Electric charge of nanopatterned silica surfaces.

The most recent technologies employ nanoscale surface patterning or roughening in order to engineer desired properties on a surface. Electrokinetic properties at the interface of such surfaces and ionic liquids show different behavior to the well-known theoretical descriptions. Basically, the ionic distribution on the surface differs due to electrical double layer overlap effects in the pits and curvature effects at the tips of surface structures. Generally, the charge density of a surface is assumed to be a material property and surface roughness effects are overlooked in most of the literature. In contrast, we properly calculated the local surface charges based on surface chemistry at the corresponding local ionic concentration (charge regulation) for various surface roughness and solution conditions. The results showed that the surface charge density of silica decreased at the pits but increased at the tips of surface patterns. Even for the simplest case of self-repeating surface structures, the average of local surface charges becomes lower than the theoretical predictions. Based on numerical calculations, a phenomenological model was developed as an extension to the existing flat surface theory, which can successfully predict the average surface charge on a nano patterned surface as a function of the surface pattern size, ionic concentration and pH.

[Investigation of role of anaerobic bacteria in cystic fibrosis patients]. / Kistik fibrozisli hastalarda anaerop bakterilerin rolünün arastirilmasi.

INTRODUCTION: Repetitive pulmonary infections are the main cause of morbidity and mortality in cystic fibrosis (CF) patients. In recent years, non-culture dependent metagenomic studies showed complex dynamics of the pulmonary environment of CF patients and pointed out the importance of anaerobic bacteria. Molecular-based studies indicate that anaerobic bacteria can be found more than aerobic or facultative anaerobic bacteria in CF lung environment. However, limited number of studies are far away to clarify the importance of anaerobic bacteria in CF pulmonary disease. MATERIALS AND METHODS: The aim of this study was to evaluate the role of anaerobic bacteria in CF patients admitted to Hacettepe University, Pediatric Respiratory Diseases Department, by using quantitative culture method for both aerobic and anaerobic bacteria. Anaerobic bacteria were identified by conventional and semi-automated methods. Antibiotic susceptibilities were performed by agar dilution method. RESULT: Seventy-seven anaerobic bacteria were isolated from 35 (81.4%) of 43 patients. The total count of anaerobes and facultative bacteria (mean 16 x 106), was higher than aerobes and facultative bacteria (mean 14.1 x 106). If anaerobe culture were not performed merely 63.65% of all species could be obtained. In patients whose samples yielded intermediate or high numbers of PMNLs, significantly more obligate anaerobic bacteria were isolated (p= 0.046). Patients older than 18 years were colonized with higher number of anaerobic bacteria. Susceptibilities of 72 isolates out of 77, against ampicillin, sulbactam-ampicillin, piperacillin, piperacillin-tazobactam, moxifloxacin, metronidazole, imipenem, and clindamycin were also evaluated. Clindamycin was found to be the least effective antibiotic among all. None of the isolates was resistant to imipenem. CONCLUSIONS: This is the first study to show the role and importance of anaerobic bacteria in CF patients in our country. The resistance rates in anaerobic bacteria isolated from CF patients is concerning. Therefore, intermittent anaerobic culture and follow-up of resistance rates will be helpful in the follow-up of these patients.

Analysis of 332 fiberoptic bronchoscopies performed in a respiratory intensive care unit: a retrospective study.

OBJECTIVE: Fiberoptic bronchoscopy (FOB) is widely used in the intensive care unit for diagnostic and therapeutic purposes. Our study aimed to evaluate FOB's indications, complications, and clinical outcomes in our intensive care unit's mechanically ventilated patients and identify the microorganisms grown in bronchoalveolar lavage (BAL) specimens. PATIENTS AND METHODS: Between January 1, 2022, and June 30, 2023, a total of 332 FOBs were performed on 178 patients in the respiratory intensive care unit. RESULTS: Patients' mean age was 64±19.4 years. Females accounted for 65 (36.6%) and males accounted for 113 (63.4%) of the cases. Leading diagnoses included pneumonia (59.5%), acute respiratory distress syndrome (ARDS) (20.7%), sepsis (17.9%), chronic obstructive pulmonary disease (COPD) attack (21.9%), pulmonary embolism (10.1%), lung malignancy (43.8%), hemoptysis (8.9%), heart failure (15.1%), neurological/neuromuscular conditions (8.4%), and post cardiopulmonary resuscitation (CPR) (2.8%). FOB purposes were BAL retrieval (43.6%), secretion clearance (30.4%), guided tracheostomy (11.7%), atelectasis (8.7%), and hemoptysis (5.4%). Hypoxemia marked the primary FOB complication (3.6%). Other issues encompassed hypotension (1.5%), bradycardia (1.2%), bleeding (1.2%), tachycardia (0.9%), and hypertension (0.6%). No statistical significance was found in arterial blood gas pH, arterial partial pressure of oxygen (PaO2), and arterial partial pressure of carbon dioxide (PaCO2) values before and after the FOB procedure (p>0.05). Predominant pathogens in aspiration samples were non-albicans Candida (28.9%), Klebsiella pneumoniae (24.8%), Pseudomonas aeruginosa (14.4%), and Acinetobacter baumannii (11.7%). CONCLUSIONS: FOB is an important diagnostic and therapeutic method with a low complication rate when performed by an experienced team with appropriate indication in the intensive care unit.

