Search

Abstract Background The predictive power of the treatment efficacy and prognosis in primary androgen deprivation therapy (ADT) for advanced prostate cancer is not satisfactory. The objective of this study was to integrate genetic and clinical data to predict castration resistance in primary ADT for advanced prostate cancer by machine learning (ML). Methods Clinical and single nucleotide polymorphisms (SNP) data obtained in the KYUCOG-1401-A study (UMIN000022852) that enrolled Japanese patients with advanced prostate cancer were used. All patients were treated with primary ADT. A point-wise linear (PWL) algorithm, logistic regression with elastic-net regularization, and eXtreme Gradient Boosting were the ML algorithms used in this study. Area under the curve for castration resistance and C-index for prognoses were calculated to evaluate the utility of the models. Results Among the three ML algorithms, the area under the curve values to predict castration resistance at 2 years was highest for the PWL algorithm with all the datasets. Three predictive models (clinical model, small SNPs model, and large SNPs model) were created by the PWL algorithm using the clinical data alone, and 2 and 46 SNPs in addition to clinical data. C-indices for overall survival by the clinical, small SNPs, and large SNPs models were 0.636, 0.621, and 0.703, respectively. Conclusion The results demonstrated that the SNPs models created by ML produced excellent prediction of castration resistance and prognosis in primary ADT for advanced prostate cancer, and will be helpful in treatment choice.

Abstract Cardiac glycosides, known as inhibitors of Na+,K+-ATPase, have anti-cancer effects such as suppression of cancer cell proliferation and induction of cancer cell death. Here, we examined the signaling pathway elicited by cardiac glycosides in the human hepatocellular carcinoma HepG2 cells and human epidermoid carcinoma KB cells. Three kinds of cardiac glycosides (ouabain, oleandrin, and digoxin) inhibited the cancer cell proliferation and decreased the expression level of thyroid adenoma-associated protein (THADA). Interestingly, the knockdown of THADA inhibited cancer cell proliferation, and the proliferation was significantly rescued by re-expression of THADA in the THADA-knockdown cells. In addition, the THADA-knockdown markedly decreased the expression level of L-type amino acid transporter LAT1. Cardiac glycosides also reduced the LAT1 expression. The LAT1 inhibitor, JPH203, significantly weakened the cancer cell proliferation. These results suggest that the binding of cardiac glycosides to Na+,K+-ATPase negatively regulates the THADA-LAT1 pathway, exerting the anti-proliferative effect in cancer cells.

Abstract Mutations in the human ATP13A2 (PARK9), a lysosomal ATPase, cause Kufor-Rakeb Syndrome, an early-onset form of Parkinson’s disease (PD). Here, we demonstrate that ATP13A2 functions as a lysosomal H+,K+-ATPase. The K+-dependent ATPase activity and the lysosomal K+-transport activity of ATP13A2 are inhibited by an inhibitor of sarco/endoplasmic reticulum Ca2+-ATPase, thapsigargin, and K+-competitive inhibitors of gastric H+,K+-ATPase, such as vonoprazan and SCH28080. Interestingly, these H+,K+-ATPase inhibitors cause lysosomal alkalinization and α-synuclein accumulation, which are pathological hallmarks of PD. Furthermore, PD-associated mutants of ATP13A2 show abnormal expression and function. Our results suggest that the H+/K+-transporting function of ATP13A2 contributes to acidification and α-synuclein degradation in lysosomes.

Abstract Background The phase 3 CLEAR study demonstrated statistically significantly improved efficacy with lenvatinib plus pembrolizumab versus sunitinib, including progression‐free survival and overall survival, in patients with previously untreated advanced renal cell carcinoma. This subset analysis investigated efficacy and safety in Japanese patients randomized to lenvatinib plus pembrolizumab or sunitinib in the CLEAR study. Methods Progression‐free survival, overall survival, tumor response, and safety were assessed in Japanese patients with previously untreated advanced renal cell carcinoma randomized to receive lenvatinib plus pembrolizumab (n = 42) or sunitinib (n = 31). Efficacy outcomes were analyzed by independent imaging review per Response Evaluation Criteria in Solid Tumors, version 1.1. Results Progression‐free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 22.1 vs. 10.9 months; hazard ratio, 0.39; 95% CI, 0.20–0.74). Median overall survival was not estimable in the lenvatinib plus pembrolizumab arm and 30.6 months in the sunitinib arm (HR, 1.20; 95% CI, 0.39–3.66). Overall survival adjusted for the imbalance of Memorial Sloan‐Kettering Cancer Center prognostic risk group favored lenvatinib plus pembrolizumab (hazard ratio, 0.67; 95% CI, 0.18–2.39). Objective response rate (69.0% vs. 45.2%; odds ratio, 2.71; 95% CI, 1.03–7.10) was higher and median duration of response (20.3 vs. 9.1 months) was longer with lenvatinib plus pembrolizumab versus sunitinib. Grade ≥ 3 treatment‐emergent adverse events occurred in 95.2% versus 87.1% of patients in the lenvatinib plus pembrolizumab versus sunitinib arms. Conclusions These findings support lenvatinib plus pembrolizumab as a potential first‐line treatment for Japanese patients with advanced renal cell carcinoma.

Abstract Bitterness is an important physiological function in the defense responses to avoid toxic foods. The taste receptor 2 family is well known to mediate bitter taste perception in Type II taste cells. Here, we report that the polycystic kidney disease 2-like 1 (PKD2L1) channel is a novel sensor for the bitter aftertaste in Type III taste cells. The PKD2L1 channel showed rebound activation after the washout of quinine, a bitter tastant, in electrophysiological whole-cell recordings of the PKD2L1-expressing HEK293T cells and Ca2+-imaging analysis of Type III taste cells isolated from wild-type PKD2L1 mice. In the short-term two-bottle preference and lick tests in vivo, the wild-type mice avoided normal water while the PKD2L1-knockout mice preferred normal water after they ingested the quinine-containing water. These results may explain the new mechanism of the quinine-triggered bitter aftertaste perception in Type III taste cells.

