Melatonin enhances NK cell function in aged mice by increasing T-bet expression via the JAK3-STAT5 signaling pathway.

Natural killer (NK) cells are crucial innate immune cells that provide defense against viruses and tumors. However, aging is associated with alterations in NK cell composition and compromised cell functions. Melatonin, known for its anti-tumor effects, has been reported to improve NK cell function. However, the molecular mechanism underlying melatonin's effect on senescent NK cells remains unclear. In this study, we aimed to elucidate the mechanism by which melatonin enhances the function of senescent NK cells. Our findings revealed that melatonin significantly increased the number and function of NK cells in aging mice. The results suggest that melatonin enhances NK cell proliferation, degranulation, and IFN-γ secretion. Further investigations demonstrated that melatonin promotes NK cell maturation and activation, mainly via the JAK3/STAT5 signaling pathway, leading to increased expression of T-bet. These discoveries provide a theoretical basis for potential immunotherapy strategies based on melatonin-mediated modulation of NK cell function in aging individuals.

[Retracted] MicroRNA­195 inhibits the behavior of cervical cancer tumors by directly targeting HDGF.

[This retracts the article DOI: 10.3892/ol.2017.6210.].

Transferring a new Fusarium head blight resistance locus FhbRc1 from Roegneria ciliaris into wheat by developing alien translocation lines.

KEY MESSAGE: A new FHB resistance locus FhbRc1 was identified from the R. ciliaris chromosome 7Sc and transferred into common wheat by developing alien translocation lines. Fusarium head blight (FHB) caused by multiple Fusarium species is a globally destructive disease of common wheat. Exploring and utilization of resources with FHB resistance are the most effective and environmentally beneficial approach for the disease control. Roegneria ciliaris (Trin.) Nevski (2n = 4x = 28, ScScYcYc), a tetraploid wheat wild relative, possesses high resistance to FHB. In the previous study, a complete set of wheat-R. ciliaris disomic addition (DA) lines were evaluated for FHB resistance. DA7Sc had stable FHB resistance, which was confirmed to be derived from alien chromosome 7Sc. We tentatively designated the resistant locus as FhbRc1. For better utilization of the resistance in wheat breeding, we developed translocations by inducing chromosome structural aberrations using iron irradiation and the homologous pairing gene mutant ph1b. Totally, 26 plants having various 7Sc structural aberrations were identified. By marker analysis, a cytological map of 7Sc was constructed and 7Sc was dissected into 16 cytological bins. Seven alien chromosome aberration lines, which all had the bin 7Sc-1 on the long arm of 7Sc, showed enhanced FHB resistance. Thus, FhbRc1 was mapped to the distal region of 7ScL. A homozygous translocation line T4BS·4BL-7ScL (NAURC001) was developed. It showed improved FHB resistance, while had no obvious genetic linkage drag for the tested agronomic traits compared with the recurrent parent Alondra's. When transferring the FhbRc1 into three different wheat cultivars, the derived progenies having the translocated chromosome 4BS·4BL-7ScL all showed improved FHB resistance. This revealed the potential value of the translocation line in wheat breeding for FHB resistance.

Recognition of glycoside hydrolase 12 proteins by the immune receptor RXEG1 confers Fusarium head blight resistance in wheat.

