Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial.

Background: Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/ß, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Methods: Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12 mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). Findings: From Jan 2021 to Aug 2022, 48 patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45 patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N = 45), Grade 3 or 4 treatment emergent adverse events occurred in 29 patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. Interpretation: The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Funding: Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Two Hematological Markers Predicting the Efficacy and Prognosis of Neoadjuvant Chemotherapy Using Lobaplatin Against Triple-Negative Breast Cancer.

BACKGROUND: Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear. METHODS: Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively. RESULTS: The tpCR rate in the PLR- group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR- group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR-NLR- (PLR- and NLR-) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR- group (P = .028 for EFS; P = .047 for OS). Patients in the PLR-NLR- group had a longer EFS than those in the PLR+/NLR+ group (P = .002). CONCLUSION: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis.

The Role of Innate Immunity in Osteoarthritis and the Connotation of "Immune-joint" Axis: A Narrative Review.

Osteoarthritis (OA) is a degenerative disease that results in constriction of the joint space due to the gradual deterioration of cartilage, alterations in subchondral bone, and synovial membrane. Recently, scientists have found that OA involves lesions in the whole joint, in addition to joint wear and tear and cartilage damage. Osteoarthritis is often accompanied by a subclinical form of synovitis, which is a chronic, relatively low-grade inflammatory response mainly mediated by the innate immune system. The "immune-joint" axis refers to an interaction of an innate immune response with joint inflammation and the whole joint range. Previous studies have underestimated the role of the immune-joint axis in OA, and there is no related research. For this reason, this review aimed to evaluate the existing evidence on the influence of innate immune mechanisms on the pathogenesis of OA. The innate immune system is the body's first line of defense. When the innate immune system is triggered, it instantly activates the downstream inflammatory signal pathway, causing an inflammatory response, while also promoting immune cells to invade joint synovial tissue and accelerate the progression of OA. We have proposed the concept of the "immune-joint" axis and explored it from two aspects of Traditional Chinese Medicine (TCM) theory and modern medical research, such as the innate immunity and OA, macrophages and OA, complement and OA, and other cells and OA, to enrich the scientific connotation of the "immune-joint" axis.

A multicenter single-arm trial of neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

The objective of this multicenter, single-arm trial (ChiCTR1900022293) was to explore the efficacy and safety of neoadjuvant therapy with epirubicin, cyclophosphamide, and pyrotinib followed by docetaxel, trastuzumab, and pyrotinib (ECPy-THPy) in the treatment of patients with stage II-III HER2-positive breast cancer. The present study enrolled patients with stage II-III HER2-positive breast cancer. Epirubicin and cyclophosphamide were administrated for four 21-day cycles, followed by four cycles of docetaxel and trastuzumab. Pyrotinib was taken orally once per day throughout the treatment period. The primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0) rate in the modified intention-to-treat (mITT) population. In total, 175 patients were included. The tpCR rate was 68.6% (95% CI, 60.7-75.8%), while the objective response rate was 89.1%. In the post-hoc subgroup analysis, no association between clinical characteristics and the tpCR rate was observed. The most common grade ≥3 adverse events were diarrhea (54.3%), followed by white blood cell count decreased (5.1%), and neutrophil count decreased (4.6%). In conclusion, the neoadjuvant regimen with ECPy-THPy showed promising pathological response and clinical benefits with an acceptable safety profile in patients with stage II-III HER2-positive breast cancer.

Pyrotinib-based therapeutic approaches for HER2-positive breast cancer: the time is now.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody-drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood-brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.

