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Celastrol is a promising antitumor drug candidate, but the poor water solubility and cytotoxicity limit its clinical application. Herein, we synthesized a Celastrol (Cel)-chitosan oligosaccharide (CSO) conjugate (Cel-CSO) for drug delivery. Celastrol was conjugated to a CSO backbone via amide bond formation, which was verified by infrared spectrum (IR) analyses. The Cel-CSO contained ∼10 wt% of Celastrol showed excellent aqueous solubility (18.6 mg/mL) in comparation with the parent Celastrol. Cel-CSO significantly inhibited tumor growth, induced apoptosis, and effectively suppressed tumor metastasis in human pancreatic cancer cells (BxPC-3). While the cytotoxicity of Cel-CSO in hepatic cells (HL7702) was lower than that of the free Celastrol. Cel-CSO enhanced the anticancer efficacy, promoted the circulation time of Celastrol, and reduced the subacute toxicity, which indicated that CSO can be a promising Celastrol delivery system for pancreatic cancer therapy.

A study to examine the efficacy and risk factors associated with pyrrotinib in the second- and third-line treatment of advanced breast cancer with Human epidermal growth factor receptor 2- (HER2-) positive cells was conducted. Progression-free survival (PFS) was assessed as the primary endpoint, and the objective response rate (ORR), overall survival (OS), and safety were secondary endpoints. Across all the patients, the ORR was 48.57%, and the disease control rate (DCR) was 94.29%. In the follow-up period, the median PFS was 15 months, and second-line treatment had significantly longer PFS than third-line treatment ( P = 0.027 ). The OS among all the patients was up to 28 months, but the median OS has not yet been reached. Diarrhea (69.57%) was the most important AE, mainly in grades 1 and 2. According to the COX regression analysis, brain metastasis was a risk factor for PFS, while second-line treatment and capecitabine chemotherapy were relevant to a longer PFS correlation among patients. In the second- and third-line treatment, pyrrotinib is still highly effective and safe. Pyrrotinib is a potential ideal salvage treatment plan for patients who failed in first-line treatments.

Terminal performance of a bullet in human body is critical for the treatment of gunshot injury and optimization of bullet design. The effects of the impact velocity (vBallistic gelatin was used to simulate human body. The 7.62 mm × 39 mm rifle bullets with different vAccording to the distribution of the damaged gelatin along the penetration depth, the damaged gelatin block could be divided into two parts: the less damaged part and the severely damaged part. The length of the less damaged part depends mostly on δThe expansion method is suitable to investigate the influence of different factors of bullets on their terminal performance. The characteristics of the damaged gelatin have a linear relationship with the initial attack angle (δ

Background and ObjectivesSpontaneous spinal epidural hematoma (SSEH) is an uncommon but serious condition with a high morbidity rate. Although SSEH is related to numerous risk factors, its etiology remains unclear. There is a paucity of data on its prognostic factors. We aim to evaluate prognostic factors for SSEH in this study.MethodA retrospective study was performed on patients who were admitted for SSEH in 3 academic neurosurgical centers from January 2010 to June 2021. Clinical parameters, including clinical condition on admission, anticoagulants use, imaging modality, the timing and type of surgery performed, and outcomes, were collected. Prognostic factors were analyzed. The Frankel scale was used to assess the clinical condition.ResultsA total of 105 patients with SSEH were retrieved from medical records, with a mean age of 51.3 years. Eighty-three patients (79%) complained of acute onset of severe neck or back pain. Eighty-two patients (78%) suffered from moderate to severe neurologic deficits (Frankel scale A–C). Anticoagulation usage was found in 20% of cases. Lower thoracic spine (p = 0.046), use of anticoagulants (p = 0.019), sphincter function disfunction (p = 0.008), severe neurologic deficits at admission (p < 0.001), and rapid deterioration (p = 0.004) were found to be associated with poor outcomes. Surgical decompression was performed in 74 (70%) cases. The univariate and multivariate analysis revealed that preoperative severe neurologic deficits (p = 0.005) and extended paraplegia time (>12 hours, p = 0.004) were independent adverse prognostic factors. The univariate analysis revealed that lower thoracic spine location (p = 0.08) and rapid progression (p = 0.005) were correlated with poor prognosis, but the multivariate analysis failed to identify them as independent prognostic factors.DiscussionAdverse prognostic factors for SSEH might include thoracic segment location, use of anticoagulation, severe neurologic deficits on admission, sphincter dysfunction, and rapid progression. Preoperative neurologic deficit and extended paraplegia time were strongly correlated with the prognosis in the subset of patients who underwent surgical decompression. Timely surgical decompression is recommended for patients with moderate/severe neurologic deficits or progressive neurologic deterioration.

