Brief Report: Tepotinib as a Treatment Option in MET Exon 14 Skipping-Positive Lung Cancers-Investigating Discordance Between ArcherMET and the Oncomine Dx Target Test.

Introduction: NSCLC is a leading cause of cancer-related mortality worldwide. Specific genetic alterations, such as MET exon 14 (METex14) skipping, have been identified in NSCLC, allowing targeted therapy. Tepotinib, a highly selective MET inhibitor, has displayed promise in patients with advanced NSCLC. Nevertheless, challenges arise when identifying treatment strategies for patients with discordant results regarding METex14 skipping detection between diagnostic tests. Methods: We investigated patients with NSCLC and discordant results for METex14 skipping between the Oncomine Dx Target Test (ODxTT) and ArcherMET. Clinical response, adverse events, and the duration of tepotinib treatment were assessed, and statistical analysis was performed. Results: Among the 19 patients deemed METex14 skipping positive by ODxTT, only 10 had concordant results with ArcherMET. The number of METex14 skipping reads detected by ODxTT was significantly lower in discordant cases. Of the 19 patients, 14 received tepotinib, and comparable response and disease control rates were observed in both concordant and discordant cases. The duration of treatment did not significantly differ between the two groups. Conclusions: Our findings suggest that tepotinib has comparable therapeutic effects in patients with METex14 skipping-positive NSCLC irrespective of the concordance of results between ODxTT and ArcherMET. Tepotinib is a possible treatment option for patients with METex14 skipping, even in patients with discordant test results.

Visualization of Modified Bisarylbutadiyne-Tagged Small Molecules in Live-Cell Nuclei by Stimulated Raman Scattering Microscopy.

Visualizing the distribution of small-molecule drugs in living cells is an important strategy for developing specific, effective, and minimally toxic drugs. As an alternative to fluorescence imaging using bulky fluorophores or cell fixation, stimulated Raman scattering (SRS) imaging combined with bisarylbutadiyne (BADY) tagging enables the observation of small molecules closer to their native intracellular state. However, there is evidence that the physicochemical properties of BADY-tagged analogues of small-molecule drugs differ significantly from those of their parent drugs, potentially affecting their intracellular distribution. Herein, we developed a modified BADY to reduce deviations in physicochemical properties (in particular, lipophilicity and membrane permeability) between tagged and parent drugs, while maintaining high Raman activity in live-cell SRS imaging. We highlight the practical application of this approach by revealing the nuclear distribution of a modified BADY-tagged analogue of JQ1, a bromodomain and extra-terminal motif inhibitor with applications in targeted cancer therapy, in living HeLa cells. The modified BADY, methoxypyridazyl pyrimidyl butadiyne (MPDY), revealed intranuclear JQ1, while BADY-tagged JQ1 did not show a clear nuclear signal. We anticipate that the present approach combining MPDY tagging with live-cell SRS imaging provides important insight into the behavior of intracellular drugs and represents a promising avenue for improving drug development.

Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2.

BACKGROUND: Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended for high-risk patients, but the potential for the development of multidrug-resistant mutations in immunocompromised patients is unclear. METHODS: To investigate the treatment course in cases of prolonged viral shedding in an immunocompromised patient with SARS-CoV-2 infection, we conducted longitudinal measurements of laboratory tests, chest computed tomography (CT) image evaluations, antibody titers, and antigen levels in nasopharyngeal swabs. Furthermore, we performed whole-genome sequencing and digital PCR analysis to examine the mechanisms of drug resistance. FINDINGS: We present a case of a 65-year-old man with a history of malignant lymphoma who was treated with multiple antiviral and antibody therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), and molnupiravir. Initially, viral antigen levels decreased after treatments. However, after the virus rebounded, the patient showed no virologic response. The viral genome analysis revealed a single Omicron subvariant (BA.1.1), which evolved within the host during the disease progression. The viruses had acquired multiple resistance mutations to nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L and E340K), and remdesivir (RNA-dependent RNA polymerase [RdRp] V166L). CONCLUSIONS: Our results indicate that viruses with multidrug-resistant mutations and survival fitness persist in the infected subpopulation after drug selection pressure. FUNDING: This study was supported by the JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid for Scientific Research (B) 20H03668 and 23H02955 (Y.H.), the YASUDA Medical Foundation (Y.H.), the Uehara Memorial Foundation (Y.H.), the Takeda Science Foundation (Y.H.), and Kato Memorial Bioscience Foundation (Y.H.).

