Socioeconomic Indicators, Tobacco and Alcohol in the Aetiology of Digestive Tract Neoplasms

Ferraroni M {Institute of Medical Statistics, University of Milan, 20133 Milan, Italy), Negri E, La Vecchia C, D'Avanzo B and Franceschi S. Socioeconomic indicators, tobacco and alcohol in the aetiology of digestive tract neoplasms. International Journal of Epidemiology 1989, 18: 556-562. The relationship between education, social class, smoking habits, alcohol consumption and the risk of digestive tract neoplasms was analysed in a case-control study of 50 cases of cancer of the mouth or pharynx, 209 of the oesophagus, 397 of the stomach, 455 of the colon, 295 of the rectum, 151 of the liver, 214 of the pancreas, and a total of 1944 control subjects admitted for acute, non-neoplastic or digestive tract disorders. Cancers of the mouth or pharynx, oesophagus and stomach were inversely and strongly related to education, with risk estimates ranging between 0.2 and 0.4 for the highest education categories. Significant, but weaker inverse relations were evident for rectal and liver cancer, too, whereas the risk of colon cancer was elevated among more educated individuals. There was no relationship between education and pancreatic cancer. The pattern of risk was largely comparable when the head of the household's occupation was used as indicator of social class. There were strong direct associations between cigarette (as well as pipe or cigar) smoking and cancers of the mouth or pharynx and oesophagus, and a moderate one with pancreatic cancer, but none of the other sites considered was related to smoking habits. Cancers of the mouth or pharynx and oesophagus were independently and strongly related to alcohol consumption, too, while the associations between alcohol and liver or pancreatic cancer were moderate and not significant. Cancers of the stomach, colon and rectum were unrelated to measures of alcohol consumptio

Fighting tertiary mutations in EGFR-driven lung-cancers: Current advances and future perspectives in medicinal chemistry

Third-generation inhibitors of the epidermal growth factor receptor (EGFR), best exemplified by osimertinib, have been developed to selectively target variants of EGFR bearing activating mutations and the mutation of gatekeeper T790 in patients with EGFR-mutated forms of Non-Small Cell Lung Cancer (NSCLC). While the application of third-generation inhibitors has represented an effective first- and second-line treatment, the efficacy of this class of inhibitors has been hampered by the novel, tertiary mutation C797S, which may occur after the treatment with osimertinib. More recently, other point mutations, including L718Q, G796D, G724S, L792 and G719, have emerged as mutations mediating resistance to third-generation inhibitors. The challenge of overcoming newly developed and recurrent resistances mediated by EGFR-mutations is thus driving the search of alternative strategies in the design of new therapeutic agents able to block EGFR-driven tumor growth. In this manuscript we review the recently emerged EGFR-dependent mechanisms of resistance to third-generation inhibitors, and the achievements lately obtained in the development of next-generation EGFR inhibitors

Smoking Habits and Risk of Benign Breast Disease

The relationship between smoking habits and the risk of benign breast disease (BBD) was analyzed using data from a case-control study conducted between 1981 and 1983 in the greater Milan area, Northern Italy. Cases (n = 288) were women with histologically confirmed BBD (203 dysplasia, 85 benign tumours) referred to the National Cancer Institute of Milan for biopsies. Controls were women (n = 291) seen on selected days for a cytological smear for cervical cancer in outpatient clinics of the same Institute. No consistent association emerged between various indicators of smoking habits (smoking status, number of cigarettes smoked per day, duration of smoking) and the risk of BBD. Compared with never smokers the relative risk (RR) of all BBD combined was 0.7 (95% confidence interval, Cl: 0.4-1.3) in exsmokers, 1.4 (95% Cl: 0.8-2.5) in smokers of less than 10 cigarettes per day, and 1.1 (95% Cl: 0.7-1.7) in smokers of 10 or more cigarettes per day. There was some suggestion that the risk may be below unity post-menopause, but the relative risks for smokers were not statistically different in pre- (RR = 1.2; 95% Cl: 0.8-1.8) and post-menopausal (RR = 0.6; 95% Cl: 0.2-1.7) women. The risk of benign tumours (chiefly fibradenoma) was higher in current smokers, but this finding was not statistically significant (RR = 1.5; 95% Cl: 0.9-2.6) and the highest risks were observed in the strata of lighter smokers and those with shorter duration of smoking. Overall these results fail to support a negative association between smoking habits and benign breast diseas

