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We hypothesized that social jetlag would be associated with prolonged sleep duration on weekends and irregularities in wake-up time and/or bedtime on weekdays. In total, 1,200 Japanese male college students were included in this study. Participants completed an eight-day sleep diary in which they recorded their wake-up time, bedtime, and sleep duration every day for a week. Mean wake-up time, bedtime, and sleep duration, standard deviations in wake-up time and bedtime, the coefficient of variation in sleep duration, social jetlag, and chronotype were calculated over seven nights. Multiple regression was used to explore the factors influencing social jetlag. Stepwise selection analysis was performed to analyze the parameters identified on multiple regression analysis. The mean chronotype of the included participants was 5.3 ± 1.5; their mean social jetlag value was 1.1 ± 1.0. The mean wake-up time, bedtime, and sleep duration values were 8.5 ± 1.1, 25.0 ± 1.1, and 7.5 ± 1.1 h, respectively. Multiple regression analysis showed five indicators exerting a statistically significant influence on social jetlag. The standard deviation in wake-up time was adopted as the first factor in the stepwise selection analysis. These results show that social jetlag is associated with not only prolonged sleep duration on weekends but also irregularities in wake-up time during the week.

Background/Aim: The duration of pembrolizumab use in actual daily practice might be shorter than that in clinical trials because termination of pembrolizumab therapy is at the discretion of the physician. We retrospectively reviewed the response to pembrolizumab in Japanese patients with metastatic urothelial carcinoma (mUC) in relation to the time to response (TTR). Patients and Methods: The records of 165 patients treated with pembrolizumab for mUC were retrospectively analyzed. Response was evaluated at 2, 4, 6 and 8 months. TTR along with time to best response were analyzed. Phase II-III clinical trials were also reviewed to compare the TTR and time to best overall response. Results: The median patient age was 70 years. The objective response rate in the total cohort was 27.1% (42 out of 155 patients). Median TTR was 2.4 months and the time to best response was 3.1 months. Radiological evaluation at each time point significantly predicted overall survival (OS). Considering the evaluation of response at 2, 4, 6 and 8 months, the response at later time points tended to predict OS better. Multivariate analysis showed that the evaluation of response at 8 months (hazard ratio=1.91, 95% confidence interval=1.16-3.16 months; p

The Thorpe–Ingold effect was applied to the design of a chiral ligand of π–copper(II) catalysts for the enantioselective α-fluorination of N-acyl-3,5-dimethylpyrazoles, and also for the enantioselective Mukaiyama–Michael, Diels–Alder, and 1,3-dipolar cycloaddition reactions of N-acryloyl-3,5-dimethylpyrazoles. The use of β,β-dimethyl-β-arylalanine-type ligand gave desired products with higher enantioselectivity compared to with previously reported β-arylalanine-type ligands.

Background/Aim: In clinical practice, platinum-based systemic chemotherapy works to shrink pelvic lymph nodes. Intra-arterial (IA) bolus infusion may result in more favorable results than systemic chemotherapy. In the present study, we investigated the distribution of cisplatin administrated by IA infusion in varying organs, specifically focusing on the node tissue, in comparison with the intra-venous (IV) route. Materials and Methods: Under anesthesia, cisplatin 0.42 mg/body was administrated by IA or IV infusion in rats to mimic a balloon-occluded arterial infusion model used in clinical practice. The kidney, bladder, lymphatic tissue, and peripheral blood were extracted to analyze the amount of cisplatin by inductively coupled plasma-mass spectrometry. Results: Concertation of cisplatin by IA infusion was higher than that by the IV route in the peripheral blood and kidney. IA infusion led to a significantly high concentration of cisplatin in the bladder compared to IV infusion (1.3±0.452 vs. 0.2 ppb/mg ± 0.055, p=0.050). Furthermore, the IA method led to an extremely high concentration of cisplatin in the lymphatic tissue compared to the IV method (0.1±0.036 vs. 13.3±5.36, p=0.048). Conclusion: High cisplatin accumulation in the lymphatic tissue and bladder by IA administration may have a potential role for treating patients with node-positive bladder cancer.

