Pneumonitis After Concurrent Chemoradiation and Immune Checkpoint Inhibition in Patients with Locally Advanced Non-small Cell Lung Cancer.

AIMS: Pneumonitis is a common and potentially deadly complication of combined chemoradiation and immune checkpoint inhibition (CRT-ICI) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). In this study we sought to identify the risk factors for pneumonitis with CRT-ICI therapy in LA-NSCLC cases and determine its impact on survival. MATERIALS AND METHODS: We conducted a retrospective chart review of 140 patients with LA-NSCLC who underwent curative-intent CRT-ICI with durvalumab between 2018 and 2021. Pneumonitis was diagnosed by a multidisciplinary team of clinical experts. We used multivariable cause-specific hazard models to identify risk factors associated with grade ≥2 pneumonitis. We constructed multivariable Cox proportional hazard models to investigate the impact of pneumonitis on all-cause mortality. RESULTS: The median age of the cohort was 67 years; most patients were current or former smokers (86%). The cumulative incidence of grade ≥2 pneumonitis was 23%. Among survivors, 25/28 patients had persistent parenchymal scarring. In multivariable analyses, the mean lung dose (hazard ratio 1.14 per Gy, 95% confidence interval 1.03-1.25) and interstitial lung disease (hazard ratio 3.8, 95% confidence interval 1.3-11.0) increased the risk for pneumonitis. In adjusted models, grade ≥2 pneumonitis (hazard ratio 2.5, 95% confidence interval 1.0-6.2, P = 0.049) and high-grade (≥3) pneumonitis (hazard ratio 8.3, 95% confidence interval 3.0-23.0, P < 0.001) were associated with higher all-cause mortality. CONCLUSIONS: Risk factors for pneumonitis in LA-NSCLC patients undergoing CRT-ICI include the mean radiation dose to the lung and pre-treatment interstitial lung disease. Although most cases are not fatal, pneumonitis in this setting is associated with markedly increased mortality.

[Association between periodontitis and mild cognitive impairment: a clinical pilot study].

Objective: To evaluate the association between periodontitis and mild cognitive impairment (MCI), and explore the potential local oral risk factors for MCI. Methods: The study included 70 middle-aged and elderly subjects (44 females and 26 males) with periodontal disease who were first diagnosed by the Department of Periodontology or referred by the Department of Geriatrics in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine from January 2021 to January 2022. In this study, the control group consisted of periodontal disease patients without cognitive impairment, and the case group (MCI group) consisted of those diagnosed with MCI referred by the geriatrics specialists. Full-mouth periodontal examinations of all subjects were performed and periodontal indicators were recorded by periodontists, while digital panoramic radiographs were taken. The severity of periodontitis was defined according to the 1999 classification, and the staging and grading of periodontitis were defined according to the 2018 American Academy of Periodontology and European Federation of Periodontology classification. The mini-mental state examination scale was chosen by geriatricians to evaluate the cognitive function of the included subjects. The cubital venous blood was drawn to detect the expression levels of inflammatory factors such as hypersensitive C-reactive protein (hs-CRP), interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α(TNF-α) in serum. Independent-samples t test and chi-square test were used to analyze the differences in population factors, periodontal-related indexes and serum inflammatory factors between the two groups (α=0.05). Odds ratios (OR) for MCI according to the severity of periodontitis and main periodontal clinical indexes were calculated by binary Logistic analysis. Results: Thirty-nine subjects were included in the control group and thirty-one in the MCI group. The age of the study population was (58.3±6.2) years (range: 45-70 years). The comparison between two groups showed that the control group was with higher educational background (χ²=9.45, P=0.024) and 2.6 years younger than the MCI group [(57.1±6.0) years vs. (59.7±6.3) years, t=-1.24, P=0.082]. The number and proportion of moderate to severe periodontitis in control group were significantly lower compared to those in MCI group (17 cases with 43.6% vs. 23 cases with 74.2%, χ²=6.61, P=0.010), and the OR of moderate to severe periodontitis adjusted by age and educational background was 3.00 (95%CI: 1.01-8.86, P=0.048). Compared with the grading (χ²=5.56, P=0.062) of periodontitis, staging had a greater impact on MCI (χ²=7.69, P=0.041), moreover the proportion of MCI in stage Ⅰ grade A periodontitis was significantly lower than any other type of periodontitis (χ²=13.86, P=0.036). In addition, less presence of deep periodontal pockets [probing depth (PD)≥6 mm] (17.9% vs. 41.9%, χ²=4.87, P=0.027), fewer number of PD≥4 mm (6.48±6.70 vs. 11.03±8.91, t=-2.44, P=0.017), lower plaque index (1.42±0.56 vs. 1.68±0.57, t=-1.91, P=0.059) and gingival index (1.68±0.29 vs. 1.96±0.30, t=-3.93, P<0.001) were in the control group than in the MCI group. However, there were no significant differences between the two groups in the levels of serum inflammatory factors, such as hs-CRP, IL-1ß, IL-6 and TNF-α (P>0.05). Conclusions: It appears a strong correlation between moderate to severe periodontitis and the incidence of MCI in middle-aged and elderly people. Moreover, deep and increased number of periodontal pockets, poor oral hygiene, and severe gingival inflammation can be potentially associated risk factors for MCI.