Fusarium head blight (FHB), caused by Fusarium graminearum, is a devastating disease in wheat (Triticum aestivum) that results in substantial yield losses and mycotoxin contamination. Reliable genetic resources for FHB resistance in wheat are lacking. In this study, we characterized glycoside hydrolase 12 (GH12) family proteins secreted by F. graminearum. We established that two GH12 proteins, Fg05851 and Fg11037, have functionally redundant roles in F. graminearum colonization of wheat. Furthermore, we determined that the GH12 proteins Fg05851 and Fg11037 are recognized by the leucine-rich-repeat receptor-like protein RXEG1 in the dicot Nicotiana benthamiana. Heterologous expression of RXEG1 conferred wheat responsiveness to Fg05851 and Fg11037, enhanced wheat resistance to F. graminearum and reduced levels of the mycotoxin deoxynivalenol in wheat grains in an Fg05851/Fg11037-dependent manner. In the RXEG1 transgenic lines, genes related to pattern-triggered plant immunity, salicylic acid, jasmonic acid, and anti-oxidative homeostasis signalling pathways were upregulated during F. graminearum infection. However, the expression of these genes was not significantly changed during infection by the deletion mutant ΔFg05851/Fg11037, suggesting that the recognition of Fg05851/Fg11037 by RXEG1 triggered plant resistance against FHB. Moreover, introducing RXEG1 into three other different wheat cultivars via crossing also conferred resistance to F. graminearum. Expression of RXEG1 did not have obvious deleterious effects on plant growth and development in wheat. Our study reveals that N. benthamiana RXEG1 remains effective when transferred into wheat, a monocot, which in turn suggests that engineering wheat with interfamily plant immune receptor transgenes is a viable strategy for increasing resistance to FHB.

Chromosome painting reveals inter-chromosomal rearrangements and evolution of subgenome D of wheat.

Aegilops species represent the most important gene pool for breeding bread wheat (Triticum aestivum). Thus, understanding the genome evolution, including chromosomal structural rearrangements and syntenic relationships among Aegilops species or between Aegilops and wheat, is important for both basic genome research and practical breeding applications. In the present study, we attempted to develop subgenome D-specific fluorescence in situ hybridization (FISH) probes by selecting D-specific oligonucleotides based on the reference genome of Chinese Spring. The oligo-based chromosome painting probes consisted of approximately 26 000 oligos per chromosome and their specificity was confirmed in both diploid and polyploid species containing the D subgenome. Two previously reported translocations involving two D chromosomes have been confirmed in wheat varieties and their derived lines. We demonstrate that the oligo painting probes can be used not only to identify the translocations involving D subgenome chromosomes, but also to determine the precise positions of chromosomal breakpoints. Chromosome painting of 56 accessions of Ae. tauschii from different origins led us to identify two novel translocations: a reciprocal 3D-7D translocation in two accessions and a complex 4D-5D-7D translocation in one accession. Painting probes were also used to analyze chromosomes from more diverse Aegilops species. These probes produced FISH signals in four different genomes. Chromosome rearrangements were identified in Aegilops umbellulata, Aegilops markgrafii, and Aegilops uniaristata, thus providing syntenic information that will be valuable for the application of these wild species in wheat breeding.

E-Commerce Picture Text Recognition Information System Based on Deep Learning.

For the accuracy requirements of commodity image detection and classification, the FPN network is improved by DPFM ablation and RFM, so as to improve the detection accuracy of commodities by the network. At the same time, in view of the narrowing of channels in the application of traditional MWI-DenseNet network, a new GTNet network is proposed to improve the classification accuracy of commodities.The results show that at different levels of evaluation indexes, the dpFPN-Netv2 algorithm improved by DPFM + RFM fusion has higher target detection accuracy than RetinaNet-50 algorithm and other algorithms. And the detection time is 52 ms, which is significantly lower than 90 ms required for RetinaNet-50 detection. In terms of target recognition, compared with the traditional MWI-DenseNet neural network, the computation amount of the improved MWI DenseNet neural network is significantly reduced under different shunt ratios, and the recognition accuracy is significantly improved. The innovation of this study lies in improving the algorithm from the perspective of target detection and recognition, so as to change the previous improvement that only can be made in a single way.

Microwave hydrothermal fabrication of 3D hierarchical Br/Bi2WO6 with enhanced photocatalytic activity for Rhodamine B and tetracycline degradation.

