High-Brightness Continuous-Wave Electron Beams from Superconducting Radio-Frequency Photoemission Gun.

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK_{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10 nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

Effect of high glucose, Porphyromonas gingivalis lipopolysaccharide and advanced glycation end-products on production of interleukin-6/-8 by gingival fibroblasts.

BACKGROUND AND OBJECTIVE: It is known that chronic periodontal infection can magnify the cytokine responses in patients with diabetes. Hyperglycemia increases the proinflammatory status, including the levels of advanced glycation end-products (AGEs), in patients with periodontitis. However, whether AGEs have additional effects on the production of those proinflammatory cytokines in diabetic patients with periodontitis is still unknown. To examine in vitro the effect of hyperglycemia and AGEs on the amounts of interleukin (IL)-6 and IL-8 produced in periodontally infected gingiva, human gingival fibroblasts (HGFs) were stimulated with glucose, AGE-modified bovine serum albumin (AGE-BSA) and Porphyromonas gingivalis LPS in the present study. MATERIAL AND METHODS: Primary culture of HGFs was incubated with various concentrations of AGE-BSA (0, 50, 100 and 200 µg/mL) and LPS (0, 10, 100 or 1000 ng/mL) at two different glucose concentrations - normal glucose (5 mm) and high glucose (25 mm). The amounts of IL-6 and IL-8 produced by HGFs were evaluated using ELISA. Expression of the AGE receptor on HGFs was determined by flow cytometry. RESULTS: High glucose stimulated a significant increase in the production of IL-6 and IL-8 by HGFs compared with normal glucose. This enhanced production of IL-6 and IL-8 could also be observed in the presence of LPS and/or AGE-BSA. When both LPS and AGE-BSA were present, especially at high concentrations (≥ 500 µg/mL of LPS and ≥ 25 µg/mL of AGE-BSA), a synergistic effect on IL-8 production was found in the high-glucose condition. CONCLUSIONS: A synergistic effect of the production of IL-8 could be induced in HGFs with the combination of high glucose, LPS and AGEs.

Histone deacetylase inhibitors increase microRNA-146a expression and enhance negative regulation of interleukin-1ß signaling in osteoarthritis fibroblast-like synoviocytes.

OBJECTIVE: MiR-146a exerts negative control on inflammatory responses by suppressing cytokine-induced expression of interleukin-1 receptor-associated kinase-1 (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) by impairing NF-κB activity and inhibiting the expression of target genes. Recent study suggests that histone deacetylases (HDACs) are involved in the regulation of microRNA (miRNA) expression. Therefore, we determined whether HDAC inhibitors can increase miR-146a expression, thereby inhibiting interleukin-1ß (IL-1ß)-induced signaling in osteoarthritis fibroblast-like synoviocytes (OA-FLS). METHOD: MiRNA expression was analyzed using real-time PCR. IL-1ß-induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA. Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays. RESULTS: IL-1ß treatment of OA-FLS induced a mild (1.7-fold) increase in miR-146a expression that was unable to appropriately downregulate IRAK1 and TRAF6 expression. HDAC inhibitors, SAHA (vorinostat), and LBH589 (panobinostat) significantly (6.1- and 5.4-fold) elevated miR-146a expression by increasing the binding of the transcription factor NF-κB to the miR-146a promoter, and negatively regulated IL-1ß-induced IKK/IκB/p65 phosphorylation signaling and IL-6 secretion. The increase in miR-146a expression induced by the HDAC inhibitors was prevented by transfection of miR-146a inhibitor or HDAC1 (class I HDAC), HDAC4 (class IIa HDAC), and HDAC6 (class IIb HDAC) overexpression, suggesting that they were due to inhibition of HDAC activity. CONCLUSIONS: Our study demonstrated that HDAC inhibitor treatment in OA-FLS significantly increased miR-146a expression and mediated markedly negative regulation to inhibit IL-1ß-induced signaling and cytokine secretion. Our results indicate the potential rationale of anti-inflammatory effects for HDAC inhibitors.

Mild fumarase deficiency and a trial of low protein diet.

We report clinical findings in a 12-year-old girl with a mild case of fumarase deficiency who continues to make progress. She has two novel mutations of the fumarase gene [c.521C>G (p.P174R) and c.908T>C (p.L303S)]. A trial of low protein diet did not reduce fumaric aciduria.

Ejection of uniform micrometer-sized droplets from Faraday waves on a millimeter-sized water drop.