Cytokine release syndrome complicated with severe rashes induced by nivolumab plus ipilimumab therapy in a patient with non-small cell lung cancer: A case report.

Cytokine release syndrome (CRS) is a severe and life-threatening toxicity typically reported in chimeric antigen receptor T cell therapy and is rarely reported in immune checkpoint inhibitor (ICI) therapy. This study reports the case of a 75-year-old Japanese woman who received nivolumab plus ipilimumab therapy for the postoperative recurrence of non-small cell lung cancer. She was admitted to our hospital with fever, hypotension, hepatic disorder, and thrombocytopenia. We observed slight skin rashes on her neck on admission, which spread rapidly across her body within a few days. We diagnosed CRS complicated by severe rashes. CRS symptoms were resolved with corticosteroid therapy, and did not recur thereafter. CRS is a rare, but important, immune-related adverse event associated with ICI therapy.

Lung tropism in hospitalized patients following infection with SARS-CoV-2 variants from D614G to Omicron BA.2.

BACKGROUND: The genetic and pathogenic characteristics of SARS-CoV-2 have evolved from the original isolated strains; however, the changes in viral virulence have not been fully defined. In this study, we analyzed the association between the severity of the pathogenesis of pneumonia in humans and SARS-CoV-2 variants that have been prevalent to date. METHODS: We examined changes in the variants and tropism of SARS-CoV-2. A total of 514 patients admitted between February 2020 and August 2022 were included and evaluated for pneumonia by computed tomography (CT) as a surrogate of viral tropism. RESULTS: The prevalence of pneumonia for each variant was as follows: D614G (57%, 65/114), Alpha (67%, 41/61), Delta (49%, 41/84), Omicron BA.1.1 (26%, 43/163), and Omicron BA.2 (11%, 10/92). The pneumonia prevalence in unvaccinated patients progressively declined from 70% to 11% as the variants changed: D614G (56%, 61/108), Alpha (70%, 26/37), Delta (60%, 38/63), BA.1.1 (52%, 15/29), and BA.2 (11%, 2/19). The presence of pneumonia in vaccinated patients was as follows: Delta (16%, 3/19), BA.1.1 (21%, 27/129), and BA.2 (11%, 8/73). Compared with D614G, the areas of lung involvement were also significantly reduced in BA.1.1 and BA.2 variants. CONCLUSIONS: Compared with previous variants, there was a marked decrease in pneumonia prevalence and lung involvement in patients infected with Omicron owing to decreased tropism in the lungs that hindered viral proliferation in the alveolar epithelial tissue. Nevertheless, older, high-risk patients with comorbidities who are infected with an Omicron variant can still develop pneumonia and require early treatment.

The SARS-CoV-2 virus changes over time with the differing viruses described as variants. The different variants of SARS-CoV-2 have an impact on how easily they infect people and the effects they have on infected individuals. Here, we examined images of the lungs of patients hospitalized with COVID-19 to investigate whether they had pneumonia, a type of swelling in the lung. Compared with the variant found early in the pandemic, the more recent Omicron variant led to a decreased rate of pneumonia in infected individuals. Our findings emphasize the need for early treatment, as pneumonia may progress in older patients or those with other illnesses.

Physiological and Psychological Effects of Volatile Organic Compounds from Dried Common Rush (Juncus effusus L. var. decipiens Buchen.) on Humans.

This study compared the participants' physiological responses and subjective evaluations of air scented with different concentrations of common rush (Juncus effusus L. var. decipiens Buchen.) (30 g and 15 g, with fresh air as a control). We asked 20 participants to complete a series of visual discrimination tasks while inhaling two different air samples. We evaluated (1) brain activity, (2) autonomic nervous activity, and (3) blood pressure and pulse rate, (4) in combination with self-evaluation. In addition, we quantified the concentrations of volatile organic compounds. The participants reported the scent to be sour, pungent, and smelly; this impression was likely caused by hexanal and acetic acid. Although the self-evaluations showed that participants did not enjoy the scent, their alpha amplitudes of electroencephalogram and parasympathetic nervous activity were increased, suggesting that participants were relaxed in this atmosphere. Moreover, a lower concentration resulted in a greater induction of relaxation. While the air was not pleasant-smelling, the volatile organic compounds present had a positive psychophysiological impact.

Effects of the dipeptide L-glutamic acid-L-tryptophan on dermatitis in mice and human keratinocytes.

