Preexisting autoantibodies as predictor of immune related adverse events (irAEs) for advanced solid tumors treated with immune checkpoint inhibitors (ICIs).

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are now standard of care in many cancers. They can generate immune-related adverse events (irAEs), but no biomarkers are available to identify patients who are more likely to develop irAEs. We assess the association between pre-existing autoantibodies and occurrence of irAEs. PATIENTS AND METHODS: We prospectively collected data from consecutive patients receiving ICIs for advanced cancers, in a single center between May 2015 and July 2021. Autoantibodies testing was performed before ICIs initiation including AntiNeutrophil Cytoplasmic Antibodies, Antinuclear Antibodies, Rheumatoid Factor anti-Thyroid Peroxidase and anti-Thyroglobulin. We analyzed the associations of pre-existing autoantibodies with onset, severity, time to irAEs and with survival outcomes. RESULTS: Of the 221 patients included, most had renal cell carcinoma (n = 99; 45%) or lung carcinoma (n = 90; 41%). Grade ≥2 irAEs were more frequent among patients with pre-existing autoantibodies: 64 (50%) vs. 20 (22%) patients (Odds-Ratio= 3.5 [95% CI=1.8-6.8]; p < 0.001) in the positive vs negative group, respectively. irAEs occurred earlier in the positive group with a median time interval between ICI initiation and irAE of 13 weeks (IQR = 8.8-21.6) vs. 28.5 weeks (IQR=10.6-55.1) in the negative group (p = 0.01). Twelve patients (9.4%) experienced multiple (≥2) irAEs in the positive group vs. 2 (2%) in the negative group (OR = 4.5 [95% CI: 0.98-36], p = 0.04). After a median follow-up of 25 months, median PFS and OS were significantly longer among patients experiencing irAE (p = 0.00034 and p = 0.016, respectively). CONCLUSION: The presence of pre-existing autoantibodies is significantly associated with the occurrence of grade ≥2 irAEs, with earlier and multiple irAEs in patients treated with ICIs.

Circulating Biomarkers in Patients With Locally Advanced or Metastatic Renal Cell Carcinoma Treated With Everolimus in the Pre-nephrectomy Setting.

Many drugs are available in renal cell carcinoma (RCC), yet clinicians are still looking for predictive biomarkers of disease recurrence or progression supporting more personalised treatments. An assessment of circulating biomarkers over time was carried out in this French, open-label, single-arm, multicentre trial conducted in 25 patients with either locally advanced (n = 14) or metastatic RCC (n = 11) who received everolimus (10 mg daily) for 6 weeks prior to nephrectomy (NEORAD, NCT01715935). Circulating biomarkers, including circulating tumour cells, haematopoietic and endothelial cells, plasma angiogenesis and inflammatory markers were quantified at baseline, upon everolimus and post-nephrectomy. We assessed tumour burden, objective response rate upon RECIST1.1, disease-free survival (DFS) and progression-free survival (PFS). The correlation between circulating biomarkers was evaluated with multiple factor analysis and biomarker association with DFS/PFS by Cox regression. No objective response rate was obtained before nephrectomy. Upon everolimus, neutrophils, platelets and sVEGFR2 significantly decreased. We did not find any association between circulating biomarkers and DFS/PFS, but patients with the highest tumour burden at baseline had significantly higher plasma levels of interleukin-6, an inflammatory circulating biomarker, and lower levels of sVEGFR2, related to angiogenesis. Further understanding of the link between these circulating biomarkers could help to optimise drug combinations in RCC.

Incidence of Infection of Enterovirus 71 and Coxsackieviruses A6 and A16 among Household Contacts of Index Cases in Dong Thap Province, Southern Vietnam.