Basing on the unique advantages of uniform and rapid volumetric heating of microwave irradiation, microwave hydrothermal method has been used to fabricate Br/Bi2WO6 for streamlining the preparation procedure and enhancing the photocatalytic activity. The results indicated that Br was successfully introduced into the lattice of Bi2WO6, which improved the absorption ability of visible light. Moreover, Br/Bi2WO6 exhibited smaller size and the enhanced separation efficiency of photogenerated carriers as compared with Bi2WO6. Br/Bi2WO6 exhibited superior reusability and photocatalytic activity of Rhodamine B (RhB) and tetracycline (TC). Furthermore, the enhanced photocatalytic activity of Br/Bi2WO6 was mainly ascribed to the increased specific surface area, wide UV-vis light absorption range, and high separation efficiency of photogenerated charge carriers originating from Br doping and microwave heating.

Astaxanthin suppresses endoplasmic reticulum stress and protects against neuron damage in Parkinson's disease by regulating miR-7/SNCA axis.

Parkinson's disease (PD) is a common neurodegenerative disorder that featured by the loss of dopaminergic neurons. Astaxanthin (AST), an important antioxidant, is demonstrated to be a neuroprotective agent for PD. However, the underlying mechanisms of AST in PD remain largely unclear. In this study, we found that AST treatment significantly not only abolished the cell viability inhibition and apoptosis promotion induced by 1-methyl-4-phenylpyridinium (MPP+) in SH-SY5Y cells via inhibiting endoplasmic reticulum (ER) stress, but also reversed the MPP+ caused dysregulation of miR-7 and SNCA expression. MiR-7 knockdown and SNCA overexpression were achieved by treating SH-SY5Y cells with miR-7 inhibitor and pcDNA3.1-SNCA plasmids, respectively. MiR-7 could bind to and negatively regulate SNCA in SH-SY5Y cells. Treated SH-SY5Y cells with miR-7 inhibitor or pcDNA3.1-SNCA abrogated the protective effects of AST on MPP+ induced cytotoxicity. Knockdown of miR-7 aggravated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neuron injury in vivo suggested by athletic performance, histopathological morphology, expression of tyrosine hydroxylase (TH) and TUNEL positvie cells, however, AST treatment could reverse these effects of miR-7 knockdown. Collectively, AST suppressed ER stress and protected against PD-caused neuron damage by targeting miR-7/SNCA axis, implying that AST might be a potential effective therapeutic agent for PD.

Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes.

Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125-S124-S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase inhibitor for T2D therapy.

Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction.

Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123-128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69-72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.

Cov_FB3D: A De Novo Covalent Drug Design Protocol Integrating the BA-SAMP Strategy and Machine-Learning-Based Synthetic Tractability Evaluation.

De novo drug design actively seeks to use sets of chemical rules for the fast and efficient identification of structurally new chemotypes with the desired set of biological properties. Fragment-based de novo design tools have been successfully applied in the discovery of noncovalent inhibitors. Nevertheless, these tools are rarely applied in the field of covalent inhibitor design. Herein, we present a new protocol, called Cov_FB3D, which involves the in silico assembly of potential novel covalent inhibitors by identifying the active fragments in the covalently binding site of the target protein. In this protocol, we propose a BA-SAMP strategy, which combines the noncovalent moiety score with the X-Score as the molecular mechanism (MM) level, and the covalent candidate score with the PM7 as the QM level. The synthetic accessibility of each suggested compound could be further evaluated with machine-learning-based synthetic complexity evaluation (SCScore). An in-depth test of this protocol against the crystal structures of 15 covalent complexes consisting of BTK inhibitors, KRAS inhibitors, EGFR inhibitors, EphB1 inhibitors, MAGL inhibitors, and MAPK inhibitors revealed that most of these inhibitors could be de novo reproduced from the fragments by Cov_FB3D. The binding modes of most generated reference poses could accurately reproduce the known binding mode of most of the reference covalent adduct in the binding site (RMSD ≤ 2 Å). In particular, most of these inhibitors were ranked in the top 2%, using the BA-SAMP strategy. Notably, the novel human ALDOA inhibitor (T1) with potent inhibitory activity (0.34 ± 0.03 µM) and greater synthetic accessibility was successfully de novo designed by this protocol. The positive results confirm the abilities of Cov_FB3D protocol.