Renal impairment is a common complication in coronavirus disease 2019 (COVID-19), although its prognostic significance remains unknown.This study determines the impact of early renal impairment on the clinical outcome of COVID-19.Patients diagnosed with COVID-19 and hospitalized in Xiaogan Central Hospital from 20 January to 29 February 2020 were retrospectively included and grouped into two cohorts (cohort with normal renal function and cohort with renal insufficiency) based on the renal function detected on admission. Records of clinical manifestation, laboratory findings and clinical outcome were collected and compared between these two cohorts.A total 543 COVID-19 patients were included. Among these patients, 70 patients developed early renal impairment, with an incidence of 12.89%. A significantly higher white blood cell (WBC) count, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatine (Cr), blood urine nitrogen (BUN) and brain natriuretic peptide (BNP) and a significantly lower blood platelet (PLT), lymphocyte count, prealbumin and albumin (ALB) were detected in the cohort with renal insufficiency (P 0.05). Patients with early renal impairment were also associated with higher incidences of haematuria/proteinuria, higher incidences of mortality and prolonged hospitalization duration. The independent risk factors for in-hospital death included age65 years old, complication of diabetes, renal impairment on admission (Cr 73 μmol/L and eGFR 60 ml/min 1.73 mEarly renal impairment is associated with higher risk of in-hospital death for patients with COVID-19. Risk stratification according to renal function can better guide the clinical management of COVID-19.

Cronkhite-Canada syndrome (CCS) is a rare hamartomatous polyposis syndrome with a proposed association with chronic autoimmune inflammation. To date, genetic background of patients with CCS remains less investigated. In this study we aimed to explore the genomic landscape of CCS.Whole exome sequencing was performed on peripheral blood samples extracted from 18 patients with CCS. Potential function-impacting germline variants were filtered by R software. Through systematic data analysis, a number of genetic variants were identified. Enrichment analysis was performed using the R package ClusterProfiler.Overall, 3960 low-frequency (0.05 or not reported in the Exome Aggregation Consortium East Asian, 1000 Genomes, or ESP6500 database) potentially function-impacting germline variants were identified, with 18 genes (FDFT1, LOC400863, MUC3A, MUC4, ZNF806, GXYLT1, MUC6, PABPC3, PSPH, ZFPM1, CIC, LOC283710, ARSD, GOLGA6L2, LOC388282, SLC25A5, TMEM247, WDR89) involved over half the patients. Functional enrichment of these genes revealed several biological processes in relation to innate immune responses and glycosylation. Only one likely pathogenic germline variant of an hamartomatous polyposis syndrome-associated gene, PTCH1, was detected in one patient.CCS has genomic alteration patterns completely distinct from those of traditional hamartomatous polyposis syndrome. The germline mutation landscape indicates potential roles of innate immune responses and glycosylation in the pathogenesis of CCS.

