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The COVID-19 pandemic is the most important public health threat in recent history. Here we study how its causal agent, SARS-CoV-2, has diversified genetically since its first emergence in December 2019. We have created a pipeline combining both phylogenetic and structural analysis to identify possible human-adaptation related mutations in a data set consisting of 4,894 SARS-CoV-2 complete genome sequences. Although the phylogenetic diversity of SARS-CoV-2 is low, the whole genome phylogenetic tree can be divided into five clusters/clades based on the tree topology and clustering of specific mutations, but its branches exhibit low genetic distance and bootstrap support values. We also identified 11 residues that are high-frequency substitutions, with four of them currently showing some signal for potential positive selection. These fast-evolving sites are in the non-structural proteins nsp2, nsp5 (3CL-protease), nsp6, nsp12 (polymerase) and nsp13 (helicase), in accessory proteins (ORF3a, ORF8) and in the structural proteins N and S. Temporal and spatial analysis of these potentially adaptive mutations revealed that the incidence of some of these sites was declining after having reached an (often local) peak, whereas the frequency of other sites is continually increasing and now exhibit a worldwide distribution. Structural analysis revealed that the mutations are located on the surface of the proteins that modulate biochemical properties. We speculate that this improves binding to cellular proteins and hence represents fine-tuning of adaptation to human cells. Our study has implications for the design of biochemical and clinical experiments to assess whether important properties of SARS-CoV-2 have changed during the epidemic.Competing Interest StatementThe authors have declared no competing interest.View Full Text
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The emergence of a novel coronavirus, SARS-CoV-2, resulted in a pandemic. Here, we used recently released X-ray structures of human ACE2 bound to the receptor-binding domain (RBD) of the spike protein (S) from SARS-CoV-2 to predict its binding to ACE2 proteins from different animals, including pets, farm animals, and putative intermediate hosts of SARS-CoV-2. Comparing the interaction sites of ACE2 proteins known to serve or not serve as receptor allows to define residues important for binding. From the 20 amino acids in ACE2 that contact S up to seven can be replaced and ACE2 can still function as the SARS-CoV-2 receptor. These variable amino acids are clustered at certain positions, mostly at the periphery of the binding site, while changes of the invariable residues prevent S-binding or infection of the respective animal. Some ACE2 proteins even tolerate the loss or the acquisition of N-glycosylation sites located near the S-interface. Of note, pigs and dogs which are not or not effectively infected, respectively, have only a few changes in the binding site have relatively low levels of ACE2 in the respiratory tract. Comparison of the RBD of S of SARS-CoV-2 with viruses from bat and pangolin revealed that the latter contains only one substitution, whereas the bat virus exhibits five. However, ACE2 of pangolin exhibit seven changes relative to human ACE2, a similar number of substitutions is present in ACE2 of bats, raccoon, and civet suggesting that SARS-CoV-2 may not especially adapted to ACE2 of any of its putative intermediate hosts. These analyses provide new insight into the receptor usage and animal source/origin of SARS-COV-2. IMPORTANCESARS-CoV-2 is threatening people worldwide and there are no drugs or vaccines available to mitigate its spread. The origin of the virus is still unclear and whether pets and livestock can be infected and transmit SARS-CoV-2 are important and unknown scientific questions. Effective binding to the host receptor ACE2 is the first prerequisite for infection of cells and determines the host range. Our analysis provides a framework for the prediction of potential hosts of SARS-CoV-2. We found that ACE2 from species known to support SARS-CoV-2 infection tolerate many amino acid changes indicating that the species barrier might be low. However, the lower expression of ACE2 in the upper respiratory tract of some pets and livestock means more research and monitoring should be done to explore the animal source of infection and the risk of potential cross-species transmission. Finally, the analysis also showed that SARS-CoV-2 may not specifically adapted to any of its putative intermediate hosts.