There has been accumulating evidence that RNA splicing is frequently dysregulated in a variety of cancers and that hotspot mutations affecting key splicing factors, SF3B1, SRSF2 and U2AF1, are commonly enriched across cancers, strongly suggesting that aberrant RNA splicing is a new class of hallmark that contributes to the initiation and/or maintenance of cancers. In parallel, a number of studies has demonstrated that cancer cells with global splicing alterations are dependent on the transcriptional products derived from wild-type spliceosome for their survival, which potentially creates a therapeutic vulnerability in cancers with mutant spliceosome. It has been approximately 10 years since the frequent mutations affecting splicing factors was reported in cancers. Based on these surprising findings, there has been a growing interest in targeting altered splicing in the treatment of cancers, which promotes a wide variety of investigations including genetic, molecular and biological studies addressing how altered splicing promotes oncogenesis and how cancers bearing alterations in splicing can be therapeutically targeted. In this mini-review we present concise trajectory of what has been elucidated regarding the pathogenesis of cancers with aberrant splicing as well as the development of therapeutic strategies to target global splicing alterations in cancers.

With an increase in the number of older adults worldwide, the oldest-old population, defined as individuals over the age of 90, is also growing. Japan is now facing the problem of a “super-aged society” in which over 21% of the population is aged over 65. The oldest-old constituted 1.8% (2.31 million) of the Japanese population in 2019. Such individuals have special health-care needs. In cases of acute or chronic (or both) renal failure in the oldest-old, it becomes difficult to decide whether dialysis should be initiated. The issue is controversial, and there is some debate on whether dialysis should be avoided in elderly people because of their frailty or if it should be initiated to enable them to spend their remaining years with their families by improving their quality of life. Herein, we describe our experience in 4 cases of hemodialysis initiated in patients over the age of 90. In our experience, dialysis enabled them to spend the rest of their lives with their families, which could not have been possible without it. Although further studies are needed, we concluded that oldest-old individuals in good general health could be eligible for and benefit from hemodialysis.

There has been accumulating evidence for the clinical benefit of chemoradiation therapy (CRT), whereas mechanisms in CRT-recurrent clones derived from the primary tumor are still elusive. Herein, we identified an aberrant BUB1B/BUBR1 expression in CRT-recurrent clones in bladder cancer (BC) by comprehensive proteomic analysis. CRT-recurrent BC cells exhibited a cell-cycle-independent upregulation of BUB1B/BUBR1 expression rendering an enhanced DNA repair activity in response to DNA double-strand breaks (DSBs). With DNA repair analyses employing the CRISPR/cas9 system, we revealed that cells with aberrant BUB1B/BUBR1 expression dominantly exploit mutagenic nonhomologous end joining (NHEJ). We further found that phosphorylated ATM interacts with BUB1B/BUBR1 after ionizing radiation (IR) treatment, and the resistance to DSBs by increased BUB1B/BUBR1 depends on the functional ATM. In vivo, tumor growth of CRT-resistant T24R cells was abrogated by ATM inhibition using AZD0156. A dataset analysis identified FOXM1 as a putative BUB1B/BUBR1-targeting transcription factor causing its increased expression. These data collectively suggest a redundant role of BUB1B/BUBR1 underlying mutagenic NHEJ in an ATM-dependent manner, aside from the canonical activity of BUB1B/BUBR1 on the G2/M checkpoint, and offer novel clues to overcome CRT resistance.

Background Randomized trials showed the survival benefits of the combined use of androgen receptor axis-targeted agents with androgen deprivation therapy in metastatic hormone-sensitive prostate cancer (mHSPC), regardless of the risk. However, treating patients with low-risk mHSPC with such intensive treatment is still debatable. Methods This retrospective study included 155 low-risk patients among 467 mHSPC patients treated in our affiliated institutions. The association between predictive factors and treatment outcomes was estimated using the Kaplan–Meier method and log-rank test. Predictive factors for castration resistant prostate cancer (CRPC)-free survival were investigated using Cox regression analyses. Results During the median follow-up of 39 months, 38.7% of patients developed CRPC and 14.2% died. In the multivariate analyses, a presence of Gleason pattern 5 (hazard ratio [HR] 2.04), high alkaline phosphatase (HR 1.007) and high lactate dehydrogenase (HR 1.009) were significant predictive factors for shorter CRPC-free survival. Finally, 155 patients were stratified into favorable- and unfavorable-risk groups based on the numbers of the predictive factors. The overall survival (OS) in the unfavorable-risk group (total scores: 2–3) was significantly worse than that of the favorable-risk group (total score: 0–1) (P = 0.02). This prognostic model was assessed with 50 low-risk mHSPC patients from the external validation dataset and found both the time to CRPC, and the OS in the unfavorable-risk group was significantly worse than that of the favorable-risk group (P Conclusions The combination of Gleason pattern 5, high alkaline phosphatase and lactate dehydrogenase can predict those with worse OS in low-risk mHSPC patients.