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are inflammatory eczematous skin diseases caused by various factors. Here, we report that topical application of the dipeptide, L-glutamic acid-L-tryptophan (L-Glu-L-Trp), improved symptoms in both ACD and AD in mice. Using a mouse model of ACD induced by repeated application of 2,4-dinitorofluorbenzene (DNFB), we demonstrated that L-Glu-L-Trp attenuated DNFB-induced skin thickening. In addition, quantification of cytokines in serum revealed that L-Glu-L-Trp suppressed the DNFB-induced increase in the interleukin (IL)-22 level. Moreover, L-Glu-L-Trp attenuated mite antigen extract-induced AD model symptoms such as the increase of skin thickening and elevation of serum IL-22. We also confirmed that the dipeptide structure rather than the individual amino acid components was important for the therapeutic effects of L-Glu-L-Trp. Furthermore, we showed that IL-22 decreased the expression level of filaggrin mRNA in human epidermal keratinocytes, and L-Glu-L-Trp attenuated that effect. These results suggested that the topical application of the dipeptide, L-Glu-L-Trp, to the skin may be useful for treating ACD and AD.

Genetic epidemiological analysis of hypouricaemia from 4993 Japanese on non-functional variants of URAT1/SLC22A12 gene.

OBJECTIVES: Up to 0.3% of Japanese have hypouricaemia. Most cases appear to result from a hereditary disease, renal hypouricaemia (RHUC), which causes exercise-induced acute kidney injury and urolithiasis. However, to what extent RHUC accounts for hypouricaemia is not known. We therefore investigated its frequency and evaluated its risks by genotyping a general Japanese population. METHODS: A cohort of 4993 Japanese was examined by genotyping the non-functional variants R90H (rs121907896) and W258X (rs121907892) of URAT1/SLC22A12, the two most common causative variants of RHUC in Japanese. RESULTS: Participants' fractional excretion of uric acid and risk allele frequencies markedly increased at lower serum uric acid (SUA) levels. Ten participants (0.200%) had an SUA level ≤2.0 mg/dl and nine had R90H or W258X and were likely to have RHUC. Logistic regression analysis revealed these URAT1 variants to be significantly and independently associated with the risk of hypouricaemia and mild hypouricaemia (SUA ≤3.0 mg/dl) as well as sex, age and BMI, but these URAT1 variants were the only risks in the hypouricaemia population (SUA ≤2.0 mg/dl). W258X was only a risk in males with SUA ≤3.0 mg/dl. CONCLUSION: Our study accurately reveals the prevalence of RHUC and provides genetic evidence for its definition (SUA ≤2.0 mg/dl). We also show that individuals with SUA ≤3.0 mg/dl, especially males, are prone to RHUC. Our findings will help to promote a better epidemiological understanding of RHUC as well as more accurate diagnosis, especially in males with mild hypouricaemia.

Zfhx4 regulates endochondral ossification as the transcriptional platform of Osterix in mice.

Endochondral ossification is regulated by transcription factors that include SRY-box transcription factor 9, runt-related protein 2 (Runx2), and Osterix. However, the sequential and harmonious regulation of the multiple steps of endochondral ossification is unclear. This study identified zinc finger homeodomain 4 (Zfhx4) as a crucial transcriptional partner of Osterix. We found that Zfhx4 was highly expressed in cartilage and that Zfhx4 deficient mice had reduced expression of matrix metallopeptidase 13 and inhibited calcification of cartilage matrices. These phenotypes were very similar to impaired chondrogenesis in Osterix deficient mice. Coimmunoprecipitation and immunofluorescence indicated a physical interaction between Zfhx4 and Osterix. Notably, Zfhx4 and Osterix double mutant mice showed more severe phenotype than Zfhx4 deficient mice. Additionally, Zfhx4 interacted with Runx2 that functions upstream of Osterix. Our findings suggest that Zfhx4 coordinates the transcriptional network of Osterix and, consequently, endochondral ossification.

A Proposal for Practical Diagnosis of Renal Hypouricemia: Evidenced from Genetic Studies of Nonfunctional Variants of URAT1/SLC22A12 among 30,685 Japanese Individuals.

