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Objective In this review, we aimed to discuss the efficacy of immunotherapy of anti-programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) and potential immune mechanism combination with various standard systemic therapies for breast cancer (BC) such as chemotherapy, targeted therapy, endocrine therapy, and radiotherapy. Background Single-drug therapy of antibodies against PD-1 and its ligand, PD-L1, have only presented modest responses in patients with BC, partly due to the deficiency of tumor-infiltrating lymphocytes (TILs) and low mutation burden. Thus, the combinations of PD-1/PD-L1 blockade with other approaches which may increase the immune therapy effect are being studied. Moreover, an understanding of the immune mechanism of PD-1/PD-L1 blockade with other approaches will contribute to better application of clinical therapy. Methods We searched the studies that focus on PD-1/PD-L1 therapy with or without other systemic therapy and relative immune mechanisms indicated between 2000 and 2020. Conclusions Anti PD-1/L1 blockade combined with therapeutic approaches is safe and effective in BC, in particular for PD-L1 antibody atezolizumab plus nab-paclitaxel by inducing PD-1/L1 expression and the number of cytotoxic T cells. Otherwise, the toxicity also exists during clinical treatment. Future researches should be evaluated to explore the immune mechanism and vast clinical trials need to be conducted for evidential support for combination therapy of BC.

Transcription factors (TFs) like a nuclear factor of activated T-cells (NFAT) and its controller calcineurin are highly expressed in primary intestinal epithelial cells (IECs) due to delamination, damage by tumor-associated flora and selective activation in the intestinal tract tumor are crucial in the progression and growth of colorectal cancer (CRC). This study sought to summarize the current findings concerning the dysregulated calcineurin/NFAT (C/N) signaling involved in CRC initiation and progression. These signalings include proliferation, T-cell functions, and glycolysis with high lactate production that remodels the acidosis, which genes in tumor cells provide an evolutionary advantage, or even increased their attack phenotype. Moreover, the relationship between C/N and gut microbiome in CRC, especially role of NFAT and toll-like receptor signaling in regulating intestinal microbiota are also discussed. Furthermore, this review will discuss the proteins and genes relating to C/N induced acidosis in CRC, which includes ASIC2 regulated C/N1 and TFs associated with the glycolytic by-product that affect T-cell functions and CRC cell growth. It is revealed that calcineurin or NFAT targeting to antitumor, selective calcineurin inhibition or targets in NFAT signaling may be useful for clinical treatment of CRC. This can further aid in the identification of specific targets via cancer patient-personalized approach. Future studies should be focused on targeting to C/N or TLR signaling by the combination of therapeutic agents to regulate T-cell functions and gut microbiome for activating potent anticancer property with the prospect of potentiating the antitumor therapy for CRC.

Aims. The prognostic value of epidermal growth factor receptor (EGFR) mutations in the context of serum carcinoembryonic antigen levels remains controversial in T1 lung adenocarcinoma. Methods. Clinical and pathological characteristics, preoperational carcinoembryonic antigen levels, EGFR mutations, and disease-free and overall survival were analysed retrospectively in 573 pathological T1 patients in East China. Results. EGFR mutations were detected in 220 of 573 patients (38.4%). Patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL had worse disease-free (P<0.001) and overall survival (P<0.001) than had others, although survival was comparable between patients with and without EGFR mutations. However, patients with exon 21 mutations in EGFR had significantly better overall survival than had patients with exon 19 mutations (P=0.016), although disease-free survival was comparable (P=0.424). Among patients with serum carcinoembryonic antigen levels ≥ 2.12 ng/mL, disease-free (P=0.019) and overall survival (P<0.001) was also better than that in those with exon 21 mutations. Finally, the exon 19 deletion was found to be an independent predictor of unfavourable overall survival (P=0.037). Conclusions. EGFR mutations were associated with preoperational serum carcinoembryonic antigen levels ≥ 2.12 ng/mL. In patients with levels above this threshold, those with the exon 19 deletion have less favourable prognosis than have those with the exon 21 mutation.