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Toad venom as a Chinese traditional natural medicine with a kind of effective chemical components has been widely used for many disease.Recently more and more research was focused on its remarkable antitumor efforts, new studies have found that the mechanism was closely associated with endoplasmic reticulum stress,tumor-related inflammation, autophagy, mitochondria-induced apoptosis pathway, heat chock protein and immuneomodulatory.In this article we reviewed the antitumor research advances of toad venom and its active compounds from several aspects mentioned above.
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The aim of this study is to analyze how patients with chronic diseases from Shanghai interpret their disease, and how these interpretations influence patients' life satisfaction, intention to escape from their illness and their ability to reflect on the implications of their illness.
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Even in secular societies, a small portion of patients find their spirituality to help cope with illness. But for the majority of patients, psychosocial and spiritual needs are neither addressed nor even considered a relevant factor by health care professionals. To measure such specific needs, the Spiritual Needs Questionnaire (SpNQ) was developed. The aim of this study was to validate the Chinese version of the SpNQ (SpNQ-Ch) and thus to measure psychosocial and spiritual needs of Chinese patients.
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Disease recurrence is a main challenge in treatment of hepatocellular carcinoma (HCC). There is no generally accepted method for preventing recurrence of HCC after resection.
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To study the traditional Chinese medicine (TCM) syndrome distribution in patients with hepatitis B virus (HBV) infection in Qidong region of Jiangsu Province, China.
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Objective To evaluate the effectiveness and safety of minimal incision laparotomy assisted endoscopic resection for polyps in small intestine in patients with Peutz-Jeghers syndrome. Methods The clinical data of patients with Peutz-Jeghers syndrome, who underwent minimal incision laparotomy assisted endoscopic resection for polyps in small intestine, were retrospectively studied. The size and number of the endoscopically rosected polyps, and the procedure related complications were documented. Results A total of 812 polyps in small-bowel were resected in 8 patients, in which 384 were smaller than 10mm, 356 with diameter ranging from 11 mm to 30mm, and 72 were larger than 30mm in diameter. Procedure related complications included intestinal dysfunction in 1 patient and abdominal pain in another. No bleeding with a fall in Hb or other severe complications were observed. Conclusion Minimal incision laparotomy assisted endoscopic resectio is a safe and reliable procedure for the treatment of mid-small bowel polyps in patients with Peutz-Jeghers syndrome. It revolutionizes the therapeutic options for polyps in the region of the mid-small bowel and limits the indications for primary surgical management.
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BACKGROUND: Currently, most therapies of postembolization syndrome following transcatheter arterial chemoembolization (TACE) aim directly at a single symptom, thus leading to limitations. OBJECTIVES: To seek for a systematic approach to prevent and treat the syndrome, we carried out this study to observe the effect of ginsenosides (GS) and dexamethasone (Dex) in alleviating the postembolization syndrome following TACE. METHODS: In the randomized, double-blinded and controlled trial, 120 patients with primary liver cancer were divided into 4 groups, with 30 patients in each group. The changes of clinical symptoms and laboratory tests before TACE and on 3 and 7 days after TACE were observed. RESULTS: The results indicated that Dex combined with GS not only markedly decreased the occurrence ratio and duration of such symptoms as nausea, vomiting, and fever, but also significantly reduced levels of total bilirubin, glutamic oxaloacetic transaminase, and glutamic-pyruvic transaminase (AST) and improved the Child-Pugh stage of liver function as compared with single use of GS or Dex. CONCLUSIONS: In conclusion, although single use of Dex or GS may improve some indices of adverse effects after TACE, the combination of Dex and GS can systematically prevent and treat the postembolization syndrome following TACE.
