Histamine H4 receptor and TRPV1 mediate itch induced by cadaverine, a metabolite of the microbiome.

Cadaverine is an endogenous metabolite produced by the gut microbiome with various activity in physiological and pathological conditions. However, whether cadaverine regulates pain or itch remains unclear. In this study, we first found that cadaverine may bind to histamine 4 receptor (H4R) with higher docking energy score using molecular docking simulations, suggesting cadaverine may act as an endogenous ligand for H4R. We subsequently found intradermal injection of cadaverine into the nape or cheek of mice induces a dose-dependent scratching response in mice, which was suppressed by a selective H4R antagonist JNJ-7777120, transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine and PLC inhibitor U73122, but not H1R antagonist or TRPA1 antagonist or TRPV4 antagonist. Consistently, cadaverine-induced itch was abolished in Trpv1-/- but not Trpa1-/- mice. Pharmacological analysis indicated that mast cells and opioid receptors were also involved in cadaverine-induced itch in mice. scRNA-Seq data analysis showed that H4R and TRPV1 are mainly co-expressed on NP2, NP3 and PEP1 DRG neurons. Calcium imaging analysis showed that cadaverine perfusion enhanced calcium influx in the dissociated dorsal root ganglion (DRG) neurons, which was suppressed by JNJ-7777120 and capsazepine, as well as in the DRG neurons from Trpv1-/- mice. Patch-clamp recordings found that cadaverine perfusion significantly increased the excitability of small diameter DRG neurons, and JNJ-7777120 abolished this effect, indicating involvement of H4R. Together, these results provide evidences that cadaverine is a novel endogenous pruritogens, which activates H4R/TRPV1 signaling pathways in the primary sensory neurons.

AMPK activator 991 specifically activates SnRK1 and thereby affects seed germination in rice.

Sucrose non-fermenting-1-related protein kinase 1 (SnRK1) and AMP-activated protein kinase (AMPK) are highly conserved. Compound 991 is an AMPK activator in mammals. However, whether 991 also activates SnRK1 remains unknown. The addition of 991 significantly increased SnRK1 activity in desalted extracts from germinating rice seeds in vitro. To determine whether 991 has biological activity, rice seeds were treated with different concentrations of 991. Germination was promoted at low concentrations but inhibited at high concentrations. The effects of 991 on germination were similar to those of OsSnRK1a overexpression. To explore whether 991 affects germination by specifically affecting SnRK1, germination of an snrk1a mutant and the wild type under 1 µM 991 treatment was compared. The snrk1a mutant was insensitive to 991. Phosphoproteomic analysis showed that the differential phosphopeptides induced by 991 and OsSnRK1a overexpression largely overlapped. Furthermore, SnRK1 might regulate rice germination in a dosage-dependent manner by regulating the phosphorylation of three phosphosites, namely S285-PIP2;4, S1013-SOS1, and S110-ABI5. These results indicate that 991 is a specific SnRK1 activator in rice. The promotion and inhibition of germination by 991 also occurred in wheat seeds. Thus, 991 is useful for exploring SnRK1 function and the chemical regulation of growth and development in crops.

Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.

This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.

Controlled Self-Assembly of the Catalytic Core of Hydrolases Using DNA Scaffolds.

Precisely organizing functional molecules of the catalytic cores in natural enzymes to promote catalytic performance is a challenging goal in respect to artificial enzyme construction. In this work, we report a DNA-scaffolded mimicry of the catalytic cores of hydrolases, which showed a controllable and hierarchical acceleration of the hydrolysis of fluorescein diacetate (FDA). The results revealed that the efficiency of hydrolysis was greatly increased by the DNA-scaffold-induced proximity of catalytic amino acid residues (histidine and arginine) with up to 4-fold improvement relative to the free amino acids. In addition, DNA-scaffolded one-dimensional and two-dimensional assemblies of multiple catalytic cores could further accelerate the hydrolysis. This work demonstrated that the DNA-guided assembly could be used as a promising platform to build enzyme mimics in a programmable and hierarchical way.

Immunogenicity of novel DNA vaccines encoding receptor-binding domain (RBD) dimer-Fc fusing antigens derived from different SARS-CoV-2 variants of concern.