Case Report: Four cases of SARS-CoV-2-associated Guillain-Barré Syndrome with SARS-CoV-2-positive cerebrospinal fluid detected by metagenomic next-generation sequencing: a retrospective case series from China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is often absent or at low levels in the cerebrospinal fluid (CSF) of patients with previous SARS-CoV-2-associated Guillain-Barré syndrome (GBS). This has led to speculation that SARS-CoV-2-associated GBS is more likely mediated by post-infectious immunity or a parainfection. This understanding has influenced the development of treatment regimens for SARS-CoV-2-associated GBS. This paper reports our experience with four Chinese patients with SARS-CoV-2-associated GBS who tested positive for SARS-CoV-2 RNA in the CSF. They developed symptoms of peripheral nerve damage 4-15 days after fever and confirmed SARS-CoV-2 infection, all of whom presented with progressive weakness of both lower limbs; three with autonomic nerve function impairment such as constipation and urination disorder; and one with polycranial neuritis and Miller-Fisher syndrome. Three patients were tested for anti-ganglioside antibodies, and one tested positive for GD1a-IgG. Four patients recovered well after treatment with anti-viral drugs combined with intravenous immunoglobulin. The present results showed that SARS-CoV-2 RNA can be detected via mNGS in the CSF of some patients with SARS-CoV-2-associated GBS, suggesting that SARS-CoV-2-associated GBS may have multiple pathogeneses.

Causal associations between type 1 diabetes and COVID-19 infection and prognosis: a two-sample Mendelian randomization study.

INTRODUCTION: It has been suggested that type 1 diabetes was associated with increased COVID-19 morbidity and mortality. However, their causal relationship is still unclear. Herein, we performed a two-sample Mendelian randomization (MR) to investigate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. RESEARCH DESIGN AND METHODS: The summary statistics of type 1 diabetes were obtained from two published genome-wide association studies of European population, one as a discovery sample including 15 573 cases and 158 408 controls, and the other data as a replication sample consisting of 5913 cases and 8828 controls. We first performed a two-sample MR analysis to evaluate the causal effect of type 1 diabetes on COVID-19 infection and prognosis. Then, reverse MR analysis was conducted to determine whether reverse causality exists. RESULTS: MR analysis results showed that the genetically predicted type 1 diabetes was associated with higher risk of severe COVID-19 (OR=1.073, 95% CI: 1.034 to 1.114, pFDR=1.15×10-3) and COVID-19 death (OR=1.075, 95% CI: 1.033 to 1.119, pFDR=1.15×10-3). Analysis of replication dataset showed similar results, namely a positive association between type 1 diabetes and severe COVID-19 (OR=1.055, 95% CI: 1.029 to 1.081, pFDR=1.59×10-4), and a positively correlated association with COVID-19 death (OR=1.053, 95% CI: 1.026 to 1.081, pFDR=3.50×10-4). No causal association was observed between type 1 diabetes and COVID-19 positive, hospitalized COVID-19, the time to the end of COVID-19 symptoms in the colchicine treatment group and placebo treatment group. Reverse MR analysis showed no reverse causality. CONCLUSIONS: Type 1 diabetes had a causal effect on severe COVID-19 and death after COVID-19 infection. Further mechanistic studies are needed to explore the relationship between type 1 diabetes and COVID-19 infection and prognosis.

Dramatic Response to Pyrotinib and T-DM1 in HER2-Negative Metastatic Breast Cancer With 2 Activating HER2 Mutations.

HER2 signaling is activated in response to somatic HER2 mutations, which are often found in invasive lobular breast cancer (ILC) and are associated with poor prognosis. Tyrosine kinase inhibitors (TKIs) have demonstrated considerable antitumor activity in patients with HER2-mutated advanced breast cancer (BC). Further, several clinical trials have indicated that HER2-targeted antibody-drug conjugates (ADCs) exhibit promising efficacy in lung cancer with HER2 mutations, and the efficacy of ADCs against HER2-mutated BC is currently being evaluated. Several preclinical studies have demonstrated that the therapeutic efficacy of ADCs in HER2-mutated cancer can be enhanced by the addition of irreversible TKIs, but the potential of such a combined treatment regimen for the treatment of HER2-mutated BC has not been reported. Herein, we describe a case in which a patient with estrogen receptor-positive/HER2-negative metastatic ILC with 2 activating HER2 mutations (D769H and V777L) exhibited a significant and durable response to anti-HER2 treatment with pyrotinib (an irreversible TKI) in combination with ado-trastuzumab emtansine, which was administered after multiple lines of therapy that had resulted in disease progression. Further, based on the evidence from the present case, TKI plus ADC seems to be a promising combination anti-HER2 regimen for patients with HER2-negative/HER2-mutated advanced BC, although further rigorous studies are warranted to confirm these findings.

