Effects of temperature and initial pH on the growth of four dominant cyanobacteria species in biological soil crusts.

Biological soil crusts are of great significance for environment health and sustainable development in arid and semi-arid areas. Cyanobacteria, Microcoleus vaginatus, Scytonema sp., Nostoc sp., and Anabaena sp. are the dominant species in microbial community of biological soil crusts worldwide. Considering their broad application prospect, it is meaningful to cultivate them extensively. We examined the effects of temperature (10, 20, 25, 30, 35 ℃) and initial pH (4, 6, 8, 10, 12) on biomass and solution pH towards the four species of cyanobacteria with liquid culture in laboratory. The results showed that the biomass of the four cyanobacterial species grew slowly under 20 ℃, and that all species could grow in 25-35 ℃, with the highest growth rate at 25 and 30 ℃. The optimum culture temperature of different cyanobacterial species was slightly different. The optimum culture temperature was 25-30 ℃ for Scytonema sp. and Nostoc sp., and 30 ℃ for M. vaginatus and Anabaena sp. The four cyanobacterial species had a strong ability to adjust solution pH and proliferate in five different initial pH conditions. The highest maximum biomass and specific growth rate were recorded in the culture environment with initial pH of 4, while the lowest maximum biomass and specific growth rate were observed in initial pH of 12. Our results would provide scientific basis for the propagation of dominant cyanobacteria in biological soil crusts.

Poor Efficacy of Immune Checkpoint Inhibitors Plus Chemotherapy in Lung Cancer Patients with EGFR/ERBB2 Exon 20 Insertion.

BACKGROUND: EGFR and ERBB2 exon 20 insertion (Ex20ins) account for a small fraction of patients with EGFR mutations. The efficacy of immune checkpoint inhibitors (ICIs) for these patients was still controversial. METHODS: This retrospective study enrolled lung cancer patients harboring either EGFR or ERBB2 Ex20ins mutations. All the patients were treated with platinum-based chemotherapy plus ICIs, or platinum-based chemotherapy. The demographic features and clinical outcome of each patient were reviewed and analyzed. RESULTS: When treated with immunochemotherapy, patients with EGFR/ERBB2 Ex20ins mutations (n = 31) had poor PFS compared with those without EGFR mutations (n = 141, 5.0 mon and 11.2 mon, p < 0.001). When compared with those with EGFR classic mutations who received immunotherapy as the salvage therapy (n = 24), these patients with EGFR/ERBB2 Ex20ins mutations had similar PFS (5.0 mon and 4.1 mon, p = 0.625), ORR (37.5% vs. 48.4%), and DCR (70.8% vs. 77.4%). In the patients with EGFR/ERBB2 Ex20ins mutations, the PFS of those treated with chemotherapy (n = 54) and those treated with immunochemotherapy (n = 31) was 6.5 mon vs. 5.0 mon (p = 0.066). In the EGFR Ex20ins subgroup, the PFS of addition of bevacizumab to chemotherapy (n = 20) and chemotherapy alone (n = 16) was 8.8 mon and 5.2 mon, respectively (p = 0.082) or immunochemotherapy (n = 15, 8.8 mon and 5.0 mon, p = 0.097). Similarly, in the ERBB2 subgroup, the combination of bevacizumab and chemotherapy achieved a numerically longer PFS over chemotherapy alone (9.1 mon and 4.5 mon, p = 0.253), but there was no statistical significance. CONCLUSIONS: This study showed that platinum-based chemotherapy plus ICIs had limited efficiency compared to platinum-based chemotherapy for patients with EGFR/ERBB2 Ex20ins. Chemotherapy plus bevacizumab may be a potential scheme for these patients.

Longer interval between neoadjuvant chemoradiotherapy and surgery is associated with improved pathological response, but does not accurately estimate survival in patients with resectable esophageal cancer.

