Ophiopogonin D attenuates the progression of murine systemic lupus erythematosus by reducing B cell numbers.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune abnormalities leading to multi-organ damage. The activation of autoreactive B cell differentiation will lead to the production of pathogenic autoantibodies, contributing to the development of SLE. However, the effects of Ophiopogonin D (OP-D) on B cell activation and autoantibody production as well as renal injury in the pathogenesis of SLE remain unclear. MRL/lpr mice, one of the most commonly used animal models of SLE, were intragastrically administered with 5 mg/kg/d OP-D at 17 weeks of age for 3 weeks. The survival rates of mice in each group were monitored for 6 weeks until 23 weeks of age. Proteinuria and serum creatinine levels were measured. Serum levels of immunoglobulin (Ig)G, IgM, and anti-dsDNA autoantibodies were detected by enzyme-linked immunosorbent assay. Numbers of CD19+ B cells in the blood, spleen and bone marrow and numbers of splenic germinal center (GC) B cells were calculated by using flow cytometry. OP-D treatment prolonged survival in MRL/lpr mice. OP-D treatment reduced proteinuria and serum creatinine levels as well as mitigated renal pathological alternation in MRL/lpr mice. Furthermore, serum levels of IgG, IgM, and anti-dsDNA autoantibodies were reduced by OP-D treatment. OP-D lessened not only CD19+ B cells in the spleen and bone marrow but also plasma cells that secreted anti-dsDNA autoantibodies, IgG and IgM in the spleen and bone marrow. OP-D ameliorated the progression of SLE by inhibiting the secretion of autoantibodies though reducing B cell numbers.

Circulating lnc-LOC as a novel noninvasive biomarker in the treatment surveillance of acute promyelocytic leukaemia.

BACKGROUND: Acute promyelocytic leukaemia (APL) is a unique subtype of acute myeloid leukaemia (AML) characterized by haematopoietic failure caused by the accumulation of abnormal promyelocytic cells in bone marrow (BM). However, indispensable BM biopsy frequently afflicts patients in leukaemia surveillance, which increases the burden on patients and reduces compliance. This study aimed to explore whether the novel circulating long noncoding RNA LOC100506453 (lnc-LOC) could be a target in diagnosis, assess the treatment response and supervise the minimal residual disease (MRD) of APL, thereby blazing a trail in noninvasive lncRNA biomarkers of APL. METHODS: Our study comprised 100 patients (40 with APL and 60 with non-APL AML) and 60 healthy donors. BM and peripheral blood (PB) sample collection was accomplished from APL patients at diagnosis and postinduction. Quantitative real-time PCR (qRT-PCR) was conducted to evaluate lnc-LOC expression. A receiver operating characteristic (ROC) analysis was implemented to analyse the value of lnc-LOC in the diagnosis of APL and treatment monitoring. For statistical analysis, the Mann-Whitney U test, a t test, and Spearman's rank correlation test were utilized. RESULTS: Our results showed that BM lnc-LOC expression was significantly different between APL and healthy donors and non-APL AML. lnc-LOC was drastically downregulated in APL patients' BM after undergoing induction therapy. Lnc-LOC was upregulated in APL cell lines and downregulated after all-trans retinoic acid (ATRA)-induced myeloid differentiation, preliminarily verifying that lnc-LOC has the potential to be considered a treatment monitoring biomarker. PB lnc-LOC was positively correlated with BM lnc-LOC in APL patients, non-APL AML patients and healthy donors and decreased sharply after complete remission (CR). However, upregulated lnc-LOC was manifested in relapsed-refractory patients. A positive correlation was revealed between PB lnc-LOC and PML-RARα transcript levels in BM samples. Furthermore, we observed a positive correlation between PB lnc-LOC and BM lnc-LOC expression in APL patients, suggesting that lnc-LOC can be utilized as a noninvasive biomarker for MRD surveillance. CONCLUSIONS: Our study demonstrated that PB lnc-LOC might serve as a novel noninvasive biomarker in the treatment surveillance of APL, and it innovated the investigation and application of newly found lncRNAs in APL noninvasive biomarkers used in diagnosis and detection.

