Iron/Copper/Phosphate nanocomposite as antimicrobial, antisnail, and wheat growth-promoting agent.

BACKGROUND: One of the current challenges is to secure wheat crop production to meet the increasing global food demand and to face the increase in its purchasing power. Therefore, the current study aimed to exploit a new synthesized nanocomposite to enhance wheat growth under both normal and drought regime. The effectiveness of this nanocomposite in improving the microbiological quality of irrigation water and inhibiting the snail's growth was also assessed. RESULTS: Upon the employed one-step synthesis process, a spherical Fe/Cu/P nanocomposite was obtained with a mean particle size of 4.35 ± 1.524 nm. Cu2+, Fe2+, and P4+ were detected in the dried nanocomposite at 14.533 ± 0.176, 5.200 ± 0.208, and 34.167 ± 0.203 mg/ml concentration, respectively. This nanocomposite was found to exert antibacterial activity against Escherichia coli and Salmonella typhi. It caused good inhibition percent against Fusarium oxysporum (43.5 ± 1.47%) and reduced both its germination rate and germination efficiency. The lethal concentration 50 (LC50) of this nanocomposite against Lanistes carinatus snails was 76 ppm. The treated snails showed disturbance in their feeding habit and reached the prevention state. Significant histological changes were observed in snail digestive tract and male and female gonads. Drought stress on wheat's growth was mitigated in response to 100 and 300 ppm treatments. An increase in all assessed growth parameters was reported, mainly in the case of 100 ppm treatment under both standard and drought regimes. Compared to control plants, this stimulative effect was accompanied by a 2.12-fold rise in mitotic index and a 3.2-fold increase in total chromosomal abnormalities. CONCLUSION: The finding of the current study could be employed to mitigate the effect of drought stress on wheat growth and to enhance the microbiological quality of irrigation water. This is due to the increased efficacy of the newly synthesized Fe/Cu/P nanocomposite against bacteria, fungi, and snails. This methodology exhibits potential for promoting sustainable wheat growth and water resource conservation.

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients.

This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer.Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities.The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12-0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07-0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs.Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.

New Au/chitosan nanocomposite modified carbon paste sensor for voltammetric detection of nicotine.

A profoundly touchy voltammetric sensor for detection of nicotine (NIC) in urine and tobacco specimens has been developed in light of the boosted electrochemical response of NIC at gold and chitosan nanocomposite modified carbon paste electrode (ACMCPE). Material characterization techniques Scanning Electron Microscope and Energy Dispersive X-ray (SEM & EDX) were utilized to describe the ACMCPE surface material. The impedance spectroscopy technique (EIS), cyclic voltammetry (CV), chronoamperometry (CA), and differential pulse voltammetry (DPV) were employed to explore the electrochemical sensing of NIC at ACMCPE. The created sensor exhibits an exceptional electrochemical sensitivity to NIC in a universal Britton-Robinson (B-R) buffer solution with a pH range of 2.0 to 8.0. The sensor shows a linear response over NIC concentration ranges of 4.0-320.0 µM, with the detection limit (LOD) of 7.6 µM. The prepared sensor has been shown to be exceptionally viable in detecting NIC with amazing selectivity and reproducibility. We suggest it as a trustworthy and useful electrochemical sensor for NIC location.

Expression status of circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 in patients with colorectal cancer.

Colorectal cancer (CRC) poses a significant burden on both the healthcare systems as well as individuals. The high mortality rate of CRC may be attributed to its metastatic potential, heterogeneity, and delayed diagnosis. CircRNAs are an essential class of regulatory RNAs that play significant roles in cancers. This study aimed to detect the expression status of circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 in patients with CRC. This study included 50 CRC patients, 30 individuals with colorectal diseases (non-cancer), and 20 healthy volunteers. By using real-time PCR, the relative expression of circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 was determined in the collected blood samples. In addition, ECLIA was used to quantify carcinoembryonic antigen (CEA) level. All circRNAs expression and CEA levels were significantly up-regulated in cancer patients (CRC, colon, rectum) as compared to healthy controls, except circ-SMARCA5. Moreover, there was a significant up-regulation of circRNAs in most non-cancer patients (UC, polyp, piles). Insignificant upregulation was observed in circRNAs and CEA when comparing cancer with non-cancer patients. No correlations were found between the studied parameters and most clinicopathological characteristics of cancer and non-cancer patients. Circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 were differentially expressed in patients with CRC as well as in non-cancer patients. Circ-SMARCA5 and circ-NOL10 may act as tumor suppressors, while circ-LDLRAD3 and circ-RHOT1 may be oncogenes. Circ-SMARCA5, circ-NOL10, circ-LDLRAD3, and circ-RHOT1 could be promising markers for the early detection of CRC.

