Copper-Catalyzed Multicomponent Coupling Reaction of Primary Aromatic Amines, Rongalite, and Alkynes: Access to N-Aryl Propargylamines.

In this work, a practical copper-catalyzed multicomponent coupling reaction of primary aromatic amines, rongalite, and alkynes for the direct synthesis of N-aryl propargylamines has been developed. This method could overcome the substrate limitation in A3 coupling reactions of primary aromatic amines, formaldehyde, and alkynes. Mechanistic studies revealed that rongalite acts as not only the active C1 unit but also the accelerator to activate the in situ-generated N-arylmethanimines for the coupling reaction with alkynes. This coupling reaction is highly efficient and features a broad substrate scope, as well as utility with scale-up synthesis and converting the corresponding product N-aryl propargylamines into useful heterocyclic skeletons.

Efficacy and safety of immune checkpoint inhibitors with or without radiotherapy in metastatic non-small cell lung cancer: A systematic review and meta-analysis.

Background and purpose: Although immune checkpoint inhibitors (ICIs) have become the first-line treatment for metastatic non-small cell lung cancer (mNSCLC), their efficacy is limited. Meanwhile, recent reports suggest that radiotherapy (RT) can activate the systemic antitumor immune response by increasing the release of antigens from tumor tissues. Therefore, in patients with mNSCLC treated with ICIs, investigations were performed to determine whether the addition of RT improved the outcomes. Furthermore, the adverse events rate was evaluated. Methods and materials: Pubmed, Embase, and Cochrane Library were searched using the keywords "radiotherapy," "immune checkpoint inhibitors," and "non-small cell lung cancer" from the date of inception to 2 May 2022. Randomized controlled trials (RCTs) and nonRCTs (NRCTs) comparing the efficacy and safety of RT combined with ICIs versus ICIs alone in metastatic NSCLC were assessed. The primary outcomes were progression-free survival (PFS) and overall survival (OS), and the secondary outcomes were abscopal response rate (ARR), abscopal control rate (ACR), adverse events rate, and pneumonia rate. The analyses were conducted using the Mantel-Haenszel fixed-effects or random-effects model. The I2 statistic was used to determine heterogeneity, whereas funnel plots and Egger's test were used to assess publication bias. Results: In 15 clinical studies, 713 patients received RT combined with ICIs and 1,275 patients received only ICIs. With regard to PFS and OS, the hazard ratios of RT combined with ICIs were 0.79 (0.70, 0.89) and 0.72 (0.63, 0.82), respectively. In terms of ARR and ACR, the odds ratios (ORs) of RT combined with ICIs were 1.94 (1.19, 3.17) and 1.79 (1.08, 2.97), respectively. Subgroup analyses based on study type (RCT/NRCT), RT target (intracranial/extracranial), number of RT sites (single site), previous ICI resistance (yes/no), and sequencing of RT and ICIs (concurrent/post-RT ICIs) revealed that the addition of RT significantly prolonged PFS and OS. However, subgroup analyses based on radiation dose/fractionation indicated that the addition of hypofractionated RT significantly prolonged OS but not PFS. When grouped according to the level of PD-L1 expression, the addition of RT prolonged PFS only in patients who were PD-L1-negative. Furthermore, subgroup analyses of ARR and ACR signified that the combination therapy resulted in better local control of lesions outside the irradiation field in the hypofractionated RT, extracranial RT, and ICI-naïve subgroups. In terms of adverse events, the addition of RT did not significantly increase the adverse events rate but was associated with a higher pneumonia rate [OR values were 1.24 (0.92, 1.67) and 1.76 (1.12, 2.77), respectively]. Conclusion: Meta-analysis of existing data suggests that the addition of RT can significantly prolong PFS and OS in patients with metastatic NSCLC receiving ICIs. In addition to lesions in the irradiation field, RT can improve the local control rate of lesions outside the irradiation field via immune activation. Combination therapy does not increase the overall risk of adverse reactions, except for pneumonia.

Closing the Infrastructure Gap for Decarbonization: The Case for an Integrated Mineral Supply Agreement.