BACKGROUND: Scarce information exists about immunity to hand, foot, and mouth disease (HFMD) among household contacts of index cases in Vietnam and what that means for reducing ongoing HFMD transmission in the community. METHODS: We analyzed neutralizing antibodies (NT) and the incidence of enterovirus (EVs) infection among household contacts of index cases in a province where HFMD remains endemic. Throat swab and 2 mL blood samples from household contacts were collected at enrollment, during and after 2 weeks follow-up. RESULTS: The incidence of EV-A71 infection among household contacts was 40/84 (47.6%, 95% Cl: 36.9-58.3%), compared with 106/336 (31.5%, 95% Cl: 26.6-36.5%) for CV-A6 and 36/107 (33.6%, 95% Cl: 24.7-42.6%) for CV-A16. The incidence of CV-A6 infection was fairly constant across ages; in contrast, CV-A71 and CV-A16 had some variation across ages. At baseline, higher geometric mean titer (GMT) of EV-A71, CV-A6, and CV-A16 antibody titers was found for 25-34-year groups (range 216.3 to 305.0) compared to the other age groups. There was a statistically significant difference in GMT values of CV-A6 and CV-A16 between those who had an infection or did not have infection among households with an index case of these serotypes. CONCLUSIONS: Our results indicated that adults were becoming infected with HFMD and could be contributing to the transmission. There is, therefore, a need for considering the household setting as an additional target for intervention programs for HFMD.

Experimental infection of clade 1.1.2 (H5N1), clade 2.3.2.1c (H5N1) and clade 2.3.4.4 (H5N6) highly pathogenic avian influenza viruses in dogs.

Since the emergence of highly pathogenic avian influenza (HPAI) H5N1 in Asia, the haemagglutinin (HA) gene of this virus lineage has continued to evolve in avian populations, and H5N1 lineage viruses now circulate concurrently worldwide. Dogs may act as an intermediate host, increasing the potential for zoonotic transmission of influenza viruses. Virus transmission and pathologic changes in HPAI clade 1.1.2 (H5N1)-, 2.3.2.1c (H5N1)- and 2.3.4.4 (H5N6)-infected dogs were investigated. Mild respiratory signs and antibody response were shown in dogs intranasally infected with the viruses. Lung histopathology showed lesions that were associated with moderate interstitial pneumonia in the infected dogs. In this study, HPAI H5N6 virus replication in dogs was demonstrated for the first time. Dogs have been suspected as a "mixing vessel" for reassortments between avian and human influenza viruses to occur. The replication of these three subtypes of the H5 lineage of HPAI viruses in dogs suggests that dogs could serve as intermediate hosts for avian-human influenza virus reassortment if they are also co-infected with human influenza viruses.

TRIM24 links glucose metabolism with transformation of human mammary epithelial cells.

Tripartite motif 24 protein (TRIM24) is a plant homeodomain/bromodomain histone reader, recently associated with poor overall survival of breast-cancer patients. At a molecular level, TRIM24 is a negative regulator of p53 levels and a co-activator of estrogen receptor. However, the role of TRIM24 in breast tumorigenesis remains largely unknown. We used an isogenic human mammary epithelial cell (HMEC) culture model, derived from reduction mammoplasty tissue, and found that ectopic expression of TRIM24 in immortalized HMECs (TRIM24 iHMECs) greatly increased cellular proliferation and induced malignant transformation. Subcutaneous injection of TRIM24 iHMECs in nude mice led to growth of intermediate to high-grade tumors in 60-70% of mice. Molecular analysis of TRIM24 iHMECs revealed a glycolytic and tricarboxylic acid cycle gene signature, alongside increased glucose uptake and activated aerobic glycolysis. Collectively, these results identify a role for TRIM24 in breast tumorigenesis through reprogramming of glucose metabolism in HMECs, further supporting TRIM24 as a viable therapeutic target in breast cancer.

Development and field application of a competitive enzyme-linked immunosorbent assay for detection of Newcastle disease virus antibodies in chickens and ducks.

A competitive enzyme-linked immunosorbent assay (C-ELISA) using a baculovirus-expressed recombinant nucleocapsid protein antigen (rNDV-N) and an rNDV-N-specific monoclonal antibody (5B3) was developed for the detection of Newcastle disease virus (NDV) antibodies, and its diagnostic performance was evaluated. The specificity and sensitivity of the C-ELISA was found to be 98.4 and 98.9%, respectively, for chickens, and 98.2 and 97.9% for ducks. However, the C-ELISA showed weak cross-reaction with hyperimmune antisera to some other avian paramyxovirus serotypes. In all experimentally vaccinated chickens, seroconversion rates at 7 d postinoculation were 100 and 40% when measured by C-ELISA and hemagglutination inhibition (HI), respectively. In field trials, the C-ELISA showed positive results in 98.9% of HI-positive sera and 40.8% of HI-negative sera from NDV-vaccinated chickens (n = 705). In domestic ducks (n = 158) from NDV-positive duck farms (n = 8), the positive rates according to C-ELISA were significantly higher than those according to the HI test. At the same time, 98.1% of ducks (n = 209) from NDV-negative duck farms (n = 11) were also negative by C-ELISA. Our results indicate that C-ELISA could be a useful alternative to HI testing for detecting NDV antibodies in different avian species such as chickens and ducks.