This Letter reports the first observation and theoretical analysis of a new phenomenon: one large spherical water drop ejecting simultaneously a very large number of monodisperse microdroplets. An ultrasonic nozzle with multiple-Fourier horns in resonance enables controlled excitation of megahertz Faraday waves on the free water surface. The temporal instability of such waves leads to the ejection of 3.5-4.4 µm monodisperse droplets at a high rate (>4.0×10(7) droplets/sec). This is in stark contrast to the Rayleigh-Plateau instability, which ejects one droplet at a time.

Clinicopathologic significance of DNA mismatch repair protein defects and endometrial cancer in women 40years of age and younger.

BACKGROUND: The hereditary basis of endometrial cancer is apparent in young women with endometrial cancer. The objective of this study was to examine risk factors and outcomes in patients 40 years of age and younger with endometrial cancer. METHODS: We performed a retrospective cohort study of patients aged 40 years or less who were diagnosed with endometrial carcinoma between 1/93 and 5/08. Clinical and pathologic data were extracted from medical records. Paraffin-embedded slides from hysterectomy specimens were obtained and DNA mismatch repair (MMR) immunohistochemistry was performed. Cases were analyzed according to the presence of DNA MMR protein defects. Standard two-sided statistical tests were performed. RESULTS: Of the 56 identified patients, the median age was 36 years (range, 24-40). The majority of the endometrial carcinomas were of endometrioid histology (91%), stage I (71%), and FIGO grade 1 (59%). Abnormal DNA MMR was found in 9 cases (16%). Cases with abnormal DNA MMR had lower body mass index (BMI) (P=0.05), and had a family history suggestive of Lynch syndrome (P=0.001). Tumors were more likely to have advanced stage disease (P<0.001), be high grade (P<0.001), have deep myometrial invasion (P<0.001), and have lymphovascular invasion (P=0.002). Cases with abnormal DNA MMR had significantly worse overall survival (P=0.028) and progression-free survival (P=0.042). CONCLUSIONS: Endometrial cancer is rare in women aged 40 years or less. In this group of patients, loss of DNA MMR was associated with lower BMI, worse clinicopathologic factors, and worse outcome. These results may have implications when young women diagnosed with endometrial cancer are counseled regarding prognosis.

Surgical cytoreduction in stage IV endometrioid endometrial carcinoma.

OBJECTIVE: To evaluate the role of surgical cytoreduction and the amount of residual disease in patients with newly diagnosed stage IV endometrioid endometrial carcinoma (EC). METHODS: Patients with stage IV EC of endometrioid histology who underwent surgery at our institution from 1977 to 2003 were identified. Patients with microscopic stage IV disease were excluded. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier method and compared with log-rank test. RESULTS: A total of 58 patients were identified, of which 9 (15.5%) had no gross residual (NGR) after surgery, 11 (19.0%) had residual disease ≤1 cm, 32 (55.1%) had residual disease >1 cm, and 6 (10.3%) had no cytoreduction attempted. The median PFS was 11.1 months (95% CI, 9.8-12.3) and the median OS was 19.2 months (95% CI, 8.5-29.9) for the cohort. The median PFS was 40.3 months (95% CI, 0-93.9) for patients with NGR disease, 11 months (95% CI, 9.9-12.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients who did not have attempted cytoreduction (P<0.001). The median OS was 42.2 months (95% CI, not estimable) for patients with NGR disease, 19 months (95% CI, 13.9-24.1) for patients with any residual disease, and 2.2 months (95% CI, 0.1-4.2) for patients that did not have attempted cytoreduction (P<0.001). CONCLUSION: Though stage IV endometrioid EC has a poor prognosis, surgical cytoreduction to no gross residual disease in a highly select group of patients is associated with improved survival.

Accuracy of frozen section diagnosis of ovarian borderline tumor.