Significant amounts of feedstock metals will be required to build the infrastructure for the green energy transition. It is currently estimated, however, that the world may be facing an "infrastructure gap" that could prevent us from meeting United Nations Sustainable Development Goal targets. Prior investigations have focused on the extractive aspects of the mining industry to meet these targets and on looming bottlenecks and regional challenges in these upstream market segments. Scant attention has been paid to the downstream processing segments of the raw materials value chain, which also has a high degree of market concentration. Growing international tensions and geopolitical events have resulted in a shift toward "reshoring" and "near-shoring" of mining processing capabilities as regional powers attempt to make metal supply chains more secure. While increasing resilience, these shifts can also dilute the overall effectiveness of the global mining supply network and subsequently hamper the world's ability to close the green energy infrastructure gap. We argue that broadening the remit of the International Renewable Energy Agency (IRENA) to include coordinating these mission-critical metal processing functions can mitigate these issues. The G20 is one potential forum for enabling an integrated mineral processing agreement under the auspices of IRENA.

[Profiles of IgE sensitization to dust mite allergen components in patients with allergic rhinitis and asthma].

Objective:To study the differences and clinical significance of dust mite allergen components in allergic rhinitis（AR） and allergic rhinitis with asthma syndrome（ARAS） patients. Methods:The clinical data of 42 AR patients were retrospectively analyzed and patients were divided into AR and ARAS group. The serum sIgE concentrations of house dust mites were detected by ImmunoCAP system. The allergen components of Der p（Der p 1, Der p 2, Der p 7, Der p 10, Der p 21, Der p 23） and Der f（Der f 1, Der f 2） were analyzed by protein microarray method. The concentration differences of dust mite allergen and its components in AR and ARAS groups were analyzed. Results:Thirty-one cases of AR and 11 cases of ARAS were included. The positive rate of Der p and Der f was 100.0% and 97.6%, respectively. The highest sensitization rates of Der p allergen components were as following: Der p 1（73.8%）, Der f 1（66.7%）, Der f 2（64.3%） and Der p 2（61.9%）. The sensitization rates of Der f 1（100.0% vs 54.8%, P=0.006）, Der p 2（90.9% vs 51.6%, P=0.021） and Der f 2（100.0% vs 51.6%, P=0.004） in ARAS group were significantly higher than those in AR group. The sIgE concentrations of Der p in AR group were significantly lower than those in ARAS group（[7.65±12.15]kUA/L vs[15.20±18.77]kUA/L, P<0.05）. The sIgE concentrations of Der p 1（[5.39±4.61]kUA/L vs[2.03±2.97]kUA/L, P=0.013）, Der p 2（[8.82± 13.58]kUA/L vs[2.78±5.80]kUA/L, P=0.001）, Der p 23（[1.76± 3.88]kUA/L vs[0.28±0.65]kUA/L, P<0.001） was significantly higher in ARAS group than that of AR group. Correlation analysis showed that Der p 1, Der p 2, Der f 1 and Der f 2 had high positive correlation（P<0.01）. The dust mite components sensitization showed a multiple-sensitized mode. 66.7% of the 42 patients were positive for two or more components while it was 58.1% of the AR group and 90.9% of the ARAS group. The sensitization rate of 3 or more components in ARAS group was significantly higher than that in AR group（54.6% vs 29.1%, P<0.05）. Conclusion:The concentration of dust mites allergens in ARAS group is higher than that in AR group. Der p 1, Der f 1, Der p 2 and Der f 2 are the main allergen components with a higher sensitization rate in ARAS group. The concentrations of Der p 1, Der p 2 and Der p 23 were higher in ARAS group. The ARAS group is prone to multi-sensitzed to allergen components.

[Application of proteomics in allergic rhinitis].

The prevalence of allergic rhinitis（AR）is increasing year by year, which seriously affects the quality of life of patients and causes a heavy burden of social diseases. At present, the diagnosis methods focus on clinical manifestations and allergen detection, but there is no accurate detection method for early diagnosis and prognosis of the disease. With the rapid development of proteomics technology and its wide application in disease research, there is a rapid, sensitive and high-throughput technology platform for the diagnosis and treatment of allergic rhinitis, which provides a platform for the early detection, therapeutic targets and prognosis of the disease. This article reviews the progress of AR in proteomics.

ZmERF21 directly regulates hormone signaling and stress-responsive gene expression to influence drought tolerance in maize seedlings.