The continuously emerging of severe acute respiratory syndrome coronavirus-2 variants of concern (VOCs) led to a decline in effectiveness of the first-generation vaccines. Therefore, optimized vaccines and vaccination strategies, which show advantages in protecting against VOCs, are urgently needed. Here we constructed an optimized DNA vaccine plasmid containing built-in CpG adjuvant, and designed vaccine candidates encoding five forms of antigens derived from Wuhan-Hu-1. The results showed that plasmid with receptor binding domain (RBD) dimer-Fc fusing antigen (2RBD-Fc) induced the highest level of RBD-specific IgG and neutralizing antibodies in mice. Then 2dRBD-Fc and 2omRBD-Fc vaccines, respectively derived from delta and omicron VOCs, were constructed. The 2dRBD-Fc induced potent humoral and cellular immune responses, while the immunogenicity of 2omRBD-Fc was low. We also observed that sequential immunization with 2RBD-Fc, 2dRBD-Fc and 2omRBD-Fc effectively elicited neutralizing antibodies against each immunized strain, and RBD-specific T cell responses. To be noted, the Wuhan-Hu-1, delta and omicron neutralizing antibody titers induced by sequential immunization were comparable to that induced by repetitive immunization with 2RBD-Fc, 2dRBD-Fc or 2omRBD-Fc respectively. The results suggest that sequential immunization with DNA vaccines encoding potent antigens derived from different VOCs, may be a promising strategy to elicit immune responses against multiple variants.

Sucrose nonfermenting-1-related protein kinase 1 regulates sheath-to-panicle transport of nonstructural carbohydrates during rice grain filling.

The remobilization of nonstructural carbohydrates (NSCs) reserved in rice (Oryza sativa) sheaths is essential for grain filling. This assimilate distribution between plant tissues and organs is determined by sucrose non-fermenting-1-related protein kinase 1 (SnRK1). However, the SnRK1-mediated mechanism regulating the sheath-to-panicle transport of NSCs in rice remains unknown. In this study, leaf cutting treatment was used to accelerate NSC transport in the rice sheaths. Accelerated NSC transport was accompanied by increased levels of OsSnRK1a mRNA expression, SnRK1a protein expression, catalytic subunit phosphorylation of SnRK1, and SnRK1 activity, indicating that SnRK1 activity plays an important role in sheath NSC transport. We also discovered that trehalose-6-phosphate, a signal of sucrose availability, slightly reduced SnRK1 activity in vitro. Since SnRK1 activity is mostly regulated by OsSnRK1a transcription in response to low sucrose content, we constructed an snrk1a mutant to verify the function of SnRK1 in NSC transport. NSCs accumulated in the sheaths of snrk1a mutant plants and resulted in a low seed setting rate and grain weight, verifying that SnRK1 activity is essential for NSC remobilization. Using phosphoproteomics and parallel reaction monitoring, we identified 20 SnRK1-dependent phosphosites that are involved in NSC transport. In addition, the SnRK1-mediated phosphorylation of the phosphosites directly affected starch degradation, sucrose metabolism, phloem transport, sugar transport across the tonoplast, and glycolysis in rice sheaths to promote NSC transport. Therefore, our findings reveal the importance, function, and possible regulatory mechanism of SnRK1 in the sheath-to-panicle transport of NSCs in rice.

The plasma levels of Dickkopf-1 elevated in patients with Juvenile Idiopathic Arthritis.

BACKGROUND: To explore the role of two major inhibitors of Wnt signal pathway, Dickkopf-1(DKK-1) and Sclerostin (SOST), in the pathogenesis of juvenile idiopathic arthritis (JIA). METHODS: 88 patients with JIA, which including 49 patients with enthesitis-related arthritis (ERA), 21 oligoarthritis (oJIA) and 18 polyarthritis (pJIA), and 36 age-and sex-matched children as healthy controls (HC) were enrolled in this study. The plasma levels of DKK-1 and SOST, measured using commercially available ELISA kits, were analyzed the correlation between the levels of DKK-1/SOST and JIA, and were analyzed in 14 patients with JIA during before and after treatment. RESULTS: Plasma levels of DKK-1 were significantly higher in the patients with JIA than that in HC, the elevation of DKK-1 level was positively correlated with HLA-B27 positive JIA. DKK-1 levels dropped significantly in patient with JIA after treatment (P < 0.05). There was no significant change in SOST levels among different subtypes of JIA, patients with JIA during before and after treatment, and HC. CONCLUSION: It was suggested that the DKK-1 may have a certain correlation with the pathogenesis of JIA, and DKK-1 levels are more closely related to the HLA-B27 positive-ERA. IMPACT: The abnormally elevated levels of Dickkopf-1 (DKK-1) may be involved in the pathogenesis of juvenile idiopathic arthritis (JIA). DKK-1 levels were more closely related to the HLA-B27 positive-enthesitis-related arthritis (ERA). DKK-1 is an inhibitor of Wnt signaling pathway that promotes osteoblastic new bone formation; it is very rare for pediatric patients with HLA-B27 positive-ERA to manifest typical spondylitis, while sacroiliac arthritis is relatively common, which may be related to the high levels of DKK-1, which is consistent with the early stage of ankylosing spondylitis (AS).