Nanodiscs belong to a category of water-soluble lipid bilayer nanoparticles. In vivo nanodisc platforms are useful for studying isolated membrane proteins in their native lipid environment. Thus, the development of a practical method for nanodisc reconstruction has garnered consider-able research interest. This paper reports the self-assembly of a mixture of bio-derived cyclic peptide, surfactin (SF), and l-α-dimyristoylphosphatidylcholine (DMPC). We found that SF induced the solubilization of DMPC multilamellar vesicles to form their nanodiscs, which was confirmed by size-exclusion chromatography, dynamic light scattering, and transmission electron microscopy analyses. Owing to its amphiphilic nature, the self-assembled structure prevents the exposure of the hydrophobic lipid core to aqueous media, thus embedding ubiquinol (CoQ10) as a hydrophobic model compound within the inner region of the nanodiscs. These results highlight the feasibility of preparing nanodiscs without the need for laborious procedures, thereby showcasing their potential to serve as promising carriers for membrane proteins and various organic compounds. Additionally, the regulated self-assembly of the DMPC/SF mixture led to the formation of fibrous architectures. These results show the potential of this mixture to function as a nanoscale membrane surface for investigating molecular recognition events.

Objectives To examine the national, 6-year trends in in-hospital clinical outcomes of patients with subarachnoid haemorrhage (SAH) who underwent clipping or coiling and the prognostic influence of temporal trends in the Comprehensive Stroke Center (CSC) capabilities on patient outcomes in Japan.Design Retrospective study.Setting Six hundred and thirty-one primary care institutions in Japan.Participants Forty-five thousand and eleven patients with SAH who were urgently hospitalised, identified using the J-ASPECT Diagnosis Procedure Combination database.Primary and secondary outcome measures Annual number of patients with SAH who remained untreated, or who received clipping or coiling, in-hospital mortality and poor functional outcomes (modified Rankin Scale: 3–6) at discharge. Each CSC was assessed using a validated scoring system (CSC score: 1–25 points).Results In the overall cohort, in-hospital mortality decreased (year for trend, OR (95% CI): 0.97 (0.96 to 0.99)), while the proportion of poor functional outcomes remained unchanged (1.00 (0.98 to 1.02)). The proportion of patients who underwent clipping gradually decreased from 46.6% to 38.5%, while that of those who received coiling and those left untreated gradually increased from 16.9% to 22.6% and 35.4% to 38%, respectively. In-hospital mortality of coiled (0.94 (0.89 to 0.98)) and untreated (0.93 (0.90 to 0.96)) patients decreased, whereas that of clipped patients remained stable. CSC score improvement was associated with increased use of coiling (per 1-point increase, 1.14 (1.08 to 1.20)) but not with short-term patient outcomes regardless of treatment modality.Conclusions The 6-year trends indicated lower in-hospital mortality for patients with SAH (attributable to better outcomes), increased use of coiling and multidisciplinary care for untreated patients. Further increasing CSC capabilities may improve overall outcomes, mainly by increasing the use of coiling. Additional studies are necessary to determine the effect of confounders such as aneurysm complexity on outcomes of clipped patients in the modern endovascular era.

α-Form hydrated crystals form a lamellar gel in which the alkyl chains of the amphiphilic molecules are hexagonally arranged within bilayers below the gel–liquid crystal phase transition temperature. In practice, the lamellar gel network with excess water is called an “α-gel”, particularly in the cosmetics industry. In this study, the hydration or water sorption of amphiphilic materials in water vapor was assessed using a humidity-controlled quartz crystal microbalance with dissipation monitoring (QCM-D) technique. The amphiphilic materials used in this study were hexadecyl phosphate salts neutralized with L-arginine (C16P-Arg), CsOH (C16P-Cs), KOH (C16P-K), and NaOH (C16P-Na). Small- and wide-angle X-ray scattering measurements revealed that C16P-Arg and C16P-Cs yielded α-form hydrated crystals. Humidity-controlled QCM-D measurements demonstrated that C16P-Arg and C16P-Cs more readily underwent hydration or water sorption than C16P-K and C16P-Na. The key conclusion is that the significant hydration ability of C16P-Arg and C16P-Cs promotes the formation of the corresponding α-form hydrated crystals.

Abstract Background Hemodialysis (HD) is a common renal replacement therapy for patients with renal failure. Cardiovascular and cerebrovascular diseases are known to shorten survival periods and worsen the quality of life of HD patients. Atherosclerosis is a major cause of vascular diseases, and various factors such as abnormality of lipid metabolism and increased macrophage activity, oxidative stress, and endothelial dysfunction are associated with its pathogenesis and progression. Further, endothelial stem cells (ESCs) have been reported to play important roles in endothelial functions. Royal jelly (RJ) affects atherosclerosis- and endothelial function-related factors. The main aim of this trial is to investigate whether oral intake of RJ can maintain endothelial function in HD patients. In addition, the effects of RJ intake on atherosclerosis, ESC count, inflammation, and oxidative stress will be analyzed. Methods This will be a multicenter, prospective, double-blind, randomized controlled trial. We will enroll 270 participants at Nagasaki Jin Hospital, Shinzato Clinic Urakami, and Maeda Clinic, Japan. The participants will be randomized into RJ and placebo groups. The trial will be conducted according to the principles of the Declaration of Helsinki, and all participants will be required to provide written informed consent. The RJ group will be treated with 3600 mg/day of RJ for 24 months, and the placebo group will be treated with starch for 24 months. The primary endpoint will be the change in flow-mediated dilation (FMD), a parameter of endothelium function, from the time before treatment initiation to 24 months after treatment initiation. The secondary and other endpoints will be changes in FMD; ESC count; serum levels of vascular endothelial cell growth factor, macrophage colony-stimulating factor, 8-hydroxydeoxyguanosine, and malondialdehyde; the incidence of cardiovascular diseases, cerebrovascular diseases, and stenosis of blood access; and safety. Discussion This trial will clarify whether oral intake of RJ can maintain endothelial function and suppress the progression of atherosclerosis in HD patients. In addition, it will clarify the effects of RJ on ESCs, oxidative stress, and angiogenic activity in blood samples. Trial registration The Japan Registry of Clinical Trials jRCTs071200031 . Registered on 7 December 2020.