Predictive and prognostic value of PIK3CA mutations in HER2-positive breast cancer treated with tyrosine kinase inhibitors: A systematic review and meta-analysis.

This systematic review and meta-analysis study investigates the predictive and prognostic value of PIK3CA mutations for HER2-positive breast cancer treated with tyrosine kinase inhibitors (TKIs). A search of the Medline, Embase, and Cochrane Library databases yielded 17 eligible studies (1706 patients). In 10 neoadjuvant studies, the pathological complete response rate was significantly higher in wild-type PIK3CA (WT) patients than in mutated PIK3CA (MT) patients (OR = 0.45; 95% CI = 0.31-0.65; P < 0.001). In five metastasis studies, the pooled objective response rate was significantly higher in WT patients than in MT patients (OR = 0.40; 95% CI = 0.23-0.70; P = 0.001). Four metastasis studies indicated that PIK3CA mutations had a marginally significant relationship with poor progression-free survival and overall survival. Thus, PIK3CA mutations have predictive value for the treatment response of early/advanced-stage HER2-positive breast cancer treated with TKI-containing regimens.

Efficacy of adjuvant chemotherapy/maintenance chemotherapy after induction chemotherapy and concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Experiences of two centers.

BACKGROUND AND OBJECTIVE: In general, there are not many studies exploring the clinical value of adjuvant chemotherapy or maintenance chemotherapy (AC/MC) after induction chemotherapy and concurrent chemoradiotherapy (IC+CCRT+AC/MC). The purpose of this study was to establish a clinical nomogram for the use of AC/MC in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). MATERIAL AND METHODS: Two centers (Guangzhou Medical University Cancer Center [N = 1226] and Zhongshan People's Hospital [N = 150]) recruited 1376 patients with LA-NPC. All the patients underwent IC+CCRT; 560 patients received AC with cisplatin/nedaplatin plus docetaxel/paclitaxel (TP) or cisplatin/nedaplatin plus fluorouracil (PF), and 81 patients received MC with S-1. Multivariate Cox regression was used to confirm optimal predictors of progression-free survival (PFS), and a nomogram was established to identify patients into low-risk and high-risk cohorts. Additionally, bootstrap internal validation was performed to further verify our nomogram. RESULTS: After propensity score matching (PSM), the survival curves were not statistically different between IC+CCRT+AC/MC and IC+CCRT (all p > 0.05). Then, a nomogram was developed based on variables that were screened by univariate and multivariate Cox regression, including N stage, cumulative platinum dose during CCRT, body mass index (BMI), IC cycles, IC regimen and cervical lymph node (CLN) necrosis and infiltration of adjacent tissues. The results of the nomogram showed that the high-risk cohort had greatly worse 5-year DMFS, LRFS, PFS and OS compared to low-risk cohort (all p < 0.05), and subgroup analysis found that the 5-year DMFS, PFS and OS of patients treated with IC+CCRT+AC/MC were better than those treated with IC+CCRT in high-risk cohort (all p < 0.05). Notably, the incidence of adverse effects for IC+CCRT+AC cohort was higher than that for IC+CCRT+MC cohort, especially leukocytopenia and neutropenia. IC+CCRT and IC+CCRT+MC were associated with similar incidences of adverse effects. CONCLUSIONS: The addition of AC or MC to IC+CCRT could improve the DMFS of patients with high-risk NPC and prolong their survival. Additionally, our findings suggest a potential role of AC/MC following IC plus CCRT in the treatment of high-risk LA-NPC.

PIK3CA mutations are associated with pathologic complete response rate to neoadjuvant pyrotinib and trastuzumab plus chemotherapy for HER2-positive breast cancer.

