Efficacy of Enfortumab Vedotin After Chemotherapy With Anti-programmed Death-Ligand 1 (PD-L1) Maintenance Treatment in a Clear Cell Variant of Invasive Urothelial Carcinoma of the Renal Pelvis: A Case Report.

Among upper urinary tract urothelial carcinoma (UUTUC) cases, there are few reports of the clear cell variant. Systemic chemotherapy will be given according to the usual treatment for urothelial cancer unless lymph nodes or organ metastases make surgical treatment inappropriate. Here, we report a clear cell variant of UUTUC of the left renal pelvis with aortic lymph node metastasis. The patient in this case was treated with systemic chemotherapy, anti-programmed death-ligand 1 (PD-L1) maintenance treatment, radiation therapy, and enfortumab vedotin (EV) therapy. To determine which of the treatments contributed to the therapeutic effect, immunostaining was used. The results indicated that Nectin-4 was expressed in clear cell variant tissues, while programmed cell death protein 1 (PD-1) and PD-L1 expression levels were weak in these tissues. The patient maintained complete remission with these treatments. Two years after the initial treatment, the patient was still alive with no progression or metastasis.

Renoprotective effects of laxative linaclotide: Inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion.

Ischemia-reperfusion (I/R) leads to tissue damage in transplanted kidneys, resulting in acute kidney injury (AKI) and chronic graft dysfunction, which critically compromises transplant outcomes, such as graft loss. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been identified to exhibit renoprotective effects in a chronic kidney disease (CKD) model. This study evaluates the therapeutic effects of linaclotide on AKI triggered by I/R in a rat model with an initial comparison with other laxatives. Here, we show that linaclotide administration resulted in substantial reduction in serum creatinine levels, reflective of enhanced renal function. Histological examination revealed diminished tubular damage, and Sirius Red staining confirmed less collagen deposition, collectively indicating preserved structural integrity and mitigation of fibrosis. Further analysis demonstrated lowered expression of TGF-ß and associated fibrotic markers, α-SMA, MMP2, and TIMP1, implicating the downregulation of the fibrogenic TGF-ß pathway by linaclotide. Furthermore, one day after I/R insult, linaclotide profoundly diminished macrophage infiltration and suppressed critical pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6, signifying its potential to disrupt initial inflammatory mechanisms integral to AKI pathology. These findings suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention for organ transplantation. Additionally, it could provide immediate and practical insights into selecting laxatives for managing patients with AKI or CKD, regardless of the cause, and for those receiving dialysis or transplant therapy.

Parahydrogen-induced 13C hyperpolarizer using a flow guide for magnetic field cycling to evoke 1H-13C spin order transfer toward metabolic MRI.

OBJECTIVE: The pair-wise addition of parahydrogen, the singlet form of molecular hydrogen, to unsaturated precursors evokes the hyperpolarization of two parahydrogen-derived 1H nuclear spins through a process known as parahydrogen-induced polarization (PHIP). Subsequent spin order transfer (SOT) from the 1H to the surrounding 13C nuclear spins via magnetic field cycling (MFC) results in substantial signal enhancement in 13C magnetic resonance imaging (MRI). Here, we report the development of a unique PHIP 13C hyperpolarizer system using a flow guide for MFC. METHODS: The optimal MFC scheme for 1H to 13C spin order transfer was quantum-chemically simulated using the J-coupling values of 13C-labeled metabolic tracers. The flow guide system was three-dimensionally designed based on the simulated MFC scheme and pre-measured magnetic field distribution in a zero-field chamber. RESULTS: The system efficiently transfers the spin order of hyperpolarized 1H to a particular 13C spin when the parahydrogenated tracer passes through the flow guide at a designated flow rate. The 13C MRI signal is enhanced more than 40,000 times in 13C-labeled pyruvate and fumarate, compared to the thermal equilibrium level at 1.5 T, was achieved for conducting in vivo metabolic MRI of mice. CONCLUSION: A fully automated PHIP-based 13C polarizer was developed using a unique flow guide to conduct the MFC for 1H to 13C SOT. SIGNIFICANCE: The PHIP hyperpolarizer with a flow guide can conduct efficient 1H-13C SOT without a MFC magnetic field sweep system and offers a cost-effective alternative to conventional dynamic nuclear polarization.