BACKGROUND: Renal hypouricemia (RHUC) is characterized by a low serum uric acid (SUA) level and high fractional excretion of uric acid (FEUA). Further studies on FEUA in hypouricemic individuals are needed for a more accurate diagnosis of RHUC. METHODS: In 30,685 Japanese health-examination participants, we genotyped the two most common nonfunctional variants of URAT1 (NFV-URAT1), W258X (rs121907892) and R90H (rs121907896), in 1040 hypouricemic individuals (SUA ≤ 3.0 mg/dL) and 2240 individuals with FEUA data. The effects of NFV-URAT1 on FEUA and SUA were also investigated using linear and multiple regression analyses. RESULTS: Frequency of hypouricemic individuals (SUA ≤ 3.0 mg/dL) was 0.97% (male) and 6.94% (female) among 30,685 participants. High frequencies of those having at least one allele of NFV-URAT1 were observed in 1040 hypouricemic individuals. Furthermore, NFV-URAT1 significantly increased FEUA and decreased SUA, enabling FEUA and SUA levels to be estimated. Conversely, FEUA and SUA data of hypouricemic individuals are revealed to be useful to predict the number of NFV-URAT1. CONCLUSIONS: Our findings reveal that specific patterns of FEUA and SUA data assist with predicting the number of nonfunctional variants of causative genes for RHUC, and can also be useful for practical diagnosis of RHUC even before genetic tests.

Both variants of A1CF and BAZ1B genes are associated with gout susceptibility: a replication study and meta-analysis in a Japanese population.

Gout is a common type of acute arthritis that results from elevated serum uric acid (SUA) levels. Recent genome-wide association studies (GWASs) have revealed several novel single nucleotide polymorphism (SNPs) associated with SUA levels. Of these, rs10821905 of A1CF and rs1178977 of BAZ1B showed the greatest and the second greatest significant effect size for increasing SUA level in the Japanese population, but their association with gout is not clear. We examined their association with gout using 1411 clinically-defined Japanese gout patients and 1285 controls, and meta-analyzed our previous gout GWAS data to investigate any association with gout. Replication studies revealed both SNPs to be significantly associated with gout (P = 0.0366, odds ratio [OR] with 95% confidence interval [CI]: 1.30 [1.02-1.68] for rs10821905 of A1CF, P = 6.49 × 10-3, OR with 95% CI: 1.29 [1.07-1.55] for rs1178977 of BAZ1B). Meta-analysis also revealed a significant association with gout in both SNPs (Pmeta = 3.16 × 10-4, OR with 95% CI: 1.39 [1.17-1.66] for rs10821905 of A1CF, Pmeta = 7.28 × 10-5, OR with 95% CI 1.32 [1.15-1.51] for rs1178977 of BAZ1B). This study shows the first known association between SNPs of A1CF, BAZ1B and clinically-defined gout cases in Japanese. Our results also suggest a shared physiological/pathophysiological background between several populations, including Japanese, for both SUA increase and gout susceptibility. Our findings will not only assist the elucidation of the pathophysiology of gout and hyperuricemia, but also suggest new molecular targets.

[CLINICAL ANALYSIS OF 95 CASES OF PERCUTANEOUS CYSTOSTOMY].

(Introduction) Percutaneous cystostomy is a standard urological procedure; however, very few reports have focused on the many cases of this procedure performed in Japan. We analyzed the background of the procedure and its approach as well as the incidence of its complications at our institution. (Material and methods) We examined 95 patients who underwent percutaneous cystostomy between April 2010 and March 2019. A comparative analysis was conducted for each type of procedure performed. Furthermore, cases that experienced accidental catheter extraction before the first catheter replacement were analyzed, and the three patient groups were compared based on the type of procedure performed and cases that needed another operation. (Result) The indications for cystostomy were urethral stricture (56.3%), neuropathic bladder (13.5%), and prostatic hyperplasia (11.5%). The complications included hemorrhage, peritoneal injury, urinary tract infection, and catheter damage caused by a puncture needle. The overall complication rate was 10.5%. Based on type of the procedure performed, the incidence of hemorrhage was found to be as high as 25% in patients who underwent the procedure using a cannula puncture needle. Accidental catheter extraction before the first catheter replacement occurred most frequently in patients treated with Seldinger technique (17.0%). The rate of complications including accidental catheter extraction ranged from 25.0% to 25.4% among the three groups. (Conclusion) We prefer the Seldinger technique for the first placement of the cystostomy catheter because of its low rate of hemorrhage, but a cannula puncture needle may also be used by using exploratory puncture if vascular damage and accidental catheter extraction are avoided.

A case of lymphocytic interstitial pneumonia presenting with a ground glass nodule as an initial finding.