Does SAPHO syndrome exist in dermatology?

In the late 1960s, palmoplantar pustulosis (PPP) with sternocostoclavicular arthropathy was first described in Japan, predominantly affecting women in the perimenopausal age. In the 1970s, the chronic non-bacterial osteomyelitis and chronic recurrent multifocal osteomyelitis were initially observed in paediatric patients with approximately 70% girls. Acne fulminans accompanied by polyarthralgia have been observed since early 1970s, which almost exclusively occurs in adolescent boys. Report on spondyloarthropathy associated with hidradenitis suppurativa can be traced back to 1982. The SAPHO syndrome was coined in 1987 to lump together synovitis, acne, pustulosis, hyperostosis and osteitis to conceptualize a group of inflammatory osteocutaneous diseases of unclear etiopathogenesis and ill-defined associations spanning disparate age and gender groups. From historical view, Sasaki syndrome is proposed to replace SAPHO syndrome to represent PPP with sternocostoclavicular arthropathy in the absence of other skin manifestations. Hidradenitis suppurativa is folliculitis in pathogenesis and no longer classified as acne. PPP accompanied by psoriasis vulgaris is more likely psoriasis pustulosa palmoplantaris in dermatological aspect, and the associated arthritis is part of psoriatic arthropathy. Pathophysiology of these disorders is incompletely understood. To echo the advancement of high-throughput sequencing, splitting but not lumping of clinical findings would be a better strategy to decipher these multigenic complex inflammatory disorders.

Protective effect of resveratrol on kidney in rats with diabetic nephropathy and its effect on endoplasmic reticulum stress.

OBJECTIVE: Diabetic nephropathy (DN) can cause chronic renal insufficiency and significantly reduce the life quality of patients with diabetes mellitus, and may eventually lead to death. The study investigated the expression of endoplasmic reticulum stress-related factors, which have important roles in the progress of DN and to explore effects of resveratrol on DN and the possible mechanism. MATERIALS AND METHODS: Specific pathogen free (SPF) grade healthy male Sprague Dawley (SD) rats were divided into different groups for different treatments. The diabetic rat model was established by intraperitoneal injection of low-dose streptozotocin (STZ) (40 mg/kg). The normal rats and diabetes model rats were divided into four groups including normal control group (N), normal control + resveratrol (N+R), model group (M), and model + resveratrol group (M+R) for different treatments. The changes of renal histology were observed by immunohistochemistry. Glucose oxidase/peroxidase method was used to measure FPG, UP 24 h content was measured by bicinchoninic acid (BCA) assay, BUN, Scr and Cys C content were measured by automatic biochemical analyzer. The expressions of 78 kDa glucose-regulated protein (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) were analyzed by Western blot. RESULTS: Resveratrol treatment significantly reduced the fasting blood glucose level, urinary protein level and renal pathological damage. The phosphorylation of PERK in the kidney of rats with diabetes was up-regulated, while resveratrol treatment reduced this change. The expression of p- PERK, GRP78, ATF4, and CHOP was significantly increased in rats with diabetes, while resveratrol treatment can reduce the increased level of those endoplasmic reticulum stress related factors. CONCLUSIONS: Resveratrol has a good therapeutic effect on DN in rats without side effect. The mechanism may be related to the regulation of endoplasmic reticulum stress response.

Using Hematuria as Detection of Post-kidney Transplantation Upper Urinary Tract Urothelial Carcinoma Is Associated With Delayed Diagnosis of Cancer Occurrence.