Generation of transmission wave with low AM noise for sub-GHz CW-EPR spectrometer.

This study describes a technique to clean amplitude modulation (AM) noise of RF transmission waves, which is used to observe the sub-GHz CW-EPR spectrum. An RF transmitter amplifier that has the function of cleaning AM noise has been developed. Cleaning of the AM noise was owing to saturation of the output at the amplifier. Three stages of the amplifiers in series could effectively suppress the AM noise to about -176 dBc/Hz and -183 dBc/Hz at offset frequency of 10 kHz and 100 kHz, respectively at the carrier frequency of 750 MHz and the output power of 29 dBm. Since phase modulation (PM) noise is suppressed by phase sensitive detection, the AM noise in the transmission is dominant cause of the noise in the sub-GHz CW-EPR absorption spectrum using a reflection bridge, which depends on the quality factor of the resonator and the power of the RF transmission. The additive phase modulation (PM) noise of this amplifier was -171 dBc/Hz at an offset frequency of 100 kHz, which indicated that the frequency modulation (FM) of the transmission wave was not distorted with this amplifier. Therefore, conventional CW-EPR spectrometers that typically require FM for automatic frequency control or automatic tunning control can use this technique to increase sensitivity.

Frequency-fixed motion compensation system for in-vivo electron paramagnetic resonance tooth dosimetry.

This article describes the design process for a motion compensation system that can suppress the spectral distortion caused by human motion and breathing during in-vivo electron paramagnetic resonance (EPR) spectroscopy on an intact incisor. The developed system consists of two elements: an electronically controlled tunable resonator and an automatic control circuit (ACC). The resonator can modify the resonant frequency and impedance by tuning and matching the voltage, while the ACC can generate a feedback signal using phase-sensitive detection (PSD). The signal is transferred into the resonator to maintain the critical coupling state. The tunable frequency range of the resonator was measured at over 10 MHz, offering approximately eight times the required range. The bandwidth of the resonator fluctuated in a negligible range (0.14% relative standard error) following the resonant frequency. With the feedback signal on, in-vivo EPR measurements were demonstrated to be a stable baseline with 35% higher signal-to-noise ratio (SNR). When one incisor sample was irradiated by an X-ray instrument, the EPR signal responses to the absorbed doses of 0-10 Gy exhibited high linearity (R2 = 0.994). In addition, the standard error of inverse prediction was estimated to be 0.35 Gy. The developed system achieved a discrimination ability of 2 Gy, which is required for triage in large-scale radiation accidents. Moreover, the compensation is fully automated, meaning that the system can be operated with simple training in an emergency.

The Effect of Medical Cooperation in the CKD Patients: 10-Year Multicenter Cohort Study.

INTRODUCTION: While chronic kidney disease (CKD) is one of the most important contributors to mortality from non-communicable diseases, the number of nephrologists is limited worldwide. Medical cooperation is a system of cooperation between primary care physicians and nephrological institutions, consisting of nephrologists and multidisciplinary care teams. Although it has been reported that multidisciplinary care teams contribute to the prevention of worsening renal functions and cardiovascular events, there are few studies on the effect of a medical cooperation system. METHODS: We aimed to evaluate the effect of medical cooperation on all-cause mortality and renal prognosis in patients with CKD. One hundred and sixty-eight patients who visited the one hundred and sixty-three clinics and seven general hospitals of Okayama city were recruited between December 2009 and September 2016, and one hundred twenty-three patients were classified into a medical cooperation group. The outcome was defined as the incidence of all-cause mortality, or renal composite outcome (end-stage renal disease or 50% eGFR decline). We evaluated the effects on renal composite outcome and pre-ESRD mortality while incorporating the competing risk for the alternate outcome into a Fine-Gray subdistribution hazard model. RESULTS: The medical cooperation group had more patients with glomerulonephritis (35.0% vs. 2.2%) and less nephrosclerosis (35.0% vs. 64.5%) than the primary care group. Throughout the follow-up period of 5.59 ± 2.78 years, 23 participants (13.7%) died, 41 participants (24.4%) reached 50% decline in eGFR, and 37 participants (22.0%) developed end-stage renal disease (ESRD). All-cause mortality was significantly reduced by medical cooperation (sHR 0.297, 95% CI 0.105-0.835, p = 0.021). However, there was a significant association between medical cooperation and CKD progression (sHR 3.069, 95% CI 1.225-7.687, p = 0.017). CONCLUSION: We evaluated mortality and ESRD using a CKD cohort with a long-term observation period and concluded that medical cooperation might be expected to influence the quality of medical care in the patients with CKD.