To assess the real-world clinical benefit of re-challenging chemotherapy after pembrolizumab in patients with metastatic urothelial carcinoma (mUC), as there have been several reports suggesting that programmed cell death protein-1/programmed death-ligand 1inhibitors can restore platinum sensitivity.Of 236 patients treated with pembrolizumab, we excluded 45 patients who did not experience progressive disease (PD) for pembrolizumab during the follow-up and 86 patients who discontinued pembrolizumab by the diagnosis of PD followed by the best supportive care. A total of 105 patients were identified for a logistic regression propensity score model to compare the survival outcomes between patients treated with continuing pembrolizumab (80) and re-challenging chemotherapy (25) after the diagnosis of PD for pembrolizumab.A median overall survival (OS) from PD for pembrolizumab was 11 months in 105 patients. Of 25 patients treated with re-challenging chemotherapy, platinum-including chemotherapy (gemcitabine and cisplatin; gemcitabine/cisplatin/paclitaxel [GCP]; methotrexate and vinblastine and adriamycin and cisplatin; and methotrexate and carboplatin and vinblastine MCAVI) was offered in 20 patients (80%). The objective response rate (ORR) for the first-line chemotherapy in the 105 patients was 30%, with a comparable ORR in 25 patients treated with re-challenging chemotherapy of 28%. GCP as a re-challenging regimen was offered in 12 of 25 (48%) patients. The ORR for the GCP regimen was 50%. Propensity score matching was performed using putative clinical factors, from which 34 patients were identified as pair-matched groups. The OS for patients treated with re-challenging chemotherapy was significantly longer than continuing pembrolizumab (a median of 13.9 and 5.8 months, respectively: P = 0.048).Re-challenging chemotherapy including platinum agents after PD with pembrolizumab offers clinical benefits in patients with mUC.

Pembrolizumab has now become a standard of care in metastatic urothelial carcinoma (mUC), although the treatment effect of the drug substantially differs among individuals. Emerging evidence suggests that radiotherapy exerts a synergistic effect with PD-1 blockade. We sought to elucidate the survival outcomes in patients who underwent palliative radiation with the pembrolizumab treatment.We retrospectively investigated our multi-institutional dataset of 235 platinum-refractory mUC patients treated with pembrolizumab as second-line treatment, collected from January 2018 and October 2021. Propensity score matching was performed to reduce biases by potential confounding factors for overall survival (OS).With a median follow-up of 6.8 months, the median OS from the initiation of pembrolizumab was 13 months in 235 patients. Palliative radiation was performed in 71 (30.2%) patients for whom the median radiation dose and fraction were 30 Gy and 10 fractions, respectively. Irradiated sites were bone in 24 (33.8%), lymph node in 17 (23.9%), lung in 3 (4.2%), brain in 8 (11.3%), and other sites in 19 (26.8%). OS from the initiation of pembrolizumab was significantly longer in patients who underwent concurrent palliative radiation with pembrolizumab (39 patients: median OS: 21 months) than in both patients with palliative radiation before pembrolizumab (32 patients: median OS: 9 months) (p = 0.001) and those without palliative radiation throughout the follow-up (164 patients: median OS: 13 months) (p = 0.019). After the propensity-score matching by putative confounding factors, longer OS in patients treated with concurrent palliative radiation with pembrolizumab (n = 36) was still observed compared to patients without the concurrent palliative radiation (n = 36) in the pair matched cohort (median OS of 29 and 13 months, respectively, p = 0.033).Our findings suggest that the concurrent administration of palliative radiation with pembrolizumab offers a favorable effect on OS in platinum-refractory mUC patients.

We newly propose and experimentally investigate an InGaAs-channel high-electron-mobility transistor integrated with a unitraveling-carrier photodiode (UTC-PD) structure on its source side for an efficient optical-to-wireless carrier frequency downconversion utilizing its photonic double-mixing functionality. It is demonstrated that the double-mixing conversion gain is significantly enhanced by 20 dB compared with a standard HEMT, owing to the integration of the UTC-PD structure. The device operation principle expected from the device structure is confirmed through measured DC characteristics and photomixing/double-mixing characteristics in the millimeter-wave region. The feasibility of the device for practical use in future optical-wireless convergence networks is addressed.