Development and application of oligonucleotide-based chromosome painting for chromosome 4D of Triticum aestivum L.

Chromosome painting is a useful technique for distinguishing specific chromosomes (fragments), elucidating the genetic relationships of different genomes or chromosomes, and identifying chromosomal rearrangements. The development of chromosome- or genome-specific probes is fundamental for chromosome painting. The possibility for developing such probes specifically painting homoeologous chromosomes in allopolyploid species has been questioned since that chromosomes belonging to the same homoeologous group share highly conserved sequences. In the present study, we attempted to construct a wheat chromosome 4D-specific oligo probe library by selecting 4D-specific sequences in reference genome of common wheat cv. Chinese Spring (CS, 2n = 6x = 42, AABBDD). The synthesized library contains 27,392 oligos. Oligo painting using the probe library confirmed its specificity, shown by that only chromosome 4D could be painted in three wheat genotypes and CS nulli-tetrasomic line N4AT4D. Oligo painting was successfully used to define the 4D breakpoints in CS deletion lines involving 4D and two wheat-Haynaldia villosa 4D-4V translocation lines. Thirteen wheat relatives and a Triticum durum-H. villosa amphiploid were used for oligo painting. Except the 4D in two Aegilops tauschii accessions, the 4M in Ae. comosa and 4U in Ae. umbellulata could be painted. In tetraploid Ae. ventricosa, both 4D and 4M could be painted; however, the signal intensity of 4M was less compared with 4D. No painted chromosome was observed for the other alien species. This indicated that the relationship among D/M/U was closer than that among D/A/B as well as D with genomes H/R/Ss/Sc/Y/P/N/J. Our successful development of 4D-specific oligo probe library may serve as a model for developing oligo probes specific for other homoeologous chromosomes.

Discovery of novel allosteric site and covalent inhibitors of FBPase with potent hypoglycemic effects.

Fructose-1,6-bisphosphatase (FBPase) is an essential enzyme of GNG pathway. Significant advances demonstrate the FBPase plays a critical role in treatment of diabetes. Numerous FBPase inhibitors were developed by targeting AMP site, nevertheless, none of these inhibitors has exhibited suitable potency and druggability. Herein, a new allosteric site (C128) on FBPase was discovered, and several nitrostyrene compounds exhibiting potent FBPase inhibitions were found covalently bind to C128 site on FBPase. Mutagenesis suggest that C128 is the only cysteine that can influence FBPase inhibition, the N125-S124-S123 pathway was most likely involved in allosteric signaling transmission between C128 and active site. However, these nitrostyrenes may bind with multiple cysteine besides C128 in FBPase. To improve pocket selectivity, a series of novel compounds (14a-14n) were re-designed rationally by integrating fragment-based covalent virtual screening and machine-learning-based synthetic complexity evaluation. As expected, the mass spectrometry validated that the proportion of title compounds binding to the C128 in FBPase was significantly higher than that of nitrostyrenes. Notably, under physiological and pathological conditions, the treatment of compounds 14b, 14c, 14i or 14n led to potent inhibition of glucose production, as well as decreased triglyceride and total cholesterol levels in mouse primary hepatocytes. We highlight a novel paradigm that molecular targeting C128 site on FBPase can have potent hypoglycemic effect.

In silico screening of a novel scaffold for fructose-1,6-bisphosatase (FBPase) inhibitors.