Molecular Weight-Dependent Oxidation and Optoelectronic Properties of Defect-Free Macrocyclic Poly(3-hexylthiophene).

The redox behaviors of macrocyclic molecules with an entirely π-conjugated system are of interest due to their unique optical, electronic, and magnetic properties. In this study, defect-free cyclic P3HT with a degree of polymerization (DPn) from 14 to 43 was synthesized based on our previously established method, and its unique redox behaviors arising from the cyclic topology were investigated. Cyclic voltammetry (CV) showed that the HOMO level of cyclic P3HT decreases from -4.86 eV (14 mer) to -4.89 eV (43 mer), in contrast to the linear counterparts increasing from -4.94 eV (14 mer) to -4.91 eV (43 mer). During the CV measurement, linear P3HT suffered from electro-oxidation at the chain ends, while cyclic P3HT was stable. ESR and UV-Vis-NIR spectroscopy suggested that cyclic P3HT has stronger dicationic properties due to the interactions between the polarons. On the other hand, linear P3HT showed characteristics of polaron pairs with multiple isolated polarons. Moreover, the dicationic properties of cyclic P3HT were more pronounced for the smaller macrocycles.

Electron Paramagnetic Resonance Implemented with Multiple Harmonic Detections Successfully Maps Extracellular pH In Vivo.

Extracellular acidification indicates a metabolic shift in cancer cells and is, along with tissue hypoxia, a hallmark of tumor malignancy. Thus, non-invasive mapping of extracellular pH (pHe) is essential for researchers to understand the tumor microenvironment and to monitor tumor response to metabolism-targeting drugs. While electron paramagnetic resonance (EPR) has been successfully used to map pHe in mouse xenograft models, this method is not sensitive enough to map pHe with a moderate amount of exogenous pH-sensitive probes. Here, we show that a modified EPR system achieves twofold higher sensitivity by using the multiple harmonic detection (MHD) method and improves the robustness of pHe mapping in mouse xenograft models. Our results demonstrate that treatment of a mouse xenograft model of human-derived pancreatic ductal adenocarcinoma cells with the carbonic anhydrase IX (CAIX) inhibitor U-104 delays tumor growth with a concurrent tendency toward further extracellular acidification. We anticipate that EPR-based pHe mapping can be expanded to monitor the response of other metabolism-targeting drugs. Furthermore, pHe monitoring can also be used for the development of improved metabolism-targeting cancer treatments.

Risks and benefits of transurethral resection of the bladder tumor using photodynamic diagnosis with oral 5-aminolevulinic acid hydrochloride according to age and history of recurrence in patients with non-muscle invasive bladder cancer.

BACKGROUND: Patient selection for transurethral resection of the bladder tumor using photodynamic diagnosis (PDD-TURBT) with oral 5-aminolevulinic acid (5-ALA) hydrochloride for non-muscle-invasive bladder cancer (NMIBC) is still unclear as to the best balance of risks (adverse events including hypotension) and benefits (reduction of intravesical recurrence). METHODS: This single-center retrospective study between April 2013 and March 2022, compared the intravesical recurrence-free survival between patients who underwent PDD-TURBT and WL-TURBT using propensity score matching. RESULTS: A total of 222 patients who underwent PDD-TURBT and 177 patients who underwent WL-TURBT for NMIBC were included. Propensity score matching was used to compare intravesical recurrence-free survival in 119 NMIBC patients in the both treatment groups. The intravesical recurrence-free survival within 500 days was significantly higher in the PDD-TURBT group than in the WL-TURBT group (P = 0.039; hazard ratio [HR] 0.48 [0.23-0.98]). Subgroup analysis showed that PDD-TURBT contributed to the reduction of short-term intravesical recurrence in patients aged < 75 years (P = 0.02; HR 0.22 [0.06-0.79]) and primary disease (P = 0.038; HR 0.35 [0.13-0.94]). Hypotension with a systolic blood pressure of < 80 mmHg was observed in 79 patients (35.6%) during PDD-TURBT surgery. In particular, age ≥75 years and general anesthesia were independent prognostic factors for predicting intraoperative hypotension. CONCLUSIONS: PDD-TURBT reduced short-term intravesical recurrence in NMIBC, whereas a higher frequency of hypotension was found in patients aged ≥ 75 years. These results suggest that the risks and benefits of PDD-TURBT are well balanced in younger patients (< 75 years) and those with primary disease.