The clinical characteristics of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation have been well studied. However, the correlation of EGFR mutation with mutant p53, Ki-67, and thyroid transcription factor 1 (TTF-1) and their prognostic value remain indistinct.Clinical and pathological characteristics and overall survival were analysed retrospectively in 523 surgically resected NSCLC patients. The expression levels of p53, Ki-67, and TTF-1 protein were detected by immunohistochemistry, and an amplification refractory mutation system was used to access the status of EGFR mutations.Of 523 patients with surgically resected NSCLC, 210 patients (38.4%) harboured EGFR mutations. Compared to the EGFR wild-type lung cancer, mutated EGFR harboured significantly increased mutant p53-positive or TTF-1-positive tumors (P0.001 and0.001, respectively). Former or current smokers, pathological stage and mutant p53-or TTF-1-positive status were independent predictors of EGFR mutation (P=0.001, 0.014, 0.014 and0.001, respectively). Patients with p53 under expression had significantly better overall survival in the whole cohort and wild-type EGFR cohort (P=0.0010 and 0.0020, respectively) as well as in Ki-67-negative and TTF-1-positive patients (P0.0001 and 0.0009, and P0.0001 and 0.0004, respectively). Interestingly, in patients harbouring EGFR mutations, p53-under expression and Ki-67-negative cases still had better survival than positive cases, whereas there was no obvious difference between TTF-1-negative and TTF-1-positive cases (P=0.0198, 0.0068 and 0.3684, respectively). Finally, in NSCLC patients with wild-type EGFR, positive Ki-67 expression was the independent predictor for the worst survival (P=0.022).The expression levels of mutant p53, Ki-67, and TTF-1 were correlated with EGFR mutation. High expression of mutant p53 and Ki-67 correlated with poor survival in the entire cohort, EGFR mutation or wild-type cohort. In addition, Ki-67 might have an impact on the prognosis for patients with NSCLC with wild-type EGFR.

Coherent X-ray diffraction imaging (CDI) method is a powerful X-ray imaging technique with high resolution up to nanometer scale. Most of the synchrotron radiation facilities and free electron laser facilities are equipped with this state-of-the-art imaging technique and have made many outstanding achievements in multiple scientific areas. Up to now, although scanning CDI (ptychography) method based on a soft X-ray source has been opened to users, the hard X-ray CDI experimental platform has not been built at Shanghai Synchrotron Radiation Facility (SSRF) which can research some relatively thick specimens and easily extend to three-dimensional imaging. As some new beamlines with undulator source were put into operation recently, it is possible and feasible to build up the CDI experimental platform with hard X-ray. In this article, we report the hard X-ray CDI experimental platform development process and preliminary experimental results of coherent diffraction pattern and image reconstruction at SSRF. Based on the operating BL19U2 biological small-angle X-ray scattering (SAXS) beamline at SSRF, the hard X-ray coherent beam is obtained through effective optical path designation at 12 keV and 13.5 keV. The hard X-ray optimization includes tuning several slits, double crystal monochromator (DCM), horizontal deflection mirror, focusing mirror system and pinhole, etc. Furthermore, hard X-ray CDI experiments are conducted. The spatial coherent length of the incident beam is also measured from the pinhole diffraction pattern. This platform can provide both conventional mode and scanning mode (ptychography) for the coherent diffraction imaging method, and the correct image reconstruction from the experimental diffraction patterns proves that the platform has the experimental capability for hard X-ray CDI. In the conventional forward scattering CDI mode, coherent diffraction patterns of pinhole are collected and used to analyse the coherence property of the optimized X-ray beam. The structure of pinhole is also reconstructed from the diffraction pattern. In the scanning CDI mode, a zone plate is used as a sample. The central area of zone plate is reconstructed correctly. About 90 nm/pixel resolution of reconstruction is achieved which is extremely dependent on the X-ray flux density from the undulator source emission. Hard X-ray CDI experimental platform based on the synchrotron radiation facility is first built in China. It will provide effective software and hardware supporting for the development and application of hard X-ray CDI experiments in China in the future.

We sought to develop and validate a clinical nomogram model for predicting overall survival (OS) in non-small-cell lung cancer (NSCLC) patients with resected tumors that were 30 mm or smaller, using clinical data and molecular marker findings. We retrospectively analyzed 786 NSCLC patients with a pathological tumor size less than 30 mm who underwent surgery between 2007 and 2017 at our institution. We identified and integrated significant prognostic factors to build the nomogram model using the training set, which was subjected to the internal data validation. The prognostic performance was calibrated and evaluated by the concordance index (C-index) and risk group stratification. Multivariable analysis identified the pathological tumor size, lymph node metastasis, and Ki-67 expression as independent prognostic factors, which were entered into the nomogram model. The nomogram-predicted probabilities of OS at 1 year, 3 years, and 5 years posttreatment represented optimal concordance with the actual observations. Harrell’s C-index of the constructed nomogram with the training set was 0.856 (95% CI: 0.804-0.908), whereas TNM staging was 0.814 (95% CI: 0.742-0.886, P=5.280221e−13). Survival analysis demonstrated that NSCLC subgroups showed significant differences in the training and validation sets (P<0.001). A nomogram model was established for predicting survival in NSCLC patients with a pathological tumor size less than 30 mm, which would be further validated using demographic and clinicopathological data. In the future, this prognostic model may assist clinicians during treatment planning and clinical studies.