Periodontal health of dental clients in a community health setting.

BACKGROUND: The aim of this study was to investigate the prevalence and severity of periodontal disease and possible risk factors in clients attending the Plenty Valley Community Health (PVCH) dental clinic. METHODS: After ethics approval and calibration of examiners, all consenting patients attending PVCH were examined for periodontal status using the Community Periodontal Index (CPI) system and a World Health Organization (WHO) probe. RESULTS: A total of 2861 patients were screened, of which 1751 were female. The majority of patients were Australian born followed by Mediterranean birth. Just under 50% brushed their teeth twice a day and only 20% flossed regularly. It was found that 28.4% had CPI scores of 3 and 4 with only 3.1% recording 0 and a widespread presence of calculus. The severity of periodontal status increased with age, male gender, decreased frequency of brushing, lower level of education, diabetes and reflected country of birth. CONCLUSIONS: PVCH has a higher prevalence of periodontal disease than the most recent national survey which reflects the population studied.

A new approach to energy-efficient treatment of wastewater produced by the fish industry in Vietnam.

Economic growth in Vietnam in the last few years has brought about an increasing demand for energy and has had a severe environmental impact. Fish processing is one of the fastest-growing industries that discharge organically-polluted wastewater. To counter these environmental problems, new technologies for energy-efficient treatment are needed. By coupling innovative nitrogen removal systems with anaerobic treatment processes, it is possible to realise such technologies. In the present project, a combined deammonification and anaerobic carbon removal system is presented. Special requirements to enable reliable treatment are discussed, taking industrial wastewater characteristics into consideration. To evaluate energetic efficiency, energy balance calculations based on data from a fish-processing factory are made. The determined specific energy consumption and production rates show that energy recovery is possible, even when COD and nitrogen removal efficiencies of over 90% are achieved. Depending on the pre-treatment employed, energy recovery rates ranging from 0.6 to 2.5 kWh/mt raw fish can be reached.

COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3σ.

14-3-3σ, a gene upregulated by p53 in response to DNA damage, exists as part of a positive-feedback loop, which activates p53 and is a human cancer epithelial marker downregulated in various cancer types. 14-3-3σ levels are critical for maintaining p53 activity in response to DNA damage and regulating signal mediators such as Akt. In this study, we identify mammalian constitutive photomorphogenic 1 (COP1) as a novel E3 ubiquitin ligase for targeting 14-3-3σ through proteasomal degradation. We show for the first time that COP9 signalosome subunit 6 (CSN6) associates with COP1 and is involved in 14-3-3σ ubiquitin-mediated degradation. Mechanistic studies show that CSN6 expression leads to stabilization of COP1 through reducing COP1 self-ubiquitination and decelerating COP1's turnover rate. We also show that CSN6-mediated 14-3-3σ ubiquitination is compromised when COP1 is knocked down. Thus, CSN6 mediates 14-3-3σ ubiquitination through enhancing COP1 stability. Subsequently, we show that CSN6 causes 14-3-3σ downregulation, thereby activating Akt and promoting cell survival. Also, CSN6 overexpression leads to increased cell growth, transformation and promotes tumorigenicity. Significantly, 14-3-3σ expression can correct the abnormalities mediated by CSN6 expression. These data suggest that the CSN6-COP1 axis is involved in 14-3-3σ degradation, and that deregulation of this axis will promote cell growth and tumorigenicity.

Epigallocatechin-3-gallate suppresses the expression of HSP70 and HSP90 and exhibits anti-tumor activity in vitro and in vivo.

