Search

Supplementary Data from EP300 Selectively Controls the Enhancer Landscape of MYCN-Amplified Neuroblastoma

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells.Significance:EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner.This article is highlighted in the In This Issue feature, p. 587

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL.

Acute pancreatitis is an acute inflammatory process of the pancreas that is becoming an increasingly common clinical issue. The most frequent underlying etiologies include gallstones and chronic alcohol use, which account for more than two-thirds of cases. We recently experienced a rare case of acute myeloid leukemia (AML) presenting with recurrent acute pancreatitis, which we later discovered was caused by diffusely infiltrating extramedullary sarcoma in the pancreas. Comprehensive analysis of previous cases of AML presenting as acute pancreatitis suggested involvement of cytogenetic alterations in chromosome 16 in its pathogenesis. Further improvement in management of acute pancreatitis is needed, and clinicians should note that this occasionally fatal condition can be the initial and only manifestation of AML. In practice, prompt initiation of intensive chemotherapy is critical for treating such cases of AML-induced acute pancreatitis.

Plasma cell leukemia is a rare yet aggressive form of multiple myeloma characterized by high levels of plasma cells circulating in the peripheral blood. We recently experienced a case of plasma cell leukemia that had been in stringent complete remission for nine years after autologous stem cell transplantations with subsequent courses of lenalidomide maintenance therapy, and then relapsed as an extramedullary plasmacytoma in the central nervous system. Assessment of the bone marrow did not prove proliferation of plasma cells at relapse, but imbalanced elevation of serum levels of free light chains was observed without changes in other clinical biomarkers including immunoglobulin levels. Salvage chemotherapy with isatuximab, pomalidomide, and dexamethasone (IsaPD) was promptly initiated. After two courses of IsaPD, significant remission was achieved and the neuronal symptoms completely resolved. When excessive serum levels of clonotypic free light chains are noted, their significance should be carefully assessed even when plasma cell propagation in the bone marrow is not observed. In such cases, hematologists should search for extramedullary proliferation of plasma cells, including in the immune-privileged central nervous system.

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest‐derived immature cells. The prognosis of patients with high‐risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti‐tumor effects of CD146‐targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA‐mediated knockdown of CD146, or treatment with an anti‐CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor‐kappa B signaling pathway. Furthermore, the anti‐CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma., Targeting CD146 inhibits in vitro proliferation of neuroblastoma (NB) cells and in vivo growth of NB tumors. Exposure of NB cells to the anti‐CD146 antibody led to a significant reduction in survival and anchorage‐independent growth. Intraperitoneal injection of the anti‐CD146 antibody into immunodeficient mice for ~50 d led to a significant inhibition of tumor growth.

Differentiation therapy is a less toxic but still a very effective treatment for a subset of acute myeloid leukaemia (AML) cases. With the goal to identify novel compounds that can effectively and safely induce the terminal differentiation of non-acute promyelocytic leukaemia (APL) AML cells, we performed a chemical screening and identified albendazole (ABZ), a widely used anti-helminthic drug, as a promising lead compound that can differentiate non-APL AML cells by stimulating the Krüppel-like factor 4-dihydropyrimidinase-like 2A (KLF4-DPYSL2A) differentiation axis to the monocytes. Our in vitro and in vivo findings demonstrate that ABZ is an attractive candidate drug as a novel differentiation chemotherapy for patients with non-APL AML.