Neoadjuvant chemoradiotherapy (nCRT) has been shown to reduce tumor burden and achieve tumor regression in patients with esophageal cancer (ESC). However, the most beneficial time interval between the administration of nCRT and surgery remains unclear. Therefore, the aim of the present study was to explore the association of the duration of time between nCRT and surgery with the prognosis of patients with ESC. Patients with ESC who received nCRT following surgical resection (n=161) were reviewed and divided into the prolonged time interval group (time interval ≥66 days) and the short time interval group (time interval <66 days), according to the median value. Subsequent analysis revealed that the prolonged time interval group achieved a higher pathological complete response (pCR) rate compared with the short time interval group (49.4 vs. 26.3%; P=0.003). Furthermore, multivariate logistic regression analysis showed that it was possible to independently estimate a higher pCR rate based on a prolonged time interval (odds ratio, 2.131; P=0.042). However, no association between a prolonged time interval and disease-free survival (DFS) was detected using Kaplan-Meier curves (P=0.252) or multivariate Cox regression (P=0.607) analyses. Similarly, no association was identified between a prolonged time interval and overall survival (OS; P=0.946) based on Kaplan-Meier curve analysis, and subsequent multivariate Cox regression analyses showed that the time interval also failed to independently estimate OS (P=0.581). Moreover, female sex (P=0.001) and a radiation dose ≥40 Gy (P=0.039) served as independent factors associated with a higher pCR rate, and the pCR rate was an independent predictor of favorable DFS (P=0.002) and OS (P=0.015) rates. In conclusion, the present study revealed that a prolonged time interval from nCRT to surgery was associated with a higher pCR rate, but it failed to estimate the survival profile of patients with ESC.

Design and Implementation of a Chain-Type Direct Push Drilling Rig for Contaminated Sites.

For sites where volatile organic compounds are present, the direct push method, in combination with other sensors for investigation, is a powerful method. The investigation process is an integrated drilling and sensing process, but the trajectory of the probe carrying the sensor is ambiguous. This paper explores and introduces the application of a chain-type direct push drilling rig by designing and building a chain-type direct push miniature drilling rig. This rig allows for indoor experimental studies of direct push trajectories. The chain-type direct push drilling model is proposed based on the mechanism of chain transmission. The drilling rig provides a steady direct thrust through the chain, which is driven by a hydraulic motor. In addition, the drilling tests and results described prove that the chain could be applied to direct push drilling. The chain-type direct push drilling rig can drill to a depth of 1940 mm in single-pass and up to 20,000 mm in multiple passes. The test results also indicate that it drills a total length of 462.461 mm and stops after 87.545 s of operation. The machine can provide a drilling angle of 0-90° and keep the borehole angle fluctuating within 0.6° with the characteristics of strong adjustability, flexibility, continuity, stability, and low disturbance, which is of great value and significance for studying the drilling trajectory of direct push tools and obtaining more accurate investigation data.

BSA-stabilized silver nanoclusters for efficient photoresponsive colorimetric detection of chromium(VI).

Hexavalent chromium is a highly toxic substance, which will pose a serious threat to human life and health and the entire ecosystem. Therefore, it is crucial to establish a simple and rapid detection method for hexavalent chromium. In this work, we fabricated bovine serum albumin-stabilized silver nanocluster (BSA-Ag13 NC) which exhibited photoresponsive oxidase-like activity, catalyzing the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to the blue oxidized state TMB (oxTMB) in a short time. Interestingly, 8-hydroxyquinoline (8-HQ) can significantly inhibit the color reaction of TMB oxidation while Cr(VI) can interact specifically with 8-HQ to restore this chromogenic reaction. Based on the above facts, a colorimetric sensing system for detecting Cr(VI) was developed. The sensing system shows a wide linear range, and good selectivity, with a low detection limit of 2.32 nM. Moreover, this sensing system could be successfully applied to the detection of Cr(VI) in lake water, tap water, and sewage with satisfactory results.

Self-deposited ultrasmall Ru nanoparticles on carbon nitride with high peroxidase-mimicking activity for the colorimetric detection of alkaline phosphatase.

