Impacts of the COVID-19 pandemic on pediatric and adult patients with hemophilia.

BACKGROUND: The coronavirus disease 2019 (COVID-19)-associated mortality rate of hemophilia patients is similar to that of the general population, but the risk of hospitalization and bleeding is higher. However, the specific impact of this infection on hemophilia patients remains unknown. We aimed to investigate the impact of the pandemic on the infection susceptibility, symptoms, drug use, and social intercourse of patients with hemophilia. METHODS: A survey was distributed to 265 patients with hemophilia (185 adults and 80 children) in the Fujian hemophilia therapeutic center (Fuzhou City, China) during the COVID-19 pandemic, and data were collected between January 2022 and January 2023. The impacts of SARS-CoV-2 infection on hemophilia symptoms, drug use, and social intercourse of these patients were investigated, and the association between the recovery time and disease conditions was explored in infected patients. RESULTS: During the pandemic, compared with adult patients, pediatric patients had significantly reduced social intercourse and outdoor activities because of the fear of contracting COVID-19 (85.0% vs. 66.5%). Bleeding events were also significantly fewer in children than in adults (61.2% vs. 81.1%). The SARS-CoV-2 infection rate was significantly higher in patients living in urban areas than in those living in rural areas (74.3% vs. 53.6%). The duration of symptomatic recovery from COVID-19 was not significantly associated with hemorrhage, type and classification of hemophilia, presence of inhibitors, complications, and vaccination status. CONCLUSION: Having COVID-19 infection did not significantly influence the symptoms and treatments in patients with hemophilia. Pediatric patients had significantly fewer bleeding events than adults.

Chronic myeloid leukemia during osimertinib treatment in a non-small cell lung cancer patient: A case report.

Case summary: A 45-year-old man presented with a 4.0cm × 4.0cm mass in right lower lobe and a right lower lobectomy was performed. The pathological diagnosis from the right lower lobe mass was adenocarcinoma with an EGFR mutation in exon 21 (L858R). He chose osimertinib as postoperative adjuvant treatment. Eight months after the administration of osimertinib, leukocytosis was detected and we diagnosed the patient with chronic myeloid leukemia (CML). After the diagnosis was made, the patient started the treatment of flumatinib immediately, and treatment of osimertinib continued. After one month treatment, leukocytosis was completely relived. The patient was receiving treatment of osimertinib and flumatinib simultaneously with both lung cancer and leukemia well-controlled, and the side effects were tolerable. Conclusion: Hemogram of non-small cell lung cancer (NSCLC) patients should be carefully monitored during EGFR-TKIs treatment. While there is a potential association between EGFR-TKIs and the development of hematologic abnormalities such as CML, more evidence is needed to clarify whether EGFR-TKIs have a leukemogenic effect. For patients with CML during EGFR-TKIs treatment, osimertinib combined with flumatinib may be an effective treatment modalities and the side effects can be tolerated.

Pretreatment pulmonary tumor necrosis is a promising prognostic imaging biomarker for first-line anti-PD-1/PD-L1 therapy in advanced lung squamous cell carcinoma: a multi-institutional, propensity score-matching cohort analysis.