We present the transfer of the spatially variant polarization of topologically structured light to the spatial spin texture in a semiconductor quantum well. The electron spin texture, which is a circular pattern with repeating spin-up and spin-down states whose repetition rate is determined by the topological charge, is directly excited by a vector vortex beam with a spatial helicity structure. The generated spin texture efficiently evolves into a helical spin wave pattern owing to the spin-orbit effective magnetic fields in the persistent spin helix state by controlling the spatial wave number of the excited spin mode. By tuning the repetition length and azimuthal angle, we simultaneously generate helical spin waves with opposite phases by a single beam., 6 pages, 4 figures

Reactivation of Epstein-Barr virus (EBV) has been considered a very rare event among patients on immunomodulatory drugs (IMiDs) such as lenalidomide, and an association between the two has not well been recognized. We have recently experienced a rare case of multiple myeloma in which the patient had suffered EBV reactivation during long-term lenalidomide maintenance therapy. The patient subsequently developed EBV-associated lymphoproliferative disease (LPD) as well as EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), which was fatal despite intensive treatment. Although rare, clinicians should be aware that such fatal EBV reactivation could occur as a minor yet critical complication of long-term maintenance therapy with IMiDs in multiple myeloma patients. Regular monitoring and early detection of EBV reactivation would be beneficial for these patients, so that proper diagnostic examinations can be initiated without delay.

Recently, we directly observed the out-of-plane Dresselhaus spin–orbit (SO) interaction field and extracted the SO coefficient β from InGaAs (110) quantum wells (QWs). However, the extracted β was much larger than that of the (001) QWs, which yielded an in-plane Dresselhaus SO field. In this study, we perform Monte-Carlo simulations and reproduce the results of time-resolved and spatiotemporally resolved Kerr rotation measurements in InGaAs (110) QWs. The results conclusively show that InGaAs (110) QWs have a strong out-of-plane Dresselhaus SO field as compared with (001) QWs.

INTRODUCTION: The aim of this study is to characterize health related quality of life (HRQOL) in Japanese patients after bladder cancer surgery and to perform cross-cultural comparison between Japanese and American patients. METHODS: Firstly, we cross-sectionally assessed HRQOL of 371 patients in Japan using the Bladder Cancer Index (BCI-Japanese). HRQOL of the four groups of patients (native bladder without intravesical therapy, native bladder with intravesical therapy, cystectomy with ileal conduit, and cystectomy with neobladder) were assessed. Secondly, we compared the Japanese with the American cohort (n = 315) from the original BCI paper. After adjusting for age and gender, the differences in each BCI subdomain score was analyzed. RESULTS: Among Japanese patients, the urinary domain function score was significantly lower among the cystectomy with neobladder group, compared to the cystectomy with ileal conduit group (p

Defining padring and its pad interconnections is one of the most time consuming steps of a microcontroller SoC design. Also, multiple device features plus testability in limited pinout packages entails more functions shared per pin. As such, the number of padring connections and complexity exponentially grows at each new design. This paper describes a methodology to configure pad connections and select correct pad cells. The methodology works out technology and function definitions for each pin using new and previous designs data stored in a metadata database in order to generate the padring RTL code for the SoC. This methodology was proven with Freescale microcontrollers, among them to check the padring connection of the commercial microcontroller MC9S08MP16 [1], and was used to implement both MC9S08QB8 [2] and MC9S08SC4 [3] microcontrollers, which resulted in reduced design time in order of 10 folds, along with high quality generated RTLs.

Introduction We validated a Japanese version of the Bladder Cancer Index (BCI) as a tool for measuring health-related quality of life (HRQOL) in bladder cancer patients treated with various surgical procedures. Methods The reliability and validity of the Japanese BCI were examined in 397 Japanese patients with bladder cancer via cross-sectional analysis. The patients simultaneously completed the Short Form (SF)-12, EQ-5D, and the Functional Assessment of Cancer Therapy-General and Bladder (FACT-G and FACT-BL). The differences in BCI subscales among various treatment groups were analyzed. Results This study involved 397 patients (301 males and 96 females), with a mean age of 70 years and a median disease duration of 29 months (IQR: 12–66 months). Of these patients, 221 underwent transurethral resection of a bladder tumor, and 176 patients underwent radical cystectomy (ileal conduit: 101 patients, ileal neobladder: 49, and ureterostomy: 26). Cronbach’s alpha coefficient was ≥ 0.78 for all subscales, except the bowel bother subscale. Despite moderate correlations being detected between the function and bother score in urinary and bowel domains, the sexual function score was inversely correlated with the sexual bother score (r = − 0.19). A missing value percentage of > 15% was associated with old age (p Conclusions Although revisions are needed to make it easier for elderly patients to comprehend, we confirmed the reliability and validity of the Japanese BCI. The Japanese BCI could be used for cross-cultural assessments of HRQOL in bladder cancer patients.

