Second-line immunosuppressant administration for steroid-refractory immune-related adverse events in patients with lung cancer.

BACKGROUND: Evidence for use of second-line immunosuppressants for immune-related adverse events (irAEs) is inadequate. Therefore, a multicenter analysis should assess the efficacy of second-line immunosuppressants for severe irAEs associated with different malignant diseases. METHODS: This descriptive study aims to investigate the effects of second-line immunosuppressants on corticosteroid-refractory irAEs in patients with lung cancer. We analyzed the effects of second-line immunosuppressants on underlying lung cancer and associated adverse effects. RESULTS: Our study included 4589 patients who had received immune checkpoint inhibitor treatment, with 73 patients (1.6%) developing irAEs requiring second-line immunosuppressants. The most commonly observed irAE was pneumonitis (26 patients), followed by hepatobiliary disorders (15 patients) and enteritis (14 patients). We found a confirmed response rate of 42.3% for pneumonitis, which was lower than the response rates of 86.7% for hepatobiliary disorders and 92.9% for enteritis. The time from the start of corticosteroid therapy to the addition of a second-line immunosuppressant correlated significantly with the resolution of irAE to Grade 1 (correlation coefficients of r = 0.701, p < 0.005). The median progression-free survival and duration of response of underlying lung cancer from second-line immunosuppressant administration were 2.1 and 3.0 months, respectively. Of the patients with irAE, 27.4% developed infections and 5.5% might die due to infection. CONCLUSION: Second-line immunosuppressant response was confirmed in 72.2% of irAEs in patients with lung cancer, with lower response rates observed in irAE pneumonitis compared to other irAEs.

Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA1) antagonists.

BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA1) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA1 antagonism, two structurally distinct LPA1 antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma BAs in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA1.

Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278.

In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA1) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA1 antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC50 1.8 µM), MRP3 (IC50 22 µM), and MRP4 (IC50 6.2 µM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 µM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 µM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC50 7.5 µM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC50 ≥20 µM) and did not inhibit MDR3 activity (IC50 >100 µM), nor did BMS-986234 inhibit BA efflux (≤50 µM) or mitochondrial function (≤30 µM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA1 antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA1 antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.

Valganciclovir prophylaxis for cytomegalovirus infection in pediatric kidney transplant recipients: a single-center experience.

BACKGROUND: There are two approaches for treating cytomegalovirus (CMV) infection occurring after kidney transplantation (KTx). One is preemptive therapy in which treatment is started after confirming positive CMV antigenemia using periodic antigenemia assay. The other approach is prophylactic therapy in which oral valganciclovir (VGCV) is started within 10 days after KTx and continued for 200 days. The Transplantation Society guidelines recommend prophylactic therapy for high-risk (donor's CMV-IgG antibody positive and recipient's negative) pediatric recipients. However, the adequate dose and side effects of VGCV are not clear in children, and there is no sufficient information about prophylaxis for Japanese pediatric recipients. METHODS: A single-center retrospective analysis was conducted on case series of high-risk pediatric patients who underwent KTx and received oral VGCV prophylaxis at the Department of Pediatric Nephrology, Tokyo Women's Medical University, between August 2018 and March 2019. Data were collected using medical records. RESULTS: The dose of administration was 450 mg in all the study patients (n = 5). Reduction or discontinuation was required in four of five patients due to adverse events, which included neutropenia in one patient, anemia in two patients, and neutropenia and digestive symptoms in one patient. Late-onset CMV disease occurred in all patients. No seroconversion was observed during prophylaxis. CONCLUSIONS: Our preliminary study suggests that the dosage endorsed by The Transplantation Society may be an overdose for Japanese pediatric recipients. Further studies are required to examine the safety and efficacy of VGCV prophylaxis in Japanese pediatric recipients.

Pembrolizumab-induced large duct cholangiopathy: Diagnosis and follow.up imaging.

Immune-checkpoint inhibitor mediated hepatobiliary injury is an emerging concern in cancer treatment. Most of these adverse reactions are attributed to nivolumab and are characterized by panlobular hepatitis. Large duct cholangiopathy related to these drugs is extremely rare. We present a case of adenocarcinoma of lung treated with pembrolizumab who developed biochemical and imaging features consistent with cholangiopathy characterized by common bile duct dilatation, wall enhancement, and gallbladder wall edema. On follow-up in the fourth month, the imaging features persisted despite the normalization of liver enzymes. To the best of our knowledge, this is the first description of diagnosis and follow-up imaging of pembrolizumab-related cholangiopathy in imaging literature.

