Tumor Response Predicts Survival Time of Nivolumab Monotherapy for Advanced Gastric Cancer: A Subgroup Analysis of the DELIVER Trial (JACCRO GC-08).

BACKGROUND: This prospective observational study evaluated the real-world effectiveness of nivolumab monotherapy in previously treated advanced gastric cancer (GC). A preplanned 2-year final analysis was performed to confirm survival and tumor behavior with nivolumab monotherapy. PATIENTS AND METHODS: The primary endpoint was overall survival (OS). The data regarding tumor size were prospectively collected and evaluated using the RECIST criteria. Exploratory analyses were performed for survival according to the tumor response and depth of response (DpR) in patients with measurable lesions who were receiving nivolumab monotherapy as third- or later-line therapy. RESULTS: In 487 patients, the median OS and progression-free survival (PFS) were 5.8 (95% CI 5.3-6.9) months and 1.8 (95% CI 1.7-2.0) months, respectively. The response rate (RR) was 14.5% in 282 patients with measurable lesions. In 234 patients treated with third- or later-line, the DpR was found to be associated with PFS and OS in the Spearman analysis (r = 0.55 and 0.44, respectively) as well as using a discrete variable. When the DpR was divided into 5 groups (-20%≥DpR; -20%

Retroperitoneal low-grade fibromyxoid sarcoma.

Introduction: Low-grade fibromyxoid sarcoma is an uncommon deep-seated soft-tissue sarcoma that occurs rarely in young adults and children. Although surgical resection provides a long-term prognosis, late local recurrence and metastasis may occur. Case presentation: A 44-year-old woman with no prior medical history presented with breathing and abdominal discomfort. Contrast-enhanced computed tomography scan revealed a retroperitoneal tumor protruding into the thoracic cavity and pleural effusion on the left side. Tumor biopsy revealed sarcoma. We performed complete resection of the tumor along with part of the diaphragm and replaced the diaphragm with a prosthetic patch. Histopathologic findings indicated low-grade fibromyxoid sarcoma. The patient experienced no postoperative complications and received no adjuvant therapy. Furthermore, she survived 4 years after surgery without recurrence. Conclusion: Complete surgical resection is effective for low-grade fibromyxoid sarcoma; therefore, it is important to plan appropriately for complete resection when biopsy reveals malignant findings.

MMP1, IL-1ß, sTNFR-1, and IL-6 are prognostic factors for patients with unresectable or metastatic renal cell carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC. METHODS: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021. Blood samples were drawn before treatment, and 73 soluble factors in the plasma were analyzed using a bead-based multiplex assay. We examined factors associated with progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAE) using the Chi-squared test, Kaplan-Meier method, and the COX proportional hazards model. RESULTS: Patients exhibited a median PFS and OS of 212 and 783 days, respectively. Significant differences in both PFS and OS were observed for MMP1 (PFS, p < 0.001; OS, p = 0.003), IL-1ß (PFS, p = 0.021; OS, p = 0.008), sTNFR-1 (PFS, p = 0.017; OS, p = 0.005), and IL-6 (PFS, p = 0.004; OS, p < 0.001). Multivariate analysis revealed significant differences in PFS for MMP1 (hazard ratio [HR] 5.305, 95% confidence interval [CI], 1.648-17.082; p = 0.005) and OS for IL-6 (HR 23.876, 95% CI, 3.426-166.386; p = 0.001). Moreover, 26 patients experienced irAE, leading to ICI discontinuation or withdrawal. MMP1 was significantly associated with irAE (p = 0.039). CONCLUSION: MMP1 may be associated with severe irAE, and MMP1, IL-1ß, sTNFR-1, and IL-6 could serve as prognostic factors in unresectable or metastatic RCC treated with ICIs. MMP1 and IL-6 were independent predictors of PFS and OS, respectively. Thus, inhibiting these soluble factors may be promising for enhancing antitumor responses in patients with RCC treated with ICIs.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Enhanced-view totally extraperitoneal repair in a morbidly obese patient with epigastric and umbilical hernias in combination with rectus diastasis: A case report.