Abstract Prostaglandin E2 plays an important role in carcinogenesis and malignant potential of prostate cancer (PC) cells by binding to its specific receptors, E-type prostanoid (EP) receptors. However, anti-carcinogenic effects of the EP receptor antagonist are unclear. In this study, we used a mouse model of PC. The mice were provided standard feed (control) or feed containing the EP1 receptor antagonist and were sacrificed at 10, 15, 30, and 52 weeks of age. Apoptosis was evaluated by immunohistochemical analysis using a cleaved caspase-3 assay. The incidence of cancer in the experimental group was significantly lower than that in the control group at 15, 30, and 52 weeks of age. The percentage of poorly differentiated PC cells was significantly lower in the experimental group than in the control group at 30 and 52 weeks of age. The percentage of apoptotic cells in the experimental group was significantly higher than that in the control group at 15, 30, and 52 weeks of age. These findings indicate that feeding with the addition of EP1 receptor antagonist delayed PC progression via the upregulation of apoptosis. We suggest that the EP1 receptor antagonist may be a novel chemopreventive agent for PC.

Introduction Neurogenic overactive bladder is a main feature of human T‐cell leukemia virus type 1‐associated myelopathy/tropical spastic paraparesis. We successfully performed intravesical onabotulinumtoxinA therapy for refractory neurogenic overactive bladder due to human T‐cell leukemia virus type 1‐associated myelopathy/tropical spastic paraparesis. Case presentation We retrospectively reviewed four neurogenic overactive bladder patients with human T‐cell leukemia virus type 1‐associated myelopathy/tropical spastic paraparesis who underwent bladder wall injections of onabotulinumtoxinA from April to October 2020. All patients were female. Their median age was 66 (range, 63–71) years. They were previously treated with β3‐adrenergic receptor agonists or anticholinergic drugs alone or in combination for ≥12 weeks. However, insufficient results were obtained. After 4 weeks of intravesical onabotulinumtoxinA therapy, overactive bladder symptoms improved and maximum cystometric capacity increased in all cases. Conclusion Intravesical onabotulinumtoxinA therapy may be useful for treating refractory overactive bladder due to human T‐cell leukemia virus type 1‐associated myelopathy/tropical spastic paraparesis.

Experienced drivers sometimes explain vehicle transient behavior to steering as "after the front wheels start to turn, the rear wheels start to turn with a delay" or "the rear wheels swing around the front wheels like a pendulum. In this paper, the former is called two-stage motion and the latter is called pendulum motion. In order to realize more fun handling performance, it would be effective to physically understand these motions and to reflect these understanding into vehicle developments. Thus, these motions were studied using equations of motion. In these studies, however, since the yaw moment of inertia has been limited to a special case, the valid ranges to which these studies results can be applied are unknown. Therefore, this paper studies these motions for general cases of yaw moments of inertia. Firstly, this paper yields the equations of motion for two-stage motion by algebraically manipulating the equations for, so-called, bicycle model whose yaw moment of inertia is not limited. These yielded equations mean that the front wheels begin to turn immediately after steering, and then the point a, where one of impact centers locates, begins to turn with a delay. Secondly, these equations are transformed into form of the true pendulum equation, whose one of the variables is the attitude angle at position e, where the attitude angle is zero on steady turn. By interpreting these equations, finally, it is pointed out that the pendulum motion is a phenomenon in which the point a accelerates toward the extension of the speed vector at the point e.

Abstract Photo-induced rapid control of molecular assemblies, such as micelles and vesicles, enables effective and on-demand release of drugs or active components, with applications such as drug delivery systems (DDS) and cosmetics. Thus far, no attempts to optimize the responsiveness of photoresponsive molecular assemblies have been published. We previously reported photoresponsive surfactants bearing a lophine dimer moiety that exhibit fast photochromism in confined spaces, such as inside a molecular assembly. However, rapid control of the micelle structures and solubilization capacity have not yet been demonstrated. In the present work, photo-induced morphological changes in micelles were monitored using in-situ small-angle neutron scattering (SANS) and UV/Vis absorption spectroscopy. An amphiphilic lophine dimer (3TEG-LPD) formed elliptical micelles. These were rapidly elongated by ultraviolet light irradiation, which could be reversed by dark treatment, both within 60 s. For a solution of 3TEG-LPD micelles solubilizing calcein as a model drug molecule, fluorescence and SANS measurements indicated rapid release of the incorporated calcein into the bulk solvent under UV irradiation. Building on these results, we investigated rapid controlled release via hierarchical chemical processes: photoisomerization, morphological changes in the micelles, and drug release. This rapid controlled release system allows for effective and on-demand DDS.

Abstract This study aimed to investigate the efficacy of salt intake restriction on overactive bladder (OAB) symptoms in patients with excessive salt intake. Patients received a brochure on nutritional guidance regarding salt intake reduction and received health education every 4 weeks for 12 weeks. Data from overactive bladder symptom score (OABSS) questionnaires and frequency volume charts (FVCs) were evaluated. The daily salt intake was estimated by determining the urinary sodium and creatinine concentrations using spot urine samples. Of the 98 patients included, 71 (72.4%) successfully restricted their daily salt intake after 12 weeks (salt restricted [R] group), while 27 (27.6%) did not (salt non-restricted [N-R] group). The scores to each OABSS question and the resulting total score improved significantly in the R group; however, the individual scores remained unchanged and the total score increased in the N-R group. The FVC data indicated improved voided volumes in the R group as compared to in the N-R group. Ultimately, 17 (23.9%) patients in the R group no longer fulfilled the OAB diagnostic criteria after salt intake reduction. Thus, salt intake reduction improved urinary symptoms in patients with OAB and may be a therapeutic option for OAB in patients with excessive daily salt intakes.