Performance and microbial community analysis of an algal-activated sludge symbiotic system: Effect of activated sludge concentration.

It was focused on the effect of different sludge concentrations on the performances of an algal-activated sludge symbiotic system in terms of wastewater treatment, algal-activated sludge characteristics and community structure. The results showed that the highest nutrient removal efficiencies were obtained in the reactor R2 with soluble chemical oxygen demand (sCOD), ammonia nitrogen (NH4+-N) and phosphate (PO43- -P) removal efficiencies of (90.6±2.3)%, (97.69±2.6)% and (83.81±2.3)%, respectively. Further investigation exhibited that sludge concentration has a great effect on the dissolved oxygen (DO) concentration, the pH, the growth of algae and the extracellular polymeric substance (EPS) production, which resulted in influencing the settleability and the performance of symbiotic system. The denaturing gradient gel electrophoresis (DGGE) analysis demonstrated that the sludge concentration had a selective power for particular members of algae. Meantime, the stimulated algal population would selectively excite the members of bacteria benefited for the formation of algal-bacterial consortia. The variation of microbial compositions, which was influenced by the different sludge concentrations, might be ultimately responsible for the different treatment performances.

LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma.

Multiple myeloma (MM), the second most common hematologic malignancy, is an incurable disease characterized by the accumulation of malignant plasma cells within the bone marrow. Though great progresses have been made in understanding the mechanisms of MM, metabolic plasticity and drug resistance remain largely unknown. In this study, we found lncRNA Protein disulfide isomerase family A member 3 pseudogene 1 (PDIA3P) is highly expressed in MM and is associated with the survival rate of MM patients. PDIA3P regulates MM growth and drug resistance through Glucose 6-phosphate dehydrogenase (G6PD) and the pentose phosphate pathway (PPP). Mechanistically, we revealed that PDIA3P interacts with c-Myc to enhance its transactivation activity and binding to G6PD promoter, stimulating G6PD expression and PPP flux. Our study identified PDIA3P as a novel c-Myc interacting lncRNA and elucidated crucial roles for PDIA3P in metabolic regulation of MM, providing a potential therapeutic target for MM patients.

An amplified fluorescence detection of T4 polynucleotide kinase activity based on coupled exonuclease III reaction and a graphene oxide platform.

A novel amplified fluorescence graphene oxide (GO) sensing platform for sensitive detection of T4 polynucleotide kinase (PNK) activity and inhibition was developed based on the exonuclease III (ExoIII) reaction. The efficient digestion capacity of ExoIII and the super quenching ability of GO both contribute to the detection sensitivity.

Development of a nomogram for predicting survival in clinical T1N0M1 lung adenocarcinoma: a population-based study.

OBJECTIVE: This study aimed to establish a prognostic model for clinical T1N0M1 (cT1N0M1) lung adenocarcinoma patients to evaluate the prognosis of patients in terms of overall survival (OS) rate and cancer-specific survival (CSS) rate. METHODS: Data of patients with metastatic lung adenocarcinoma from 2010 to 2016 were collected from the Surveillance, Epidemiology and End Results database. Multivariate Cox regression analysis was conducted to identify relevant prognostic factors and used to develop nomograms. The receiver operating characteristic (ROC) curve and calibration curve are used to evaluate the predictive ability of the nomograms. RESULTS: A total of 45610 patients were finally included in this study. The OS and CSS nomograms were constructed by same clinical indicators such as age (<60 years or ≥60 years), sex (female or male), race (white, black, or others), surgery, radiation, chemotherapy, and the number of metastatic sites, based on the results of statistical Cox analysis. From the perspective of OS and CSS, surgery contributed the most to the prognosis. The ROC curve analysis showed that the survival nomograms could accurately predict OS and CSS. According to the points obtained from the nomograms, survival was estimated by the Kaplan-Meier method, then cT1N0M1 patients were divided into three groups: low-risk group, intermediate-risk group, and high-risk group, and the OS ( P  < 0.001) and CSS ( P  < 0.001) were significantly different among the three groups. CONCLUSION: The nomograms and risk stratification model provide a convenient and reliable tool for individualized evaluation and clinical decision-making of patients with cT1N0M1 lung adenocarcinoma.

