Case report: Sustained remission after combined sintilimab, anti-VEGF therapy, and chemotherapy in a patient with non-small cell lung cancer harboring acquired EGFR 19Del/T790M/cis-C797S mutation resistance.

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are highly effective against tumors harboring the T790M mutation. However, patients treated with these inhibitors ultimately develop resistance, and the most common mechanism is the emergence of the EGFR C797S mutation. Few treatment regimens have been reported for this condition. In this report, we present a successful combination treatment with the programmed cell death 1 (PD-1) inhibitor sintilimab, anti-vascular endothelial growth factor (VEGF) therapy, and chemotherapy with pemetrexed and cisplatin in a patient with non-small cell lung cancer (NSCLC) who developed acquired resistance with EGFR 19 exon deletion (19Del)/T790M/cis-C797S mutation following progression with ametinib therapy. This regimen was well tolerated, and the patient has remained progression-free for 15 months. Our case provides clinical evidence that the combination of PD-1 inhibitor, anti-VEGF therapy, and chemotherapy may be an efficacious therapeutic strategy for NSCLC patients with acquired EGFR 19Del/T790M/cis-C797S mutation resistance following progression with EGFR TKI therapy.

CO2 improves the anaerobic biodegradation intensity and selectivity of heterocyclic hydrocarbons in heavy oil.

Heterocyclic hydrocarbons pollution generated by oil spills and oilfield wastewater discharges threatens the ecological environment and human health. Here we described a strategy that combines the greenhouse gas CO2 reduction with microbial remediation. In the presence of nitrate, CO2 can improve the biodegradation efficiency of the resins and asphaltenes in heavy oil, particularly the biodegradation selectivity of the polar heterocyclic compounds by the newly isolated Klebsiella michiganensis. This strain encoded 80 genes for the xenobiotic biodegradation and metabolism, and can efficiently utilize CO2 when degrading heavy oil. The total abundance of resins and asphaltenes decreased significantly with CO2, from 40.816% to 26.909%, to 28.873% with O2, and to 36.985% with N2. The transcripts per million (TPM) value of accA gene was 57.81 under CO2 condition, while respectively 8.86 and 21.23 under O2 and N2 conditions. Under CO2 condition, the total relative percentage of N1-type heterocyclic compounds was selectively decreased from 32.25% to 22.78%, resulting in the heavy oil viscosity decreased by 46.29%. These results demonstrated a novel anaerobic degradation mechanism that CO2 can promote the anaerobic biodegradation of heterocyclic hydrocarbons in heavy oil, which provides a promising biotreatment technology for the oil-contaminated water.

Effect of Induction Chemotherapy With Paclitaxel, Cisplatin, and Capecitabine vs Cisplatin and Fluorouracil on Failure-Free Survival for Patients With Stage IVA to IVB Nasopharyngeal Carcinoma: A Multicenter Phase 3 Randomized Clinical Trial.