Fast Identification of Adverse Drug Reactions (ADRs) of Digestive and Nervous Systems of Organic Drugs by In Silico Models.

This study aimed to discover concurrences of adverse drug reactions (ADRs) and derive models of the most frequent items of ADRs based on the SIDER database, which included 1430 marketed drugs and 5868 ADRs. First, common ADRs of organic drugs were manually reclassified according to side effects in the human system and followed by an association rule analysis, which found ADRs of digestive and nervous systems often occurred at the same time with a good association rule. Then, three algorithms, linear discriminant analysis (LDA), support vector machine (SVM) and deep learning, were used to derive models of ADRs of digestive and nervous systems based on 497 organic monomer drugs and to identify key structural features in defining these ADRs. The statistical results indicated that these kinds of QSAR models were good tools for screening ADRs of digestive and nervous systems, which gave the ROC AUC values of 81.5%, 98.9%, 91.5%, 69.5%, 78.4% and 78.8%, respectively. Then, these models were applied to investigate ADRs of 1536 organic compounds with four phase and zero rule-of-five (RO5) violations from the ChEMBL database. Based on the consensus ADRs' predictions of models, 58.1% and 42.6% of compounds were predicted to cause these two ADRs, respectively, indicating the significance of initial assessment of ADRs in early drug discovery.

Immune-related adverse reactions in the hepatobiliary system: second-generation check-point inhibitors highlight diverse histological changes.

AIMS: Immune check-point inhibitors are known to cause immune-mediated adverse liver injury, but our knowledge is mainly based on cases treated with ipilimumab or nivolumab. METHODS AND RESULTS: Clinicopathological features of 10 patients with hepatobiliary adverse reactions caused by second-generation drugs, pembrolizumab (n = 6) and atezolizumab (n = 4), were reviewed. Liver dysfunction developed during a median period of 3.5 weeks after administration of the check-point inhibitor (3 days-1 year). Antinuclear antibodies were detected in two patients at a low titre (1/80), and serum IgG concentrations were also only mildly elevated in two patients. Liver biopsies showed panlobular hepatitis (n = 5), cholangiopathic changes (n = 2), granulomatous injury (n = 2) and bland cholestasis (n = 1). Two cases of cholangiopathy (both pembrolizumab-treated) showed diffuse sclerosing cholangitis on imaging, and one also presented lymphocytic cholangitis resembling primary biliary cholangitis on biopsy. In two atezolizumab-treated cases, Küpffer cells were hyperplastic and aggregated, forming microgranulomas. Confluent necrosis and eosinophilic or plasma cell infiltration were rare. On immunostaining, the ratio of CD8+ /CD4+ cells was 12.2 ± 5.1, which was significantly higher than that in autoimmune hepatitis (2.7 ± 1.1; P < 0.001) or idiosyncratic drug-induced liver injury (5.0 ± 1.1; P = 0.014). All patients responded to steroid therapy, but it was less effective in patients with sclerosing cholangitis. CONCLUSIONS: Pembrolizumab and atezolizumab manifested not only lobular hepatitis but also sclerosing cholangitis, lymphocytic duct injury and granulomatous hepatitis, probably representing various impaired cellular functions in CD8+ lymphocytes and macrophages due to blockage of PD-1-PD-L1 interaction.

Capecitabine and Temozolomide as a Promising Therapy for Advanced Thymic Atypical Carcinoid.