Indication, complication, and prognosis of fiberoptic bronchoscopy guided percutaneous dilatation tracheostomy opening in respiratory intensive care unit: a retrospective study.

OBJECTIVE: Percutaneous dilatational tracheostomy (PDT) is a bedside applicable procedure in intensive care unit patients requiring long-term mechanical ventilation. Fiber optic bronchoscopy (FOB) makes it easier and reduces complications. Our study aimed to evaluate the indications, complications, and prognosis of PDTs performed with FOB. PATIENTS AND METHODS: Our study included 114 patients undergoing PDT through FOB-guided Griggs method in the Respiratory Intensive Care Unit between January 01, 2018, and January 31, 2023. RESULTS: Among the patients undergoing PDT with FOB, 81 (71.1%) were male. The mean age was 62.1±11.5. The median Glasgow Coma Scale (GCS) score was 9, the median Acute Physiology and Chronic Health Evaluation-II (APACHE-II) score was 19, and the median Sequential Organ Failure Assessment (SOFA) score was 8. Tracheostomy was opened for prolonged mechanical-ventilator requirement in 80 patients (70.2%), to protect the airway in 19 (16.7%), and for poor neurologic status in 15 patients (13.2%). Complications during the procedure included hypoxemia in 3 patients (2.6%), minor bleeding in 3 patients (2.6%), perforation of the FOB in one patient (0.8%), and perforation of the intubation tube cuff in one patient (0.8%). 79 patients (69.3%) were discharged, and 35 (30.7%) were exited. There was a significant difference between the GCS, APACHE-II, and SOFA scores of the patients discharged and those who exited (p < 0.001). CONCLUSIONS: FOB-guided PDT application should be encouraged as it reduces complications but it is still limited because it requires experienced specialists and equipment for a standard approach.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study.

BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. METHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. RESULTS: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. CONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

Postoperative infection-related mortality and lymphocyte-to-C-reactive protein ratio in patients undergoing on-pump cardiac surgery: a novel predictor of mortality?

OBJECTIVE: This study aims to investigate the relationship between postoperative infection-related mortality and lymphocyte-to-C-reactive protein ratio (LCR), a newly defined parameter with the combination of inflammatory and immune parameters, in patients undergoing cardiac surgery. PATIENTS AND METHODS: Between January 2016 and November 2021, 236 patients who underwent on-pomp cardiac surgery with median sternotomy and developed postoperative infection were analyzed retrospectively. Patients were divided into six groups according to the types of postoperative infection. Preoperative, perioperative, and postoperative variables of the patient groups were compared, and factors affecting postoperative mortality were evaluated. RESULTS: The mortality rate in the patient group we included in the study was 22.9%. Mortality rates did not differ significantly between the infection groups. However, when the LCR value was evaluated between the groups, there was a statistically significant difference (p<0.001). The preoperative LCR cut-off value, which predicts postoperative infection-related mortality, was determined as 133.46 (area under the curve (AUC): 0.607, p=0.017, 48.1% sensitivity, and 47.8% specificity). In the multivariate analysis, postoperative cerebrovascular event (OR: 78.365, 95% CI: 12.367-496.547, p<0.001) and Intensive Care Unit (ICU) stay (odds ratio (OR): 1.136, 95% confidence interval (CI): 1.004-1.284, p=0.042) variables were found to be independent predictive factors of postoperative infection-related mortality in the model. There was no positive differentiation of the type of infection in predicting mortality. CONCLUSIONS: The calculated LCR value is a novel and remarkable parameter in estimating postoperative infection-related mortality in patients undergoing cardiac surgery.