Background: Tumor necrosis (TN) is a common feature in lung squamous cell carcinoma (LSCC), which could provide useful predictive and prognostic information. Objectives: This study aimed to investigate the effect of pretreatment pulmonary TN (PTN) on the prognosis of first-line anti-programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) inhibitor in advanced LSCC. Design: We conducted a retrospective study to analyze the association between the presence of PTN and clinical outcomes in advanced LSCC patients treated with anti-PD-1/PD-L1 inhibitors. Methods: Data from 240 eligible patients were collected from 27 hospitals across China between 2016 and 2020. The presence of PTN was assessed using contrast-enhanced chest computed tomography (CT) imaging at baseline. We utilized the Cox proportional-hazards regression model to analyze the association between PTN and clinical outcomes. In addition, to account for potential confounding factors and ensure comparability between groups, we employed propensity score-matching (PSM) analysis. Results: In the overall patient cohort, the presence of PTN was 39.6%. The median follow-up duration was 20.3 months. The positive PTN group exhibited a notably inferior median progression-free survival (PFS; 6.5 months vs 8.6 months, p = 0.012) compared to the negative PTN group. Within the Cox proportional-hazards regression model, PTN emerged as an independent predictor of unfavorable PFS (hazard ratio (HR) = 1.354, 95% confidence interval (CI): 1.002-1.830, p = 0.049). After PSM, the median PFS for the positive PTN group (6.5 months vs 8.0 months, p = 0.027) remained worse than that of the negative PTN group. Multivariate analyses also further underscored that the presence of PTN independently posed a risk for shorter PFS (HR = 1.494, 95% CI: 1.056-2.112, p = 0.023). However, no statistically significant difference in overall survival was observed between the two groups. Conclusion: Our study suggests that the presence of PTN on baseline contrast-enhanced chest CT is a potential negative prognostic imaging biomarker for the outcome of anti-PD-1/PD-L1 inhibitor therapy in advanced LSCC. Further studies are warranted to validate these findings and explore the underlying mechanisms.

Predicting anti-PD-1/PD-L1 inhibitor treatment outcomes: pulmonary tumor necrosis in lung squamous cell carcinoma Our study focused on lung squamous cell carcinoma (LSCC) patients receiving first-line anti-PD-1/PD-L1 therapy. We explored the impact of a feature called pretreatment pulmonary tumor necrosis (PTN) on their prognosis. PTN was identified in 39.6% of patients using baseline chest CT scans. Results revealed that patients with PTN had a shorter time without disease progression (median PFS of 6.5 months compared to 8.6 months) and a higher risk of unfavorable outcomes. This suggests that PTN may serve as a negative prognostic imaging marker for anti-PD-1/PD-L1 therapy in advanced LSCC. Further research is needed to confirm and understand these findings better.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Emerging delivery strategy for oncolytic virotherapy.

Oncolytic virotherapy represents a promising approach in cancer immunotherapy. The primary delivery method for oncolytic viruses (OVs) is intratumoral injection, which apparently limits their clinical application. For patients with advanced cancer with disseminated metastasis, systemic administration is considered the optimal approach. However, the direct delivery of naked viruses through intravenous injection presents challenges, including rapid clearance by the immune system, inadequate accumulation in tumors, and significant side effects. Consequently, the development of drug delivery strategies has led to the emergence of various bio-materials serving as viral vectors, thereby improving the anti-tumor efficacy of oncolytic virotherapy. This review provides an overview of innovative strategies for delivering OVs, with a focus on nanoparticle-based or cell-based delivery systems. Recent pre-clinical and clinical studies are examined to highlight the enhanced efficacy of systemic delivery using these novel platforms. In addition, prevalent challenges in current research are briefly discussed, and potential solutions are proposed.

T-Cell Posttransplant Lymphoproliferative Disorders After Allogeneic Hematopoietic Stem Cell Transplantation: Case Series and Systemic Review.

Posttransplant lymphoproliferative disorder (PTLD) is a rare lymphoid and/or plasmocytic proliferation that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We aimed to identify the pathologic features and clinical outcomes of T-cell PTLD, an extremely rare subtype of PTLD, after allo-HSCT. In this study, six allo-HSCT recipients with T-cell PTLD from five transplant centers in China were enrolled. All the T-cell PTLD were donor-derived, and three patients were with monomorphic and three with polymorphic types, respectively. All patients received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-based chemotherapy. Five patients achieved complete response (CR), and one experienced progressive disease (PD). The median time from HSCT to onset was 4 (range: 0.6-72) months, analyzed in combination with the other 16 patients with T-cell PTLD identified from previous reports. About 56.3% of the T-cell samples (9/16) were positive for in situ hybridization with an Epstein-Barr virus (EBV)-encoded small nuclear early region (EBER ISH). CHOP-based chemotherapy might be the optimal strategy for patients who showed no response to empiric therapy with a CR rate of 87.5%. In conclusion, our study observed that T-cell PTLD has distinct clinical manifestations and morphological features, which characterized by less relation to EBV, later occurrence, and poorer prognosis when compared with B-cell PTLD.

Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

[Afatinib Treatment for Advanced Mixed Non-small Cell Lung Cancer 
with CRISPLD2-NRG1 Fusion: A Case Report and Literature Review].

Lung cancer is the most common malignant disease and the leading cause of cancer death in China. Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancers, and the probability of NSCLC gene mutations is high, with a wide variety of types. With the development of next-generation sequencing (NGS) detection technology, more and more patients with rare fusion gene mutations are detected. Neuregulin 1 (NRG1) gene is a rare oncogenic driver that can lead to activation of human epidermal growth factor receptor 3 (Her3/ErbB3) mediated pathway, resulting in tumor formation. In this article, we reported a case of mixed NSCLC with CRISPLD2-NRG1 fusion detected by RNA-based NGS, who responsed to Afatinib well after 1 month of treatment, and magnetic resonance imaging (MRI) showed shrinkage of intracranial lesions. Meanwhile, we also compiled previously reported NSCLC patients with NRG1 rare gene fusion mutation, in order to provide effective references for clinical diagnosis and treatment.
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Zuberitamab, an innovative anti-CD20 monoclonal antibody, for patients with primary immune thrombocytopenia in China: a randomized, double-blind, placebo-controlled, phase 2 study.

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease, and rituximab (RTX) induces long-term effect as second-line treatments. Zuberitamab is an innovative anti-CD20 monoclonal antibody, which was first developed in China and launched in diffuse large B lymphoma. This study aimed to investigate the safety, efficacy, and anticipated therapeutic dose of zuberitamab in Chinese ITP patients. Methods: This randomised, double-blind, placebo-controlled, phase 2 study was conducted at 26 hospitals in China. Eligible patients were aged 18-70 years, had primary immune thrombocytopenia for more than 6 months, and did not respond or relapsed after previous treatment and had a pre-treatment platelet count of <30 × 109/L. Patients randomly received zuberitamab in a dose escalation (100/300/600 mg) or placebo once-weekly for 4 weeks and followed up to 24 weeks. The primary endpoint is the proportion of patients with a platelet count ≥50 × 109/L at week 8. Secondary endpoints include the proportion of patients with platelet counts ≥50 × 109/L or ≥100 × 109/L at least once within week 12/24, the proportion of patients experiencing platelets increased twice more than baseline as well as ≥30 × 109/L at least once during the treatment. Adverse events, pharmacokinetic, B cell depletion and immunogenicity were also assessed. This study is registered with https://www.chictr.org.cn/as ChiCTR2100050513. Findings: From October 2021 to March 2023, 50 patients were screened for eligibility, of whom 32 patients were enrolled and randomly assigned to placebo (n = 4), zuberitamab 100 mg (n = 10), 300 mg (n = 8) and 600 mg (n = 10) groups. The primary endpoint (PLT ≥50 × 109/L at week 8) was achieved by 40% of patients in the 100 mg group, while none in the other groups. Within 12 weeks, the proportions of patients in each treatment group achieving at least one instance of platelet count ≥50 × 109/L or ≥100 × 109/L or an increase twice more than baseline as well as ≥30 × 109/L were (70%, 38%, 50%), (60%, 13%, 30%), and (80%, 50%, 70%) in zuberitamab 100/300/600 mg groups, respectively. By week 24, the proportions of patients achieving these secondary endpoints remained relatively stable or showed a mild increase of around 10%. The anticipated therapeutic dose of zuberitamab was 100 mg. The plasma concentration of zuberitamab showed an increasing trend with dose (100 mg-600 mg) and linear pharmacokinetic behavior. CD19+ B cells and CD20+ B lymphocytes rapidly declined to 0% within one week and consistently maintained reduced levels throughout the entire treatment phase in three groups. Adverse events occurred in all patients with most of them were mild to moderate, no severe infections occurred. A slight decrease in immunoglobulins was observed in the 600 mg group, but gradually recovered at week 20. Three patients (2 in 100 mg and 1 in 600 mg group) were tested positive for anti-zuberitamab antibodies. We also observed that women, disease duration <12 months, and MAIPA + patients may have higher response rates. Interpretation: This study preliminarily confirmed that 100 mg zuberitamab was safe and effective in treating ITP and was recommended to support further investigation. Funding: National Natural Science Foundation of China and Zhejiang Bioray Biopharmaceutical Co. Ltd.