BACKGROUND: Thymic atypical carcinoid (TAC) is a rare thymic neuroendocrine tumor that originates in the neuroendocrine system and lacks a standardized treatment. The combination of capecitabine (CAP) and temozolomide (TEM) is associated with an extremely high and long-lasting response rate in patients with metastatic pancreatic neuroendocrine tumors. However, there is little evidence showing that the CAPTEM regimen is effective for TAC. For patients with unresectable or metastatic atypical carcinoid of the thymus, few treatment options are available, and the treatment efficacy is not satisfactory. To explore the efficacy and safety of the CAPTEM regimen against TAC, we conducted a retrospective review. PATIENTS AND METHODS: A total of nine patients with advanced atypical carcinoid of the thymus in the China-Japan Friendship Hospital were treated with capecitabine (750 mg/m2 twice daily, days 1-14) and temozolomide (200 mg/m2 once daily, days 10-14) every 28 days between 2014 and 2018. The disease control rate (DCR), progression-free survival (PFS), and adverse effects after treatment were analyzed. The DCR was calculated by RECIST version 1.1. Progression-free survival was calculated by the Kaplan-Meier survival method. RESULTS: A total of nine patients (six male and three female) were included. The median age at CAPTEM initiation was 50 years (range, 26-58). The median number of CAPTEM cycles was 8 (range, 3-23). The DCR was 89% (8/9), with eight patients achieving stable disease. Only one patient (11%) showed progressive disease. The median PFS was 8 months. Because we applied vitamin B6 and ondansetron before administering the drugs, the side effects of this regimen were very small. Adverse reactions were all below grade 3 and included myelosuppression and digestive tract reaction. CONCLUSION: Our results suggest that the CAPTEM regimen may be effective and well tolerated for the treatment of TAC. More evidence is needed to validate the effectiveness of this regimen. IMPLICATIONS FOR PRACTICE: Capecitabine and temozolomide regimen is effective and well tolerated in patients with advanced thymic atypical carcinoid.

Retrospective study of the digestive tract mucositis derived from myeloablative and non-myeloablative/reduced-intensity conditionings with busulfan in hematopoietic cell transplantation patient.

Busulfan is a major component of chemotherapy conditioning in hematopoietic cell transplantation (HCT). This alkylating agent is highly toxic at myeloablative doses, exposing HCT patients to risks of mortality. Non-myeloablative (NMA) and reduced-intensity conditioning (RIC) using busulfan have shown impaired toxicity. However, the toxicity of NMA/RIC in the digestive tract is poorly described. This study aimed to characterize the mucositis in the oral cavity (OM), oropharynx/esophagus, and gastrointestinal tract derived from conditionings with myeloablative and non-myeloablative doses of busulfan. We retrospectively retrieved clinical data of HCT patients (n = 100) who underwent myeloablative conditioning (MAC) or NMA/RIC with busulfan. Frequency and time duration of mucositis in the oral cavity and oropharynx/esophagus, diarrhea, and prescription of total parenteral nutrition (TPN) and opioids were also collected. OM severity (p = 0.009) and time duration of mucositis in oropharynx/esophagus (p = 0.022) were frequently higher in MAC than NMA/RIC. A myeloablative dose of busulfan was a risk factor for OM grade ≥ 2 (OR = 4.8, p = 0.002) and for mucositis in oropharynx/esophagus ≥ 5 days (OR = 2.64, p = 0.035). A longer duration of mucositis in the oropharynx/esophagus was also associated with an increase in the prescription of opioids (OR = 7.10, p < 0.001).Overall survival (OS) in MAC was significantly higher than that in NMA/RIC (p = 0.017). No variables related to mucositis interfere significantly in OS. In conclusion, myelosuppression in busulfan-based regimens are predisposed to a high risk for severe OM and to prolonged mucositis in the oropharynx/esophagus.

PREVALENCE OF DISEASES AMONG ADOLESCENT POPULATION IN DNEPROPETROVSK REGION (UKRAINE), CORRELATED WITH DRINKING WATER QUALITY DETERIORATION.

Purpose of research was to study dynamics prevalence of diseases among children' population in the separate rural tacsons of Dnepropetrovsk region; to carry out correlation analysis between some indicators of drinking water quality and prevalence of diseases. Research indicators of prevalence of diseases was carried out in the 6 types of tacsons of Dnipropetrovsk region (Ukraine) during 2008 - 2013 years (totally 522720 indicators). It was proved that (I, II, III, XI, XIII, XIV) classes of diseases takes the first place by the prevalence of diseases in the majority of rural tacsons. Correlation between higher salt content of the potable water taking from decentralized sources and content of some heavy metals (Zn, Cu, Mn) and some substances (pH, F, Al, nitrogen ammonia, nitrites, nitrates, oxidability) and the prevalence of diseases among children: tumors (r=0.87); diseases of blood and hematopoetic organs (r=0.74-0.95); anemia (r=0.79-0.87); diseases of genitourinary system (r=0.79-0.82); congenital anomalies (r=0.87), including circulatory system (r=0.74-0.95) was revealed in the separate tacsons of Dnepropetrovsk region (p<0.001).