Injectable Double Crosslinked Hydrogel-Polypropylene Composite Mesh for Repairing Full-Thickness Abdominal Wall Defects.

Abdominal wall defects are common clinical diseases, and mesh repair is the standard treatment method. The most commonly used polypropylene (PP) mesh in clinical practice has the advantages of good mechanical properties, stable performance, and effective tissue integration effect. However, direct contact between abdominal viscera and PP mesh can lead to severe abdominal adhesions. To prevent this, the development of a hydrogel-PP composite mesh with anti-adhesive properties may be an effective measure. Herein, biofunctional hydrogel loaded with rosmarinic acid is developed by modifying chitosan and Pluronic F127, which possesses suitable physical and chemical properties and commendable in vitro biocompatibility. In the repair of full-thickness abdominal wall defects in rats, hydrogels are injected onto the surface of PP mesh and applied to intraperitoneal repair. The results indicate that the use of hydrogel-PP composite mesh can alleviate abdominal adhesions resulting from traditional PP mesh implantation by decreasing local inflammatory response, reducing oxidative stress, and regulating the fibrinolytic system. Combined with the tissue integration ability of PP mesh, hydrogel-PP composite mesh has great potential for repairing full-thickness abdominal wall defects.

The prognostic impact of severe grade immune checkpoint inhibitor related pneumonitis in non-small cell lung cancer patients.

Objective: To compare the prognostic differences between non-small cell lung cancer (NSCLC) patients with mild and severe checkpoint inhibitor-associated pneumonitis (CIP), and explore the causes of death and prognostic risk factors in NSCLC patients with severe CIP. Methods: A retrospective study of a cohort of 116 patients with unresectable stage III or IV NSCLC with any grade CIP from April 2016 to August 2022 were conducted. To analyze the clinical characteristics of patients with different CIP grades, patients were divided into mild CIP group (grade 1-2, n=49) and severe CIP group (grade 3-5, n=67) according to the grade of CIP. To explore the OS-related risk factors in the severe CIP group, the patients were divided into a good prognosis (GP) group (≥ median OS, n=30) and a poor prognosis (PP) group (< median OS, n=37) based on whether their overall survival (OS) were greater than median OS. Baseline clinical and laboratory data were collected for analysis. Results: The median OS of all NSCLC patients combined with CIP was 11.4 months (95%CI, 8.070-16.100), The median OS for mild CIP and severe CIP was 22.1 months and 4.4 months respectively (HR=3.076, 95%CI, 1.904-4.970, P<0.0001). The results showed that the most common cause of death among severe CIP patients in the PP group was CIP and the most common cause in the GP group was tumor. The univariate regression analysis showed that suspension of antitumor therapy was a risk factor for poor prognosis (OR=3.598, 95%CI, 1.307-9.905, p=0.013). The multivariate logistic regression analysis showed that suspension of anti-tumor therapy (OR=4.24, 95%CI, 1.067-16.915, p=0.040) and elevated KL-6 (OR=1.002, 95%CI, 1.001-1.002, p<0.001) were independent risk factors for poor prognosis. Conclusion: In conclusion, patients with severe CIP had a poor prognosis, especially those with elevated KL-6, and the main cause of death is immune checkpoint inhibitor-associated pneumonitis complicated with infection. In addition, anti-tumor therapy for severe CIP patients should be resumed in time and should not be delayed for too long.

Protective effects of erythropoietin on endotoxin-related organ injury in rats.