Carbon nitride (C3N4) nanosheets are known as peroxidase mimics, but the low activity hinders their further application. Embedding active metal nanoparticles onto the C3N4 nanosheets is expected to break this limitation. Herein, highly dispersed ultrasmall Ru nanoparticles are anchored onto the C3N4 through spontaneous redox reaction. The as-obtained Ru-C3N4 exhibits excellent peroxidase-like activity, which can be further regulated by adjusting the loading of Ru nanoparticles on C3N4. Using Ru-C3N4 as a mimetic peroxidase, a colorimetric sensing method for alkaline phosphatase (ALP) detection is developed based on the inhibitory effect of ascorbic acid produced by hydrolysis of ALP and l-ascorbic acid 2-phosphate (AAP) on the color development reaction of TMB catalyzed by Ru-C3N4. The sensor exhibits wide linear range and low detection limit for the ALP sensing. Finally, the assay is applied to ALP detection in human serum and satisfactory results are obtained, which provides a promising strategy for colorimetric sensing of ALP.

In situ formed silicon-based nanoparticles enabled highly efficient dual-mode biosensing of chlorpyrifos.

Chlorpyrifos is widely used in agriculture but their residue is a threat to food safety and human health. The study aims to find an accurate and sensitive detection method for chlorpyrifos. Silicon-based nanoparticles (Si BNPs) with fluorescent and colorimetric dual signals are in-situ formed through the alkaline phosphatase (ALP) triggered reaction. The dual-mode sensor for chlorpyrifos can be facilely fabricated because the existence of chlorpyrifos would inhibit the activity of ALP and thus affect the production of Si BNPs. Under optimal condition, the fluorescence intensity and absorption intensity linearly correlate with the logarithm of chlorpyrifos concentration over wide range of 0.5-5000 ng/mL and 1-5000 ng/mL with low detection limit by the two detection modes, respectively. The dual-mode sensor is further applied to the detection of spiked chlorpyrifos in practical samples with satisfactory recovery, rendering it as a promising candidate to current methodologies for the simple and accurate detection of chlorpyrifos.

Comparison of clinicopathological features and survival analysis between esophageal neuroendocrine carcinoma and esophageal squamous cell carcinoma based on the SEER database, alongside nomogram analysis for esophageal neuroendocrine carcinoma.

Background: Esophageal neuroendocrine carcinoma (ENEC) is a rare subtype of esophageal cancer (EC). It presents distinctive clinical and pathological features in comparison to esophageal squamous cell carcinoma (ESCC). To better elucidate the disparities between the two and establish a prognostic prediction model for ENEC, we conducted this study. Methods: Data of ENEC and ESCC patients (1975 to 2016) were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Patients with a confirmed pathological diagnosis of ENEC and ESCC were enrolled in the study. The Chi-square test was employed to compare categorical variables, and the median survival time was analyzed using the Kaplan-Meier curve. Training and validation groups were randomly assigned at a ratio of 7:3. Factors with a significance level of <0.05 in the multifactor regression model as well as age were integrated into the nomogram model. Concordance index (C-index), calibration curves, and decision curve analyses (DCA) were generated for model validation. Results: This study encompassed a total of 737 ENEC patients and 29,420 ESCC. Compared to ESCC, ENEC patients had higher probability of liver metastasis (13.8% vs. 1.9%, P<0.001), poor differentiation (68.0% vs. 37.1%, P<0.001), and late SEER stage (52.8% vs. 26.9%, P<0.001). Patients who received either surgery, radiotherapy (RT), or chemotherapy had a significantly longer disease-specific survival (DSS) and overall survival (OS) (all P<0.001). After propensity score matching (PSM), ENEC patients were associated with shorter DSS (7.0 months vs. not reached, P<0.0001) and OS (7.0 vs. 12.0 months, P<0.0001) compared to ESCC. Race, SEER stage, surgery, RT, and chemotherapy were identified as predictors of DSS and were incorporated into the nomogram model together with age. The validation of the model using C-index (0.751 and 0.706, respectively) and calibration curves reflected the better discrimination power of the model. In addition, DCA supported the favorable potential clinical effect of the predictive model. Lastly, a risk classification based on the nomogram also verified the reliability of the model. Conclusions: ENEC and ESCC exhibit distinct clinicopathological features. Patients with ENEC experience significantly poorer survival outcomes compared to those with ESCC. Surgical intervention, radiation therapy, and chemotherapy significantly improve OS and DSS for ENEC patients. The nomogram prediction model, constructed based on age, race, stage, and treatment regimen, demonstrates accurate and effective predictive capabilities for prognostic factors in ENEC patients.