Adaptation mechanism of three Impatiens species to different habitats based on stem morphology, lignin and MYB4 gene.

BACKGROUND: Impatiens is an important genus with rich species of garden plants, and its distribution is extremely extensive, which is reflected in its diverse ecological environment. However, the specific mechanisms of Impatiens' adaptation to various environments and the mechanism related to lignin remain unclear. RESULTS: Three representative Impatiens species,Impatiens chlorosepala (wet, low degree of lignification), Impatiens uliginosa (aquatic, moderate degree of lignification) and Impatiens rubrostriata (terrestrial, high degree of lignification), were selected and analyzed for their anatomical structures, lignin content and composition, and lignin-related gene expression. There are significant differences in anatomical parameters among the stems of three Impatiens species, and the anatomical structure is consistent with the determination results of lignin content. Furthermore, the thickness of the xylem and cell walls, as well as the ratio of cell wall thickness to stem diameter have a strong correlation with lignin content. The anatomical structure and degree of lignification in Impatiens can be attributed to the plant's growth environment, morphology, and growth rate. Our analysis of lignin-related genes revealed a negative correlation between the MYB4 gene and lignin content. The MYB4 gene may control the lignin synthesis in Impatiens by controlling the structural genes involved in the lignin synthesis pathway, such as HCT, C3H, and COMT. Nonetheless, the regulation pathway differs between species of Impatiens. CONCLUSIONS: This study demonstrated consistency between the stem anatomy of Impatiens and the results obtained from lignin content and composition analyses. It is speculated that MYB4 negatively regulates the lignin synthesis in the stems of three Impatiens species by regulating the expression of structural genes, and its regulation mechanism appears to vary across different Impatiens species. This study analyses the variations among different Impatiens plants in diverse habitats, and can guide further molecular investigations of lignin biosynthesis in Impatiens.

Immunotherapy for patients with advanced non-small cell lung cancer harboring oncogenic driver alterations other than EGFR: a multicenter real-world analysis.

Background: The administration of immune checkpoint inhibitors (ICIs) in advanced non-small cell lung cancer (NSCLC) with oncogenic driver alterations other than epidermal growth factor receptor (EGFR) aroused a heated discussion. We thus aimed to evaluate ICI treatment in these patients in real-world routine clinical practice. Methods: A multicenter, retrospective study was conducted for NSCLC patients with at least one gene alteration (KRAS, HER2, BRAF, MET, RET, ALK, ROS1) receiving ICI monotherapy or combination treatment. The data regarding clinicopathologic characteristics, clinical efficacy, and safety were investigated. Results: A total of 216 patients were included, the median age was 60 years, 72.7% of patients were male, and 46.8% had a smoking history. The molecular alterations involved KRAS (n=95), HER2 (n=42), BRAF (n=22), MET (n=21), RET (n=14), ALK (n=14), and ROS1 (n=8); 56.5% of patients received immunotherapy in the first-line, and the rest 43.5% were treated as a second-line and above. For the entire cohort who received immunotherapy-based regimens in the first-line, the median progression-free survival (PFS) was 7.5 months and the median overall survival (OS) was 24.8 months. For the entire cohort who received immunotherapy-based regimens in the second-line and above, the median PFS was 4.7 months and median OS was 17.1 months. KRAS mutated NSCLC treated with immunotherapy-based regimens in the first-line setting had a median PFS and OS were 7.8 and 26.1 months, respectively. Moreover, the median PFS and OS of immunotherapy-based regimens for KRAS-mutant NSCLC that progressed after chemotherapy were 5.9 and 17.1 months. Programmed death ligand 1 (PD-L1) expression level was not consistently associated with response to immunotherapy across different gene alteration subsets. In the KRAS group, PD-L1 positivity [tumor proportion score (TPS) ≥1%] was associated with better PFS and OS according to the multivariate Cox analysis. No statistically significant association was found for smoking status, age, or gender with clinical efficacy in any gene group analyses. Conclusions: KRAS-mutant NSCLC could obtain clinical benefits from ICIs either for treatment-naive patients or those who have experienced progression after chemotherapy, and PD-L1 positive expression (TPS >1%) may be a potential positive predictor. For NSCLC with ALK, RET and ROS1 rearrangement, MET exon 14 skipping mutation, or BRAF V600E mutation, effectiveness of single or combined ICI therapy remains limited, therefore, targeted therapies should be considered prior to immunotherapy regimens. Future studies should address the investigation of better predictive biomarkers for immunotherapy response in oncogene-driven NSCLC.