Defined positive charge patterns created on DNA nanostructures determine cellular uptake efficiency.

We provide an effective method to create DNA nanostructures below 100 nm with defined charge patterns and explore whether the density and location of charges affect the cellular uptake efficiency of nanoparticles (NPs). To avoid spontaneous charge neutralization, the negatively charged polymer nanopatterns were first created by in situ polymerization using photoresponsive monomers on DNA origami. Subsequent irradiation generated positive charges on the immobilized polymers, achieving precise positively charged patterns on the negatively charged DNA surface. Via this method, we have discovered that the positive charges located on the edges of nanostructures facilitate more efficient cellular uptake in comparison to the central counterparts. In addition, the high-density positive charge decoration could also enhance particle penetration into 3D multicellular spheroids. This strategy paves a new way to construct elaborate charge-separated substructures on NP surfaces and holds great promise for a deeper understanding of the influence between the surface charge distribution and nano-bio interactions.

Iodine-Modified Ag NPs for Highly Sensitive SERS Detection of Deltamethrin Residues on Surfaces.

It is essential to estimate the indoor pesticides/insecticides exposure risk since reports show that 80% of human exposure to pesticides occurs indoors. As one of the three major contamination sources, surface collected pesticides contributed significantly to this risk. Here, a highly sensitive liquid freestanding membrane (FSM) SERS method based on iodide modified silver nanoparticles (Ag NPs) was developed for quantitative detection of insecticide deltamethrin (DM) residues in solution phase samples and on surfaces with good accuracy and high sensitivity. The DM SERS spectrum from 500 to 2500 cm-1 resembled the normal Raman counterpart of solid DM. Similar bands at 563, 1000, 1165, 1207, 1735, and 2253 cm-1 were observed as in the literature. For the quantitative analysis, the strongest peak at 1000 cm-1 that was assigned to the stretching mode of the benzene ring and the deformation mode of C-C was selected. The peak intensity at 1000 cm-1 and the concentration of DM showed excellent linearity from 39 to 5000 ppb with a regression equation I = 649.428 + 1.327 C (correlation coefficient R2 = 0.991). The limit of detection (LOD) of the DM was found to be as low as 11 ppb. Statistical comparison between the proposed and the HPLC methods for the analysis of insecticide deltamethrin (DM) residues in solution phase samples showed no significant difference. DM residue analysis on the surface was mimicked by dropping DM pesticide on the glass surface. It is found that DM exhibited high residue levels up to one week after exposure. This proposed SERS method could find application in the household pesticide residues analysis.

Gate-Level Circuit Partitioning Algorithm Based on Clustering and an Improved Genetic Algorithm.

Gate-level circuit partitioning is an important development trend for improving the efficiency of simulation in EDA software. In this paper, a gate-level circuit partitioning algorithm, based on clustering and an improved genetic algorithm, is proposed for the gate-level simulation task. First, a clustering algorithm based on betweenness centrality is proposed to quickly identify clusters in the original circuit and achieve the circuit coarse. Next, a constraint-based genetic algorithm is proposed which provides absolute and probabilistic genetic strategies for clustered circuits and other circuits, respectively. This new genetic strategy guarantees the integrity of clusters and is effective for realizing the fine partitioning of gate-level circuits. The experimental results using 12 ISCAS '89 and ISCAS '85 benchmark circuits show that the proposed algorithm is 5% better than Metis, 80% better than KL, and 61% better than traditional genetic algorithms for finding the minimum number of connections between subsets.