BACKGROUND: Neoadjuvant treatment with a dual anti-human epidermal growth factor receptor 2 (HER2) blockade with pyrotinib and trastuzumab has been shown to be effective for HER2-positive breast cancer. METHODS: The genomic characteristics of 425 cancer-related genes from the archived tumour blocks of 50 patients enrolled in a prospective neoadjuvant pyrotinib and trastuzumab plus chemotherapy clinical trial (ChiCTR1900022293) were assessed by next-generation sequencing (NGS). The relationship between tumour biomarkers and the postoperative pathological complete response (pCR) were explored. RESULTS: Forty-five patients completed neoadjuvant chemotherapy and final surgery, of which 26 (58%) achieved a pCR. Among all driver gene mutations, PIK3CA mutation was screened out for having a significant relationship with the treatment response. The pCR rate of patients with wild-type PIK3CA was significantly higher than patients with mutated PIK3CA (80.8% vs. 26.3%; P = 0.00057), and remained significant after a multiple comparison adjustment (Padjusted = 0.024). We further evaluated the predictive value with logistic regression model of clinical features, genetic biomarkers or both, an AUC of 0.912 (95% CI: 0.827-0.997) was achieved in the integrated model. CONCLUSIONS: Our data suggest that HER2-positive breast cancers with activating mutations in PIK3CA are less likely to benefit from pyrotinib combined with trastuzumab neoadjuvant therapy.

Association of Long-term Oncologic Prognosis With Minimal Access Breast Surgery vs Conventional Breast Surgery.

Importance: Minimal access breast surgery (MABS) has been used in breast cancer management. However, long-term prognostic data associated with MABS vs conventional breast surgery (CBS) are lacking. Objective: To investigate long-term therapeutic outcomes associated with MABS vs CBS for breast cancer management. Design, Setting, and Participants: In this single-center retrospective cohort study, 9184 individuals were assessed for inclusion. After exclusions, 2412 adult female individuals were included who were diagnosed with stage 0 to III breast cancer, underwent unilateral breast surgery between January 2004 and December 2017, and had no distant metastasis or history of severe underlying disease. Propensity score matching was performed to minimize selection bias. Data were analyzed from January 1, 2004, to December 31, 2019. Exposures: MABS or CBS. Main Outcomes and Measures: Data on demographic and tumor characteristics and long-term outcomes were collected and analyzed. Results: This study included 2412 patients (100% female; median [IQR] age, 44 [40-49] years). Of these, 603 patients underwent MABS (endoscopic, endoscopy-assisted, or robot-assisted procedures in 289, 302, and 12 patients, respectively) and 1809 patients underwent CBS. The median follow-up time was 84 months (93 in the MABS group and 80 months in the CBS group). Intergroup differences were not significant for the following parameters: 10-year local recurrence-free survival (93.3% vs 96.3%; hazard ratio [HR], 1.39; 95% CI, 0.86-2.27; P = .18), regional recurrence-free survival (95.5% vs 96.7%; HR, 1.38; 95% CI, 0.81-2.36; P = .23), and distant metastasis-free survival (81.0% vs 82.0%; HR, 0.95; 95% CI, 0.74-1.23; P = .72). The 5-, 10-, and 15-year disease-free survival rates in the MABS group were 85.9%, 72.6%, and 69.1%, respectively. The corresponding rates in the CBS group were 85.0%, 76.6%, and 70.7%. The intergroup differences were not significant (HR, 1.07; 95% CI, 0.86-1.31; P = .55). The 5-, 10-, and 15-year overall survival rates in the MABS group were 92.0%, 83.7%, and 83.0%, respectively. The corresponding rates in the CBS group were 93.6%, 88.7%, and 81.0%. The intergroup differences were not significant (HR, 1.29; 95% CI, 0.97-1.72; P = .09). Post hoc subgroup analysis showed no significant intergroup differences in disease-free survival. Conclusions and Relevance: In this cohort study, long-term outcomes following MABS were not significantly different from those following CBS in patients with early-stage breast cancer. MABS may be a safe and feasible alternative in this patient population.