The efficacy of trimodal chemoradiotherapy with gemcitabine and cisplatin as a bladder-preserving strategy for the treatment of muscle-invasive bladder cancer: a single-arm phase II study.

OBJECTIVE: Radical cystectomy remains the standard treatment for muscle-invasive bladder cancer; however, a substantial number of patients with muscle-invasive bladder cancer are not appropriate candidates to radical cystectomy due to co-morbidities or anxiety regarding bladder preservation. Trimodal bladder-sparing therapy is an intelligent and attractive treatment option for such patients. We established a novel treatment strategy using trimodal treatment with gemcitabine and cisplatin. METHODS: Patients diagnosed with muscle-invasive bladder cancer by transurethral resection of bladder tumor and who wished for bladder preservation were recruited. The regimens were gemcitabine 300 mg/m2 and cisplatin 30 mg/m2 in day 1 and concomitant irradiation 1.8 Gy/Fr, five fractions per week. Irradiation was administered to the true pelvis up to 36 Gy and was then boosted to the entire bladder until a total of 54 Gy. Transurethral resection of bladder tumor was also performed after chemoradiotherapy to evaluate pathological response to treatment. We evaluated treatment efficacy and survival, safety of chemoradiotherapy with gemcitabine and cisplatin. RESULTS: Thirty-eight patients were enrolled, and three patients were excluded. Pathological complete response after chemoradiotherapy was observed in 31 patients, and the 5-year bladder-intact metastasis-free survival rate was 76%. The 5-year cancer-specific and overall survival rates for chemoradiotherapy were 85 and 75%, respectively, which were not significantly different from those for radical cystectomy (73 and 71%, respectively). Grade 3/4 adverse events included neutropenia (63%), anemia (18%) and thrombocytopenia (37%); however, treatment-related deaths were not observed. CONCLUSIONS: Chemoradiotherapy using gemcitabine and cisplatin for muscle-invasive bladder cancer is effective for local cancer control and shows no significant difference in oncological prognosis compared with radical cystectomy.

Identification of Inhibitory Activities of Dietary Flavonoids against URAT1, a Renal Urate Re-Absorber: In Vitro Screening and Fractional Approach Focused on Rooibos Leaves.

Hyperuricemia, a lifestyle-related disease characterized by elevated serum urate levels, is the main risk factor for gout; therefore, the serum urate-lowering effects of human diets or dietary ingredients have attracted widespread interest. As Urate transporter 1 (URAT1) governs most urate reabsorption from primary urine into blood, URAT1 inhibition helps decrease serum urate levels by increasing the net renal urate excretion. In this study, we used a cell-based urate transport assay to investigate the URAT1-inhibitory effects of 162 extracts of plant materials consumed by humans. Among these, we focused on Aspalathus linearis, the source of rooibos tea, to explore its active ingredients. Using liquid-liquid extraction with subsequent column chromatography, as well as spectrometric analyses for chemical characterization, we identified quercetin as a URAT1 inhibitor. We also investigated the URAT1-inhibitory activities of 23 dietary ingredients including nine flavanols, two flavanonols, two flavones, two isoflavonoids, eight chalcones, and a coumarin. Among the tested authentic chemicals, fisetin and quercetin showed the strongest and second-strongest URAT1-inhibitory activities, with IC50 values of 7.5 and 12.6 µM, respectively. Although these effects of phytochemicals should be investigated further in human studies, our findings may provide new clues for using nutraceuticals to promote health.

Redox-Sensitive Mapping of a Mouse Tumor Model Using Sparse Projection Sampling of Electron Paramagnetic Resonance.

