Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.

Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.

IL-17RA-signaling in Lgr5+ intestinal stem cells induces expression of transcription factor ATOH1 to promote secretory cell lineage commitment.

The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.

Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing. FINDINGS: Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9-30·2) for the talazoparib group and 24·6 months (14·4-30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months-not reached) for talazoparib plus enzalutamide and 21·9 months (16·6-25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51-0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3-4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group. INTERPRETATION: Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations. FUNDING: Pfizer.

Spatial and Single-Cell Transcriptomics Reveals the Regional Division of the Spatial Structure of MASH Fibrosis.

OBJECTIVE: To elucidate the regional distribution of metabolic dysfunction-associated steatohepatitis (MASH) fibrosis within the liver and to identify potential therapeutic targets for MASH fibrosis. METHODS: Liver sections from healthy controls, patients with simple steatosis and MASH patients were analysed using spatial transcriptomics integrated with single-cell RNA-seq. RESULTS: Spatial transcriptomics analysis of liver tissues revealed that the fibrotic region (Cluster 9) was primarily distributed in lobules, with some fibrosis also found in the surrounding area. Integration of the single-cell-sequencing data set (GSE189175) showed a greater proportion of inflammatory cells (Kupffer cells and T cells) and myofibroblasts in MASH. Six genes, showing high- or low-specific expression in Cluster 9, namely, ADAMTSL2, PTGDS, S100A6, PPP1R1A, ASS1 and G6PC, were identified in combination with pathology. The average expression levels of ADAMTSL2, PTGDS and S100A6 on the pathological HE staining map were positively correlated with the increase in the degree of fibrosis and aligned strongly with the distribution of fibrosis. ADAMTSL2+ myofibroblasts play a role in TNF signalling pathways and in the production of ECM structural components. Pseudotime analysis indicated that in the early stages of MASH, infiltration by T cells and Kupffer cells triggers a significant inflammatory response. Subsequently, this inflammation leads to the activation of hepatic stellate cells (HSCs), transforming them into myofibroblasts and promoting the development of liver fibrosis. CONCLUSION: This study is the first to characterise lineage-specific changes in gene expression, subpopulation composition, and pseudotime analysis in MASH fibrosis and reveals potential therapeutic targets for this condition.

Plain language summary of the results from the TALAPRO-2 study: Talazoparib plus enzalutamide versus placebo plus enzalutamide for patients with advanced prostate cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from the TALAPRO-2 research study (also known as a clinical trial). The TALAPRO-2 study tested the combination of two medicines called talazoparib plus enzalutamide. This combination of medicines was used as the first treatment for adult patients with metastatic castration-resistant prostate cancer. The combination of talazoparib plus enzalutamide was compared with a placebo plus enzalutamide. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that starts in the prostate and has spread to other parts of the body. Castration-resistant means that the cancer continues to grow even when testosterone levels in the blood are reduced to very low levels. Taking medicines to lower testosterone levels in the blood is a standard treatment for men with advanced prostate cancer. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: TALAPRO-2 looked at if combining talazoparib plus enzalutamide would increase the length of time patients lived before their cancer got worse or they died compared with a placebo plus enzalutamide. Researchers looked at how treatment affected the size and number of tumors and the length of time before patients needed to change to a new cancer medicine. Researchers also looked at any side effects patients had during the study. WHAT ARE THE KEY TAKEAWAYS?: A total of 805 patients with metastatic castration-resistant prostate cancer took part in the study. Compared with patients who took a placebo plus enzalutamide, the group of patients who took talazoparib plus enzalutamide had a 37% reduced risk of their cancer getting worse or dying. Some patients had tumors that at the start of the study could be measured with scans. Sixty-two percent of patients who took talazoparib plus enzalutamide had their tumors decrease or shrink to the point that they could no longer be seen on scans versus 44% of patients who took a placebo plus enzalutamide. Patients who took talazoparib plus enzalutamide were more likely to have a longer time before they needed to change to a new cancer medicine. The most common side effects of talazoparib plus enzalutamide were low levels of red blood cells (66% of patients) and neutrophils (36% of patients), and excessive tiredness or exhaustion (34% of patients).Clinical Trial Registration: NCT03395197 (TALAPRO-2) (ClinicalTrials.gov).

