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Objective Over the past decade, several studies have highlighted that axillary lymph node ratio (ratio of involved over excised axillary lymph nodes) was a superior predictor for survival outcomes compared with ypN staging. Thus, this study aimed to integrate the prognostic value of axillary lymph node ratio to improve individualized prediction of survival in node-positive breast cancer patients after neoadjuvant chemotherapy. Methods A clinical data of 339 node-positive breast cancer patients after neoadjuvant chemotherapy from two independent centers were retrospectively reviewed. A nomogram incorporating axillary lymph node ratio was constructed to predict disease-free survival based on Cox proportional hazards model. The discrimination, calibration ability, and clinical usefulness of the axillary lymph node ratio-based model were evaluated using C-index, calibration curve, risk group stratification and decision curve analysis and were compared with the TNM staging system. Results Independent prognostic factors for disease-free survival were age, pathological T stage, axillary lymph node ratio, histological grade, estrogen receptor status, Ki67 and lymphovascular invasion, which were entered into the nomogram. The C-index of the axillary lymph node ratio-based nomogram was higher than that of the TNM staging system (0.773 vs 0.610). The calibration plot indicated close agreement between model predictions and actual observations. Based on the risk group stratification of the nomogram, Kaplan-Meier curves demonstrated significant differences between the low-risk and high-risk groups (P < 0.0001). Conclusions The axillary lymph node ratio-based nomogram provided more accurate individualized risk prediction of disease-free survival in node-positive breast cancer patients after neoadjuvant chemotherapy. This practical tool may assist oncologists in selecting the high-risk patients who are in need of a specific treatment strategy.

The accurate prediction of overall survival (OS) is important in clinical decision-making for breast cancer treatment. We developed a model to predict the OS of non-metastatic breast cancer patients in China. This multicenter study included 1844 non-metastatic breast cancer patients who underwent breast cancer surgery between January 2009 and December 2011 in 3 tertiary teaching hospitals in China. Data were collected retrospectively from the database of each hospital. We used univariate and multivariate Cox proportional hazard regression analyses to screen for predictors. A nomogram was developed in the training cohort (from Sun Yat-sen Memorial Hospital [SYSMH]), externally validated in 2 validation cohorts (from the First People’s Hospital of Foshan [FPHF] and Sun Yat-sen University Cancer Center (SYUCC)), and compared with CancerMath, a mathematical-based model. We used Receiver Operating Characteristic curves and calibration plots to assess the models. At median follow-ups of 65.9, 68.6, and 66.2 months, the 5-year OS rates were 93.0%, 86.7%, and 91.0% in the SYSMH, FPHF, and SYUCC cohorts, respectively. We identified age, T stage, lymph node status, estrogen receptor, and human epidermal growth factor receptor 2 statuses as significant prognostic factors. A nomogram was developed and externally validated in the FPHF (area under the curve= 0.74) and SYUCC (area under the curve= 0.77) cohorts. Calibration plots showed that the predicted OS was consistent with the actual OS. The nomogram outperformed CancerMath in our study population. In summary, we developed a nomogram to predict survival among non-metastatic breast cancer patientsin China. This nomogram is superior to the CancerMath model in Chinese populations. Key words: breast cancer; nomogram; overall survival; prediction

A new electrosilicothermic method has been proposed in the present paper to produce Ni–Cr ferroalloy, which can be used for the production of 300 series stainless steel. Based on this new process, the Ni–Si ferroalloy is first produced as the intermediate alloy, and then the desiliconization process of Ni–Si ferroalloy melt with chromium concentrate is carried out to generate Ni–Cr ferroalloy. The silicon content in the Ni–Si ferroalloy produced in the submerged arc furnace should be more than 15 mass% (for the propose of reducing dephosphorization), in order to make sure the phosphorus content in the subsequently produced Ni–Cr ferroalloy is less than 0.03 mass%. A high utilization ratio of Si and a high recovery ratio of Cr can be obtained after the desiliconization reaction between Ni–Si ferroalloy and chromium concentrate in the electric arc furnace (EAF)–shaking ladle (SL) process.