Objectives To develop a wet laboratory training model for learning core laparoscopic surgical skills and evaluating learners' competency level outside the operating room. Methods Participants completed three tasks (task 1: tissue dissection around the aorta; task 2: tissue dissection and division of the renal artery; task 3: renal parenchymal closure). Each performance was video recorded and subsequently evaluated by two experts, according to the Global Operative Assessment of Laparoscopic Skills and task-specific metrics that we developed (Assessment Sheet of Laparoscopic Skills in Wet Lab score). Mean scores were used for analyses. The subjective mental workload was also assessed (NASA Task Load Index). Results The 54 participants included 32 urologists, eight young trainees and 14 medical students. A total of 13 participants were categorized as experts (>= 50 laparoscopic surgeries), eight as intermediates (10-49) and 33 as novices (0-9). There were significant differences in the Global Operative Assessment of Laparoscopic Skills and Assessment Sheet of Laparoscopic Skills in Wet Lab scores among the three groups in all three tasks. Higher NASA Task Load Index scores were observed in novices, and there were significant differences in tasks 1 (Kruskal-Wallis test,P = 0.0004) and 2 (P = 0.0002), and marginal differences in task 3 (P = 0.0745) among the three groups. Conclusions Our training model has good construct validity, and differences in the NASA Task Load Index score reflect previous laparoscopic surgical experiences. Our findings show the ability to assess both laparoscopic surgical skills and mental workloads, which could help educators comprehend trainees' level outside the operating room. Given the decreasing opportunity to carry out pure laparoscopic surgeries because of the dissemination of robotic surgery, especially in urology, our model can offer practical training opportunities.

The present study aimed to evaluate the efficacy of the real‐world use of axitinib and to develop a prognostic model for stratifying patients who could derive long‐term benefit from axitinib. This was a retrospective, descriptive study evaluating the efficacy of axitinib in patients with metastatic renal cell carcinoma that had been treated with 1 or 2 systemic antiangiogenic therapy regimens at 1 of 36 hospitals belonging to the Japan Urologic Oncology Group between January 2012 and February 2019. The primary outcome was overall survival (OS). Using a split‐sample method, candidate variables that exhibited significant relationships with OS were chosen to create a model. The new model was validated using the rest of the cohort. In total, 485 patients were enrolled. The median OS was 34 months in the entire study population, whereas it was not reached, 27 months, and 14 months in the favorable, intermediate, and poor risk groups, respectively, according to the new risk classification model. The following 4 variables were included in the final risk model: the disease stage at diagnosis, number of metastatic sites at the start of axitinib therapy, serum albumin level, and neutrophil : lymphocyte ratio. The adjusted area under the curve values of the new model at 12, 36, and 60 months were 0.77, 0.82, and 0.82, respectively. The efficacy of axitinib in routine practice is comparable or even superior to that reported previously. The patients in the new model’s favorable risk group might derive a long‐term survival benefit from axitinib treatment., The accuracy of the overall survival predictions made after the initiation of axitinib treatment, area under the curve (AUC) values were calculated for each model. The adjusted AUC values at 12, 36, and 60 months after the initiation of axitinib were 0.77, 0.82, and 0.82, respectively, for the axitinib treatment prediction model, and 0.69, 0.67 and 0.56, respectively, for the International Metastatic Renal Cell Carcinoma Database Consortium model.