Flower development and a functional analysis of related genes in Impatiens uliginosa.

Impatiens uliginosa is a plant of the Impatiens, with peculiar flowers. In this study, we combined morphogenesis and molecular biology to explore its development of flowers. An analysis of basic observational data and paraffin sectioning showed that it took approximately 13 d for the floral organs to differentiate. An analysis of the development of inflorescences and floral organs by scanning electron microscopy showed that the inflorescence of I. uliginosa is a spiral raceme. The floral organs differentiated in the following order: lateral sepals (Ls), posterior sepal (Ps), anterior sepals (As), anterior petal (Ap), lateral petals (Lp), stamens (St) and gynoecium (Gy). I. uliginosa was found to have four sepals, and the connate stamens are caused by the fusion and growth of filament appendages. The results of fluorescence quantification and virus-induced gene silencing showed that I. uliginosa had its own unique model for flower development, and there was functional diversity of IuAP1 and IuDEF. Among them, IuAP1 controls the formation of bract s (Br), regulates the morphogenesis of posterior sepal, controls the anthocyanin precipitation of the anterior petals and the formation of lateral petals. IuDEF regulates the morphogenesis of lateral sepals, the length of development of the spur, and controls the size of yellow flower color plaques of the lateral petals. In this study, the process of flower development and the function of flower development genes of I. uliginosa were preliminarily verified. This study provides basic guidance and new concepts that can be used to study the development of Impatiens flowers.

Non-viral Gene Therapy for Melanoma Using Lysenin from Eisenia Foetida.

Earthworms, long utilized in traditional medicine, serve as a source of inspiration for modern therapeutics. Lysenin, a defensive factor in the coelom fluid of the earthworm Eisenia fetida, has multiple bioactivities. However, the inherent toxicity of Lysenin as a pore-forming protein (PFP) restricts its application in therapy. Here, a gene therapy strategy based on Lysenin for cancer treatment is presented. The formulation consists of polymeric nanoparticles complexed with the plasmid encoding Lysenin. After transfection in vitro, melanoma cells can express Lysenin, resulting in necrosis, autophagy, and immunogenic cell death. The secretory signal peptide alters the intracellular distribution of the expressed product of Lysenin, thereby potentiating its anticancer efficacy. The intratumor injection of Lysenin gene formulation can efficiently kill the transfected melanoma cells and activate the antitumor immune response. Notably, no obvious systemic toxicity is observed during the treatment. Non-viral gene therapy based on Lysenin derived from Eisenia foetida exhibits potential in cancer therapy, which can inspire future cancer therapeutics.

The cellular and molecular basis of the spur development in Impatiens uliginosa.

