Prostaglandin F_(2α)synthase promotes oxaliplatin resistance in colorectal cancer through prostaglandin F_(2α)-dependent and F_(2α)-independent mechanism

BACKGROUND Oxaliplatin(Oxa)is the first-line chemotherapy drug for colorectal cancer(CRC),and Oxa resistance is crucial for treatment failure.Prostaglandin F_(2α)synthase(PGF 2α)(PGFS),an enzyme that catalyzes the production of PGF_(2α),is involved in the proliferation and growth of a variety of tumors.However,the role of PGFS in Oxa resistance in CRC remains unclear.AIM To explore the role and related mechanisms of PGFS in mediating Oxa resistance in CRC.METHODS The PGFS expression level was examined in 37 pairs of CRC tissues and paracancerous tissues at both the mRNA and protein levels.Overexpression or knockdown of PGFS was performed in CRC cell lines with acquired Oxa resistance(HCT116-OxR and HCT8-OxR)and their parental cell lines(HCT116 and HCT8)to assess its influence on cell proliferation,chemoresistance,apoptosis,and DNA damage.For determination of the underlying mechanisms,CRC cells were examined for platinum-DNA adducts and reactive oxygen species(ROS)levels in the presence of a PGFS inhibitor or its products.RESULTS Both the protein and mRNA levels of PGFS were increased in the 37 examined CRC tissues compared to the adjacent normal tissues.Oxa induced PGFS expression in the parental HCT116 and HCT8 cells in a dosedependent manner.Furthermore,overexpression of PGFS in parental CRC cells significantly attenuated Oxainduced proliferative suppression,apoptosis,and DNA damage.In contrast,knockdown of PGFS in Oxa-resistant HCT116 and HCT8 cells(HCT116-OxR and HCT8-OxR)accentuated the effect of Oxa treatment in vitro and in vivo.The addition of the PGFS inhibitor indomethacin enhanced the cytotoxicity caused by Oxa.Treatment with the PGFS-catalyzed product PGF_(2α)reversed the effect of PGFS knockdown on Oxa sensitivity.Interestingly,PGFS inhibited the formation of platinum-DNA adducts in a PGF_(2α)-independent manner.PGF_(2α)exerts its protective effect against DNA damage by reducing ROS levels.CONCLUSION PGFS promotes resistance to Oxa in CRC via both PGF_(2α)-dependent and PGF_(2α)-independent mechanisms.

Y-box binding protein 1 augments sorafenib resistance via the PI3K/Akt signaling pathway in hepatocellular carcinoma

BACKGROUND Sorafenib is the first-line treatment for patients with advanced hepatocellular carcinoma(HCC).Y-box binding protein 1(YB-1)is closely correlated with tumors and drug resistance.However,the relationship between YB-1 and sorafenib resistance and the underlying mechanism in HCC remain unknown.AIM To explore the role and related mechanisms of YB-1 in mediating sorafenib resistance in HCC.METHODS The protein expression levels of YB-1 were assessed in human HCC tissues and adjacent nontumor tissues.Next,we constructed YB-1 overexpression and knockdown hepatocarcinoma cell lines with lentiviruses and stimulated these cell lines with different concentrations of sorafenib.Then,we detected the proliferation and apoptosis in these cells by terminal deoxynucleotidyl transferase dUTP nick end labeling,flow cytometry and Western blotting assays.We also constructed a xenograft tumor model to explore the effect of YB-1 on the efficacy of sorafenib in vivo.Moreover,we studied and verified the specific molecular mechanism of YB-1 mediating sorafenib resistance in hepatoma cells by digital gene expression sequencing(DGE-seq).RESULTS YB-1 protein levels were found to be higher in HCC tissues than in corresponding nontumor tissues.YB-1 suppressed the effect of sorafenib on cell proliferation and apoptosis.Consistently,the efficacy of sorafenib in vivo was enhanced after YB-1 was knocked down.Furthermore,KEGG pathway enrichment analysis of DGEseq demonstrated that the phosphoinositide-3-kinase(PI3K)/protein kinase B(Akt)signaling pathway was essential for the sorafenib resistance induced by YB-1.Subsequently,YB-1 interacted with two key proteins of the PI3K/Akt signaling pathway(Akt1 and PIK3R1)as shown by searching the BioGRID and HitPredict websites.Finally,YB-1 suppressed the inactivation of the PI3K/Akt signaling pathway induced by sorafenib,and the blockade of the PI3K/Akt signaling pathway by LY294002 mitigated YB-1-induced sorafenib resistance.CONCLUSION Overall,we concluded that YB-1 augments sorafenib resistance through the PI3K/Akt signaling pathway in HCC and suggest that YB-1 is a key drug resistance-related gene,which is of great significance for the application of sorafenib in advanced-stage HCC.