The protective effect of erythropoietin (EPO) on tissues following ischemia and reperfusion injuries remains poorly understood. We aimed to investigate the effect of EPO in preventing endotoxin-induced organ damage. Rat model of multiple organ failure (MOF) was established by tail vein injection of 10 mg/kg lipopolysaccharide (LPS). Recombinant human EPO treatment (5000 U/kg) was administered by tail vein injection at 30 min after LPS challenge. Twenty-four h after EPO treatment, changes in serum enzyme levels, including aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN) and creatinine (Cr), were evaluated by biochemical analysis. Serum levels of tumor necrosis factor-α (TNF-α) were determined by using immunoradiometric assay. Histological examination of tissue sections was carried out by hematoxylin and eosin staining, while ultrastructure evaluation of organ tissues was assessed by transmission electron microscopy. Protein expression levels were detected by using Western blotting. EPO treatment showed a modest effect in preventing LPS-induced elevation of AST, ALT, BUN, Cr, and TNF-α levels, and in protecting against LPS-induced tissue degeneration and injured ultrastructure in the lung, liver, and kidney. Moreover, LPS promoted phosphorylation of alanine aminotransferase (AKT) and increased nuclear factor-κB (NF-κB) activation in the lung, liver, and kidney (P<0.05 vs. control). However, EPO treatment significantly decreased the LPS-induced pAKT up-regulation in these tissues (P<0.05 vs. LPS treatment alone). The present study demonstrates that EPO may play a protective role against LPS-induced MOF by reducing the inflammatory response and tissue degeneration, possibly via the phosphatidylinositol 3-kinase/AKT and NF-κB signaling pathways.

[Incidence of pulmonary embolism in patients with acute exacerbations of chronic obstructive pulmonary disease: a meta-analysis].

OBJECTIVE: To evaluate the incidence of pulmonary embolism in patients with acute exacerbations of chronic obstructive pulmonary disease (COPD). METHODS: Comprehensive searches as of June 2012 were performed in PubMed (1966-), Embase (1974-), Chinese Biomedical Literature Database (1978-), Chinese Journal Full-text Database (1979-) and VIP Database (1989-) for literatures on the incidence of pulmonary embolism in patients with acute exacerbations of COPD. Meta-analysis was conducted with Stata version 11.0. RESULTS: Among 2273 articles identified, 5 studies met the inclusion criteria (4 in English, 1 in Chinese). The total sample size was 762 patients, among whom 145 were diagnosed with pulmonary embolism. The incidence of pulmonary embolism ranged from 3.3% to 33.0%. Meta-analysis showed that the combined incidence was 15.8% (95%CI: 5.1%-26.4%). Among patients with acute exacerbations of COPD of unknown etiology, the incidence was 29.0% (95%CI: 20.8%-37.1%). CONCLUSIONS: There is a high incidence of pulmonary embolism in patients with acute exacerbations of COPD, especially among those of an unknown etiology. More attention should be paid to this population.

The efficacy and adverse effects of anlotinib in the treatment of high-grade glioma: A retrospective analysis.

Introduction: Anlotinib, a novel multi-kinase inhibitor, was found to improve progression-free survival (PFS) in brain metastases. Methods: This paper retrospectively analyzed 26 newly diagnosed or recurrent high-grade gliomas from 2017 to 2022, and the patients received oral anlotinib during concurrent postoperative chemoradiotherapy or after recurrence. Efficacy was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria, and the main study endpoints were PFS at 6 months and overall survival (OS) at 1 year. Results: After the follow-up, until May 2022, 13 patients survived and 13 patients died, with a median follow-up time of 25.6 months. The disease control rate (DCR) was 96.2% (25/26), and the overall response rate (ORR) rate was 73.1% (19/26). The median PFS after oral anlotinib was 8.9 months (0.8-15.1), and the PFS at 6 months was 72.5%. The median OS after oral anlotinib was 12 months (1.6-24.4), and the OS at 12 months was 42.6%. Anlotinib-related toxicities were observed in 11 patients, mostly grades 1-2. In the multivariate analysis, patients with Karnofsky Performance Scale (KPS) above 80 had a highermedian PFS of 9.9months (p = 0.02), and their sex, age, IDH mutation, MGMTmethylation, and whether anlotinib was combined with chemoradiotherapy or maintenance treatment had no effect on PFS. Conclusion: We found that anlotinib combined with chemoradiotherapy in treating high-grade central nervous system (CNS) tumors can prolong PFS and OS and that it was safe.

Suppression of Autophagy Can Augment PIK3 Inhibitor Induced Apoptosis in T Lymphoblastic Leukemia Cell Lines.

