Perspectives on Protein-Nanoparticle Interactions at the In Vivo Level.

The distinct features of nanoparticles have provided a vast opportunity of developing new diagnosis and therapy strategies for miscellaneous diseases. Although a few nanomedicines are available in the market or in the translation stage, many important issues are still unsolved. When entering the body, nanomaterials will be quickly coated by proteins from their surroundings, forming a corona on their surface, the so-called protein corona. Studies have shown that the protein corona has many important biological implications, particularly at the in vivo level. For example, they can promote the immune system to rapidly clear these outer materials and prevent nanoparticles from playing their designed role in therapy. In this Perspective, the available techniques for characterizing protein-nanoparticle interactions are critically summarized. Effects of nanoparticle properties and environmental factors on protein corona formation, which can further regulate the in vivo fate of nanoparticles, are highlighted and discussed. Moreover, recent progress on the biomedical application of protein corona-engineered nanoparticles is introduced, and future directions for this important yet challenging research area are also briefly discussed.

Prognostic nomograms for breast cancer with lung metastasis: a SEER-based population study.

BACKGROUND: Lung metastasis is a significant adverse predictor of prognosis in patients with breast cancer. Accurate estimation for the prognosis of patients with lung metastasis and population-based validation for the models are lacking. In the present study, we aimed to establish the nomogram to identify prognostic factors correlated with lung metastases and evaluate individualized survival in patients with lung metastasis based on SEER (Surveillance, Epidemiology, and End Results) database. METHODS: We selected 1197 patients diagnosed with breast cancer with lung metastasis (BCLM) from the SEER database and randomly assigned them to the training group (n = 837) and the testing group (n = 360). Based on univariate and multivariate Cox regression analysis, we evaluated the effects of multiple variables on survival in the training group and constructed a nomogram to predict the 1-, 2-, and 3-year survival probability of patients. The nomogram were verified internally and externally by Concordance index (C-index), Net Reclassification (NRI), Integrated Discrimination Improvement (IDI), Decision Curve Analysis (DCA), and calibration plots. RESULTS: According to the results of multi-factor Cox regression analysis, age, histopathology, grade, marital status, bone metastasis, brain metastasis, liver metastasis, human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), progesterone receptor (PR), surgery, neoadjuvant therapy and chemotherapy were considered as independent prognostic factors for patients with BCLM. The C-index in the training group was 0.719 and the testing group was 0.695, respectively. The AUC values of the 1-, 2-, and 3-year prognostic nomogram in the training group were 0.798, 0.790 and 0.793, and the corresponding AUC values in the testing group were 0.765, 0.761 and 0.722. The calculation results of IDI and NRI were shown. The nomograms significantly improved the risk reclassification for 1-, 2-, and 3-year overall mortality prediction compared with the AJCC 7th staging system. According to the calibration plot, nomograms showed good consistency between predicted and actual overall survival (OS) values for the patients with BCLM. DCA showed that nomograms had better net benefits at different threshold probabilities at different time points compared with the AJCC 7th staging system. CONCLUSIONS: Nomograms that predicted 1-, 2-, and 3-year OS for patients with BCLM were successfully constructed and validated to help physicians in evaluating the high risk of mortality in breast cancer patients.

Photochromic Tungsten Oxide Quantum Dots-based Fluorescent Photoswitches towards Dual-mode Anti-counterfeiting Application.