BACKGROUND: Epigallocatechin-3-gallate (EGCG), one of the major catechins in green tea, is a potential chemopreventive agent for various cancers. The aim of this study was to examine the effect of EGCG on the expression of heat shock proteins (HSPs) and tumor suppression. METHODS: Cell colony formation was evaluated by a soft agar assay. Transcriptional activity of HSP70 and HSP90 was determined by luciferase reporter assay. An EGCG-HSPs complex was prepared using EGCG attached to the cyanogen bromide (CNBr)-activated Sepharose 4B. In vivo effect of EGCG on tumor growth was examined in a xenograft model. RESULTS: Treatment with EGCG decreased cell proliferation and colony formation of MCF-7 human breast cancer cells. EGCG specifically inhibited the expression of HSP70 and HSP90 by inhibiting the promoter activity of HSP70 and HSP90. Pretreatment with EGCG increased the stress sensitivity of MCF-7 cells upon heat shock (44 degrees C for 1 h) or oxidative stress (H2O2, 500 microM for 24 h). Moreover, treatment with EGCG (10 mg/kg) in a xenograft model resulted in delayed tumor incidence and reduced tumor size, as well as the inhibition of HSP70 and HSP90 expression. CONCLUSIONS: Overall, these findings demonstrate that HSP70 and HSP90 are potent molecular targets of EGCG and suggest EGCG as a drug candidate for the treatment of human cancer.

Vital function of PRELI and essential requirement of its LEA motif.

Proteins containing the late embryogenesis abundant (LEA) motif comprise a conserved family, postulated to act as cell protectors. However, their function and mechanisms of action remain unclear. Here we show that PRELI, a mammalian LEA-containing homolog of yeast Ups1p, can associate with dynamin-like GTPase Optic Atrophy-1 (OPA1) and contribute to the maintenance of mitochondrial morphology. Accordingly, PRELI can uphold mitochondrial membrane potential (ΔΨ(m)) and enhance respiratory chain (RC) function, shown by its capacity to induce complex-I/NADH dehydrogenase and ATP synthase expression, increase oxygen consumption and reduce reactive oxygen species (ROS) production. PRELI can also inhibit cell death induced by STS, TNF-α or UV irradiation. Moreover, in vitro and in vivo dominant-negative overexpression of mutant PRELI/LEA(-) (lacking the LEA motif) and transient in vitro PRELI-specific knockdown can render lymphocytes vulnerable to apoptosis, cause mouse embryo lethality and revert the resistance of lymphoma cells to induced death. Collectively, these data support the long-presumed notion of LEA protein-dependent mechanisms of cytoprotection and suggest that PRELI interacts with OPA1 to maintain mitochondria structures intact, sustain balanced ion(-)/proton(+) gradients, promote oxidative phosphorylation reactions, regulate pro- and antiapoptotic protein traffic and enable cell responses to induced death. These findings may help to understand how bioenergetics is mechanistically connected with cell survival cues.

First report on clinical features of Mycoplasma pneumoniae infections in Vietnamese children.

Mycoplasma pneumoniae is a common cause of community-acquired pneumonia (CAP) in children, but there has been no clinical report on M. pneumoniae infections in Vietnamese children. We investigated the clinical features of M. pneumoniae infection when the pathogen was detected in the respiratory tract in hospitalized children aged 1-15 years due to lower respiratory tract infections or CAP in Vietnamese children. Throat swabs from 47 patients (18.6%) of 252 patients with a clinical diagnosis of CAP were PCR positive (male, 34; female, 13), and 21 throat swabs (8.3%) showed culture positive for M. pneumoniae. The M. pneumoniae pathogen could be detected by PCR and/or culture in 52 patients (male, 36; female, 16). The major clinical signs in the 52 patients were fever (>38 degrees C) in 100%, pharyngitis in 100%, tachypnea in 94%, dry cough in 86.5%, and rough breathing in 83% of patients. The average term of illness prior to hospitalization was 7.5+/-4.1 days, and the average number of hospitalized days was 7.9+/-3.5 days. Beta-lactam group antibiotics, which were ineffective against M. pneumoniae infection, were used in 37 cases (71%).