INTRODUCTION: The use of enhanced-view totally extraperitoneal (eTEP) repair for patients with ventral hernias has become more widespread due to its ability to prevent mesh-and-tacker-related complications by placing the mesh in the retrorectus space. However, the efficacy of eTEP repair in obese patients remains unknown. Herein, we report a case of a morbidly obese patient with epigastric and umbilical hernias in combination with a rectus diastasis repaired using the eTEP technique. PRESENTATION OF CASE: A 42-year-old man with a history of spontaneously reduced incarcerated epigastric hernia two weeks previously was referred to our hospital. His body mass index (BMI) was 42.9 kg/m2. Abdominal computed tomography revealed a small epigastric hernia, an umbilical hernia, and a rectus diastasis. We performed eTEP repair. The postoperative course was uneventful, and the patient was discharged on postoperative day 3. There has been no evidence of hernia recurrence after a follow-up period of 2 years. DISCUSSION: We consider that the eTEP technique is rarely affected by intra-abdominal fat because endoscopic manipulation is performed in the bilateral retrorectus and preperitoneal spaces. Moreover, the eTEP allows the epigastric artery perforator to be spared. Therefore, eTEP repair is considered the best surgical option for morbidly obese patients with ventral hernias in combination with rectus diastasis. CONCLUSIONS: This case provides support for the efficacy of eTEP repair in morbidly obese patients with epigastric and umbilical hernias in combination with a rectus diastasis.

Crucial Residue for Tuning Thermal Relaxation Kinetics in the Biliverdin-binding Cyanobacteriochrome Photoreceptor Revealed by Site-saturation Mutagenesis.

Cyanobacteriochromes (CBCRs) are cyanobacterial photoreceptors distantly related to the phytochromes sensing red and far-red light reversibly. Only the cGMP phosphodiesterase/Adenylate cyclase/FhlA (GAF) domain is needed for chromophore incorporation and proper photoconversion. The CBCR GAF domains covalently ligate linear tetrapyrrole chromophores and show reversible photoconversion between two light-absorbing states. In most cases, the two light-absorbing states are stable under dark conditions, but in some cases, the photoproduct state undergoes thermal relaxation back to the dark-adapted state during thermal relaxation. In this study, we examined the engineered CBCR GAF domain, AnPixJg2_BV4. AnPixJg2_BV4 covalently binds biliverdin IX-alpha (BV) and shows reversible photoconversion between a far-red-absorbing Pfr dark-adapted state and an orange-absorbing Po photoproduct state. Because the BV is an intrinsic chromophore of mammalian cells and absorbs far-red light penetrating into deep tissues, BV-binding CBCR molecules are useful for the development of optogenetic and bioimaging tools used in mammals. To obtain a better developmental platform molecule, we performed site-saturation random mutagenesis on the Phe319 position. We succeeded in obtaining variant molecules with higher chromophore-binding efficiency and higher molar extinction coefficient. Furthermore, we observed a wide variation in thermal relaxation kinetics, with an 81-fold difference between the slowest and fastest rates. Both molecules with relatively slow and fast thermal relaxation would be advantageous for optogenetic control.

Effect of body fat mass loss on prognosis of radical resection for pancreatic ductal adenocarcinoma based on bioelectrical impedance analysis.