Development of new anti-counterfeiting technology to increase the difficulty of imitation and decoding is becoming increasingly important, but still remains challenging yet. In this work, we report the design of new fluorescence photoswitches based on photochromic tungsten oxide quantum dots (WO3 QDs) for dual-mode anti-counterfeiting applications. Complexing photochromic WO3 QDs with fluorescent gold nanoclusters (AuNCs) enables the construction of a photoswitchable fluorescence system (WO3-AuNCs) based on fluorescence resonance energy transfer. Detailed spectral and photophysical characterization showed that WO3 QDs well-retain the photochromic properties within the WO3-AuNCs composite. Importantly, photoresponsive and highly reversible switching of both color and fluorescence signals was successfully achieved by simply alternating the irradiation with UV and visible light. Potential utility of photoswitchable WO3-AuNCs composite as novel dual-mode anti-counterfeiting materials has been successfully demonstrated, including photoswitchable ink, rewritable paper and number encryption. Compared with other anti-counterfeiting materials, the present photochromic WO3 QDs-based fluorescent switches are easily synthesized and handled, and they can provide dual security mode (color and fluorescence). This work provides a generable WO3 QDs-assisted strategy of fabricating advanced fluorescence photoswitches for versatile optical counterfeiting applications.

A retrospective cohort study of tamoxifen versus surgical treatment for ER-positive gynecomastia.

BACKGROUND: Gynecomastia is a common condition in clinical practice. The present study aimed to review the clinical data of ER-positive gynecomastia patients treated by tamoxifen (TAM) versus surgery and discussed the clinical effects of the two treatment strategies. METHOD: We retrospectively collected the clinical indicators of patients with unilateral or bilateral gynecomastia who received treatment at our hospital between April 2018 and December 2021. Depending on the treatment received, the patients were divided into TAM and surgery groups. RESULT: A total of 170 patients were recruited, including 91 patients in TAM group and 79 patients in surgery group. The age of the patients differed significantly between the TAM and surgery groups (P < 0.01). The estrogen level was closer in patients with stable and progressive disease, but significantly different in patients of glandular shrinkage in TAM group (P < 0.01). The proportion of patients achieving stable disease was higher among those with clinical grade 1-2. Among patients classified as clinical grade 3, the proportion of patients achieving glandular shrinkage of the breast was higher after TAM treatment (P < 0.05). The age and length of hospital stay were significantly different in patients undergoing open surgery than minimally invasive rotary cutting surgery and mammoscopic-assisted glandular resection (P < 0.01). Patients had significantly different complications including mild postoperative pain, hematoma, nipple necrosis, nipple paresthesias and effusions among the surgery subgroups (all P < 0.05). The estrogen level and the type of surgery were significantly different between the surgical recurrence and non-recurrence subgroups (P < 0.05). The difference in the thickness of glandular tissues upon the color Doppler ultrasound also reached a statistical significance between the two groups (P = 0.050). An elevated estrogen level was a factor leading to TAM failure. Among surgical patients, the thickness of glandular tissues, estrogen level, and type of surgery performed were risk factors for postoperative recurrence (all P < 0.05). CONCLUSION: Both treatment strategies can effectively treat gynecomastia, but different treatment methods can benefit different patients. TAM treatment is more beneficial than surgery for patients who cannot tolerate surgery, have a low estrogen level, and are clinical grade 1-2. Surgery treatment is better than TAM for patients of clinical grade 3. Different surgery options may lead to different complications. Patients with a greater glandular tissue thickness and a higher estrogen level were shown to have a higher risk of recurrence.

Chiral NIR-II fluorescent Ag2S quantum dots with stereospecific biological interactions and tumor accumulation behaviors.

Near-infrared II (NIR-II) fluorescent nanoprobes hold great potential for biomedical applications. Elucidating the relationship between surface properties of NIR-II nanoprobes and their biological behaviors is particularly important for future probe design and their performance optimization. Despite the rapid development of NIR-II nanoprobes, the distinct role of surface chirality on their biological fates has rarely been exploited. Herein, chiral NIR-II fluorescent Ag2S quantum dots (QDs) are synthesized to investigate the relationship between their chirality and biological functions at both in vitro and in vivo levels. D-/L-Ag2S QDs exhibit significant differences on their interactions with serum proteins, which further affect the cellular uptake. As a result, D-Ag2S QDs can be internalized with higher efficiency (over 2-fold) than that of L-Ag2S QDs. Moreover, in vivo studies reveal that the chirality determines the primary localization of these chiral QDs, where a more efficient renal elimination of D-Ag2S QDs was observed than that of L-Ag2S QDs. Importantly, D-Ag2S QDs show preferential accumulation in tumor region than that of L-Ag2S QDs in orthotopic kidney tumor model, which points out a new avenue of enhancing targeting capabilities of nanoprobes by engineering their surface chirality.