The nectar spur is an important feature of pollination and ecological adaptation in flowering plants, and it is a key innovation to promote species diversity in certain plant lineages. The development mechanism of spurs varies among different plant taxa. As one of the largest angiosperm genera, we have little understanding of the mechanism of spur development in Impatiens. Here, we investigated the initiation and growth process of spurs of Impatiens uliginosa based on histology and hormone levels, and the roles of AUXIN BINDING PROTEIN (ABP) and extensin (EXT) in spur development were explored. Our results indicate that the spur development of I. uliginosa is composed of cell division and anisotropic cell elongation. Imbalances in spur proximal-distal cell division lead to the formation of curved structures. Endogenous hormones, such as auxin and cytokinins, were enriched at different developmental stages of spurs. IuABP knockdown led to an increase in spur curves and distortion of morphology. IuEXT knockdown resulted in reduced spur length and loss of curve and inner epidermal papillae structures. This study provides new insights into the mechanism of spur development in core eudicots.

Effects of cell morphology, physiology, biochemistry and CHS genes on four flower colors of Impatiens uliginosa.

Introduction: Flower color is one of the important ornamental traits in the plants, which plays an active role in attracting pollinators to pollinate plants and reproduce their offspring. The flower color of Impatiens uliginosa is rich, there are four main flower colors in nature: deep red, red, pink, and white. However, it remains unclear whether on four different flower colors mechanism of I. uliginosa. Methods: We investigate colorimetric measurement, observation of epidermal cells, cellular pH determination, extraction and determination of total anthocyanins and flavonoid, semi-quantitative determination of pigment components, and gene cloning and qRT-PCR of CHS genes to study four flower colors of I. uliginosa. Results: The L* and b* values were the highest in white flower, while the a* values were the highest in pink flower. The same shape of epidermal cells was observed in different flower colors, which was all irregular flat polygons, and there were partial lignification. Their cellular pH values were weakly acidic, while the pH values of the deep red flower was the highest and the white flower was the lowest. The highest pigment content of the four flower colors was total anthocyanin content. And malvidin-3-galactosidechloride (C23H25ClO12), cyanidin-3-O-glucoside (C21H21O11) and delphinidin (C15H11O7) were the main pigment components affecting the color of four different flower colors. The anthocyanin synthesis gene IuCHS was expressed in four flowers, and all three copies of it had the highest expression level in pink flower and the lowest expression level in white flower. Discussion: These results revealed the influence of main internal factors on four different flower colors of I. uliginosa, and provided a basis for further understanding of the intracellular and molecular regulatory mechanisms of flower color variation, and laid a foundation for the improvement of flower color breeding of Impatiens.

Epithelial Malignant Pleural Mesothelioma Mimics Lymphoma on 18 F-FDG PET/MRI : A Case Report.

ABSTRACT: Malignant pleural mesothelioma is a rare tumor with a poor prognosis. We describe a case of 55-year-old man without asbestos exposure history presenting with extensive lymph nodes with high 18 F-FDG uptake in PET/MRI but atypical pleural manifestations thereby being misdiagnosed for lymphoma. Pathological examination concludes for an epithelioid mesothelioma-associated lymph node metastasis. This case emphasizes that with the extensive lymph node abnormalities shown in PET imaging, in addition to the general consideration of lymphoma, it is still necessary to be vigilant about the possibility of mesothelioma and emphasizes the necessity of pathological examination.

First-line treatment of driver gene-negative metastatic lung adenocarcinoma with malignant pleural effusion: Should chemotherapy be combined with an immune checkpoint inhibitor or bevacizumab?