OBJECTIVE: The objective of this study was to determine the incidence of invasive cancer in ovarian masses diagnosed as borderline tumor (BT) at the time of frozen section. METHODS: We performed a retrospective review of all patients diagnosed with ovarian BT on frozen section (FS) at our institution between 2000 and 2010. Clinical and pathologic data were extracted. Univariate and multivariate analyses were performed using standard two-sided statistical tests. RESULTS: A total of 120 patients were identified, of which 104 (86.7%) had BT on frozen section that was confirmed on final pathology. In 15 (12.5%) patients, BT was diagnosed on FS but was reclassified as invasive cancer on final pathology. One patient (0.8%) had BT on FS but benign pathology on final diagnosis. Histologies included serous in 79 (65.8%), seromucinous in 13 (10.8%), mucinous in 21 (17.5), endometrioid in 5 (4.2%), and clear cell in 2 (1.7%) patients. Reclassification of pathologic diagnosis was related to histologic subtype, but only for endometrioid and clear cell tumors (P<0.001). The rate of invasive cancer for serous micropapillary tumors on frozen section was 42.8% compared with 2.8% for serous non-micropapillary tumors (P<0.001). Tumor size >8 cm was associated with a 22.4% incidence of invasive cancer on final pathology compared to 3.2% in tumors ≤ 8 cm (P=0.004). CONCLUSION: Comprehensive surgical staging can be considered in BT >8 cm in diameter, as well as those with micropapillary serous, endometrioid, and clear cell histology diagnosed at the time of frozen section analysis.

Risk factors for recurrence of ovarian borderline tumors.

OBJECTIVE: The objective of this study was to identify clinicopathologic features that are associated with an increased risk of recurrence for borderline ovarian tumors (BOT). METHODS: We performed a retrospective review of all patients treated for BOT at our institution from 1979 to 2008. Progression-free survival (PFS) was defined as the time of diagnosis to time of recurrence/death or last follow-up. The Kaplan-Meier method was used to calculate the PFS rate and the Wilcoxon-Gehan test was performed to identify prognostic factors. RESULTS: A total of 266 patients were identified. The median age was 43 years (range, 15-94 years). The majority of patients (68.4%) had FIGO stage I disease and serous histology (73.7%). Only 23 (8.6%) patients developed recurrent disease. The median PFS was 19 years and the median follow-up was 4 years. Abnormal baseline CA-125 (>35 U/ml), advanced stage, age at diagnosis, and invasive implants were associated with decreased PFS. Of the 196 patients with serous BOT, those with a micropapillary pattern had a 3-year PFS of 75.9% (95%CI, 55.6-87.8) compared with 94.3% (95% CI, 88.4-97.3) for patients without micropapillary pattern (P<0.001). CONCLUSION: Age at diagnosis, an elevated preoperative CA-125, invasive implants, and micropapillary histology were clinical factors associated with increased risk of recurrence in women with BOT. Including these clinicopathologic features will likely identify patients at higher risk for recurrence, for whom development of new treatment strategies would be appropriate.

Long lifetime of bialkali photocathodes operating in high gradient superconducting radio frequency gun.

High brightness, high charge electron beams are critical for a number of advanced accelerator applications. The initial emittance of the electron beam, which is determined by the mean transverse energy (MTE) and laser spot size, is one of the most important parameters determining the beam quality. The bialkali photocathodes illuminated by a visible laser have the advantages of high quantum efficiency (QE) and low MTE. Furthermore, Superconducting Radio Frequency (SRF) guns can operate in the continuous wave (CW) mode at high accelerating gradients, e.g. with significant reduction of the laser spot size at the photocathode. Combining the bialkali photocathode with the SRF gun enables generation of high charge, high brightness, and possibly high average current electron beams. However, integrating the high QE semiconductor photocathode into the SRF guns has been challenging. In this article, we report on the development of bialkali photocathodes for successful operation in the SRF gun with months-long lifetime while delivering CW beams with nano-coulomb charge per bunch. This achievement opens a new era for high charge, high brightness CW electron beams.

Avelumab in patients with previously treated metastatic Merkel cell carcinoma (JAVELIN Merkel 200): updated overall survival data after >5 years of follow-up.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer that has a poor prognosis in patients with advanced disease. Avelumab [anti-programmed death-ligand 1 (PD-L1)] became the first approved treatment for patients with metastatic MCC (mMCC), based on efficacy and safety data observed in the JAVELIN Merkel 200 trial. We report long-term overall survival (OS) data after >5 years of follow-up from the cohort of patients with mMCC whose disease had progressed after one or more prior lines of chemotherapy. PATIENTS AND METHODS: In Part A of the single-arm, open-label, phase II JAVELIN Merkel 200 trial, patients with mMCC that had progressed following one or more prior lines of chemotherapy received avelumab 10 mg/kg by intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. In this analysis, long-term OS was analyzed. RESULTS: In total, 88 patients were treated with avelumab. At data cut-off (25 September 2020), median follow-up was 65.1 months (range 60.8-74.1 months). One patient (1.1%) remained on treatment, and an additional patient (1.1%) had reinitiated avelumab after previously discontinuing treatment. Median OS was 12.6 months [95% confidence interval (CI) 7.5-17.1 months], with a 5-year OS rate of 26% (95% CI 17% to 36%). In patients with PD-L1+ versus PD-L1- tumors, median OS was 12.9 months (95% CI 8.7-29.6 months) versus 7.3 months (95% CI 3.4-14.0 months), and the 5-year OS rate was 28% (95% CI 17% to 40%) versus 19% (95% CI 5% to 40%), respectively (HR 0.67; 95% CI 0.36-1.25). CONCLUSION: Avelumab monotherapy resulted in meaningful long-term OS in patients with mMCC whose disease had progressed following chemotherapy. These results further support the role of avelumab as a standard of care for patients with mMCC.