Toxicity of oxaliplatin plus fluorouracil/leucovorin adjuvant chemotherapy in elderly patients with stage III colon cancer: a population-based study.

BACKGROUND: Results concerning the side effects of oxaliplatin associated with fluorouracil and leucovorin (FOLFOX) in older patients are controversial. The objective of this study was to assess the use and the toxicity of FOLFOX in patients aged 70 years and older as administered in current practice. METHODS: Among 305 stage III colon cancers registered in a well-defined population in Burgundy between 2004 and 2009, 210 had adjuvant chemotherapy, including 156 with FOLFOX. The cumulated rates of toxicity were calculated by using the Kaplan-Meier method. The risks of overall toxicity and of severe toxicity (grade 3 or 4) in patients less than 70 years and in older patients were compared by using a Cox model. RESULTS: There was no difference between the group of the patients less than 70 years and the older age group for the cumulative incidence of hematologic, neurologic, digestive, and general toxicity. There was also no difference between the two groups for the severity of side effects (grade 3 or 4, 31.4 vs. 39.0 %; p = 0.576). The multivariate analysis indicated after adjustment on sex and the Charlson comorbidity score that there was no difference between the two age groups for toxicity (hazard ratio = 1.28; 95 % CI 0.68-2.41; p = 0.439). CONCLUSIONS: Cancer registries can be used to evaluate the toxicity of chemotherapy at the population level. Tolerance to the FOLFOX regimen among elderly patients did not significantly differ from that in younger patients. This treatment should be considered regardless of patients' age alone, but consideration should be given to the capacity of patients to tolerate adverse events.

Tributyrin supplementation protects mice from acute ethanol-induced gut injury.

BACKGROUND: Excessive alcohol consumption leads to liver disease. Interorgan crosstalk contributes to ethanol (EtOH)-induced liver injury. EtOH exposure causes gut dysbiosis resulting in negative alterations in intestinal fermentation byproducts, particularly decreased luminal butyrate concentrations. Therefore, in the present work, we investigated the effect of butyrate supplementation, in the form of trybutyrin, as a prophylactic treatment against EtOH-induced gut injury. METHODS: C57BL/6J mice were treated with 3 different EtOH feeding protocols: chronic feeding (25 days, 32% of kcal), short-term (2 days, 32%), or acute single gavage (5 g/kg). Tributyrin (0.83 to 10 mM) was supplemented either into the liquid diet or by oral gavage. Intestinal expression of tight junction (TJ) proteins and a butyrate receptor and transporter were evaluated, as well as liver enzymes and inflammatory markers. RESULTS: All 3 EtOH exposure protocols reduced the expression and co-localization of TJ proteins (ZO-1, occludin) and the expression of a butyrate receptor (GPR109A) and transporter (SLC5A8) in the ileum and proximal colon. Importantly, tributyrin supplementation protected against these effects. Protection of the intestine with tributyrin supplementation was accompanied by mitigation of EtOH-induced increases in aspartate aminotransferase and inflammatory measures in the short-term and acute EtOH exposure protocols, but not after chronic EtOH feeding. CONCLUSIONS: These findings suggest that tributyrin supplementation could serve as a prophylactic treatment against gut injury caused by short-term EtOH exposure.

Maternal hyperthyroidism increases the prevalence of foregut atresias in fetal rats exposed to adriamycin.