Importance: Induction chemotherapy added to concurrent chemoradiotherapy significantly improves survival for patients with locoregionally advanced nasopharyngeal carcinoma, but the optimal induction regimen remains unclear. Objective: To determine whether induction chemotherapy with paclitaxel, cisplatin, and capecitabine (TPC) improves survival vs cisplatin and fluorouracil (PF) prior to chemoradiotherapy for patients with stage IVA to IVB nasopharyngeal carcinoma. Design, Setting, and Participants: This randomized, open-label, phase 3 clinical trial recruited 238 patients at 4 hospitals in China from October 20, 2016, to August 29, 2019. Patients were 18 to 65 years of age with treatment-naive, nonkeratinizing stage IVA to IVB nasopharyngeal carcinoma and an Eastern Cooperative Oncology Group performance status of 0 to 1. Interventions: Patients were randomly assigned (1:1) to receive induction chemotherapy with two 21-day cycles of TPC (intravenous paclitaxel [150 mg/m2, day 1], intravenous cisplatin [60 mg/m2, day 1], and oral capecitabine [1000 mg/m2 orally twice daily, days 1-14]) or PF (intravenous cisplatin [100 mg/m2, day 1] and fluorouracil [800 mg/m2 daily, days 1-5]), followed by chemoradiotherapy. Main Outcomes and Measures: The primary end point was failure-free survival in the intention-to-treat population. Secondary end points included distant metastasis-free survival, locoregional relapse-free survival, overall survival, tumor response, and safety. Results: Overall, 238 eligible patients (187 men [78.6%]; median age, 45 years [range, 18-65 years]) were randomly assigned to receive TPC (n = 118) or PF (n = 120). The median follow-up duration was 48.4 months (IQR, 39.6-53.3 months). Failure-free survival at 3 years was 83.5% (95% CI, 77.0%-90.6%) in the TPC group and 68.9% (95% CI, 61.1%-77.8%) in the PF group (stratified hazard ratio [HR] for recurrence or death, 0.47; 95% CI, 0.28-0.79; P = .004). Induction with the TPC regimen resulted in a significant reduction in the risk of distant metastases (stratified HR, 0.49 [95% CI, 0.24-0.98]; P = .04) and locoregional recurrence (stratified HR, 0.40 [95% CI, 0.18-0.93]; P = .03) compared with the PF regimen. However, there was no effect on early overall survival (stratified HR, 0.45 [95% CI, 0.17-1.18]; P = .10). The incidences of grade 3 to 4 acute adverse events and late-onset toxicities were 57.6% (n = 68) and 13.6% (16 of 118), respectively, in the TPC group and 65.8% (n = 79) and 17.9% (21 of 117), respectively, in the PF group. One treatment-related death occurred in the PF group. Conclusions and Relevance: This randomized clinical trial found that induction chemotherapy with 2 cycles of TPC for patients with stage IVA to IVB nasopharyngeal carcinoma improved failure-free survival compared with 2 cycles of PF, with no increase in the toxicity profile. Trial Registration: ClinicalTrials.gov Identifier: NCT02940925.

Does adenocarcinoma have a worse prognosis than squamous cell carcinoma in patients with cervical cancer? A real-world study with a propensity score matching analysis.

OBJECTIVE: To compare survival outcomes between cervical adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using a propensity score matching (PSM) analysis based on the Surveillance, Epidemiology, and End Results (SEER) Program. METHODS: Patients diagnosed with cervical cancer between 1998 and 2016 were identified from the SEER database. The Kaplan-Meier method and Cox regression analysis were used to analyze survival. A subgroup analysis of overall survival (OS) between patients with ADC and SCC was performed after the 1:1 PSM analysis. RESULTS: Of the 33,148 patients, 24,591 (79.19%) had SCC and 8,557 (25.81%) had ADC. In the unmatched cohort, after adjustment in multivariate analysis, patients with ADC had a worse prognosis than patients with SCC (hazard ratio [HR]=1.12; 95% confidence interval [CI]=1.07-1.18; p<0.001). In the propensity matched cohort, Kaplan-Meier analysis and subgroup analysis showed that ADC was associated with a worse prognosis than SCC (p=0.001). An analysis stratified by SEER stage revealed a worse prognosis for patients with ADC patients presenting with a regional disease than patients with SCC (HR=1.24; 95% CI=1.14-1.36 p<0.001), but no statistically significant differences were observed between the localized disease (HR=0.97; 95% CI=0.86-1.10; p=0.664) and distant disease (HR=1.09; 95% CI=0.97-1.22; p=0.162) subgroups. CONCLUSION: The significant differences in survival outcomes between patients with cervical ADC and SCC were only observed in the regional disease subgroup, but not in the localized disease and distant disease subgroups.

CDYL promotes the chemoresistance of small cell lung cancer by regulating H3K27 trimethylation at the CDKN1C promoter.