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

BACKGROUND: Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported. METHODS: In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O'Brien-Fleming-type alpha-spending function. RESULTS: As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events. CONCLUSIONS: Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

PURPOSE: This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. MATERIALS AND METHODS: PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. RESULTS: In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. CONCLUSIONS: There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

Nrf2 through Aryl Hydrocarbon Receptor Regulates IL-22 Response in CD4+ T Cells.

IL-17A and IL-22 derived from Th17 cells play a significant role in mucosal immunity and inflammation. TGF-ß and IL-6 promote Th17 differentiation; however, these cytokines have multiple targets. The identification and screening of additional molecules that regulate IL-17A and IL-22 responses in certain inflammatory conditions is of great clinical significance. In this study, we show that CDDO-Im, a specific Nrf2 activator, promotes IL-17A and IL-22 responses in murine Th17 cells. In contrast, CDDO-Im inhibits IL-17A response in multiple sclerosis patient-derived PBMCs. However, Nrf2 specifically regulates IL-22 response in vivo. Nrf2 acts through the regulation of antioxidant response element (ARE) binding motifs in target genes to induce or repress transcription. Promoter analysis revealed that Il17a, Rorc, and Ahr genes have several ARE motifs. We showed that Nrf2 bound to ARE repressor (ARE-R2) of Rorc and inhibited Rorc-dependent IL-17A transactivation. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity. Chromatin immunoprecipitation quantitative PCR data showed that Nrf2 bound to ARE of AhR. Finally, we confirmed that the CDDO-Im-mediated induction of IL-22 production in CD4+ T cells was abrogated in CD4-specific Ahr knockout mice (AhrCD4 ). CH-223191, a specific AhR antagonist, inhibits CDDO-Im-induced IL-22 production in CD4+ T cells, which further confirmed the AhR-dependent regulation. Collectively, our data showed that Nrf2 via AhR pathways regulated IL-22 response in CD4+ T cells.

Plain language summary: Can declines in prostate-specific antigen level indicate how long patients with advanced prostate cancer will live when treated with enzalutamide?

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in the Journal of Urology. The PROSPER study involved men who had a type of advanced prostate cancer called non-metastatic castration-resistant prostate cancer (nmCRPC). In patients with nmCRPC, their prostate cancer keeps growing even after traditional hormone treatments. In these patients, rising prostate-specific antigen (PSA) levels suggest that cancer is active but CT and bone scans show that it has not spread to other parts of the body. Everyone in this study received androgen deprivation therapy (ADT) either with the medicine enzalutamide or a placebo. Enzalutamide is a medicine that can slow or stop androgens, such as testosterone, from making prostate cancer grow. The main results of the PROSPER study showed that patients with nmCRPC treated with enzalutamide and ADT lived longer than patients treated with placebo and ADT. In this study, researchers wanted to know if the findings were different depending on how much patients' PSA level declined after enzalutamide treatment. Researchers also wanted to know if this made a difference in how long patients lived without the cancer spreading to other parts of their body. WHAT WERE THE RESULTS?: Researchers found that patients with a large decline in PSA level after treatment were more likely to live longer and without their cancer spreading. WHAT DO THE RESULTS MEAN?: This study shows a link between PSA level changes and how long patients with nmCRPC live when treated with enzalutamide and ADT. These results may help health professionals monitor patients with different PSA level changes after enzalutamide treatment. Patients with a large decline in PSA level may not need to be monitored as closely as patients with a small decline in PSA level.

Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design.

PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197). Clinical Trial Registration: NCT03395197 (ClinicalTrials.gov).