Subject(s)
Antineoplastic Agents/therapeutic use , Chemoembolization, Therapeutic/adverse effects , Dexamethasone/therapeutic use , Ginsenosides/therapeutic use , Liver Neoplasms/drug therapy , Panax/chemistry , Plant Extracts/therapeutic use , Adult , Aged , Alanine Transaminase/blood , Antineoplastic Agents/adverse effects , Aspartate Aminotransferases/blood , Bilirubin/blood , Chemoembolization, Therapeutic/methods , Combined Modality Therapy , Double-Blind Method , Drug Therapy, Combination , Female , Fever/drug therapy , Fever/etiology , Humans , Liver Neoplasms/blood , Liver Neoplasms/complications , Male , Middle Aged , Nausea/drug therapy , Nausea/etiology , Phytotherapy , Vomiting/drug therapy , Vomiting/etiologyABSTRACT
To observe the effects of cinobufacini injection on serum levels of thyroid-stimulating hormone (TSH) and adrenaline (ADR) in rats, and to speculate the property (cold or heat) of the drug.
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OBJECTIVE: To construct a system of therapeutic effect evaluation for patients with primary liver cancer according to the theory of syndrome differentiation in traditional Chinese medicine (TCM), and to examine its reliability. METHODS: Analytic hierarchy process and 100 mm surveyor's rod method were applied to obtain bottom layer and top level syndromes, which were used to construct the method of therapeutic effect evaluation, and its reliability was verified in clinical practice by comparing with some evaluation criteria in Western medicine, such as cancer severity scale; Karnofsky performance scale; Child-Pugh classification, cancer staging classification, and quality of life scale, etc. RESULTS: A system of therapeutic effect evaluation was constructed, and it could reflect the progress of tumor, changes of hepatic function and constitution. The evaluation scores acquired from the system were highly associated with the quality of life of the patients. CONCLUSION: The system of therapeutic effect evaluation can reflect the severity of disease and the characteristics of TCM treatment.
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OBJECTIVE: To explore the correlation between the width of lingual varix and changes of hemodynamics of portal system in patients with primary liver cancer so as to supply the data for the forecast of portal hypertension by observing lingual varix. METHODS: The diameter of lingual vein (Dlv) was measured by vernier caliper as dependent variable, and the diameters and indexes of hemodynamics of portal vessels were measured by Doppler as independent variables, then a multipe stepwise analysis was performed. RESULTS: The diameters of portal vein (Dpv) and splenic vein (Dsv) entered the formula Dlv (mm) = 0.185 + 0.311 Dsv (mm) + 0.236 Dpv (mm) when the entry and removal values were alpha(in)=0.10 and alpha(out)=0.15, respectively. CONCLUSION: The width of lingual vein is closely correlated with the diameters of portal vein and splenic vein in patients with primary liver cancer.
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OBJECTIVE: To establish a staging standard for a transplanted hepatoma model in rats, which may be equivalent to the human primary liver cancer. METHODS: A transplanted hepatoma model was made in SD rats by implantation of histologically intact Walker-256 tumor fragment into the left lateral lobe of the liver. The body weight, tumor volume and serum albumin level of the rats were measured and assayed in different periods. Pathological sections were also fabricated to detect the invasion and metastasis of the neighboring tissues. RESULTS: The body weight loss and ascites occurred at the 12th and 18th day separately. The serum albumin level was (35.32+/-2.45) g/L at the 11th day, which showed no statistical difference as compared with the healthy rats (P>0.05), and the albumin level at the 18th day was significantly lower than that at the 11th day (P<0.05). At the 23rd day, 56.25% of the rats developed bloody ascites. CONCLUSION: The period between 5-11 days in the model rats may be correspondent to the early stage of human primary liver cancer, and the biological behavior of the model rats at the18th day may be correspondent to the late stage of human primary liver cancer. This staging standard might be the guideline for model selection in experimental study of primary liver cancer.