OBJECTIVE: The present study aimed to investigate the effects of the PI3K inhibitor PX-866 or PI-103 combined with the autophagy inhibitor 3-methyladenine (3-MA) on the apoptosis of T lymphoblastic leukemia cells. METHODS: The proliferation and apoptosis of T lymphoblastic leukemia cell lines were detected by CCK-8 and flow cytometer. The expression of proteins was measured by western blot. The effect of PI3K inhibitors combined with 3-MA on the number of autophagosomes was detected by transmission electron microscopy (TEM). RESULTS: We found PX-866 and PI-103 treatment reduced cell viability while increasing apoptosis in CCRF-CEM and Jurkat cells, which was further enhanced when combined with 3-MA. The phosphorylation levels of AKT and mTOR were suppressed by PX-866 or PI-103, which were reversed by 3-MA. Further, the expression of LC3, ATG5, ATG12 and Beclin-1 was upregulated by PX-866 or PI-103 and downregulated by 3-MA. TEM results revealed that the number of autophagosome was increased by PX-866 or PI-103 treatment, which was reversed by 3-MA. CONCLUSIONS: The results demonstrated that 3-MA could suppress PI3K inhibitor-mediated activation of autophagy to promote the apoptosis of tumor cells. This discovery provided experimental support for constituting a promising strategy for T-cell acute lymphoblastic leukemia (T-ALL) therapy.

Effects of combining immune checkpoint inhibitors and anti-angiogenic agents on bone metastasis in non-small cell lung cancer patients.

This study aimed to evaluate the efficacy of combining immune checkpoint inhibitors (ICIs) and anti-angiogenic agents in treating lung cancer patients with bone metastases (BMs), as it is unclear whether this combination is effective for this condition. Non-small cell lung cancer patients with BMs receiving ICIs were divided into experimental and control groups based on anti-angiogenic treatment. Progression-free survival (PFS) and overall survival (OS) were evaluated using the Kaplan-Meier method, with log-rank test for comparisons. Prognostic factors were determined by univariate and multivariate Cox regression analyses. The study included 95 patients. The experimental group (n = 42) had a higher disease control rate (DCR) (90.5% vs. 68.6%, p = .009), objective response rate (ORR) (35.7% vs. 24.5%, p = .235), and longer median bone PFS (14.3 months vs. 8.3 months, p = .011) for bone metastasis. However, there were no significant differences in overall DCR (92.8% vs. 86.7%, p = .339), ORR (64.3% vs. 62.3%, p = .839), and PFS (12.4 months vs. 11.6 months, p = 0.383) between the 2 groups. The experimental group had a lower incidence of skeleton-related events (SREs) (28.6% vs. 35.8%, p = .425), and SRE patients had shorter PFS (7.7 vs. 14.3 months, p < .001) and OS (12.1 vs. 19.0 months, p = .028). Anti-angiogenic therapy (HR = 0.55, p = .012) and SRE (HR = 2.93, p < .001) were identified as independent prognostic factors for bone metastatic PFS. Adverse events were slightly higher in the experimental group (29.3% vs. 18.9%, p = .238), but not statistically significant. The combination of ICIs and anti-angiogenic agents leads to a significant PFS for BMs and potentially decreases SRE.

Real-world data on severe lung cancer: a multicenter retrospective study.

Background: Severe lung cancer is a novel concept that describes a patient with poor performance status (PS; 2-4) but with a high probability of receiving survival benefit and improvement in the PS score. However, there is currently no relevant research or real-world data on those with severe lung cancer, such as incidence, cause, clinical features, and risk factors. Methods: The data from patients with advanced lung cancer attending multiple centers from January 1, 2022, to June 30, 2022, were collected for a cross-sectional study. In addition, data from fatal cases from January 1, 2019, to June 30, 2022, were retrospectively collected as another cohort. And we developed a questionnaire to assess clinicians' mastery of severe lung cancer. Results: Three participating institutes enrolled the data set of 1,725 patients, and the dataset of 269 fatal cases were included in another cohort; the incidence of severe lung cancer was 13.10% and 37.55%, respectively. Severe lung cancer patients were mainly stage IV elderly male patients without gene mutation and a history of resection. And the proportion of smoking and comorbidities in severe lung cancer patients is more than in non-severe lung cancer patients (50.4% vs. 40.8%, P=0.006; 46.9% vs. 36.4%, P=0.002). Treatment-related adverse events (AEs) (46.0%) accounted for the largest proportion of the primary causes of severe lung cancer in the cross-sectional study, while cancer-related symptoms (54.5%) accounted for the largest proportion of the primary causes of sever lung cancer in the 101 fatal cases. For the fatal cases, the overall survival of severe lung cancer patients caused by cancer-related symptoms was longer than that caused by treatment-related AEs (8 vs. 3 months; P=0.019). A total of 616 clinicians completed the questionnaire; 90.26% of clinicians agreed with the concept of severe lung cancer. Conclusions: The incidence of severe lung cancer cannot be ignored based on real-world data. Treatment-related AEs are gradually account for more of the causes of severe lung cancer, surpassing cancer-related symptoms and comorbidities. Furthermore, the prognosis of patients with advanced lung cancer who develop severe lung cancer due to treatment-related AEs is worse than cancer-related symptoms.