Enzymes of type II fatty acid synthesis and apicoplast differentiation and division in Eimeria tenella.

Apicomplexan parasites, Eimeria tenella, Plasmodium spp. and Toxoplasma gondii, possess a homologous plastid-like organelle termed the apicoplast, derived from the endosymbiotic enslavement of a photosynthetic alga. However, currently no eimerian nuclear encoded apicoplast targeted proteins have been identified, unlike in Plasmodium spp. and T. gondii. In this study, we demonstrate that nuclear encoded enoyl reductase of E. tenella (EtENR) has a predicted N-terminal bipartite transit sequence, typical of apicoplast-targeted proteins. Using a combination of immunocytochemistry and EM we demonstrate that this fatty acid biosynthesis protein is located in the apicoplast of E. tenella. Using the EtENR as a tool to mark apicoplast development during the Eimeria lifecycle, we demonstrate that nuclear and apicoplast division appear to be independent events, both organelles dividing prior to daughter cell formation, with each daughter cell possessing one to four apicoplasts. We believe this is the first report of multiple apicoplasts present in the infectious stage of an apicomplexan parasite. Furthermore, the microgametes lacked an identifiable apicoplast consistent with maternal inheritance via the macrogamete. It was found that the size of the organelle and the abundance of EtENR varied with developmental stage of the E. tenella lifecycle. The high levels of EtENR protein observed during asexual development and macrogametogony is potentially associated with the increased synthesis of fatty acids required for the rapid formation of numerous merozoites and for the extracellular development and survival of the oocyst. Taken together the data demonstrate that the E. tenella apicoplast participates in type II fatty acid biosynthesis with increased expression of ENR during parasite growth. Apicoplast division results in the simultaneous formation of multiple fragments. The division mechanism is unknown, but is independent of nuclear division and occurs prior to daughter formation.

Modification of ASM3 for the determination of biomass adsorption/storage capacity in bulking sludge control.

The selector activated sludge (SAS) systems are known to prevent excessive growth of filamentous microorganisms responsible for bulking sludge, but these systems were hardly ever modelled. This study aimed to develop a model capable of predicting rapid substrate removal in the SAS systems. For this purpose, the Activated Sludge Model No. 3 (ASM3) was extended with three processes (adsorption, direct growth on the adsorbed substrate under aerobic or anoxic conditions). The modified ASM3 was tested against the results of batch experiments with the biomass originating from two full-scale SAS systems in Germany. The endogenous biomass was mixed with various readily biodegradable substrates (acetate, peptone, glucose and wastewater) and the utilisation of substrate (expresses as COD) and oxygen uptake rates (OURs) were measured during the experiments. In general, model predictions fitted to the experimental data, but a considerable number of kinetic (5) and stoichiometric (2) parameters needed to be adjusted during model calibration. The simulation results revealed that storage was generally a dominating process compared to direct growth in terms of the adsorbed substrate utilisation. The contribution of storage ranged from 65-71% (Plant A) and 69-92% (Plant B).

Genetic and phenotypic characterization of Haemophilus influenzae type b isolated from children with meningitis and their family members in Vietnam.

To investigate Haemophilus influenzae type b (Hib) infection in Vietnamese children under the age of 5 years, cerebrospinal fluid (CSF) samples from patients with meningitis were screened for Hib, and isolates were subjected to evaluation of susceptibility to 12 antibiotics, biotyping, and genotyping with pulsed-field gel electrophoresis (PFGE). The major biotype was type II (68.3%), followed by type I (22.8%). Among 79 Hib isolates, 45 (57%) were beta-lactamase-producing and ampicillin-resistant (44 and 1 isolates produced TEM-1- and ROB-1-type beta-lactamases, respectively), and 34 isolates (43%) were beta-lactamase-nonproducing and ampicillin-sensitive. No beta-lactamase-nonproducing and ampicillin-resistant isolates were found. The PFGE patterns of Hib isolates were highly divergent, but most could be classified into three clusters. We also investigated Hib colonization in household contacts of patients, and found that Hib isolates from the CSF of patients and from nasopharyngeal cavities of household contacts showed the same PFGE patterns. This observation suggested that household contacts of patients are a possible reservoir of Hib.

