Autologous rectus abdominis fascia sling surgery following unsuccessful synthetic midurethral sling.

Introduction: We performed autologous rectus abdominis fascia sling surgery using Advantage™ following an unsuccessful synthetic midurethral sling. Case presentation: At the age of 76 years, the patient experienced stress urinary incontinence recurrence. A 1-h pad test resulted in 259 g of leakage. A pressure flow study verified urine leakage while coughing and straining without detrusor overactivity. Abdominal leak point pressure was 10 cmH2O. Autologous rectus abdominis fascia sling surgery was performed using Advantage™. One month postoperatively, a 1-h pad test resulted in 0 g of leakage. Conclusion: We believe that this method will allow the fascia sling procedure to be performed reliably even if one is unfamiliar with conventional autologous rectus abdominis fascia sling surgery.

Differences in oncological benefits from second transurethral resection between white-light initial surgery and photodynamic diagnosis-guided initial surgery for primary high-risk non-muscle invasive bladder cancer.

OBJECTIVES: The aim of this study was to compare clinical outcomes between patients receiving second TUR after initial white-light transurethral resection of bladder tumor (WL-TURBT) and initial photodynamic diagnosis (PDD)-assisted TURBT. METHODS: A total of 1007 patients were divided into four groups based on the treatment pattern: WL-TURBT with second TUR (161 patients, WL-second group) or without second TUR (540 patients, WL-alone group) and PDD-TURBT with second TUR (112 patients, PDD-second group) or without second TUR (194 patients, PDD-alone group). Oncologic outcomes (bladder cancer recurrence, progression, urothelial cancer-specific mortality) and rates of residual tumor and risk stratification of non-muscle-invasive bladder cancer (NMIBC) after second TUR were evaluated. RESULTS: After propensity score-matching 121 patients were included each in the WL-alone and WL-second groups, and 63 patients each in the PDD-alone and PDD-second groups. In the WL group, the second TUR was significantly associated with improved progression-free (p = 0.012) and urothelial cancer-specific free survival (p = 0.011), but not with recurrence-free survival (p = 0.93). Patients initially treated with PDD-TURBT, and with a tumor diameter <30 mm and multifocality had a relatively high benefit from second TUR. The rates of residual tumor and risk stratification of NMIBC did not significantly differ between WL-TURBT and PDD-TURBT groups. CONCLUSIONS: Our findings suggested that a second TUR could be omitted after an initial PDD-TURBT in selected patients with high-risk NMIBC.

Rational in silico design identifies two mutations that restore UT28K SARS-CoV-2 monoclonal antibody activity against Omicron BA.1.

SARS-CoV-2 rapidly mutates and acquires resistance to neutralizing antibodies. We report an in-silico-designed antibody that restores the neutralizing activity of a neutralizing antibody. Our previously generated antibody, UT28K, exhibited broad neutralizing activity against mutant variants; however, its efficacy against Omicron BA.1 was compromised by the mutation. Using previously determined structural information, we designed a modified-UT28K (VH T28R/N57D), UT28K-RD targeting the mutation site. In vitro and in vivo experiments demonstrated the efficacy of UT28K-RD in neutralizing Omicron BA.1. Although the experimentally determined structure partially differed from the predicted model, our study serves as a successful case of antibody design, wherein the predicted amino acid substitution enhanced the recognition of the previously elusive Omicron BA.1. We anticipate that numerous similar cases will be reported, showcasing the potential of this approach for improving protein-protein interactions. Our findings will contribute to the development of novel therapeutic strategies for highly mutable viruses, such as SARS-CoV-2.

Real-world prostate-specific antigen response and progression to castration-resistant prostate cancer among men with metastatic castration-sensitive prostate cancer treated with apalutamide: a multi-institutional study in the Chu-shikoku Japan Urological Consortium.