Chirality-Dependent Dynamic Evolution of the Protein Corona on the Surface of Quantum Dots.

Elucidating the biological behavior of engineered nanoparticles, for example, the protein corona, is important for the development of safe and efficient nanomedicine, but our current understanding is still limited due to its highly dynamic nature and lack of adequate analytical tools. In the present work, we demonstrate the establishment of a fluorescence resonance energy transfer (FRET)-based platform for monitoring the dynamic evolution behavior of the protein corona in complex biological media. With human serum albumin and lysozyme as the model serum proteins, the protein exchange process of the preformed corona on the surface of chiral quantum dots (QDs) upon feeding either individual protein or human serum was monitored in situ by FRET. Important parameters characterizing the evolution process of protein corona could be obtained upon quantitative analysis of FRET data. Further combining real-time FRET monitoring with gel electrophoresis experiments revealed that the nature of the protein initially adsorbed on the surface of QDs significantly affects the subsequent dynamic exchange behavior of the protein corona. Furthermore, our results also revealed that only a limited proportion of proteins are involved in the protein exchange, and the exchange process exhibits a significant dependence on the surface chirality of QDs. This work demonstrates the feasibility of FRET as a powerful tool to exploit the dynamic evolution process of the protein corona, which can provide theoretical guidance for further design of advanced nanomaterials for biomedical applications.

Differential expression profile of mRNAs, lncRNAs, and circRNAs reveals potential molecular mechanism in breast cancer.

In recent years, breast cancer attracts more and more attention because of its high incidence. To explore the molecular functions and mechanisms, we performed RNA sequencing on the tumor tissues and their paired normal tissues from three breast cancer patients. By differential expression analysis, we found 3764 differentially expressed (DE) mRNAs, 5416 DE lncRNAs, and 148 DE circRNAs. Enrichment analysis suggested that the DE lncRNAs and DE circRNAs were enriched in mitochondria and nucleus, which indicated that they may participate in the vital metabolism directly or indirectly, such as fatty acid metabolism. Subsequently, the protein-protein interaction (PPI) network was constructed and we got 8 key proteins, of which the matrix metalloproteinase-9 (MMP9; degree 5) draws our attention. Based on the 38 up-regulated circRNAs and 14 down-regulated circRNAs, we constructed competing endogenous RNA (ceRNA) networks, from which the has-miR-6794-5p has been identified to enriched in the up-regulated network and correlated with the circNFIX directly. At this point, we presented that the circNFIX and MMP9 may play a significant role by regulating fatty acid metabolism in breast cancer.

High-Throughput Colorimetric Analysis of Nanoparticle-Protein Interactions Based on the Enzyme-Mimic Properties of Nanoparticles.

While an in-depth understanding of the biological behavior of engineered nanoparticles (NPs) is of great importance for their various applications, it remains challenging to quantitatively characterize NP-protein interactions in a simple and high-throughput manner. In the present work, we propose a new, colorimetric approach capable of quantitatively analyzing the adsorption of proteins onto the surface of NPs by their distinct peroxidase-mimic properties. Taking cationic AuNPs as an example, we demonstrate that this colorimetric method is capable of evaluating NP-protein interactions in a simple and high-throughput manner in multiwell plates. Important binding parameters (e.g., the binding affinity) of three different serum proteins (bovine serum albumin, transferrin, and lysozyme) as well as human serum to AuNPs with three different sizes (average diameters of 5, 10, and 15 nm) have been obtained. Based on a quantitative analysis of NP-protein interactions, we observe that the binding affinity and the inhibition efficiency of the nanozyme activity of AuNPs are strongly affected by the characteristics of proteins as well as the sizes of NPs. These results illustrate the great potential of the present colorimetric method as a simple, low-cost, and high-throughput platform for quantitatively investigating NP-protein interactions.