College students’ social and eating jet lags and chronotypes may be related to irregular eating habits. Therefore, we examined the relationship between social and eating jet lags, chronotypes, variability in first and last mealtimes, and non-eating duration, as well as the effects of snacking between dinner and bedtime on social and eating jet lags, chronotypes, and mealtime variation. A total of 1900 Japanese male college students were recruited in this study. Mean wake-up time, bedtime, sleeping time, first and last mealtimes, snacks between meals, non-eating duration, the midpoint of non-eating duration, social and eating jet lags, and chronotype were calculated. Standard deviations in first and last mealtimes, the midpoint of non-eating duration, and the coefficient of variation in non-eating duration were used to evaluate mealtime variations. Mealtime variations were significantly associated with social and eating jet lags, chronotype, the midpoint of non-eating duration, and the difference in first and last mealtime between school holidays and class days. Chronotype and the midpoint of non-eating duration were significantly delayed with increased snacking after dinner. Mealtime variations were significantly lower in those who avoided snacking than in those who did not. Thus, social and eating jet lags and chronotypes are associated with sleep habits and mealtime irregularities.

The UVA and UVB components of sunlight can produce three classes of bipyrimidine DNA photolesions [cyclobutane pyrimidine dimers (CPDs), pyrimidine (6‐4) pyrimidone photoproducts (6‐4PPs) and related Dewar valence isomers (DewarPPs)]. The UVA/UVB ratio of sunlight is high in winter and low in summer in the Northern Hemisphere. Since UVB radiation produces 6‐4PPs and UVA radiation converts them into DewarPPs through photoisomerization, it is expected that there may be differences in the photoisomerization of 6‐4PPs between summer and winter, although that has never been documented. To determine that, isolated DNA was exposed to natural sunlight for 8 h in late summer and in winter, and absolute levels of the three classes of photolesions were quantified using calibrated ELISAs. It was found that sunlight produces CPDs and 6‐4PPs in DNA at a ratio of about 9:1 and converts approximately 80% of 6‐4PPs into DewarPPs within 3 h. Moreover, photoisomerization is more efficient in winter than in late summer after sunlight irradiation for the same duration, at similar solar UV doses and with the same induction level of CPDs. These results demonstrate that seasonal differences in the UVA/UVB ratio influence the efficiency of the photoisomerization of 6‐4PPs into DewarPPs., The UVA and UVB components of sunlight produce three main classes of bipyrimidine DNA photolesions. The UVA/UVB ratio of sunlight is high in winter and low in summer in the Northern Hemisphere. Since UVB produces (6‐4) photoproducts (6‐4PPs) and UVA converts them into Dewar valence isomers (DewarPPs) through photoisomerization, it is expected that there may be seasonal differences in the photoisomerization of 6‐4PPs. Indeed, photoisomerization is more efficient in winter than in late summer after sunlight irradiation, demonstrating that seasonal differences in the UVA/UVB ratio influence the efficiency of the photoisomerization of 6‐4PPs into DewarPPs.

Catalytic enantioselective α-fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α-fluorinated carbonyl compounds. Nevertheless, α-fluorination of α-nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pKa values of their α-hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3-(2-naphthyl)-l-alanine-derived amides are highly effective catalysts for the enantio- and site-selective α-fluorination of N-(α-arylacetyl) and N-(α-alkylacetyl) 3,5-dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α-fluorinated α-amino acid derivative). α-Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.