A Risk-Scoring Model for Severe Checkpoint Inhibitor-Related Pneumonitis: A Case-Control Study.

BACKGROUND AND OBJECTIVE: Checkpoint inhibitor-related pneumonitis (CIP) is one of the most common serious and fatal adverse events associated with immune checkpoint inhibitors (ICIs). The study sought to identify risk factors of all-grade and severe CIP and to construct a risk-scoring model specifically for severe CIP. METHODS: This observational, retrospective case-control study involved 666 lung cancer patients who received ICIs between April 2018 and March 2021. The study analyzed patient demographic, preexisting lung diseases, and the characteristics and treatment of lung cancer to determine the risk factors for all-grade and severe CIP. A risk score for severe CIP was developed and validated in a separate patient cohort of 187 patients. RESULTS: Among 666 patients, 95 patients were afflicted with CIP, of which 37 were severe cases. Multivariate analysis revealed age ≥ 65 years, current smoking, chronic obstructive pulmonary disease, squamous cell carcinoma, prior thoracic radiotherapy, and extra-thoracic radiotherapy during ICI were independently associated with CIP events. Five factors, emphysema (odds ratio [OR] 2.87), interstitial lung disease (OR 4.76), pleural effusion (OR 3.00), history of radiotherapy during ICI (OR 4.30), and single-agent immunotherapy (OR 2.44) were independently associated with severe CIP and were incorporated into a risk-score model (score ranging 0-17). The area under the model receiver operating characteristic curve for the model was 0.769 in the development cohort and 0.749 in the validation cohort. CONCLUSIONS: The simple risk-scoring model may predict severe CIP in lung cancer patients receiving ICIs. For patients with high scores, clinicians should use ICIs with caution or strengthen the monitoring of these patients.

Prognostic and risk factor analysis of cancer patients after unplanned ICU admission: a real-world multicenter study.

To investigate the occurrence and 90-day mortality of cancer patients following unplanned admission to the intensive care unit (ICU), as well as to develop a risk prediction model for their 90-day prognosis. We prospectively analyzed data from cancer patients who were admitted to the ICU without prior planning within the past 7 days, specifically between May 12, 2021, and July 12, 2021. The patients were grouped based on their 90-day survival status, and the aim was to identify the risk factors influencing their survival status. A total of 1488 cases were included in the study, with an average age of 63.2 ± 12.4 years. The most common reason for ICU admission was sepsis (n = 940, 63.2%). During their ICU stay, 29.7% of patients required vasoactive drug support (n = 442), 39.8% needed invasive mechanical ventilation support (n = 592), and 82 patients (5.5%) received renal replacement therapy. We conducted a multivariate COX proportional hazards model analysis, which revealed that BMI and a history of hypertension were protective factors. On the other hand, antitumor treatment within the 3 months prior to admission, transfer from the emergency department, general ward, or external hospital, high APACHE score, diagnosis of shock and respiratory failure, receiving invasive ventilation, and experiencing acute kidney injury (AKI) were identified as risk factors for poor prognosis within 90 days after ICU admission. The average length of stay in the ICU was 4 days, while the hospital stay duration was 18 days. A total of 415 patients died within 90 days after ICU admission, resulting in a mortality rate of 27.9%. We selected 8 indicators to construct the predictive model, which demonstrated good discrimination and calibration. The prognosis of cancer patients who are unplanned transferred to the ICU is generally poor. Assessing the risk factors and developing a risk prediction model for these patients can play a significant role in evaluating their prognosis.

