Quercetin inhibits truncated isoform of dopamine-and cAMP-regulated phosphoprotein as adjuvant treatment for trastuzumab therapy resistance in HER2-positive breast cancer

Trastuzumab resistance is one of the causes of poor prognosis in patients with human epidermal growth factor receptor 2(HER2)-positive(HER2+)breast cancer(BC).The truncated isoform of dopamine-and cAMPregulated phosphoprotein(t-DARPP)has been reported to be involved in trastuzumab therapy resistance and promoting tumor progression.To evaluate the t-DARPP expression in BC,paired tumors and surrounding normal tissues were analyzed by real-time polymerase chain reaction and confirmed higher DARPP-32 kDa family mRNA expression in HER2+BC tumor tissues.We established 2 patient-derived xenografts(PDX)mice models to test the efficacy of trastuzumab,named model 1(non-responder)and model 2(responder).t-DARPP and p95-HER2 protein-protein interactions were detected in PDX tumor tissue from non-responders using Förster resonance energy transfer assays.Instead,there is no response from the responder.Furthermore,mechanistic studies using transwell and western blot assays demonstrated that t-DARPP could upregulate epithelial-mesenchymal transition signaling proteins,enhance p95-HER2 expression and promote cell migration.We found that quercetin effectively reduced t-DARPP expression in HER2+BC cells.In t-DARPP ShRNA-suppressed cells,quercetin synergistically enhanced trastuzumab-induced apoptotic cell death and G2/M phase arrest.In conclusion,the combination of quercetin and trastuzumab treatment by targeting t-DARPP in HER2+BC patients has the potential as a biomarker for mitigating drug resistance.

Involvement of fatty acid-CoA ligase 4 in hepatocellular carcinoma growth: Roles of cyclic AMP and p38 mitogen-activated protein kinase

AIM: Fatty acid-CoA ligase 4 (FACL4) is an arachidonatepreferring enzyme which has been shown to be up-regulated in human colon cancer tissues and implicated in the colon tumorigenesis. The purpose of this study was to investigatethe role of FACL4 in the human hepatocellular carcinoma (HCC) tumorigenesis and the specific signal pathways involved in this process.METHODS: We investigated the expression and regulation of FACL4 in HCC, adjacent non-tumorous liver tissues, and cell lines.RESULTS: In HCC patients, we demonstrated that FACL4 gene expression was markedly elevated in the cancerous tissues than in the adjacent non-cancerous liver tissues.In addition, several human hepatoma cell lines, including Hep3B and HepG2, expressed high levels of FACL4. Stable overex-pression of FACL4 knockdown plasmids (small interfering RNA, siRNA) to Hep3B cells significantly decreased FACL4 expression and subsequently limited the cell proliferation. Treatment of Hep3B cells with 8bromo-cAMP and SB203508 (p38 MAPK inhibitor) significantly suppressed the FACL4 expression. CONCLUSION: FACL4 is involved in the HCC tumorigenesis and both cAMP and p38 MAPK pathways are associated with the regulation of FACL4 in HCC.

Nomogram to predict permanent stoma in rectal cancer patients after sphincter-saving surgery

BACKGROUND Approximately 20 percent of patients with a tumour localized in the low rectum still encounter the possibility of requiring permanent stoma(PS), which can cause drastic changes in lifestyle and physical perceptions.AIM To determine the risk factors for PS and to develop a prediction model to predict the probability of PS in rectal cancer patients after sphincter-saving surgery.METHODS A retrospective cohort of 421 rectal cancer patients who underwent radical surgery at Taipei Medical University Hospital between January 2012 and December 2020 was included in this study. Univariate and multivariate analyses were performed to identify the independent risk factors for PS. A nomogram was developed according to the independent risk factors obtained in the multivariate analysis. The performance of the nomogram was assessed using a receiver operating characteristic curve and a calibration curve.RESULTS The PS rate after sphincter-saving surgery was 15.1%(59/391) in our study after a median follow-up of 47.3 mo(range 7–114 mo). Multivariate logistic regression analysis demonstrated that local recurrence, perirectal abscess, anastomosis site stenosis, perineural invasion, tumor size and operative time were independent risk factors for PS. These identified risk factors were incorporated into the nomogram, and the concordance index of this model was 0.903(95%CI: 0.851-0.955). According to the calibration curves, the nomogram represents a perfect prediction model.CONCLUSION Several risk factors for PS after sphincter-saving surgery were identified. Our nomogram exhibited perfect predictive ability and will improve a physician’s ability to communicate the benefits and risks of various treatment options in shared decision making.

An endoluminal aortic prosthesis infection presenting as pneumoaorta and aortoduodenal fistula

Herein, we present a case of pneumoaorta and aorto-duodenal fistula (ADF) caused by an endoluminal aortic prosthesis infection. An 82-year-old man underwent endovascular aneurysm repair with a stent graft to exclude a 5.1-cm abdominal aortic aneurysm. Three months after the index procedure, the patient was taken to the emergency department at a medical university hospital. He presented with a 2-d history of bloody diarrhea. An endoluminal aortic stent graft infection was diagnosed, and an ADF was identified. The patient died of septic shock despite emergency surgery and intensive care. When encountered, stent graft infections require appropriate antibiotics and graft explantation.The diagnosis of an ADF is important, and surgery remains the most effective management if septic shock presents despite conservative treatment.

Streptococcal toxic shock syndrome after hemorrhoidectomy: A case report

BACKGROUND Streptococcal toxic-shock syndrome after hemorrhoidectomy is rare but may be catastrophic.Group A streptococci have produced various surface proteins and exotoxins due to genetic changes to fight the human body’s immune response.Though life threatening infection after hemorrhoidectomy rarely occurs,all surgeons should be aware of the potential complications of severe sepsis after hemorrhoidectomy and keep in mind their clinical presenting features in order to diagnose early and administer appropriate and effective therapeutic drugs early.CASE SUMMARY Here,we present a case of a 56-year-old man with a painful thrombotic external hemorrhoid who presented to our outpatient department for management.There was no history of systemic diseases or recent disease infection.Hemorrhoidectomy was suggested and performed.After surgery,the patient developed hypotension,tachycardia,fever with chills and renal function impairment on day 2 post-operation.The clinical condition progressed to severe septic shock and metabolic acidosis.The patient responded poorly to treatment and expired after 1 d even with use of extracorporeal membrane oxygenation.The results of the blood and wound cultures showed group A streptococcus pyogenes.CONCLUSION Although extremely uncommon,all surgeons should be aware of these potential life-threatening septic complications and alert to the presenting features for patients receiving hemorrhoidectomy.