FBXO45 levels regulated ferroptosis renal tubular epithelial cells in a model of diabetic nephropathy by PLK1.

Objective: This research aims to investigate the role and underlying biological mechanism of FBXO45 in regulating ferroptosis of renal fibrocytes in a diabetic nephropathy (DN) model. Methods: C57BL/6 mice were fed with a high-fat diet and injected with streptozotocin to induce diabetes. Human renal glomerular endothelial cells stimulated with d-glucose. Results: Serum FBXO45 mRNA expression was found to be down-regulated in patients with DN. There was a negative correlation between the expression of serum FBXO45 mRNA and serum α-SMA, Collagen I, and E-cadherin mRNA in patients with DN. Additionally, the expression of serum FBXO45 mRNA showed a negative correlation with blood sugar levels. Based on a 3D model prediction, it was observed that FBXO45 interacts with polo-like kinase 1 (PLK1) at GLY-271, ILE-226, GLY-166, LEU-165, ARG-245, and ASN-220, while PLK1 interacts with FBXO45 at TYR-417, ARG-516, HIS-489, TYR-485, GLN-536, and ARG-557. This interaction was confirmed through immunoprecipitation assay, which showed the interlinking of FBXO45 protein with PLK1 protein. Conclusions: These findings indicate that FBXO45 plays a role in mitigating ferroptosis in DN through the regulation of the PLK1/GPX4/SOX2 pathway. This highlights the potential of targeting FBXO45 as a therapeutic approach to ameliorate ferroptosis in DN.

Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma.

PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML.

PURPOSE: Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML. METHODS: In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation. RESULTS: After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated. CONCLUSION: These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Screening and validation of potential markers associated with uterine corpus endometrial carcinoma and polycystic ovary syndrome based on bioinformatics methods.

Background: Endometrial cancer (UCEC) is a commonly occurring tumor in females, and polycystic ovary syndrome (PCOS) is closely related to UCEC, but the molecular mechanisms remain unclear. This article aims to explore potential molecular mechanisms in UCEC and PCOS, as well as identify prognostic genes for UCEC. Methods: Bioinformatics methods were employed to screen for DEGs in UCEC and PCOS. The shared DEGs were analyzed by constructing a protein-protein interaction (PPI) network using the String database and Cytoscape software. The enrichment analysis was performed using Metascape. The shared DEGs associated with the prognosis of UCEC were identified through univariate and lasso Cox regression methods. A multivariate Cox regression model was constructed and internally validated. The expression and test efficiency of the key prognostic genes were verified using external datasets for UCEC and PCOS. Furthermore, the Gepia database was utilized to analyze the expression of key prognostic genes and their correlation with the disease-free survival (RFS) of UCEC. Tumor mutation burden (TMB), immune infiltration, and the correlation of immune cells were assessed for the prognostic genes of UCEC. Results: There were 151 shared DEGs identified between UCEC and PCOS through bioinformatics screening. These shared DEGs were primarily enriched in leukocyte activation. Following model construction and verification, nine genes were determined to be prognostic for UCEC from the shared DEGs. Among them, TSPYL5, KCNJ15, RTN1, HMOX1, DCAF12L1, VNN2, and ANXA1 were confirmed as prognostic genes in UCEC through external validation. Additionally, RTN1 was identified as a key gene in both UCEC and PCOS. Gepia analysis revealed that higher expression of RTN1 was associated with RFS in UCEC. Immune infiltration analysis of the shared DEGs demonstrated significant differences in the expression of various immune cells between UCEC high and low TMB groups. The seven key prognostic genes in UCEC exhibited regulatory relationships with immune cells. Conclusion: This study identified TSPYL5, KCNJ15, RTN1, HMOX1, DCAF12L1, VNN2, and ANXA1 as the key prognostic DEGs of UCEC. These genes are associated with UCEC survival, TMB, immune cell infiltration, and immune cell regulation. Among them, RTN1 may serve as a potential biomarker for both UCEC and PCOS.

Integrated analysis of lncRNA and mRNA expression profiles in patients with unexplained recurrent spontaneous abortion.