BACKGROUND: Japanese men receiving apalutamide often experience skin-adverse events (AEs), possibly requiring treatment interruption or dose reduction. However, concerns have arisen regarding the impact of these adjustments on the efficacy of apalutamide. Our study evaluated the efficacy, safety, and persistence of apalutamide in men with metastatic castration-sensitive prostate cancer (mCSPC). METHODS: We retrospectively reviewed the medical records of 108 men with mCSPC from 14 Japanese institutions. The primary outcomes were the efficacy of apalutamide: prostate-specific antigen (PSA) response (50%, 90% and < 0.2 decline) and progression to castration-resistant prostate cancer (CRPC). The secondary outcomes were the skin-AE and compliance of apalutamide. RESULTS: PSA50%, PSA90% and PSA < 0.2 declines were observed in 89.8, 84.3 and 65.7%, and the median time to CRPC progression was not reached. PSA < 0.2 decline and an initial full dose of apalutamide were significantly associated with a longer time to CRPC. The most common AE was skin-AE (50.9%), and there was no association between the occurrence of skin-AE and the time to CRPC (P = 0.72). The median apalutamide persistence was 29 months, which was longer in the initial full dose recipients than in the reduced dose recipients. The dosage is reduced in about 60% of patients within the first year of treatment in the initial full dose recipients. CONCLUSIONS: Our findings indicate the effectiveness of apalutamide in Japanese men with mCSPC, despite a substantial portion requiring dose reduction within a year among the initial full dose recipients.

Comparative assessment of disease recurrence after transurethral resection of non-muscle-invasive bladder cancer with and without a photodynamic diagnosis using 5-aminolevulinic acid: a propensity score-matching analysis.

BACKGROUND: Among patients with non-muscle-invasive bladder cancer (NMIBC), systematic reviews showed lower recurrence rate in patients treated with photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT) than with white-light (WL) TURBT. However, the result is not consistent between clinical trials and the significance of preoperatively available factors in disease recurrence after PDD-TURBT remains unclear. METHODS: The present study retrospectively analyzed 1174 NMIBC patients who underwent TURBT and were followed up for ≥ 6 months. Among 1174 patients, 385 and 789 underwent PDD-TURBT with oral 5-aminolevulinic acid (the PDD group) and WL-TURBT (the WL group), respectively. Recurrence-free survival (RFS) was compared between the PDD and WL groups before and after propensity score matching, and the impact of several baseline parameters on RFS between the 2 groups was investigated after matching. RESULTS: Before propensity score matching, RFS was significantly longer in the PDD group than in the WL group (P = 0.006). After matching, 383 patients were included in both groups, and RFS was significantly longer in the PDD group than in the WL group (P < 0.001). In the cohort after matching, RFS between the two groups was compared in each subgroup classified according to baseline parameters, including age, sex, history of previous or concomitant upper urinary tract urothelial carcinoma, preoperative urinary cytology, tumor multiplicity, and tumor size, and significantly longer RFS was observed in the PDD group in all subgroups, except for the patients with tumors ≥ 30 mm (P = 0.21). CONCLUSION: These results suggest that PDD-TURBT prolongs RFS in NMIBC patients, except for those with tumors ≥ 30 mm.

Mangostin enhances efficacy of aminolevulinic acid-photodynamic therapy against cancer through inhibition of ABCG2 activity.

BACKGROUND: Aminolevulinic acid-photodynamic therapy (ALA-PDT) is gaining attention as a potential method for treating select cancers due to its high specificity and low side effect feature. ALA enters cancer cells and accumulate as protoporphyrin IX (PpIX), which will then trigger phototoxicity following light irradiation. However, it is reported that some cancer cells have reduced efficacy of ALA-PDT due to high expression of ABCG2, a transporter involved in the PpIX efflux. In this study, we evaluated the effect of mangostin, a natural compound containing anti-tumor property, on the efficacy of ALA-PDT against cancer and the mechanism involved. METHODS: We utilized TMK1 gastric cancer cell line, which has high ABCG2 expression, to evaluate the PpIX accumulation and phototoxicity exerted by ALA and mangostin co-addition. RESULTS: We found that co-addition of ALA and mangostin significantly increase the phototoxicity and PpIX accumulation in TMK1 cells. We also investigated the effect of mangostin on porphyrin-heme pathway enzymes and ABCG2 and found that the addition of mangostin reduce the activity of ABCG2, reducing PpIX efflux. CONCLUSION: These findings suggest that mangostin enhances the efficacy of ALA-PDT in cancer through inhibition of ABCG2 activity.