Abstract A biomembrane's role is to be a barrier for interior cytosol from an exterior environment to execute the cell's normal biological functions. However, a water-soluble peptide called cell-penetrating peptide (CPP) has been known for its ability to directly penetrate through the biomembranes into cells (cytolysis) without perturbating cell viability and expected to be a promising drug delivery vector. Examples of CPP include peptides with multiple arginine units with strong cationic properties, which is the key to cytolysis. Here we show the conclusive evidence to support the mechanism of CPP’s cytolysis and way to control it. The mechanism we proposed is attributed to biomembrane’s physicochemical nature as lamellar liquid crystal (Lα). Cytolysis occurs as the temporal and local dynamic phase transitions from Lα to an undulated lamellar with pores called Mesh1. We have shown this phase transfer of Lα composed of dioleoyl-phosphatidylcholine (DOPC) with water by adding oligo-arginine (Rx) as CPP at the equilibrium. Using giant unilamellar vesicle composed of DOPC as a single cell model, we could control the level of cytolysis of CPP (FITC-R8) by changing the curvature of the membrane through osmotic pressure modulation. The cytolysis of CPP utilizes biomembrane's inherent topological and functional flexibility corresponding to the stimuli.

Abstract Background Renal hypouricemia (RHUC) is a genetic disorder caused by mutations in the SLC22A12 gene, which encodes the major uric acid (UA) transporter, URAT1. The clinical course of related, living donor-derived RHUC in patients undergoing kidney transplantation is poorly understood. Here, we report a case of kidney transplantation from a living relative who had an SLC22A12 mutation. After the transplantation, the recipient’s fractional excretion of UA (FEUA) decreased, and chimeric tubular epithelium was observed. Case presentation A 40-year-old man underwent kidney transplantation. His sister was the kidney donor. Three weeks after the transplantation, he had low serum-UA, 148.7 μmol/L, and elevated FEUA, 20.8% (normal:

Abstract Brain metastasis from prostate cancer may be becoming more common and may be associated with occurrence of diffuse systemic metastases.

Current methods to measure extracellular pH are often limited in resolution and response times. Here the authors present a label-free nanoprobe, consisting of a zwitterionic nanomembrane at the tip of a nanopipette, which enables high spatiotemporal resolution pH measurements and topography-pH 3D mapping in live cancer cells.

Spontaneous intraperitoneal renal rupture with urinoma formation in fetuses is an unusual condition that is caused by upper or lower urinary tract obstruction. We report the case of a neonatal male infant who presented with a spontaneous intraperitoneal right renal rupture accompanying ipsilateral ureterovesical junction obstruction (UVJO). Fetuses with UVJO accompanying contralateral multicystic dysplastic kidney should be observed carefully because of the risk of spontaneous renal rupture.

Bleeding from a dural arteriovenous fistula (DAVF) typically occurs in the form of an intracerebral or subarachnoid hemorrhage. Here, we report a rare case of a DAVF with an acute subdural hematoma (ASDH). A 29-year-old male presented to the emergency department with a complaint of progressing headache and nausea, with no reported episode of head trauma. Non-contrast CT revealed a left ASDH with a moderate midline shift. Digital subtraction angiography revealed a DAVF on the left parietal convexity. The DAVF was fed by the middle meningeal artery and drained into the superior sagittal sinus and the sphenoparietal sinus via the diploic vein without cortical venous reflux. The DAVF was treated with transarterial embolization using 25% diluted n-butyl cyanoacrylate prior to hematoma removal. The bleeding point was confirmed on the inner surface of the dura mater. The patient recovered well without any neurological deficits.

Abstract Background Higher serum uric acid (UA) levels are associated with poorer renal prognosis. In kidney transplantation, both donors and recipients are diagnosed as having chronic kidney diseases (CKD) based on renal function; however, their UA levels slightly vary. Elucidating the differences in UA would help improve kidney prognosis, especially for recipients. Therefore, we investigated UA levels in kidney transplant recipients by comparing them to those in their donors. Methods In this retrospective cross-sectional survey, background information and blood examination results were collected from the donors just before donation and after transplantation in the donors and recipients. Associations between UA and sex estimated glomerular filtration rate (eGFR), and body mass index (BMI) were evaluated. Data were assessed by the Wilcoxon rank-sum test for continuous variables and the chi-squared test for categorical variables; multiple linear regression analyses were performed to determine which factors were associated with renal function before and after transplantation. Results Participant characteristics were as follows. The mean donor age (n = 45, 16 men and 29 women) was 55 ± 11 years, and the mean recipient age (n = 45, 25 men and 20 women) was 46 ± 16 years. Sex-related differences (UA levels in men were predominant) existed in the UA of donors before (P < 0.001) and after donation (P < 0.001). Conversely, there were no significant sex-related differences in the UA of recipients (P = 0.51); the mean standardized eGFRs were similar in donors and recipients after transplantation. Multivariate linear regression analysis showed donor UA only correlated with donor sex before donation (P = 0.008). After donation, donor UA was associated with donor sex (P = 0.006), eGFR (P < 0.001), and BMI (P = 0.02). Notably, the UA of recipients after transplantation was only associated with eGFR (P = 0.003). Conclusions Sex has less impact on UA in recipients than in donors. UA has a greater impact on renal prognosis in women than men, even at the same UA level. Therefore, attention should be given to UA levels in female recipients. These findings can be useful for determining patient prognosis following kidney transplantation in both donors and recipients.

Introduction Paragangliomas have a rich blood flow and are located around large vessels; thus, resection is often difficult. We herein report a case of a paraganglioma that was located immediately behind the inferior vena cava and bilateral renal veins and successfully resected by laparoscopic surgery. Case presentation A 72‐year‐old man was incidentally diagnosed with a 7‐cm retroperitoneal mass immediately behind the inferior vena cava and bilateral renal veins by computed tomography. The mass was diagnosed as a retroperitoneal paraganglioma. The patient underwent laparoscopic surgery in the left lateral decubitus position. The tumor was dissected completely with no complications. Conclusion Resection of retroperitoneal paragangliomas is often a surgical challenge. The feasibility of the laparoscopic approach to such paragangliomas was demonstrated in the present case.