PROBLEM: Unexplained recurrent spontaneous abortion (URSA) is one of the most frustrating and confounding conditions in reproductive medicine, and its exact pathogenesis has not been clearly established. METHOD OF STUDY: In this study, we used RNA sequencing to characterize the mRNA and lncRNA expression profiles in peripheral blood. Thereafter, enrichment analysis was performed to determine the functions of the differentially expressed genes, and Cytoscape was used to construct lncRNA-mRNA interaction networks. RESULTS: Our results showed that the peripheral blood of patients with URSA has distinct mRNA and lncRNA expression profiles, with a total of 359 mRNAs and 683 lncRNAs being differentially expressed. Moreover, the top hub genes, including IGF1, PPARG, CCL3, RETN, SERPINE1, HESX1, and PRL, were identified and further validated using real-time quantitative PCR. Furthermore, we demonstrated a lncRNA-mRNA interaction network that achieved 12 key lncRNAs and their targeted mRNAs are involved in systemic lupus erythematosus, allograft rejection, and complement and coagulation cascades. Finally, the correlation between immune cell subtypes and IGF1 expression was evaluated; a negative correlation was observed with the proportion of natural killer cells, which increased significantly in URSA. CONCLUSION: We identified seven top hub genes, constructed a lncRNA-related network and suggested that IGF1 plays a key role in regulating maternal immune response by affecting NK and T cells' function, which helps to identify the pathogenesis of URSA.

Phase 3 trial of gilteritinib plus azacitidine vs azacitidine for newly diagnosed FLT3mut+ AML ineligible for intensive chemotherapy.

Treatment results for patients with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive chemotherapy are disappointing. This multicenter, open-label, phase 3 trial randomized (2:1) untreated adults with FLT3mut+ AML ineligible for intensive induction chemotherapy to receive gilteritinib (120 mg/d orally) and azacitidine (GIL + AZA) or azacitidine (AZA) alone. The primary end point was overall survival (OS). At the interim analysis (August 26, 2020), a total of 123 patients were randomized to treatment (GIL + AZA, n = 74; AZA, n = 49). Subsequent AML therapy, including FLT3 inhibitors, was received by 20.3% (GIL + AZA) and 44.9% (AZA) of patients. Median OS was 9.82 (GIL + AZA) and 8.87 (AZA) months (hazard ratio, 0.916; 95% CI, 0.529-1.585; P = .753). The study was closed based on the protocol-specified boundary for futility. Median event-free survival was 0.03 month in both arms. Event-free survival defined by using composite complete remission (CRc) was 4.53 months for GIL + AZA and 0.03 month for AZA (hazard ratio, 0.686; 95% CI, 0.433-1.087; P = .156). CRc rates were 58.1% (GIL + AZA) and 26.5% (AZA) (difference, 31.4%; 95% CI, 13.1-49.7; P < .001). Adverse event (AE) rates were similar for GIL + AZA (100%) and AZA (95.7%); grade ≥3 AEs were 95.9% and 89.4%, respectively. Common AEs with GIL + AZA included pyrexia (47.9%) and diarrhea (38.4%). Gilteritinib steady-state trough concentrations did not differ between GIL + AZA and gilteritinib. GIL + AZA resulted in significantly higher CRc rates, although similar OS compared with AZA. Results support the safety/tolerability and clinical activity of upfront therapy with GIL + AZA in older/unfit patients with FLT3mut+ AML. This trial was registered at www.clinicaltrials.gov as #NCT02752035.

A randomized phase 1 single-dose polysomnography study of ASP8062, a GABAB receptor positive allosteric modulator.

RATIONALE: Previous research suggests that sleep polysomnography and EEG endpoints can be used to assess GABAergic activity; however, the impact of GABAB receptor positive allosteric modulators on sleep endpoints remains unclear. OBJECTIVES: This phase 1 study compared a single dose of ASP8062 (35 mg or 70 mg), a GABAB receptor positive allosteric modulator, with placebo and paroxetine (40 mg). METHODS: Healthy adult volunteers were randomized to four treatments (35 mg ASP8062, 70 mg ASP8062, paroxetine 40 mg, or matching placebo), each separated by a 14-day washout. Primary endpoints obtained by polysomnography were time in stage N3 or SWS and time in rapid eye movement (REM) sleep. Secondary endpoints included impact on sleep stages and electroencephalography parameters, pharmacokinetics, nighttime growth hormone (GH), and safety/tolerability. RESULTS: In 20 randomized volunteers, ASP8062 led to a significant and seemingly dose-dependent increase in SWS over the entire night; this increase was mainly observed during the first third of the night. ASP8062 did not impact time in REM sleep. Paroxetine had no effect on SWS but produced a significant reduction in time spent in REM sleep. A dose-dependent trend in increased GH release was also observed with ASP8062. Headache and nausea were the most commonly reported treatment-emergent adverse events (TEAEs) for ASP8062; most TEAEs were mild in severity. CONCLUSIONS: Single-dose ASP8062 (35 and 70 mg) appeared to result in CNS penetration and enhanced GABAergic activity as measured by increases in slow-wave sleep and growth hormone release.

