Search

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.

Background: While surgery remains the primary treatment for oral squamous cell carcinoma (OCSCC), induction chemotherapy (IC) can be used as a bridging or neoadjuvant therapy. This nationwide study in Taiwan examines the survival outcomes of OCSCC patients who received IC before surgery. Methods: We analyzed data from 29,891 patients with OCSCC. Of these, 29,058 initially underwent surgery (OP group), whereas 833 received IC before surgery (IC + OP group). A propensity score (PS)‐matched analysis (4, 1 ratio, 3260 vs. 815 patients) was performed considering tumor subsite, sex, age, Charlson comorbidity index, clinical T1–T4b tumors, clinical N0–3 disease, and clinical stage I–IV. Results: In the PS‐matched cohort, the 5‐year disease‐specific survival (DSS) and overall survival (OS) rates were 65% and 57%, respectively. When comparing the OP and IC + OP groups, the 5‐year DSS rates were 66% and 62%, respectively (p = 0.1162). Additionally, the 5‐year OS rates were 57% and 56%, respectively (p = 0.9917). No significant intergroup differences in survival were observed for specific subgroups with cT4a tumors, cT4b tumors, cN3 disease, pT4b tumors, and pN3 disease. However, for patients with pT4a tumors, the OP group demonstrated superior 5‐year outcomes compared to the IC + OP group, with a DSS of 62% versus 52% (p = 0.0006) and an OS of 53% versus 44% (p = 0.0060). Notably, patients with cT2–3, cN1, and c‐Stage II disease in the IC + OP group were significantly more likely to achieve pT0–1 status (p < 0.05). Conclusions: Following PS matching, the IC + OP group generally exhibited similar prognosis to the OP group. However, for pT4a tumors, the OP group showed superior 5‐year outcomes. While IC may not universally improve survival, it could be advantageous for patients who respond positively to the treatment. [ABSTRACT FROM AUTHOR]

Background: Elective tracheotomy is commonly performed in resected oral squamous cell carcinoma (OCSCC) to maintain airway patency. However, the indications for this procedure vary among surgeons. This nationwide study evaluated the impact of tracheotomy on both the duration of in‐hospital stay and long‐term survival outcomes in patients with OCSCC. Methods: A total of 18,416 patients with OCSCC were included in the analysis, comprising 7981 patients who underwent elective tracheotomy and 10,435 who did not. The primary outcomes assessed were 5‐year disease‐specific survival (DSS) and overall survival (OS). To minimize potential confounding factors, a propensity score (PS)‐matched analysis was performed on 4301 patients from each group. The duration of hospital stay was not included as a variable in the PS‐matched analysis. Results: Prior to PS matching, patients with tracheotomy had significantly lower 5‐year DSS and OS rates compared to those without (71% vs. 82%, p < 0.0001; 62% vs. 75%, p < 0.0001, respectively). Multivariable analysis identified tracheotomy as an independent adverse prognostic factor for 5‐year DSS (hazard ratio = 1.10 [1.03–1.18], p = 0.0063) and OS (hazard ratio = 1.10 [1.04–1.17], p = 0.0015). In the PS‐matched cohort, the 5‐year DSS was 75% for patients with tracheotomy and 76% for those without (p = 0.1488). Five‐year OS rates were 66% and 67%, respectively (p = 0.0808). Prior to PS matching, patients with tracheotomy had a significantly longer mean hospital stay compared to those without (23.37 ± 10.56 days vs. 14.19 ± 8.34 days; p < 0.0001). Following PS matching, the difference in hospital stay duration between the two groups remained significant (22.34 ± 10.25 days vs. 17.59 ± 9.54 days; p < 0.0001). Conclusions: While elective tracheotomy in resected OCSCC patients may not significantly affect survival, it could be associated with prolonged hospital stays. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to evaluate the influence of glutathione-S-transferase (GST) M1 and T1 polymorphisms in 184 patients with different stages of liver fibrosis and hepatitis C virus infection and 173 healthy control subjects. Methods: DNA samples were extracted from whole blood, and the polymorphisms of GSTM1 and GSTT1 were determined with PCR using fluorescence-labeled Taq Man probes. Associations between specific genotypes and progression of liver fibrosis were examined by use of the logistic regression analysis to calculate the odds ratio (OR) and 95% confidence intervals (CI). Results: Results show that no differences were found between the frequencies of GSTM1 (49.8% versus 50.2%) and GSTT1 (52.2% versus 47.8%) null genotypes in HCV-infected patients and healthy controls, respectively. In addition, there was also no significant relation between the frequency of GSTM1 or GSTT1 gene polymorphisms and fibrosis stage as classified by the METAVIR group. Conclusions: The combined GSTM1 and GSTT1 null genotypes showed an association between GSTM1 [-]/GSTT1 [-] and progression of liver fibrosis.

This paper proposes a single-phase two-wire inverter system for photovoltaic (PV) power injection and active power filtering (APF) with nonlinear inductor consideration. The proposed system can fully or partially perform APF, process PV power, eliminate harmonic currents, improve power factor, and take into account the nonlinear effect of its output filter inductor. In the system, even though only the utility current is sensed, both APF and maximum power point tracking features can be still achieved, reducing the number of current sensors and cost significantly. To prevent output current from exceeding switch ratings, inverter current is properly controlled through a current estimator and a defined limit circle. A self-learning algorithm is also proposed to determine nonlinear inductance, which can increase the accuracy of the estimated current. Simulations and experimental results have verified the feasibility of the proposed PV inverter system and the algorithm. Index Terms--Current estimator, nonlinear inductor consideration, photovoltaic (PV) power injection, self-learning algorithm, single-phase two-wire (1 [empty set] 2W) inverter system.