Rare neonatal malignant primary orbital tumors: Three case reports

BACKGROUND Aggressive malignant primary orbital tumors are extremely rare in newborns.The current cases further clarify the clinical features of malignant primary orbital tumors in neonates.CASE SUMMARY At the time of presentation at the Seventh Center of People’s Liberation Army General(PLAG)Hospital,the children were 1-,2-and 5-mo-old,respectively,and included 2 boys and 1 girl.All three cases had unilateral proptosis at birth,and underwent mass excision and histopathologic examination.A peripheral primary neuroectodermal tumor,an aggressive infantile fibromatosis and an embryonic rhabdomyosarcoma were diagnosed,respectively.The first case underwent routine chemotherapy following surgery but died within three months due to worsening condition as the tumor spread throughout the body.The other two children were treated by surgery,and at the follow-up visits 6 mo and 1 year after surgery,respectively,the wound was completed healed,and they had normal growth and development without radiotherapy or chemotherapy.A review of highly uncommon orbital tumors in newborns is also provided.CONCLUSION Malignant primary tumors should be considered in the presence of unilateral proptosis in newborns.

Fanconi-Bickel syndrome in an infant with cytomegalovirus infection: A case report and review of the literature

BACKGROUND Fanconi–Bickel syndrome(FBS)is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene,which encodes glucose transporter protein 2(GLUT2).CASE SUMMARY We report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly,jaundice,liver transaminase elevation,fasting hypoglycemia,hyperglycosuria,proteinuria,hypophosphatemia,rickets,and growth retardation.After prescription of ganciclovir,the levels of bilirubin and alanine aminotransferase decreased to normal,while she still had aggravating hepatomegaly and severe hyperglycosuria.Then,whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents,which was predicted to change alanine 139 to valine(p.A139Vfs*3),indicating a diagnosis of FBS.During the follow-up,the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch.Her weight increased to normal range at 3 years old without hepatomegaly.However,she still had short stature.Although there was heterogeneity between phenotype and genotype,Chinese children had typical clinical manifestations.No hot spot mutation or association between severity and mutations was found,but nonsense and missense mutations were more common.Data of long-term follow-up were rare,leading to insufficient assessment of the prognosis in Chinese children.CONCLUSION FBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction.Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants.Genetic sequencing is indispensable for diagnosis.Since the diversity of disease severity,early identification and long-term follow-up could help improve patients’quality of life and decrease mortality.

Current status of fecal calprotectin as a diagnostic or monitoring biomarker for cow's milk protein allergy in children:a scoping review

Background There are few approved biomarkers for diagnosis and monitoring of cow's milk protein allergy(CMPA),thus the oral food challenge remains to be the golden diagnostic standard.A potential biomarker is fecal calprotectin,a cytosolic protein,elevating in the presence of intestinal mucosal inflammation.We aimed to undertake a scoping review of the evi-dence pertaining to the current status of fecal calprotectin used for diagnosis and monitoring CMPA in children,and tried to indicate the aspects needed to be concerned in the future investigations and researches.Methods A scoping review was performed using the literature searched from PUBMED,EMBASE,and Web of Science Databases until July 2019 on the studies about the application of fecal calprotectin as a biomarker of CMPA in children.Studies were examined according to the inclusion and exclusion criteria.Data were extracted,and a narrative synthesis was conducted to summarize and analyze.Results Thirteen studies with different study design embracing 1238 children were included.The age range was from infants to adolescents.Most children with CMPA presented gastrointestinal symptoms,among which hematochezia was most com-mon.Amount of data suggested that infants with CMPA represented elevated levels of fecal calprotectin,particularly with distinct significance in non-IgE-mediated CMPA groups.Decreases of fecal calprotectin after elimination diet were demon-strated in enrolled studies.However,no matter in the CMPA positive or negative groups,the changes of fecal calprotectin before or after challenge showed no significance.Contradictory results were generated from studies on the role of fecal calprotectin in predicting allergic disease.Conclusions Available evidence is not sufficient to confirm the utilization of fecal calprotectin both in diagnosis and moni-toring of CMPA and predicting for allergic disease.More clinical and bench researches with elaborate design should be conducted and the exact cut-off values of fecal calprotectin in different groups remain to be determined.

Protein sequence analysis based on hydropathy profile of amino acids

Biology sequence comparison is a fundamental task in computational biology.According to the hydropathy profile of amino acids,a protein sequence is taken as a string with three letters.Three curves of the new protein sequence were defined to describe the protein sequence.A new method to analyze the similarity/dissimilarity of protein sequence was proposed based on the conditional probability of the protein sequence.Finally,the protein sequences of ND6(NADH dehydrogenase subunit 6)protein of eight species were taken as an example to illustrate the new approach.The results demonstrated that the method is convenient and efficient.