Pharmacokinetics of ASP4345 from Single Ascending-Dose and Multiple Ascending-Dose Phase I Studies.

BACKGROUND: Cognitive impairment is a core feature of schizophrenia. While first- and second-generation antipsychotic drugs treat psychotic exacerbations, no treatment is approved for the cognitive dysfunction. We have identified ASP4345, a positive allosteric modulator of the dopamine type 1 (D1) receptor that selectively binds to, and enhances the activity of, D1 receptors. ASP4345 has the potential to be an effective and well-tolerated treatment option for cognitive impairment associated with schizophrenia. OBJECTIVE: The objective of this study was to determine the pharmacokinetics of ASP4345 in two phase I single ascending-dose and multiple ascending-dose studies. METHODS: Both phase I studies were randomized, double blind, and placebo controlled. The single dose-ascending study assessed pharmacokinetics of single oral doses of 3-900 mg of ASP4345 or placebo in the fasted state in healthy adult volunteers. This study also assessed cerebrospinal fluid pharmacokinetics, as well as the effects of food on pharmacokinetic parameters. The multiple ascending-dose study (NCT02720263) assessed the pharmacokinetics of multiple oral doses of 3-150 mg of ASP4345 in patients with schizophrenia or schizoaffective disorder receiving stable antipsychotic drug treatment. The pharmacokinetic data from both studies were summarized using descriptive statistics. RESULTS: The plasma concentration-time profile in both studies showed a rapid increase in concentrations of ASP4345. The median time to maximum concentration range was 1.00-2.26 h in the single ascending-dose study in the fasted state and 1.25-3.02 h in the multiple ascending-dose study at steady state. There were less than dose-proportional increases in maximum concentration and area under the curve in the single ascending-dose study, where doses had a range from 3 to 900 mg, and in the multiple ascending-dose study in patients with stabilized schizophrenia or schizoaffective disorder, where doses had a range from 3 to 150 mg. The mean terminal elimination half-life was dose independent and had a range from 9.12 to 14.3 h in the single ascending-dose study and from 11.1 to 26.8 h in the multiple ascending-dose study. Additionally, in the single ascending-dose study, absorption of 300 mg of ASP4345 was slightly delayed when administered in the fed state compared with the fasted state; median time to maximum concentration was 1.5 h under the fasting state and 4.0 h under fed states. All other pharmacokinetic parameters were comparable for both conditions. ASP4345 appeared in the cerebrospinal fluid with some delay; time to maximum concentration range was from 2.48 to 7.98 h in cerebrospinal fluid compared with 0.75 to 1.03 h in plasma (median cerebrospinal fluid/plasma = 0.188). The ratio of cerebrospinal fluid to total plasma for area under the curve from 0 to 24 h (0.157-0.573%) and maximum concentration (0.0899-0.311%) and the ratio of cerebrospinal fluid to unbound plasma for maximum concentration (25.0-86.4%) confirm the distribution of ASP4345 into the brain. CONCLUSIONS: The pharmacokinetics of ASP4345 suggest that single daily dosing is appropriate for ASP4345. Furthermore, the concentration of ASP4345 in cerebrospinal fluid compared to free drug concentrations in plasma provides evidence of penetration of ASP4345 into the brain.

Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia.