Plain language summary of the design of the TALAPRO-2 study comparing talazoparib and enzalutamide versus enzalutamide and placebo in men with metastatic castration-resistant prostate cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the design of an ongoing research study (also known as a clinical trial) called TALAPRO-2. The TALAPRO-2 trial is testing the combination of two medicines called talazoparib and enzalutamide as a first treatment in adult men with metastatic castration-resistant prostate cancer. The study began in December 2017 and has enrolled 1037 adult men with metastatic castration-resistant prostate cancer from 26 countries. WHAT IS METASTATIC CASTRATION-RESISTANT PROSTATE CANCER?: Metastatic castration-resistant prostate cancer is a type of cancer that has advanced beyond the prostate and continues to grow even when testosterone levels in the blood are suppressed. WHICH MEDICINES ARE BEING TESTED?: The combination of talazoparib plus enzalutamide will be compared with enzalutamide plus placebo. Enzalutamide is approved to treat men with prostate cancer. Talazoparib is not approved to treat men with prostate cancer. A placebo does not contain any active ingredients and is also known as a sugar pill. WHAT ARE THE AIMS OF THE TALAPRO-2 TRIAL?: The TALAPRO-2 trial will find out if combining talazoparib with enzalutamide increases the length of time the men in the study live without their cancer getting worse compared with enzalutamide plus placebo. The study will also measure how long men in the study live and any side effects the men have while they are taking the study medicines. Researchers are also testing the DNA from the tumor cells of all men in the study to find out if they have faulty DNA repair genes. Clinical Trial Registration: NCT0339519 (ClinicalTrials.gov).

Which traits affect how long patients with advanced prostate cancer live when treated with enzalutamide?

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a research article originally published in European Journal of Cancer. The PROSPER study involved men who had a type of advanced prostate cancer called nonmetastatic castration-resistant prostate cancer (nmCRPC). In men with nmCRPC, their cancer has progressed on traditional hormone therapy but scans show that it has not spread to other parts of the body. The main results of the PROSPER study showed that patients treated with enzalutamide lived longer than patients treated with placebo. For this analysis, researchers looked at whether this was different depending on patients' traits. WHAT WERE THE RESULTS?: Researchers found that age and location did not affect how long patients lived when treated with enzalutamide. They found three patient traits that did make a difference. Being able to carry out daily activities, low prostate-specific antigen level (PSA level), and receiving no other prostate cancer treatments after the study meant that patients were more likely to live longer. WHAT DO THE RESULTS OF THE STUDY MEAN?: Patients with nmCRPC treated with enzalutamide lived longer than patients treated with placebo. Age and location did not affect how long these patients lived, but other traits did. Clinical Trial Registration: NCT02003924 (ClinicalTrials.gov).

[Value of Blood Urea Nitrogen-to-Creatinine Ratio for Differentiating the Site of Gastrointestinal Bleeding and Assessing the Prognosis of Patients with Acute Nonvariceal Upper Gastrointestinal Bleeding].

Objective: To explore the diagnostic performance of blood urea nitrogen-to-creatinine (BUN/Cr) ratio in differentiating the site of gastrointestinal bleeding, and to assess the predictive value of early elevated BUN/Cr ratio for clinical outcomes in patients with acute nonvariceal upper gastrointestinal bleeding (ANVUGIB). Methods: The adult patients diagnosed with gastrointestinal bleeding who were hospitalized in the Department of Gastroenterology, Zhongshan Hospital, Xiamen University between May 2020 and May 2021 were retrospectively enrolled. According to the site of gastrointestinal bleeding, the patients were divided into the upper gastrointestinal tract group, the proximal small intestinal bleeding group, and the distal small intestinal and colonic bleeding group. According to the early dynamic changes of BUN/Cr ratio within 6-48 hours after admission, patients with ANVUGIB were divided into early dynamic elevated BUN/Cr ratio group and non-early dynamic elevated BUN/Cr ratio group. Receiver operating characteristic (ROC) curve was used to analyze the diagnostic performance of BUN/Cr ratio in differentiating the site of gastrointestinal bleeding and examine the predictive efficacy of early dynamic elevated BUN/Cr ratio after admission, Rockall scoring system, and the combined indicator of the two for estimating the primary clinical outcomes in ANVUGIB patients. Results: A total of 266 patients were enrolled. Among them, 204 cases were in the upper gastrointestinal bleeding group, 15 cases were in the proximal small intestinal bleeding group, and 47 cases were in the distal small intestinal and colonic bleeding group. In the ANVUGIB patients, 16 were in the group with early dynamic elevated BUN/Cr ratio after admission, and 146 were in the group with non-early dynamic elevated BUN/Cr ratio after admission. The area under the ROC curve of the BUN/Cr ratio was 0.831 (95% CI: 0.780-0.874), the optimal cut-off value being 34.59 mg/g for differentiation between upper and lower gastrointestinal bleeding. The area under the ROC curve of the BUN/Cr ratio was 0.901 (95% CI: 0.798-0.963) and the optimal cut-off value was 19.27 mg/g for differentiation between proximal small intestinal bleeding and the distal small intestinal and colonic bleeding. The area under the ROC curve of the early dynamic elevated BUN/Cr ratio after admission was 0.806 (95% CI: 0.737-0.864) for predicting the primary clinical outcome in patients with ANVUGIB. The area under the ROC curve of the combined indicator included the early dynamic elevated BUN/Cr ratio after admission and the Rockall scoring system was 0.909 (95% CI: 0.854-0.949) for predicting the primary clinical outcome in patients with ANVUGIB. Conclusion: The BUN/Cr ratio shows rather reliable diagnostic performance for identifying the site of gastrointestinal bleeding, and the early dynamic elevated BUN/Cr ratio after admission is a reliable indicator for predicting clinical outcomes in patients with ANVUGIB.