Miniaturized multiple Fourier-horn ultrasonic droplet generators for biomedical applications.

Here we report micro-electro-mechanical system (MEMS)-based miniaturized silicon ultrasonic droplet generators of a new and simple nozzle architecture with multiple Fourier horns in resonance but without a central channel. The centimetre-sized nozzles operate at one to two MHz and a single vibration mode which readily facilitates temporal instability of Faraday waves to produce monodisperse droplets. Droplets with diameter range 2.2-4.6 µm are produced at high throughput of 420 µl min(-1) and very low electrical drive power of 80 mW. We also report the first theoretical prediction of the droplet diameter. The resulting MHz ultrasonic devices possess important advantages and demonstrate superior performance over earlier devices with a central channel and thus have high potential for biomedical applications such as efficient and effective delivery of inhaled medications and encapsulated therapy to the lung.

Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study.

To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.

Beyond tertiary cytoreduction in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer.

BACKGROUND: Primary, secondary, and possibly tertiary surgical cytoreduction in patients with recurrent epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) cancer appears to be associated with a survival benefit. The objective of this study was to assess if cytoreduction of recurrences after tertiary cytoreduction offers any potential benefit in these patients. METHODS: We performed a retrospective chart review of all patients with recurrent EOC, FTC, or PPC who underwent additional cytoreductive procedures after a prior tertiary cytoreduction (quaternary cytoreduction) at our institution between 1991 and 2008. Disease-specific survival (DSS) was calculated from the time of quaternary cytoreduction to last follow-up. Univariate analyses were used to analyze outcomes and to identify potential prognostic factors. RESULTS: A total of 15 patients were identified, of which 7 (47%) have died of disease. All patients had undergone prior optimal secondary and tertiary surgical cytoreductive procedures. The size of residual disease varied from 0 (in 10 cases/67%) to >1 cm (in 2 cases, 13%). Residual disease (1 cm) and number of recurrence sites (single vs multiple) were found to be significant prognostic factors on univariate analysis. CONCLUSIONS: Cytoreductive surgery beyond tertiary cytoreduction may be a reasonable option in highly select patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, especially in the setting of a single site of recurrent disease.

Tertiary cytoreduction in patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer: an updated series.

OBJECTIVE: Surgical cytoreduction is an integral therapeutic modality for patients with epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) cancer in the primary setting. The role of surgical cytoreduction in the recurrent setting is not clearly defined and remains controversial. The objective of this study was to assess this potential survival benefit in a large cohort of patients with a long follow-up period. METHODS: We performed a retrospective chart review of all patients with recurrent EOC, FTC, or PPC who underwent tertiary cytoreduction at our institution from 2/98 to 2/08. Disease-specific survival (DSS) was calculated from the time of tertiary cytoreduction to death or last follow-up. Univariate and multivariate analyses were used to analyze outcomes and to identify potential prognostic factors. RESULTS: A total of 77 patients were identified, of which 38 (49%) have died of disease. The median time from secondary to tertiary cytoreduction was 25.7 months (range, 4.1-99.4 months). The median follow-up after tertiary cytoreduction was 28.9 months (range, 0.7-123.7 months), with a median DSS for the entire cohort of 47.7 months (95% CI, 25.5-69.9 months). On univariate analysis, residual disease after tertiary cytoreduction and TFI were found to be significant prognostic factors. On multivariate analysis, only residual disease after tertiary cytoreduction retained prognostic significance (P<0.001). CONCLUSION: Tertiary surgical cytoreduction may offer a survival benefit in a highly select group of patients with recurrent EOC, FTC, or PPC. This benefit appears to be greatest in patients in whom a complete gross resection can be achieved.