Family structure and substance use in 6,178 American Indian youth: a cross-sectional study.

OBJECTIVE: Adolescents from single-parent families are at significantly higher risk of substance use compared to those from mother-father families. More than half of American Indian (AI) children live in single-parent families, the second highest percentage among all groups. Given the paucity of research pertaining to the role of family structure and substance use in the AI population, we sought to examine this relationship. MATERIALS AND METHODS: Data from this study were obtained from the Substance Use Among American Indian Youth: Epidemiology and Etiology, [US], 2015-2020 study. Response variables of interest included age at first substance use, number of substances used, ever-use of substance, and substance use type (i.e., alcohol, cigarette, marijuana, etc.). RESULTS: Living in a father-only or mother-only setting showed a similar pattern of drug use. There was a significant increase in the risk of cigarette, alcohol and marijuana use. For cigarettes, the odds ratio was (OR = 2.60, 95% CI 1.80-3.75) in father-only setting compared to (OR = 1.42, 95% CI 1.13-1.78) for mother only setting. Alcohol use showed (OR = 1.72, 95% CI 1.19-2.50 and OR = 1.40, 95% CI 1.12-1.74) for father-only and mother-only respectively and marijuana use showed (OR = 1.59, 95% CI 1.10-2.30 and OR = 1.54, 95% CI -1.24-1.92) for father-only and mother-only respectively. CONCLUSIONS: Disturbed family structure is associated with increased risk of substance use among AI youth. This indicates the importance and need for policy and community level interventions to reduce youth substance exposure.

Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism.

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor.

Nano-TiO2 modified carbon paste sensor for electrochemical nicotine detection using anionic surfactant.

A newly competitive electrochemical sensor for nicotine (NIC) detection was successfully achieved. Nano-TiO2 with a carbon paste electrode (CPE) were used for the sensor construction, where Nano-TiO2 was considered as one of the richest and highly variable class of materials. The sensor showed electrocatalytic activity in both aqueous and micellar media toward the oxidation of NIC at Britton-Robinson (B-R) buffer solution (4×10(-2)M) of pH range (2.0-8.0) containing (1.0mM) sodium dodecylsulfate (SDS) using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) techniques. Scanning electron microscope (SEM) and Energy Dispersive X-Ray Analysis (EDX) techniques were also used. The linear range of detection for NIC using the new Nano-TiO2 Modified Carbon Paste sensor (NTMCP) was detected using diffrential pulse voltammetry (DPV) technique and it was found between 2×10(-6)M and 5.4×10(-4)M with a detection limit of 1.34×10(-8)M. The obtained results clarified the simplicity, high sensitivity and selectivity of the new NTMCPE for nicotine determination in real cigarettes and urine samples.

Giant haemangioma of the liver with haemangiodudenal fistula: the first reported case in literature.

Giant liver haemangiomas are usually asymptomatic with normal liver function, which makes the course long and uneventful. The most commonly reported complications of giant haemangiomas are rupture with intraperitoneal haemorrhage that is either traumatic or non-traumatic, consumption coagulopathy, Budd-Chiari syndrome and congestive heart failure. We describe the first reported complications of a giant liver haemangioma as a fistula between the haemangioma and the gastrointestinal tract.

Metronomic capecitabine as extended adjuvant chemotherapy in women with triple negative breast cancer.