Smoking Habits and Risk of Benign Breast Disease

The relationship between smoking habits and the risk of benign breast disease (BBD) was analyzed using data from a case-control study conducted between 1981 and 1983 in the greater Milan area, Northern Italy. Cases (n = 288) were women with histologically confirmed BBD (203 dysplasia, 85 benign tumours) referred to the National Cancer Institute of Milan for biopsies. Controls were women (n = 291) seen on selected days for a cytological smear for cervical cancer in outpatient clinics of the same Institute. No consistent association emerged between various indicators of smoking habits (smoking status, number of cigarettes smoked per day, duration of smoking) and the risk of BBD. Compared with never smokers the relative risk (RR) of all BBD combined was 0.7 (95% confidence interval, Cl: 0.4-1.3) in exsmokers, 1.4 (95% Cl: 0.8-2.5) in smokers of less than 10 cigarettes per day, and 1.1 (95% Cl: 0.7-1.7) in smokers of 10 or more cigarettes per day. There was some suggestion that the risk may be below unity post-menopause, but the relative risks for smokers were not statistically different in pre- (RR = 1.2; 95% Cl: 0.8-1.8) and post-menopausal (RR = 0.6; 95% Cl: 0.2-1.7) women. The risk of benign tumours (chiefly fibradenoma) was higher in current smokers, but this finding was not statistically significant (RR = 1.5; 95% Cl: 0.9-2.6) and the highest risks were observed in the strata of lighter smokers and those with shorter duration of smoking. Overall these results fail to support a negative association between smoking habits and benign breast disease

Socioeconomic Indicators, Tobacco and Alcohol in the Aetiology of Digestive Tract Neoplasms

The relationship between education, social class, smoking habits, alcohol consumption and the risk of digestive tract neoplasms was analysed in a case-control study of 50 cases of cancer of the mouth or pharynx, 209 of the oesophagus, 397 of the stomach, 455 of the colon, 295 of the rectum, 151 of the liver, 214 of the pancreas, and a total of 1944 control subjects admitted for acute, non-neoplastic or digestive tract disorders. Cancers of the mouth or pharynx, oesophagus and stomach were inversely and strongly related to education, with risk estimates ranging between 0.2 and 0.4 for the highest education categories. Significant, but weaker inverse relations were evident for rectal and liver cancer, too, whereas the risk of colon cancer was elevated among more educated individuals. There was no relationship between education and pancreatic cancer. The pattern of risk was largely comparable when the head of the household's occupation was used as indicator of social class. There were strong direct associations between cigarette (as well as pipe or cigar) smoking and cancers of the mouth or pharynx and oesophagus, and a moderate one with pancreatic cancer, but none of the other sites considered was related to smoking habits. Cancers of the mouth or pharynx and oesophagus were independently and strongly related to alcohol consumption, too, while the associations between alcohol and liver or pancreatic cancer were moderate and not significant. Cancers of the stomach, colon and rectum were unrelated to measures of alcohol consumption

Cumulus Cell DNA damage as an index of human oocyte competence

The determination of oocyte quality is crucial for achieving effective syngamy post-sperm injection and embryonic development. Cumulus cells (CCs) have been proposed as biomarkers of oocyte quality because of their close bio-dynamic relationship with the oocyte. To determine the quality of the oocyte, CCs were sampled during oocyte preparation for ICSI to determine a CC DNA fragmentation index (CCDFI) of each individual oocyte using a variant of the chromatin dispersion test. One hundred and thirty oocytes were selected and studied from two Spanish fertility clinics, 90 of which were fertilized and developed to embryos. Significant differences were found between the CCDFI of unfertilized and fertilized oocytes (p <.001) and between the CCDFI of embryos that were discarded and those that developed suitable for transfer or cryopreservation (p <.001). Oocyte quality was negatively correlated with CCDFI (Spearman’s rho = − 0.45; p <.001). Receiver operator characteristics curves (ROC) suggested that a cut-off value of 24% CCDFI was able to discriminate the capacity of the gametes to result in syngamy with a sensitivity and specificity of 75.6% and 65%, respectively. This cut-off supports the application of CCDFI as potential index for the evaluation of the reproductive potential of oocytes prior to fertilizatio