Abstract Background High serum calcium levels should be avoided in patients on hemodialysis (HD) because they can induce cardiovascular diseases and worsen the patient’s prognosis. In contrast, low serum calcium levels worsen the prognosis of patients with cerebral hemorrhage in the general population. So far, whether serum calcium levels in patients on HD are associated with cerebral hemorrhage remains unknown. This study aimed to reveal the association between serum calcium and cerebral hemorrhage in patients on HD, including in-hospital death, volume of hematoma, and onset of cerebral hemorrhage. Methods This cross-sectional case-control study included 99 patients on HD with cerebral hemorrhage at a single center between July 1, 2007 and December 31, 2017. Controls included 339 patients on HD at a single HD center between July 1, 2011 and June 30, 2012. Data on serum calcium level, patient demographics, and comorbid conditions were collected, and associations between cerebral hemorrhage and subsequent death were evaluated by multivariate logistic regression analysis. Further, the association of these backgrounds and hematoma volume was evaluated by multiple regression analysis. Results Of the 99 patients, 32 (32%) died from cerebral hemorrhage. The corrected serum calcium level (odds ratio [OR], 2.49; 95% confidence interval [CI], 1.43–4.35; P

Abstract Background Transurethral resection (TUR) is the standard operation used for non-muscle invasive bladder cancer (NMIBC). Although most solid tumors are principally removed via single block resection without incising the mass, disruption of the lesion is unavoidable in traditional TUR. Furthermore, pathological diagnosis is often difficult due to heat-related denaturation of tissues in TUR. Although transurethral en-bloc resection is useful for judging tumor invasion, it is associated with a prolonged operative duration. We attempted to show the safety and usefulness of combined endoscopic mucosal resection (EMR) and en-bloc resection in NMIBC patients. Methods We investigated 39 patients with clinical NMIBC who were treated using our original EMR + en-bloc resection technique, which involved removal of the tumor mass that protruded from the mucosa, using a polypectomy snare similar to that used for EMR. The residual lesion was removed using en-bloc resection. The operative period, duration of hospitalization, and recurrence rates were compared with those of conventional TUR (n = 31). Results The mean (standard deviation, range) time interval for EMR and total operative duration were 1.6 (1.1, 1–5) min and 18.3 (10.5, 3–48) min, respectively. The total operative duration was comparable to that of TUR (17.3 min, p = 0.691). The mean duration of catheterization in the EMR + en-bloc resection group (4.2 days) was also similar to that in the TUR group (3.7 days; p = 0.285). No severe complications were observed with EMR + en-bloc resection. The pathologists were able to determine tumor invasiveness with considerable certainty in all specimens obtained via the EMR + en-bloc procedure than via TUR, and the difference in the ease of diagnosis was statistically significant (p = 0.016). Recurrence rates were comparable (p = 0.662) between the EMR + en-bloc (15.4%) and TUR groups (19.4%). Conclusions Our results demonstrated that the EMR + en-bloc resection technique is feasible, safe, and useful for treating patients with NMIBC. Furthermore, this technique helps provide a more accurate pathological diagnosis.

This paper starts with describing a method of deriving the resonance mode of a pendulum utilizing its equation of motion. Its resonance mode is that the particle accelerates toward the equilibrium position in the vertical plane including its fixed point. Therefore, a resonance mode can be derived by finding its equilibrium position and something to accelerate from its equation of motion. To derive the yaw resonance mode, the former paper transformed the equation of motion of vehicles into a structure that matches the equation of motion of the pendulum by assuming a special vehicle speed. This paper derives the yaw resonance mode at general velocities by modifying the variables that satisfy the configuration of the equation of motion derived in the former paper. As a result, this paper found that the yaw resonance equilibrium position is on the vehicle speed vector at the position where the side slip angle of the vehicle body is 0 in a steady state turning. This paper also found that something that accelerates towards equilibrium is the rear wheel. This acceleration of the rear wheels toward this extension is the restoration of yaw resonance.

Summary: Beginning of metastasis, cancer cells detach from the primary tumor and they can survive even under loss of anchorage; however, the detachment-elicited mechanisms have remained unknown. Here, we found that Na+,K+-ATPase α3-isoform (α3NaK) in human cancer cells is dynamically translocated from intracellular vesicles to the plasma membrane when the attached cells are detached and that this mechanism contributes to the survival of the detached (floating) cancer cells. α3NaK was detected in the plasma membrane of floating cancer cells in peritoneal fluids of patients, while it was in the cytoplasm of the cells in primary tumor tissues. On cancer cell detachment, we also found the focal-adhesion-kinase-dependent Ca2+ response that induces the α3NaK translocation via nicotinic acid adenine dinucleotide phosphate pathway. Activation of AMP-activated protein kinase was associated with the translocated α3NaK in the plasma membrane. Collectively, our study identifies a unique mechanism for survival of detached cancer cells, opening up new opportunities for development of cancer medicines.

Cisplatin [cis-diamminedichloroplatinum (II)] is a platinum-based anticancer drug widely used for the treatment of various cancers. It forms interstrand and intrastrand cross-linking with DNA and block DNA replication, resulting in apoptosis. On the other hand, intrinsic and acquired cisplatin resistance restricts its therapeutic effects. Although some studies suggest that dramatic epigenetic alternations are involved in the resistance triggered by cisplatin, the mechanism is complicated and remains poorly understood. Recent studies reported that cytoskeletal structures regulate cisplatin sensitivity and that activities of membrane transporters contribute to the development of resistance to cisplatin. Therefore, we focus on the roles of actin filaments and membrane transporters in cisplatin-induced apoptosis. In this review, we summarize the relationship between actin cytoskeleton and membrane transporters in the cisplatin resistance of cancer cells.

Abstract Background High-dose methotrexate (HD-MTX) therapy has been used to treat a wide range of oncological malignancies. While the therapy can be tolerated with hydration, urine pH control, and leucovorin rescue therapy, HD-MTX is cytotoxic and can cause renal failure. There have been several case reports of HD-MTX toxicity in patients with solid tumors; however, few case series of hematological malignancies have been published. Patients with hematological malignancies tend to be administered many concomitant drugs, which can affect the elimination of MTX and result in acute kidney injury. Case presentation Here, we present three cases of HD-MTX-induced acute kidney injury in patients with hematological malignancies. Several blood purification methods were used to attempt to eliminate MTX. Conclusions Rapid elimination of MTX is needed for patients with higher serum MTX concentrations to avoid additional cytotoxic effects, especially in patients who have experienced many complications. Although the most effective method for MTX elimination remains unknown, the results of our retrospective survey suggest that combined modalities, such as hemodialysis and plasma exchange, may be suitable for treatment of patients with hematological malignancies.