The impact of the Adenotonsillectomy on cardiac functions and oxidative stress.

OBJECTIVE: Obstructive sleep apnea syndrome (OSAS) causes cardiovascular comorbidities and increased oxidative stress. Adenotonsillectomy is the first treatment option for OSAS secondary to adenotonsillar hypertrophy (ATH). This study evaluated the presence of cardiovascular changes, hypertension and oxidative stress before and after adenotonsillectomy in patients with OSAS secondary to ATH. METHODS: Patients with ATH diagnosed with OSAS by polysomnography (PSG) were included. All participants received an Echocardiography (ECHO) and 24-h ambulatory blood pressure measurement (ABPM). Serum malonyldialdehyde (MDA) and total oxidant activity (TOS) levels of oxidant parameters; total antioxidant activity (TAS), catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) levels of antioxidant parameters were measured. All patients received an adenotonsillectomy. Postoperative evaluation was performed at the 6th month. In the postoperative period, PSG, ECHO, ABPM and the oxidant-antioxidant parameter levels in the serum was repeated. RESULTS: Twenty-eight patients (13 males, 15 females; mean age 8.2 ± 2.06 years) were included in the study. In the preoperative period, concentric remodeling was observed in 14,8% of the patients, although they had no cardiovascular system complaints. The apnea-hypopnea index (AHI) scores were classified as mild in 39.3% (n = 11), moderate in 21.4% (n = 6) and severe in 39.3% (n = 11) preoperatively. In the postoperative period, 22 patients were evaluated. It was observed that the severity of OSAS decreased, ventricular functions improved, oxidant parameters decreased and antioxidant parameters increased postoperatively. CONCLUSION: Adenotonsillectomy provides a positive change in cardiovascular system parameters and an antioxidant change in the oxidative balance in patients with OSAS.

Size dependent influence of contact line pinning on wetting of nano-textured/patterned silica surfaces.

Wetting behavior on a heterogeneous surface undergoes contact angle hysteresis as the droplet stabilized at a metastable state with a contact angle significantly different from its equilibrium value due to contact line pinning. However, there is a lack of consensus on how to calculate the influence of pinning forces. In general, the pinning effect can be characterized as (i) microscopic behavior when a droplet is pinned and the contact angle increases/decreases as the droplet volume increases/decreases and (ii) macroscopic behavior as the pinning effects decrease and ultimately, disappear with the increase of the droplet size. The current work studied both behaviors using molecular dynamics (MD) simulation with more than 300 different size water droplets on silica surfaces with three different patterns across two different wetting conditions. Results showed that the contact angle increases linearly with increasing droplet volume through the microscopic behavior, while the droplet is pinned on top of a certain number of patterns. When we normalized the droplet size with the corresponding pattern size, we observed a "wetting similarity" that linear microscopic contact angle variations over different size heterogeneities continuously line up. This shows that the pinning force remains constant and the resulting pinning effects are scalable by the size ratio between the droplet and pattern, independent of the size-scale. The slope of these microscopic linear variations decreases with an increase in the droplet size as observed through the macroscopic behavior. We further found a universal behavior in the variation of the corresponding pinning forces, independent of the wetting condition. In macroscopic behavior, pinning effects become negligible and the contact angle reaches the equilibrium value of the corresponding surface when the diameter of the free-standing droplet is approximately equal to 24 times the size of the surface structure. We found that the pinning effect is scalable with the droplet volume, not the size of the droplet base.

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA).

BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Hereditary haemorrhagic telangiectasia: mutation detection, test sensitivity and novel mutations.