Aims: This work aimed to establish an accelerated imaging system for redox-sensitive mapping in a mouse tumor model using electron paramagnetic resonance (EPR) and nitroxyl radicals. Results: Sparse sampling of EPR spectral projections was demonstrated for a solution phantom. The reconstructed three-dimensional (3D) images with filtered back-projection (FBP) and compressed sensing image reconstruction were quantitatively assessed for the solution phantom. Mouse xenograft models of a human-derived pancreatic ductal adenocarcinoma cell line, MIA PaCa-2, were also measured for redox-sensitive mapping with the sparse sampling technique. Innovation: A short-lifetime redox-sensitive nitroxyl radical (15N-labeled perdeuterated Tempone) could be measured to map the decay rates of the EPR signals for the mouse xenograft models. Acceleration of 3D EPR image acquisition broadened the choices of nitroxyl radical probes with various redox sensitivities to biological environments. Conclusion: Sparse sampling of EPR spectral projections accelerated image acquisition in the 3D redox-sensitive mapping of mouse tumor-bearing legs fourfold compared with conventional image acquisition with FBP. Antioxid. Redox Signal. 36, 57-69.

Hyperpolarized 13C Magnetic Resonance Imaging as a Tool for Imaging Tissue Redox State, Oxidative Stress, Inflammation, and Cellular Metabolism.

Significance: Magnetic resonance imaging (MRI) with hyperpolarized (HP) 13C-labeled redox-sensitive metabolic tracers can provide noninvasive functional imaging biomarkers, reflecting tissue redox state, oxidative stress, and inflammation, among others. The capability to use endogenous metabolites as 13C-enriched imaging tracers without structural modification makes HP 13C MRI a promising tool to evaluate redox state in patients with various diseases. Recent Advances: Recent studies have demonstrated the feasibility of in vivo metabolic imaging of 13C-labeled tracers polarized by parahydrogen-induced polarization techniques, which offer a cost-effective alternative to the more widely used dissolution dynamic nuclear polarization-based hyperpolarizers. Critical Issues: Although the fluxes of many metabolic pathways reflect the change in tissue redox state, they are not functionally specific. In the present review, we summarize recent challenges in the development of specific 13C metabolic tracers for biomarkers of redox state, including that for detecting reactive oxygen species. Future Directions: Applications of HP 13C metabolic MRI to evaluate redox state have only just begun to be investigated. The possibility to gain a comprehensive understanding of the correlations between tissue redox potential and metabolism under different pathological conditions by using HP 13C MRI is promoting its interest in the clinical arena, along with its noninvasive biomarkers to evaluate the extent of disease and treatment response.

Endoscopic laser treatment for urine leakage caused by an isolated calyx after robot-assisted partial nephrectomy.

INTRODUCTION: An isolated calyx is a rare complication in which the renal calyx and pelvis are disconnected. The treatment is often complicated. CASE PRESENTATION: An 81-year-old man underwent robot-assisted partial nephrectomy for the treatment of renal cell carcinoma (cT1bN0M0). Postoperatively, urine leakage was observed and did not improve with conservative measures. Retrograde pyelography and computed tomography revealed that urine leakage originated from the isolated calyx caused by infundibular stenosis. Endoscopic treatment via the transurethral approach was selected to preserve renal function. Ureteroscopy showed that the upper calyx was completely obstructed by the sutures. Therefore, we cut the suture thread using laser, and a ureteral stent was placed in the upper renal calyx. Fluid drainage immediately disappeared after the procedure, and the patient did not lose renal function. CONCLUSION: Endoscopic management might be an option for isolated calyx after robot-assisted partial nephrectomy.

A 2.0-GHz compact ESR spectrometer for monitoring automobile lubrication oil degradation.

This article reports a simple, compact, and cost-effective electron spin resonance (ESR) spectrometer for monitoring automobile lubrication oil degradation. Lubrication oil degradation strongly correlates with the concentration of stable free radicals caused by hydrocarbon chain decomposition due to heating. For the prototype spectrometer, the amplitude shift in a marginal oscillator output detects ESR absorption in a sample. The spectrometer's spin sensitivity of 2.3 × 1014 spins for a used oil sample was achieved using the marginal oscillator with a loop-gap resonator. For the prototype spectrometer, the oscillation frequency was 2.09 GHz. The volume of the prototype spectrometer was 1.3 L, including a permanent magnet, microwave circuits, and digital communication circuitry on printed circuit boards. The weight of the spectrometer setup was 1.45 kg. This prototype spectrometer successfully detected the ESR signal from a 50 µL oil sample (spin concentration 8.3 x1019 spins/L) with a signal-to-noise ratio of 37 and an acquisition time of 30 s.