ASP4345, a novel dopamine D1 receptor positive allosteric modulator, is being evaluated for the treatment of cognitive impairment associated with schizophrenia (CIAS). This phase 1 multiple ascending-dose study (NCT02720263) assessed the safety, tolerability, and pharmacodynamics of ASP4345 in patients with schizophrenia/schizoaffective disorder. Pharmacodynamic assessments were Cogstate cognitive tests and electrophysiological biomarkers, including gamma-band power and phase synchronization in response to 40-Hz auditory steady-state stimulation, as well as mismatch negativity (MMN) and P3a event-related potentials. The sample size determination was based on standard practice in assessing safety and tolerability of a new chemical entity. Data were summarized by conversion of this data into effect sizes using descriptive and inferential statistics. A total of 36 randomized patients received ASP4345 (3, 15, 50, and 150 mg; n = 9 each dose) and 12 patients received placebo. Patients in the ASP4345 group experienced 73 treatment-emergent adverse events (TEAEs) and 34 TEAEs were reported for the placebo group. The most common TEAEs were headache and somnolence and nearly all TEAEs were mild in severity. No changes in mood or self-reports of suicidal ideation/behavior were observed. Improvements in performance on cognitive tests were noted, which suggests a potential improvement in psychomotor function and visual attention. Furthermore, positive changes in neurophysiological biomarkers (auditory steady-state response [ASSR] and MMN) suggest improvement in information processing. The findings need to be confirmed in studies with a larger patient population. Nonetheless, the trends in safety and pharmacodynamic data support further clinical development of ASP4345 for the treatment of CIAS.

Pharmacokinetics and Immunogenicity of ASP0113 in CMV-Seronegative Dialysis Patients and CMV-Seronegative and -Seropositive Healthy Subjects.

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in immunocompromised transplant patients. ASP0113, a first-in-class DNA vaccine containing plasmids encoding CMV phosphoprotein 65 and glycoprotein B (gB), was evaluated in a phase 1b, subject-blinded study in CMV-seropositive (n = 13) and CMV-seronegative (n = 12) healthy and CMV-seronegative dialysis subjects (n = 12) randomized to ASP0113 or placebo. End points included pharmacokinetics, anti-gB antibody levels, phosphoprotein 65-specific T-cell responses measured by ex vivo enzyme-linked immune absorbent spot (ELISpot) assay and 10-day cultured ELISpot and Stat T-cell activation assays, and safety. ASP0113 concentrations peaked at 2-10 and 24-48 hours; the pharmacokinetics were similar across groups. No group demonstrated significant anti-gB antibody responses. T-cell responder rates in the cultured ELISpot assay were 8/12 (66.7%, 95%CI 35% to 90%) and 4/12 (33.3%, 95%CI 10% to 65%) in CMV-seronegative healthy subjects and dialysis patients, respectively, whereas ex vivo ELISpot assay response rates were 4/11 (36.4%, 95%CI 11% to 69%) and 0/12, respectively. Responses peaked at week 27, with lower magnitude observed in CMV-seronegative dialysis patients versus CMV-seronegative healthy subjects. No serious adverse events occurred; the most common adverse event in ASP0113-vaccinated patients was injection-site pain (64.9%). Some CMV-seronegative healthy subjects and dialysis patients had T-cell responses; no humoral responses were detected.

Circular RNA circFBXO11 modulates hepatocellular carcinoma progress and oxaliplatin resistance through miR-605/FOXO3/ABCB1 axis.

Increasing findings suggest the critical role of circular RNA (circRNA) in human cancer, and chemotherapy resistance is a poor prognostic factor for hepatocellular carcinoma (HCC). The function of circRNA in the HCC oxaliplatin (OXA) resistance remains largely unknown. In this study, we found that circRNA circFBXO11 was significantly up-regulated in HCC tissues, and the circFBXO11 overexpression was associated with poor prognosis. CircFBXO11 was found to promote the HCC proliferation, cycle progress and OXA resistance. Mechanistically, circFBXO11 was predominantly localized in the cytoplasm and harboured the miR-605, thereby targeting FOXO3 protein. Furthermore, FOXO3 targeted the promoter region of ABCB1 to accelerate its expression. In conclusion, this research reveals the role of circFBXO11/miR-605/FOXO3/ABCB1 axis in the HCC OXA resistance, providing new insight for circRNA-based diagnostic and therapeutic strategies.

Single- and Multiple-Dose Safety, Tolerability, and Pharmacokinetic Profiles of ASP8062: Results From 2 Phase 1 Studies.