Real-world experience with 5-aminolevulinic acid for photodynamic diagnosis of bladder cancer (3rd report): Cost impact of transurethral resection of bladder tumor in Japan.

BACKGROUND: Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) showed improvement of diagnostic accuracy and treatment efficacy compared to white light TURBT (WL-TURBT). While PDD-TURBT is highly effective, PDD-TURBT requires the use of PDD device and light-sensitive substance precursor, which increases the medical cost compared to WL-TURBT. In this study, the impact on health care economic costs were examined between PDD-TURBT and WL-TURBT. METHODS: Of the total 265 patients, 88 patients for WL-TURBT and 105 patients for PDD-TURBT were available for analysis. Costs were also examined between 34 patients without false-positives and 36 patients with false-positives with a follow-up period of at least 200 days. To compare costs between the two treatments, we calculated the cost/person/year of TURBT using Japanese Diagnosis Procedure Combination and Per-Diem Payment System (DPC/PDPS). RESULTS: The total number of surgeries including the first TURBT was 135 (47 recurrences) in the WL-TURBT group and 133 (28 recurrences) in the PDD-TURBT group. The cost per person for hospitalization and surgery was 366,310 Japanese yen (JPY) for the WL-TURBT and 501,930 JPY for the PDD-TURBT. The cost per person per year was 491,622 JPY in the WL-TURBT group and 506,405 JPY in the PDD-TURBT group. Regarding false-positives, the cost per person per year was 494,544 JPY in the group without false-positives and 328,086 JPY in the group with false-positives. CONCLUSIONS: Although PDD-TURBT is cost more than WL-TURBT for one surgical hospitalization, the cost per person per year for PDD-TURBT and WL-TURBT is cost-neutral.

Impact on Japanese healthcare economics of photodynamic diagnosis-assisted transurethral resection of bladder tumor for non-muscle invasive bladder cancer: A multicenter retrospective cohort study.

OBJECTIVES: Bladder cancer, especially non-muscle invasive bladder cancer (NMIBC), is one of the most costly cancers owing to its long-term management. Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) reduces the risk of intravesical recurrence. However, its impact on healthcare economics in Japan remains unclear. We evaluated the comprehensive medical costs of Japanese healthcare economics regarding PDD-TURBT. METHODS: This large-scale, multicenter, retrospective study included a dataset of 1531 patients who were diagnosed with primary NMIBC who underwent initial TURBT between April 2006 and June 2021. A one-to-one propensity-score matching analysis was used for an unbiased comparison based on postTURBT follow-up periods. The total medical costs, including hospitalization, surgical procedures for TURBT and salvage radical cystectomy, adjuvant intravesical therapies, and follow-up examinations, were compared between white light (WL)-TURBT and PDD-TURBT groups. RESULTS: After propensity-score matching, 468 patients each of WL- and PDD-TURBT groups were matched. Total costs were 510 337 128 and 514 659 328 ¥ in WL- and PDD-TURBT groups, respectively. The costs of adjuvant intravesical therapies, follow-up examinations, and salvage radical cystectomy in PDD-TURBT group were equivalent to or lower than those in WL-TURBT group. Furthermore, total costs of high- and highest-risk NMIBC in PDD-TURBT group were either equivalent or lower compared to those in WL-TURBT group. CONCLUSIONS: The total costs associated with PDD-TURBT were higher compared to WL-TURBT, while there is the potential of PDD-TURBT to reduce the burden on healthcare economics in limited cases.

Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants.

SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. Y489 was identified as a site of virus vulnerability and a common footprint of broadly neutralizing antibodies against the subvariants. Multiple Y489-binding antibodies were encoded by public clonotypes and additionally recognized F486, potentially accounting for the emergence of Omicron subvariants harboring the F486V mutation. However, a subclass of antibodies broadly neutralized BA.4/BA.5 variants via hydrophobic binding sites of rare clonotypes along with high mutation-resilience under escape mutation screening. A computationally designed antibody based on one of the Y489-binding antibodies, NIV-10/FD03, was able to bind XBB with any 486 mutation and neutralized XBB.1.5. The structural basis for the mutation-resilience of this Y489-binding antibody group may provide important insights into the design of therapeutics resistant to viral escape.