The total synthesis of two decahydroquinoline poison frog alkaloids ent-cis-195A and cis-211A were achieved in 16 steps (38% overall yield) and 19 steps (31% overall yield), respectively, starting from known compound 1. Both alkaloids were synthesized from the common key intermediate 11 in a divergent fashion, and the absolute stereochemistry of natural cis-211A was determined to be 2R, 4aR, 5R, 6S, and 8aS. Interestingly, the absolute configuration of the parent decahydroquinoline nuclei of cis-211A was the mirror image of that of cis-195A, although both alkaloids were isolated from the same poison frog species, Oophaga (Dendrobates) pumilio, from Panama.

Erectile function is regulated by complex mechanisms centered on vascular- and nerve-related systems. Hence, dysregulation of these systems leads to erectile dysfunction (ED), which causes mental distress and decreases the quality of life of patients and their partners. At the molecular level, many factors, such as fibrosis, lipid metabolism abnormalities, the immune system, and stem cells, play crucial roles in the etiology and development of ED. Although phosphodiesterase type 5 (PDE5) inhibitors are currently the standard treatment agents for patients with ED, they are effective only in a subgroup of patients. Therefore, further insight into the pathological mechanism underlying ED is needed to discuss ED treatment strategies. In this review, we focused on the biological and pathological significance of macrophages in ED because the interaction of macrophages with ED-related mechanisms have not been well explored, despite their important roles in vasculogenic and neurogenic diseases. Furthermore, we examined the pathological significance of macrophages in Peyronie’s disease (PD), a cause of ED characterized by penile deformation (visible curvature) during erection and pain. Although microinjury and the subsequent abnormal healing process of the tunica albuginea are known to be important processes in this disease, the detailed etiology and pathophysiology of PD are not fully understood. This is the first review on the pathological role of macrophages in PD.

Voltage‐dependent inactivation of ion channels contributes to the regulation of the membrane potential of excitable cells. Mouse polycystic kidney disease 2‐like 1 (PKD2L1) forms voltage‐dependent nonselective cation channels, which are activated but subsequently inactivated in response to membrane depolarization. Here, we found that the mutation of an asparagine 533 residue (N533Q) in the outer pore loop region of PKD2L1 caused a marked increase in outward currents induced by depolarization. In addition, the tail current analysis demonstrated that the N533Q mutants are activated during depolarization but the subsequent inactivation does not occur. Interestingly, the N533Q mutants lacked the channel activation triggered by the removal of stimuli such as extracellular alkalization and heating. Our findings suggest that the N533 residue in the outer pore loop region of PKD2L1 has a key role in the voltage‐dependent channel inactivation.

Benign prostatic hyperplasia (BPH) is arguably the most common benign disease among men. This disease is often associated with lower urinary tract symptoms (LUTS) in men and significantly decreases the quality of life. Polyphenol consumption reportedly plays an important role in the prevention of many diseases, including BPH. In recent years, in addition to disease prevention, many studies have reported the efficacy and safety of polyphenol treatment against various pathological conditions in vivo and in vitro. Furthermore, numerous studies have also revealed the molecular mechanisms of the antioxidant and anti-inflammatory effects of polyphenols. We believe that an improved understanding of the detailed pharmacological roles of polyphenol-induced activities at a molecular level is important for the prevention and treatment of BPH. Polyphenols are composed of many members, and their biological roles differ. In this review, we first provide information regarding the pathological roles of oxidative stress and inflammation in BPH. Next, the antioxidant and anti-inflammatory effects of polyphenols, including those of flavonoids and non-flavonoids, are discussed. Finally, we talk about the results and limitations of previous clinical trials that have used polyphenols in BPH, with particular focus on their molecular mechanisms of action.

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy.

We, the authors, wish to make the following correction to our published paper [...]

Inflammation is a common adverse event of anti-cancer therapy. Royal jelly (RJ) modulates inflammation by regulating the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and interleukin (IL)-6 produced by macrophages. Macrophage colony stimulating factor (M-CSF) is a crucial regulator of macrophage activities, and we hypothesized that RJ alters M-CSF levels. In this randomized controlled trial, we investigated the association between M-CSF and adverse events in renal cell carcinoma patients treated with tyrosine kinase inhibitors (TKIs) after an oral intake of RJ (n = 16) or placebo (n = 17). The serum levels of M-CSF, TNF-α, TGF-β, and IL-6 were measured by an enzyme-linked immunosorbent assay, and their temporal changes and correlation between such changes were analyzed. The post-/pretreatment ratio of M-CSF levels was associated with anorexia after 2 weeks and fatigue after 2, 4, and 12 weeks. The M-CSF level in the RJ group was higher than that in the placebo group at the same timepoints. The TNF-α level in the RJ group was lower than that in the placebo group between 6 and 12 weeks, and the TGF-β level in the RJ group was higher than that in the placebo group; however, contrasting findings were detected after 12 weeks. Additionally, the M-CSF level was significantly correlated with the TGF-β level after 4 weeks and IL-6 level after 8 and 10 weeks. Among TNF-α, TGF-β, and IL-6, the post-/pretreatment ratio of TGF-β after 12 weeks was associated with TKI-induced anorexia, and the ratios after 10 and 12 weeks were associated with fatigue. Our results demonstrated that an oral intake of RJ suppressed anorexia and fatigue via complex mechanisms associated with inflammation-related factors, such as M-CSF and TGF-β in renal cell carcinoma patients treated with TKIs. In addition, we newly found that such RJ-related effects were dependent on the treatment duration.