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OBJECTIVE: To work out a qualitative diagnostic criterion for basic syndromes of traditional Chinese medicine in patients with primary liver cancer. METHODS: Based on the collection and analysis of related medical literature, clinical investigation, and experts' discussion, a preliminary qualitative diagnostic criterion for basic syndromes of traditional Chinese medicine in patients with primary liver cancer was formulated. Then it was used in clinic to be verified and revised repeatedly till it was improved to be a satisfied formal criterion. RESULTS: The basic syndromes listed in the qualitative diagnostic criterion for basic syndromes in patients with primary liver cancer consisted of two parts: excessive syndromes, including the syndromes of stagnation of qi, blood stasis, excess-heat and dampness, and deficient syndromes, including the syndromes of deficiency of qi, deficiency of blood, deficiency of yin and deficiency of yang. Each of the above syndromes could be diagnosed according to specific combination of its corresponding symptoms or signs. The clinical verification results showed that the total matching ratio was 73.92% between the diagnoses made according to the criterion and the diagnoses acquired from the experts' experience. CONCLUSIONS: The qualitative diagnostic criterion for basic syndromes of traditional Chinese medicine in patients with primary liver cancer is coincident with the experts' clinical practice. However, it needs to be further studied.
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OBJECTIVE: To observe the clinical effect of cinobufacini injection in treating moderate and advanced primary liver cancer (PLC). METHODS: One hundred patients with moderate and advanced PLC were randomly divided into cino-treated group (50 patients) and control group (50 patients). The quality of life, tumor size, some changes of laboratory tests, and survival time were observed. RESULTS: The progressive rate of cino-treated group (18%) was lower than that of the control group (32%). The quality of life of the cino-treated group (80%) was better than that of the control group (72%), but without statistical significance. The survival rate of >12 months of the cino-treated group (30%) was higher than that of the control group (18%). The patients' liver function such as serum total bilirubin and ALT decreased obviously in the cino-treated group while increased a lot in the control group. The level of AFP increased after treatment with statistical significance in the control group while there was no statistical significance in the cino-treated group. CONCLUSION: Cinobufacini injection can not only inhibit the proliferation of cancer, but also protect liver function, improve quality of life and prolong survival time.
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Objective: To investigate the therapeutic effects of norcantharidin poloxamer 407(NCTD P407) slow released preparation on advanced primary liver cancer by local intratumoral injection. Methods: Fifty six advanced primary liver cancer patients with maximum diameter from 6 to 12 cm were randomly divided into test and control groups. Patients in test group (29 case) were treated by NCTD 407 intratumoral injection under ultrasonic and patients in control group (27 case) by PEI (percutaneous intratumoral absolute ethanol injection). Clinical therapeutic effects were observed respectively and compared. Results: Twelve months survival rates of patients in 2 groups were significantly different, being 31.0% in test group and 22.2% in control group ( P 0.05) in 2 groups. No evident poisonous and side effects were found in either test or control group. Conclusion: NTCD P407 administration exhibits therapeutic effects in relatively big advanced liver cancer because of the high concentration and prolonged action in the tumor foci, its comprehensive therapeutic effect is better than that of absolute ethanol administration. [
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Objective To study the reversal effect on acquired multidrug resistance (MDR) of human hepatocellular caricinoma (HCC) by Ganli Injection. Methods Proliferative inhibition rate of HCC BEL-7402/5-Fu cell line and reversal index of 5-Fu acquired MDR were measured by MTT assay. Cell morphological changes were observed under inverted microscope and Wright-Giemsa stain method. Fluorescence intensity of Adriamycin (ADM) was detected by Flow cytometry. Results HCC BEL-7402/5-Fu cell line exhibited cross-resistance to general chemotherapeutics in clinic. Proliferative inhibition rates of HCC BEL-7402/5-Fu cell line treated for 72 h by Ganli Injection at the (matrine) concentration of 0.230, 0.115, 0.058 mg/mL were (9.25?2.38)%, (8.46?1.90)%, and (4.23?2.05)%, respectively. The corresponding reversal indexes to 5-Fu were 5.50, 3.83, and 2.25. Pre-treatment of Galli Injection at the concentration of 0.230 mg/mL for 2 h could increase the accumulation of ADM in cells to 38.61%.Conclusion Ganli Injection has the effect on reversing 5-Fu acquired MDR of human hepatocellular carcinoma in vitro.
