ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones

Mesenchymal-epithelial transition factor (MET) gene mutation is a large class of mutations commonly seen in non-small cell lung cancer (NSCLC). MET mutation includes subtypes such as MET exon 14 skipping mutation (METex14m) and MET amplification (METamp). For advanced NSCLC with METex14m, Savolitinib has a high sensitivity as a member of tyrosine kinase inhibitors (TKIs). METamp is a relatively rare genetic mutation type which can serve as a driver gene to mediate primary and later acquired drug resistance of epidermal growth factor receptor (EGFR)-TKIs. For advanced NSCLC with secondary METamp, EGFR-TKIs combined with MET-TKIs are usually used in clinical treatment, while the optimal treatment strategy for advanced NSCLC with primary METamp has not yet been determined. For locally advanced NSCLC patients with positive driver gene mutations such as EGFR, anaplastic lymphoma kinase (ALK) fusion and METex14m, there have been relevant cases reported that neoadjuvant targeted therapy could achieve a good prognosis, but there have been no cases of neoadjuvant targeted therapy for locally advanced NSCLC patients with METamp. This report describes a case of a locally advanced NSCLC patient with dual driver gene mutations (EGFR L858R combined with primary METamp), the tumor did not shrink after 1 month of Gefitinib monotherapy, but significantly subsided after 4 months of Savolitinib monotherapy. After radical surgery, the pathological results proved pathological complete response (pCR) of the tumor, and the patient had a good response to postoperative continual Savolitinib treatment, with no recurrence nor metastasis observed to date. This case reports the feasibility and effectiveness of neoadjuvant targeted therapy for locally advanced NSCLC with primary METamp, aiming to provide effective reference for perioperative treatment of locally advanced NSCLC with primary METamp.
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Humans ; Acrylamides/therapeutic use* ; Carcinoma, Non-Small-Cell Lung/pathology* ; Gene Amplification ; Lung Neoplasms/pathology* ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-met/genetics* ; Triazines

Hexazinone is a post-emergence herbicide/arboricides, and its acute poisoning has rarely been reported. Hexazinone is low-toxic to humans, but mass intake of hexazinone would still lead to organ impairment. This article analyzes a case of acute hexazinone poisoning from the poisoning treatment center of our hospital, and summarizes the symptoms and treatment effects of hexazinone poisoning, which is aimed at improving the comprehension, diagnosis and treatment of the disease.
Administration, Oral ; Herbicides ; Humans ; Poisoning ; Triazines

OBJECTIVE: To investigate the antileukemia activity of phosphatidylinositol-3 kinase (PI3K) inhibitor ZSTK474 on human leukemia cell line U937. METHODS: MTT, soft agar assay, flow cytometric analysis and western blot were used to detect the effect of ZSTK474 on U937 cell proliferation, tumorigenicity, cell cycle, cell apoptosis and phosphorylation levels of the key factor of PI3K/AKT pathway. Chou-Talalay method was used to evaluate the combination of ZSTK474 with Cytarabine or Homoharringtonine. RESULTS: PI3K inhibitor ZSTK474 could inhibit the proliferation and tumorigenicity of U937 cell, induce G CONCLUSION ZSTK474 can inhibit the pathway of PI3K/AKT, ZSTK474 alone or in combination with Homoharringtonine shows potential antileukemia activity on U937 cells.
Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Glycogen Synthase Kinase 3 beta ; Humans ; Phosphatidylinositol 3-Kinases ; Proto-Oncogene Proteins c-akt ; Triazines ; U937 Cells