Patients with metastatic lung adenocarcinoma (MLA) and malignant pleural effusion (MPE) without driver gene mutations have a poor prognosis. None of the standard treatment strategies is recommended for such patients. We retrospectively analyzed the efficacy of the first-line treatment for this specific population: standard platinum-based doublet chemotherapy (CT), CT plus an immune checkpoint inhibitor (CT plus ICI), and CT plus bevacizumab (CT plus Bev). A total of 323 eligible patients were enrolled: CT alone (n = 166), CT plus Bev (n = 72), and CT plus ICI (n = 85). Treatment efficacy assessments were performed every two cycles according to the RECIST guidelines. The endpoints were overall survival (OS) and progression-free survival (PFS). Kaplan-Meier (K‒M) curves and the log-rank test were used to compare OS and PFS. p < 0.05 was the threshold of significance (statistical software: SPSS). The median follow-up was 11.4 months (range, 2.1-49.6 months). PFS and OS in the CT plus ICI/CT plus Bev cohort were significantly longer than those in the CT group (PFS: 7.8/6.4/3.9 months, p < 0.0001; OS: 16.4/15.6/9.6 months, p < 0.0001, respectively). CT plus Bev had better PFS and OS than CT plus ICI/CT in PD-L1 < 1% patients (PFS: 8.4/5.0/3.8 months, p < 0.0001; OS: 15.6/12.9/9.3 months, p < 0.0001). Among patients with PD-L1 1-49%, CT plus ICI led to a longer PFS and OS (PFS: 8.9/5.8/4.2 months, p = 0.009; OS: 24.2/18.8/11.5 months, p = 0.03). In the cohort with PD-L1 ≥ 50%, CT plus ICI was still the best first-line treatment (PFS: 19.7/13.8/9.6 months, p = 0.033; OS: 27.2/19.6/14.9 months, p = 0.047). In driver gene-negative MLA with MPE, CT plus Bev or ICI better controlled MPE and significantly prolonged survival compared to CT alone. PD-L1 expression (negative/positive) may be a key factor influencing the choice of CT plus Bev or ICI.

Novel membrane-targeting isoxanthohumol-amine conjugates for combating methicillin-resistant Staphylococcus aureus (MRSA) infections.

Methicillin-resistant Staphylococcus aureus (MRSA) is a widespread pathogen causing clinical infections and is multi-resistant to many antibiotics, making it urgent need to develop novel antibacterials to combat MRSA. Here, a series of novel isoxanthohumol-amine conjugates were synthesized as antibacterials. After bioactivity evaluation, a compound E2 was obtained, which showed excellent antibacterial activity against S. aureus and clinical MRSA isolates (MICs = 0.25-1 µg/mL), superior to vancomycin, and with negligible hemolysis and good membrane selectivity. Additionally, E2 exhibited fast bacterial killing, less susceptible to resistance, relatively low cytotoxicity, and good plasma stability. Mechanism investigation revealed that E2 can disrupt bacterial membranes by specifically binding to phosphatidylglycerol on the bacterial membrane, thus causing elevated intracellular ROS and leakage of DNA and proteins, and ultimately killing bacteria. Noticeably, E2 displayed a good in vivo safety profile and better in vivo therapeutic efficacy than the same dose of vancomycin, allowing it to be a potential antibacterial to conquer MRSA infections.

Current Development of Thiazole-Containing Compounds as Potential Antibacterials against Methicillin-Resistant Staphylococcus aureus.

The emergence of multi-drug-resistant bacteria is threatening to human health and life around the world. In particular, methicillin-resistant Staphylococcus aureus (MRSA) causes fatal injuries to human beings and serious economic losses to animal husbandry due to its easy transmission and difficult treatment. Currently, the development of novel, highly effective, and low-toxicity antimicrobials is important to combat MRSA infections. Thiazole-containing compounds with good biological activity are widely used in clinical practice, and appropriate structural modifications make it possible to develop new antimicrobials. Here, we review thiazole-containing compounds and their antibacterial effects against MRSA reported in the past two decades and discuss their structure-activity relationships as well as the corresponding antimicrobial mechanisms. Some thiazole-containing compounds exhibit potent antibacterial efficacy in vitro and in vivo after appropriate structural modifications and could be used as antibacterial candidates. This Review provides insights into the development of thiazole-containing compounds as antimicrobials to combat MRSA infections.

Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.