Transcriptome analysis of Neocaridina denticulate sinensis challenged by Vibrio parahemolyticus.

As a common aquatic pathogen, Vibrio parahaemolyticus can cause a variety of diseases of shrimp, especially acute hepatopancreatic necrosis disease (AHPND), which leads to great losses to the aquaculture industry around the world. However, the molecular mechanism of V. parahaemolyticus infection is still unclear. Neocaridina denticulate sinensis is a kind of small ornamental shrimp that is popular in aquarium trade, and due to its tenacious vitality, rapid growth, high reproductive capacity, it is very suitable to be developed as an animal model for basic research on decapod crustaceans. Thus, in this paper, transcriptomes of N. denticulate sinensis hepatopancreas with or without V. parahaemolyticus injection were explored. The results showed that a total of 23,624 genes with the N50 of 2705 bp were obtained. Comparative transcriptomic analysis revealed 21,464 differentially expressed genes between the V. parahaemolyticus infected and non-infected group, of which, 11,127 genes were up-regulated and 10,337 genes were down-regulated. Functional enrichment analysis suggested that many DEGs enriched in immune related pathways, including MAPK signaling pathway, Phosphatidylinositol signaling system, Chemokine signaling pathway, Phagosome and Jak-STAT signaling pathway and so on. Eight genes were selected randomly for qRT-PCR to verify the transcriptome sequencing results and the results showed the expression of these genes were consistent with the transcriptome results. Our work provides a unique and important dataset that contributes to the understanding of the molecular mechanisms of the immune response to V. parahaemolyticus infection and may further provide the basis for the prevention and resolution of bacterial diseases.

Kikuchi-Fujimoto disease as the initial manifestation of systemic lupus erythematosus complicated with macrophage activation syndrome: two case reports and a review of literature.

BACKGROUND: Kikuchi-Fujimoto disease (KFD) is a self-limiting and benign disease characterized by cervical lymphadenopathy and fever. Although KFD should be made differentially diagnosed from infectious, autoimmune, and malignant diseases, it sometimes occurs in patients with systemic lupus erythematosus (SLE) and can be complicated with macrophage activation syndrome (MAS). However, it is rare that KFD is the initial manifestation of SLE and to be complicated with MAS. CASE PRESENTATION: A 9.6-year-old girl presented with high-grade fever, double-side cervical lymphadenopathy with mild pain of one week, leukopenia, alopecia, and rash on the cheek. During hospitalization, laboratory investigations showed positive antinuclear antibody (ANA), low complement 3 (C3), and low complement 4 (C4). Imaging investigations showed pleural and pericardial effusion. A 10.3-year-old girl presented with intermittent high-grade fever, double-sided cervical lymphadenopathy with obvious pain of 1-month duration, and discoid lesion on the cheek. During hospitalization, laboratory investigations showed positive ANA, leukopenia, thrombocytopenia, anemia with positive Coombs' test, low C3, and positive Smith antibodies. Both cases were diagnosed with KFD using lymph node biopsy, simultaneously fulfilling the diagnostic criteria of SLE. Subsequently, the two girls became complicated with MAS, followed by interstitial lung disease and neuropsychiatric lupus, respectively. Both patients benefited from high-dose methylprednisolone pulse therapy combined with intravenous cyclophosphamide. CONCLUSIONS: More attention should be paid to differential diagnosis, especially SLE, in children diagnosed with KFD. In addition, children with SLE who presented with KFD as the initial manifestation seem to have a higher risk of developing MAS and experiencing organ involvement.

Methane emission via sediment and water interface in the Bohai Sea, China.

Sediment is recognized as the largest reservoir and source of methane (CH4) in the ocean, especially in the shallow coastal areas. To date, few data of CH4 concentration in sediment have been reported in the China shelf seas. In this study, we measured CH4 concentration in sediment and overlying seawater columns, and conducted an incubation experiment in the Bohai Sea in May 2017. CH4 concentration was found to be ranged from 3.075 to 1.795 µmol/L in sediment, which was 2 to 3 orders of magnitude higher than that in overlying seawater columns. The surface sediment was an important source of CH4, while bottom seawater acted as its sink. Furthermore, the net emission rate via sediment water interface (SWI) was calculated as 2.45 µmol/(m2∙day) based on the incubation experiment at station 73, and the earthquake may enhance CH4 release from sediment to seawater column in the eastern Bohai Sea.