Partner and localizer of BRCA2 (PALB2), plays an important functional role in DNA damage repair. Recent studies indicate that germline mutations in PALB2 predispose individuals to a high risk of developing familial breast cancer. Therefore, comprehensive identification of PALB2 germline mutations is potentially important for understanding their roles in tumorigenesis and for testing their potential utility as clinical targets. Most of the previous studies of PALB2 have focused on familial breast cancer cases with normal/wild-type BRCA1 and BRCA2 (BRCAx). We hypothesize that PALB2 genetic mutations also exist in individuals with BRCA mutations (BRCA+). To test this hypothesis, PALB2 germline mutations were screened in 107 exome data sets collected from familial breast cancer families who were either BRCA1+ or BRCAx. Two novel heterozygous mutations predicted to alter the function of PALB2 were identified (c.2014G>C, p.E672Q and c.2993G>A, p.G998E). Notably, both of these mutations co-existed in BRCA1+ and BRCA1x families. These studies show that mutations in PALB2 can occur independent of the status of BRCA1 mutations, and they highlight the importance to include BRCA1+ families in PALB2 mutation screens.

In the present study, the dephosphorization of Fe-Ni-Si melt by CaO-saturated CaO-CaF2 slag was investigated, from which it was found that the dephosphorization efficiency increases as increasing the silicon content, meanwhile the increase rate becomes rapid when the silicon content is more than 10 mass pct. By analyzing the phase compositions of the dephosphorization slag of a high silicon Fe-Ni-Si melt, it was first found the dephosphorization products change with the silicon content. When Si contents are 10.5, 31.48, 34.71, and 43.15 mass pct, the de-P products are Ca2P2, Ca10+x Si12−2x P16, Ca4SiP4, and Ca10+x Si12−2x P16, as well as Ca4SiP4, respectively. The corresponding dephosphorization mechanism can be described as $$ (2x)({\text{CaO}}) + (x + 2y)[{\text{Si}}] + 2z[{\text{P}}] = x({\text{SiO}}_{2} ) + 2({\text{Ca}}_{x} {\text{Si}}_{y} {\text{P}}_{z} ) $$ .

Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.

The burden calculation of ferromanganese alloy was calculated based on the slag composition and designed product. The calculation results showed the total error rate of this method was 1.53% and the error rate of ore, coke and silicon was 4.66%, 1.71%, and 5.66% respectively, which was much better than using the traditional elements recovery method with the total error rate was 8.00% and the silicon error rate reached to 18.55%. This new method is more accurate than the traditional method and much closer to the actual production data. And it can apply to different ferroalloy factories because it is based on phase diagram and the mass conservation law. At the same time, the calculation result can reflect the gap between enterprise production craft level and ideal production level. This method has certain reference value to improve production technology, product quality and economic profit of enterprise.

Background BRCA1 plays an essential role in maintaining genome stability. Inherited BRCA1 germline mutation (BRCA1+) is a determined genetic predisposition leading to high risk of breast cancer. While BRCA1+ induces breast cancer by causing genome instability, most of the knowledge is known about somatic genome instability in breast cancer cells but not germline genome instability. Methods Using the exome-sequencing method, we analyzed the genomes of blood cells in a typical BRCA1+ breast cancer family with an exon 13-duplicated founder mutation, including six breast cancer-affected and two breast cancer unaffected members. Results We identified 23 deleterious mutations in the breast cancer-affected family members, which are absent in the unaffected members. Multiple mutations damaged functionally important and breast cancer-related genes, including transcriptional factor BPTF and FOXP1, ubiquitin ligase CUL4B, phosphorylase kinase PHKG2, and nuclear receptor activator SRA1. Analysis of the mutations between the mothers and daughters shows that most mutations were germline mutation inherited from the ancestor(s) while only a few were somatic mutation generated de novo. Conclusion Our study indicates that BRCA1+ can cause genome instability with both germline and somatic mutations in non-breast cells.

Fluorescence in situ hybridization (FISH) of uncultured chorionic villus diploid cells with a chromosome 18 alpha-satellite DNA probe (D18Z1) revealed a third small signal in addition to two large signals. FISH analysis of diploid metaphase cells from cultured chorionic villus cells and from maternal lymphocytes revealed that the third signal resulted from hybridization to the centromere of chromosome 22. This is the first report of a variant involving D18Z1 detected by FISH and of hybridization of alpha-satellite from a sub-metacentric chromosome to the centromere of an acrocentric chromosome. We propose that this inherited variant resulted from insertion of chromosome 18 specific alpha-satellite DNA sequences into the centromeric region of chromosome 22.