BACKGROUND: Few reports have performed a prognostic analysis based on bioelectrical impedance analysis in patients with radical resection of pancreatic ductal adenocarcinoma (PDAC), and its usefulness in prognostic analysis remains unclear. This study aimed to evaluate body composition changes in patients undergoing radical resection for PDAC and analyze its impact on prognosis. METHODS: The medical records of radical resection for patients with PDAC were retrospectively reviewed, and the parameters of body composition, including body weight, skeletal muscle mass, body fat mass (BFM), and extracellular water-total body water ratio, from preoperatively to 12 months postoperatively, for each surgical procedure were measured based on direct segmental multifrequency bioelectrical impedance analysis with an InBody 770 (InBody Inc., Tokyo, Japan) device. The clinicopathological and prognostic factors were analyzed. RESULTS: Among 79 patients who underwent radical resection for PDAC, 36 (46%), 7 (8%), and 36 (46%) underwent pancreatoduodenectomy, total pancreatectomy, and distal pancreatectomy, respectively. The multivariate overall survival analysis demonstrated that BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021), lymph node metastasis (p = 0.014), and non-adjuvant chemotherapy (p <  0.001) were independent poor prognostic factors. Multivariate analysis revealed that preoperative BFM < 12 kg and preoperative albumin < 3.5 g/dL were independently associated with BFM loss percentage at 1 month postoperatively ≧14% (p = 0.021 and p = 0.047, respectively). CONCLUSIONS: Loss of BFM in the early postoperative period may have a poor prognosis in radical resection of PDAC.

Artificial intelligence in a prediction model for postendoscopic retrograde cholangiopancreatography pancreatitis.

OBJECTIVES: In this study we aimed to develop an artificial intelligence-based model for predicting postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). METHODS: We retrospectively reviewed ERCP patients at Nagoya University Hospital (NUH) and Toyota Memorial Hospital (TMH). We constructed two prediction models, a random forest (RF), one of the machine-learning algorithms, and a logistic regression (LR) model. First, we selected features of each model from 40 possible features. Then the models were trained and validated using three fold cross-validation in the NUH cohort and tested in the TMH cohort. The area under the receiver operating characteristic curve (AUROC) was used to assess model performance. Finally, using the output parameters of the RF model, we classified the patients into low-, medium-, and high-risk groups. RESULTS: A total of 615 patients at NUH and 544 patients at TMH were enrolled. Ten features were selected for the RF model, including albumin, creatinine, biliary tract cancer, pancreatic cancer, bile duct stone, total procedure time, pancreatic duct injection, pancreatic guidewire-assisted technique without a pancreatic stent, intraductal ultrasonography, and bile duct biopsy. In the three fold cross-validation, the RF model showed better predictive ability than the LR model (AUROC 0.821 vs. 0.660). In the test, the RF model also showed better performance (AUROC 0.770 vs. 0.663, P = 0.002). Based on the RF model, we classified the patients according to the incidence of PEP (2.9%, 10.0%, and 23.9%). CONCLUSION: We developed an RF model. Machine-learning algorithms could be powerful tools to develop accurate prediction models.

Kinesin Family Member B18 Is Related to Gastric Mucin Phenotype and Contributes to Gastric Cancer Progression by Regulating Epithelial-Mesenchymal Transition.

INTRODUCTION: Gastric cancer (GC) remains a common health concern worldwide and is the third leading cause of death in Japan. It can be broadly classified into gastric and intestinal mucin phenotypes using immunohistochemistry. We previously reported numerous associations of kinesin family member (KIF) genes and mucin phenotypes with GC. However, no previous studies have reported on the importance of KIF18B in GC using immunostaining. Thus, in this study, we investigated the expression and functions of KIF18B, which is highly expressed in gastric mucin phenotype GC. METHODS: We performed RNA-seq of gastric and intestinal mucin type GCs, and clinicopathological studies of the KIF18B we found were performed using 96 GC cases. We also performed functional analysis using GC-derived cell lines. RESULT: RNA-seq showed the upregulation of matrisome-associated genes in gastric mucin phenotype GC and a high expression of KIF18B. KIF18B was detected in 52 of the 96 GC cases (54%) through immunohistochemistry. Low KIF18B expression was significantly associated with poor overall survival (p < 0.01). Other molecules that were significantly associated with KIF18B were MUC5AC and claudin 18; these were also significantly associated with the gastric mucin phenotype. KIF18B small interfering RNA (siRNA)-transfected GC cells showed greater growth and spheroid colony formation than the negative control siRNA-transfected cells. Furthermore, expression of snail family transcriptional repressor 1 and cadherin 2 was significantly increased and that of cadherin 1 was significantly decreased in KIF18B siRNA-transfected GC cells. CONCLUSION: These findings not only suggest that KIF18B may be a useful prognostic marker, but also provide insight into the pathogenesis of the GC phenotype.