PURPOSE: High interest in triple-negative breast cancers is not surprising as this category of patients benefits neither from hormonal therapies nor from anti HER2 treatments. Blockade of angiogenesis by metronomic chemotherapy as well as other antiangiogenics might improve outcomes in this group of patients. This study aims to evaluate the tolerability and efficacy of metronomic capecitabine as extended adjuvant treatment for women with triple-negative breast cancer. METHODS: This is a prospective phase II study that included 41 patients diagnosed with triple-negative breast cancer and who were indicated for adjuvant chemotherapy. They received capecitabine 500mg PO twice daily and continuously for six months after finishing six cycles of adjuvant FEC100±postoperative radiotherapy. RESULTS: Forty-one patients were enrolled in this study between June 2010 and December 2013. Median age was 50years ranging from 27 to 67years. Treatment was well tolerated. Adverse effects were grade 1 palmar-plantar erythrodysesthesia in 13 patients (31.7%); grade 1 diarrhea in five patients (12.2%); and grade 1 vomiting in two patients (4.9%). Estimated median follow-up duration was 34 months. Estimated mean disease-free survival (DFS) was 42.4months (95% CI, 39.02-45.79), while median DFS was not reached. Estimated mean overall survival was 44.34months (95% CI 41.9-46.9). CONCLUSION: Extended adjuvant metronomic capecitabine is well tolerated with patient compliance. These results need to be compared in a study with control arm, larger sample, as well as longer follow-up.

Assessment of natural and artificial radioactivity levels and radiation hazards and their relation to heavy metals in the industrial area of Port Said city, Egypt.

A detailed gamma ray spectrometry survey was carried out to make an action in environmental impact assessment of urbanization and industrialization on Port Said city, Egypt. The concentrations of the measured radioelements U-238, Th-232 in ppm, and K-40 %, in addition to the total counts of three selected randomly dumping sites (A, B, and C) were mapped. The concentration maps represent a base line for the radioactivity in the study area in order to detect any future radioactive contamination. These concentrations are ranging between 0.2 and 21 ppm for U-238 and 0.01 to 13.4 ppm for Th-232 as well as 0.15 to 3.8 % for K-40, whereas the total count values range from 8.7 to 123.6 uR. Moreover, the dose rate was mapped using the same spectrometer and survey parameters in order to assess the radiological effect of these radioelements. The dose rate values range from 0.12 to 1.61 mSv/year. Eighteen soil samples were collected from the sites with high radioelement concentrations and dose rates to determine the activity concentrations of Ra-226, Th-232, and K-40 using HPGe spectrometer. The activity concentrations of Ra-226, Th-232, and K-40 in the measured samples range from 18.03 to 398.66 Bq kg(-1), 5.28 to 75.7 Bq kg(-1), and 3,237.88 to 583.12 Bq kg(-1), respectively. In addition to analyze heavy metal for two high reading samples (a 1 and a 10) which give concentrations of Cd and Zn elements (a 1 40 ppm and a 10 42 ppm) and (a 1 0.90 ppm and a 10 0.97 ppm), respectively, that are in the range of phosphate fertilizer products that suggested a dumped man-made waste in site A. All indicate that the measured values for the soil samples in the two sites of three falls within the world ranges of soil in areas with normal levels of radioactivity, while site A shows a potential radiological risk for human beings, and it is important to carry out dose assessment program with a specifically detailed monitoring program periodically.

Cardioprotective effects of intracoronary adenosine in diabetic patients undergoing elective percutaneous coronary intervention.

AIM: Myocardial injury commonly occurs during percutaneous coronary intervention (PCI). Several agents that mimic ischemic preconditioning could help minimize this phenomenon. This study evaluated the cardio-protective role of intracoronary Adenosine in elective PCI. METHODS: A total of 100 diabetic patients with chronic stable angina were prospectively enrolled, then randomly assigned to undergo PCI with intracoronary Adenosine; 100 µg/stented vessel (group-A, 50 patients) or standard PCI (group-B, 50 patients). Cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) levels were measured before and 6, 12 and 24 hours post-PCI. RESULTS: Mean age of the study cohort was 57±8 years (males=63%). cTnI level was significantly lower in group-A (6 hours: 7.5±0.2 vs. 15.5±0.5 pg/mL, 12 hours: 13.7±0.7 vs. 25.5±0.6 pg/mL and 24 hours: 7.6±0.5 vs. 16±0.3 pg/mL, P<0.001). After 3 months, the same group showed significantly higher left ventricle ejection fraction (LVEF %), i.e. 64.5±5.7 vs. 56.5±5.3 (P<0.05). There was no statistically significant difference between both groups of patients regarding incidence of major adverse cardiac events (MACE). CONCLUSION: In diabetic patients undergoing elective PCI, intracoronary Adenosine was associated with decreased incidence of PCI-related myocardial injury & improvement of LVEF% after 3 months.