Small-caliber artificial blood vessels with inner diameters of smaller than 4 mm have not been put into practical use because of early thrombus formation and graft occlusion. To realize small-caliber artificial blood vessels with anti-thrombus property and long-term patency, one of the promising approaches is endothelialization of the lumen by tissue engineering approaches. Integrin α4β1 on the endothelial cell membrane is known to act as a receptor for Arg-Glu-Asp-Val (REDV) tetra-peptide, and this peptide can be used as a specific ligand to introduce endothelial cell attachment onto the surfaces of polymer scaffold. In this study, biodegradable polymer surface immobilizing REDV peptide were prepared, and the specific attachment of endothelial cells on it was investigated as a preliminary study for tissue-engineered small-caliber blood vessels in a future application. We synthesized copolymer of ε-caprolactone and depsipeptide having reactive carboxylic acid side-chain groups (PGDCL), and REDV peptide was attached to the copolymer to give PGDCL-REDV. The attachment of human umbilical vein endothelial cells (HUVECs) were investigated for the blend polymer film prepared by mixing PGDCL and PGDCL-REDV. The obtained blend polymer films exhibited sequence- and cell-specific HUVECs attachment through REDV peptide recognition. This technique should be useful not only to obtain artificial blood vessels which induce endothelialization and but also to provide biodegradable scaffolds with specific ligands immobilized surfaces for tissue regeneration.

Adenosine deaminase 2 (ADA2) regulates extracellular levels of adenosine and the optimal expression of ADA2 is essential for modulating the immune system. However, the mechanisms regulating the production of active ADA2 enzyme are not fully understood. In this study, we examined the role of N-glycosylation in the formation of functional structures and the secretory pathway of ADA2.We investigated the roles of N-glycosylation in the activity, homodimerization, and secretion of ADA2 via site-directed mutagenesis and the application of N-glycosylation inhibitors. Subcellular localization of ADA2 along with the endoplasmic reticulum (ER) glucosidase inhibitor was observed under confocal fluorescence microscope.Inhibiting the initial N-glycosylation of ADA2 in the ER via site-directed mutagenesis or treatment with N-glycosylation inhibitors reduced the intracellular ADA2 activity and secretion. At this time, decreases in the ADA2 homodimers and ADA2 aggregation were observed in the cells. Treating the cells with castanospermine, an inhibitor of N-glycan editing in the ER, resulted in a reduction of the localization rate to the Golgi and markedly suppressed the ADA2 secretion.These data suggest that the initial N-glycosylation and N-glycan editing in the ER are essential for the production of an active ADA2 enzyme and proper trafficking to the extracellular space.With sufficient N-glycosylation in the ER, ADA2 exerts its function and is secreted extracellularly.

Serum C-reactive protein (CRP) is known to be a biomarker for systemic inflammatory reactions. In the present study, we sought to measure the predictive value of serum CRP level for metastatic renal cell carcinoma (mRCC) treated with first-line ipilimumab and nivolumab using our real-world clinical dataset including non-clear cell RCC (nccRCC). The clinical record of patients who underwent the first-line ipilimumab plus nivolumab treatment for mRCC including ccRCC and nccRCC from 2018 to 2021 was retrospectively analyzed. All patients were diagnosed with either intermediate or poor-risk group defined by IMCD (international metastatic RCC database consortium). In total, 74 patients were involved. The median age was 68 years and 24 (32.4%) patients deceased during the follow-up. Forty-five (61%) and 29 (39%) patients were classified into intermediate and poor-risk groups. The one-year overall survival (OS) rate and objective response rate were 65% and 41% for all 74 mRCC patients, respectively. The receiver operating characteristic curve identified 1.0 mg/dL of serum CRP level as an ideal cut-off for predicting overall survival (OS). Serum CRP > 1.0 mg/dL and nccRCC were the independent predictors for OS in 74 mRCC patients. OS for patients with CRP > 1 mg/dL was significantly shorter than those with CRP < 1 mg/dL in both ccRCC (58 patient: p = 0.009) and nccRCC (16 patients: p = 0.008). The present study indicated that serum CRP level is a prognostic indicator for OS in both ccRCC and nccRCC patients treated with the first-line ipilimumab plus nivolumab treatment.

Pembrolizumab has emerged as the new standard of care in patients with platinum-refractory metastatic urothelial carcinoma (mUC), whereas the optimal risk stratification to predict survival outcomes is still controversial. We examined a risk model for overall survival (OS) in mUC treated with pembrolizumab using our multi-institutional dataset (212 patients). The median age was 72 years old. Median OS from the initiation of pembrolizumab treatment was 11.7 months. The objective response rate (ORR) was 26.4%. On multivariate analysis, multiple metastatic sites and an NLR &gt, 3.50 at the initiation of pembrolizumab treatment were identified as independent predictors for OS. We next developed a risk model using those two predictors. Patients without any factors were assigned to the favorable-risk group (26.5%). Patients with either factor and both factors were assigned to the intermediate-risk group (44.3%), and poor-risk group (29.2%), respectively. Kaplan–Meier curves showed clear discrimination of OS among the risk groups (p &lt, 0.001). The ORR in each group was 35.7% in the favorable-risk group, 27.7% in the intermediate-risk group, and 17.7% in the poor-risk group. Given that the model can be concisely determined at the initiation of pembrolizumab treatment, physicians may be encouraged to consider the risk group for daily practice.