ASP8062 is an orally active γ-amino-butyric acid type B (GABAB ) receptor positive allosteric modulator currently in phase 2 development. Safety and pharmacokinetic (PK) profiles of ASP8062 were evaluated in 2 studies in healthy subjects. The first study (a first-in-human study) evaluated single ascending doses (SAD) of ASP8062. The second study was composed of 2 parts: part 1 evaluated multiple ascending doses (MAD) of ASP8062 for 14 days, and part 2 was a single-dose arm to assess the PK of ASP8062 in cerebrospinal fluid (CSF). Fifty-six men (SAD) and 56 subjects (24 women and 32 men; MAD) were enrolled. Across the SAD dosing range, area under the concentration-time curve was dose proportional; increases in maximum plasma concentration appeared linear but were slightly less than dose proportional. Time to maximal concentration and half-life were 1-4 hours and ∼40-50 hours, respectively; no food effect was observed. ASP8062 PK properties at steady state were similar to those following a single dose. Steady state was achieved by ∼day 9 with ∼2-fold accumulation, and ASP8062 was detected in CSF. ASP8062 was well tolerated; no clear evidence of ASP8062's effects on safety, cognition, drug withdrawal, or suicidal ideation/behavior was observed. These data support the development of ASP8062 in indications where the GABAB receptor is a target.

Isorhamnetin inhibits IL­1ß­induced expression of inflammatory mediators in human chondrocytes.

Isorhamnetin (ISH) is a flavonoid primarily obtained from the fruit of Hippophae rhamnoides L., which possesses anti­inflammatory properties. However, the effect of ISH on the expression of inflammatory mediators in response to interleukin (IL)­1ß stimulation has not been elucidated. The present study investigated the effects of ISH on the expression of inflammatory mediators in human chondrocytes, induced by IL­1ß. The results of the present study demonstrated that pretreatment with ISH inhibited the expression of stromelysin­1 and collagenase 3 in chondrocytes, induced by IL­1ß. Pretreatment with ISH inhibited the IL­1ß­stimulated synthesis of NO and prostaglandin E2 induced by IL­1ß, in addition to the expression of inducible nitric oxide synthase and prostaglandin G/H synthase 2 in chondrocytes. Additionally, ISH inhibited the expression of nuclear factor (NF)­κB and transcription factor p65, and the degradation of NF­κB inhibitor α induced by IL­1ß in chondrocytes. In conclusion, the results of the present study indicated that ISH exhibited anti­inflammatory and chondroprotective effects in IL­1ß­stimulated chondrocytes. The results of the present study suggest that ISH may be a potential agent in the future treatment of osteoarthritis.

Predicting invasions of Wedelia trilobata (L.) Hitchc. with Maxent and GARP models.

Wedelia trilobata (L.) Hitchc., an ornamental groundcover plant introduced to areas around the world from Central America, has become invasive in many regions. To increase understanding of its geographic distribution and potential extent of spread, two presence-only niche-based modeling approaches (Maxent and GARP) were employed to create models based on occurrence records from its: (1) native range only and (2) full range (native and invasive). Models were then projected globally to identify areas vulnerable to W. trilobata invasion. W. trilobata prefers hot and humid environments and can occur in areas with different environmental conditions than experienced in its native range. Based on native and full occurrence points, GARP and Maxent models produced consistent distributional maps of W. trilobata, although Maxent model results were more conservative. When used to estimate the global invasive distribution of the species, both modeling approaches projected the species to occur in Africa. The GARP full model succeeded in predicting the known occurrences in Australia, while the other models failed to identify favorable habitats in this region. Given the rapid spread of W. trilobata and the serious risk of this species poses to local ecosystems, practical strategies to prevent the establishment and expansion of this species should be sought.

Expression of Skp2 and p27kip1 proteins in hypopharyngeal squamous cell carcinoma and its clinical significance.

The aim of the present study was to determine the effect of S-phase kinase-associated protein 2 (Skp2) and cyclin-dependent kinase inhibitor p27kinase-interacting protein 1 (p27kip1) protein expression on the occurrence and development of hypopharyngeal squamous cell carcinoma. The protein expression levels of Skp2 and p27kip1 were detected in 42 hypopharyngeal squamous cell carcinoma and 15 normal hypopharyngeal mucous membrane specimens using the an immunohistochemical PV-9000 two-step method. The expression levels of Skp2 protein were significantly different in hypopharyngeal squamous cell carcinomas and normal hypopharyngeal mucous membranes (61.90 vs. 26.67%; P<0.05). By contrast, the protein expression levels of Skp2 were significantly positively correlated with tumor T stage (rs=0.329, P<0.05) and cervical lymph node metastasis (rs=0.402, P<0.05). Furthermore, the expression levels of p27kip1 protein were significantly different in hypopharyngeal squamous cell carcinomas and normal hypopharyngeal mucous membranes (11.9 vs. 53.33%; P<0.05), while p27kip1 protein expression was significantly negatively correlated with tumor T-stage (rs=-0.351, P<0.05) and cervical lymph node metastasis (rs=-0.371, P<0.05). Notably, a significant negative correlation was observed between the expression levels of Skp2 and p27kip1 proteins in hypopharyngeal squamous cell carcinoma (P<0.05). In addition, abnormal expression levels of Skp2 and p27kip1 proteins were observed in hypopharyngeal squamous cell carcinoma tissues. Thus, Skp2 and p27kip1 proteins may be involved in the development of hypopharyngeal squamous cell carcinoma. The current study proposed that combined detection of Skp2 and p27kip1 may be useful for assessing the characteristics and prognosis of hypopharyngeal squamous cell carcinoma.