The number of kidney transplants has gradually increased in the last decade; it was 1742 in Japan in 2017. The outcomes have improved year by year, with the indications for transplantation expanding accordingly. In this paper, we will report the unique trends and outcomes of kidney transplantation in Japan. The detailed transplant characteristics and outcomes are also shown as an updated version of the previous report in the Renal Replacement Therapy. Transplantations in elderly, diabetic, and ABO-incompatible living donors have been more widely performed recently, with the outcomes of these transplants having improved remarkably. However, the number of deceased donor transplants is still quite small, and further efforts to increase deceased organ donation continue to be of utmost necessity in Japan.

Objectives: With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. Methods and materials: We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. Results: The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). Conclusions: Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints. (C) 2021 The Authors. Published by Elsevier Inc.

Gene expression is regulated by promoters and enhancers marked by histone H3 lysine 27 acetylation (H3K27ac), which is established by the paralogous histone acetyltransferases (HAT) EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma (NB) depends on EP300, whereas CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining transcriptional core regulatory circuitry (CRC) in NB. To disrupt EP300, we developed a proteolysis-targeting chimera (PROTAC) compound termed “JQAD1” that selectively targets EP300 for degradation. JQAD1 treatment causes loss of H3K27ac at CRC enhancers and rapid NB apoptosis, with limited toxicity to untransformed cells where CBP may compensate. Furthermore, JQAD1 activity is critically determined by cereblon (CRBN) expression across NB cells. Significance: EP300, but not CBP, controls oncogenic CRC-driven transcription in high-risk NB by binding TFAP2β. We developed JQAD1, a CRBN-dependent PROTAC degrader with preferential activity against EP300 and demonstrated its activity in NB. JQAD1 has limited toxicity to untransformed cells and is effective in vivo in a CRBN-dependent manner. This article is highlighted in the In This Issue feature, p. 587

Longitudinal optical (LO) phonon has strong electric interaction with particles and fields. Particularly, the interaction in III-nitrides is more significant than that in conventional III-V materials. We show phonon-exciton interaction properties in experimental PL spectrum analysis and theoretical calculation of population transfers of excitonic levels. Thermally nonequilibrium occupations of LO phonons and other modes generated by the LO-phonon decomposition are thought to shift the population distribution in principal quantum number states and kinetic energy to the higher energy side. The radiative exciton recombination lifetime is determined by the population distribution in the excitonic states, which is determined by the balance of the electronic and phononic elementary processes. The interaction of excitons and phonons releases the excess energy to the thermal bath of the lattice system, which sometimes yields negligible lattice temperature increase in the excited region or the nonequilibrium state between electron and phonon systems. A Raman scattering imaging measure is introduced to exhibit spatial transport of phonons generated by the energy relaxation and nonradiative recombination of the excited electrons and holes, where pump-probe measurements are enabled by the simultaneous irradiation of two laser beams. It is found that the phonon transport is blocked by the misfit dislocations located on a Ga0.84In0.16N/GaN heterointerface.

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive pediatric malignancy primarily affecting infants and young children. Intensive multimodal therapies currently given to MRT patients are not sufficiently potent to control this highly malignant tumor. Therefore, additive or alternative therapy for these patients with a poor prognosis is necessary. We herein demonstrated that the inhibition of runt-related transcription factor 1 (RUNX1) by novel alkylating conjugated pyrrole-imidazole (PI) polyamides, which specifically recognize and bind to RUNX-binding DNA sequences, was highly effective in the treatment of rhabdoid tumor cell lines in vitro as well as in an in vivo mouse model. Therefore, suppression of RUNX1 activity may be a novel strategy for MRT therapy.

THz-mid infrared electric-dipole radiation resonating with longitudinal optical (LO) phonon energy is obtained from metal-semiconductor surface microstructures by heating samples for various types of semiconductors. The structures using undoped GaAs yield emission peaked at 8.5 THz. The emission properties depending on structural parameters are consistent to the electric dipole properties. The emission from n+-GaP resonates with the LO phonon, which indicates the feasibility of THz emission by optical excitation using indirect electronic transition type materials. The emission from undoped and p-type doped Ga 0.5 In 0.5 P presents two peaks, which indicates the feasibility of electromagnetically induced transparency at an emission energy toward optical gain.