Genetic diversity and signature of divergence in the genome of grapevine clones of Southern Italy varieties

Sexual reproduction has contributed to a significant degree of variability in cultivated grapevine populations. However, the additional influence of spontaneous somatic mutations has played a pivotal role in shaping the diverse landscape of grapevine agrobiodiversity. These naturally occurring selections, termed 'clones,' represent a vast reservoir of potentially valuable traits and alleles that hold promise for enhancing grape quality and bolstering plant resilience against environmental and biotic challenges. Despite their potential, many of these clones remain largely untapped.In light of this context, this study aims to delve into the population structure, genetic diversity, and distinctive genetic loci within a collection of 138 clones derived from six Campanian and Apulian grapevine varieties, known for their desirable attributes in viticulture and winemaking. Employing two reduced representation sequencing methods, we extracted Single-Nucleotide Polymorphism (SNP) markers. Population structure analysis and fixation index (FST) calculations were conducted both between populations and at individual loci. Notably, varieties originating from the same geographical region exhibited pronounced genetic similarity.The resulting SNP dataset facilitated the identification of approximately two hundred loci featuring divergent markers (FST ≥ 0.80) within annotated exons. Several of these loci exhibited associations with essential traits like phenotypic adaptability and environmental responsiveness, offering compelling opportunities for grapevine breeding initiatives. By shedding light on the genetic variability inherent in these treasured traditional grapevines, our study contributes to the broader understanding of their potential. Importantly, it underscores the urgency of preserving and characterizing these valuable genetic resources to safeguard their intra-varietal diversity and foster future advancements in grapevine cultivation

Metabolism of the EGFR tyrosin kinase inhibitor gefitinib by cytochrome P450 1A1 enzyme in EGFR-wild type non small cell lung cancer cell lines

<p>Abstract</p> <p>Background</p> <p>Gefitinib is a tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) especially effective in tumors with activating EGFR gene mutations while EGFR wild-type non small cell lung cancer (NSCLC) patients at present do not benefit from this treatment.</p> <p>The primary site of gefitinib metabolism is the liver, nevertheless tumor cell metabolism can significantly affect treatment effectiveness.</p> <p>Results</p> <p>In this study, we investigated the intracellular metabolism of gefitinib in a panel of EGFR wild-type gefitinib-sensitive and -resistant NSCLC cell lines, assessing the role of cytochrome P450 1A1 (CYP1A1) inhibition on gefitinib efficacy. Our results indicate that there is a significant difference in drug metabolism between gefitinib-sensitive and -resistant cell lines. Unexpectedly, only sensitive cells metabolized gefitinib, producing metabolites which were detected both inside and outside the cells. As a consequence of gefitinib metabolism, the intracellular level of gefitinib was markedly reduced after 12-24 h of treatment. Consistent with this observation, RT-PCR analysis and EROD assay showed that mRNA and activity of CYP1A1 were present at significant levels and were induced by gefitinib only in sensitive cells. Gefitinib metabolism was elevated in crowded cells, stimulated by exposure to cigarette smoke extract and prevented by hypoxic condition. It is worth noting that the metabolism of gefitinib in the sensitive cells is a consequence and not the cause of drug responsiveness, indeed treatment with a CYP1A1 inhibitor increased the efficacy of the drug because it prevented the fall in intracellular gefitinib level and significantly enhanced the inhibition of EGFR autophosphorylation, MAPK and PI3K/AKT/mTOR signalling pathways and cell proliferation.</p> <p>Conclusion</p> <p>Our findings suggest that gefitinib metabolism in lung cancer cells, elicited by CYP1A1 activity, might represent an early assessment of gefitinib responsiveness in NSCLC cells lacking activating mutations. On the other hand, in metabolizing cells, the inhibition of CYP1A1 might lead to increased local exposure to the active drug and thus increase gefitinib potency.</p