Fructose-1, 6-bisphosphatase (FBPase) has been regarded as an attractive drug target to control blood glucose against Type 2 diabetes (T2D). In this study, by using the strategy of pharmacophore-based virtual screening, a novel scaffold inhibitor targeted the AMP allosteric site of human liver FBPase were screened, their inhibitory activities were further tested. The experimental results showed that compound H27 exhibited high inhibitory activities with the IC50 value of 5.3 µM. Therefore, compound H27 was chosen as the probe molecule, it's possible binding conformation targeted into FBPase was identified by using DOX2.0 strategy. The importance of key residues (T27, T31, K112 and R140) in allosteric site of FBPase for the binding inhibitors were validated by mutation experiments. The agreement between theory and experiment suggest that the interactional information of FBPase and inhibitors (H27) were reliable. On basis of these rational interactional information, the compound H29 was further designed to exhibit more potential FBPase inhibition (IC50 = 2.5 µM).

Mechanistic evaluation of neuroprotective effect of estradiol on rotenone and 6-OHDA induced Parkinson's disease.

BACKGROUND: The present study was intended to investigate the protective effect of estradiol against Parkinson's disease through the use of rotenone-induced neurotoxicity model. METHODS: To define the effect on the behavioral function, Tail suspension test, morris water maize test and cylinder tests were performed. Several biochemical and histological markers related to Parkinson's disease was determined in animal and cell culture models. To evaluate the effect of estradiol on the cellular architecture in rotenone-induced brain tissue, the histopathological examination was carried out by using Haemotoxylin and Eosin staining. Moreover, estradiol effect was also been investigated for its protective effect against Parkinson's disease using cell culture model with use of brain endothelial cells. The flowcytometric analysis was carried out to measure apoptosis in cell culture model. RESULTS: The abnormal level of antioxidant enzymes and lipid peroxidation were regulated toward the normal intensity under the influence of estradiol. Furthermore, intracellular ROS level and apoptosis were found to be reduced following estradiol treatment. During the 6-OHDA induced PD, the level of antioxidant marker such as GSH, ROS and TRAP, found to be significantly modulated by the estradiol. CONCLUSION: In view of the above results, it may be suggested that the estradiol may be as a useful therapeutic agent against rotenone-induced neurotoxicity such as Parkinson's disease.

MicroRNA-195 inhibits the behavior of cervical cancer tumors by directly targeting HDGF.

MicroRNAs (miRNAs/miRs) are a class of conserved non-coding endogenous small regulatory RNAs that regulate target gene expression by binding to the 3'-untranslated region of target mRNAs in a base-pairing manner, resulting in repression of transcription or degradation of target mRNAs. It has been demonstrated previously that the abnormal expression of miRNAs is involved in the carcinogenesis and progression of cervical cancer. The aim of the present study was to investigate the expression, biological functions and underlying molecular mechanisms of miR-195 in cervical cancer. The reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression level of miR-195 in cervical cancer tissues and cell lines. Following transfection, an MTT assay, cell migration and invasion assays, western blot analysis and a dual-luciferase reporter assay were performed in human cervical cancer cells. In the present study, it was identified that miR-195 was downregulated in cervical cancer tissues and cell lines. Additionally, upregulation of miR-195 and knockdown of hepatoma-derived growth factor (HDGF) inhibited proliferation, migration and invasion of cervical cancer cells. Furthermore, a dual-luciferase reporter assay identified that HDGF was a direct target gene of miR-195. RT-qPCR and western blot analysis demonstrated that miR-195 mimic inhibited HDGF expression at the mRNA and protein levels, whereas miR-195 inhibitor enhanced HDGF expression at the mRNA and protein levels. These results indicated that miR-195 targeted HDGF to inhibit the behavior of tumors in cervical cancer. These results also suggested that miR-195 was a potential therapeutic biomarker of cervical cancer.

Effect of Melatonin and Resveratrol against Memory Impairment and Hippocampal Damage in a Rat Model of Vascular Dementia.