Although the biological importance of Krüppel-like factor 4 (KLF4) transcription factor in the terminal differentiation of hematopoietic cells to the monocytes has been well established, the underlying mechanisms remain elusive. To clarify the molecular basis of KLF4-mediated monocytic differentiation, we performed detailed genetic studies in acute myeloid leukemia (AML) cells. Here, we report that dihydropyrimidinase like 2 (DPYSL2), also known as CRMP2, is a novel key differentiation mediator downstream of KLF4 in AML cells. Interestingly, we discovered that KLF4-mediated monocytic differentiation is selectively dependent on one specific isoform, DPYSL2A, but not on other DPYSL family genes. Terminal differentiation to the monocytes and proliferation arrest in AML cells induced by genetic or pharmacological upregulation of KLF4 were significantly reversed by short hairpin RNA (shRNA)-mediated selective depletion of DPYSL2A. Chromatin immunoprecipitation assay revealed that KLF4 associates with the proximal gene promoter of DPYSL2A and directly transactivates its expression. Together with the unique expression patterns of KLF4 and DPYSL2 limited to the differentiated monocytes in the hematopoietic system both in human and mouse, the identified KLF4-DPYSL2 axis in leukemia cells may serve as a potential therapeutic target for the development of novel differentiation therapies for patients with AML.

Local heat transport in two GaxIn1-xN/GaN-heterostructures on sapphire substrates is investigated by microscopic Raman imaging using two lasers of 532 nm (Raman observation) and 325 nm (heat generation and Raman observation), which enables the separation of heat generation and Raman observation positions. It is found that E2(high) and A1(LO) modes of the Ga0.84In0.16N layer exhibit mutually different characteristics, which indicates the analysis of the occupation of the A1(LO) mode is available. E2(high) mode of the GaN layer observed by the 532-nm laser reveals that the transport of the heat energy generated in the Ga0.84In0.16N layer to the GaN under layer is blocked in the high-density area of misfit dislocation in the vicinity of the heterointerface.

Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.

The case of a patient with metastatic renal cell carcinoma who exhibited the abscopal effect following treatment by anti-programmed death-1 (PD-1) antibody is presented. A 40-year-old woman was diagnosed with an 8.2-cm renal tumor without distant metastases, and radical nephrectomy was subsequently performed. Pathological examination revealed a clear cell renal cell carcinoma. At 3 months after surgery, the patient developed one lung metastasis. Following treatment with interferon and three types of tyrosine kinase inhibitors, anti-PD1 antibody (nivolumab) was started. During the treatment, para-aortic/supraclavicular lymph nodes and several lung lesions remained, although other lesions decreased markedly. The patient was subsequently treated by palliative radiotherapy to the para-aortic and supraclavicular lymph nodes for pain control. After the radiotherapy, the lung lesions previously refractory to nivolumab started to decrease, probably due to an abscopal effect. Additionally, the laboratory data and Karnofsky Performance Status improved. Histological re-examination of the primary lesion revealed heterogeneity of the immunological microenvironment, which may be associated with the heterogeneity of treatment sensitivity.

Room-temperature spin relaxation rates resulting from the D’yakonov–Perel (DP) and Elliot–Yafet (EY) mechanisms were determined by combining microscopic and macroscopic Kerr rotation measurements in narrow-gap (001) InGaAs/InAlAs quantum wells (QWs). Two samples with different DP relaxation rate were compared and we found that EY relaxation rate ( 3.80 GHz ) was approximately double the value of the average DP relaxation rate even in the asymmetric QWs with large spin–orbit parameters. We also found that the anisotropy of spin relaxation time owing to the DP mechanism is weakened significantly in the system in which the EY mechanism dominates the spin relaxation.