Neoadjuvant immunotherapy for resectable esophageal cancer: A review.

Esophageal cancer (EC) is one of the most common cancers worldwide, especially in China. Despite therapeutic advances, the 5-year survival rate of EC is still dismal. For patients with resectable disease, neoadjuvant chemoradiotherapy (nCRT) in combination with esophagectomy is the mainstay of treatment. However, the pathological complete response (pCR) rate to nCRT of 29.2% to 43.2% is not satisfactory, and approximately half of the patients will develop either a locoregional recurrence or distant metastasis. It is, therefore, necessary to explore novel and effective treatment strategies to improve the clinical efficacy of treatment. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has significantly changed the treatment paradigm for a wide variety of advanced cancers, including EC. More recently, increasing clinical evidence has demonstrated that neoadjuvant immunotherapy can potentially improve the survival of patients with resectable cancers. Furthermore, accumulating findings support the idea that chemotherapy and/or radiotherapy can activate the immune system through a variety of mechanisms, so a combination of chemotherapy and/or radiotherapy with immunotherapy can have a synergistic antitumor effect. Therefore, it is reasonable to evaluate the role of neoadjuvant immunotherapy for patients with surgically resectable EC. In this review, we discuss the rationale for neoadjuvant immunotherapy in patients with EC, summarize the current results of utilizing this strategy, review the planned and ongoing studies, and highlight the challenges and future research needs.

Brain parenchymal and leptomeningeal metastasis in non-small cell lung cancer.

Patients with advanced non-small cell lung cancer (NSCLC) are prone to brain metastases (BM), which essentially include brain parenchymal metastases (PM) and leptomeningeal metastases (LM). We conducted a retrospective study to comprehensively assess the clinical characteristics and risk factors of patients with advanced NSCLC who develop PM and LM. Patients with advanced NSCLC were enrolled. These patients were then divided into three groups for analysis: patients without BM (No-BM), patients with PM and patients with LM. Data on clinical characteristics of each patient at the time of diagnosis advanced NSCLC were extracted and analyzed. In addition, prediction models were developed and evaluated for PM and LM. A total of 592 patients were enrolled in the study. BM was present in 287 patients (48.5%). Among them, 185 and 102 patients had PM or LM. Patients with LM had a higher proportion of EGFR exon 21point mutations (L858R) compared to patients with No-BM and PM (p < 0.0001). The median time to the onset of PM and LM from the diagnosis of advanced NSCLC was 0 months and 8.3 months, respectively. Patients with LM had a statistically shorter over survival (OS) compared to either No-BM or PM patients (p < 0.0001). Based on independent predictive variables, two nomogram models were constructed to predict the development of PM and LM in advanced NSCLC patients, and the C-indexes were 0.656 and 0.767, respectively. Although both considered as BM, PM and LM had different clinical characteristics. And the nomogram showed good performance in predicting LM development, but not PM.

Dramatic response to neoadjuvant savolitinib in marginally resectable lung adenocarcinoma with MET exon 14 skipping mutation: A case report and literature review.

Mesenchymal-epithelial transition (MET) exon 14 skipping mutation (METex14) is a low-frequency driver mutation in metastatic non-small cell lung cancer (NSCLC) (3%-4%) and is associated with a poor prognosis. With the advent of selective MET inhibitors such as capmatinib, tepotinib, and savolitinib, the outcome for these patients was significantly improved. Here, we report a 76-year-old male patient with marginally resectable stage IIIB lung adenocarcinoma harboring METex14 who was successfully treated with savolitinib for neoadjuvant therapy. An 82% shrinkage of the primary tumor was observed, and only 5% of the tumor was viable by pathology in the following radical surgery. A dozen of studies tested the efficiency of neoadjuvant immunotherapy or immunochemotherapy, but for NSCLC with driver mutations, neoadjuvant targeted therapy might be more appropriate. We advocated the neoadjuvant MET TKI treatment for NSCLC.