Photocatalytic hydrogen generation from water under visible light using core/shell nano-catalysts.

A microemulsion technique was employed to synthesize nano-sized photocatalysts with a core (CdS)/shell (ZnS) structure. The primary particles of the photocatalysts were around 10 nm, and the mean size of the catalyst clusters in water was about 100 nm. The band gaps of the catalysts ranged from 2.25 to 2.46 eV. The experiments of photocatalytic H(2) generation showed that the catalysts (CdS)(x)/(ZnS)(1-x) with x ranging from 0.1 to 1 were able to produce hydrogen from water photolysis under visible light. The catalyst with x=0.9 had the highest rate of hydrogen production. The catalyst loading density also influenced the photo-hydrogen production rate, and the best catalyst concentration in water was 1 g L(-1). The stability of the nano-catalysts in terms of size, morphology and activity was satisfactory during an extended test period for a specific hydrogen production rate of 2.38 mmol g(-1) L(-1) h(-1) and a quantum yield of 16.1% under visible light (165 W Xe lamp, lambda>420 nm). The results demonstrate that the (CdS)/(ZnS) core/shell nano-particles are a novel photo-catalyst for renewable hydrogen generation from water under visible light. This is attributable to the large band-gap ZnS shell that separates the electron/hole pairs generated by the CdS core and hence reduces their recombinations.

Chloramine mutagenesis in Bacillus subtilis.

Chloramine (which occurs widely as a by-product of sanitary chlorination of water supplies) is shown to be a weak mutagen, when reversion of trpC to trpC in Bacillus subtilis is used as an assay. Some DNA-repair mutants appear to be more sensitive to chloramine, suggesting the involvement of DNA targets in bactericide. The influence of plating media on survival of cells treated with chloramine suggests a bacterial repair system acting upon potentially lethal lesions induced by chloramine.

Diagnosis of insulin resistance in hypertensive patients by the metabolic syndrome: AHA vs. IDF definitions.

BACKGROUND: Subjects with the metabolic syndrome are accompanied by insulin resistance (IR). However, it is not clear how well the newly defined metabolic syndrome identifies IR specifically in hypertensive subjects. AIMS: The purpose of the study was to evaluate the performance of the metabolic syndrome, defined by the American Heart Association (AHA) and the International Diabetes Federation (IDF) definitions, in identifying IR in hypertension. METHODS: The analysis is a cross-sectional study. Totally, 228 hypertensive patients and 92 non-diabetic normotensive controls who received insulin suppressive tests for direct evaluation of their insulin sensitivity were included from the Stanford Asia and Pacific Program for Hypertension and IR. McNemar's tests were used to compare sensitivity and specificity of the AHA-defined with the IDF-defined metabolic syndrome in diagnosis of IR. RESULTS: The sensitivity of the metabolic syndrome for IR in hypertension was 89.7% and the specificity 45.9% by the AHA definition. Using the IDF definition, the sensitivity was 77.6%, and the specificity increased to 63.5%. The diagnostic power of individual components of the syndrome was also modest. The predictive discrimination of wider waist circumference was similar to that of the AHA-defined metabolic syndrome. CONCLUSIONS: Use of the metabolic syndrome by the AHA definition provided good sensitivity, but low specificity to diagnose IR in hypertension. The IDF definition improved in false-positive rate, but it was still not specific enough to identify IR in hypertension.

A systematic review on the impact of diabetes mellitus on the ocular surface.

Diabetes mellitus is associated with extensive morbidity and mortality in any human community. It is well understood that the burden of diabetes is attributed to chronic progressive damage in major end-organs, but it is underappreciated that the most superficial and transparent organ affected by diabetes is the cornea. Different corneal components (epithelium, nerves, immune cells and endothelium) underpin specific systemic complications of diabetes. Just as diabetic retinopathy is a marker of more generalized microvascular disease, corneal nerve changes can predict peripheral and autonomic neuropathy, providing a window of opportunity for early treatment. In addition, alterations of immune cells in corneas suggest an inflammatory component in diabetic complications. Furthermore, impaired corneal epithelial wound healing may also imply more widespread disease. The non-invasiveness and improvement in imaging technology facilitates the emergence of new screening tools. Systemic control of diabetes can improve ocular surface health, possibly aided by anti-inflammatory and vasoprotective agents.