OBJECTIVES: Kidney transplantation (KT) is an important renal replacement therapy for end-stage renal disease (ESRD). The incidence of upper urinary tract urothelial carcinoma (UTUC) is relatively higher in Taiwan. According to our institutional database, early onset of post-KT UTUC is not uncommon. Early detection of post-KT UTUC is an important issue to improve oncologic outcome. Because painless hematuria is a common symptom for UTUC, this study analyzes whether using hematuria as post-KT UTUC screening delayed cancer diagnosis or not. METHODS: From 2005 to 2012, 128 ESRD patients were found to have UTUCs. There were 28 patients who underwent KT and were regularly followed up at our institution. All the patients underwent standard nephroureterectomy. RESULTS: In ESRD patients with UTUC, the post-KT group revealed significantly less gross hematuria and microscopic hematuria at presentation compared with the non-KT group (43% versus 76%, P = .001 and 64% versus 86%, P = .011). For those patients with gross hematuria, non-organ-confined UTUC occurred more in the post-KT group compared with the non-KT group (42% versus 12%, P = .009). For those patients with microscopic hematuria, non-organ-confined UTUC occurred more in the post-KT group compared with the non-KT group with borderline significance (33% versus 16%, P = .085). CONCLUSIONS: According to our observation, using gross or microscopic hematuria as detection of post-KT UTUC is associated with delayed diagnosis of cancer occurrence. Closer upper urinary tract image study such as sonography may help earlier cancer screening.

To use or not to use? Compulsive behavior and its role in smartphone addiction.

Global smartphone penetration has led to unprecedented addictive behaviors. To develop a smartphone use/non-use pattern by mobile application (App) in order to identify problematic smartphone use, a total of 79 college students were monitored by the App for 1 month. The App-generated parameters included the daily use/non-use frequency, the total duration and the daily median of the duration per epoch. We introduced two other parameters, the root mean square of the successive differences (RMSSD) and the Similarity Index, in order to explore the similarity in use and non-use between participants. The non-use frequency, non-use duration and non-use-median parameters were able to significantly predict problematic smartphone use. A lower value for the RMSSD and Similarity Index, which represent a higher use/non-use similarity, were also associated with the problematic smartphone use. The use/non-use similarity is able to predict problematic smartphone use and reach beyond just determining whether a person shows excessive use.

[Study of coenzyme Q10 in the liver of preeclampsia pregnant rats].

OBJECTIVE: To investigate the protective effect of coenzyme Q10 (CoQ10) in the liver of preeclampsiapregnant rats and the potential etiology. METHODS: Fifty pregnant SD rats were equally divided into the normal pregnant (NP) group (n=10) and the preeclampsia (PE) group (n=40) randomly. The PE rats (n=40) were equally divided into four groups randomly, distilled water (DW) group, CoQ10 group, CoQ10 combined magnesium(CM) group and magnesium (Mg) group were established by treating the preeclampsia rats on day 15 to 21 of gestation with different measures. As for all the 50 rats, systolic blood pressure (SBP) of rat tail was detected on day 10, 15 and 21 of gestation respectively, 24 hours proteinuria analysis were detected on day 10, 15 and 21 of gestation respectively, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) in blood andsuperoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), caspase-3, Bcl-2 and Bax protein expression in liver tissue were detected by western blot assay on day 21 of gestation. RESULTS: (1) SBP and 24 hours proteinuria analysis: there was no statistic difference among all the five groups on day 10 of gestation (P>0.05). Whereas, SBP and 24 hours proteinuria analysis were significantly higher in CoQ10 group, CoQ10 combined CM group, CM group and DW group than that in NP group on day 15, 21 of gestation (P<0.05). And SBP and 24 hours proteinuria analysis were significantly lower in CoQ10 group, CoQ10 combined CM group and CM group than that in DW group on day 21 of gestation (P<0.05). (2) Liver function: among CoQ10 group, CoQ10 combined CM group, CM group, DW group and NP group, serum levels of ALT were respectively (52±7) , (34±9) , (49±10) , (70±19) , (30±7) U/L; and serum levels of AST were respectively (169±25) , (84±11) , (159±20) , (281±26) and (78±18) U/L. ALT and AST serum levels were significantly higher in CoQ10 group, CM group and DW group than that in NP group (P<0.05). ALT and AST serum levels were significant lower in CoQ10 combined CM group than those in CoQ10 group, CM group and DW group, respectively (P<0.05). ALT and AST serum levels were significant lower in CoQ10 group and CM group than that in DW group, respectively (P<0.05). (3) SOD, GSH-PX, MDA, caspase-3, Bcl-2 and Bax expression in liver tissue of rats: SOD expression was significant higher in CoQ10 group, CoQ10 combined CM group than thoes in CM group, DW group and NP group (P<0.05) ; SOD expression was significant lower in CM group, DW grouo than thoes in NP group (P<0.05) ; and SOD expression was significant higher in CM group than that in DW group (P<0.05) . Compared with CoQ10 group, CoQ10 combined CM group, CW group and DW group respectively, the GSH-PX and Bcl-2 protein expressions were significant higher in NP group (P<0.05) , while MDA, caspase-3 and Bax protein expressions were significant lower in NP group (P<0.05) ; compared with CoQ10 group, CoQ10 combined CM group and CW group respectively, the GSH-PX and Bcl-2 protein expressions were significant lower in DW group (P<0.05) , while MDA, caspase-3 and Bax protein expressions were significant higher in DW group (P<0.05) . CONCLUSIONS: Oxidative stress and apoptosis levles were upregulated in PE pregnant liver tissues. CoQ10 could effectively protect the liver by improving the liver functions and decreasing the apoptosis of liver cells in PE pregnant rats, and markedly decrease the oxidative stress and apoptosis in the livers. The protective roles of CoQ10 in liver might through its function of anti-oxidative stress and inhibiting cell apoptosis by regulating the balance of Bcl-2/Bax.