Possible involvement of brain hydrogen sulphide in the inhibition of the rat micturition reflex induced by activation of brain alpha7 nicotinic acetylcholine receptors.

We previously reported that brain α7 nicotinic acetylcholine receptors inhibited the rat micturition reflex. To elucidate the mechanisms underlying this inhibition, we focused on the relationship between α7 nicotinic acetylcholine receptors and hydrogen sulphide (H2S) because we found that H2S also inhibits the rat micturition reflex in the brain. Therefore, we investigated whether H2S is involved in the inhibition of the micturition reflex induced by the activation of α7 nicotinic acetylcholine receptors in the brain. Cystometry was performed in male Wistar rats under urethane anesthesia (0.8 g/kg, ip) to examine the effects of icv pre-treated GYY4137 (H2S donor, 1 or 3 nmol/rat) or aminooxyacetic acid (AOAA; non-selective H2S synthesis inhibitor, 3 or 10 µg/rat) on PHA568487 (α7 nicotinic acetylcholine receptor agonist, icv)-induced prolongation of intercontraction intervals. PHA568487 administration at a lower dose (0.3 nmol/rat, icv) had no significant effect on intercontraction intervals, while under pre-treatment with GYY4137 (3 nmol/rat icv), PHA568487 (0.3 nmol/rat, icv) significantly prolonged intercontraction intervals. PHA568487 at a higher dose (1 nmol/rat, icv) induced intercontraction interval prolongation, and the PHA568487-induced prolongation was significantly suppressed by AOAA (10 µg/rat, icv). The AOAA-induced suppression of the PHA568487-induced intercontraction interval prolongation was negated by supplementing H2S via GYY4137 at a lower dose (1 nmol/rat, icv) in the brain. GYY4137 or AOAA alone showed no significant effect on intercontraction intervals at each dose used in this study. These findings suggest a possible involvement of brain H2S in inhibiting the rat micturition reflex induced by activation of brain α7 nicotinic acetylcholine receptors.

Vibegron 50 mg Once Daily Improves OABSS, OAB-q SF Score in OAB Patients ≥80 Years Old in Real-World Clinical Settings and Switching from Other OAB Drugs May Reduce Residual Urine Volume.

Objective: The treatment effects of vibegron have not previously been evaluated in a prospective, non-interventional observational study of elderly Japanese patients, particularly those ≥80 years old. In addition, no reports have referred to residual urine volume in switching cases. We therefore grouped patients by condition and investigated the treatment effects of vibegron on Overactive Bladder Symptom Score (OABSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and residual urine volume in each group. Methods: This multicenter, prospective, non-interventional, observational study consecutively enrolled OAB patients with total OABSS score ≥3 and OABSS question 3 score ≥2. Sixty-three patients from six centers were recruited. Vibegron 50 mg once daily was administered for 12 weeks as first-line monotherapy (first-line group), monotherapy switching from antimuscarinics or mirabegron due to failure of prior therapy (no washout period), or combination therapy with antimuscarinics (second-line group). OABSS, OAB-q SF, and residual urine volume were collected after 4 and 12 weeks. Adverse events were also recorded at each visit. Results: Of the 63 patients registered, 61 were eligible for analysis (first line, n=36; second line, n=25). The OABSS, excluding daytime frequency scores, and OAB-q SF scale showed significant improvement in all conditions. Switching from mirabegron to vibegron significantly reduced residual urine volume. No serious treatment-related adverse events were encountered. Conclusion: Vibegron 50 mg once daily significantly improved OABSS and OAB-q SF even in patients ≥80 years old. Notably, switching from mirabegron to vibegron resulted in significant improvements to residual urine volume.

Increased fluorescence observation intensity during the photodynamic diagnosis of deeply located tumors by fluorescence photoswitching of protoporphyrin IX.