The effects of Jiawei Duhuo Jisheng mixture on Wnt/ß-catenin signaling pathway in the synovium inflamed by knee osteoarthritis: An in vitro and in vivo experiment.

ETHNOPHARMACOLOGICAL RELEVANCE: Knee osteoarthritis (KOA) is one of the common age-degenerative diseases. Recent studies have demonstrated that the pathogenesis of KOA is closely related to synovial lesions. Jiawei Duhuo Jisheng mixture (JDJM) has shown great potential in the treatment of KOA. However, the effect and mechanism of JDJM on synovial lesions of KOA remain unclear. AIM OF THE STUDY: The regulatory effect of JDJM on the Wnt/ß-catenin signaling pathway in KOA inflamed synovium was studied via in vitro and in vivo experiments, respectively. MATERIALS AND METHODS: For the in vitro experiment, fibroblasts were isolated from the rabbit synovium with KOA. The fibroblasts were grouped as follows: the vehicle group was given 0.5% FBS; the inhibitor group was treated with 0.5% volume fraction of XAV939; the normal serum groups and JDJM serum groups were treated with 5%, 10%, and 20% volume fractions of normal serum and JDJM-containing serum. The expression levels of Wnt3a, ß-catenin, Cyclin D1, metalloproteinase-7(MMP-7) and cyclooxygenase-2(COX-2) were detected by different assays 48 and 72 h after the intervention. For the in vivo experiment, the rabbit KOA model was prepared using the improved Hulth modeling method, whereby all rabbits were randomly divided into normal control, model control, positive control, and traditional Chinese medicine (TCM) groups. The expression levels of Wnt3a, ß-catenin, Cyclin D1, MMP-7 and COX-2 were detected by different assays in the 2, 4, and 8 weeks of treatment. RESULTS: In the two test results of in vitro experiments, the normal serum group was compared with the JDJM-containing serum group with the same volume fraction, demonstrating that mRNA transcription and protein expression levels of Wnt3a, ß-catenin, Cyclin D1, MMP-7, and COX-2 in the latter decreased (P < 0.05), with more pronounced effects observed in the group treated with 20% volume fraction of JDJM serum. Compared with the inhibitor group, there was no significant difference (P > 0.05) in the mRNA transcription and protein expression levels, i.e., Wnt3a, ß-catenin, Cyclin D1, and MMP-7 were observed in the JDJM serum groups, except for a significant decrease (P < 0.05) in the level of mRNA transcription and protein expression of COX-2. Based on the in vivo experiment, compared to the model control group, articular cartilage, synovial hyperplasia, and the inflammatory reaction of the TCM group at different treatment times were significantly improved. The mRNA transcription level of Wnt3a, ß-catenin, Cyclin D1, MMP-7 and COX-2 detected by RT-qPCR and the protein expression level of Wnt3a, ß-catenin, Cyclin D1, MMP-7 and COX-2 detected by Western blot were significantly reduced (P < 0.05), and the effect was more evident at the eighth week. CONCLUSION: JDJM can regulate the synovial Wnt/ß-catenin signaling pathway in KOA models, reduce the mRNA transcription and protein expression levels of Wnt3a, ß-catenin, Cyclin D1, MMP-7, and COX-2 in the synovium, thus inhibiting synovial inflammation and protecting articular cartilage, which could be the key mechanism of action in treating this disease.

Chromobox Family Proteins as Putative Biomarkers for Breast Cancer Management: A Preliminary Study Based on Bioinformatics Analysis and qRT-PCR Validation.