Quantum-mechanical approach to predissociation of water dimers in the vibrational adiabatic representation: Importance of channel interactions.

The results of application of the quantum-mechanical adiabatic theory to vibrational predissociation (VPD) of water dimers, (H2O)2 and (D2O)2, are presented. We consider the VPD processes including the totally symmetric OH mode of the dimer and the bending mode of the fragment. The VPD in the adiabatic representation is induced by breakdown of the vibrational adiabatic approximation, and two types of nonadiabatic coupling matrix elements are involved: one provides the VPD induced by the low-frequency dissociation mode and the other provides the VPD through channel interactions induced by the low-frequency modes. The VPD rate constants were calculated using the Fermi golden rule expression. A closed form for the nonadiabatic transition matrix element between the discrete and continuum states was derived in the Morse potential model. All of the parameters used were obtained from the potential surfaces of the water dimers, which were calculated by the density functional theory procedures. The VPD rate constants for the two processes were calculated in the non-Condon scheme beyond the so-called Condon approximation. The channel interactions in and between the initial and final states were taken into account, and those are found to increase the VPD rates by 3(1) orders of magnitude for the VPD processes in (H2O)2 ((D2O)2). The fraction of the bending-excited donor fragments is larger than that of the bending-excited acceptor fragments. The results obtained by quantum-mechanical approach are compared with both experimental and quasi-classical trajectory calculation results.

Plasma metabolic signatures reveal the regulatory effect of exercise training in db/db mice.

Type 2 diabetes (T2DM) is caused by a complex set of interactions between genetic modifications and life styles. This complexity creates challenges for a full understanding of the altered metabolic pathways that contribute to the development of T2DM, which needs a comprehensive metabolic analysis. Exercise training is a common therapeutic approach known to antagonize the metabolic consequences of T2DM. However, the metabolic phenotypes of exercise effected in T2DM have not been clearly characterized. Here, we present the effect of physical activity on biochemical changes in diabetic db/db mice. An untargeted metabolomics study based on liquid chromatography coupled with high resolution mass spectrometry was carried out to delineate the plasma metabolic signatures in conjunction with a multivariate statistical analysis. As a result, a total of 24 differential metabolites were identified, covering amino acids, organic acids and lipids. Three biomarkers, including lysine, creatine and uridine, were significantly reversed by exercise training in db/db diabetic mice groups compared to lean db/m+ groups. Of note, pantothenic acid and palmitoylcarnitine, which are involved in fatty acid ß-oxidation (FAO), were promoted by exercise training in diabetic mice rather than in lean mice. These findings indicated that diabetic mice might be more susceptible to exercise for energy expenditure. Together, the results might demonstrate that exercise could mitigate insulin resistance in T2DM through improving FAO and that uridine in blood might be an important indicator to reflect insulin sensitivity promoted by exercise training in T2DM mice.

Overexpression of the RNA-binding proteins Lin28B and IGF2BP3 (IMP3) is associated with chemoresistance and poor disease outcome in ovarian cancer.