Exploratory analysis of the platelet-to-lymphocyte ratio prognostic value in the adjuvant renal cell cancer setting.

Aim: To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Materials & methods: Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). Results: In 609 patients, DFS was similar for baseline PLR <140 versus ≥140 overall (median: 6.4 vs 5.9 years; hazard ratio: 0.9; 95% CI: 0.7-1.2). A ≥25% decrease in PLR at week 4 overall was associated with longer DFS versus no change (hazard ratio: 0.8; 95% CI: 0.6-1.0). Conclusion: Baseline PLR was not prognostic for DFS with adjuvant sunitinib treatment in patients with renal cell carcinoma. Clinical Trials Registration: NCT00375674 (ClinicalTrials.gov).

The Perceived Beauty of Convex Polygon Tilings: The Influence of Regularity, Curvature, and Density.

Polygon tilings in natural and man-made objects show great variety. Unlike previous studies that have mainly focused on their classification and production methods, this study aimed at exploring factors that may contribute to the perceived beauty of convex polygon tilings. We analyze the dimensions of regularity, curvature, and density, as well as individual differences. Triangle tilings and hexagon tilings were tested in Experiment 1 and 2, respectively. The results showed that the perceived beauty of convex polygon tilings can be enhanced by higher levels of regularity and nonobvious local curvature. Surprisingly, the effect of density appeared to be different, with the dense triangle tilings and the less dense hexagon tilings scoring higher than the reverse. We discuss a possible explanation based on trypophobia caused by different types of polygons, as well as the observers' personality trait of agreeableness.

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients.

BACKGROUND: Metastatic renal cell carcinoma (mRCC) prognostic models may be improved by incorporating treatment-induced toxicities. METHODS: In sunitinib-treated mRCC patients (N=770), baseline prognostic factors and treatment-induced toxicities (hypertension (systolic blood pressure ⩾140 mm Hg), neutropenia (grade ⩾2), thrombocytopenia (grade ⩾2), hand-foot syndrome (grade >0), and asthenia/fatigue (grade >0)) were analysed in multivariate analyses of progression-free survival (PFS) and overall survival (OS) end points. RESULTS: On-treatment neutropenia and hypertension were associated with longer PFS (P=0.0276 and P<0.0001, respectively) and OS (P=0.0014 and P<0.0001, respectively), independent of baseline prognostic factors, including International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. By 12-week landmark analysis, neutropenia was significantly associated with longer PFS and OS (P=0.013 and P=0.0122, respectively) and hypertension or hand-foot syndrome with longer OS (P=0.0036 and P=0.0218, respectively). The concordance index was 0.65 (95% CI: 0.63-0.67) for IMDC classification alone and 0.72 (95% CI: 0.70-0.74) when combined with hypertension and neutropenia. Considering hypertension and neutropenia (developing both vs neither) changed IMDC-predicted median OS in each IMDC risk group (favourable: 45.3 vs 19.5 months; intermediate: 32.5 vs 8.0 months; poor: 21.1 vs 4.8 months). CONCLUSIONS: On-treatment neutropenia and hypertension are independent biomarkers of sunitinib efficacy and may add prognostic accuracy to the IMDC model.