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.

Background: Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established. Methods: Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened. The samples of pre-osimertinib and osimertinib-resistance were all detected by next-generation sequencing (NGS) panels. Statistical analyses were carried out using SPSS 23.0 software. Survival analyses were performed using the Kaplan-Meier method and compared using a log-rank test between groups. Results: Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA). A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%). A total of 15 patients received subsequent treatments, with mPFS of 7.3 months (95% CI 5.0 months -NA). Among them, 7 patients with EGFR C797 S or/and MET amplification received subsequent second-line targeted therapy, achieving mPFS of 7.3 months (95% CI 4.5 months -NA). Of note, 3 patients received immunotherapy as second- or third-line treatment after osimertinib resistance, achieving median clinical benefit of 37.3 months. Conclusions: MET amplification and C797S mutation are main resistance mechanisms, which could be targeted by crizotinib and gefitinib, respectively. More than 50% patients could receive subsequent anticancer targetable therapies after first-line osimertinib resistance. Immunotherapy may also be an acceptable choice after osimertinib resistance.

Identification pyroptosis-related gene signature to predict prognosis and associated regulation axis in colon cancer.

Background: Pyroptosis is an important component of the tumor microenvironment and associated with the occurrence and progression of cancer. As the expression of pyroptosis-related genes and its impact on the prognosis of colon cancer (CC) remains unclear, we constructed and validated a pyroptosis-related genes signature to predict the prognosis of patients with CC. Methods: Microarray datasets and the follow-up clinical information of CC patients were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Candidate genes were screened out for further analysis. Various methods were combined to construct a robust pyroptosis-related genes signature for predicting the prognosis of patients with CC. Based on the gene signature and clinical features, a decision tree and nomogram were developed to improve risk stratification and quantify risk assessment for individual patients. Results: The pyroptosis-related genes signature successfully discriminated CC patients with high-risk in the training cohorts. The prognostic value of this signature was further confirmed in independent validation cohort. Multivariable Cox regression and stratified survival analysis revealed this signature was an independent prognostic factor for CC patients. The decision tree identified risk subgroups powerfully, and the nomogram incorporating the gene signature and clinical risk factors performed well in the calibration plots. Conclusion: Pyroptosis-related genes signature was an independent prognostic factor, and can be used to predict the prognosis of patients with CC.

Zoledronic acid enhances the efficacy of immunotherapy in non-small cell lung cancer.

BACKGROUND: Only a minority of patients benefit from immune checkpoint inhibitors (ICIs) therapy, although they have become the standard of care for patients of non-small cell lung cancer (NSCLC) without driver mutations. Zoledronic acid (ZA) enhances the anti-tumor efficacy of endocrine therapy, chemotherapy and targeted therapy. However, little is known about the effect of ZA on the clinical outcomes of ICIs, or its possible mechanisms. METHODS: Patients with advanced NSCLC treated with ICIs alone or in combination with ZA were recruited. The clinical efficacy was compared between the two cohorts. We used an LL2 mouse model to confirm the combined effects of ZA with ICIs. Immune cell populations and cytokines in the tumor microenvironment and circulation were assayed and analyzed. RESULTS: The median PFS for the patients treated with and without ZA was 5.4 months and 2.8 months, respectively. The combination group showed a higher rate of disease control. In the mouse LL2 lung cancer model, tumor growth was significantly inhibited in mice treated with the combination treatment. More CD8 + IFN-γ + T cells and γδ T cells, and fewer CD11b cells were found in the circulation and TILs in the combination group. Anti-tumor cytokines INF-γ and IL-18 were elevated in the sera after combination therapy. CONCLUSION: Our study provides preclinical and clinical evidence to show that ZA could improve the therapeutic effects of ICIs. This effect was likely related to the activation of immune cells and elevated cytokines, which provided a new way to improve the effect of ICIs therapy, and is worth exploring further.