CD14(+) HLA-DR low/(-) monocytes as indicator of disease aggressiveness in B-cell non-Hodgkin lymphoma.

INTRODUCTION: This study aimed to assess the correlation between the percentage of CD14(+) HLA-DR(low/-) immunosuppressive monocytes, plasma arginase 1 level, and disease aggressiveness in patients with B-cell non-Hodgkin lymphoma. METHODS: Forty-two patients with B-cell non-Hodgkin lymphoma and 20 healthy volunteers were enrolled in this study. Peripheral blood CD14+ HLA-DR(low/-) monocytes were detected by Flow cytometry, and their correlation with disease relapse and refractoriness was analyzed. RESULTS: The percent of CD14(+) HLA-DR(low/-) monocytes was significantly higher in the lymphoma patients than in the healthy controls (control, 9.3 ± 4%; lymphoma, 35.8 ± 20.2%; P < 0.0001), higher in stage III& IV than stage II (stage II, 26.48 ± 17%, n = 26; stage III & IV, 50.8 ± 15.4%, n = 16; P < 0.0001), more in diffuse large cell lymphoma than other pathology types and in relapsed/refractory patients than in patients who achieved remission during follow-up (relapsed/refractory, n = 18, 45.7 ± 16.7%; remission, n = 16, 21.4 ± 16.2%; P < 0.0001). The arginase I level correlated with increased percent of CD14(+) HLA-DR(low/-) monocytes (P < 0.0001). CONCLUSION: Increased CD14(+) monocytes with loss of HLA expression were seen in patients with higher stage disease, more aggressive pathology, and in relapse or refractoriness to treatment. Identifying therapeutic strategies to overcome the suppressive properties of these monocytes could be of value.

Induction of DNA double-strand breaks by monochlorophenol isomers and ChKM in human gingival fibroblasts.

Phenol has been traditionally used in dental treatment as a sedative for the pulp or as disinfectant for carious cavity and root canal. However, phenol is regarded as a mutagenic and carcinogenic agent and its use in dental practice is now therefore restricted. Monochlorophenols are derivatives of phenol, which are still used clinically as root canal disinfectants, they are even more active antiseptics/disinfectants than phenol, and the so-called Walkhoff (ChKM) solution makes use of monochlorophenol for root canal disinfection. Ingredients in the ChKM solution are the monochlorophenol compound 4-chlorophenol (4-CP), camphor, and menthol. In literature, the use of the ChKM solution is controversial because of a possible DNA toxicity of the ingredient 4-CP. However, it is unknown whether ChKM can really induce DNA damage in human oral cells. In this study, the induction of DNA double-strand breaks (DSBs) by ChKM and monochlorophenol compounds (2-chlorophenol, 2-CP; 3-chlorophenol, 3-CP; and 4-chlorophenol, 4-CP) was tested in human gingival fibroblasts (HGFs). DNA DSBs (foci) induced in HGFs unexposed and exposed to monochlorophenols or ChKM solution were investigated using the γ-H2AX DNA focus assay, which is a direct marker for DSBs. DSBs result in the ATM-dependent phosphorylation of the histone H2AX. When cells were exposed to medium or medium + DMSO (1 %) (negative controls), an average of 3 foci per cell were found. In positive control cells (H2O2 + medium, or H2O2 + medium + DMSO (1 %), an average of 35 foci each were found. About 20 DSB foci per cell were found, when HGFs were exposed to 2-CP (4 mM), 3-CP (2.3 mM), 4-CP (2.1 mM), or ChKM (corresponding to 1.5 mM 4-CP). Our results show increasing DNA toxicities in the order of 2-CP < 3-CP < 4-CP < ChKM solution. An additive DNA toxicity was found for 4-CP in combination with camphor in the ChKM solution, compared to the 4-CP alone. No significant differences regarding multi-foci cells (cells that contain more than 40 foci) were found when HGFs were exposed to the EC50 concentrations (given in parenthesis) of ChKM (1.5 mM), 4-CP (2.1 mM), or 2-CP (4 mM). Significantly fewer multi-foci cells were found when HGFs were exposed to the EC50 concentration (given in parenthesis) of 3-CP (2.3 mM), compared to the EC50 concentrations of ChKM, 4-CP, or 2-CP. Monochlorophenol compounds and/or ChKM solution can induce DSBs in primary human oral (cavity) cells, which underscores their genotoxic capacity.