PURPOSE: Gastrointestinal malformations such as esophageal atresia with tracheoesophageal fistula (EA/TEF) and duodenal atresia (DA) have been reported in infants born to hyperthyroid mothers or with congenital hypothyroidism. The present study aimed to test whether maternal thyroid status during embryonic foregut division has any influence on the prevalence of EA/TEF and DA in an accepted rat model of these malformations. METHODS: Pregnant rats received either vehicle or 1.75 mg/kg i.p. adriamycin on gestational days 7, 8 and 9. Transient maternal hyper or hypothyroidism was induced by oral administration of levothyroxine (LT4, 50 µg/kg/day) or propylthiouracil (PTU, 2 mg/kg/day), respectively, on days 7 to 12 of gestation. Plasma cholesterol, total T3, free T4 and TSH were measured at gestational days 7, 12, and 21. At the end of gestation, the mothers were sacrificed and embryo-fetal mortality was recorded. Fetuses were dissected to determine the prevalence of esophageal and intestinal atresias. RESULTS: At gestational day 12, mothers treated with LT4 or PTU had hyper or hypothyroid status, respectively; plasma cholesterol levels were similar. In the adriamycin-exposed fetuses from hyperthyroid mothers, the embryonal resorption rate and the prevalence of both EA/TEF and DA were significantly higher than in the other groups; maternal hypothyroidism during the same period did not have significant effect on the prevalence of atresias. CONCLUSIONS: Maternal hyperthyroidism during the embryonic window corresponding to foregut cleavage increased the prevalence of both EA/TEF and duodenal atresia in fetal rats exposed to adriamycin. This suggests that maternal thyroid hormone status might be involved in the pathogenesis of foregut atresias and invites further research on this likely clinically relevant issue in humans.

Health effects of benzene exposure among children following a flaring incident at the British Petroleum Refinery in Texas City.

Human exposure to benzene is associated with multiple adverse health effects leading to hematological malignancies. The objective of this retrospective study was to evaluate the health consequences of benzene exposure in children following a flaring incident at the British petroleum (BP) refinery in Texas City, Texas. The study included children aged <17 years who had been exposed and unexposed to benzene. Using medical charts, clinical data including white blood cell (WBC) counts, platelets counts, hemoglobin, hematocrit, blood urea nitrogen (BUN), creatinine, alkaline phosphatase (ALP), aspartate amino transferase (AST), alanine amino transferase (ALT), and somatic symptom complaints by the children exposed to benzene were reviewed and analyzed. A total of 312 subjects (benzene exposed, n = 157 and unexposed, n = 155) were included. Hematologic analysis showed that WBC counts were significantly decreased in benzene-exposed children compared with the unexposed children (6.8 ± 2.1 versus 7.3 ± 1.7, P = .022). Conversely, platelet (X 10(3) per µL) counts were increased significantly in the benzene-exposed group compared with the unexposed group (278.4 ± 59.9 versus 261.6 ± 51.7, P = .005). Similarly, benzene-exposed children had significantly higher levels of ALP (183.7± 95.6 versus 165 ± 70.3 IU/L, P = .04), AST (23.6 ± 15.3 versus 20.5 ± 5.5 IU/L, P = .015), and ALT (19.2 ± 7.8 versus 16.9 ± 6.9 IU/L, P = .005) compared with the unexposed children. Together, the results of the study reveal that children exposed to benzene experienced significantly altered blood profiles, liver enzymes, and somatic symptoms indicating that children exposed to benzene are at a higher risk of developing hepatic or blood related disorders.

[Alcoholism, an addiction leading to multiple somatic complications]. / L'alcoolisme, un modèle d'addiction aux complications somatiques multiples.

Alcoholism is, after smoking, the most common addiction in our society. It is associated with multiple familial, social and professional negative consequences. In addition, alcohol disturbs cellular metabolism and its excessive chronic consumption may lead to multiple dysfunctions that can provoke somatic complications targeting numerous tissues or organs. The present article describes the most important ones involving the liver, the digestive tract, the heart, both the central and peripheral nervous system, and bone marrow. We also discuss the metabolic disturbances associated with chronic alcohol consumption, among which those affecting glucose regulation, lipid profile, uric acid and various vitamins. Finally, we describe the nutritional deficiencies that may be observed in alcoholic people and may contribute to aggravate somatic complications.

[Mediko-social aspects of ecological gastroenterology].

Are investigated infringements of indicators antioxigion organism protection at hectare-stroenterology diseases at the patients living in territory of Krasnodarsky edge with various levels of pollution of an inhabitancy by pesticides and heavy metals. The ecological concept of an aetiology form chronic inflammatory diseases of bodies of digestive system which assumes the mechanism of decrease in resistance of an organism, development nonspetial the processes conducting to chronisation and complication of a current of diseases is considered.

[Effect of CYP3A4*18B, CYP3A5*3 gene polymorphism on dosage and concentration of tacrolimus in renal transplant patients].