Significance: Photobleaching of the photosensitizer reduces fluorescence observation time and the intensity of fluorescence emitted for tumor detection during 5-aminolevulinic acid-based photodynamic diagnosis. Aim: This study aims to utilize the concept of fluorescence photoswitching, which uses the fluorescence emission from photosensitizer excitation followed by the simultaneous excitation of the photosensitizer and its photoproduct to increase the fluorescence detection intensity during PDD of deeply located tumors. Approach: The fluorescence photobleaching of protoporphyrin IX (PpIX) and the formation of its photoproduct, photoprotoporhyrin (Ppp), caused by exposure to 505 nm light were investigated in solution, ex vivo, and in vivo, and the fluorescence photoswitching was analyzed. The fluorescence observations of PpIX and Ppp were performed with 505 and 450 or 455 nm excitation, respectively, which is the suited wavelength for the primary excitation of each fluorophore. Results: Fluorescence photoswitching was observed in all forms of PpIX investigated, and the fluorescence photoswitching time, fluorescence intensity relative to the initial PpIX and Ppp intensity, and fluorescence intensity relative to PpIX after photobleaching were obtained. The dependence of the fluorescence photoswitching time and intensity on the irradiation power density was noted. A fluorescence intensity increase between 1.6 and 3.9 times was achieved with simultaneous excitation of PpIX and Ppp after fluorescence photoswitching, compared with the excitation of PpIX alone. Conclusions: We have demonstrated the potential of fluorescence photoswitching for the improvement of the fluorescence observation intensity for the PDD of deeply located tumors.

Cell senescence-associated porphyrin metabolism affects the efficacy of aminolevulinic acid-photodynamic diagnosis in bladder cancer.

Aminolevulinic acid-photodynamic diagnosis (ALA-PDD) is a promising alternative method to detect cancer cells because of its high specificity and low rate of side effects. Exogenous ALA is administered and accumulates as protoporphyrin IX (PpIX) in cancer cells, which then emit red fluorescence following light irradiation to enable surgeons to accurately identify and remove cancerous tissue. Recent reports suggested that PpIX failed to accumulate in some patients who underwent ALA-PDD. We hypothesized that cell senescence, which is a relatively inactive state, affects porphyrin accumulation in bladder cancer cells. In this study, we evaluated the relationship between cell senescence and porphyrin accumulation in affecting the efficacy of ALA-PDD. First, we utilized three bladder cancer cell lines to evaluate senescence-related indicators and establish a cell senescence model. Then, we identified the differences in porphyrin production and the proteins involved in porphyrin accumulation between old and young cells. We found that compared with young cells, old cells possessed higher concentration of PpIX and had lower ABCG2 expression. The increase in PpIX levels following ABCG2 inhibition is three times higher in old cells than in young cells, suggesting that cell senescence was closely related with porphyrin accumulation in cancer. In conclusion, we found that the efficacy of ALA-PDD and porphyrin accumulation was relatively high in senescent cancer cells and that inhibition of ABCG2 could improve the efficacy of ALA-PDD in young bladder cancer cells.

Additional oncological benefit of photodynamic diagnosis with blue light cystoscopy in transurethral resection for primary non-muscle-invasive bladder cancer: A comparative study from experienced institutes.

Objectives: The objective of this work is to evaluate the additional oncological benefit of photodynamic diagnosis (PDD) using blue-light cystoscopy in transurethral resection (TURBT) for primary non-muscle-invasive bladder cancer (NMIBC) based on the International Bladder Cancer Group (IBCG)-defined progression and the subsequent pathological pathways. Patients and Methods: We reviewed 1578 consecutive primary NMIBC patients undergoing white-light TURBT (WL-TURBT) or PDD-TURBT during 2006-2020. One-to-one propensity score-matching was performed using multivariable logistic regression to obtain balanced groups. IBCG-defined progression of NMIBC included stage-up and grade-up as well as conventional definitions such as the development of muscle-invasive BC or metastatic disease. Nine oncological endpoints were evaluated. Sankey diagrams were generated to visualize follow-up pathological pathways after the initial TURBT. Results: Comparison of event-free survival between the matched groups revealed that PDD use decreased the bladder cancer recurrence risk and IBCG-defined progression risk, whereas no significant difference was noted in conventionally defined progression. This was attributable to a reduced risk of stage-up, from Ta to T1, and grade-up. Sankey diagrams of the matched groups showed that patients with primary Ta low-grade tumour and first-recurrence Ta low-grade tumour did not have bladder recurrence or progression, while some of those in the WL-TURBT group developed recurrence after treatment. Conclusions: The multiple survival analysis demonstrated that the risk of IBCG-defined progression was significantly decreased by PDD use in NMIBC patients. Sankey diagrams revealed possible differences in pathological pathways after the initial TURBT between the two groups, demonstrating that repeated recurrence could be prevented by PDD use.