OBJECTIVES: This study was intended to investigate whether treatment with resveratrol and melatonin alone or in combination can exert neurorestorative effects in a rat model of vascular dementia. METHODS: Briefly, male Wistar rats were subjected to permanent bilateral common carotid artery occlusion (BCCAO) by surgery. After 4 weeks, the cognitive deficits were assessed using the Morris water maze and novel object recognition tests. The biochemical parameters of oxidative stress and inflammation were also assessed. RESULTS: Rats in the BCCAO group showed cognitive deficits, accompanied by oxidonitrosative stress, neuroinflammation, and a reduction in brain-derived neurotrophic factor (BDNF) in the hippocampus region. Moreover, the acetylcholinesterase activity in the hippocampus was found to be increased in the BCCAO group compared to the sham group. The 4-week treatment with melatonin (10 mg/kg) and resveratrol (20 mg/kg) alone and in combination (melatonin 5 mg/kg and reseveratrol 10 mg/kg) caused a significant improvement in the cognitive deficits induced by BCCAO, accompanied by a reversal of oxidonitrosative stress, neuroinflammation, and BDNF depletion in the hippocampus region. Additionally, the treatment with melatonin and resveratrol significantly decreased acetylcholinesterase activity compared to in the BCCAO group. Melatonin and resveratrol ameliorated the BDNF expression of hippocampal protein. CONCLUSION: These results emphasize that coadministration of melatonin and resveratrol can be beneficial in BCCAO-induced vascular dementia through changes in BDNF expressions.

[Alterations of ALK gene and protein expression in prostatic cancer and its clinical significance].

OBJECTIVE: To investigate ALK genomic rearrangements and expression in prostate cancer, and their clinical implications. METHODS: Two hundred and eighty-one cases of prostate cancer were included. ALK gene rearrangements were assessed by FISH in all cases, and ALK protein expression was assessed by immunohistochemistry in 191 cases. RESULTS: The ALK gene was truncated (mostly 5' deletion) in 18 of 281 (6.4%) cases. EML4-ALK fusion gene was not detected. Genomic rearrangement of ALK gene was not statistically associated with Gleason score, age, TNM or baseline PSA level (P > 0.05). In all 18 cases, there were nuclear expression of ALK protein; in 12 cases, the expression was seen in 5%-30% of the tumor cells, and in the remaining 6 cases, the expression was seen in < 5% of the tumor cells. CONCLUSIONS: ALK gene rearrangements occurred in 6.4%, of prostate cancer, and these may not be associated with disease progressions. The ALK protein expresses in the nucleus. The EML4-ALK fusion gene was not found in prostate cancer.

High frequency of the SDK1:AMACR fusion transcript in Chinese prostate cancer.

Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer (CaP) specific fusion genes, SDK1:AMACR, RAD50:PDLIM4, CTAGE5:KHDRBS3 and USP9Y:TTTY15 have been reported in Chinese CaP samples through a transcriptome sequencing study. We previously reported that USP9Y:TTTY15 is a transcription-mediated chimeric RNA, which is expressed in both tumor and non-malignant samples, and here we attempted to confirm the existence of the other three fusion genes SDK1:AMACR, RAD50:PDLIM and CTAGE5:KHDRBS3. We detected SDK1:AMACR fusion transcript in 23 of 100 Chinese CaP samples, but did not detect RAD50:PDLIM4 and CTAGE5:KHDRBS3 transcripts in any of those samples. SDK1:AMACR fusion transcript is Chinese CaP specific, which was neither detected in non-malignant prostate tissues adjacent to cancer from Chinese patient nor in CaP samples from UK patients. However, we did not detect genomic rearrangement of SDK1 gene by fluorescence in situ hybridization analysis, indicating that SDK1:AMACR is also a transcription-mediated chimeric RNA. Quantitative analysis demonstrated that high level AMACR expression was associated with SDK1:AMACR fusion status (P=0.004), suggesting that SDK1:AMACR fusion transcript may promote prostate carcinogenesis through increasing AMACR expression. However, the fusion status was not significantly correlated with any poor disease progression clinical features. The identification of the SDK1:AMACR fusion transcript in CaP cases from China but not from UK further supports our previous observation that different genetic alterations contribute to CaP in China and Western countries, although many genetic changes are also shared. Further studies are required to establish if CaPs with SDK1:AMACR represent a distinct subtype.