[Radiological study on rat lumbar vertebral semidislocation model].

OBJECTIVE: To investigate the impact of fixation in part lumbar segment on rat model with radiography. METHODS: One hundred and twenty SPF male SD rats (350～450g) were randomly divided into simple fixation group (SF group), rotary fixation group (RF group) and sham-operation group (Sham group). The external link fixation system was implanted into the L4-L6 of SF group and RF group rats. In RF group, L5 spinous process of rats was rotated to the right side, making the L4, L6 and L5 spinous process not in a straight line. In SF group, the external link fixation system was implanted simply and not rotated. The anterior and posterior diameter in the intervertebral space and the distance between spinous processes were examined 1, 4, 8 and 12 weeks after fixation. RESULTS: The anterior diameter in the intervertebral space between L3-L4, L4-L5, L5-L6, and L6-S1 of SF groups 4 weeks after fixation were 28.11 ± 3.94, 25.73 ± 4.70, 29.51 ± 6.34 and 34.97 ± 4.65 pixels; the posterior diameter were 7.39 ± 1.63, 6.65 ± 1.76, 7.02±1.52 and 9.62 ± 2.50 pixels; the distance between spinous process were 39.33 ± 11.74, 14.11 ± 5.75, 21.32 ± 6.84 and 77.43 ± 13.69 pixels, the values were less than those in Sham groups (P<0.05). The anterior and posterior diameter in the intervertebral space and the distance between spinous process of SF groups 8 and 12 weeks after fixation continuously decreased compared with Sham group rats (P<0.05). The results of RF groups were consistent with the measurement of SF groups, the anterior and posterior diameter in the intervertebral space and the distance between spinous process of RF group rats were less than those in Sham groups 4, 8 and 12 weeks after fixation (P<0.05). Osteophyte formation was observed in SF and RF groups 8 weeks after fixation. CONCLUSION: The fixation in part lumbar segment can result in the decrease of intervertebral space and the formation of osteophytes.

Can the integration of sports and health industries drive the upgrade of the sports industry?-An empirical study based on Chinese-style modernization.

BACKGROUND: In the course of China's modernization, the sports industry's advancement plays a dual role in enhancing national health and driving economic transformation. The integration and coalescence of the sports and health sectors have emerged as pivotal avenues for the structural elevation of China's sports industry. Hence, empirically scrutinizing the influential mechanisms and outcomes of sports and health industry integration on the sports industry's structural enhancement holds substantial practical significance. METHOD: This study formulates theoretical hypotheses regarding the impact mechanism of sports and health industry integration on the sports industry's sophisticated industrial structure. Drawing insights from literature review and categorization, three dimensions-industrial integration, government role, and market mechanism-are delineated. Employing panel data spanning 2015 to 2020 from four primary Chinese cities, an econometric model is devised to empirically dissect the influence of sports and health industry integration on the sports industry's structural advancement. FINDINGS: The three pivotal explanatory variables-integration of sports and health industries, government role, and market mechanism-exert a positive influence on the sports industry's sophisticated industrial structure. Notably, the impact of market mechanisms outweighs that of government roles, with government roles exhibiting comparatively weaker individual impact effects. CONCLUSION: The dynamic development process characterizing the structural advancement of China's sports industry in first-tier cities exhibits positive and sustained developmental traits, with discernible convergence in trends. While market mechanisms demonstrate a more immediate and pronounced direct promotional effect than government roles, the enduring influence of government roles over an extended timeframe is evident from a dynamic long-term development perspective. Building upon these findings, the study suggests relevant stakeholders foster advanced sports industry structures by: refining the integration system of sports and health industries; fortifying the fundamental role of market mechanisms; and fully leveraging the government's impact in promoting sports and health industry integration.