Historical and current records of aquarium cetaceans in China.

The number of cetaceans housed in aquariums in China is increasing. Detailed information on the historical and current population status has not been reported, despite its importance for successful breeding and population management. Questionnaires were conducted between December 2006 and May 2009, and the information was used to construct studbooks. Our survey showed that 10 species had been introduced to aquariums since 1978, including 26 (with 15 in the current population) finless porpoises (Neophocaena phocaenoides), 5 (5) false killer whales (Pseudorca crassidens), 94 (80) common bottlenose dolphins (Tursiops truncatus), 48 (30) Indo-Pacific bottlenose dolphins (Tursiops aduncus), 36 (32) beluga whales (Delphinapterus leucas), 10 (10) pantropical spotted dolphins (Stenella attenuata), 8 (8) Risso's dolphins (Grampus griseus), 2 (2) short-finned pilot whales (Globicephala macrorhynchus), 2 (2) Pacific white-sided dolphins (Lagenorhynchus obliquidens), and 5 (0) baiji dolphins (Lipotes vexillifer). The number of cetaceans has increased markedly in the past 32 years, especially since 1995. Currently, 184 individuals are under human care throughout China, a number larger than any other country with an International Species Information System membership. In addition, the Annual Survival Rates of bottlenose dolphins (0.959) and beluga whales (0.968) were found higher than those reported previously (0.93-0.951 and 0.94-0.954, respectively).

Selenium Deficiency Leads to Inflammation, Autophagy, Endoplasmic Reticulum Stress, Apoptosis and Contraction Abnormalities via Affecting Intestinal Flora in Intestinal Smooth Muscle of Mice.

Selenium (Se) is a micronutrient that plays a predominant role in various physiological processes in humans and animals. Long-term lack of Se will lead to many metabolic diseases. Studies have found that chronic Se deficiency can cause chronic diarrhea. The gut flora is closely related to the health of the body. Changes in environmental factors can cause changes in the intestinal flora. Our study found that Se deficiency can disrupt intestinal flora. Through 16s high-throughput sequencing analysis of small intestinal contents of mice, we found that compared with CSe group, the abundance of Lactobacillus, Bifidobacterium, and Ileibacterium in the low selenium group was significantly increased, while Romboutsia abundance was significantly decreased. Histological analysis showed that compared with CSe group, the small intestine tissues of the LSe group had obvious pathological changes. We examined mRNA expression levels in the small intestine associated with inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junctions, and smooth muscle contraction. The mRNA levels of NF-κB, IκB, p38, IL-1ß, TNF-α, Beclin, ATG7, ATG5, LC3α, BaK, Pum, Caspase-3, RIP1, RIPK3, PERK, IRE1, elF2α, GRP78, CHOP2, ZO-1, ZO-2, Occludin, E-cadherin, CaM, MLC, MLCK, Rho, and RhoA in the LSe group were significantly increased. The mRNA levels of IL-10, p62 BcL-2 and BcL-w were significantly decreased in the LSe group compared with the CSe group. These results suggest that changes in the abundance of Lactobacillus, bifidobacterium, ileum, and Romboutsia may be associated with cellular inflammation, autophagy, endoplasmic reticulum stress, apoptosis, tight junction, and abnormal smooth muscle contraction. Intestinal flora may play an important role in chronic diarrhea caused by selenium deficiency.

The Treatment Status of Patients in NSCLC With RET Fusion Under the Prelude of Selective RET-TKI Application in China: A Multicenter Retrospective Research.

