B cells and tertiary lymphoid structures are associated with survival in papillary thyroid cancer.

PURPOSE: The function of B cells in papillary thyroid cancer (PTC) is controversial. The role of B-cell-related tertiary lymphoid structures (TLSs) is still unclear. Whether B cells exert their anti-tumor effect through forming TLS in PTC needs further investigation. METHODS: We detected the percentage of B cells in PTC tissues by multi-parameter flow cytometry. Paraffin-embedded tumor tissues of 125 PTC patients were collected and stained with Haematoxylin-Eosin (H&E) for inflammatory infiltration analysis in combination with clinical features. Multiplexed immunohistochemistry (mIHC) was performed to verify the TLSs in above inflammatory infiltration. Correlation of B cells and TLSs with prognosis was analyzed using the TCGA database. RESULTS: We observed that PTC patients with higher expression of B lineage cell genes had improved survival and the percentage of B cells in the PTC tumor tissues was variable. Moreover, PTC tumor tissues with more B cells were surrounded by immune cell aggregates of varying sizes. We furtherly confirmed the immune cell aggregates as TLSs with different maturation stages. By analyzing PTC data from TCGA database, we found the maturation stages of TLSs were associated with genders and clinical stages among PTC patients. Moreover, patients with high TLSs survived longer and had a better prognosis. CONCLUSION: B cells are associated with the existence of TLSs which have different maturation stages in PTC. Both B cells and TLSs are associated with the survival rate of PTC. These observations indicate that the anti-tumor effects of B cells in PTC are associated with TLSs formation.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

[Orbital cellulitis secondary to odontogenic superior maxillary sinus septum infection: a case report].

A 66-year-old woman presented with recurrent erythema, swelling and pain in her right eye. She had a history of extraction of the right upper second molar 5 months ago with subsequent development of an abscess which was incised and drained 4 months ago. Orbital CT scan revealed the formation of subperiosteal sinus cavity with an abscess in the right maxillary sinus and infraorbital foramen. The diagnosis was orbital honeycombing caused by odontogenic maxillary sinus septum infection. Utilizing the anterior lacrimal recess approach under nasal endoscope,incision and drainage of ocular abscess and debridement and drainage of right orbital abscess plus partial resection of the inner wall of the jaw were performed successfully with maxillary sinus septal drainage and maxillary sinus opening. The patient improved significantly after the operation.

Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set.

BACKGROUND: A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool. PATIENTS AND METHODS: This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured. RESULTS: Specificity for cancer signal detection was 99.5% [95% confidence interval (CI): 99.0% to 99.8%]. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage [stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%)]. Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%). CONCLUSION: In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests. CLINICAL TRIAL NUMBER: NCT02889978.

Circulating tumor DNA in neoadjuvant-treated breast cancer reflects response and survival.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence. PATIENTS AND METHODS: Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years. RESULTS: At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence [hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6]; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5). CONCLUSIONS: Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA.

BACKGROUND: Early cancer detection could identify tumors at a time when outcomes are superior and treatment is less morbid. This prospective case-control sub-study (from NCT02889978 and NCT03085888) assessed the performance of targeted methylation analysis of circulating cell-free DNA (cfDNA) to detect and localize multiple cancer types across all stages at high specificity. PARTICIPANTS AND METHODS: The 6689 participants [2482 cancer (>50 cancer types), 4207 non-cancer] were divided into training and validation sets. Plasma cfDNA underwent bisulfite sequencing targeting a panel of >100 000 informative methylation regions. A classifier was developed and validated for cancer detection and tissue of origin (TOO) localization. RESULTS: Performance was consistent in training and validation sets. In validation, specificity was 99.3% [95% confidence interval (CI): 98.3% to 99.8%; 0.7% false-positive rate (FPR)]. Stage I-III sensitivity was 67.3% (CI: 60.7% to 73.3%) in a pre-specified set of 12 cancer types (anus, bladder, colon/rectum, esophagus, head and neck, liver/bile-duct, lung, lymphoma, ovary, pancreas, plasma cell neoplasm, stomach), which account for ∼63% of US cancer deaths annually, and was 43.9% (CI: 39.4% to 48.5%) in all cancer types. Detection increased with increasing stage: in the pre-specified cancer types sensitivity was 39% (CI: 27% to 52%) in stage I, 69% (CI: 56% to 80%) in stage II, 83% (CI: 75% to 90%) in stage III, and 92% (CI: 86% to 96%) in stage IV. In all cancer types sensitivity was 18% (CI: 13% to 25%) in stage I, 43% (CI: 35% to 51%) in stage II, 81% (CI: 73% to 87%) in stage III, and 93% (CI: 87% to 96%) in stage IV. TOO was predicted in 96% of samples with cancer-like signal; of those, the TOO localization was accurate in 93%. CONCLUSIONS: cfDNA sequencing leveraging informative methylation patterns detected more than 50 cancer types across stages. Considering the potential value of early detection in deadly malignancies, further evaluation of this test is justified in prospective population-level studies.

Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.

BACKGROUND: Standard first-line treatment of metastatic triple-negative breast cancer (mTNBC) is chemotherapy. However, outcomes are poor, and new treatment options are needed. In cohort B of the phase II KEYNOTE-086 study, we evaluated pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. PATIENTS AND METHODS: Eligible patients had centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, measurable disease at baseline per RECIST v1.1 by central review, no radiographic evidence of central nervous system metastases, and a tumor PD-L1 combined positive score ≥1. Patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years. The primary end point was safety. Secondary end points included objective response rate, disease control rate (percentage of patients with complete or partial response or stable disease for ≥24 weeks), duration of response, progression-free survival and overall survival. RESULTS: All 84 patients enrolled were women, and 73 (86.9%) received prior (neo)adjuvant therapy. Fifty-three (63.1%) patients had treatment-related adverse events (AEs), including 8 patients (9.5%) with grade 3 severity; no patients experienced grade 4 AEs or died because of treatment-related AEs. Four patients had a complete response and 14 had a partial response, for an objective response rate of 21.4% (95% CI 13.9-31.4). Of the 13 patients with stable disease, 2 had stable disease lasting ≥24 weeks, for a disease control rate of 23.8% (95% CI 15.9-34.0). At data cut-off, 8 of 18 (44.4%) responses were ongoing, and median duration of response was 10.4 months (range 4.2 to 19.2+). Median progression-free survival was 2.1 months (95% CI 2.0-2.2), and median overall survival was 18.0 months (95% CI 12.9-23.0). CONCLUSIONS: Pembrolizumab monotherapy had a manageable safety profile and showed durable antitumor activity as first-line therapy for patients with PD-L1-positive mTNBC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02447003.

Enhanced antigen presenting and T cell functions during late-phase allergic responses in the lung.

BACKGROUND: Allergic inflammation is a common feature of asthma and may contribute to both development and perpetuation of disease. The interaction of antigen-presenting cells (APC) with sensitized helper T lymphocytes (TC) producing Th2 cytokines may determine the inflammatory response. Recruitment of APC and TC to the lung during allergic responses has been demonstrated, but functional studies in humans have been limited. OBJECTIVE: This study examined the function of APC and TC accumulating at sites of inflammation after segmental allergen challenge (SAC). METHODS: Fifteen allergic patients underwent SAC, and cells from bronchoalveolar lavage (BAL) were collected after 24 hours. APC and TC from the blood and BAL were purified based on expression of the monocyte marker, CD14; the plasmacytoid dendritic cell (pDC) marker, BDCA4, identifying neuropilin-1 (NRP1); and the helper T cell marker, CD4. Functional activity was assessed using allergen-induced T cell proliferation. Flow cytometry identified cells expressing CD14 and NRP1. RESULTS: SAC resulted in a 12-fold increase in mononuclear cells having the morphologic appearance of blood monocytes. Most of these cells co-expressed CD14 and NRP1. After saline challenge, BAL mononuclear cells demonstrated little APC function. Following SAC, BAL mononuclear cells showed function equal to pDC from blood and greater than blood monocytes. Purified NRP1+ cells from BAL had even greater function than pDC cells from blood (P = .008). Using consistent sources of APC, enhanced proliferation of TC from lung compared to blood was also demonstrated (P = .002). CONCLUSIONS: The marked increase in APC function for allergen-specific TC proliferation during allergic inflammation is largely due to the recruitment of monocytes and dendritic cells. There is also an enhanced response in the lung TC population, consistent with recruitment of allergen-specific T cells. Interactions between recruited APC and TC may occur as an early event promoting allergic airway inflammation.

[Effect of ginsenoside pre-treatment on 5-hydroxytryptamine system in SD rats with myocardial infarction and depression].