Objectives: During the past 2 decades, in order to improve perioperative and ontological outcomes, a minimally invasive approach, neoadjuvant chemotherapy (NAC), and an enhanced postoperative recovery program after surgery have been introduced into routine clinical practice of radical cystectomy (RC). Our aim was to examine the differences in clinical practice and postoperative complications after RC by comparing our previous and current cohorts. Materials and methods: A retrospective multi-institutional study. We collected all complications within 90 days after surgery between 2011 and 2017 (current cohort), and categorized them according to a standardized methodology. Then, we compared the outcomes with those in our previous study (previous cohort, 1997-2010). A multivariate logistic regression model was utilized to determine predictors of complications in the current cohort. Results: A total of 838 patients were newly collected (current cohort), and 919 from the previous cohort were included in the subsequent analyses. In the current cohort, the rate of performing NAC was significantly higher (13% vs. 4%, respectively, P < 0.0001), and 26% (222/ 838) underwent laparoscopic RC (LRC, without robotic assistance: n = 210, with robotic assistance: n = 12). There was no significant difference in the overall complication [69% (580/838) vs. 68% (629/919), respectively, P = 0.7284] or major complication (Grades 3-5) [25% (211/838) vs. 22% (201/919), respectively, P = 0.1022] rates between the 2 cohorts. In both cohorts, the most frequent categories were infectious, gastrointestinal, wound-related, and genitourinary. In the current cohort, the performance status (odds ratio, OR = 2.11, P = 0.0013) and operative time (OR = 1.003, P = 0.0016) remained significant predictors of major complications. NAC was not associated with any or major complications. Conclusions: Surgical complications related to RC still remain significant problems, despite the recent improvements in surgical techniques and perioperative care. NAC did not increase the complications. (C) 2021 The Authors. Published by Elsevier Inc.

Introduction: Laparoscopic surgery has been a standard procedure of living donor nephrectomy (LDN). Transperitoneal hand-assisted laparoscopic LDN (HALDN) has been commonly reported by man...

Although the function of Runt-related (RUNX) transcription factors has been well characterized in leukemogenesis and regarded as an ideal target in antileukemia strategies, the effect of RUNX-inhibition therapy on bone marrow niche cells andr its impact on the engraftment of acute myeloid leukemia (AML) cells have largely been unknown. Here, we provide evidence suggesting the possible involvement of RUNX transcription factors in the transactivation of E-selectin, a member of selectin family of cell adhesion molecules, on the vascular endothelial cells of the mice bone marrow niche. In our experiments, gene switch-mediated silencing of RUNX downregulated E-selectin expression in the vascular niche and negatively controlled the engraftment of AML cells in the bone marrow, extending the overall survival of leukemic mice. Our work identified the novel role of RUNX family genes in the vascular niche and showed that the vascular niche, a home for AML cells, could be strategically targeted with RUNX-silencing antileukemia therapies. Considering the excellent efficacy of RUNX-inhibition therapy on AML cells themselves as we have previously reported, this strategy potentially targets AML cells both directly and indirectly, thus providing a better chance of cure for poor-prognostic AML patients., 骨髄微少環境を制御する新手法で白血病の延命効果を確認 --白血病治療に新しいコンセプトを提示--. 京都大学プレスリリース. 2018-04-06.

Spin–orbit (SO) magnetic fields caused by the Dresselhaus SO interaction in slightly misoriented (110) InGaAs/InAlAs quantum wells (QWs) are investigated using the time-resolved and spatially resolved optical Kerr rotation technique. The Dresselhaus SO magnetic field is directed along the in-plane in the (001) QWs and along the out-of-plane in the (110) QWs. On the contrary, in QWs grown on a slightly misoriented (110) substrate, the out-of-plane and in-plane components of the Dresselhaus SO magnetic field coexist. In this study, the strong out-of-plane and the in-plane SO magnetic fields peculiar to the misoriented (110) InGaAs QWs are revealed at room temperature by analyzing spatially resolved diffusion-driven spin precession dynamics with a diagonally applied external magnetic field. Based on the scan position dependence of the spin precession frequency induced by the SO magnetic field, the simultaneous observations of the out-of-plane and the in-plane SO magnetic fields are achieved and Dresselhaus SO parameter is extracted to be 1.9 × 10 − 12 eV m. This value accounts for the scan position dependencies with various magnetic fields and reveals the reliability of the extracted SO parameter.