Immune mediators as predictive biomarkers for anti-PD-1 antibody therapy in urothelial carcinoma.

Introduction: This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). Methods: We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6 weeks after initiating pembrolizumab therapy. The association of estimated soluble immune mediators with clinical outcomes, including overall survival (OS), progression-free survival (PFS), anti-tumor responses, and irAEs, were statistically evaluated. Results: In the multivariate analysis, levels of 18 factors at baseline and 12 factors during treatment were significantly associated with OS. Regarding PFS, baseline levels of 17 factors were significantly associated with PFS. Higher levels of interleukin (IL)-6, IL-8, soluble tumor necrosis factor receptor 1 (sTNF-R1), and IL-12 (p40), both at baseline and post-treatment, were significantly associated with worse OS. Conversely, low IL-6 and high TWEAK levels at baseline were associated with irAEs. Among identified factors, interferon (IFN) γ and IL-12 (p40) were repeatedly identified; high baseline levels of these factors were risk factors for worse OS and PFS, as well as progressive disease. Notably, using correlation and principal component analysis, factors significantly associated with clinical outcomes were broadly classified into three groups exhibiting similar expression patterns. Discussion: Measuring plasma levels of soluble immune mediators, such as IL-6, IL-8, sTNF-R1, IFNγ, and IL-12 (p40), could be recommended for predicting prognosis and irAEs in ICI-treated patients with aUC.

Conformational change in an engineered biliverdin-binding cyanobacteriochrome during the photoconversion process.

Cyanobacteriochromes (CBCRs) derived from cyanobacteria are linear-tetrapyrrole-binding photoreceptors related to the canonical red/far-red reversible phytochrome photoreceptors. CBCRs contain chromophore-binding cGMP-specific phosphodiesterase/adenylate cyclase/FhlA (GAF) domains that are highly diverse in their primary sequences and are categorized into many subfamilies. Among this repertoire, the biliverdin (BV)-binding CBCR GAF domains receive considerable attention for their in vivo optogenetic and bioimaging applications because BV is a mammalian intrinsic chromophore and can absorb far-red light that penetrates deep into the mammalian body. The typical BV-binding CBCR GAF domain exhibits reversible photoconversion between far-red-absorbing dark-adapted and orange-absorbing photoproduct states. Herein, we applied various biochemical and spectral studies to identify the details of the conformational change during this photoconversion process. No oligomeric state change was observed, whereas the surface charge would change with a modification of the α-helix structures during the photoconversion process. Combinatorial analysis using partial protease digestion and mass spectrometry identified the region where the conformational change occurred. These results provide clues for the future development of optogenetic tools.

Equation Elucidating the Catalyst-Layer Proton Conductivity in a Polymer Electrolyte Fuel Cell Based on the Ionomer Distribution Determined Using Small-Angle Neutron Scattering.

The performance of a polymer electrolyte fuel cell can be enhanced by improving the proton conductivity of the catalyst layer, where the oxygen reduction reaction generates electrochemical power. Protons are conducted through the ionomer coatings on catalyst-supporting carbon particles, which form porous structures that facilitate oxygen diffusion during the reaction within the catalyst layer. Therefore, while a higher ionomer content in the catalyst layer is favorable, the proton conductivity is additionally governed by the type of carbon support. As the influence of the ionomer distribution is not fully understood, we introduce a novel proton conductivity model for use in simulating catalyst layers with various amounts of ionomers and different carbon types. This proton conductivity model considers that several ionomers occur as thin films with drastically suppressed proton conductivities. Although evaluating the thin-film ionomer fraction is challenging, proton-conducting ion clusters in thick-film ionomers have been detected by characterizing the catalyst layers via small-angle neutron scattering. Our model reveals that reducing the fraction of the thin-film ionomer or avoiding factors that suppress its proton conduction improves the performance of the catalyst layer.