Drought stress adversely impacts crop development and yield. Maize frequently encounters drought stress during its life cycle. Improvement of drought tolerance is a priority of maize breeding programs. Here, we identified a novel transcription factor encoding gene, APETALA2 (AP2)/Ethylene response factor (ERF), which is tightly associated with drought tolerance in maize seedlings. ZmERF21 is mainly expressed in the root and leaf and it can be highly induced by polyethylene glycol treatment. Genetic analysis showed that the zmerf21 mutant plants displayed a reduced drought tolerance phenotype, accompanied by phenotypical and physiological changes that are commonly observed in drought conditions. Overexpression of ZmERF21 in maize significantly increased the chlorophyll content and activities of antioxidant enzymes under drought conditions. RNA-Seq and DNA affinity purification sequencing analysis further revealed that ZmERF21 may directly regulate the expression of genes related to hormone (ethylene, abscisic acid) and Ca signaling as well as other stress-response genes through binding to the promoters of potential target genes. Our results thereby provided molecular evidence of ZmERF21 is involved in the drought stress response of maize.

[Sensitization pattern of cat and dog dander allergen in 16 426 patients with allergic diseases].

Objective:To explore the sensitization feature of cat and dog dander and time trend in northern region. Methods:During year 2017 to year 2019, subjects with self-reported allergic diseases received skin prick test for cat and dog dander allergen. Skin index（SI） ≥2+ was considered as positive SPT. SI2+ was defined as mild sensitization, SI3+ was defined as moderate sensitization while SI4+ was defined as severe sensitization. The age and gender difference of sensitization rate between cat and dog dander allergen was analyzed. Meanwhile, the trend of cat and dog dander sensitization rate was analyzed. Results:Overall, 16 426 subjects were enrolled in this study. ① The sensitization rate of cat dander was significantly higher than dog dander（11.8% vs 6.0%, P<0.001）. Severe sensitization rate of cat dander was significantly higher than dog dander（5.9% vs 1.7%, P<0.001） while there was no significant difference of mild sensitization rate. ②Sensitization age of cat dander was younger than dog dander（P<0.001）. Sensitization rate of cat and dog dander was higher in subjects ≤18y compared with those >18y（20.2% vs 10.9%, P<0.001; 8.1% vs 5.7%, P<0, 001）. The highest sensitization rate was presented in 13-18y age group（27.3% vs 9.9%, P<0.001）, following by 7-12y age group（26.0% vs 9.2%, P<0.001）. Sensitization rate of cat dander was higher in male than in female（13.7% vs 10.7%, P<0.001） while no gender difference was observed in dog dander sensitization（6.2% vs 5.8%, P=0.411）. ③595 subjects（3.6%） were both sensitized to cat and dog dander while 1733 subjects（10.6%） were sensitized either to cat or dog dander. Single sensitization rate of cat dander was higher than single sensitization rate of dog dander（8.2% vs 2.3%, P<0.001）. There was a positive correlation between the cat and dog dander sensitization rate（r=0.386, P<0.001）. ④During 2017-2019, the sensitization rate of cat dander increased but without significantly statistic difference while dog dander sensitization rate was descending from 7.4% to 4.6% significantly（χ²=38.298, P<0.001）. Conclusion:Cat dander sensitization rate was higher than dog dander with a peak age in adolescence. A trend of rising for cat dander allergy and descending for dog dander allergy was observed during the past three years.

Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.

BACKGROUND: Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. CASE SUMMARY: We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important. CONCLUSION: XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.

Circulating Tumor-Cell-Associated White Blood Cell Clusters in Peripheral Blood Indicate Poor Prognosis in Patients With Hepatocellular Carcinoma.