Programmable and Site-Specific Patterning on DNA Origami Templates with Heterogeneous Condensation of Silver and Silica.

DNA origami has been widely used as a modular platform for condensation of functional molecules to assemble optical, electronic, and biological components. However, the heterogeneous condensation with greater diversities in chemical composition templated with DNA origami is still challenging. Herein, a programmable deposition method is developed to precisely condense silver-silica nanohybrids on DNA origami templates. First, the site-specific metallization of Ag is achieved by thiol group-initiated silver reduction at the designed areas of DNA origami. Next, cysteamine is used to selectively modify the condensed Ag surface with positively charged amino groups for creating an electronically different environment for site-specific placement of silica by a modified Stöber method. Using these strategies, customized patterning of both silver and silica on tubular and rectangular DNA origami nanostructures is successfully achieved with nanoscale spatial resolution. These findings will greatly facilitate the development of DNA nanotechnology-based bottom-up nanofabrication.

PAMI syndrome: A rare cause that can be easily misdiagnosed.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome caused by mutations in PSTPIP1 is a rare inflammatory disorder that can be easily misdiagnosed. It is characterized by anemia, arthritis, cutaneous inflammation, recurrent infections, growth failure, hepatosplenomegaly, lymphadenopathy, hyperzincemia/hypercalprotectinemia, neutropenia, thrombocytopenia, and elevated inflammatory indicators. This study describes the cases of two pediatric female patients with long-standing recurrent arthralgia in different parts of the extremities and severe anemia, respectively, who were misdiagnosed and treated for aseptic necrosis of the femoral head and severe autoimmune hemolytic anemia, respectively. High-throughput sequencing analysis revealed a de novo heterozygous missense mutation (c.748G > A, p. Glu250Lys) in exon 11 of PSTPIP1 (NM_003978.5) in both patients, which supported a diagnosis of PAMI. The patients were treated with prednisone and etanercept, which improved their symptoms, but neutropenia remained unchanged. These cases highlight the importance of genetic assessment for the accurate diagnosis of PAMI and to ensure adequate and timely treatment of these patients.

Induction of cross-neutralizing antibodies by sequential immunization with heterologous papillomavirus L1VLPs and its implications for HPV prophylactic vaccines.

Sequential immunization with antigens from different strains of HIV-1, influenza viruses or dengue viruses induced cross-neutralizing antibodies and enhanced the antibody responses against previous antigens. The characteristics of neutralizing antibodies induced by sequential immunization with different types of human papillomavirus (HPV) L1 virus-like particles (L1VLPs) are unclear. In this study, mice were primed with one or two types (HPV-16 or HPV16/18) of L1VLPs, then boosted sequentially with HPV6/18/45/11/31/58 or HPV6/45/11/31/58 L1VLPs, and sera were analyzed with HPV pseudovirus-based neutralization assay. The results showed that neutralizing activities against earlier immunized vaccine types were enhanced gradually by subsequent immunizations, and low levels of neutralizing activities against nonvaccine types (HPV33/35/52/59/68) were also observed. After absorbing the immune sera with vaccine-type (HPV16/18/45) L1VLPs, neutralizing activities against tested priming and boosting types (HPV16/18/58) decreased significantly, and that against nonvaccine type (HPV-33) was also partially eliminated. Moreover, neutralizing activities against vaccine types (HPV16/58) were significantly reduced after absorbing with nonvaccine-type VLPs (HPV33/52). These data suggest that cross-neutralizing epitopes exist among different HPV L1VLPs. The cross-neutralizing activities against nonvaccine types and the enhanced neutralizing activities against earlier immunized vaccine types may result from sequential boosting with these cross-neutralizing epitopes. These observations support early vaccination with more types of L1VLPs derived from HPVs that cause a serious threat to the population.

An Intelligent DNA Nanorobot for Autonomous Anticoagulation.

Artificial nanorobots that can recognize molecular triggers and respond with programable operations provide an inspiring proof-of-principle for personalized theragnostic applications. We have constructed an intelligent DNA nanorobot for autonomous blood anticoagulation in human plasma. The DNA nanorobot comprises a barrel-shaped DNA nanostructure as the framework and molecular reaction cascades embedded as the computing core. This nanorobot can intelligently sense the concentration of thrombin in the local environment and trigger an autonomous anticoagulation when excess thrombin is present. The triggering concentration of thrombin at which the nanorobot responds can be tuned arbitrarily to avoid possible side effects induced by excess thrombin. This makes the nanorobot useful for autonomous anticoagulation in various medical scenarios and inspires a more efficient and safer strategy for future personalized medicine.