Osteogenesis Performance of Boronized Ti6Al4V/HA Composites Prepared by Microwave Sintering: In Vitro and In Vivo Studies.

The boronized Ti6Al4V/HA composite is deemed to be an important biomaterial because of its potential remarkable mechanical and biological properties. This paper reports the osteogenesis performance of the boronized Ti6Al4V/HA composite, which was prepared by microwave sintering of powders of Ti6Al4V, hydroxyapatite (HA), and TiB2 in high-purity Ar gas at 1050 °C for 30 min, as dental implant based on both cell experiments in vitro and animal experiments in vivo. The comparison between the boronized Ti6Al4V/HA composite and Ti, Ti6Al4V, and boronized Ti6Al4V in the terms of adhesion, proliferation, alkaline phosphate (ALP) activity, and mineralization of MG-63 cells on their surfaces confirmed that the composite exhibited the best inductive osteogenesis potential. It exerted a more significant effect on promoting the early osteogenic differentiation of osteoblasts and exhibited the maximum optical density (OD) value in the MTT assay and the highest levels of ALP activity and mineralization ability, primarily ascribed to its bioactive HA component, porous structure, and relatively rough micro-morphology. The in vivo study in rabbits based on the micro-computed tomography (micro-CT) analysis, histological and histomorphometric evaluation, and biomechanical testing further confirmed that the boronized Ti6Al4V/HA composite had the highest new bone formation potential and the best osseointegration property after implantation for up to 12 weeks, mainly revealed by the measured values of bone volume fraction, bone implant contact, and maximum push-out force which, for example, reached 48.64%, 61%, and 150.3 ± 6.07 N at the 12th week. Owing to these inspiring features, it can serve as a highly promising dental implant.

Ultrathin porous Pd metallene as highly efficient oxidase mimics for colorimetric analysis.

Pd-based nanomaterials have shown great promise as promising mimic enzymes, but traditional catalysts can only expose only part of the active sites, resulting in low atomic utilization. Herein, we demonstrated that ultrathin Pd metallene with abundant accessible active sites could be served as highly efficient oxidase mimics. Due to their ultrathin porous structure, nearly all the Pd atoms of the Pd metallenezymes could be efficiently utilized during the catalytic process. By using the 3,3',5,5'-tetramethyl benzidine (TMB) as a typical chromogenic substrate, the Pd metallenezymes with excellent oxidase-like activity are successfully applied for some colorimetric-based analysis applications. Benefiting from the sensitive Pd metallene/TMB detection system, the TAC of some commercial beverages and vitamin C chewable pieces are proved to meet the description and the activity of alkaline phosphatase (ALP) was successfully detected in 0-20 U/L range, achieving a lowest detect limit of 0.41 U/L. This work provides not only one kind of novel nanozymes, but also an effective strategy to maximize the atom utilization as enzyme mimics.

Immune checkpoint inhibitor (ICI)-based treatment beyond progression with prior immunotherapy in patients with stage IV non-small cell lung cancer: a retrospective study.

