Humans ; Anniversaries and Special Events ; Hypersensitivity

MEK is a canonical effector of mutant KRAS; however, MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers. Here, we identified mitochondrial oxidative phosphorylation (OXPHOS) induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer (NSCLC) resistance to the clinical MEK inhibitor trametinib. Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment, satisfying their energy demand and protecting them from apoptosis. As molecular events in this process, the pyruvate dehydrogenase complex (PDHc) and carnitine palmitoyl transferase IA (CPTIA), two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation. Importantly, the co-administration of trametinib and IACS-010759, a clinical mitochondrial complex I inhibitor that blocks OXPHOS, significantly impeded tumor growth and prolonged mouse survival. Overall, our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.

Objective: To explore the safety and effectiveness of stereotactic body radiation therapy (SBRT) for oligometastases from colorectal cancer (CRC). Methods: This is a prospective, single-arm phase Ⅱ trial. Patients who had histologically proven CRC, 1 to 5 detectable liver or lung metastatic lesions with maximum diameter of any metastases ≤5 cm were eligible. SBRT was delivered to all lesions. The primary endpoint was 3-year local control (LC). The secondary endpoints were treatment-related acute toxicities of grade 3 and above, 1-year and 3-year overall survival (OS) and progression free survival (PFS). Survival analysis was performed using the Kaplan-Meier method and Log rank test. Results: Petients from 2016 to 2019 who were treated in Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Forty-eight patients with 60 lesions were enrolled, including 37 liver lesions and 23 lung lesions. Forty-six patients had 1 or 2 lesions, with median diameter of 1.3 cm, the median biologically effective dose (BED(10)) was 100.0 Gy. The median follow-up was 19.5 months for all lesions. Twenty-five lesions developed local failure, the median local progression free survival was 15 months. The 1-year LC, OS and PFS was 70.2% (95% CI, 63.7%~76.7%), 89.0% (95% CI, 84.3%~93.7%) and 40.4% (95%CI, 33.0%~47.8%). The univariate analysis revealed that planning target volume (PTV) and total dose were independent prognostic factors of LC (P<0.05). For liver and lung lesions, the 1-year LC, OS and PFS was 58.7% and 89.4% (P=0.015), 89.3% and 86.5% (P=0.732), 30.5% and 65.6% (P=0.024), respectively. No patients developed acute toxicity of grade 3 and above. Conclusion: SBRT is safe and effective treatment method for oligometastases from CRC under precise respiratory motion management and robust quality assurance.
Colorectal Neoplasms ; Humans ; Liver/pathology* ; Lung/pathology* ; Prospective Studies ; Radiosurgery/methods*

Objective: To explore the types and clinical characteristics of chronic rhinosinusitis with nasal polyps (CRSwNP) based on artificial intelligence and whole-slide imaging (WSI), and to explore the consistency of the diagnostic criteria of the Japanese epidemiological survey of refractory eosinophilic chronic rhinosinusitis (JESREC) in Chinese CRSwNP patients. Methods: The data of 136 patients with CRSwNP (101 males and 35 females, aging 14 to 70 years) who underwent endoscopic sinus surgery from 2018 to 2019 in the Department of Otorhinolaryngology Head and Neck Surgery, the Third Affiliated Hospital of Sun Yat-sen University were analysed retrospectively. The preoperative clinical characteristics of patients were collected, such as visual analogue scale (VAS) of nasal symptoms, peripheral blood inflammatory cell count, total immunoglobulin E (IgE), Lund-Kennedy score and Lund-Mackay score. The proportion of inflammatory cells such as eosinophils, lymphocytes, plasma cells and neutrophils were calculated on the WSI of each patient through artificial intelligence chronic rhinosinusitis evaluation platform 2.0 (AICEP 2.0), and the specific type of nasal polyps was then obtained as eosinophilic CRSwNP (eCRSwNP) or non-eosinophilic CRSwNP (non-eCRSwNP). In addition, the JESREC diagnostic criteria was used to classify the nasal polyps, and the classification results were compared with the current gold standard for nasal polyps diagnosis (pathological diagnosis based on WSI). The accuracy, sensitivity and specificity of the diagnostic criteria of JESREC were evaluated. The data were expressed in M (Q₁, Q₃) and statistically analyzed by SPSS 17.0. Results: There was no significant difference between eCRSwNP and non-eCRSwNP in age distribution, gender, time of onset, total VAS score, Lund-Kennedy score or Lund-Mackay score. However, there was a significant difference in the ratio of nasal polyp inflammatory cells (eosinophils 40.5% (22.8%, 54.7%) vs 2.5% (1.0%, 5.3%), neutrophils 0.3% (0.1%, 0.7%) vs 1.3% (0.5%, 3.6%), lymphocytes 49.9% (39.3%, 65.9%) vs 82.0% (72.8%, 87.5%), plasma cells 5.1% (3.6%, 10.5%) vs 13.0% (7.4%, 16.3%), χ² value was 9.91, 4.66, 8.28, 5.06, respectively, all P<0.05). In addition, eCRSwNP had a significantly higher level of proportion of allergic symptoms (nasal itching and sneezing), asthma, peripheral blood eosinophil and total IgE (all P<0.05). The overall accuracy, sensitivity and specificity of the JESREC diagnostic criteria was 74.3%, 81.3% and 64.3%, respectively. Conclusions: The eCRSwNP based on artificial intelligence and WSI has significant high level of allergic symptoms, asthma, peripheral blood eosinophils and total IgE, and the percentages of inflammatory cells in nasal polyps are different from that of non-eCRSwNP. The JESREC diagnostic criteria has good consistency in our research.
Artificial Intelligence ; Chronic Disease ; Eosinophils/metabolism* ; Female ; Humans ; Male ; Nasal Polyps/pathology* ; Retrospective Studies ; Rhinitis/pathology* ; Sinusitis/pathology*