Most patients with metastatic urothelial carcinoma experience no objective response to pembrolizumab and have poor overall survival (OS). Here, we investigated the prognostic value of fluctuation in the neutrophil-lymphocyte ratio (NLR) at 6 weeks of pembrolizumab treatment, focusing on its association with the achievement of objective response.The clinical records of 177 metastatic urothelial carcinoma patients treated with pembrolizumab were retrospectively analyzed.The median age was 72 years, and the median OS was 14 months. The objective response rate in the total cohort was 26.5% (47 of 177 patients). Multivariable analysis showed that objective response achievement (hazard ratio 0.3 [95% confidence interval 0.15-0.59], P0.001) and decline in NLR from that at baseline at 6 weeks of treatment (0.54 [0.34-0.88], P = 0.013) were independent prognostic factors for improved OS. For 47 (26.5%) patients who achieved an objective response, OS was similar regardless of NLR fluctuation at 6 weeks of treatment (P = 0.723). Intriguingly, of the 130 (73.5%) patients with no objective response, those who showed a decreased NLR at 6 weeks of pembrolizumab treatment (57 patients) from that at baseline had significantly longer OS than those with elevated NLR (73 patients) (14 vs. 6 months, P = 0.007).The fluctuation in NLR from that at baseline at 6 weeks of pembrolizumab treatment may be useful for patients without an objective response. This could potentially aid decision-making for post pembrolizumab therapies.

The association of concurrent proton pump inhibitor (PPI) use with treatment outcome of metastatic urothelial carcinoma (UC) remains controversial.We retrospectively analyzed the records of 227 patients with platinum-treated metastatic UC treated with pembrolizumab. The primary outcome was overall survival (OS). Immune progression-free survival (iPFS) and objective response per immune response evaluation criteria in solid tumors were also compared. Inverse probability of treatment weighting (IPTW)-adjusted multivariable Cox regression models and an IPTW-adjusted multivariable logistic regression model were used to evaluate the oncological outcomes. Furthermore, the heterogeneity of the treatment effect on OS was examined using interaction terms within the IPTW-adjusted univariate Cox regression models.Overall, 86 patients (37.9%) used PPIs. After weighting, no significant differences in patient characteristics were observed between PPI users and non-users. PPI use was significantly associated with a shorter OS (hazard ratio [HR]: 2.02, 95% confidence interval [CI]: 1.28-3.18, P = 0.003) and iPFS (HR: 1.70, 95% CI: 1.23-2.35, P = 0.001). Although not statistically significant, PPI use was associated with objective response as well (OR: 0.61, 95% CI: 0.36-1.02, P = 0.06). The interaction analyses showed that the effect of PPI significantly decreased with age (HR: 0.97, 95% CI: 0.93-1.00, P[interaction] = 0.048) and was increased in males (HR: 2.97, 95% CI: 1.10-8.05, P[interaction] = 0.032).PPI use was significantly associated with worse survival of patients with metastatic UC treated with pembrolizumab. Furthermore, the results suggested that its effects decreased with age and was increased in males.

To realize future ultra-broadband ubiquitous, resilient 6G/7G communication networks, the seamless, transparent linkage between optical and wireless networks is required [1] . We have studied the so-called photonic double-mixing functionality of transistors as a candidate of an efficient carrier frequency down-converter [2] . Its down-conversion process consists of photomixing of an optical carrier and subcarrier signals, generating the difference-frequency beat-note of the MMW/THz data signal, and RF mixing of the beat-note MMW/THz data and LO signals, generating an IF data signal. Recently, we have developed a MMW/THz carrier frequency down-converter based on an InGaAs-channel high-electron-mobility transistor (HEMT) with the uni-traveling-carrier photodiode (UTC-PD) structure (UTC-PD-integrated HEMT, see Fig. 1(a) ), demonstrating the significant enhancement of its double-mixing conversion gain by over 34 dB from that of a standard HEMT [3] . The conversion gain of the UTC-PD-integrated HEMT depends on various material and geometrical parameters through cutoff frequencies of the UTC-PD and HEMT, photoabsorption efficiency of the UTC-PD, etc. with complicated trade-off relations, so that the comprehensive device design principles are to be developed. In this work, we studied the scaling rule of the conversion gain on UTC-PD mesa size, and experimentally revealed the conversion gain increases with decreasing the mesa size up to the diffraction limit.