BACKGROUND: Hereditary haemorrhagic telangiectasia (HHT) is a genetic disorder present in 1 in 8000 people and associated with arteriovenous malformations. Genetic testing can identify individuals at risk of developing the disease and is a useful diagnostic tool. OBJECTIVE: To present a strategy for mutation detection in families clinically diagnosed with HHT. METHODS: An optimised strategy for detecting mutations that predispose to HHT is presented. The strategy includes quantitative multiplex polymerase chain reaction, sequence analysis, RNA analysis, validation of missense mutations by amino acid conservation analysis for the ENG (endoglin) and ACVRL1 (ALK1) genes, and analysis of an ACVRL1 protein structural model. If no causative ENG or ACVRL1 mutation is found, proband samples are referred for sequence analysis of MADH4 (associated with a combined syndrome of juvenile polyposis and HHT). RESULTS: Data obtained over the past eight years were summarised and 16 novel mutations described. Mutations were identified in 155 of 194 families with a confirmed clinical diagnosis (80% sensitivity). Of 155 mutations identified, 94 were in ENG (61%), 58 in ACVRL1 (37%), and three in MADH4 (2%). CONCLUSIONS: For most missense variants of ENG and ACVRL1 reported to date, study of amino acid conservation showed good concordance between prediction of altered protein function and disease occurrence. The 39 families (20%) yet to be resolved may carry ENG, ACVRL1, or MADH4 mutations too complex or difficult to detect, or mutations in genes yet to be identified.

Quality of Life Questionnaire for Turkish Patients with Primary Ciliary Dyskinesia.

OBJECTIVES: Primary ciliary dyskinesia (PCD) is a major cause of progressive lung disease, and physiological measures do not reflect the impact of the disease on patients' daily symptoms or physical and social functions. We need valid and reliable health-related quality-of-life (HRQOL) measures in PCD to assess the symptoms and daily functions from the patient's perspective. Our aim was to develop a Turkish translation of PCD-specific HRQOL questionnairre to be used as outcomes in clinical trials. MATERIAL AND METHODS: This study was conducted at the Division of Pediatric Pulmonology, Hacettepe University Faculty of Medicine and the Division of Pediatric Pulmonology, Marmara University Faculty of Medicine. Forward and back translations were performed by three different translators. We recruited participants with PCD from different age groups of both sexes, with an aim to represent a wide spectrum of disease severity and performed the prototype of the translation in these participants. RESULTS: Five participants from each age group [children (6-12 years), teenagers (13-17 years), adults (18+ years) and parents of children aged from 6 to 12 years] responded to the HRQOL questionnaire. Content analysis of the questions included the following domains depending on age: Respiratory Symptoms, Physical Functioning, Emotional Functioning, Treatment Burden, Ears and Hearing, Sinus Symptoms, Social Functioning, Role Functioning, Vitality, Health Perceptions, School Functioning, Eating and Weight. After the participants have completed the questionnaire, a cognitive debriefing interview was conducted with them, and the results of the interviews were used to form a final version of PCD-specific HRQOL, ready for formal validation. CONCLUSION: A Turkish translation of PCD-specific HRQOL questionnaire was developed to meet the standards set by international guidelines. This questionnaire is expected to be useful as end points in clinical trials for monitoring health outcomes and for improving clinical decisions.

Evaluation of carotid intima-media thickness with vascular endothelial growth factor and malondialdehyde levels in patients with sarcoidosis.

PURPOSE: To assess the impact of sarcoidosis on endothelial function by measuring carotid intima-media thickness (CIMT) and serum levels of malondialdehyde and vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: We prospectively analyzed 41 patients with sarcoidosis (9 men, 32 women) with a mean age of 44.9±10.2 (SD) years and 34 healthy subjects (9 men, 24 women) with a mean age of 37.26±8.9 (SD) years who served as a control group. Sarcoidosis patients receiving steroids were included in Group 1 while those not under steroid treatment were included in Group 2. CIMT measurements were performed using B-mode ultrasound. Malondialdehyde and VEGF serum levels were obtained in all sarcoidosis patients and control subjects. RESULTS: Both right and left CIMT was significantly higher in Group 1 and Group 2 than in control subjects. Serum levels of malondialdehyde and VEGF in Group 1 and Group 2 were significantly higher than in healthy subjects. No differences in CIMT, malondialdehyde and VEGF were found between Group 1 and Group 2. CONCLUSION: Sarcoidosis results in increased CIMT, VEGF and malondialdehyde serum levels. However, there was no difference in terms of CIMT, VEGF and malondialdehyde levels between sarcoidosis patients with or without steroid treatment, suggesting that new treatment strategies for sarcoidosis vascular involvement should consider this result.

Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations.

