group, significantly more vomiting (p = 0.046) and edema (p = 0.046) occurred in the ≥40 group than in the <40 group. CONCLUSIONS: Chemotherapy after surgery for high-risk patients had similar efficacy and a different toxicity profile compared with CCRT, and a more radical surgical procedure would improve the survival outcome. However, CCRT was associated with worse toxicity than CT. We advocate a prospective randomized study to compare CT with CCRT for patients with high-risk factors for recurrence.

[Successful Case of Coil Embolization for Repeated Pulmonary Arterial Bleeding in Postoperative Empyema with Bronchopleural Fistula].

A 78-year-old woman underwent right S6 segmentectomy and upper lobe partial resection for adenocarcinoma. About 11 months after the operation, she was diagnosed as having empyema with bronchopleural fistula and open thoracotomy was performed. From the following day, active hemorrhage from the pulmonary artery into the thoracic cavity(500~800 ml) repeated. Tamponade, surgical treatment such as putting hemostasis sheet, or covering with a pedicled latissimus dorsi muscle flap could not prevent rebleeding. Therefore selective pulmonary artery coil embolization was performed, after that the rebleeding did not occur.

Mediator MED18 subunit plays a negative role in transcription via the CDK/cyclin module.

The Mediator complex (Mediator) is conserved among eukaryotes and is comprised of head, middle, tail and CDK/cyclin modules. The head module has received the most attention because its interaction with RNA polymerase II (Pol II) and the general transcription factors TFIIH and TBP facilitates phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of Pol II. We studied the human head module subunit hMED18 to elucidate how Mediator is involved in both transcriptional activation and repression. siRNA-mediated hMED18 depletion augmented transcription, indicating that hMED18 functions in transcriptional repression. Treatment of cells with two histone deacetylase (HDAC) inhibitors, the HDAC inhibitor trichostatin A (TSA) and the SIRT inhibitor nicotinamide showed that this repression was not caused by those HDAC activities. A screen for hMED18-target genes showed that the promoters for cap RNA methyltransferase RNMT-activating mini protein (RAM/FAM103A1) and divalent metal transporter 1 (DMT1/SLC11A2) genes were bound by hMED18. Depletion of hMED18 showed hMED18 and the middle module subunit hMED1 were lost from the promoters of those genes, whereas the CDK/cyclin module subunit hCDK8 remained bound. This indicates a novel transcriptional repression mechanism of hMED18 mediated by hCDK8 and further a novel positive role of free CDK/cyclin module in transcriptional activation. [Correction added on 12 June 2014, after first online publication: SLC11A2 amended from SCL11A2.].

Transcription cofactor PC4 plays essential roles in collaboration with the small subunit of general transcription factor TFIIE.

In eukaryotes, positive cofactor 4 (PC4) stimulates activator-dependent transcription by facilitating transcription initiation and the transition from initiation to elongation. It also forms homodimers and binds to single-stranded DNA and various transcriptional activators, including the general transcription factor TFIIH. In this study, we further investigated PC4 from Homo sapiens and the nematode Caenorhabditis elegans (hPC4 and cePC4, respectively). hPC4 strongly stimulated transcription on a linearized template, whereas it alleviated transcription on a supercoiled template. Transcriptional stimulation by PC4 was also alleviated by increasing the amount of TFIID. GST pull-down studies with general transcription factors indicated that both hPC4 and cePC4 bind strongly to TFIIB, TFIIEß, TFIIFα, TFIIFß and TFIIH XPB subunits and weakly to TBP and TFIIH p62. However, only hPC4 bound to CDK7. The effect of each PC4 on transcription was studied in combination with TFIIEß. hPC4 stimulated both basal and activated transcription, whereas cePC4 primarily stimulated activated transcription, especially in the presence of TFIIEß from C. elegans. Finally, hPC4 bound to the C-terminal region of hTFIIEß adjacent to the basic region. These results indicate that PC4 plays essential roles in the transition step from transcription initiation to elongation by binding to melted DNA in collaboration with TFIIEß.