Breast and dorsal spine relapse of granulocytic sarcoma after allogeneic stem cell transplantation for acute myelomonocytic leukemia: A case report.

BACKGROUND: Granulocytic sarcoma (GS) is a rare malignant tumor, and relapse is even rarer in the breast and dorsal spine following allogeneic hematopoietic stem cell transplantation. Currently, a standard treatment regimen is not available. CASE SUMMARY: A rare case of GS of the right breast and dorsal spine after complete remission of acute myelogenous leukemia is reported here. A 55-year-old female patient presented with a palpable, growing, painless lump as well as worsening dorsal compressive myelopathy. She had a history of acute myelomonocytic leukemia (AML M4) and achieved complete remission after chemotherapy following allogeneic hematopoietic stem cell transplantation. Imaging examinations showed the breast lump and C7-T1 epidural masses suspected of malignancy. Histologic results were compatible with GS in both the right breast and dorsal spine, which were considered extramedullary relapse of the AML treated 4 years earlier. CONCLUSION: A rare case of GS relapse following allogeneic hematopoietic stem cell transplantation and guidelines for treatment are discussed.

Surface chemistry regulates the optical properties and cellular interactions of ultrasmall MoS2 quantum dots for biomedical applications.

Molybdenum disulfide quantum dots (MoS2 QDs) have drawn increasing attention owing to their distinct optical properties and potential applications in many fields such as biosensing, photocatalysis and cell imaging. Elucidating the relationship between the surface chemistry of MoS2 QDs and their optical properties as well as biological behaviors is critical for their practical applications, which remain largely unclear. Herein, by adopting a sulfur vacancy modification strategy, a toolbox of MoS2 QDs functionalized with different thiolate ligands was prepared. The effect of surface chemistry on the optical properties of MoS2 QDs was systematically explored by various spectroscopic techniques, revealing the important role of surface ligands in defining their absorption band gap and luminescence quantum yield. Furthermore, cellular experiments showed that the cytotoxicity and intracellular fate (i.e., lysosomal accumulation) of MoS2 QDs are closely related to the properties of surface ligands. Our results underscore the important roles of surface ligands in regulating the properties and biological interactions of these QDs, which will facilitate the future development of MoS2-based materials with precisely controlled functions for biomedical applications.

The Vacuum-Assisted Breast Biopsy System is an Effective Strategy for the Treatment of Gynecomastia.

BACKGROUND: Gynecomastia is the most common benign disease in males with an increasing prevalence in recent years. It may cause local pain and psychological disorders. The vacuum-assisted breast biopsy system has been reported to be a novel surgical approach for the treatment of gynecomastia. However, there are little detailed reports comparing the curative effect between traditional surgery and vacuum-assisted breast biopsy for gynecomastia. Besides, there was little study which compared the application of two different systems for the treatment of gynecomastia. Our study aimed to investigate the effectiveness of vacuum-assisted breast biopsy systems for patients with gynecomastia. METHODS: We retrospectively reviewed 83 patients with gynecomastia between January 2015 and December 2019. Open surgery was performed in 56 patients, and vacuum-assisted breast biopsy was performed in 27 patients. The characteristics of patients as well as the curative effects between the two groups were analyzed. The two vacuum-assisted breast biopsy systems (Mammotome and Encor) were performed for the patients with gynecomastia. The efficacy, safety, complications, and patient satisfactions were recorded during postoperative follow-up periods. RESULTS: Compared with the open surgery group, the vacuum-assisted breast biopsy group had significantly smaller scar sizes left after the operation (5.5 ± 1.3 cm vs 0.8 ± 0.2 cm, p < 0.001), and shorter hospital stay time (5.5 ± 2.4 ds vs 3.1 ± 1.6 ds, p < 0.001). Patients in vacuum-assisted breast biopsy group had a better cosmetic outcome than those in open surgery group. There were no statistically significant differences between the two vacuum-assisted breast biopsy systems according to the mean age, the mean operation time, sites, or grade. In addition, no serious complications were observed in vacuum-assisted breast biopsy group. All the patients recovered well and were satisfied with the cosmetic outcomes. CONCLUSION: The vacuum-assisted breast biopsy system can be used as a feasible and minimally invasive approach for the treatment of gynecomastia. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