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.
Adenosine Monophosphate/therapeutic use* ; Alanine/therapeutic use* ; Alveolar Epithelial Cells/virology* ; Antibodies, Neutralizing/therapeutic use* ; COVID-19/virology* ; Down-Regulation ; Drug Discovery ; Human Embryonic Stem Cells/metabolism* ; Humans ; Immunity ; Lipid Metabolism ; Lung/virology* ; RNA, Viral/metabolism* ; SARS-CoV-2/physiology* ; Virus Replication/drug effects*

OBJECTIVE: The present study was to evaluate the anti-tumor effects of acidic RNA protein complex (FA-2-b-β) extracted from the wild edible Qinba mushroom in inducing of apoptosis and immunoregulation of tumor cell. METHODS: Cell proliferation inducing rate of FA-2-b-β to K562 cell was measured using CCK-8. Apoptosis rate was detected by using flow cytometry. Chronic myeloid leukemia model was developed by tail vein injection/subcutaneous inoculation of K562 cells in NCG mice. The tumor burden of mice was observed. The general condition of the mice was monitored twice daily. The peripherivcal full blood counts of mice was tested daily. RT-qPCR and Western blot was FA-2-b-β performed to determine involvement of apoptotic-related gene and protenin, Immunofluorescence and immunohistochemistry was used to detected the expression of CD3, CD4 and CD8. RESULTS: The proliferation and apoptosis of K562 cell could be inhibitied and induced by FA-2-b-β, there was 100% successful in the tumor formation in vivo, after treated by drug for 21 days there were significantly increased peripheral leucocytes, but decreased hemoglobin of mice treated by FA-2-b-β as compared with those in control group. The CD3, CD4 and CD8 showed positive in mice, and the propotation was imbalance, but it showed reserved after treated by FA-2-b-β. CONCLUSION FA-2-b-β is strong anti-leukemia effect in vitro and in vivo, suggesting the traditional Chinese medicine maybe contribute to the anti-cancer and immunoregulation research.
Agaricales ; Animals ; Apoptosis ; Cell Proliferation ; Humans ; K562 Cells ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; Mice

Objective:To study the clinicopathological features and PD-L1 expression of microsatellite instability-high (MSI-H) gastric cancer.Methods:The clinicopathological data of the 2 472 patients who had undergone radical surgical resection and been performed immunohistochemical staining of four major mismatch repair (MMR) proteins (MLH1, PMS2, MSH2 and MSH6) from March 2014 to December 2018 at Peking University Cancer Hospital were collected. One hundred and seventy-one patients showed mismatch repair-deficient (dMMR), and microsatellite instability of these patients were detected with polymerase chain reaction (PCR). Then, taken PCR results as the standard, PD-L1 was assessed using immunohistochemistry (IHC) in the MSI-H gastric cancers.Results:MSI-H (vs. MSI-L) in gastric cancers was associated with female gender, advanced age, gastric-antrum location, intestinal type, lesion diameter exceeding 5 cm, absence of lymph node metastasis and positive PD-L1 expression ( P<0.05, respectively). Combined positive score (CPS) was an independent risk factor ( P=0.026, HR=8.385, 95% CI=1.293-54.367). Although no relationship between PD-L1 expression pattern and prognosis was observed,"diffuse-pattern" of the PD-L1 expression was related to lymphatic-vascular invasion ( P=0.007) and infiltration depth ( P=0.04). Among the patients with MSI-H and PD-L1 positive gastric cancer, the patients who experienced recurrence or died all had the pattern of "diffuse" PD-L1 expression. Also, regarding the expression level and staining pattern of PD-L1, the metastasis lesion of lymph node had a high coincidence with primary site ( P=0.45). Conclusions:MSI-H gastric cancer shows distinctive clinicopathological characteristics. The CPS can be used as a prognostic indicator in MSI-H gastric cancers, while the "diffuse-pattern" of PD-L1 expression could possibly be used as a prognostic indicator. The patients with advanced gastric cancer could obtain the expression level and staining pattern of PD-L1 using the biopsy material of metastatic lesions.