Topo2α protein expression predicts response to anthracycline combination neo-adjuvant chemotherapy in locally advanced primary breast cancer.

BACKGROUND: this study aimed to identify predictors of response to anthracycline-based chemotherapy (5-fluoro-uracil, epirubicin, cyclophosphamide (FEC)) in locally advanced primary breast cancer (LAPC). METHODS: a total of 91 LAPC patients were treated with six cycles of FEC before surgery. Protein expression of nine biomarkers (topoisomerase2α (Topo2α), ER, PR, HER2, Ki67, p53, EGFR, CK5/6 and CK14) was assessed in pre-chemotherapy core biopsies using immunohistochemistry (IHC) and results correlated with clinical and pathological response. RESULTS: clinical (cCR) and pathological (pCR) complete response were seen in 34.1% (n=31) and 20% (n=18), respectively. Pathological complete response was concordant with cCR in 14/31 cases; in four cases of cPR with palpable residual breast tumours, histology showed fibrous tissue only (pCR). On univariate analysis, pre-chemotherapy high expression of Topo2α protein (P=0.031), and negativity for ER and EGFR (P=0.001 and P=0.005, respectively) correlated with pCR. Positivity for p53 also showed significance (P=0.015), whereas basal phenotype, HER2, and all the clinicopathological variables of LAPC included in this study did not show significant correlation with response. On multivariate analysis, Topo2α expression had the strongest correlation with pCR (P=0.021) followed by EGFR (P=0.044). CONCLUSION: the study suggests that pre-chemotherapy Topo2α protein expression measured by IHC strongly correlates with pathological CR to neo-adjuvant anthracyclines in this group of LAPC studied.

Treatment of HER2-positive metastatic breast cancer with lapatinib and capecitabine in the lapatinib expanded access programme, including efficacy in brain metastases--the UK experience.

BACKGROUND: The global lapatinib expanded access programme provided access to lapatinib combined with capecitabine for women with HER2-positive metastatic breast cancer (MBC) who previously received anthracycline, taxane and trastuzumab. METHODS: Progression-free survival (PFS) and safety data for 356 patients recruited from the United Kingdom are reported. Efficacy was assessed in 162 patients from the five lead centres, including objective tumour response rate (ORR), time to disease progression (TTP) and efficacy in those with central nervous system (CNS) metastases. Correlation of PFS and ORR with previous capecitabine treatment was also documented. RESULTS: Overall, PFS for the 356 UK patients was 21 weeks (95% CI: 17.6-24.7). In the 162 assessable patients, ORR was 21% (95% CI: 15-27%) and median TTP was 22 weeks (95% CI: 17-27). Efficacy was greater in capecitabine-naive patients (ORR 23 vs 16.3%, P=0.008). For 34 patients with CNS metastases, ORR was 21% (95% CI: 9-39%), with evidence of improvement in neurological symptoms, and median TTP was 22 weeks (95% CI: 15-28). CONCLUSIONS: Lapatinib combined with capecitabine is an active treatment option for women with refractory HER2-positive MBC, including those with progressive CNS disease.

Human apurinic/apyrimidinic endonuclease (APE1) is a prognostic factor in ovarian, gastro-oesophageal and pancreatico-biliary cancers.

BACKGROUND: Altered DNA repair may be associated with aggressive tumour biology and impact upon response to chemotherapy and radiotherapy. We investigated whether expression of human AP endonuclease (APE1), a key multifunctional protein involved in DNA BER, would impact on clinicopathological outcomes in ovarian, gastro-oesophageal, and pancreatico-biliary cancer. METHODS: Formalin-fixed human ovarian, gastro-oesophageal, and pancreatico-biliary cancers were constructed into TMAs. Expression of APE1 was analysed by IHC and correlated to clinicopathological variables. RESULTS: In ovarian cancer, nuclear APE1 expression was seen in 71.9% (97 out of 135) of tumours and correlated with tumour type (P=0.006), optimal debulking (P=0.009), and overall survival (P=0.05). In gastro-oesophageal cancers previously exposed to neoadjuvant chemotherapy, 34.8% (16 out of 46) of tumours were positive in the nucleus and this correlated with shorter overall survival (P=0.005), whereas cytoplasmic localisation correlated with tumour dedifferentiation (P=0.034). In pancreatico-biliary cancer, nuclear staining was seen in 44% (32 out of 72) of tumours. Absence of cytoplasmic staining was associated with perineural invasion (P=0.007), vascular invasion (P=0.05), and poorly differentiated tumours (P=0.068). A trend was noticed with advanced stage (P=0.077). CONCLUSIONS: Positive clinicopathological correlations of APE1 expression suggest that APE1 is a potential drug target in ovarian, gastro-oesophageal, and pancreatico-biliary cancers.