A specific series of peptides, called a cell-penetrating peptide (CPP), is known to be free to directly permeate through cell membranes into the cytosol (cytolysis); hence, this CPP would be a potent carrier for a drug delivery system (DDS). Previously, we proposed the mechanism of cytolysis as a temporal and local phase transfer of membrane lipid caused by positive membrane curvature generation. Moreover, we showed how to control the CPP cytolysis. Here, we investigate the phospholipid vesicle’s size effect on CPP cytolysis because this is the most straightforward way to control membrane curvature. Contrary to our expectation, we found that the smaller the vesicle diameter (meaning a higher membrane curvature), the more cytolysis was suppressed. Such controversial findings led us to seek the reason for the unexpected results, and we ended up finding out that the mobility of membrane lipids as a liquid crystal is the key to cytolysis. As a result, we could explain the cause of cytolysis suppression by reducing the vesicle size (because of the restriction of lipid mobility); osmotic pressure reduction to enhance positive curvature generation works as long as the membrane is mobile enough to modulate the local structure. Taking all the revealed vital factors and their effects as a tool, we will further explore how to control CPP cytolysis for developing a DDS system combined with appropriate cargo selection to be tagged with CPPs.

Cell-penetrating peptide (CPP) can directly penetrate the cytosol (cytolysis) and is expected to be a potent vector for a drug delivery system (DDS). Although there is general agreement that CPP cytolysis is related to dynamic membrane deformation, a distinctive process has yet to be established. Here, we report the key process and factors controlling CPP cytolysis. To elucidate the task, we have introduced trypsin digestion of adsorbed CPP onto giant unilamellar vesicle (GUV) to quantify the adsorption and internalization (cytolysis) separately. Also, the time-course analysis was introduced for the geometric calculation of adsorption and internalization amount per lipid molecule consisting of GUV. As a result, we found that adsorption and internalization assumed to occur successively by CPP molecule come into contact with membrane lipid. Adsorption is quick to saturate within 10 min, while cytolysis of each CPP on the membrane follows successively. After adsorption is saturated, cytolysis proceeds further linearly by time with a different rate constant that is dependent on the osmotic pressure. We also found that temperature and lipid composition influence cytolysis by modulating lipid mobility. The electrolyte in the outer media is also affected as a chemical mediator to control CPP cytolysis by following the Hoffmeister effect for membrane hydration. These results confirmed the mechanism of cytolysis as temporal and local phase transfer of membrane lipid from Lα to Mesh1, which has punctured bilayer morphologies.

Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds—allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate—in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

This paper starts with describing a method of deriving the resonance mode of a pendulum utilizing its equation of motion. This resonance mode is that the equilibrium position of the pendulum locates the vertical plane including its fixed point and the mass accelerates in proportion to the distance from the equilibrium position to its mass. Further, the equation of motion of vehicles was converted to a form conforming to the equation of motion of the pendulum. As a result, it was found that the equilibrium position of yaw resonance is the extension line of the vehicle speed vector at the front wheel position. Moreover, it turned out that its rear wheel accelerates toward this extension line in proportion to the distance from this extension line to the rear wheel is the yaw resonance mode under a special condition. Finally, the step steering response was considered. At the moment of steering input, the mode of the yaw lead time constant appears, and then the yaw resonance mode becomes apparent. Hence, the yaw resonance is revealed in the latter half of the transient response. Therefore, it is considered that the yaw natural frequency is suitable as a metric of the latter half behavior of the transient response.

This paper considers ways to increase stability of wheelset hunting. The aim of this study is to introduce formulas which represent the damped natural frequency and its damping. This has been done by analytical and not by numerical calculation. These formulas are functions of mass, creep coefficient and other wheelset parameters. These formulas are obtained with a 2 degree of freedom wheelset model whose radius of gyration of yaw equals to a half of gauge and whose creep coefficient is isotropic, in the first part of this paper. In the second part, based on one of these formulas, ways to increase damping of wheelset hunting are discussed. First, it is shown that a longer wavelength of geometrical hunting is effective in reducing hunting at all vehicle speeds. Secondly, it is shown that at speeds slower than a certain speed, the damping is increased when the ratio of the wheelset mass to the creep coefficient is larger. Further, a symbolic formula for this boundary speed is obtained. Thirdly, if it is assumed that the wheelset mass is proportional to the square of the wheel radius, then at speeds higher than a certain speed, the damping is increased when the wheel radius is larger. Moreover a symbolic formula for this boundary speed is also obtained.

Sport riding performance on racing circuits and other locations is seen as an important element in the marketability of motorcycles. In sport riding, some riders start a turn while braking or start acceleration (driving) while turning. Furthermore, the braking aspect of sport riding performance is also critical to accident avoidance performance since it is similar to that of the braking during cornering performance. Consequently, in this paper a fundamental study was carried out to determine methods for improving the cornering limit performance during driving and braking. In the case of four-wheeled vehicles, the G-G diagram is used as a method to indicate the cornering limit performance. In the G-G diagram the longitudinal driving and lateral driving of the vehicle are set as the two axes. Therefore, the first part of this paper proposes a G-G diagram for motorcycles theoretically. In the latter part of this paper, this paper discusses the braking force distribution ratio of front wheel that would maximize the maximum lateral driving, the influence of the normal load distribution ratio of front wheel on the limit cornering property and the influence of the height of the center of gravity on it. From these result, this paper proposes methods for improving the cornering limit performance while braking.

Background. Delayed perforation is a rare but severe complication of endoscopic submucosal dissection (ESD) for early gastric neoplasm (EGN). The aim of this study was to clarify clinical factors related to delayed perforation after ESD. Methods. A total of 1158 consecutive patients with 1199 EGNs underwent ESD at our hospital between January 2000 and December 2015. Univariate analysis was used to identify clinicopathological factors related to delayed perforation. Moreover, duration of cautery needed for hemostasis was measured by comparison between perforated and nonperforated points in patients with delayed perforation. Results. Delayed perforation occurred in 5 of 1158 consecutive patients with 1199 EGNs who underwent ESD (0.42%). All cases were diagnosed within 24 h after ESD and recovered with conservative management. On univariate analysis, location in the upper stomach was the factor most significantly associated with delayed perforation (P

Green tea polyphenol (GTP) suppresses carcinogenesis and aggressiveness in many types of malignancies including bladder cancer. However, the mechanistic basis of these effects is not well understood. This was investigated in the present study using a mouse model of chemically induced bladder cancer. C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14-24 weeks. Mice in the BBN + GTP group (n = 47) were also treated with 0.5% GTP solution over the same period. Tumor cell proliferation and microvessel density were evaluated along with immunohistochemical analysis of human antigen (Hu)R, vascular endothelial growth factor (VEGF)-A, cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Cytoplasmic HuR expression in cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. A multivariate analysis of GTP intake and cytoplasmic HuR expression revealed that GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of VEGF-A and HO-1 was associated with angiogenesis. Nuclear HuR expression was not associated with any parameters such as carcinogenesis, muscle invasion, and GTP intake. These results indicate that GTP intake can suppress tumor progression and malignant behavior in an animal model of bladder cancer. We also speculate that GTP directly and indirectly suppresses tumor cell proliferation and angiogenesis via HuR-related pathways in bladder cancer.