Background: Rearranged during transfection (RET) fusion is a kind of uncommon mutation (about 1%) in non-small cell lung cancer (NSCLC). Although selective tyrosine kinase inhibitors (TKI) (selpercatinib and pralsetinib) have been available, there are no real-world data about the difference in the efficacy between RET-TKI and other regimens in China. Methods: We conducted a multicenter retrospective analysis of 49 patients with RET-fusion-positive NSCLC. The characteristics and the clinical outcomes with RET-TKI, multi-kinase inhibitor (MKI), systematic chemotherapy, and immune-checkpoint inhibitor (ICI)-based regimens were evaluated. Results: Of the 92 treatments in patients included, RET-TKI was administered 24 times (26.1%), systematic chemotherapy was 35 times (38.0%), ICI-based regimens was 26 times (28.3%), and MKI was 7 times (7.6%). RET-TKI had a higher objective response rate than the chemotherapy and ICI-based regimens (63.6% vs. 14.3% vs. 21.0%, p < 0.001). The median progress-free survival (mPFS) of RET-TKI, chemotherapy, immunotherapy, and MKI was 16.9 (95% CI: 1.8-32.0) months, 11.9 (95% CI: 7.7-16.1) months, 6.7 (95% CI: 2.9-10.5) months, and 2.8 (95% CI: 1.1-4.4) months, respectively. The mPFS of RET-TKI was longer than MKI and immunotherapy (p < 0.001), while without difference with chemotherapy (p = 0.096). Moreover, chemotherapy had longer mPFS than MKI (p < 0.001). In subgroup analysis, patients with brain metastases in RET-TKI treatment had worse mPFS than the one of patients without brain metastases (6.1 (95% CI: 0.0-13.9) months and 8.5 (95% CI: 6.3-10.6) months, p = 0.012). For patients having chemotherapy with or without angiogenesis inhibitors, the mPFS was 12.0 (95% CI: 11.05-13.02) months and 9.1 (95% CI: 8.31-9.89) months (p = 0.468). In the group of ICI-based regimens, the expression level of PD-L1 did not affect the mPFS of ICI [PD-L1 (+) vs. PD-L1 (-): 4.7 (95% CI: 1.8-9.0) months vs. 7.6 (95% CI: 1.1-14.0) months, p = 0.910]. For overall patients, ECOG PS score, therapy lines, and therapeutic regimens were the independent factors affecting the prognosis. Conclusions: In RET-fusion-positive NSCLC, RET-TKI is the best choice for a better response rate and PFS. In addition, chemotherapy which may bring a good PFS, is still a good choice for this group of patients.

Proposed clinical phases for the improvement of personalized treatment of checkpoint inhibitor-related pneumonitis.

Background: Checkpoint inhibitor-related pneumonitis (CIP) is a lethal immune-related adverse event. However, the development process of CIP, which may provide insight into more effective management, has not been extensively examined. Methods: We conducted a multicenter retrospective analysis of 56 patients who developed CIP. Clinical characteristics, radiological features, histologic features, and laboratory tests were analyzed. After a comprehensive analysis, we proposed acute, subacute, and chronic phases of CIP and summarized each phase's characteristics. Results: There were 51 patients in the acute phase, 22 in the subacute phase, and 11 in the chronic phase. The median interval time from the beginning of CIP to the different phases was calculated (acute phase: ≤4.9 weeks; subacute phase: 4.9~13.1 weeks; and chronic phase: ≥13.1 weeks). The symptoms relieved from the acute phase to the chronic phase, and the CIP grade and Performance Status score decreased (P<0.05). The main change in radiologic features was the absorption of the lesions, and 3 (3/11) patients in the chronic phase had persistent traction bronchiectasis. For histologic features, most patients had acute fibrinous pneumonitis in the acute phase (5/8), and most had organizing pneumonia in the subacute phase (5/6). Other histologic changes advanced over time, with the lesions entering a state of fibrosis. Moreover, the levels of interleukin-6, interleukin-10 and high-sensitivity C-reactive protein (hsCRP) increased in the acute phase and decreased as CIP progressed (IL-6: 17.9 vs. 9.8 vs. 5.7, P=0.018; IL-10: 4.6 vs 3.0 vs. 2.0, P=0.041; hsCRP: 88.2 vs. 19.4 vs. 14.4, P=0.005). Conclusions: The general development process of CIP can be divided into acute, subacute, and chronic phases, upon which a better management strategy might be based devised.