OBJECTIVE: To evaluate the effect of ginsenoside pre-treatment on serotonin (5-hydroxytryptamine, 5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter, SERT) in serum, platelet lysate and brain tissue homogenates in SD rats with myocardial infarction (MI) or depression. METHODS: Eighty SD rats were randomized treated with ginsenoside or normal saline(NS). After 4 weeks, the rats were, then, randomized to four subgroups: the MI, the depression, the MI in combination with depression and sham subgroups.5-HT, 5-HT2AR and SERT levels were detected in serum, platelet or brain. RESULTS: In the NS pre-treatment groups, serum 5-HT levels in sham rats (237.1±32.0) pg/ml were higher than in MI (58.0±11.6) pg/ml, depression (72.8±2.3) pg/ml, and MI with depression rats (62.5±10.2) pg/ml (all P=0.000). Pre-treatment of ginsenoside increased serum and platelet 5-HT in MI, depression and MI with depression rats compared with each corresponding NS treated subgroups (all P<0.005). However, treatment of ginsenoside lowered the 5-HT2AR expression in MI, depression, and MI with depression subgroups both in platelet and brain tissue homogenates compared with each corresponding NS treated subgroups (all P<0.05). As to SERT in platelet, treatment of ginsenoside increased its levels in depression rats (P=0.019), but lowered the levels in MI rats (P=0.001) compared with NS treated rats.There were no differences in brain 5-HT and SERT between ginsenoside and NS treated groups. CONCLUSIONS: The 5-HT system responses differently to ginsenoside treatment under different cardiac and mental stress conditions.Ginsenoside plays an important role in regulation of 5-HT system.

Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial.

BACKGROUND: To investigate in the NeoSphere trial the contribution of the immune system to pathologic complete response in the breast (pCRB) after neoadjuvant docetaxel with trastuzumab (TH), pertuzumab (TP), or both (THP), or monoclonal antibodies alone (HP). PATIENTS AND METHODS: Immune gene mRNA expression (n = 350, 83.8%), lymphocyte infiltration (TIL, n = 243, 58.3%), and PDL1 by immunohistochemistry (n = 305, 73.1%) were correlated with pCRB. We studied five selected genes (IFNG, PD1, PDL1, PDL2, CTLA4) and six immune metagenes corresponding to plasma cells (IGG), T cells (CD8A), antigen-presenting cells (MHC2), and to MHC1 genes (MHC1), STAT1 co-expressed genes (STAT1), and interferon-inducible genes (IF-I). Gene expression data from the NOAH trial were used for validation. RESULTS: TIL as continuous variable and PDL1 protein expression were not significantly associated with pCRB. Expression of immune genes/metagenes had different association with pCRB after THP than after other therapies. With THP, higher expression of PD1 and STAT1, or any among PDL1, CTLA4, MHC1, and IF-I were linked with lower pCRB. In the combined TH/TP/HP treatment group, in multivariate analysis, higher expression of PD1, MHC2, and STAT1 were linked with pCRB, and higher PDL1, MHC1, or IF-I to lower pCRB. In the NOAH, a similar association of higher STAT1 with higher pCRB, and higher MHC1 and IF-I with lower pCRB was found for trastuzumab/chemotherapy but not for chemotherapy treatment only. CONCLUSIONS: The immune system modulates response to therapies containing trastuzumab and pertuzumab. Greatest benefit from THP is observed for low expression of some immune markers (i.e. MHC1, CTLA4). The involvement of PDL1 in resistance supports testing combinations of HER2-directed antibodies and immune-checkpoint inhibitors.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND: In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS: Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS: Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS: The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

First Report of Rust Caused by Puccinia xanthii on Xanthium orientale subsp. italicum in China.