A case of acute lymphocytic gastritis related to treatment with pembrolizumab for metastatic urothelial carcinoma.

Introduction: Immune checkpoint inhibitors such as programmed cell death/-ligand 1 inhibitor and cytotoxic T-lymphocyte-associated antigen-4 inhibitors have been widely used for various advanced malignancies. The mechanism of action for these inhibitors is the improvement of antitumor immunity via T-cell modulation. On the contrary, immune-related adverse events such as autoimmune colitis might arise in association with T-cell activation. Upper gastrointestinal adverse events related to pembrolizumab have rarely been reported. Case presentation: A 72-year-old man underwent laparoscopic radical cystectomy for muscle-invasive bladder cancer (pT2N0M0). Multiple lymph node metastases appeared in the paraaortic region. First-line chemotherapy comprising gemcitabine and carboplatin failed to stop disease progression. After the administration of pembrolizumab as second-line treatment, the patient showed symptomatic gastroesophageal reflux disease. Esophagogastroduodenoscopic biopsy of the gastric body showed severe lymphoplasmacytic and neutrophilic infiltration. Conclusion: We present acute gastritis related to pembrolizumab. Early eradication therapy may be able to control immune checkpoint inhibitor-related gastritis.

Metabolic shift towards oxidative phosphorylation reduces cell-density-induced cancer-stem-cell-like characteristics in prostate cancer in vitro.

Numerous cancer patients undergoing conventional cancer therapies such as radiotherapy, chemotherapy and surgical tumour removal face relapses several years or even decades later. This may be due to the presence of cancer stem cells (CSCs) that survived said therapies. In this study, we aimed to uncover the relationship between cell density and CSCs, and the role of the Warburg effect in regulating CSC-like characteristics. A prostate cancer cell line, PC3, was used in this study. To investigate the Warburg effect effect and CSC-like characteristics in prostate cancer, we measured the expression levels of glycolysis and OXPHOS-related genes, and performed spheroid forming, cell viability and various glycolysis and OXPHOS-assays. We observed that increased cell density caused a metabolic shift from glycolysis to OXPHOS and higher CSC-like characteristics. However, the use of dichloroacetate (DCA), an inhibitor of the Warburg effect, significantly inhibited the cell-density-induced metabolic shift and CSC-like characteristics. Changes in cell density strongly influenced the preferred metabolic pathway of prostate cancer cells, regulating their CSC-like characteristics. It is possible that DCA, an inhibitor of the Warburg effect, could be a novel drug used to treat CSCs by distinguishing Warburg effect, preventing future cancer relapses.

Primary adrenal Ewing's sarcoma family of tumors with tumor thrombus of the inferior vena cava: a case report.

BACKGROUND: Ewing's sarcoma is a malignant neoplasm that mainly occurs in skeletal tissue but can rarely arise in soft tissues. Recently, small round cell tumors (including Ewing's sarcoma) caused by chromosomal translocations have been collectively termed Ewing's sarcoma family of tumors. We report a rare case of primary adrenal Ewing's sarcoma family of tumors with tumor thrombus. CASE PRESENTATION: A 22-year-old Asian woman was referred to our hospital with a left retroperitoneal tumor 19 cm in diameter. Tumor thrombus was identified from the left adrenal vein to the inferior vena cava, infiltrating the right atrium. Total tumor excision with left adrenalectomy, nephrectomy, and thrombectomy was performed under hypothermic circulatory arrest, followed by seven courses of adjuvant chemotherapy. The patient has shown no signs of recurrence as of 26 months postoperatively. CONCLUSION: Radical surgery combined with systemic chemotherapy may contribute to good prognosis in patients with primary adrenal Ewing's sarcoma family of tumors.