Age variation and sexual dimorphism in the sixteen diagnostic clusters of risk factors for the metabolic syndrome.

OBJECTIVE: To document age- and sex-related differences in the 16 phenotypes of risk factors for the metabolic syndrome (MS) among adults in the Fels Longitudinal Study (FLS). METHODS: Data on risk factors for the MS were analyzed in 471 white men and 503 white women in the FLS. We used the Cochran-Armitage test to compare age- and sex-related differences in the prevalence of the 16 diagnostic clusters of positive risk factors. RESULTS: Of the 974 subjects, 238 were found to meet diagnostic criteria for 15 of a possible 16 phenotypes of the MS. The prevalence of the MS was four times greater in subjects older than 40 years than in subjects 20-40 years old. Older subjects had more risk factors exceeding criterion values than younger subjects. Among those who met three-to-five criteria for the MS, younger subjects were more likely to have dyslipidemia, less likely to have high blood pressure (HBP), and two times less likely to have impaired fasting plasma glucose (IFG) than subjects 40+ years old. Older men were more likely than older women to have HBP and IFG. . We found that if one of the five risk factors reaches a criterion value, the values for the other four risk factors move closer to their own diagnostic criterion values in apparent synchrony. CONCLUSIONS: Subjects 40+ years old are four times likelier to have the MS than younger subjects, and older men are at higher risk than older women. The mean values for each of the five risk factors get progressively worse as the number of risk factors meeting diagnostic criteria increases. Therefore, when one factor is found to meet its diagnostic criterion, levels of the other four risk factors should be measured. The different phenotypic patterns that comprise the MS should prompt clinicians to target specific risk factors for prevention or treatment. Certain phenotypes were found more commonly in women and certain others more commonly in men. Similarly, certain phenotypes were found more commonly in older than in younger age groups. These age- and sex-specific phenotypes should help clinicians to identify subjects at highest risk for certain risk factors and to initiate specifically tailored preventive and therapeutic interventions. Our observations should also stimulate clinical investigators and epidemiologists to ascertain what factors determine the sex and age specificity of certain phenotypes of the MS.

Family history and risk of hair loss.

INTRODUCTION: The genetic basis of androgenetic alopecia (AGA) is well accepted in the medical community and among the general population. However, rigorous studies investigating the familial basis of AGA are lacking. The purpose of the current study was to explore the relationship between family history and expression of AGA in a sample of men from the general community. METHODS: Hair loss was assessed by an independent observer trained by an expert dermatologist using the Norwood/Hamilton classification scale and a 7-point global description of hair loss. Men were classified into two groups, one as having little or no hair loss and the other having hair loss. The family history of hair loss in parents and grandparents was assessed by subject self-report. RESULTS: Adjusting for age, men whose fathers had hair loss were 2.5 times as likely to have had some level of hair loss compared to men whose fathers had no hair loss (95% CI: 1.3-4.9). Likewise, men whose fathers had hair loss were twice as likely to have hair loss than men whose fathers had no hair loss even after adjusting for age (OR = 2.1, 95% CI: 1.2-3.7 and OR = 2.5, 95% CI: 1.4-4.7 for Norwood/Hamilton and global description of hair loss assessments, respectively). CONCLUSION: Results suggest that the probability of male pattern hair loss is dependent on family history and age. Hair loss in a man's father also appears to play an important role in increasing a man's risk of hair loss, either in conjunction with a history of hair loss in the mother or hair loss in the maternal grandfather.