BACKGROUND: Breast carcinomas occurring in carriers of BRCA1 gene mutations may have a distinctly different pathway of molecular pathogenesis from those occurring in noncarriers. Data from murine models implicate loss of p53 (also known as TP53) gene function as a critical early event in the malignant transformation of cells with a BRCA1 mutation. Therefore, breast tumors from BRCA1 mutation carriers might be expected to exhibit a high frequency of p53 mutations. This study examined the frequency of p53 mutations in the breast tumors of Ashkenazi Jewish carriers and noncarriers of BRCA1 mutations. METHODS: Tumor DNA from carriers and noncarriers of BRCA1 mutations was screened for mutations in exons 4 through 10 of the p53 gene by use of the polymerase chain reaction and single-strand conformation polymorphism (SSCP) analysis of the amplified DNA. Direct sequencing was performed on gene fragments that showed altered mobility in SSCP analysis. RESULTS: Mutations in the p53 gene were detected in 10 of 13 tumors from BRCA1 mutation carriers versus 10 of 33 tumors from non-carriers (two-sided P = .007). The p53 mutations were distributed throughout exons 4 through 10 and included both protein-truncating and missense mutations in both groups. CONCLUSIONS: A statistically significantly higher frequency of p53 mutations was found in breast tumors from carriers of BRCA1 mutations than from noncarriers, which adds to the accumulating evidence that loss of p53 function is an important step in the molecular pathogenesis of BRCA1 mutation-associated breast tumors. This finding may have implications for understanding phenotypic differences and potential prognostic differences between BRCA1 mutation-associated hereditary breast cancers and sporadic cancers.

Prevalence and penetrance of BRCA1 and BRCA2 gene mutations in unselected Ashkenazi Jewish women with breast cancer.

BACKGROUND: Approximately 2.0%-2.5% of Ashkenazi Jewish women carry one of three founding mutations in the BRCA1 and BRCA2 genes, and each mutation is associated with a high lifetime risk of invasive breast cancer. We investigated the extent to which these three mutations contribute to breast cancer incidence in the Ashkenazi Jewish population. METHODS: We ascertained 457 Jewish women with prevalent cases of breast cancer who were unselected for age or family history of the disease; 412 of these women were tested for the three founder mutations (case patients). Control subjects consisted of 360 non-Jewish women with breast cancer (control patients) and 380 healthy Jewish women with no history of cancer (control subjects). RESULTS: Mutations were found in 48 (11.7%) of 412 Jewish case patients. Forty-six of 48 mutations occurred in women with early-onset breast cancer (<50 years) or a history of ovarian or early-onset breast cancer in a first-, second-, or third-degree relative. The estimated penetrance to age 70 years for breast cancer was 59.9% for the BRCA1 gene mutations and 28.3% for the BRCA2 gene mutation. Compared with Jewish control subjects, the relative risk (RR) of breast cancer for first-degree relatives of mutation carriers was 5.16 (95% confidence interval [CI] = 3.14-8. 48), but risk was also increased for relatives of noncarriers (RR = 1.66; 95% CI = 1.18-2.33). The RR of prostate cancer for first-degree relatives of Jewish case patients was 3.36 (95% CI = 1. 49-7.56). CONCLUSIONS: Approximately 12% of breast cancers in the Ashkenazi Jewish population are attributable to mutations in the BRCA1 or BRCA2 gene. Genetic testing may be useful when Jewish women with breast cancer are diagnosed before age 50 years or have a close relative with ovarian or early-onset breast cancer. An association between breast and prostate cancers was observed in our study population.

Diterpenoid alkaloids from the roots of Aconitum cochleare.

From the roots of Aconitum cochleare Woroschin, collected in Turkey, a new diterpenoid alkaloid named acochlearine has been isolated along with the known diterpenoid alkaloids talatisamine, 14-O-acetyltalatisamine, senbusine C and condelphine. The structure for acochlearine was established on the basis of 1H, 13C, DEPT, homonuclear 1H COSY, NOESY, HSQC and HMBC NMR studies.

Inherited predisposition to pancreatic adenocarcinoma: role of family history and germ-line p16, BRCA1, and BRCA2 mutations.