Objective: To investigate the clinicopathological features of gastrointestinal stromal tumor (GIST) with KIT/PDGFRA "homozygous mutation", the efficacy of targeted therapy and the prognosis. Methods: A retrospective cohort study and propensity score matching were used. "Homozygous mutation" was defined as the detection of KIT/PDGFRA gene status of GIST by Sanger sequencing, which showed that there was only mutant gene sequence in the sequencing map, lack of wild-type sequence or the peak height of mutant gene sequence was much higher than that of wild-type gene sequence (> 3 times). "Heterozygous mutation" was defined as the mutant gene sequences coexisted with wild type gene sequences, and the peak height was similar (3 times or less). The clinicopathological data and follow-up information of 92 GIST patients with KIT/PDGFRA "homozygous mutation" were collected from 4 hospitals in Shanghai from January 2008 to May 2021 (Renji Hospital, Shanghai Jiaotong University School of Medicine: 70 cases; Zhongshan Hospital, Fudan University: 14 cases; Changhai Hospital, Naval Military Medical University: 6 cases and Ruijin Hospital, Shanghai Jiaotong University School of Medicine: 2 cases). Patients with perioperative death, other malignancies, and incomplete clinicopathological information were excluded. The clinicopathological features of the patients and the efficacy of targeted drug therapy were observed and analyzed. The efficacy was evaluated using Choi criteria, which were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, a total of 230 patients with high-risk GIST with "heterozygous mutation" in exon 11 of KIT gene and 117 patients with recurrent or metastatic GIST with "heterozygous mutation" in exon 11 of KIT gene were included. The propensity score matching method was used to match GIST patients with "heterozygous" and "homozygous" mutations in exon 11 of KIT gene (1∶1) for survival analysis. The disease-free survival (DFS) between two groups of high-risk GIST patients who underwent complete surgical resection were compared. And progression-free survival (PFS) in patients with recurrent or metastatic GIST were compared. Results: Of the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 58 were males and 34 were females, with a median onset age of 62 (31-91) years. Primary GIST 83 cases. Primary high-risk GIST (53 cases), metastatic GIST (21 cases) and recurrent GIST (9 cases) accounted for 90.2% (83/92). There were 90 cases of KIT gene"homozygous mutation" (exon 11 for 88 cases, exon 13 for 1 case, exon 17 for 1 case), and 2 cases of PDGFRA gene "homozygous mutation" (exon 12 for 1 case, exon 18 for 1 case). The median follow-up time was 49 (8-181) months. Among the 61 cases of primary localized GIST undergoing complete surgical resection, 2 cases were intermediate-risk GIST, 5 cases were low-risk GIST, and 1 case was very low-risk GIST, of whom 1 case of intermediate-risk GIST received 1-year adjuvant imatinib mesylate (IM) therapy after operation, and no tumor recurrence developed during the follow-up period. The remaining 53 cases were high-risk GIST, and follow-up data were obtained from 50 cases, of whom 22 developed tumor recurrence during follow-up. Of 9 patients directly receiving neoadjuvant targeted therapy (IM or avapritinib), 5 had complete imaging follow-up data, and the evaluation of efficacy achieved PR. Of all the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 50 (54.4%) had tumor metastasis or tumor recurrence or progression during follow-up, and 12 (13.0%) died of the tumor. Survival analysis combined with propensity score showed that in 100 cases of high-risk GISTs with complete resection, GISTs with "homozygous mutation" in exon 11 of KIT gene had shorter disease-free survival (DFS) than GISTs with "heterozygous mutation" in exon 11 of KIT gene (median DFS: 72 months vs. 148 months, P=0.015). In 60 cases of recurrent or metastatic GISTs with KIT gene exon 11 mutation, IM was used as the first-line treatment, and the progression-free survival (PFS) of GISTs with "homozygous mutation" was shorter compared to GISTs with "heterozygous mutation" (median PFS: 38 months vs. 69 months, P=0.044). The differences were statistically significant. Conclusions: "Homozygous mutation" in KIT/PDGFRA gene is associated with the progression of GIST. The corresponding targeted therapeutic drugs are still effective for GIST with KIT/PDGFRA gene "homozygous mutation". Compared with GIST patients with "heterozygous mutation" in KIT exon 11, GIST patients with "homozygous mutation" in KIT exon 11 are more likely to relapse after surgery and to develop resistance to IM. Therefore, it is still necessary to seek more effective treatment methods for this subset of cases.
Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use* ; China ; Female ; Gastrointestinal Stromal Tumors/genetics* ; Humans ; Male ; Middle Aged ; Mutation ; Neoplasm Recurrence, Local ; Prognosis ; Proto-Oncogene Proteins c-kit/genetics* ; Pyrazoles ; Pyrroles ; Receptor, Platelet-Derived Growth Factor alpha/genetics* ; Retrospective Studies ; Triazines