Aim: Circulating tumor cells (CTC) are a precursor to metastasis in several types of cancer and are occasionally found in the bloodstream in association with immune cells, such as white blood cells (WBCs). CTC-associated WBC (CTC-WBC) clusters can promote CTC appreciation and metastasis, suggesting that patients with CTC-WBC clusters found in the peripheral blood may have a worse prognosis. However, it is unclear whether CTC-WBC clusters are present in the peripheral blood of patients with hepatocellular carcinoma (HCC) and suggest a poor prognosis for HCC. Methods: We collected peripheral blood from 214 patients with HCC from January 2014 to December 2016. CanPatrol™ CTC analysis technology was used to isolate and count CTCs and CTC-WBC clusters in the patients' peripheral blood. Chi-squared analysis was used to calculate the correlation between the CTC-WBC clusters and clinicopathological characteristics. Kaplan-Meier survival analysis and Cox regression analysis were used to assess patient prognosis. Results: We used CanPatrol™ CTC analysis technology to count different types of CTCs and CTC-WBC clusters. The results showed that CTC-WBC clusters and tumor size (P = 0.001), tumor number (P = 0.005), portal vein tumor thrombus (P = 0.026), BCLC stage (P < 0.001), AFP level (P = 0.002), and total number of CTCs (P < 0.001) were statistically related. Cox regression analysis revealed that CTC-WBC clusters are an independent prognostic indicator of DFS (HR = 1.951, 95%CI:1.348-2.824, P < 0.001) and OS (HR = 3.026, 95%CI:1.906-4.802, P < 0.001) in HCC patients. Using Kaplan-Meier analysis, we found that positive CTC-WBC cluster patients had significantly shorter DFS and OS than patients with negative CTC-WBC (P < 0.001 and P < 0.001, respectively). Conclusions: CTC-WBC clusters in the peripheral blood are an independent predictor of DFS and OS, and their presence indicates poor prognosis in patients with HCC.

A case of durvalumab-treated double primary cancers of the colon and lung.

Cases of double primary cancers of the colon and lung are rare, and the treatment regimens are highly individualized. Here, we report a case of double primary cancers of the colon and lung. The patient underwent radical resection for cancer of the left colon (pT4aN0Mx, IIb). Two months later, he sought treatment due to chest pain and painful swelling in his left axilla for one month and was diagnosed with adenocarcinoma of the right lung (cT4N3M1c, stage IVB). At the time before receiving radical resection of the left colon tumor, a chest computed tomography examination showed a space-occupying lesion in the upper lobe of the right lung, but the histological analysis was not performed at that time because abdominal computed tomography examination suggested the presence of incomplete obstruction, and emergency radical resection for colon cancer was conducted. Molecular pathological examination of the lung mass at the most recent admission suggested KRAS mutation and strongly positive programmed cell death-ligand 1 (PD-L1). Considering the patient's pain and compression symptoms, he was given palliative radiotherapy for the lung lesion, followed by sequential durvalumab maintenance therapy, along with a capecitabine plus oxaliplatin (CAPOX) regimen for colon cancer for 3 months. The patient signed informed consent forms for all treatments. After the treatments, the patient achieved partial remission of the lung lesion and complete remission of the lymph node metastases in the neck and left axilla. The only toxic effects were chemotherapy-related grade II bone marrow suppression and grade I radiation-induced lung injury. No recurrence or metastasis was observed during the 6-month follow-up. After a trade-off between the efficacy and toxicity of the treatment regimen of double cancers, this patient was given an individualized treatment regimen-maintenance treatment with the low-toxicity durvalumab for anti-PD-L1 immunotherapy following palliative radiotherapy and evidence-supported 3-month CAPOX chemotherapy after surgery for high-risk stage II colon cancer. The regimen not only avoided possible toxic effects but also achieved a sufficient treatment intensity. We believe that the combined use of radiotherapy, chemotherapy and lowtoxicity immune-targeted drugs has good application prospects in the individualized treatment of patients with multiple cancers.

Colorectal Cancer Immune Infiltrates: Significance in Patient Prognosis and Immunotherapeutic Efficacy.

Colorectal cancer occurrence and progression involve multiple aspects of host immune deficiencies. In these events, immune cells vary their phenotypes and functions over time, thus enabling the immune microenvironment to be "tumor-inhibiting" as well as "tumor-promoting" as a whole. Because of the association of tumoricidal T cell infiltration with favorable survival in cancer patients, the Immunoscore system was established. Critically, the tumoral Immunoscore serves as an indicator of CRC patient prognosis independent of patient TNM stage and suggests that patients with high Immunoscores in their tumors have prolonged survival in general. Accordingly, stratifications according to tumoral Immunoscores provide new insights into CRC in terms of comparing disease severity, forecasting disease progression, and making treatment decisions. An important application of this system will be to shed light on candidate selection in immunotherapy for CRC, because the T cells responsible for determining the Immunoscore serve as responders to immune checkpoint inhibitors. However, the Immunoscore system merely provides a standard procedure for identifying the tumoral infiltration of cytotoxic and memory T cells, while information concerning the survival and function of these cells is still absent. Moreover, other infiltrates, such as dendritic cells, macrophages, and B cells, can still influence CRC prognosis, implying that those might also influence the therapeutic efficacy of immune checkpoint inhibitors. On these bases, this review is designed to introduce the Immunoscore system by presenting its clinical significance and application in CRC.