BACKGROUND: RNA-binding proteins have an important role in messenger RNA (mRNA) regulation during tumour development and carcinogenesis. In the present study, we examined the insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; hereafter refered to as IMPs) and Lin28 family expressions in epithelial ovarian carcinoma (EOC) patients and correlated their expression levels with the response to chemotherapy, hCTR1 expression and patient survival. METHODS: Patients clinical information, real-time RT-PCR, immunohistochemistry, western blot, Transwell migration invasion assays, and cytotoxicity assays were used. RESULTS: From 140 EOC patients, high expression of IMP3 or Lin28B was associated with poor survival, and women diagnosed at advanced stages with elevated IMP3 and Lin28B were at higher risk of developing chemoresistance. High IMP3 levels combined with high Lin28B levels significantly correlated with the poorest 5-year survival rates. Knockdown of IMP3 or Lin28B decreased cell proliferation, migration, and invasion, and increased the platinum sensitivity, but not taxol sensitivity, of ovarian cancer cells through increased expression of hCTR1, a copper transporter involved in platinum uptake. High expression of hCTR1 correlated with low expression of IMP3/Lin28B and better progression-free survival in advanced-stage EOC patients. CONCLUSION: Testing for a combination of elevated IMP3 and Lin28B levels could further facilitate the identification of a patient subgroup with the worst prognosis.

Role of the CKIP1 gene in proliferation and apoptosis of the human lung cancer cell line H1299.

Casein kinase 2 interacting protein 1 (CKIP1) is a specific interacting protein of the casein kinase 2 (CK2) α subunit, and, by binding CK2 and other proteins, functions as an adaptor to regulate a series of cellular functions. Previous studies suggested that CKIP1 might play an important role in regulating oncogenic activities. However, few studies examining the function of CKIP1 in cancer cells have been performed. The present study aimed to investigate the role of CKIP1 in lung cancer. CKIP1 mRNA expression was detected in 5 human lung cancer cell lines (H-125, H1299, LTEP-A-2, SPC-A-1, and NCL-H446) by semi-quantitative RT-PCR, and in 10 noncancerous lung tissues and 30 non-small lung cancer tissues by real-time quantitative PCR. A lentivirus-mediated small interfering RNA (siRNA) was used to knock down CKIP1 expression in the H1299 cell line. To elucidate the impact of CKIP1 downregulation on H1299 cells, cell proliferation, DNA synthesis, and cell cycle distribution and apoptosis were measured by high content screening assay, BrdU incorporation, and flow cytometric analyses, respectively. CKIP1 mRNA was highly expressed both in H1299 cells and lung cancer tissues. We found that downregulation of CKIP1 resulted in suppression of proliferation and colony-forming ability of H1299 cells, and led to S phase cell cycle arrest and G2 phase promotion, as well as a significant enhancement of H1299 cell apoptosis. Our study indicated that high expression levels of CKIP1 were associated with the development of lung cancer, and that CKIP1 knockdown may block tumor cell growth mainly by promoting cell apoptosis.

Therapeutic effect of prenatal alkalization and PTC124 in Na(+)/HCO3(-) cotransporter 1 p.W516* knock-in mice.

We created Na(+)/HCO3(-) cotransporter 1 (NBCe1) p.W516* knock-in mice as a model of isolated proximal renal tubular acidosis showing early lethality associated with severe metabolic acidosis to investigate the therapeutic effects of prenatal alkalization or posttranscriptional control 124 (PTC124). NBCe1(W516*/W516*) mice were treated with non-alkalization (control, n=12), prenatal alkalization postcoitus (prenatal group, n=7) and postnatal alkalization from postnatal day 6 (postnatal group, n=12). Mutation-specific therapy, PTC124 (60 mg kg(-1)) or gentamicin (30 mg kg(-1)), was administered intraperitoneally from postnatal day 6. Blood and urine biochemistry, acid-base analysis, survival rate and renal histology were examined. NBCe1 protein, mRNA abundance and activity ex vivo were assessed after PTC124 and gentamicin treatment. Prenatal group mice had similar initial body weight to wild-type mice and achieved significant weight gain thereafter compared with controls. They had higher serum bicarbonate level (15.5 ± 1.4 vs 5.5 ± 0.1 mmol l(-1), P<0.05) on postnatal day 14 and better renal function, histology and survival rates (60.8 ± 23.5 vs 41.1 ± 15.8 days, P<0.05) than the postnatal group. Compared with the control and gentamicin therapies, PTC124 therapy significantly increased NBCe1 protein abundance despite unchanged mRNA transcription. Only PTC124 therapy significantly increased survival rate and partially rescued NBCe1 activity ex vivo. In NBCe1(W516*/W516*) mice, prenatal alkali therapy achieved higher survival rates and ameliorated organ dysfunction. PTC124 therapy for this nonsense mutation was partially effective in increasing NBCe1 expression and activity.