Lupus enteritis masquerading as Crohn's disease.

BACKGROUND: Systemic lupus erythematosus is an autoimmune disease which can affect multiple organs, resulting in significant mortality and morbidity. Lupus enteritis is one of the rare complications of SLE, defined as vasculitis of the intestinal tract, with supportive biopsy findings and/or image. However, lupus enteritis is seldom confirmed on histology or image and the changes of intestinal mucosa are nonspecific. Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract which affects any part of the gastrointestinal tract. The diagnosis of CD is confirmed by clinical evaluation and a combination of endoscopic, histology, radiology, and/or biochemical investigations. CASE PRESENTATION: Here we report a rare case of a 71-years-old Chinese male has been diagnosed with lupus enteritis which similar to CD in the aspects of endoscopic, histology, and radiology. So far, there are no relevant cases reported. CONCLUSIONS: The endoscopic appearance of lupus enteritis is nonspecific, on the basis of our case, the features of lupus enteritis can be described as spacious, clean and no moss ulcers which discontinuous involved all gastrointestinal tract.

Proliferation Potential-Related Protein Promotes the Esophageal Cancer Cell Proliferation, Migration and Suppresses Apoptosis by Mediating the Expression of p53 and Interleukin-17.

OBJECTIVE: This study aims to investigate the mechanism of proliferation potential-related protein (PP-RP) in influencing the proliferation, migration, and apoptosis of esophageal cancer cells. METHODS: Quantitative real-time PCR and western blotting were performed to analyze the expression of PP-RP gene, p53, and interleukin (IL)-17 in human normal tissues and tumor tissues, as well as the expression of p53 and IL-17 in Eca109 and TE3 cells. The esophageal cancer cell proliferation was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), cell apoptosis was detected by flow cytometry, and cell migration was detected by transwell migration. RESULTS: PP-RP expressed highly in tumor tissue and Eca109 and TE3 cells, PP-RP overexpression inhibited the expression of p53 and promoted the expression of IL-17 in Eca109 and TE3 cells. PP-RP overexpression increased the expression of F-actin, promoted cell proliferation, and migration and suppressed cell apoptosis. Cell proliferation ability and cell migration ability were significantly strengthened while apoptosis was suppressed by PP-RP + pyruvate carboxylase deoxyribonucleic acid (PCDNA)-p53 group and PP-RP + IL-17 siRNA group in TE3 cells. CONCLUSION: Our data suggest that PP-RP promotes esophageal cancer cell proliferation and migration, and suppresses apoptosis by mediating the expression of p53 and IL-17.

Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients.

Background Solid tumor tissue testing is the gold standard for molecular-based assays for metastatic colorectal cancer (mCRC). This poses challenges during treatment monitoring. Total DNA derived from urine specimens offers clear advantages to track the disease dynamics. Our study aims to evaluate the sensitivity for total DNA recovered from urine and its clinical relevance to mCRC. Methods KRAS mutations in urine specimens were examined in 150 mCRC patients. Baseline concordance was established to determined clinical relevance. The total DNA quantities were also prospectively examined in serial samplings during treatment. Results Analysis of the genetic mutations showed good agreement for baseline samples. Matched tumor and urine specimens' molecular profiles were observed to have 90% concordance. Comparing with healthy volunteers, we established a cutoff of 8.15 ng that demonstrated elevated total DNA levels was associated with mCRC patients (sensitivity: 90.7%; specificity: 82.0%). For patients treated with chemotherapy or anti-epidermal growth factor receptor inhibitors, DNA quantity mirrored early treatment response. Survival analysis showed that patients with sustained elevated quantities of KRAS mutations had poorer outcome. Conclusions Total urine DNA offers a viable complement for mutation profiling in mCRC patients, given the good agreement with matched tumor samples. Our study also established that this is specific based on the results from healthy individuals. Serial monitoring of total DNA levels allowed early prediction to treatment response and was effective to identify high risk patients. This is potentially useful to complement current disease management.