Rationale: Chemoresistance frequently occurs in patients with small cell lung cancer (SCLC) and leads to a dismal prognosis. However, the mechanisms underlying this process remain largely unclear. Methods: The effects of chromodomain Y-like (CDYL) on chemoresistance in SCLC were determined using Western blotting, immunohistochemistry, cell counting kit-8 assays, flow cytometry, and tumorigenicity experiments, and the underlying mechanisms were investigated using mRNA sequencing, chromatin immunoprecipitation-qPCR, electrophoretic mobility shift assays, co-immunoprecipitation, GST pull down assays, bisulfite sequencing PCR, ELISA, and bioinformatics analyses. Results: CDYL is expressed at high levels in chemoresistant SCLC tissues from patients, and elevated CDYL levels correlate with an advanced clinical stage and a poor prognosis. Furthermore, CDYL expression is significantly upregulated in chemoresistant SCLC cells. Using gain- and loss-of-function methods, we show that CDYL promotes chemoresistance in SCLC in vitro and in vivo. Mechanistically, CDYL promotes SCLC chemoresistance by silencing its downstream mediator cyclin-dependent kinase inhibitor 1C (CDKN1C). Further mechanistic investigations showed that CDYL recruits the enhancer of zeste homolog 2 (EZH2) to regulate trimethylation of lysine 27 in histone 3 (H3K27me3) at the CDKN1C promoter region and promotes transcriptional silencing. Accordingly, the EZH2 inhibitor GSK126 de-represses CDKN1C and decreases CDYL-induced chemoresistance in SCLC. Principal conclusions: Based on these results, the CDYL/EZH2/CDKN1C axis promotes chemoresistance in SCLC, and these markers represent promising therapeutic targets for overcoming chemoresistance in patients with SCLC.

Nomogram for predicting the overall survival of patients with inflammatory breast cancer: A SEER-based study.

OBJECTIVES: Inflammatory breast cancer (IBC) is a rare malignancy that is a unique biologic subtype of breast cancer. A nomogram to predict the overall survival (OS) of IBC patients is lacking. The aim of the study was to construct and validate a nomogram to predict the OS of IBC patients based on the Surveillance, Epidemiology, and End Results (SEER) Program. METHODS: Patients diagnosed with IBC between 2010 and 2016 were selected from the SEER database. Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors. A nomogram was constructed to predict the 1-, 3- and 5-year OS of these patients. The nomogram was internally and externally validated by Harrell's C-indexes and calibration plots. RESULTS: Patients were randomly divided into a training set (n = 2464) and a validation set (n = 1052). The training set was used to establish a nomogram. Multivariate analysis identified that race, age at diagnosis, breast cancer subtype, grade, N stage, M stage, radiation, chemotherapy, and surgery were significant prognostic factors for the OS. The internally and externally validated Harrell's C-indexes were 0.763 and 0.786, respectively. The calibration plots for predictions of the 1-, 3-, and 5-year OS were in excellent agreement. CONCLUSIONS: A nomogram was constructed to predict the OS for IBC patients based on the SEER database and to provide accurate and individualised survival predictions.

A simplified T classification based on the 8th edition of the UICC/AJCC staging system for nasopharyngeal carcinoma.

Objective: This study aimed to establish a simplified T classification based on the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) staging system for nasopharyngeal carcinoma (NPC). Methods: In total, 325 patients with NPC were included in this study. All patients underwent magnetic resonance imaging, and the staging criteria were recorded. These patients were subjected to staging with the 8th edition of the UICC/AJCC staging system for NPC. Results:  Involvement of the oropharynx, nasal cavity, adjacent soft tissue (medial pterygoid, lateral pterygoid, and prevertebral muscles), cervical vertebra, orbit, and hypopharynx were always accompanied by other equivalently or more advanced T-stage classifications. All cases with involvement of the paranasal sinuses showed skull base erosion. The majority of cases with involvement of the pterygoid structure showed skull base erosion. Conclusion: According to the simplification principle, the following new T classification based on the 8th edition of the UICC/AJCC staging system was established: T1, tumor confined to nasopharynx, or beyond the nasopharynx without parapharyngeal involvement; T2, tumor with extension to the parapharyngeal space; T3, tumor with infiltration to bony structures at the skull base; T4, tumor with intracranial extension, involvement of the cranial nerves or parotid gland, and/or extensive soft tissue infiltration beyond the lateral surface of the lateral pterygoid muscle. Validation with a large series of patients is needed.

MiR-335 regulates the chemo-radioresistance of small cell lung cancer cells by targeting PARP-1.