The catalytic α-subunit of oligomeric P-type ATPases such as Na-K-ATPase and H-K-ATPase requires association with a β-subunit after synthesis in the endoplasmic reticulum (ER) to become stably expressed and functionally active. In this study, we have expressed the β-subunit of Xenopus gastric H-K-ATPase (βHK) in Xenopus oocytes together with α-subunits of H-K-ATPase (αHK) or Na-K-ATPase (αNK) and have followed the biosynthesis, assembly, and cell surface expression of functional pumps. Immunoprecipitations of Xenopus βHK from metabolically labeled oocytes show that it is well expressed and, when synthesized without α-subunits, can leave the ER and become fully glycosylated. Xenopus βHK can associate with both coexpressed αHK and αNK, but the α-β complexes formed are degraded rapidly in or close to the ER and do not produce functional pumps at the cell surface as assessed by86Rb uptake. A possible explanation of these results is that Xenopus βHK may contain a tissue-specific signal that is important in the formation or correct targeting of functional α-β complexes in the stomach but that cannot be recognized in Xenopusoocytes and in consequence leads to cellular degradation of the α-β complexes in this experimental system.

To examine the effect of short-term occupational lead exposure on the inflammatory response system in blood among workers.A total of 255 lead-exposed workers (length of service ≤1 year) at an electronics factory in Dongguan, China (exposure group), as well as 205 managers without any occupational exposure at another factory (control group), were included in the study. Occupational physical examination was done to get peripheral blood counts. The blood lead levels of workers were determined by atomic absorption spectrometry. The relationship between blood lead and peripheral hemogram was analyzed using SPSS software.The exposure group had blood lead levels of 0.07∼1.70 µmol/L, falling within the normal range. The leukocyte count, percentage of granulocytes, and absolute value of granulocytes were significantly higher in the exposure group than in the control group, and the results remained unchanged after adjustment for age and sex (P0.05). There were no significant differences in red blood cell count and hemoglobin value between the two groups (P0.05).Short-term occupational lead exposure may increase the counts of inflammatory cells in blood, but it has little effect on red blood cells and hemoglobin.

Genetic studies often use genomic DNA from whole blood cells, of which the majority are the polymorphonuclear myeloid cells. Those cells undergo dramatic change of nuclear morphology following cellular differentiation. It remains elusive if the nuclear morphological change accompanies sequence alternations from the intact genome. If such event exists, it will cause a serious problem in using such type of genomic DNA for genetic study as the sequences will not represent the intact genome in the host individuals. Using exome sequencing, we compared the coding regions between neutrophil, which is the major type of polymorphonuclear cells, and CD4+ T cell, which has an intact genome, from the same individual. The results show that exon sequences between the two cell types are essentially the same. The minor differences represented by the missed exons and base changes between the two cell types were validated to be mainly caused by experimental errors. Our study concludes that genomic DNA from whole blood cells can be safely used for genetic studies.

Genetic predisposition plays a key role in the development of familial breast cancer. In spite of strong familial clustering of the disease and extensive efforts made during the past decade; however, progress has been slow in identifying genetic predisposition for the majority of familial breast cancer families. The question arises therefore as to whether current approaches are adequate in identifying the unknown genetic predisposition. We analyzed eight members of a BRCA1-, BRCA2-, p53-, and PTEN-negative breast cancer family, of which five had breast cancer, one is an obligate gene carrier, and two were unaffected. We sequenced the entire coding region of the genome for each member using exome sequencing to identify nonsynonymous variants. We identified 55 nonsynonymous germline variants affecting 49 genes in multiple members of the family, of which 22 are predicted to have damaging effects. We validated 20 of the 22 selected variants in the family by Sanger sequencing. Two variants in KAT6B, an acetal transferase gene, were identified in six family members of which five were affected with breast cancer and one is the unaffected obligate carrier. We further examined the presence of the identified variants in a cohort of 40 additional breast cancer cases from 22 familial breast cancer families, but none of the 22 variants was detected in these cases. Sequencing the entire coding exons in KAT6B detects no variants in these cases. Our results show that genetic predisposition for familial breast cancer can be rich in an affected family, but the predisposition can be family-specific. As such, it will be difficult to detect them by applying population-based approach. Our study supports the concept that focusing on each affected family will be required to determine the genetic predisposition for many familial breast cancer families whose genetic dispositions remain unknown.