Background: Although immune checkpoint inhibitors (ICIs) provide unprecedented survival improvement for patients with advanced non-small cell lung cancer (NSCLC), disease progression inevitably occurs. After ICIs failure, limited data exist on whether ICI-based treatment beyond progression (TBP) may be beneficial to advanced NSCLC. This retrospective study aimed to evaluate the efficacy of this treatment approach in advanced NSCLC and identify potential beneficial factors. Methods: Patients with stage IV NSCLC who received ICI-based treatment after the failure of prior PD-1/PD-L1 inhibitor treatments (monotherapy or combination therapy) between January 2016 and July 2020 were enrolled. Their clinical characteristics and treatment procedures were collected, and the follow-up would be performed. Results: A total of 204 patients were included. All patients had disease progression after prior immunotherapy, with 49.5% (101/204) of patients presenting with new metastasis lesions and the rest 50.5% (103/204) of patients' progression on originate lesions. Within the entire cohort, the median progression-free survival (PFS) and median overall survival (OS) of ICI-based TBP with prior immunotherapy were 5.0 months (95% CI: 4.5-5.5 months) and 15.7 months (95% CI: 14.7-16.8 months), respectively. The objective response rate (ORR) and disease control rate (DCR) were 9.3% and 74.0%, respectively. According to the multivariate analysis, ICI-based combination therapy [PFS: hazard ratio (HR), 0.48, 95% confidence interval (CI): 0.28-0.84, P=0.011] (OS: HR, 0.44, 95% CI: 0.23-0.85, P=0.014), not having targetable gene alterations (PFS: HR, 0.56, 95% CI: 0.40-0.79, P=0.001) (OS: HR, 0.57, 95% CI: 0.37-0.87, P=0.009), and good response to prior immunotherapy (PFS: HR, 0.36, 95% CI: 0.24-0.53, P<0.0001) (OS: HR, 0.31, 95% CI: 0.19-0.52, P<0.0001) were independently associated with improved PFS and OS. Moreover, disease progression due to appearances of new metastasis (OS: HR, 0.56, 95% CI: 0.37-0.84, P=0.005) was only associated with better OS. Conclusions: While the ORR in patients with advanced NSCLC receiving ICI-based TBP with prior immunotherapy was limited, the DCR was relatively high in our study which is encouraging. ICI-based treatment strategy may be a reasonable option for patients who progressed from prior immunotherapy. Further prospective studies on larger sample size are warranted.

Identifying tumor antigens and immuno-subtyping in colon adenocarcinoma to facilitate the development of mRNA vaccine.

The mRNA vaccine has provided a promising approach for cancer immunotherapies. However, only a few mRNA vaccines have been developed against colon adenocarcinoma (COAD). Screening potential targets for mRNA vaccines from numerous candidates is a substantial challenge. Considering the tumor heterogeneity, only a subset of patients might respond to vaccinations. This study was conducted to identify potential candidates for mRNA vaccines, and distinguish appropriate subgroups of COAD patients for vaccination. A total of five tumor antigens with prognostic values were identified, including IGF2BP3, DPCR1, HOXD10, TRIM7, and ZIC5. The COAD patients were stratified into five immune subtypes (IS1-IS5), according to consensus clustering analysis. Higher tumor mutation burden (TMB) was observed in IS1 and IS5 subtypes. The IS1 and IS5 subtypes have shown the baseline of immune-hot tumor microenvironment, while other subtypes displayed immune desert phenotype. Distinct expressions of immune checkpoints (ICPs)-related genes and immunogenic cell death (ICD) modulators were observed among five immune subtypes. Finally, the immune landscape was conducted to narrow the immune components for better personalized mRNA-based vaccination. The IFIT3, PARP9, TAP1, STAT1, and OAS2 were confirmed as hub genes, and COAD patients with higher expressions of these genes might be more appropriate for mRNA vaccination. In conclusion, the IGF2BP3, DPCR1, HOXD10, TRIM7, and ZIC5 were identified as potential candidates for developing mRNA vaccines against COAD, and patients in IS1 and IS5 subtypes might respond better to mRNA vaccination.

Immunotherapy for a POLE Mutation Advanced Non-Small-Cell Lung Cancer Patient.

Currently, the predictive role of POLE mutations for immunotherapy is under intense investigation. The POLE gene encodes one of the four subunits of DNA polymerase important for DNA replication and repair. POLE mutations are related to other favorable predicative factors such as high expression of PD-L1, high TMB, and infiltration of CD8+ cells in the tumor microenvironment. No formal clinical trials studied the efficacy of immunotherapy in lung patients harboring POLE mutation, and only few cases were mentioned in the literature. Moreover, lung cancer patients are prone to brain metastasis, which is notorious for the unresponsiveness to chemotherapy. The efficacy of immunotherapy for brain metastasis is still controversial. Here, we described a case of a POLEmt non-small-cell lung cancer (NSCLC) patient with brain metastasis who was treated with immunotherapy. His brain lesions disappeared after treatment. Our report strongly supported the benefit of immune-combined therapy for advanced NSCLC patients with POLE mutation, even with brain metastasis.