The role of miR-335 in the regulation of chemosensitivity and radiosensitivity of small cell lung cancer (SCLC) was investigated. miR-335 was significantly downregulated in multi-drug-resistant SCLC H69AR and H446DDP cells compared with parental cells as detected by qRT-PCR. Then, we demonstrated the negative correlation between miR-335 expression and the chemo-radiosensitivity of SCLC cells, including cell proliferation, cell clonality and cell apoptosis. In addition, miR-335 overexpression inhibited cell migration in vitro and tumor growth in vivo, whereas inhibition of miR-335 promoted cell migration and tumor growth. The underlying mechanism was further studied. Poly [ADP-ribose] polymerase 1 (PARP-1) was identified as a direct target gene of miR-335 in SCLC by bioinformatics analysis and validated via luciferase reporter assay. Overexpression of miR-335 decreased the expression of PARP-1 mRNA and protein, and NF-κB protein levels were correspondingly downregulated, thus regulating the chemo-radiosensitivity of SCLC. Taken together, these findings indicate that miR-335 may serve as a critical regulator of chemo-radiotherapy resistance in SCLC and a new potential therapeutic target.

KH-type splicing regulatory protein (KHSRP) contributes to tumorigenesis by promoting miR-26a maturation in small cell lung cancer.

KH-type splicing regulatory protein (KHSRP) is a multifunctional RNA-binding protein that has a role in tumorigenesis of small cell lung cancer. The KHSRP protein level was shown to be significantly increased in small cell lung cancer (SCLC) tumor tissues compared with normal lung tissues by immunohistochemical staining. Moreover, KHSRP protein levels were strongly associated with T stage in patients with SCLC. Using in vitro assays, we found that knockdown of the KHSRP gene inhibited cell proliferation and increased cell apoptosis but had no effect on cell migration and invasion. We also showed that down-regulation of the KHSRP gene suppressed tumor growth in vivo. Further analyses indicated that KHSRP was involved in miR-26a maturation and inhibited the expression of PTEN in SCLC cells. Taken together, these findings suggested that KHSRP plays an important role in SCLC tumorigenesis and could be a potential novel therapeutic target for SCLC treatment.

Toward a sustainable utilization of land resources in China: problems, policies, and practices.

China's economy is growing explosively with double-digit rates of growth. However, behind the scenes of this economic miracle, a dark underbelly exists. The potential impact of the unsustainable use of land resources is increasing. Each parcel of land has a stationary geographic location, while its utilization is optional. The re-adjustment and optimization of land use patterns ought to be encouraged. Spatial reconstruction refers to the combination of various land elements, which can promote the rational and efficient allocation of land resources through a four-layer action framework: the development of unused land, urban renewal, ecological reconstruction, and spatial displacement. The feasibility and validity of these methods are illustrated by practical cases in different provinces in China. We thus propose that pursuing sustainable development and building an ecological civilization will be necessary for China in future decades.

[Determination of iridoids and triterpenes in herb of Swertia pseudochinesis by RP-HPLC].

OBJECTIVE: To establish a RP-HPLC method for the determination of swertiamarin, sweroside, gentiopicrin and oleanolic acid in different parts of Swertia pseudochinesis. METHOD: A Zorbax SB-C18 (4.6 mm x 250 mm, 5 microm) column was used with acetonitrile-water (10:90) and methnol-water(86:14) at detection wavelengths of 238 nm, 246 nm, 274 nm and 207 nm for swertiamarin, sweroside, gentiopicrin and oleanolic acid respectively. The flow rate was 1.0 mL x min(-1) and the column temperature was 25 degrees C. RESULT: All of the compounds were based--isolated. The linear ranges of swertiamarin, sweroside, gentiopicrin and oleanolic acid were 0.068 9-0.344 4(r = 0.999 2) , 0.001 1-0.014 0 (r2 = 0. 999 8), 0.001 1-0.013 4 (r2 = 0.999 9) and 0.001 1-0.008 8 mg x mL(-1) (r2 = 0. 999 6), respectively. CONCLUSION: The method is simple and accurate, which can be used for quality control of S. pseudochinesis.