Background: Epigenetic modification of chromatin is an important step in the regulation of gene expression. The chromobox family proteins (CBXs), as epigenetic modifier, may play a vital role in tumorigenesis and cancer progression. Herein we explored the correlation between CBXs and breast cancer (BC) via the bioinformatics approach and qRT-PCR validation. Methods: Several databases, including GEPIA, TCGA, GEO, K-M plotter, STRING, DAVID, cBioPortal, CIBERSORT, and HPA were employed to analyze the expression levels of CBXs and the correlations between CBXs and prognosis (overall and recurrence-free survival) in BC. We analyzed molecular functions, genetic variations, transcription factors of CBXs, and immune cell infiltration status. ROC curve analysis was performed to determine the predictive value of CBXs. RNA extracted from 11 human BC and paired adjacent normal tissues were subjected to qRT-PCR. Results: The mRNA expression level of CBX1-5 was significantly upregulated, while that of CBX7 was significantly downregulated in BC; no expression disparities were observed in CBX6/8 expression. Further, high mRNA expression of CBX1/2/3/4/8 correlated with advanced BC, whereas high mRNA expression of CBX6/7 correlated with early BC. High mRNA expressions of CBX1/2/3/5 predict poor OS and RFS, while higher mRNA expressions of CBX6/7 predict better OS and RFS in patients with BC. ROC curve analysis revealed that CBX3 showed excellent discriminatory ability. Gene ontology enrichment analysis showed that CBXs primarily participated in SUMOylation and post-/transcriptional regulation. Moreover, they presented varying degrees of amplification in BC tissues and were related to the infiltration of various immune cells. Conclusion: CBXs can serve as putative biomarkers for BC. Further studies are warranted to determine the exact molecular mechanisms underlying the action of CBXs in BC, particularly CBX1/2/3/5/7.

Development and validation of a prognostic nomogram for early HER2-positive and lymph node-negative breast cancer.

BACKGROUND: Dual-targeted therapy is currently the standard adjuvant treatment for human epidermal growth factor receptor 2-positive (HER2+) and lymph node-positive (LN+) breast cancer. However, the optimal therapeutic strategy for patients with HER2+ and lymph node-negative (LN-) breast cancer remains unclear. This population-based study aimed to explore the factors associated with survival in patients with HER2+ and LN- breast cancer, and develop a survival-predicting nomogram in the era of trastuzumab-based single-targeted therapy. METHODS: We collected the clinicopathological information of HER2+ and LN- breast cancer patients who underwent chemotherapy and surgery from The Surveillance, Epidemiology, and End Results (SEER) database (2010-2016, the Trastuzumab-based single-targeted therapy era). We subsequently explored the risk factors for breast cancer-specific survival (BCSS) and overall survival (OS) using a Cox proportional hazards regression model, aiming to identify subgroups with worse prognosis, which would indicate potential demand for dual-targeted therapy. Three- and 5-year survival probability-predictive nomograms were established and subjected to bootstrap internal validation. The concordance index (C-index) and calibration curve were applied to evaluate the performance of the model. RESULTS: After data cleansing, a total of 13,755 patients were included in the current analysis. Using univariate and multivariate Cox proportional hazards regression, higher clinical T stage, hormone receptors-negative (HR-), and partial mastectomy without radiotherapy were identified as independent risk factors for BCSS and OS in patients with HER2+ and LN- breast cancer. Nomograms for 3- and 5-year BCSS and OS incorporating the selected prognostic factors were established. Calibration curves verified good consistency between the actual and nomogram-predicted survival probability. The C-index values of the BCSS and OS predictions and 95% confidence interval (CI) were 0.773 (0.740-0.806) and 0.764 (0.737-0.791), respectively. CONCLUSIONS: Higher clinical T stage, HR-, and partial mastectomy without radiotherapy predicted worse prognosis in patients with HER2+ and LN- breast cancer. In clinical practice, patients can be recommended for single-targeted or dual-targeted therapy according to the individualized factors.

Decreased expression of programmed death-1 on CD8+ effector memory T lymphocytes correlates with the pathogenesis of type 1 diabetes.