Laparoscopic repair for interparietal hernia after enhanced-view totally extraperitoneal hernia repair: A case report.

INTRODUCTION: The enhanced-view totally extraperitoneal (eTEP) technique, an endoscopically performed Rives-Stoppa method, has been used extensively for ventral hernia repairs. However, in this technique, the necessity of posterior rectus sheath re-approximation and mesh fixation remains unclear. There are a few reports of post-eTEP interparietal hernias (IHs) occurring because of dehiscence of the re-approximated posterior rectus sheath; however, IH secondary to mesh migration is rare. Herein, we report a rare case of IH due to mesh migration after eTEP repair for an incisional hernia. PRESENTATION OF CASE: A 70-year-old man underwent eTEP repair for an incisional hernia using a self-gripping mesh without mesh fixation and posterior rectus sheath re-approximation one year previously, developed an IH. An elective laparoscopic surgery revealed an orifice to the retrorectus space as though the IH sac between the retrorectus muscle and the posterior layer including the bilateral posterior rectus sheaths, peritoneum, and mesh. We placed eight transmural sutures with 0 nylon thread and closed the orifice. The patient was then discharged on postoperative day two and was asymptomatic at 24 months without evidence of ventral hernia recurrence. DISCUSSION: We consider that strenuous activity and deep bending may cause mesh migration or dislocation. If that occurs in the early post-eTEP period without posterior rectus sheaths closure, the vulnerable peritoneal area will be exposed, which consider to be an IH orifice. CONCLUSIONS: Even after using the self-gripping mesh in eTEP repair, mesh fixation remains the best option to prevent postoperative complications, including IH.

Introduction of reversible cysteine ligation ability to the biliverdin-binding cyanobacteriochrome photoreceptor.

Cyanobacteriochrome (CBCR) photoreceptors are distantly related to the canonical red/far-red reversible phytochrome photoreceptors. In the case of the CBCRs, only the GAF domain is required for chromophore incorporation and photoconversion. The GAF domains of CBCR are highly diversified into many lineages to sense various colors of light. These CBCR GAF domains are divided into two types: those possessing only the canonical Cys residue and those with both canonical and second Cys residues. The canonical Cys residue stably ligates to the chromophore in both cases. The second Cys residue mostly shows reversible adduct formation with the chromophore during photoconversion for spectral tuning. In this study, we focused on the CBCR GAF domain AnPixJg2_BV4, which possesses only the canonical Cys residue. AnPixJg2_BV4 covalently ligates to the biliverdin (BV) chromophore and shows far-red/orange reversible photoconversion. Because BV is a mammalian intrinsic chromophore, BV-binding molecules are advantageous for in vivo optogenetic and bioimaging tool development. To obtain a better developmental platform molecule, we performed site-saturation random mutagenesis and serendipitously obtained a unique variant molecule that showed far-red/blue reversible photoconversion, in which the Cys residue was introduced near the chromophore. This introduced Cys residue functioned as the second Cys residue that reversibly ligated with the chromophore. Because the position of the introduced Cys residue is distinct from the known second Cys residues, the variant molecule obtained in this study would expand our knowledge about the spectral tuning mechanism of CBCRs and contribute to tool development.

Analysis of Acquisition of COVID-2019 Neutralizing Antibodies in Organ Transplant Recipients.