Gene expression is regulated by promoters and enhancers marked by histone H3-lysine-27 acetylation (H3K27ac) and established by the paralogous histone acetyltransferases (HATs), EP300 and CBP. These enzymes display overlapping regulatory roles in untransformed cells, but less characterized roles in cancer cells. We demonstrate that the majority of high-risk pediatric neuroblastoma depend on EP300, while CBP has a limited role. EP300 controls enhancer acetylation by interacting with TFAP2β, a transcription factor member of the lineage-defining core-regulatory transcriptional circuitry (CRC). To disrupt EP300, we developed a proteolysis-targeted-chimaera (PROTAC) compound “JQAD1” that selectively targets EP300 for degradation. This results in loss of H3K27ac at CRC enhancers and neuroblastoma apoptosis, with limited toxicity to untransformed cells where CBP compensates. EP300 physically interacts with the MYCN oncoprotein, promoting its chromatin localization in neuroblastoma. EP300 degradation therefore capitalizes on EP300 dependency in neuroblastoma by controlling MYCN localization and preventing MYCN from sustaining the malignant cell state. Citation Format: Adam D. Durbin, Tingjian Wang, Virangika K. Wimalasena, Mark W. Zimmerman, Deyao Li, Neekesh V. Dharia, Luca Mariani, Paul M. Park, Logan H. Sigua, Ken Morita, Amy S. Conway, Amanda L. Robichaud, Antonio Perez-Atayde, Melissa Bikowitz, Taylor Quinn, Olaf Wiest, Ernst Schonbrunn, Martha Bulyk, Brian J. Abraham, Kimberly Stegmaier, A. Thomas Look, Jun Qi. EP300 selectively controls the enhancer landscape of high risk neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2318.

Besides being a classical tumor suppressor, runt-related transcription factor 1 (RUNX1) is now widely recognized for its oncogenic role in the development of acute myeloid leukemia (AML). Here we report that this bidirectional function of RUNX1 possibly arises from the total level of RUNX family expressions. Indeed, analysis of clinical data revealed that intermediate-level gene expression of RUNX1 marked the poorest-prognostic cohort in relation to AML patients with high- or low-level RUNX1 expressions. Through a series of RUNX1 knockdown experiments with various RUNX1 attenuation potentials, we found that moderate attenuation of RUNX1 contributed to the enhanced propagation of AML cells through accelerated cell-cycle progression, whereas profound RUNX1 depletion led to cell-cycle arrest and apoptosis. In these RUNX1-silenced tumors, amounts of compensative upregulation of RUNX2 and RUNX3 expressions were roughly equivalent and created an absolute elevation of total RUNX (RUNX1 + RUNX2 + RUNX3) expression levels in RUNX1 moderately attenuated AML cells. This elevation resulted in enhanced transactivation of glutathione S-transferase α 2 (GSTA2) expression, a vital enzyme handling the catabolization of intracellular reactive oxygen species (ROS) as well as advancing the cell-cycle progressions, and thus ultimately led to the acquisition of proliferative advantage in RUNX1 moderately attenuated AML cells. Besides, treatment with ethacrynic acid, which is known for its GSTA inhibiting property, actually prolonged the survival of AML mice in vivo. Collectively, our findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in antileukemia strategy., 急性骨髄性白血病の新しい転写因子調節メカニズムを解明 --従来とは逆にがん抑制遺伝子をターゲットにした治療戦略を提唱--. 京都大学プレスリリース. 2017-08-09.