AIMS: Chronic inflammation of autoimmune diseases, including type 1 diabetes (T1D), is mainly mediated by memory T(Tm) cells, predominantly effector memory T (Tem) cells. The roles of the programmed death-1 (PD-1) receptor on lymphocytes have been well studied in tumor and other infection models. However, little is known about the relationship between the expression of PD-1 on CD8+ Tem cells and the pathogenesis of T1D. METHODS: A total of 52 patients diagnosed with T1D and 39 gender-, age-, and ethnically matched health control individuals were enrolled in this study. Peripheral blood mononuclear cells from these individuals were isolated and analyzed by flow cytometry. We evaluated the frequencies of PD-1+ CD8+ memory T cell subsets from patients' peripheral blood with T1D and the spleen cells of nonobese diabetic (NOD) mice in the present study. We also investigated the effects of blocking PD-1/PD-L1 pathway on islet's inflammation in NOD mice. RESULTS: Frequencies of PD-1+ CD8+ Tem cells were decreased significantly in PBMC of patients with T1D (40.73 ± 12.72 vs 47.43 ± 15.56, *p < 0.05). The frequencies of PD-1+ CD8+ Tem cells were decreased in patients with T1D who were positive for two or more autoantibodies compared with the patients with one autoantibody (13.46% vs 46.95 ± 12.72%, *p < 0.05). Meanwhile, the frequencies of PD-1+ CD8+ central memory T (Tcm) cells were also significantly decreased in patients with two or more autoantibodies compared with other groups (≥ 2AAb vs HC 33.1 ± 8.92% vs 43.71 ± 11.78%, *p < 0.05; ≥ 2AAb vs AAb-33.1 ± 8.92% vs 41.65 ± 11.2%, *p < 0.05; ≥ 2AAb vs 1AAb 33.1 ± 8.92% vs 48.09 ± 10.58%, ***p < 0.001). The frequencies of PD-1+CD8+ Tem cells were positively correlated with fasting serum C-peptide levels (r = 0.4308, *p < 0.05) and C-peptide levels 2 h after meal in T1D patients (r = 0.5723, **p < 0.01). The frequencies of PD-1+CD8+ Tcm cells were only negatively correlated with the levels of HbA1c (r = - 0.2992, *p < 0.05). Similarly, the frequencies of PD-1+CD8+ Tem were significantly decreased in intervention group (anti-mouse PD-1 mAb) compared with the control group (14.22 ± 6.455% vs 27.69 ± 9.837%, *p < 0.05). Pathologically, CD8, PD-1 and PD-L1 were strongly expressed in the islets of diabetic mice after PD-1 blockade. CONCLUSIONS: It is the first report of the expression of PD-1 on CD8+ Tem cells in T1D in the present study. Our observations suggest that the PD-1/PD-L1 signal pathway on CD8+ Tem cells of T1D subjects might identify a new pathway for delaying the occurrence and development by inhibiting autoimmunity.

"Sclerotic Band" type of classification system and measurement of necrotic area for osteonecrosis of the femoral head.

Osteonecrosis of the femoral head is a common orthopedic disease. Based on years of clinical experience and significant imaging data, this study aimed to elucidate a new type of it, to help improve prognosis in young adults and provide a basis for hip preservation treatment.From January 2014 to December 2016, a total of 211 patients undergoing hip preservation surgery for femoral head necrosis at our hospital were enrolled in this study. Coronal plane classification and cross-sectional area analysis were performed by nuclear magnetic resonance imaging (computed tomography optional) in cases meeting the inclusion criteria. Meanwhile, a new method of classification and calculating the necrotic area was proposed. The application simulation was conducted using sample cases. Additionally, treatment methods were recommended. We used our method to compare the outcome of the selected patients with the JIC classification so as to judge the advantages and disadvantages.The " pressure bone trabecular angle " of the femoral head was measured, and the "sclerotic band" (Zhang Ying) type of classification system and the "quartile" (Zhang Ying) method of measurement were used in 2 sample cases. After analysis, it is more accurate than JIC.The "Sclerotic band" type of classification system and 'quartile' methods are new methods to evaluate the stability of femoral head necrosis. They are convenient for clinical application and easily adopted.

Facilitators and Barriers to Access to Pediatric Medical Services in a Community Hospital.