BACKGROUND: This study confirmed the kinetics of antibodies acquired by SARS-CoV-2 vaccination in solid-organ transplant recipients and examined their association with the development of COVID-19 and immunosuppressive status in organ transplant recipients. METHODS: We measured COVID-19 neutralizing antibody titer in 21 organ transplant recipients vaccinated with the COVID-19 vaccine and 14 nontransplant recipients (control group) 3 times before and at 1 and 6 months after the third dose of vaccine. By confirming the kinetics of the acquired antibodies, we examined the relevance of the background characteristics of organ transplant recipients, such as the development of infectious diseases and immunosuppressive status. RESULTS: The proportion of patients with neutralizing antibodies was significantly higher in the nontransplant group than in the transplant group. Neutralizing antibody titers were significantly lower in transplant recipients when they were compared before the third dose and 1 month later. In the transplant recipient group, 11 patients were positive, and 10 were negative for neutralizing antibodies. When the causal relationship between the neutralizing antibody titer and background was examined, a positive correlation was found between the antibody titer and the number of years since transplantation, and a negative correlation was found between the tacrolimus trough values, amount of mycophenolate mofetil or steroids taken internally, and antibody titer. CONCLUSION: This study suggests that the effectiveness of vaccination in transplant recipients is associated with the post-transplant period before vaccination and the dose of immunosuppressive agents.

A Multicenter, Phase II Trial of Schedule Modification for Nab-Paclitaxel in Combination with Ramucirumab for Patients with Previously Treated Advanced Gastric or Gastroesophageal Junction Cancer: The B-RAX Trial (JACCRO GC-09).

BACKGROUND: This study investigated whether schedule modification of bi-weekly nanoparticle albumin-bound paclitaxel (nab-PTX) plus ramucirumab (RAM) is efficacious against gastric cancer (GC) or gastroesophageal junction cancer (GJC). PATIENTS AND METHODS: Patients with unresectable GC or GJC who were previously treated with fluoropyrimidine-containing regimens received nab-PTX (100 mg/m2) on days 1, 8, and 15 and RAM (8 mg/kg) on days 1 and 15 of a 28-day cycle. Based on the incidence of severe adverse events (AEs) during the first cycle, patients were modified to bi-weekly therapy from the second cycle. The primary endpoint was progression-free survival (PFS) in the bi-weekly therapy population. Based on the hypothesis that bi-weekly nab-PTX plus RAM would improve PFS from 4.5 to 7.0 months, 40 patients were required for power of 0.8 with a one-sided α of 0.05. RESULTS: Of the 81 patients enrolled, 47 patients (58%) were assigned to bi-weekly therapy. Patient characteristics were Eastern Cooperative Oncology Group performance status of 1 (19%) and diffuse type (45%). Median PFS was 4.7 months (95% confidence interval [CI] 3.7-5.6 months) and overall response rate was 25% (95% CI 11-39%). Severe AEs of grade 3 or worse were mainly neutropenia (83%) and hypertension (23%). EQ-5D scores were maintained during the treatment. In patients who continued standard-schedule therapy, median PFS was 2.7 months (95% CI 1.8-4.0 months). CONCLUSIONS: The primary endpoint for PFS was statistically not met, but modification of nab-PTX plus RAM to a bi-weekly schedule might be a feasible treatment option as second-line treatment for advanced GC/GJC patients, especially elderly patients, with severe AEs during the first cycle.

Therapeutic effects of p38 mitogen-activated protein kinase inhibition on hyperexcitability of capsaicin sensitive bladder afferent neurons in mice with spinal cord injury.