A 65-year-old woman had a ground glass nodule, which was suspicious for lung cancer, in her right lung S6 by chest computed tomography. For diagnosis, video-assisted thoracoscopic surgery was performed, and the specimen showed a pathological pattern of lymphocytic interstitial pneumonia (LIP). Four years after surgery, new localized ground glass shadows gradually increased on the base of the lung. However, because she had no respiratory symptoms and had normal respiratory function, she was observed with no medication. Subsequently, no other underlying diseases associated with LIP developed. The ground glass nodule was the initial lesion of LIP.

Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically defined gout patients.

OBJECTIVES: Genome-wide meta-analyses of clinically defined gout were performed to identify subtype-specific susceptibility loci. Evaluation using selection pressure analysis with these loci was also conducted to investigate genetic risks characteristic of the Japanese population over the last 2000-3000 years. METHODS: Two genome-wide association studies (GWASs) of 3053 clinically defined gout cases and 4554 controls from Japanese males were performed using the Japonica Array and Illumina Array platforms. About 7.2 million single-nucleotide polymorphisms were meta-analysed after imputation. Patients were then divided into four clinical subtypes (the renal underexcretion type, renal overload type, combined type and normal type), and meta-analyses were conducted in the same manner. Selection pressure analyses using singleton density score were also performed on each subtype. RESULTS: In addition to the eight loci we reported previously, two novel loci, PIBF1 and ACSM2B, were identified at a genome-wide significance level (p<5.0×10-8) from a GWAS meta-analysis of all gout patients, and other two novel intergenic loci, CD2-PTGFRN and SLC28A3-NTRK2, from normal type gout patients. Subtype-dependent patterns of Manhattan plots were observed with subtype GWASs of gout patients, indicating that these subtype-specific loci suggest differences in pathophysiology along patients' gout subtypes. Selection pressure analysis revealed significant enrichment of selection pressure on ABCG2 in addition to ALDH2 loci for all subtypes except for normal type gout. CONCLUSIONS: Our findings on subtype GWAS meta-analyses and selection pressure analysis of gout will assist elucidation of the subtype-dependent molecular targets and evolutionary involvement among genotype, phenotype and subtype-specific tailor-made medicine/prevention of gout and hyperuricaemia.

Virtual-freezing fluorescence imaging flow cytometry.

By virtue of the combined merits of flow cytometry and fluorescence microscopy, imaging flow cytometry (IFC) has become an established tool for cell analysis in diverse biomedical fields such as cancer biology, microbiology, immunology, hematology, and stem cell biology. However, the performance and utility of IFC are severely limited by the fundamental trade-off between throughput, sensitivity, and spatial resolution. Here we present an optomechanical imaging method that overcomes the trade-off by virtually freezing the motion of flowing cells on the image sensor to effectively achieve 1000 times longer exposure time for microscopy-grade fluorescence image acquisition. Consequently, it enables high-throughput IFC of single cells at >10,000 cells s-1 without sacrificing sensitivity and spatial resolution. The availability of numerous information-rich fluorescence cell images allows high-dimensional statistical analysis and accurate classification with deep learning, as evidenced by our demonstration of unique applications in hematology and microbiology.

A common variant of LDL receptor related protein 2 (LRP2) gene is associated with gout susceptibility: a meta-analysis in a Japanese population.

Gout, which results from elevated serum uric acid (SUA), is a common form of arthritis that is induced by urate crystals. A single nucleotide polymorphism, rs2544390, of LDL receptor related protein 2 (LRP2/Megalin), has previously been reported to be associated with SUA by a genome-wide association study in a Japanese population. However, it was controversial as to whether rs2544390 is associated with gout in a Japanese population, since previous studies with Japanese populations have reported an association between gout and rs2544390 both with and without significance. This prompted us to investigate the association between gout and rs2544390 of LRP2. Using 1208 clinically diagnosed gout patients and 1223 controls in a Japanese male population, our results showed that while rs2544390 did not show a significant association with gout susceptibility in the present study (p = 0.0793, odds ratio [OR] with 95% confidential interval [CI] 1.11 [0.99-1.24]). However, a meta-analysis using previous studies on Japanese populations revealed a significant association with gout (pmeta = 0.0314, OR with 95% CI 1.09 [1.01-1.18]). We have therefore for the first time confirmed a positive association between rs2544390 and gout with only a Japanese male population. Our study provides clues to a better understanding of the pathogenesis of gout and has the potential to lead to novel therapeutic strategies against gout using LRP2 as a molecular target.

Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout.

OBJECTIVE: The first ever genome-wide association study (GWAS) of clinically defined gout cases and asymptomatic hyperuricaemia (AHUA) controls was performed to identify novel gout loci that aggravate AHUA into gout. METHODS: We carried out a GWAS of 945 clinically defined gout cases and 1003 AHUA controls followed by 2 replication studies. In total, 2860 gout cases and 3149 AHUA controls (all Japanese men) were analysed. We also compared the ORs for each locus in the present GWAS (gout vs AHUA) with those in the previous GWAS (gout vs normouricaemia). RESULTS: This new approach enabled us to identify two novel gout loci (rs7927466 of CNTN5 and rs9952962 of MIR302F) and one suggestive locus (rs12980365 of ZNF724) at the genome-wide significance level (p<5.0×10-8). The present study also identified the loci of ABCG2, ALDH2 and SLC2A9. One of them, rs671 of ALDH2, was identified as a gout locus by GWAS for the first time. Comparing ORs for each locus in the present versus the previous GWAS revealed three 'gout vs AHUA GWAS'-specific loci (CNTN5, MIR302F and ZNF724) to be clearly associated with mechanisms of gout development which distinctly differ from the known gout risk loci that basically elevate serum uric acid level. CONCLUSIONS: This meta-analysis is the first to reveal the loci associated with crystal-induced inflammation, the last step in gout development that aggravates AHUA into gout. Our findings should help to elucidate the molecular mechanisms of gout development and assist the prevention of gout attacks in high-risk AHUA individuals.

Chronic kidney disease and positive surgical margins as prognosticators for upper urinary tract urothelial carcinoma patients undergoing radical nephroureterectomy.

Chronic kidney disease (CKD) is a common condition among elderly patients and has been reported to be a biomarker for the presence of malignant disease. In addition, unfavorable outcomes for patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy can be due to independent clinical factors. Therefore, the present study analyzed the clinicopathological data of patients with UTUC, who underwent radical nephroureterectomy at our institution, to clarify whether preoperative CKD and other factors are independent predictors of the shorter disease-specific and/or recurrence-free survival time of these patients. A retrospective review of 187 patients who underwent radical nephroureterectomy was conducted, and patients were followed for at least 3 months postoperatively. The clinicopathological factors that are thought to have potentially significant roles in the progression and metastasis of malignant tumors and for disease-specific and recurrence-free survival were evaluated. Positive surgical margins and an estimation of the glomerular filtration rate (eGFR) of <60 were independent factors for the shorter disease-specific survival time in multivariate analysis with Cox's proportional hazards model [hazard ratio (HR), 2.401: 95% confidence interval (CI), 1.044-5.255; and HR, 2.371: 95% CI, 1.024-5.898, respectively]. Another multivariate analysis also revealed that positive surgical margins (HR, 4.477; 95% CI, 2.042-9.469), and preoperative eGFR <60 (HR, 2.362; 95% CI, 1.067-5.592) were independent factors for the worse recurrence-free survival rate in all patients. Patients with UTUC who had eGFR <60 as well as positive surgical margins had significantly shorter time to disease-specific mortality and extraurothelial recurrence. The present study demonstrated that patients with UTUC undergoing radical nephroureterectomy who have CKD as well as positive surgical margins should be carefully followed up postoperatively.

Genome-wide meta-analysis identifies multiple novel loci associated with serum uric acid levels in Japanese individuals.

Gout is a common arthritis caused by elevated serum uric acid (SUA) levels. Here we investigated loci influencing SUA in a genome-wide meta-analysis with 121,745 Japanese subjects. We identified 8948 variants at 36 genomic loci (P<5 × 10-8) including eight novel loci. Of these, missense variants of SESN2 and PNPLA3 were predicted to be damaging to the function of these proteins; another five loci-TMEM18, TM4SF4, MXD3-LMAN2, PSORS1C1-PSORS1C2, and HNF4A-are related to cell metabolism, proliferation, or oxidative stress; and the remaining locus, LINC01578, is unknown. We also identified 132 correlated genes whose expression levels are associated with SUA-increasing alleles. These genes are enriched for the UniProt transport term, suggesting the importance of transport-related genes in SUA regulation. Furthermore, trans-ethnic meta-analysis across our own meta-analysis and the Global Urate Genetics Consortium has revealed 15 more novel loci associated with SUA. Our findings provide insight into the pathogenesis, treatment, and prevention of hyperuricemia/gout.