The identification of early or primary resistance to androgen signaling inhibitors (ASIs) is of great value for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the predictive value of prostate-specific antigen (PSA) response at dour weeks of first-line ASIs treatment for mCRPC patients. A total of 254 patients treated with ASIs (abiraterone acetate: AA and enzalutamide: Enz) at the first-line treatment are retrospectively analyzed. Patients are stratified according to the achievement of &gt, 30% PSA decline at 4 and 12 weeks from the treatment initiation. At four weeks of the treatment, 157 patients (61.8%) achieved &gt, 30% PSA decline from the baseline. Thereafter, 177 patients (69.7%) achieved &gt, 30% PSA decline at 12 weeks of the treatment. A multivariate analysis exhibits &gt, 30% PSA decline at four weeks as an independent predictor for overall survival (OS). We note that 30 of 97 (30.9%) patients who did not achieve &gt, 30% PSA decline at four weeks consequently achieved &gt, 30% PSA decline at 12 weeks, and had a comparable favorable three years OS rate as the 147 patients achieving &gt, 30% PSA decline at both 4 and 12 weeks. To identify the variables that discriminate the patient survival in 97 patients without achieving &gt, 30% PSA decline at four weeks, a multivariate analysis is performed. The duration of androgen deprivation therapy before CRPC &le, 12 months and Eastern Cooperative Oncology Group Performance Status &ge, 1 are identified as independent predictors for shorter OS for those patients. These data offer a concept of early treatment switch after four weeks of first-line ASIs when not observing &gt, 30% PSA decline at four weeks&mdash, particularly in patients with a modest effect of ADT and poor performance status.

Catalytic enantioselective α-fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α-fluorinated carbonyl compounds. Nevertheless, α-fluorination of α-nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK

We developed a novel InGaAs-channel high-electron-mobility transistor (HEMT) integrated with a uni-traveling-carrier photodiode (UTC-PD) structure for the optical-to-wireless carrier frequency down-conversion. We experimentally demonstrated that the output intensity of the down-converted signal is significantly enhanced by 34 dB compared with a standard HEMT, owning to the integration of the UTC-PD structure. We also verified the feasibility of the UTC-PDintegrated HEMT for practical use in the future full coherent network systems.

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial carcinoma, although it is unknown whether the efficacy of pembrolizumab in patients previously treated with curative CRT varies from the results of benchmark trials.MethodsWe retrospectively assessed whether the survival benefit of pembrolizumab differs between patients previously treated with TC or CRT as radical treatment. A total of 212 patient records were collected for a logistic regression propensity score model. An independent dataset with next-generation sequencing (n=289) and PD-L1 Combined Positive Score (CPS: n=266) was analyzed to assess whether CRT-recurrent tumor harbors distinct CD274/PD-L1 profiles.ResultsPropensity score matching was performed using putative clinical factors, from which 30 patients in each arm were identified as pair-matched groups. There was no significant difference in overall survival from the initiation of pembrolizumab (p=0.80) and objective response rate (p=0.59) between CRT and TC treatment groups. In the independent 289 BC cohort, 22 samples (7.6%) were collected as CRT-recurrent tumors. There was no significant difference in CD274 mRNA expression level between CRT-naïve and CRT-recurrent tumors. The compositions of CD274 isoforms were comparable among all isoforms detected from RNAseq between CRT-naïve (n=267) and CRT-recurrent (n=22) tumors. No actionable exonic mutation in CD274 was detected in CRT-recurrent tumors. PD-L1 CPS was positively correlated with CD274 mRNA expression level, and PD-L1 CPS was comparable between CRT-naïve and CRT-recurrent tumors.ConclusionsThe efficacy of pembrolizumab for patients previously treated with CRT was similar to those treated with TC. The enhanced tumor regression by combining programmed cell death protein 1/PD-L1 inhibitor and CRT might be expected only in the concurrent administration.