The effect of CYP3A4*18B and CYP3A5*3 on concentration/dosage x body surface area ratios (C/D'), adverse effects and acute rejection of tacrolimus in renal transplant patients were investigated. The CYP3A4*18B genotypes of 227 renal transplant patients were determined by PCR-RFLP method. The differences of C/D' ratios, adverse reactions and acute rejection were compared among all of the genotype groups treated with tacrolimus. The frequencies of CYP3A4*18 and CYP3A5*3 alleles in renal transplant patients were 30.8% and 74.2%, respectively. No significant association was found between the C/D's of tacrolimus and CYP3A4*18B genotypes when they were classified by two CYP3A5 genotypes (P > 0.05). While after the effects of CYP3A4*18B genotype were eliminated, the C/D' ratio of tacrolimus in patients with CYP3A5*1/*1 and *1/*3 genotype group was significantly lower than those with CYP3A5*3/*3 genotype groups (P < 0.01). There is no significant difference in adverse effects and acute rejection among different genotypes (P > 0.05).

[Genetically modified food--great unknown]. / Zywnosc genetycznie modyfikowana--wielka niewiadoma.

Genetically modified food (GMF) creates evident threat to consumers' health. In spite of assurances of biotechnologists, DNA of transgenic plants is instable, so, synthesis of foreign, allergenic proteins is possible. Due to high trypsin inhibitor content the GMF is digested much more slowly what, alike Bt toxin presence, increases probability of alimentary canal diseases. Next threats are bound to the presence of fitoestrogens and residues of Roundup pesticide, that can diminish reproductiveness; and even lead to cancerogenic transformation through disturbance of human hormonal metabolism. In spite of food producers and distributors assurances that food made of GMF raw materials is marked, de facto consumers have no choice. Moreover, along the food law products containing less than 0.9% of GMF protein are not included into genetically modified food.

[Digestive system diseases in workers engaged into chemical production of methanol and formalin].

The article covers digestive system morbidity in workers engaged into chemical production of methanol and formalin. Blood changes, abnormal blood biochemistry (increased GGT level and GGT/GOT ratio) prove early development of toxic hepatitis. Other finding is increased incidence of liver disorders (diffuse changes proved by ultrasound examination).

Curcumae rhizoma and its major constituents against hepatobiliary disease: Pharmacotherapeutic properties and potential clinical applications.

BACKGROUND: Hepatobiliary disease currently serves as an urgent health issue in public due to health-modulating factors such as extension of life expectancy, increasingly sedentary lifestyles and over-nutrition. A definite treatment remains lacking owing to different stages of the disease itself and its intricate pathogenesis. Traditional Chinese medicine (TCM) has been gradually popularized in clinic with the satisfactory efficacy and good safety. Curcumae Rhizoma (called E Zhu, EZ in Chinese) is a representative herb, which has been used to treat hepatobiliary disease for thousands of years. PURPOSE: To systematically summarize the recent research advances on the pharmacological activities of EZ and its constituents, explain the underlying mechanisms of preventing and treating hepatobiliary diseases, and assess the shortcomings of existing work. Besides, ethnopharmacology, phytochemicals, and toxicology of EZ have been researched. METHODS: The information about EZ was collected from various sources including classic books about Chinese herbal medicine, and scientific databases including Web of Science, PubMed, ScienceDirect, Springer, ACS, SCOPUS, CNKI, CSTJ, and WANFANG using keywords given below and terms like pharmacological and phytochemical details of this plant. RESULTS: The chemical constituents isolated and identified from EZ, such as terpenoids including ß-elemene, furanodiene, germacrone, etc. and curcuminoids including curcumin, demethoxycurcumin, bisdemethoxycurcumin, etc. prove to have hepatoprotective effect, anti-liver fibrotic effect, anti-fatty liver effect, anti-liver neoplastic effect, and cholagogic effect through TGF-ß1/Smad, JNK1/2-ROS, NF-κB and other anti-inflammatory and antioxidant signaling pathways. Also, EZ is often combined with other Chinese herbs in the treatment of hepatobiliary diseases with good clinical efficacy and no obvious adverse reactions. CONCLUSION: It provides a preclinical basis for the efficacy of EZ as an effective therapeutic agent for the prevention and treatment of hepatobiliary diseases. Even so, the further studies still needed to alleviate hepatotoxicity and expand clinical application.