Quantifying midbrain serotonin transporter in depression: a preliminary study of diagnosis and naturalistic treatment outcome.

INTRODUCTION: Serotonin may play an important role in the pathology of major depressive disorder (MDD). However, the relationship between serotonin transporter (SERT) availability and the medical outcome of antidepressant treatment is uncertain. METHODS: In this naturalistic study, SERT availability (expressed as the specific uptake ratio, SUR) in the midbrain of 17 drug-free patients with MDD and 17 controls matched for age and gender was measured using SPECT with [(123)I]ADAM. The severity of MDD was measured by the Hamilton Depression Rating Scale before, and after 6 weeks of non-standardized antidepressant treatment. RESULTS: A total of 12 patients completed the study. The SUR of the patients with MDD was significantly lower than that of the healthy controls. The SUR of SERT was not found to have a linear relationship with the treatment outcome; however, supplemental analysis found a curvilinear relationship between treatment outcome and the SUR of SERT. DISCUSSION: The findings indicate that the SUR of SERT is lower in patients with MDD; however it did not predict treatment outcome in a linear fashion. Studies with larger sample sizes are required.

First Report of Fusarium Head Blight of Wheat Caused by Fusarium sacchari in China.

Fusarium head blight (FHB), or scab, caused by Fusarium species, is an economically devastating disease of wheat and other cereal crops worldwide. FHB epidemics in wheat occur frequently in China, especially along the middle and lower reaches of the Yangtze River, including Jiangsu and Shanghai. In 2013, wheat spikes showing clear FHB symptoms were collected from fields in Jiangsu and Shanghai. Symptomatic seeds were surface-sterilized for 1 min with a 5% sodium hypochlorite solution and dipping in 70% ethanol for 30 s, then rinsed three times in sterile distilled water and dried. They were placed onto potato dextrose agar (PDA) and incubated for 3 to 5 days at 28°C in the dark. Fungal colonies displaying morphological characteristics of Fusarium spp. (1,2) were purified by the single-spore technique and characterized at the species level by morphological observations (1,2) and translation elongation factor 1-α (TEF) gene sequencing. The results indicated that members of the Fusarium graminearum clade were predominant on wheat, while the morphological characteristics of 16 isolates were found to be identical to those of F. sacchari (1,2). Colonies on PDA were densely cottony, initially pale but becoming violet with age. The average growth rate was 6 to 8 mm per day at 25°C in the dark. Reverse pigmentation was brownish red to violet-brown. Microconidia, abundant in the aerial mycelium and formed in false heads, were oval to ellipsoidal in shape, primarily zero-septate, measuring 5.7 to 18.8 (average 10.6) µm in length. Macroconidia were slender, three- to five-septate, with a curved apical cell and a poorly developed basal cell, 26.3 to 68.9 (average 44.0) µm in length. No chlamydospores were observed. Two F. sacchari strains (Y37 and S43), isolated from Jiangsu and Shanghai, respectively, were investigated by sequence comparison of their partial TEF gene sequences (Accession Nos. KM233195 and KM233196). BLASTn analysis of the TEF sequences obtained with sequences available in the GenBank database revealed 99.8 and 99.5% sequence identity to F. sacchari (GenBank Accession Nos. JF740708 and JF740709). Pathogenicity tests were conducted by injecting 10 µl of a spore suspension (5 × 105 spores/ml) into wheat florets (20 per isolate of cv. Yangmai16), which were then grown under field conditions in Shanghai. Control plants were inoculated with sterile distilled water. Spikes were harvested and evaluated 14 days post-inoculation. Reddish white mold was observed on inoculated wheat spikes; in addition, spikelets adjacent to the inoculation point and the infected florets were brown. No symptoms were observed on water controls. Koch's postulates were fulfilled by reisolating the pathogen from infected florets and identifying them by TEF gene sequencing. F. sacchari is the cause of an important disease of sugar cane, pokkah boeng (1), and has been reported to produce the mycotoxin beauvericin, which causes toxicosis in human and other animals (3). To our knowledge, this is the first report of F. sacchari causing wheat head blight in China. The report contributes to an improved understanding of the composition of Fusarium species on wheat in the lower reaches of the Yangtze River in China, which will be useful for exploring appropriate disease management strategies in this region. References: (1) J. F. Leslie and B. A. Summerell. The Fusarium Laboratory Manual. Blackwell Publishing, Ames, IA, 2006. (2) J. F. Leslie et al. Mycologia 97:718, 2005. (3) A. Moretti et al. Int. J. Food Microbiol. 118:158, 2007.