ContextFluid methylated DNA may be a suitable biomarker for cancer patients.ObjectiveTo investigate whether circulating methylated tissue inhibitor of metalloproteinase 3 (TIMP-3) DNA in body fluids is a useful prognostic biomarker in gastric cancer (GC).DesignTIMP-3 methylation was detected by real-time methylation-specific polymerase chain reaction in tumor tissues, paired preoperative peritoneal washes (PPWs), and paired serum samples from 92 GC patients.ResultsThe frequency of TIMP-3 methylation was significantly elevated in GC tissues (63.04%; 58 of 92) compared with that in paired adjacent normal tissue (4.3%; 4 of 92) (P < .001). TIMP-3 methylation correlated closely with peritoneal metastasis and TNM stage (all P < .001). The frequency of TIMP-3 methylation in preoperative peritoneal washes and serum samples was 53.3% (49 of 92) and 58.7% (54 of 92), respectively. The Aζ values of the receiver operator characteristic curve for methylated TIMP-3 were 0.966 and 0.922 for serum and preoperative peritoneal washes, respectively, compared with those in GC tissues. The patients with elevated methylated TIMP-3 levels in body fluids had poorer disease-free survival rates than those without (all P < .001). Cox regression analysis showed that detection of methylated TIMP-3 DNA in body fluids was an independent risk factor for GC patients, with a remarkable decrease in disease-free survival 30 months after surgical resection of the gastric tumor.ConclusionPresence of methylated TIMP-3 DNA in body fluids is a useful biomarker for predicting the progression and prognosis of GC patients.

Lung adenocarcinoma, characterized by its early and aggressive local invasion and high metastatic potential, is the most frequently observed histological type of non-small-cell lung cancer (NSCLC). Visceral pleural invasion (VPI) caused by peripheral lung adenocarcinomas is closely associated with the poor prognosis of patients with NSCLC. The association between VPI and some clinicopathological characteristics has been observed in the past few decades. However, the molecular mechanism of VPI in lung adenocarcinomas is unknown. In the present, the expression level of microRNA (miR-)135b and epidermal growth factor receptor (EGFR) mutations using the reverse transcription-quantitative polymerase chain reaction and DNA sequencing, respectively. In addition, the present study aimed at exploring the association between the miR-135b level, EGFR mutations and VPI in peripheral lung adenocarcinoma. The results of the present study demonstrated that miR-135b was significantly upregulated in lung adenocarcinoma compared with adjacent normal tissue and positively associated EGFR mutations in peripheral lung adenocarcinoma. Furthermore, it was identified that lung adenocarcinomas with EGFR mutations and miR-135b overexpression were more likely to invade visceral pleura. Taken together, these findings indicate that miR-135b overexpression is positively associated with mutations to EGFR, which may promote the development of peripheral lung adenocarcinomas by the formation of VPI. This indicates that the two factors may serve as prognostic markers and molecular targets for the treatment of peripheral lung adenocarcinomas.

Background Lymph node involvement could help to predict the prognosis of pathological T1 (pT1, diameters of ≤3 cm) non-small cell lung cancer (NSCLC). This study assessed the clinicopathological factors and associated lymph node involvement in invasive lung adenocarcinoma (IAC) and squamous cell lung cancer (SCC) and the overall and disease-free survival associated with these factors. Methods Three hundred and twenty-five patients with pathological T1 NSCLC (253 IAC and 72 SCC) were retrospectively analyzed from a pool of 1094 primary lung cancer patients. The data were assessed using multiple logistic regression, Kaplan-Meier curves and multivariable analyses. Results Among patients with a ≤30-mm tumor lesion (N = 325), N1 and N2 lymph node involvement was found in 28 (8.6%) and 34 (10.4%) patients, respectively. Lymph node metastasis occurred in 13.0% (33/253) of pT1 IAC patients and 40.3% (29/72) of SCC patients. Carcinoembryonic antigen (CEA) levels, SCC by histology, and tumor lesions larger than 1.0 cm were associated with lymph node involvement (P

Aberrant expression of various microRNAs (miRNA) has shown diagnostic and prognostic significance in non-small cell lung cancer (NSCLC). qRT-PCR analysis confirmed altered expression of miR-125a-5p, let-7e, miR-30a, miR-30e and miR-30e-3p in 70 paired tissue and serum samples from NSCLC patients. The reduced expression of miR-125a-5p, let-7e and miR-30e was strongly associated with NSCLC dedifferentiation. The lost expression of miR-125a-5p and let-7e was associated with shorter overall survival and let-7e was an independent prognostic factor for NSCLC patients. These five miRNA expressions should be further evaluated as biomarkers for the early detection and prognosis of NSCLC patients.