In Situ Investigation on the Protein Corona Formation of Quantum Dots by Using Fluorescence Resonance Energy Transfer.

A fundamental understanding of nanoparticle-protein corona and its interactions with biological systems is essential for future application of engineered nanomaterials. In this work, fluorescence resonance energy transfer (FRET) is employed for studying the protein adsorption behavior of nanoparticles. The adsorption of human serum albumin (HSA) onto the surface of InP@ZnS quantum dots (QDs) with different chirality (d- and l-penicillamine) shows strong discernible differences in the binding behaviors including affinity and adsorption orientation that are obtained upon quantitative analysis of FRET data. Circular dichroism spectroscopy further confirms the differences in the conformational changes of HSA upon interaction with d- and l-chiral QD surfaces. Consequently, the formed protein corona on chiral surfaces may affect their following biological interactions, such as possible protein exchange with serum proteins plasma as well as cellular interactions. These results vividly illustrate the potential of the FRET method as a simple yet versatile platform for quantitatively investigating biological interactions of nanoparticles.

The Vacuum-Assisted Breast Biopsy System is an Effective Treatment Strategy for Breast Lumps After Augmentation with Autologous Fat Grafting.

BACKGROUND: With the extensive application of autologous fat grafting (AFG) to the breasts, postoperative complications such as breast lumps attract high attention. Breast lumps greatly reduce patient satisfaction and bring mental stress. However, there are few detailed reports about minimally invasive treatment strategies for breast lumps after AFG. Our study aimed to investigate the effectiveness of the vacuum-assisted breast biopsy (VABB) system for patients with lumps after AFG. MATERIALS AND METHODS: We retrospectively reviewed 37 patients with breast lumps between April 2015 and January 2019. The characteristics of patients and breast lumps were analyzed. Breast lumps were classified into four types, including cystic, solid, complex and calcification. The vacuum-assisted breast biopsy (Mammotome and Encor) was performed for the patients with lumps after AFG. The efficacy, safety, complications and patient satisfactions were recorded during postoperative follow-up periods. RESULTS: Under the guidance of ultrasound, the breast lumps could be thoroughly and accurately excised by the vacuum-assisted biopsy system. No patient experienced breast infections or major complications requiring treatment. Hematoma was observed in only 2 patients and gradually resolved without any special management. With a median follow-up of 29 months, no recurrence was observed. Furthermore, there were no statistical differences in duration of the procedures and complications between the two VABB systems. All the patients recovered well and were satisfied with the cosmetic outcome. CONCLUSION: The vacuum-assisted breast biopsy system can be used as an effective and minimally invasive approach for the surgical management of lumps after AFG. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Enhanced Photoelectrochemical Properties of Ti3+ Self-Doped Branched TiO2 Nanorod Arrays with Visible Light Absorption.