Susceptibility to pancreatic adenocarcinoma appears to be linked to germ-line mutations in genes causing various familial cancer syndromes. The objectives of this study were to estimate the proportion of unselected pancreatic cancer patients belonging to hereditary cancer syndrome families and to determine the frequency ofp16, BRCA1, BRCA2, hMSH2, and hMLH1 germ-line mutations in patients with a personal or family history of cancer. The study population consisted of 102 patients with histologically verified pancreatic adenocarcinoma, unselected for age, sex, family history, or ethnic origin. Patients completed a family history questionnaire and provided blood for mutation analysis. Three-generation pedigrees were constructed and classified as high risk/familial, intermediate risk/ familial, intermediate risk/nonfamilial, or low risk according to defined criteria. High- and intermediate-risk cases were analyzed for germ-line mutations using a combination of methods. Thirty-eight of 102 (37%) patients were characterized as high or intermediate risk, and the remainder were classified as low risk. Germ-line mutations were identified in five (13%) of these cases [one in p16 (I49S); one in BRCA1 (5382 insC); and three in BRCA2 (6174delT)]. The BRCA1 and BRCA2 mutations were identified in Ashkenazi Jewish patients. Four of the mutation carriers had strong family histories of the syndromes associated with the mutated genes. No mutations were identified in patients in whom the sole risk factor was a family history of pancreatic cancer, and only one mutation was found among patients with early-onset disease. We conclude that known causes of genetic predisposition are an important risk factor in a small proportion of pancreatic cancer patients, especially if associated with a strong family history of syndromes associated with the disease. The lack of detectable germ-line mutations in most high- and intermediate-risk cases suggests that there are probably additional, as yet unidentified genes predisposing to this disease.

p53 mutations in mammary ductal carcinoma in situ but not in epithelial hyperplasias.

The development and progression of human breast neoplasia is characterized by the accumulation of numerous somatic genetic alterations. Although mutation of the p53 tumor suppressor gene is one of the most common alterations identified in invasive carcinomas, it is not clear whether mutations usually occur in noninvasive lesions before the development of invasion. To investigate the presence and heterogeneity of p53 mutations in breast neoplasia, we studied a morphological spectrum of paired lesions including invasive carcinomas and adjacent noninvasive epithelial lesions. Using 18 invasive ductal carcinomas with known p53 mutations, tissue samples were microdissected from formalin-fixed, paraffin-embedded tissue sections, and mutations in exons 4-8 of the p53 gene were identified by PCR amplification, single-strand conformational polymorphism, and direct sequencing. Multiple geographically distinct foci of invasive carcinoma were microdissected from six different invasive carcinomas, and all samples from each case had the same mutation. The absence of mutation heterogeneity provides evidence that p53 mutations occurred at the time of, or before, the clonal selection of the dominant component of the invasive carcinoma. To delineate the timing of p53 inactivation further in these cases, histological slides were reviewed to identify all noninvasive epithelial lesions. There were eight cases with associated ductal carcinoma in situ (DCIS), and in total, 27 distinct tissue samples representing a spectrum of histological subtypes and grades of DCIS were microdissected. In all 27 samples, the identical p53 mutation was identified in the DCIS as was present in the invasive carcinoma. In contrast, no p53 mutations were identified in any of the 21 microdissected foci of epithelial hyperplasia analyzed, including one sample with atypia. Together, these findings provide support that p53 mutations commonly occur early in breast neoplasia, usually at the stage of DCIS, but are not often identified in foci of hyperplasia. These findings support an important biological role for p53 mutation in progression from noninvasive precursors in breast neoplasia and provide further evidence that p53 mutation could have potential use as a molecular marker.

Somatic mutations in the BRCA1 gene in Chinese sporadic breast and ovarian cancer.

Inherited mutations in the BRCA1 gene confer increased susceptibility to breast and ovarian cancer. Its role in sporadic carcinogenesis is not well defined. Somatic mutations in breast cancers have not been reported and to date there are only three reports of somatic mutations in sporadic ovarian cancers. To investigate the contribution of BRCA1 mutations to sporadic breast and ovarian cancer in the Chinese population, we analysed 62 samples from Chinese women using the protein truncation test. There were 40 cases of breast cancer under age 50 and 22 cases of ovarian cancer, all unselected for family history. There was no age selection for the ovarian cancers. We found two somatic BRCA1 mutations in exon 11, one in a breast cancer and the other in an ovarian cancer, both of which result in truncated proteins. Our results indicate that somatic BRCA1 mutations, like somatic mutations in the BRCA2 gene, though very rare, can be found in both breast and ovarian cancers and support a tumor suppressor function for BRCA1 in sporadic tumors.