Prostate cancer is the second most common cancer in men worldwide. There are many occupational factors that have been suggested to cause prostate cancer. Our aim was to evaluate the evidence for causality by a literature review of occupational factors. We searched literature in Medline and SCOPUS from 1966 to June 30, 2015 to identify occupational risk factors for prostate cancer. The following risk factors were selected: farmers/agricultural workers, pesticides – whole group, and separately organophosphate and organochlorine pesticides, carbamates and triazines, cadmium, chromium, cutting fluids, acrylonitrile, rubber manufacturing, whole body vibration, shift work, flight personnel, ionizing radiation, and occupational physical activity. For each factor a literature search was performed and presented as meta-analysis of relative risk and heterogeneity (Q and I² index). A total of 168 original studies met the inclusion criteria with 90,688 prostate cancer cases. Significantly increased risks were observed for the following occupational exposures: pesticides (metaRR = 1.15, 95% confidence interval [CI] = 1.01–1.32; I² = 84%), and specifically group of organochlorine pesticides (meta relative risk [metaRR] = 1.08, 95% CI = 1.03–1.14; I² = 0%), chromium (metaRR = 1.19, 95% CI = 1.07–1.34; I² = 31%), shift work (metaRR = 1.25, 95% CI = 1.05–1.49; I² = 78%) and pilots (metaRR = 1.41, 95% CI = 1.02–1.94; I² = 63%) and occupational physical activity in cohort studies (metaRR = 0.87, 95% CI = 0.81–0.94; I² = 0%). The literature review supports a causal association for a few of the previously suggested factors.
Acrylonitrile ; Cadmium ; Carbamates ; Chromium ; Cohort Studies ; Epidemiologic Studies ; Humans ; Male ; Motor Activity ; Occupational Exposure ; Pesticides ; Population Characteristics ; Prostate ; Prostatic Neoplasms ; Radiation, Ionizing ; Risk Factors ; Rubber ; Triazines ; Vibration

OBJECTIVE: To study the effects of the overexpression of autophagy-related gene 3 (ATG3) on autophagy and salinomycin-induced apoptosis in breast cancer cells and explore the underlying mechanisms. METHODS: We used the lentivirus approach to establish a breast cancer cell line with stable overexpression of ATG3. Western blotting, immunofluorescence staining and transmission electron microscopy were used to analyze the effect of ATG3 overexpression on autophagy in breast cancer MCF-7 cells. Using the AKT/mTOR agonists SC79 and MHY1485, we analyzed the effect of AKT/mTOR signal pathway activation on ATG3 overexpression-induced autophagy. Western blotting and flow cytometry were used to analyze the effect of autophagy on apoptosis of the ATG3-overexpressing cells treated with salinomycin and 3-MA (an autophagy inhibitor). RESULTS: In ATG3-overexpressing MCF-7 cells, ATG3 overexpression obviously promoted autophagy, inhibited the AKT/mTOR signaling pathway, significantly weakened salinomycin-induced apoptosis ( < 0.01), caused significant reduction of the levels of the pro-apoptotic proteins cleaved-caspase 3 ( < 0.01) and Bax ( < 0.05), and enhanced the expression of the anti-apoptotic protein Bcl-2 ( < 0.05). The inhibition of autophagy obviously weakened the inhibitory effect of ATG3 overexpression on salinomycin-induced apoptosis. CONCLUSIONS ATG3 overexpression promotes autophagy possibly by inhibiting the AKT/mTOR signaling pathway to decrease salinomycin-induced apoptosis in MCF-7 cells, suggesting that autophagy induction might be one of the mechanisms of drug resistance in breast cancer cells.
Acetates ; pharmacology ; Apoptosis ; drug effects ; genetics ; Autophagy ; drug effects ; Autophagy-Related Proteins ; metabolism ; Benzopyrans ; pharmacology ; Breast Neoplasms ; metabolism ; pathology ; Cell Line, Tumor ; Cell Proliferation ; Drug Resistance, Neoplasm ; Female ; Gene Expression Regulation ; Humans ; MCF-7 Cells ; Morpholines ; pharmacology ; Proto-Oncogene Proteins c-akt ; antagonists & inhibitors ; metabolism ; Pyrans ; pharmacology ; TOR Serine-Threonine Kinases ; antagonists & inhibitors ; metabolism ; Triazines ; pharmacology ; Ubiquitin-Conjugating Enzymes ; metabolism