A novel Ti3+ self-doped branched rutile TiO2 nanorod arrays (NRAs) was successfully grown on an F-doped tin oxide (FTO) transparent conductive glass by a combined hydrothermal and magnetron sputtering method. Surface morphology, structure, optical properties, and photoelectrochemical behavior of the branched TiO2 NRAs are determined. Using TiO2 nanoparticles (NPs) deposited on the top of the nanorods as seeds, TiO2 nanobranches can easily grow on the top of the nanorods. Moreover, the Ti3+ defects in the TiO2 NPs and associated oxygen vacancies, and the nanobranches expend the optical absorption edge of the TiO2 NRAs from 400 nm to 510 nm. Branched TiO2 NRAs exhibit excellent photoelectrochemical properties compared to the pure TiO2 NRAs, as revealed by photoelectrochemical measurements. This enhanced photoelectrochemical properties is induced by the increased surface area and expanded optical absorption range. Due to their favorable characteristics, these novel branched TiO2 NRAs will provide a new path to the fabrication of hierarchical nanostructured materials.

Circulating HOTAIR expression predicts the clinical response to neoadjuvant chemotherapy in patients with breast cancer.

BACKGROUND: Long noncoding RNA HOTAIR has been detected in the serum of patients with various malignances and may be served as novel biomarker for diagnosis and prognosis prediction of breast cancer. However, the value of circulating HOTAIR to predict the response to neoadjuvant chemotherapy (NAC) remains unclear. OBJECTIVE: In the present study, we analyzed whether pretreatment circulating HOTAIR levels predict the response to NAC and investigated prognostic impact of circulating HOTAIR on disease-free survival (DFS) in breast cancer patients treated with NAC. METHODS: Circulating HOTAIR levels in the serum of 112 breast cancer patients before NAC were measured using quantitative real-time PCR. The correlation of circulating HOTAIR with the clinicopathologic status and the response to NAC were analyzed. Kaplan-Meier survival analysis and log-rank test were used to estimate the DFS. RESULTS: In 112 serum samples obtained before NAC, high circulating HOTAIR was associated with larger tumor size, more positive lymph nodes as well as more distant metastasis. However, there was no significant correlation between the circulating HOTAIR levels and age, Ki67 status or hormone receptor. Furthermore, patients with high circulating HOTAIR achieved less clinical response as well as pathologic complete response than those with low circulating HOTAIR (p< 0.05). The Kaplan-Meier survival curve with a median follow-up of 48 months demonstrated that patients with high circulating HOTAIR expression had a worse disease-free survival than those with low circulating HOTAIR (log-rank p= 0.012). CONCLUSIONS: High circulating HOTAIR level correlates with less response to neoadjuvant chemotherapy as well as a worse prognosis in breast cancer patients. Therefore, the present study provides a favorable basis to use circulating HOTAIR as a predictor of neoadjuvant chemotherapy response.

MicroRNAs and cancer: Key paradigms in molecular therapy.

MicroRNAs (miRNAs) are a type of small non-coding RNA molecule that performs an important role in post-transcriptional gene regulation. Since miRNAs were first identified in 1993, a number of studies have demonstrated that they act as tumor suppressors or oncogenes in human cancer, including colorectal, lung, brain, breast and liver cancer, and leukemia. Large high-throughput studies have previously revealed that miRNA profiling is critical for the diagnosis and prognosis of patients with cancer, while certain miRNAs possess the potential to be used as diagnostic and prognostic biomarkers or therapeutic targets in cancer. The present study reviews the studies and examines the roles of miRNAs in cancer diagnosis, prognosis and treatment, and discusses the potential therapeutic modality of exploiting miRNAs.

Fast Synthesis of Pt Nanocrystals and Pt/Microporous La2O3 Materials Using Acoustic Levitation.

Usually, we must use an appropriate support material to keep the metal species stable and finely dispersed as supported metal nanoparticles for industry application. Therefore, the choice of support material is a key factor in determining the dispersion and particle size of the noble metal species. Here, we report the synthesis of a single-atom Pt material in the solution and supported Pt nanoclusters on microporous La2O3 by a one-step acoustic levitation method without any pretreatment/modification of raw oxide. We have strongly contributed to the synthetic methodology of the surface/interfacial heterogeneous catalysts in this study, and this finding could open another door for synthesis of supported metal nanoparticles on porous materials for environmental catalysis.

