ObjectivePrognostic nutritional index (PNI), calculated as serum albumin (ALB) (g/L) + 5 × total lymphocyte count (109/L), is initially used to evaluate nutritional status in patients undergoing surgery and may evaluate the therapeutic effects and predict the survival of various solid tumors. The present study aimed to evaluate the potential prognostic significance of PNI in breast cancer patients receiving neoadjuvant chemotherapy (NACT).MethodsA total of 785 breast cancer patients treated with neoadjuvant chemotherapy were enrolled in this retrospective study. The optimal cutoff value of PNI by receiver operating characteristic curve stratified patients into a low-PNI group (<51) and a high PNI group (≥51). The associations between breast cancer and clinicopathological variables by PNI were determined by chi-square test or Fisher’s exact test. Kaplan–Meier plots and log-rank test were used to evaluate the clinical outcomes of disease-free survival (DFS) and overall survival (OS). The prognostic value of PNI was analyzed by univariate and multivariate Cox proportional hazards regression models. The toxicity of NACT was accessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC).ResultsThe results indicated that PNI had prognostic significance by an optimal cutoff value of 51 on DFS and OS in univariate and multivariate Cox regression survival analyses. Breast cancer patients with a high PNI value had longer DFS and OS than those with a low PNI value [47.64 vs. 36.60 months, P < 0.0001, hazard ratio (HR) = 0.264, 95%CI = 0.160–0.435; 73.61 vs. 64.97 months, P < 0.0001, HR = 0.319, 95%CI = 0.207–0.491, respectively]. Furthermore, the results indicated that patients with high PNI had longer DFS and OS than those with low PNI in early stage and advanced breast cancer, especially in advanced breast cancer. The mean DFS and OS times for breast cancer patients with high PNI by the log-rank test were longer than in those with low PNI in different molecular subtypes. Moreover, the mean DFS and OS times in patients with high PNI by the log-rank test were longer than in those patients with low PNI without or with lymph vessel invasion. The common toxicities after neoadjuvant chemotherapy were hematologic and gastrointestinal reaction, and the PNI had no significance on the toxicities of all enrolled patients, except in anemia, leukopenia, and myelosuppression.ConclusionPretreatment PNI with the advantages of being convenient, noninvasive, and reproducible was a useful prognostic indicator for breast cancer patients receiving neoadjuvant chemotherapy and is a promising biomarker for breast cancer on treatment strategy decisions.

Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus that replicates in the nucleus of its human host cell and is known to interact with many cellular DNA repair proteins. In this study, we examined the role of cellular mismatch repair (MMR) proteins in the virus life cycle. Both MSH2 and MLH1 are required for efficient replication of HSV-1 in normal human cells and are localized to viral replication compartments. In addition, a previously reported interaction between MSH6 and ICP8 was confirmed by coimmunoprecipitation and extended to show that UL12 is also present in this complex. We also report for the first time that MLH1 associates with ND10 nuclear bodies and that like other ND10 proteins, MLH1 is recruited to the incoming genome. Knockdown of MLH1 inhibits immediate-early viral gene expression. MSH2, on the other hand, which is generally thought to play a role in mismatch repair at a step prior to that of MLH1, is not recruited to incoming genomes and appears to act at a later step in the viral life cycle. Silencing of MSH2 appears to inhibit early gene expression. Thus, both MLH1 and MSH2 are required but appear to participate in distinct events in the virus life cycle. The observation that MLH1 plays an earlier role in HSV-1 infection than does MSH2 is surprising and may indicate a novel function for MLH1 distinct from its known MSH2-dependent role in mismatch repair.Herpes simplex virus 1 (HSV-1) is a large double-stranded DNA virus that replicates in the nucleus of the host cell. Although cis-and trans-acting functions involved in HSV-1 replication in infected cells have been identified (69), the mechanism of HSV-1 DNA replication remains poorly understood. The appearance of viral genomes in the nucleus might be expected to induce a cellular DNA damage response, and it is now clear that HSV-1 has evolved a complex relationship with the host DNA damage response pathways (33,48,60,66,70,71). During infection, cellular factors that are beneficial to the virus are hijacked and recruited, while other factors and pathways are degraded or inactivated. Previous work from our group and others has shown that the ATR (ATM-and Rad3-related) and DNA-PK (DNA-dependent protein kinase) DNA damage-sensing kinases are attenuated in HSV-1-infected cells, while the ATM (ataxia-telangiectasia-mutated) kinase is activated (31,34,48,50). In addition, other components of the DNA damage repair and response pathways also appear to be beneficial to the virus and are utilized during viral replication (35). Many host cellular DNA damage proteins are known to localize to viral replication compartments (33,48,60,66,71). Furthermore, in a recent proteomic analysis of replication compartments, several DNA repair proteins were identified as potential interacting partners of the viral single-stranded DNA (ssDNA) binding protein ICP8 (66). One such potential interacting partner, the DNA mismatch repair (MMR) protein MSH2, was shown to localize to the replication compartments in infected cells (66).The DNA MMR system is highly c...

The herpes simplex virus type 1 (HSV-1) alkaline nuclease, encoded by the UL12 gene, plays an important role in HSV-1 replication, as a UL12 null mutant displays a severe growth defect. The HSV-1 alkaline exonuclease UL12 interacts with the viral single-stranded DNA binding protein ICP8 and promotes strand exchange in vitro in conjunction with ICP8. We proposed that UL12 and ICP8 form a two-subunit recombinase reminiscent of the phage lambda Red ␣/␤ recombination system and that the viral and cellular recombinases contribute to viral genome replication through a homologous recombination-dependent DNA replication mechanism. To test this hypothesis, we identified cellular interaction partners of UL12 by using coimmunoprecipitation. We report for the first time a specific interaction between UL12 and components of the cellular MRN complex, an important factor in the ATM-mediated homologous recombination repair (HRR) pathway. This interaction is detected early during infection and does not require viral DNA or other viral or cellular proteins. The region of UL12 responsible for the interaction has been mapped to the first 125 residues, and coimmunoprecipitation can be abolished by deletion of residues 100 to 126. These observations support the hypothesis that cellular and viral recombination factors work together to promote efficient HSV-1 growth.The herpes simplex virus (HSV) genome replicates in the nucleus of an infected host cell, resulting in the production of longer-than-unit-length head-to-tail concatemers of viral DNA. Production of infectious virus requires the processing of concatemeric DNA into unit-length genomes by the packaging machinery followed by encapsidation into preassembled capsids (63). Several lines of evidence suggest that recombination plays a role in concatemer formation (69). Genomic inversions, proposed to occur through recombination, can be detected very early during infection, and these inversions require sequence homology (2,23,56). In addition, replication intermediates in HSV type 1 (HSV-1)-infected cells adopt a complex nonlinear structure that does not migrate in a pulsed-field gel, even after digestion with an enzyme that cuts once per unit length of the genome (1,33,51,71). Electron micrographs have revealed that replication intermediates are branched and contain Y-and X-shaped junctions (19,52). Furthermore, high levels of recombination have been reported not only between coinfecting viral strains (4, 17, 50, 62, 66) but also in plasmids containing repeated sequence elements (10, 11). These observations, taken together, are not consistent with a simple rolling circle mechanism of replication and suggest that, reminiscent of the bacteriophages T4 and lambda, HSV-1 utilizes a recombination-dependent replication mechanism to generate concatemeric viral DNA.We have previously reported that virus-encoded proteins are capable of participating in recombination events in vitro. The viral 5Ј-3Ј alkaline exonuclease (UL12) and the single-strand binding protein (ICP8) together mediate stra...

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