Kangfu Xiaoyan Suppository is widely used in the treatment of gynecological inflammatory diseases. Long-term clinical application and a certain amount of research evidences show that Kangfu Xiaoyan Suppository can alleviate the clinical symptoms of pelvic inflammatory diseases,reduce the recurrence rate,and relieve sequelae,with a better safety and economic characteristics. As a type of nationally protected traditional Chinese medicine and type B medicine included in medical insurance,it has been selected as a Chinese patent medicine for rectal administration. It was included in the Guidelines for diagnosis and treatment of common gynecological diseases of traditional Chinese medicine published by the Chinese Academy of Traditional Chinese Medicine in 2012,the Pelvic inflammatory diseases diagnosis and treatment guidelines issued by the Infectious Diseases Collaborative Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association in 2014,and the group standard of Single use of traditional Chinese medicine/combined antibiot guidelines for clinical practice-pelvic inflammatory diseases of the Chinese Academy of Traditional Chinese Medicine in 2017. To further enhance clinicians' understanding of the drug and better guide its rational clinical use,experts from the field of gynecology of traditional Chinese and Western medicine were invited to develop and compile this expert consensus. This consensus takes full account of clinical evidences and expert clinical experience,and form recommendations for clinical problems based on evidences and consensus recommendations for clinical problems without evidence by nominal grouping method. The expert consensus is mainly formed in the consideration of six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on clinical research evidences and expert experience,this consensus provides a preliminary reference for the clinical use of the drug in a concise and clear format. However,evidence-based support is still required in a large number of high-quality studies,and this consensus will be revised in the future according to new clinical problems and the update of evidence-based evidence in practical application.
Consensus ; Drugs, Chinese Herbal/therapeutic use* ; Female ; Humans ; Medicine, Chinese Traditional ; Nonprescription Drugs ; Pelvic Inflammatory Disease/drug therapy* ; Suppositories

Objective To evaluate the actual effect of the schistosomiasis control program in Jiangsu Province from 2010 to 2015. Methods A total of 67 schistosomiasis-endemic counties in 10 cities were selected, and a combination of retrospective investigation and on-site investigation was adopted to collect and record the epidemic data of the counties from 2010 to 2015, and a retrospective survey database of epidemic situation was established. The effects of integrated control strategies with both Oncomelania hupensis snail control and infection source control were evaluated. Results From 2010 to 2015, 2 465 911 persons who lived in endemic areas were detected for schistosomiasis, with 16 974 positive cases of blood examinations, and 8 positive cases of fecal examinations. Totally 5 145 people with advanced schistosomiasis were treated and 40 460 people with the history of schistosome cercarial-infested water contact received the expanded chemotherapy. A total of 127 636 cattle raised in the endemic areas were detected, and 51 619 cattle (head-times) with the history of cercarial-infested water contact also received the expanded chemotherapy. The area with snails control by molluscicides was 18 604.84 hm². By the end of 2015, schistosomeinfected snails had not been found and there was no zoological schistosome infection for 5 consecutive years, and in addition, there had been no acute schistosome-infected persons for 6 consecutive years in the whole province. The area with snails dropped to 1 977.18 hm², with a decreasing rate of 55.24% compared with that in 2010. Conclusion After the implementation of the plan for the prevention and control of schistosomiasis in Jiangsu Province (2010–2015), the prevention and control of schistosomiasis has achieved remarkable effects and realized the goal of the plan.

Objective To study the effect of myocardial bridge oppression on blood flow, positive pressure, circumferential stress and shear stress of the coronary artery. Methods The original myocardial bridge simulative device was greatly improved to be able to measure multi-hemodynamic parameters, such as normal stress, circumferential stress and shear stress, so as to exactly simulate real blood dynamics environment with the common effect of several stresses, and comprehensively investigate the relationship between hemodynamics and atherosclerosis of mural coronary artery under the combined effects of several stresses. Results The results from the myocardial bridge simulative device indicated that the hemodynamic abnormalities were mainly located in the proximal end of mural coronary artery, and the mean and oscillation values of normal stress at the proximal end were increased by 27.8% and 139%, respectively, showing a significant increase with the intensification of myocardial bridge oppression. Conclusions It is myocardial oppression that causes the hemodynamic abnormity of proximal coronary artery, which is quite important for understanding the hemodynamic mechanism of coronary atherosclerotic diseases and valuable for studying pathological effects and treatments of the myocardial bridge in clinic.