First Report of Corn Kernel Brown Spot Disease Caused by Mucor irregularis in China.

In October 2012, a brown spot disease was found on corn kernels during a field survey in Nanyang city (33°01' N, 112°29' E), China. The incidences of affected ears and kernels were 2 to 10% (n = 600) and 0.08 to 0.4% (n = 25,000), respectively. Symptoms first appeared as circular or irregular brown spots on the endosperm. These spots subsequently enlarged or coalesced, resulting in the formation of a large light-brown or light-yellow irregular speckle commonly surrounded by a dark-brown edge. Pure fungal cultures with similar morphological characteristics were obtained from surface-disinfected symptomatic kernels using a conventional method for isolation of culturable microbes. The isolated fungal cultures were purified by single-spore isolation (3). A representative isolate F1 was randomly selected, used for pathogenicity tests, and identified using morphological and molecular methods. Colonies on PDA were circular with abundant villiform aerial mycelia. The color of colonies was white-gray at first and turned to light yellow or became ochraceous after 3 days of incubation at 28°C. Hyphae were hyaline and less septate, with rectangular branches. Sporangiophores were erect and unbranched or branched, with globose sporangia formed on their tips. Sporangiospores were elliptical to round, 3.6 to 7.3 × 1.6 to 3.7 µm (n = 100) in size. Two gene regions were amplified for multilocus sequence typing. The D1/D2 region of the nuclear large subunit ribosomal RNA gene (nucLSU) was amplified with primers NL1 and NL4 and the rDNA internal transcribed spacer (ITS) with primers ITS1 and ITS4. PCR products were purified using an Axygen nucleic acid purification kit for sequencing. Both rDNA D1/D2 and rDNA-ITS sequences were submitted to GenBank with accession numbers KM093834 and KM203872, respectively. The isolate F1 showed 98% identity with two isolates of Mucor irregularis (KC524427 and KC461926) in rDNA-ITS sequences and 99% identity with multiple isolates (JX976221, JX976203, and JX976219) of M. irregularis in rDNA D1/D2 sequences. Pathogenicity tests of isolate F1 were conducted based on Koch's postulates. Thirty kernels of fresh ears (milk stage) were pricked by sterilized toothpicks and separately inoculated with a sporangiospore suspension (1 × 106 spores/ml) and 5-day-old mycelial plugs (5 × 5 mm) of isolate F1. Kernels on ears that were inoculated with sterilized water and pure PDA plugs were separately used as controls. After 7 days of incubation, brown spot symptoms developed on the F1-inoculated kernels, which were similar to those observed on the naturally infected ears from the field samples. The control ears remained symptomless during the inoculation tests. Fungal cultures showing the same morphological characteristics as those of isolate F1 were consistently recovered from the diseased cobs inoculated by isolate F1, indicating that M. irregularis was responsible for corn kernel brown spot disease. M. irregularis was reported as a pathogen causing human skin diseases in China (5), America (1), and India (2) and as a phytopathogen causing fruit rot on durian (4). This is the first report of M. irregularis causing corn kernel brown spot disease in China. References: (1) M. M. Abuali et al. J. Clin. Microbiol. 47:4176, 2009. (2) B. M. Hemashettar et al. J. Clin. Microbiol. 49:2372, 2011. (3) S. L. Huang and K. Kohmoto. Bull. Fac. Agric., Tottori Univ. 44:1, 1991. (4) W. F. Wang et al. Plant Quarant. l23:60, 2009. (5) Y. Zhao et al. Mycopathologia 168:243, 2009.

Efficacy of percutaneous radiofrequency ablation for the treatment of hepatocellular carcinoma.