Background Living donor liver transplantation (LDLT) has recently emerged as an effective therapeutic alternative for patients with end-stage liver disease. In the meantime, the health-related quality of life (HRQoL) of the donors is becoming better appreciated. Here we aimed to review the current literature and summarize the effects of liver donation on the long-term HRQoL of living donors. Data Sources A literature search of PubMed using “donors”, “living donor liver transplantation”, “health-related quality of life”, and “donation” was performed, and all the information was collected. Results The varied postoperative outcomes of liver donors are attributive to the different evaluation instruments used. On the whole, donors experienced good long-term physical and mental well-being with a few complaining of compromised quality of life due to mild symptoms or psychiatric problems. The psychosocial dimension has received increasing attention with the vocational, interpersonal and financial impact of liver donation on donors mostly studied. Conclusions Generally, donors have a good HRQoL after LDLT. Nevertheless, to achieve an ideal donor outcome, further work is necessary to minimize the negative effects as well as to incorporate recent progress in regenerative medicine.

Denaturing high-performance liquid chromatography (DHPLC) is an accurate and efficient screening technique used for detecting deoxyribonucleic acid sequence changes by heteroduplex analysis. It can also be used for genotyping of single-nucleotide polymorphisms. The high-sensitivity of DHPLC has made this technique one of the most reliable approaches to mutation analysis and is used in various areas of genetics, both in the research and clinical arena. This chapter describes the methods used for mutation detection analysis and the genotyping of single-nucleotide polymorphisms by DHPLC on the WAVETM system from Transgenomic Inc.

Genetic aberrations contribute to acute myeloid leukemia (AML). However, half of AML cases do not contain the well-known aberrations detectable mostly by cytogenetic analysis, and these cases are classified as normal karyotype AML. Different outcomes of normal karyotype AML suggest that this subgroup of AML could be genetically heterogeneous. But lack of genetic markers makes it difficult to further study this subgroup of AML. Using paired-end RNAseq method, we performed a transcriptome analysis in 45 AML cases including 29 normal karyotype AML, 8 abnormal karyotype AML and 8 AML without karyotype informaiton. Our study identified 134 fusion transcripts, all of which were formed between the partner genes adjacent in the same chromosome and distributed at different frequencies in the AML cases. Seven fusions are exclusively present in normal karyotype AML, and the rest fusions are shared between the normal karyotype AML and abnormal karyotype AML. CIITA, a master regulator of MHC class II gene expression and truncated in B-cell lymphoma and Hodgkin disease, is found to fuse with DEXI in 48% of normal karyotype AML cases. The fusion transcripts formed between adjacent genes highlight the possibility that certain such fusions could be involved in oncological process in AML, and provide a new source to identify genetic markers for normal karyotype AML.

1538 Background: Familial breast cancer was described in the early 1970s with its syndromy confirmed by the discovery of BRCA germline mutations in the 1990s. BRCA mutations account for less than 10% of affected families. Efforts made in the past two decades have resulted in limited results in identifying additional susceptibility genes for familial breast cancer. Methods: Using exome sequencing, we analyzed eight members in a BRCA1-, BRCA2-, p53- and PTEN-negative breast cancer family; five with breast cancer and three unaffected. Mutation candidates were idenified by bioinformatics analysis, experimentally validated by Sanger sequencing and their damaging effect was predicted by the SIFT program. Validated mutations were also tested in 42 additional breast cancer samples from BRCA-negative breast cancer families. Results: We identified 55 non-synonymous germline mutations affecting 49 genes in multiple members of this family, 20 of 22 selected mutations predicted to cause damaging effects were validated. As an exemplar, two mutations in the MYST4 gene were detected at the C terminal (p.D1516Y and p.R1577C), validated, and predicted to cause damaging consequences. MYST4 is a histone acetyltransferase (Champagne, N. et al. JBC. 274, 28528-28536,1999). It contains a C2HC-type finger and a PHD-type zinc finger. Its N-terminal is involved in transcriptional repression while its C-terminal is involved in transcriptional activation and interacts with important transcriptional regulators RUNX1 and RUNX2. MYST4 is involved in DNA replication, transcriptional regulation, and epigenetic modification of chromatin structure. A translocation t(10;16)(q22;p13) between CREBBP and MYST4 was identified in acute myeloid leukemia. The 20 validated germline mutations were tested by Sanger sequencing in 42 additional breast cancer cases from 26 BRCA-negative families. None of the 20 mutations were detected. Conclusions: Results show that remaining unknown susceptibility genes are likely family-specific and can be detected in each affected family using genome sequencing approaches. These results may be the first reported in an exome sequencing study of BRCA-negative breast cancer families.