Coumarin-Based Fluorescent Probe for Hypochlorites and Real Application in Tap Water.

Taking advantages of both the oxidation property of hypochlorite and different coordination properties of Cu+ and Cu2+ ions, we developed a new fluorescent probe for hypochlorite anion, namely, compound C1. In the presence of ClO-, the sensing system displayed extraordinary fluorescence quenching, which was beneficial to the production of a high signal output during detection process. By virtue of its special oxidation property, the probe displayed high selectivity for ClO- over other anions. Moreover, this novel sensing system could be used for the analysis of ClO- levels in tap water and potentially in environmental samples.

Pretreatment neutrophil-to-lymphocyte ratio is correlated with response to neoadjuvant chemotherapy as an independent prognostic indicator in breast cancer patients: a retrospective study.

BACKGROUND: A high neutrophil-to-lymphocyte ratio (NLR) may be related to increased mortality in patients with lung, colorectal, stomach, liver, and pancreatic cancer. To date, the utility of NLR to predict the response to neoadjuvant chemotherapy (NAC) has not been studied. The aim of our study was to determine whether the NLR is a predictor of response to NAC and to investigate the prognostic impact of the NLR on relapse-free survival (RFS) and breast cancer-specific survival (BCSS) in patients with breast cancer who received NAC. METHODS: We retrospectively studied patients who received NAC and subsequent surgical therapy for stage II-III invasive breast carcinoma at Sun Yat-sen Memorial Hospital between 2001 and 2010. The correlation of NLR with the pathological complete response (pCR) rate of invasive breast cancer to NAC was analyzed. Survival analysis was used to evaluate the predictive value of NLR. RESULTS: A total of 215 patients were eligible for analysis. The pCR rate in patients with lower pretreatment NLR (NLR < 2.06) was higher than those with higher NLR (NLR ≥ 2.06) (24.5 % vs.14.3 %, p < 0.05). Those patients with higher pretreatment NLR (NLR ≥ 2.1) had more advanced stages of cancer and higher disease-specific mortality. Through a multivariate analysis including all known predictive clinicopathologic factors, NLR ≥ 2.1 was a significant independent parameter affecting RFS (HR: 1.57, 95 % CI: 1.05-3.57, p < 0.05) and BCSS (HR: 2.21, 95 % CI: 1.01-4.39, p < 0.05). Patients with higher NLR (NLR ≥ 2.1) before treatment showed significantly lower relapse-free survival rate and breast cancer-specific survival rate than those with lower NLR (NLR <2.1) (log-rank p = 0.0242 and 0.186, respectively). CONCLUSIONS: Pretreatment NLR < 2.06 is associated with pCR rate, suggesting that NLR may be an important factor predicting the response to NAC in breast cancer patients. NLR is an independent predictor of RFS and BCSS in breast cancer patients with NLR ≥ 2.1 who receive NAC. We suggest prospective studies to evaluate NLR as a simple prognostic test for breast cancer.

Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy.

Circulating tumor cells (CTCs) are seeds for cancer metastasis and are predictive of poor prognosis in breast cancer patients. Whether CTCs and primary tumor cells (PTCs) respond to chemotherapy differently is not known. Here, we show that CTCs of breast cancer are more resistant to chemotherapy than PTCs because of potentiated DNA repair. Surprisingly, the chemoresistance of CTCs was recapitulated in PTCs when they were detached from the extracellular matrix. Detachment of PTCs increased the levels of reactive oxygen species and partially activated the DNA damage checkpoint, converting PTCs to a CTC-like state. Inhibition of checkpoint kinases Chk1 and Chk2 in CTCs reduces the basal checkpoint response and sensitizes CTCs to DNA damage in vitro and in mouse xenografts. Our results suggest that DNA damage checkpoint inhibitors may benefit the chemotherapy of breast cancer patients by suppressing the chemoresistance of CTCs and reducing the risk of cancer metastasis.