In this study, we sought to evaluate the efficacy of transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA; experimental group) versus RFA treatment (control group) in patients receiving palliative treatment for hepatocellular carcinoma. To summarize the available evidence, we used the Review Manager 5.1 software to perform a meta-analysis of English-language articles published in public databases prior to 2014. Based on 6 studies that met the inclusion criteria, a total of 531 (experimental group, 272; control group, 259) patients with hepatocellular carcinoma were included in the meta-analysis. The meta-analysis demonstrated that the experimental group had a higher 3-year survival rate [risk ratios (RRs) = 1.41; 95% confidence interval (CI) = 1.03-1.94; P < 0.05] and a higher 2-year survival rate (RR = 1.11; 95%CI = 1.01-1.23; P < 0.05) than the control group. In the overall meta-analysis, the overall RRs were 2.02 (95%CI = 1.40-2.91; P < 0.05) and 1.63 (95%CI = 1.06-2.51; P < 0.05) for 3- and 5-year recurrence-free survival, respectively. Furthermore, the overall meta-analysis showed an overall RR of 0.75 (95%CI = 0.60-0.93; P < 0.05) for the incidence of tumor progression and an overall RR of 1.19 (95%CI = 0.33-4.33; P > 0.05) for the major complication rate. In a sensitivity analysis, the above mentioned meta-analytic estimates were unchanged by the removal of 1 study at a time. The meta-analysis suggested that the experimental group had a higher survival rate, a higher recurrence-free survival rate, and a lower incidence of tumor progression than the corresponding control group.

Minor physical anomalies and craniofacial measures in patients with treatment-resistant schizophrenia.

BACKGROUND: Schizophrenia patients have higher rates of minor physical anomalies (MPAs) than controls, particularly in the craniofacial region; this difference lends support to the neurodevelopmental model of schizophrenia. Whether MPAs are associated with treatment response in schizophrenia remains unknown. The aim of this case-control study was to investigate whether more MPAs and specific quantitative craniofacial features in patients with schizophrenia are associated with operationally defined treatment resistance. METHOD: A comprehensive scale, consisting of both qualitatively measured MPAs and quantitative measurements of the head and face, was applied in 108 patients with treatment-resistant schizophrenia (TRS) and in 104 non-TRS patients. Treatment resistance was determined according to the criteria proposed by Conley & Kelly (2001; Biological Psychiatry 50, 898-911). RESULTS: Our results revealed that patients with TRS had higher MPA scores in the mouth region than non-TRS patients, and the two groups also differed in four quantitative measurements (facial width, lower facial height, facial height, and length of the philtrum), after controlling for multiple comparisons using the false discovery rate. Among these dysmorphological measurements, three MPA item types (mouth MPA score, facial width, and lower facial height) and earlier disease onset were further demonstrated to have good discriminant validity in distinguishing TRS from non-TRS patients in a multivariable logistic regression analysis, with an area under the curve of 0.84 and a generalized R 2 of 0.32. CONCLUSIONS: These findings suggest that certain MPAs and craniofacial features may serve as useful markers for identifying TRS at early stages of the illness.

Talin1 phosphorylation activates ß1 integrins: a novel mechanism to promote prostate cancer bone metastasis.

Talins are adaptor proteins that regulate focal adhesion signaling by conjugating integrins to the cytoskeleton. Talins directly bind integrins and are essential for integrin activation. We previously showed that ß1 integrins are activated in metastatic prostate cancer (PCa) cells, increasing PCa metastasis to lymph nodes and bone. However, how ß1 integrins are activated in PCa cells is unknown. In this study, we identified a novel mechanism of ß1 integrin activation. Using knockdown experiments, we first demonstrated that talin1, but not talin2, is important in ß1 integrin activation. We next showed that talin1 S425 phosphorylation, but not total talin1 expression, correlates with metastatic potential of PCa cells. Expressing a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 and C4-2B4 PCa cells, decreased activation of ß1 integrins, integrin-mediated adhesion, motility and increased the sensitivity of the cells to anoikis. In contrast, reexpression of the phosphorylation-mimicking mutant talin1(S425D) led to increased ß1 integrin activation and generated biologic effects opposite to talin1(S425A) expression. In the highly metastatic PC3-MM2 cells, expression of a non-phosphorylatable mutant, talin1(S425A), in talin1-silenced PC3-MM2 cells, abolished their ability to colonize in the bone following intracardiac injection, while reexpression of phosphorylation-mimicking mutant talin1(S425D) restored their ability to metastasize to bone. Immunohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in human bone metastases when compared with normal tissues, primary tumors or lymph node metastases. We further showed that p35 expression, an activator of Cdk5, and Cdk5 activity were increased in metastatic tumor cells, and that Cdk5 kinase activity is responsible for talin1 phosphorylation and subsequent ß1 integrin activation. Together, our study reveals Cdk5-mediated phosphorylation of talin1 leading to ß1 integrin activation is a novel mechanism that increases metastatic potential of PCa cells.