Xanthium orientale subsp. italicum (Moretti) Greuter is an annual herbaceous plant in the Asteraceae family, native to North America. It was first found in Beijing, China, in 1991. Since then, it has spread into many provinces such as Heilongjiang, Jilin, Liaoning, Hebei, Shandong, Xinjiang, and so on. Furthermore, it has been listed as one of the dangerous quarantine weeds in China (4). This noxious invasive weed has a strong ability to acclimatize to new environments. X. orientale subsp. italicum can usually be found in alluvial flatlands, riverbanks, wastelands, roadsides, pastures, as well as farmlands. The presence of this plant decreases the native biodiversity and influences the production of agriculture and stockbreeding. In August 2013, a rust disease was first observed on X. orientale subsp. italicum in Dalian, Liaoning Province, northeast China. Various sized lesions were found on approximately one third of the leaves of each infected plant. These lesions were yellow in the early stage of infection; gradually the center of each lesion turned brown, and eventually the infected lesions became necrotic and ruptured. The small (on average 4 mm in diameter) and dark brown raised telia appeared in the center of the lesions on the lower leaf surface. The teliospores were brown, clavate, two-celled, and measured 42 to 58 × 12 to 21 µm. Teliospores had a conical top, constricted septa, and a persistent pedicel (22 to 70 µm in length). The walls of the teliospores were smooth, 0.8 to 1.2 µm thick at the side and 4 to 8 µm thick at the apex. The size, color, and morphology of the teliospores fit the description of Puccinia xanthii (1,3). A pathogenicity test was conducted by the method of detached leaf inoculation (2). We collected 48 healthy leaves from six individuals of X. orientale subsp. italicum plants, eight from each individual. Teliospores from disease samples were suspended to 1 × 105 spores per ml with sterile water and then smeared on 24 leaves (four per individual); the remaining leaves were inoculated with sterile water as control. Each of the leaves was put on a moist filter paper in a petri dish, and was cultured in a chamber with a 12-h photoperiod at 25°C. Seven days later, dark brown raised telia were observed on all inoculated leaves but not on control ones. The teliospores were removed from the sorus on inoculated leaves, and according to the morphology confirmed to be those of P. xanthii. The rust caused by P. xanthii has been documented in different hosts in many other countries such as Spain, France, Italy, former Yugoslavia, Australia, the United States, and South Africa. In addition, the rust fungus was found to infect X. orientale subsp. italicum in eastern Hungary (1). To our knowledge, this is the first report of P. xanthii attacking the invasive plant X. orientale subsp. italicum in China. It is important to study the potential of using this rust fungus as a biological control agent of X. orientale subsp. italicum. This work was supported by the Project of the National Natural Science Foundation of China (31270582). References: (1) I. Dávid et al. Plant Dis. 87:1536, 2003. (2) Z. D. Fang. Research Methods of Plant Disease, 1998. (3) J. A. Parmelee. Can. J. Bot. 47:1391, 1969. (4) F. H. Wan et al. Biological Invasion: Color Illustration of Invasive Alien Plants in China, 2012.

Surveillance of avian influenza A(H7N9) virus infection in humans and detection of the first imported human case in Taiwan, 3 April to 10 May 2013.

On 3 April 2013, suspected and confirmed cases of influenza A(H7N9) virus infection became notifiable in the primary care sector in Taiwan, and detection of the virus became part of the surveillance of severe community-acquired pneumonia. On 24 April, the first imported case, reported through both surveillance systems, was confirmed in a man returning from China by sequencing from endotracheal aspirates after two negative throat swabs. Three of 139 contacts were ill and tested influenza A(H7N9)-negative.

Association of vitamin D and antimicrobial peptide production during late-phase allergic responses in the lung.

BACKGROUND: Vitamin D may play important roles in regulating immune responses and in defence against infectious diseases by effects on both innate and adaptive immune responses. Little is known regarding activation of vitamin D within airway tissues and its relationship to inflammation and antimicrobial responses. OBJECTIVE: The objective of this study was to investigate the activation of vitamin D within the airways and to define relationships between vitamin D metabolites and measures of inflammatory and antimicrobial responses assessed by bronchoalveolar lavage (BAL) during late-phase responses following allergen challenge of allergic subjects. METHODS: Segmental allergen challenge was performed with saline and allergen in 16 adult allergic subjects. BAL was performed in both saline and allergen-challenged sites 20-24 h. after challenge. Following extraction from BAL fluids, levels of 25-hydroxy-vitamin D (25(OH)D) and 1,25-dihydroxy-vitamin D (1,25(OH)(2)D) were assayed by specific radioimmunoassays. The cleavage product of cathelicidin, LL-37, was assayed by ELISA. Cellular constituents and albumin were measured. RESULTS: Levels of vitamin D metabolites were increased in concentrated BAL fluids after allergen compared to saline challenge. Levels of 1,25(OH)(2)D increased from largely undetectable to 2.5 pm (median; range: 1-29.5; P = 0.005) while 25(OH)D increased from 3.2 (0.8-6.2) to 6.2 (1.5-184.9) nm (P = 0.0006). Levels of LL-37 increased from 2.1 (1.4-4.1) to 14.5 (2.2-106.7) ng/mL BAL (P = 0.0005). Levels of LL-37, 1,25(OH)(2)D, and 25(OH)D following allergen challenge were correlated with each other (P < 0.0001), cellular changes, and levels of albumin (P < 0.001). CONCLUSIONS AND CLINICAL RELEVANCE: Levels of vitamin D metabolites, particularly 1,25(OH)(2)D, were low within the airways and increased after allergen challenge. The increases correlated with the magnitude of inflammation and increases in cathelicidin. Normalization to albumin suggested plasma exudation as a mechanism for the increases. The findings support a role for vitamin D in allergic and innate immune responses in the lung.