SIRRUS: evaluation software of the technical and economic profitability of rainwater on an industrial site.

In a sustainable development context, the storm water reuse in industry seems a promising and original alternative, but few experiences exist. A project, sponsored by the European Community and the Artois-Picardie Water Agency, has been carried out by the Renault MCA factory in Maubeuge, demonstrating that it can be profitable, in certain conditions, to reuse storm water in industrial processes. This article summarises this experience, and presents a decision making tool (SIRRUS) that has been developed in this framework by Anjou Recherche (Vivendi Water) to evaluate, on the basis of simple criteria, if this experience is or is not reproducible on a given site, and how much time is necessary to pay the investment back. Its application and different results are also discussed.

Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens.

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to erythromycin. These compounds are characterized by having an aryl group tethered to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising compounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that the new macrolides are potent protein synthesis inhibitors, which interact with methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and balanced pharmacokinetic profiles.

Use of real time control modelling on the urban sewage system of Nancy.

Since 1991, European Legislation on the urban treatment of wastewater requires local authorities to take into account the treatment of polluted water transported by the sewerage system and this during dry and wet weather conditions. In the seventies, the urban Community of Grand Nancy constructed storage tanks in its sewerage system in order to prevent flooding and wish today to use them to reduce and control the pollution discharges into the receiving water. This action is a part of a European LIFE project 1996-2000. The main aim of this project was to assess the effectiveness of reducing pollution of one particular retention basin, the 12,000 m3 Gentilly tank. This one has two operating modes: protection against floods during heavy rain and reduction of pollutant overflows during lighter rain. To assess its effect on the pollutant discharge, the HYDROWORKS DM software and its Real Time Control Module have been used, calibrated and validated. As this study is still in progress, this paper describes the studied site and the modelling results under different weather conditions and shows that the mathematical model can be used to simulate the operation of the catchment area and its associated sewerage system realistically.

Saccharomyces cerevisiae protein Pci8p and human protein eIF3e/Int-6 interact with the eIF3 core complex by binding to cognate eIF3b subunits.

Mammalian, plant, and Schizosaccharomyces pombe eukaryotic initiation factor-3 (eIF3) contains a protein homologous to the product of int-6 (eIF3e), a frequent integration site of mouse mammary tumor viruses. By contrast, Saccharomyces cerevisiae does not encode a protein closely related to eIF3e/Int-6. Here, we characterize a novel S. cerevisiae protein (Pci8p, Yil071cp) that contains a PCI (proteasome-COP9 signalosome-eIF3) domain conserved in eIF3e/Int-6. We show that both Pci8p and human eIF3e/Int-6 expressed in budding yeast interact with the yeast eIF3 complex in vivo and in vitro by binding to a discrete segment of its eIF3b subunit Prt1p and that human eIF3e/Int-6 interacts with the human eIF3b segment homologous to the Pci8p-binding site of yeast Prt1p. These results refine our understanding of subunit interactions in the eIF3 complex and suggest structural similarity between human eIF3e/Int-6 and yeast Pci8p. However, deletion of PCI8 had no discernible effect on cell growth or translation initiation as judged by polysome analysis, suggesting that Pci8p is not required for the essential function of eIF3 in translation initiation. Motivated by the involvement of Int-6 in transcriptional control, we investigated the effects of deleting PCI8 on the total mRNA expression profile by oligonucleotide microarray analysis and found reduced mRNA levels for a subset of heat shock proteins in the pci8Delta mutant. We discuss possible dual functions of Pci8p and Int-6 in transcriptional and translational control.

Reclaimed municipal wastewater--a potential water resource in China.

Due to water resource shortage and socio-economic development within twenty years, China faces serious problems of water supply and water pollution. Several criteria and suitable reclamation processes related to water reuse have been created in China, which are helpful to improve the situation of water scarcity. In the future, reclaimed municipal wastewater reuse will mainly be developed for urban and industrial use. Potential supply quantity of reclaimed water, quality of reclaimed water, and reclamation cost are favorable to potential reuses. Based on further public environmental education, on a relevant development of national and local standards for reclaimed water quality, and on an increase of sanitary rate, more and more planned reclaimed water reuse projects would be expected in China.