Chronic kidney disease (CKD) is characterized by kidney damage with proteinuria, hematuria, and progressive loss of kidney function. The final stage of CKD is known as end-stage renal disease, which usually indicates that approximately 90% of normal renal function is lost, and necessitates renal replacement therapy for survival. The most widespread renal replacement therapy is dialysis, which includes peritoneal dialysis (PD) and hemodialysis (HD). However, despite the development of novel medical instruments and agents, both dialysis procedures have complications and disadvantages, such as cardiovascular disease due to excessive blood fluid and infections caused by impaired immunity. Periodontal disease is chronic inflammation induced by various pathogens and its frequency and severity in patients undergoing dialysis are higher compared to those in healthy individuals. Therefore, several investigators have paid special attention to the impact of periodontal disease on inflammation-, nutrient-, and bone metabolism-related markers; the immune system; and complications in patients undergoing dialysis. Furthermore, the influence of diabetes on the prevalence and severity of manifestations of periodontal disease, and the properties of saliva in HD patients with periodontitis have been reported. Conversely, there are few reviews discussing periodontal disease in patients with dialysis. In this review, we discuss the available studies and review the pathological roles and clinical significance of periodontal disease in patients receiving PD or HD. In addition, this review underlines the importance of oral health and adequate periodontal treatment to maintain quality of life and prolong survival in these patients.

Chronic kidney disease (CKD) is recognized as an irreversible reduction of functional nephrons and leads to an increased risk of various pathological conditions, including cardiovascular disease and neurological disorders, such as coronary artery calcification, hypertension, and stroke. In addition, CKD patients have impaired immunity against bacteria and viruses. Conversely, kidney transplantation (KT) is performed for patients with end-stage renal disease as a renal replacement therapy. Although kidney function is almost normalized by KT, immunosuppressive therapy is essential to maintain kidney allograft function and to prevent rejection. However, these patients are more susceptible to infection due to the immunosuppressive therapy required to maintain kidney allograft function. Thus, both CKD and KT present disadvantages in terms of suppression of immune function. Periodontal disease is defined as a chronic infection and inflammation of oral and periodontal tissues. Periodontal disease is characterized by the destruction of connective tissues of the periodontium and alveolar bone, which may lead to not only local symptoms but also systemic diseases, such as cardiovascular diseases, diabetes, liver disease, chronic obstructive pulmonary disease, and several types of cancer. In addition, the prevalence and severity of periodontal disease are significantly associated with mortality. Many researchers pay special attention to the pathological roles and clinical impact of periodontal disease in patients with CKD or KT. In this review, we provide information regarding important modulators of periodontal disease to better understand the relationship between periodontal disease and CKD and/or KT. Furthermore; we evaluate the impact of periodontal disease on various pathological conditions in patients with CKD and KT. Moreover, pathogens of periodontal disease common to CKD and KT are also discussed. Finally, we examine the importance of periodontal care in these patients. Thus, this review provides a comprehensive overview of the pathological roles and clinical significance of periodontal disease in patients with CKD and KT.

Urinary dysfunction is a common pathological condition that can significantly decrease the quality of life. Bladder outlet obstruction (BOO) is a major cause of urinary dysfunction, and various lower urinary tract diseases including benign prostatic hyperplasia and urethral stricture disease cause BOO. According to the results of a variety of animal experiments on partial BOO (PBOO), there is a general agreement that ischemic conditions and repeated ischemia/reperfusion of the bladder are closely associated with BOO-induced bladder damage, and that increased oxidative stress by ischemia/reperfusion plays a crucial role in the pathological mechanisms underlying urinary dysfunction. Changes in biomarkers of oxidative stress in PBOO animal models support this association between oxidative stress and urinary dysfunction. Oxidative stress is defined as an imbalance between the production of pro-oxidants, such as free radicals and reactive species, and their elimination through protective mechanisms of antioxidants. Therefore, organizing the knowledge on the state of oxidative stress, changes in biomarkers, and biological roles of antioxidants in systemic and bladder tissues is essential to understand the detailed pathological characteristics of the urinary dysfunction caused by PBOO. Furthermore, information on drugs and supplements that have antioxidant effects is important for defining treatment strategies for urinary dysfunction with PBOO. In this review, we paid special attention to the following three issues; (1) changes in oxidative stress, including its biomarkers, (2) antioxidant status, and (3) previous reports on treatment strategies involving agents with antioxidative activity for urinary dysfunction caused by BOO. In particular, we provide systematic information on the detailed mechanisms underlying the antioxidative effects of agents used to treat PBOO. In addition, we show present research issues and research limitations, as well as suggest possible future antioxidant treatment strategies for patients with PBOO.

Prostate cancer is the most common cancer among men. Green tea consumption is reported to play an important role in the prevention of carcinogenesis in many types of malignancies, including prostate cancer; however, epidemiological studies show conflicting results regarding these anti-cancer effects. In recent years, in addition to prevention, many investigators have shown the efficacy and safety of green tea polyphenols and combination therapies with green tea extracts and anti-cancer agents in in vivo and in vitro studies. Furthermore, numerous studies have revealed the molecular mechanisms of the anti-cancer effects of green tea extracts. We believe that improved understanding of the detailed pathological roles at the molecular level is important to evaluate the prevention and treatment of prostate cancer. Therefore, in this review, we present current knowledge regarding the anti-cancer effects of green tea extracts in the prevention and treatment of prostate cancer, with a particular focus on the molecular mechanisms of action, such as influencing tumor growth, apoptosis, androgen receptor signaling, cell cycle, and various malignant behaviors. Finally, the future direction for the use of green tea extracts as treatment strategies in patients with prostate cancer is introduced.