Novel bone microenvironment model of castration-resistant prostate cancer with chitosan fiber matrix and osteoblasts.

The interaction between prostate cancer cells and osteoblasts is essential for the development of bone metastasis. Previously, novel androgen receptor axis-targeted agents (ARATs) were approved for metastatic castration-naïve and non-metastatic castration-resistant prostate cancer (CRPC); both of which are pivotal for investigating the association between the bone microenvironment and tumors. The present study established a novel in vitro 3D microenvironment model that simulated the bone microenvironment of CRPC, and evaluated the drug susceptibility of ARATs and the efficacy of the combination of abiraterone and dutasteride. Green fluorescent protein-transferred C4-2 cells (a CRPC cell line) and red fluorescent protein-transferred human osteoblasts differentiated from human mesenchymal stem cells were co-cultured in chitosan nanofiber matrix-coated culture plates to simulate the 3D scaffold of the bone microenvironment. The growth of C4-2 was quantified using live-cell imaging and the Cell3 iMager duos analysis system. The growth of C4-2 colonies were quantified for a maximum of 30 days. The expression of TGF-ß increased and promoted EMT in C4-2 cells co-cultured with osteoblasts, indicating resistance to ARATs. The IC50 of each drug and the combination effect of abiraterone and dutasteride were evaluated using this model. Combination treatment with abiraterone and dutasteride synergistically inhibited the growth of C2-4 colonies compared with individual investigational agents. This could be attributed to the reduction of 3-keto-5α-abiraterone, an androgen receptor agonist. The bone microenvironment model of the present study is unique and useful for evaluating new drug susceptibility testing in prostate cancer cells. This model may help to reveal the unknown mechanisms underlying micro- to clinical bone metastasis in prostate cancer.

High fidelity triangular sweep of the magnetic field for millisecond scan EPR imaging.

Linearity of the magnetic field sweep is important for high resolution continuous wave EPR imaging. Driving the field with triangular wave function is the most efficient way to scan EPR projections. However, the magnetic field sweep profile can be significantly distorted during fast millisecond projection scan. In this work, we introduce a method to generate highly linear and properly symmetrical triangular sweeps of the magnetic field using calibrated harmonics of the triangular wave function. First, the frequency response function of the EPR magnet and its power circuitry was obtained. For this, the field sweeping coil was driven with sinusoidal signals of different frequencies and the actual magnetic field inside the magnet was recorded. To cover wide range of frequencies, the measurements were carried out independently using gaussmeter, Hall-effect linear sensor integrated circuit, and an inductance coil. For each frequency, the system gain and the phase delay were determined. These data were used to adjust the amplitudes and the phases of individual harmonics of the triangular wave function. After the calibration, the maximum deviation of the magnetic field from the linear function was 0.05% of sweep width for 4 ms scan. The maximum discrepancy between the forward and the reverse scan was less than 0.04%. Sweep overhead time for changing the scan direction was 5%. The proposed approach allows generation of high fidelity triangular magnetic field sweeps with accuracy better than 0.1% for the range of the magnetic field sweep widths up to 48 G and scan duration from 10 s down to 1 ms.

Hyperpolarized 13 C Magnetic Resonance Imaging of Fumarate Metabolism by Parahydrogen-induced Polarization: A Proof-of-Concept in†vivo Study.

The front cover artwork is provided by the group of Dr. Neil J. Stewart, Prof. Hiroshi Hirata, and Dr. Shingo Matsumoto (Hokkaido University, Japan) as well as Dr. Takuya Hashimoto (Chiba University, Japan). The image shows hyperpolarized 13 C fumarate metabolism to hyperpolarized 13 C malate, which is released into the extracellular space in regions of necrotic cell death, where the cell membrane is disrupted. Read the full text of the Article at 10.1002/cphc.202001038.