Human leukocyte antigen class I expression is an independent prognostic factor in advanced ovarian cancer resistant to first-line platinum chemotherapy.

BACKGROUND: Loss of HLA class I is important in ovarian cancer prognosis but its role as a prognostic indicator in relation to therapy remains unproven. We studied the prognostic potential of this antigen and its significance in relation to platinum therapy. METHODS: A total of 157 primary ovarian cancers were assessed for HLA class I immunohistochemically and linked to a comprehensive database of clinicopathological variables, treatment details, and platinum sensitivity. RESULTS: Tumours expressing high levels of HLA class I had significantly improved survival (P=0.044). There was a 19-month difference in the median overall survival between tumours with high and low antigen expression. HLA class I antigen expression, stage, and platinum sensitivity were independently predictive of prognosis on multivariate analysis. HLA class I antigen was shown to be expressed at higher levels in patients with good overall survival in platinum-resistant patients (P=0.042). HLA class I significantly correlated with overall survival on multivariate analyses (P=0.034). CONCLUSION: Low-level HLA class I expression is an independent prognostic indicator of poor clinical outcome in ovarian cancer. The survival advantage of patients with platinum-resistant tumours expressing high levels of HLA class I suggests that immunotherapy may be of use in these ovarian cancers resistant to standard chemotherapy.

New cellular tools reveal complex epithelial-mesenchymal interactions in hepatocarcinogenesis.

To enable detailed analyses of cell interactions in tumour development, new epithelial and mesenchymal cell lines were established from human hepatocellular carcinoma by spontaneous outgrowth in culture. We obtained several hepatocarcinoma (HCC)-, B-lymphoblastoid (BLC)-, and myofibroblastoid (MF)-lines from seven cases. In-depth characterisation included cell kinetics, genotype, tumourigenicity, expression of cell-type specific markers, and proteome patterns. Many functions of the cells of origin were found to be preserved. We studied the impact of the mesenchymal lines on hepatocarcinogenesis by in vitro assays. BLC- and MF-supernatants strongly increased the DNA replication of premalignant hepatocytes. The stimulation by MF-lines was mainly attributed to HGF secretion. In HCC-cells, MF-supernatant had only minor effects on cell growth but enhanced migration. MF-lines also stimulated neoangiogenesis through vEGF release. BLC-supernatant dramatically induced death of HCC-cells, which could be largely abrogated by preincubating the supernatant with TNFbeta-antiserum. Thus, the new cell lines reveal stage-specific stimulatory and inhibitory interactions between mesenchymal and epithelial tumour cells. In conclusion, the new cell lines provide unique tools to analyse essential components of the complex interplay between the microenvironment and the developing liver cancer, and to identify factors affecting proliferation, migration and death of tumour cells, neoangiogenesis, and outgrowth of additional malignancy.

Lapatinib: a tyrosine kinase inhibitor with a clinical role in breast cancer.

Lapatinib is a dual (ErbB-1 and ErB-2) receptor tyrosine kinase inhibitor (TKI) that was recently approved by the FDA for the treatment of advanced breast cancer. It shows synergy with trastuzumab, and has demonstrated clinical activity in trastuzumab-resistant tumour. This paper reviews the drug development of lapatinib from preclinical studies to the pivotal Phase III trial and ongoing clinical studies. Areas of interest include the advantages of small molecule TKIs versus antibodies in targeting HER receptors and the efficacy of lapatinib in the treatment of cerebral metastases. The surprisingly high response rate in inflammatory breast cancer raises the possibility of other novel predictive biomarkers. The potential for combination and sequencing with other biological and cytotoxic agents is both exciting and challenging.