AIMS: Nerve growth factor (NGF) has been implicated as a key molecule of pathology-induced changes in C-fiber afferent nerve excitability, which contributes to the emergence of neurogenic detrusor overactivity due to spinal cord injury (SCI). It is also known that the second messenger signaling pathways activated by NGF utilize p38 Mitogen-Activated Protein Kinase (MAPK). We examined the roles of p38 MAPK on electrophysiological properties of capsaicin sensitive bladder afferent neurons with SCI mice. MAIN METHODS: We used female C57BL/6 mice and transected their spinal cord at the Th8/9 level. Two weeks later, continuous administration of p38 MAPK inhibitor (0.51 µg/h, i.t. for two weeks) was started. Bladder afferent neurons were labelled with a fluorescent retrograde tracer, Fast-Blue (FB), injected into the bladder wall three weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurons were prepared and whole cell patch clamp recordings were performed in FB-labelled neurons. After recording action potentials or voltage-gated K+ currents, the sensitivity of each neuron to capsaicin was evaluated. KEY FINDINGS: In capsaicin-sensitive FB-labelled neurons, SCI significantly reduced the spike threshold and increased the number of action potentials during 800 ms membrane depolarization. Densities of slow-decaying A-type K+ (KA) and sustained delayed rectifier-type K+ (KDR) currents were significantly reduced by SCI. The reduction of KA, but not KDR, current density was reversed by the treatment with p38 MAPK inhibitor. SIGNIFICANCE: P38 MAPK plays an important role in hyperexcitability of capsaicin-sensitive bladder afferent neurons due to the reduction in KA channel activity in SCI mice.

Cribriform pattern and intraductal carcinoma of the prostate can have a clinicopathological impact, regardless of their percentage and/or number of cores.

Cribriform pattern and intraductal carcinoma of the prostate (IDC-P) are widely accepted as poor prognostic factors in prostate cancer. However, it remains unclear to what extent the presence of these morphological features in prostate biopsy specimens, as diagnosed by hematoxylin-eosin-stained specimens only, affects the clinicopathological impact. In this study, we summarized the characteristics of the cribriform pattern and IDC-P in 850 prostate biopsy cases. The results showed a statistically significant increase in the incidence of cribriform pattern and IDC-P as grade group (GG) increased (especially in cases ≥ GG4, Chi-square test P < 0.001). The independent risk factors for cribriform pattern and IDC-P in biopsy specimens in the multivariate logistic regression analysis were the former GG, presence of IDC-P, lesion length of the highest GG core, latter GG, presence of the cribriform pattern, number of biopsies obtained, and number of highest GG core. Overall, 125 cases in which radical prostatectomy was conducted after biopsy were selected for further analysis. Multivariate logistic regression analysis using biopsy and surgical specimens confirmed that the presence of the cribriform pattern and IDC-P in biopsy specimens were independent risk factors for lymph node metastasis (odds ratios [95% confidence interval] were 6.54 [1.15-37.05] for the cribriform pattern and 23.71 [1.74-322.42] for IDC-P). The presence of the cribriform pattern and/or IDC-P in a biopsy specimen was a significant factor, even if only partially present, indicating lymph node metastasis. However, further validation is required to predict poor prognostic factors more accurately.

Effects of media on preventive behaviour during the COVID-19 pandemic.

The novel coronavirus 2019 (COVID-19) pandemic required implementation of a variety of measures. In addition to pharmaceutical measures, such as vaccines, changing individuals' nonpharmaceutical preventive behaviour is essential to prevent the spread of infection. In uncertain situations, such as a pandemic, media sources are important for guiding individuals' decision-making behaviour. In this study, we examined the effects of media use on preventive behaviour during COVID-19. Earlier studies have shown that social networking service (SNS) browsing promotes preventive behaviour. However, those studies only assessed a single point during the early stages of the pandemic; therefore, the effects on ongoing preventive behaviour are unclear. Thus, a two-wave panel survey was conducted in 2020 and 2021 for an exploratory analysis of changes in the effects of media on individuals' preventive behaviour over time. The results show that the effect of SNS browsing on preventing going out was confirmed only during the early stage of the pandemic and was not observed 1 year later. It is also shown that those who shifted from self-restraint to going out within 1 year were not affected by the type of media use, but by cognitive factors. As the situation changes during a pandemic, analyses that consider time-series changes are essential for gaining insights about the effects of media on the promotion and maintenance of continuous prevention behaviours.