Virological characteristics of the SARS-CoV-2 Omicron BA.2.75 variant.

The SARS-CoV-2 Omicron BA.2.75 variant emerged in May 2022. BA.2.75 is a BA.2 descendant but is phylogenetically distinct from BA.5, the currently predominant BA.2 descendant. Here, we show that BA.2.75 has a greater effective reproduction number and different immunogenicity profile than BA.5. We determined the sensitivity of BA.2.75 to vaccinee and convalescent sera as well as a panel of clinically available antiviral drugs and antibodies. Antiviral drugs largely retained potency, but antibody sensitivity varied depending on several key BA.2.75-specific substitutions. The BA.2.75 spike exhibited a profoundly higher affinity for its human receptor, ACE2. Additionally, the fusogenicity, growth efficiency in human alveolar epithelial cells, and intrinsic pathogenicity in hamsters of BA.2.75 were greater than those of BA.2. Our multilevel investigations suggest that BA.2.75 acquired virological properties independent of BA.5, and the potential risk of BA.2.75 to global health is greater than that of BA.5.

Structure of the human galanin receptor 2 bound to galanin and Gq reveals the basis of ligand specificity and how binding affects the G-protein interface.

Galanin is a neuropeptide expressed in the central and peripheral nervous systems, where it regulates various processes including neuroendocrine release, cognition, and nerve regeneration. Three G-protein coupled receptors (GPCRs) for galanin have been discovered, which is the focus of efforts to treat diseases including Alzheimer's disease, anxiety, and addiction. To understand the basis of the ligand preferences of the receptors and to assist structure-based drug design, we used cryo-electron microscopy (cryo-EM) to solve the molecular structure of GALR2 bound to galanin and a cognate heterotrimeric G-protein, providing a molecular view of the neuropeptide binding site. Mutant proteins were assayed to help reveal the basis of ligand specificity, and structural comparison between the activated GALR2 and inactive hß2AR was used to relate galanin binding to the movements of transmembrane (TM) helices and the G-protein interface.

Site-specific Risk Stratification Models for Postoperative Recurrence and Survival Prediction in Patients with Upper Tract Urothelial Carcinoma Undergoing Radical Nephroureterectomy: Better Stratification for Adjuvant Therapy.

Background: Site-specific postoperative risk models for localized upper tract urothelial carcinoma (UTUC) are unavailable. Objective: To create specific risk models for renal pelvic urothelial carcinoma (RPUC) and ureteral urothelial carcinoma (UUC), and to compare the predictive accuracy with the overall UTUC risk model. Design setting and participants: A multi-institutional database retrospective study of 1917 UTUC patients who underwent radical nephroureterectomy (RNU) between 2000 and 2018 was conducted. Outcome measurements and statistical analysis: A multivariate hazard model was used to identify the prognostic factors for extraurinary tract recurrence (EUTR), cancer-specific death (CSD), and intravesical recurrence (IVR) after RNU. Patients were stratified into low-, intermediate-, high-, and highest-risk groups. External validation was performed to estimate a concordance index of the created risk models. We investigated whether our risk models could aid decision-making regarding adjuvant chemotherapy (AC) after RNU. Results and limitations: The UTUC risk models could stratify the risk of cumulative incidence of three endpoints. The RPUC- and UUC-specific risk models showed better stratification than the overall UTUC risk model for all the three endpoints, EUTR, CSD, and IVR (RPUC: concordance index, 0.719 vs 0.770, 0.714 vs 0.794, and 0.538 vs 0.569, respectively; UUC: 0.716 vs 0.767, 0.766 vs 0.809, and 0.553 vs 0.594, respectively). The UUC-specific risk model can identify the high- and highest-risk patients likely to benefit from AC after RNU. A major limitation was the potential selection bias owing to the retrospective nature of this study. Conclusions: We recommend using site-specific risk models instead of the overall UTUC risk model for better risk stratification and decision-making for AC after RNU. Patient summary: Upper tract urothelial carcinoma comprises renal pelvic and ureteral carcinomas. We recommend using site-specific risk models instead of the overall upper tract urothelial carcinoma risk model in risk prediction and decision-making for adjuvant therapy after radical surgery.