The Changing Landscape for the Treatment of Painful Spinal Metastases: is Stereotactic Body Radiation Therapy the New Standard of Care?

Due to advancements in systemic targeted and immunotherapies resulting in improved disease control and overall survival, and the increasing use of computed tomography and spine magnetic resonance imaging surveillance, the number of patients presenting with both asymptomatic and symptomatic spinal metastases is increasing. The need for versatile tumour ablative local management strategies, beyond the limits afforded by conventional palliative external beam radiation therapy (cEBRT), is increasingly more important. Stereotactic body radiation therapy (SBRT) was developed to meet such a need. This highly conformal technique allows the delivery of high biologically effective doses of radiation to the vertebral target, while controlling the differential dose exposure to the adjacent critical neural tissue. Identifying patients with painful spine metastases who would gain the most benefit from this important therapeutic option can be challenging. Here we summarise the randomised evidence specific to spine SBRT, comparing cEBRT with SBRT for pain control in patients with spine metastases in the palliative setting to better understand the role of spine SBRT in modern oncological spinal care.

Distinct association between aberrant methylation of Wnt inhibitors and genetic alterations in acute myeloid leukaemia.

BACKGROUND: Aberrant activation of Wnt signalling through hypermethylation of Wnt inhibitor genes is involved in several human malignancies, including acute myeloid leukaemia (AML). It remains unclear whether hypermethylation of Wnt inhibitors is associated with molecular gene mutations in the development of AML. METHODS: We investigated the association of the promoter hypermethylation of six Wnt inhibitors (Wif-1, SFRP1, SFRR2, SFRP4, SFRP5, and DKK1) with gene aberrations in the leukaemogenesis of 269 AML patients. RESULTS: In total, 166 patients (61.7%) had hypermethylation of at least one Wnt inhibitor. The majority (68.5%) of patients with Wnt inhibitor hypermethylation had concurrent Class II gene mutations that affect transcription factors or cofactors. There was a close association of Wif-1 hypermethylation with t(15;17) (P=0.0005) and CEBPA mutation (P<0.0001), DKK1 hypermethylation with t(8;21) (P<0.0001) and ASXL1 mutation (P=0.0078), SFRP-1 hypermethylation with t(8;21) (P<0.0001), SFRP-2 hypermethylation with AML1/RUNX1 mutation (P=0.0012), and SFRP-5 hypermethylation with MLL/PTD (P=0.0505). On the other side, hypermethylation of Wnt inhibitors was always negatively associated with NPM1 mutation and FLT3/ITD. CONCLUSION: There was distinct association between hypermethylation of individual Wnt inhibitors and specific gene aberrations, especially Class II mutations. The Wnt inhibitor hypermethylation might interact with genetic alterations in the leukaemogenesis.

HIF-1α repairs degenerative chondrocyte glycolytic metabolism by the transcriptional regulation of Runx2.

OBJECTIVE: HIF-1α and Runx2 expression usually increase in chondrocytes (CHs) during osteoarthritis (OA), which involves the changes in glycolytic metabolism. However, the molecular regulation of HIF-1α related to the CHs glycolytic metabolism is still unclear. In this study, we aimed to reveal the mediation of HIF-1α by Runx2 and its effect on the glycolytic metabolism of degenerative CHs. PATIENTS AND METHODS: The expression of HIF-1α, Runx2, and the degenerative markers of CHs in both natural conditions from the OA patients and IL-1ß treated in vitro model was analyzed by a Western blot or real-time polymerase chain reaction (RT-PCR). The glycolytic metabolism was determined by the intracellular glucose uptake and adenosine triphosphate (ATP) generation. Transfection of siRNA coding HIF-1α or Runx2 was used to clear the function between HIF-1α and Runx2 in the glycolytic metabolism of degenerated CHs caused by IL-1ß. Chromatin immunoprecipitation (ChIP) and Luciferase reporter gene assay were used to verify the Runx2 protein binds to the promoter of HIF-1α and promote its expression. RESULTS: HIF-1α and Runx2 were increased, and glucose uptake and ATP generation were decreased in the degenerative CHs from both OA and IL-1ß conditions. Under the stimulation of IL-1ß, Runx2 silencing rejected the upregulation of HIF-1α and further aggravated the glycolytic metabolism. When HIF-1α was silenced, the glycolytic metabolism of CHs was also suppressed. Besides, Runx2 protein could regulate HIF-1α expression in the transcriptional level by binding to its promoter. CONCLUSIONS: OHIF-1α plays a role in the self-repair of the glycolytic metabolism of degenerative CHs via the transcriptional regulation of Runx2.