A case of a 17-year-old nulligravid with onset of seizure episodes since menarcheis reported. She was diagnosed with Seizure Disorder treated with Phenobarbital and was seizure free for 2 years. Two years prior to consult, seizure recurrences were noted to coincide with menstruation, hence, was diagnosed with Catamenial Epilepsy. Patient was shifted to Lamotrigine but seizure exacerbations were still observed, prompting referral to the Reproductive Medicine service for adjunctive hormonal therapy. Depot medroxyprogesterone acetate was added to the antiepileptic drug which provided seizure control. Adjunctive hormonal therapy proved to be helpful in the management of intractable seizures in this patient.

The report aims to give a better understanding of the neuroactive properties of estrogen and progesterone and its role in the development of Catamenial Epilepsy. Gender-related and psychosocial issues in the treatment of Epilepsy in the child-bearing years up to the menopause are also discussed.

Human ; Female ; Adolescent ; Anticonvulsants ; Seizures ; Progesterone ; Lamotrigine ; Medroxyprogesterone Acetate ; Menstruation ; Epilepsy ; Triazines ; Phenobarbital ; Menopause ; Estrogens ; Reproductive Medicine

A case of a 17-year-old nulligravid with onset of seizure episodes since menarcheis reported. She was diagnosed with Seizure Disorder treated with Phenobarbital and was seizure free for 2 years. Two years prior to consult, seizure recurrences were noted to coincide with menstruation, hence, was diagnosed with Catamenial Epilepsy. Patient was shifted to Lamotrigine but seizure exacerbations were still observed, prompting referral to the Reproductive Medicine service for adjunctive hormonal therapy. Depot medroxyprogesterone acetate was added to the antiepileptic drug which provided seizure control. Adjunctive hormonal therapy proved to be helpful in the management of intractable seizures in this patient.

The report aims to give a better understanding of the neuroactive properties of estrogen and progesterone and its role in the development of Catamenial Epilepsy. Gender-related and psychosocial issues in the treatment of Epilepsy in the child-bearing years up to the menopause are also discussed.

Human ; Female ; Adolescent ; Anticonvulsants ; Seizures ; Progesterone ; Lamotrigine ; Medroxyprogesterone Acetate ; Menstruation ; Epilepsy ; Triazines ; Phenobarbital ; Menopause ; Estrogens ; Reproductive Medicine

OBJECTIVETo investigate the efficacy and safety of lamotrigine monotherapy in children with epilepsy via a systematic review.

METHODSPubMed, Cochrane, CNKI, VIP, CBM, Wanfang Data were searched for randomized controlled trials (RCTs) of lamotrigine monotherapy in children with epilepsy. Literature screening, data extraction, and quality assessment were performed according to the method recommended by Cochrane Collaboration. RevMan 5.2 software was used to conduct the Meta analysis.

RESULTSA total of 9 RCTs involving 1 016 participants were included. Lamotrigine yielded a significantly lower complete control rate of seizure than ethosuximide, but the complete control rate of seizure showed no significant differences between lamotrigine and carbamazepine/sodium valproate. Patients treated with lamotrigine had a significantly lower incidence rate of adverse events than those treated with carbamazepine, but the incidence rate of adverse events showed no significant differences between patients treated with lamotrigine and sodium valproate/carbamazepine. The drop-out rate showed no significant differences between the three treatment groups.

CONCLUSIONSLamotrigine is an ideal alternative drug for children who do not respond to traditional antiepileptic medication or experience significant adverse reactions; however, more high-quality RCTs with a large sample size and a long follow-up time are needed to confirm these conclusions.

Anticonvulsants ; therapeutic use ; Epilepsy ; drug therapy ; Humans ; Randomized Controlled Trials as Topic ; Triazines ; adverse effects ; therapeutic use