Mesenchymal Stem Cell-Derived Exosomes: Biological Function and Their Therapeutic Potential in Radiation Damage.

Radiation-induced damage is a common occurrence in cancer patients who undergo radiotherapy. In this setting, radiation-induced damage can be refractory because the regeneration responses of injured tissues or organs are not well stimulated. Mesenchymal stem cells have become ideal candidates for managing radiation-induced damage. Moreover, accumulating evidence suggests that exosomes derived from mesenchymal stem cells have a similar effect on repairing tissue damage mainly because these exosomes carry various bioactive substances, such as miRNAs, proteins and lipids, which can affect immunomodulation, angiogenesis, and cell survival and proliferation. Although the mechanisms by which mesenchymal stem cell-derived exosomes repair radiation damage have not been fully elucidated, we intend to translate their biological features into a radiation damage model and aim to provide new insight into the management of radiation damage.

Performance of LC/MS/MS in Analyzing Multiple Amino Acids and Acylcarnitines in Dried Blood Spot of Very Low Birth Weight, Low Birth Weight, and Normal Weight Neonates.

BACKGROUND: Amino acid (AA) and acylcarnitine (AC) are important biomarkers of protein and fatty acid metabolism. Examining their levels in newborns may reveal multiple inherited metabolic diseases. However, they have rarely been assessed in very low birth weight (VLBW) neonates, low birth weight (LBW) neonates and rarely been compared with normal weight (NW) neonates. The aim of the study was to identify the AA and AC profiles in dried blood spot (DBS) specimens of LBW and VLBW neonates, then compare with NW neonates, and make a contribution to the determination of cutoff values of VLBW and LBW neonates. METHODS: Liquid Chromatography tandem mass spectrometry (LC/MS/MS) is an excellent tool for quantitatively detecting AA and AC profiles. This article verified the precision, accuracy, and linearity of the LC/MS/MS method in AA and AC detection, then analyzed AA and AC profiles in DBS of VLBW, LBW and NW neonates, and compared the difference of AA and AC in the three groups. RESULTS: The results showed that the LC/MS/MS method had wide linear range, satisfied precision and reproducibility in detecting AA and AC in DBS specimens; most AA and AC concentrations significantly correlated with birth weight in DBS samples (p < 0.05). CONCLUSIONS: The results suggested that VLBW and LBW neonates have different metabolic or nutritional status with NW neonates and different AA and AC cutoffs should be defined for them to reduce the risk of false-positive cases.

Classification of circulating tumor cells by epithelial-mesenchymal transition markers.

In cancer, epithelial-mesenchymal transition (EMT) is associated with metastasis. Characterizing EMT phenotypes in circulating tumor cells (CTCs) has been challenging because epithelial marker-based methods have typically been used for the isolation and detection of CTCs from blood samples. The aim of this study was to use the optimized CanPatrol CTC enrichment technique to classify CTCs using EMT markers in different types of cancers. The first step of this technique was to isolate CTCs via a filter-based method; then, an RNA in situ hybridization (RNA-ISH) method based on the branched DNA signal amplification technology was used to classify the CTCs according to EMT markers. Our results indicated that the efficiency of tumor cell recovery with this technique was at least 80%. When compared with the non-optimized method, the new method was more sensitive and more CTCs were detected in the 5-ml blood samples. To further validate the new method, 164 blood samples from patients with liver, nasopharyngeal, breast, colon, gastric cancer, or non-small-cell lung cancer (NSCLC) were collected for CTC isolation and characterization. CTCs were detected in 107 (65%) of 164 blood samples, and three CTC subpopulations were identified using EMT markers, including epithelial CTCs, biophenotypic epithelial/mesenchymal CTCs, and mesenchymal CTCs. Compared with the earlier stages of cancer, mesenchymal CTCs were more commonly found in patients in the metastatic stages of the disease in different types of cancers. Circulating tumor microemboli (CTM) with a mesenchymal phenotype were also detected in the metastatic stages of cancer. Classifying CTCs by EMT markers helps to identify the more aggressive CTC subpopulation and provides useful evidence for determining an appropriate clinical approach. This method is suitable for a broad range of carcinomas.