Background: Missed medical appointments decrease continuity of medical care, waste resources, and may affect health outcomes. We examined the factors associated with missed children's supervision visits in Eastern Brooklyn, NY, USA. Methods: We surveyed guardians whose children received routine medical care at four pediatric clinics. Participants filled out a questionnaire that queried: demographics, food security, recent relocation, parental support of healthy behaviors, and length of knowing provider. Preexisting disease(s) and missed visits were retrieved from medical records. Regression analyses were used to determine factors that were associated with missing medical appointments. Results: Among 213 families, 33% faced food insecurity and 16.4% reported moving within the past 12 months. Forty percent of children missed at least 1 visit. Food insecurity (adjusted odds ratio [aOR] 2.3, 95% confidence interval [CI 1.0% to 5.2%) and recent relocation (aOR 1.8, 95% CI 1.1-3.4 were associated with missed health supervision visits, whereas greater parental healthy behaviors (aOR 0.5, 95% CI 0.3-0.9) and longer length of knowing provider (aOR 0.8, 95% CI 0.7-1.0) were associated with fewer missed appointments. Conclusion: This study indicates that social inequity may contribute to poor adherence to medical appointments through multiple mechanisms, including food insecurity, lack of social stability, and parental health behaviors. Multidimensional proactive prevention, and reactive tolerance should be considered as opportunities to mitigate the impact of social inequity on health outcomes.

Low Income and Nonadherence to Health Supervision Visits Predispose Children to More Emergency Room Utilization.

Social inequity can have broad health impacts. The purpose of this study was to examine the effects of low income and nonadherence to health supervision visits on emergency room (ER) utilization in Eastern Brooklyn, New York. This study surveyed parents/guardians of children who received routine medical care at Brookdale ambulatory clinics from June 2017 to February 2018. Participants were asked to fill out a questionnaire on social demographics, food insecurity, and relocation. Electronic medical records (EMRs) were reviewed to retrieve numbers of missing health supervision and ER visit in past 12 months. Comorbidity was identified through EMR by International Classification of Diseases. Logistic regression analyses were used to examine the effects of nonadherence to health supervision visits on ER utilization when controlling for demographics, food insecurity, recent moving, and comorbidity. Among 268 participants, 56.0% reported their household income was less than $20,000 annually, 39.6% missed at least 1 health supervision visit, and 31.7% had at least 1 ER visit within the past 12 months. Younger age (adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI] = 0.86-0.97, P < .01), household income less than $20,000 (aOR = 1.86, 95% CI = 1.02-3.39), preexisting comorbidity (aOR = 2.36, 95% CI = 1.26-4.42), and nonadherence to health supervision visits (aOR = 5.83, 95% CI = 3.21-10.56) were associated with increased ER utilization. Nonadherence to health supervision visits is an independent risk factor and potentially modifiable. Evaluation and remediation should be pursued as a means of improving health outcomes of children in vulnerable circumstances.

Comparison of the Short-Term and Long-Term Effects of Surgery and Nonsurgical Intervention in Treating Carpal Tunnel Syndrome: A Systematic Review and Meta-Analysis.

Background: The objective of the study is to examine the short-term and long-term efficacy of surgical treatment of carpal tunnel syndrome (CTS) compared with conservative treatment (ie, splint, steroid injection, or physical therapy). Methods: Two reviewers searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and PEDro up to September 2017. Quality appraisal and data extraction were performed in duplicate. Patient self-reported functional and symptom changes, as well as improvement of electrophysiological studies, were assessed as outcomes. Meta-analyses were performed in RevMan. Results: From 1438 studies identified after searching, 10 remained for analysis after exclusion criteria were applied. Moderate-quality evidence indicated that surgical interventions were superior to splint or steroid injection at 6 months with a weighted mean difference of 0.25 (95% confidence interval [CI], 0.07-0.44) for functional status and 0.64 (95% CI, 0.07-1.21) for symptom severity. The surgical group had better nerve conduction outcomes at 6 months (0.57 [95% CI, 0.05-0.50] ms). No significant differences were observed at 3 or 12 months. Conclusions: Both surgical and conservative interventions provide treatment benefits in CTS. Further studies on long-term outcome are needed.