A previously fit and well 3-month-old baby was admitted to his local hospital with worsening stridor following a 2-week history of croup-like symptoms. Chest radiograph shows a large area of mediastinal and bilateral upper-zone opacification ([figure 1][1]). Due to concerns of progressive airway

Increasing evidence has shown that circular RNAs (circRNAs) participate in the process of cardiac remodeling. CircRNA circ_0036176 originating from the back-splicing of exon 2 to exon4 of myosin IXA (Myo9a) gene was shown to be increased in the myocardium of patients with heart failure (HF) and riched in exosomes from human AC16 cardiomyocytes with overexpression of circ_0036176. Proliferation activity was inhibited in mCFs subjected to exosomal circ_0036176 treatment and in mCFs with overexpression of circ_0036176. Interestingly, circ_0036176 contains an IRES element and an ORF of 627 nt encoding a 208-amino acid protein (termed as Myo9a-208). Myo9a-208 was shown to mediate the inhibitory effect of circ_0036176 on CFs proliferation, and miR-218-5p could inhibit Myo9a-208 expression by binding to circ_0036176, resulting in abolishing the effect of circ_0036176 on inactivating cyclin/Rb signal and suppressing CFs proliferation. Our findings suggest that circ_0036176 inhibits mCFs proliferation by translating Myo9a-208 protein to suppress cyclin/Rb pathway.

Although recent advances in systemic chemotherapy have improved the clinical outcomes of gastric cancer patients with peritoneal metastasis, the peritoneum still represents a common site of treatment failure and disease recurrence. Neoadjuvant intraperitoneal-systemic chemotherapy has been acknowledged as a more aggressive treatment for gastric cancer patients with peritoneal metastasis. In this multicenter phase III randomized controlled trial, 238 patients will be randomly separated into two groups in a 2:1 ratio after laparoscopic exploration. The experimental arm will receive the proposed neoadjuvant intraperitoneal-systemic chemotherapy regimen, whereas the control group will receive a Paclitaxel + S-1 (PS) chemotherapy regimen. The endpoints for the study are overall survival, response rate, gastrectomy radicality rate, progression-free survival and adverse events.Recent advances in technology have improved the outcomes of stomach cancer patients. However, there are still many patients who die of cancer that has spread from another part of the body. Neoadjuvant intraperitoneal–systemic chemotherapy has been acknowledged as a more aggressive treatment for stomach cancer patients with peritoneal metastasis (cancer that has spread to the very thin layer of tissue on the inside of the abdomen that covers the stomach and other organs). In this study, 238 patients will be randomly separated into two groups in a 2:1 ratio after evaluation. The experimental group will receive the proposed neoadjuvant intraperitoneal–systemic chemotherapy regimen, whereas the control group will receive a Paclitaxel + S-1 (PS) chemotherapy regimen. The endpoints for the study are how long patients live, number of patients who respond to treatment, number of patients who undergo surgery, how long patients live without their disease getting worse and problems caused by treatment.

Background aims Despite the great advances in immunosuppressive therapy for severe aplastic anemia (SAA), most patients are not completely cured. Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been recommended as an alternative treatment in adult SAA patients. However, haplo-HSCT presents a higher incidence of graft failure and graft-versus-host disease (GVHD). The authors designed a combination of haplo-HSCT and umbilical cord-derived mesenchymal stem cells (UC-MSCs) for treatment of SAA in adult patients and evaluated its effects. Methods Adult patients (≥18 years) with SAA (N = 25) were given HLA-haploidentical hematopoietic stem cells (HSCs) combined with UC-MSCs after a conditioning regimen consisting of busulfan, cyclophosphamide, fludarabine and anti-thymocyte globulin and intensive GVHD prophylaxis, including cyclosporine, basiliximab, mycophenolate mofetil and short-term methotrexate. Additionally, the effects of the protocol in adult SSA patients were compared with those observed in juvenile SAA patients (N = 75). Results All patients achieved myeloid engraftment after haplo-HSCT at a median of 16.12 days (range, 11–26). The median time of platelet engraftment was 28.30 days (range, 13–143). The cumulative incidence of grade II acute GVHD (aGVHD) at day +100 was 32.00 ± 0.91%. No one had grade III–IV aGVHD at day +100. The cumulative incidence of total chronic GVHD was 28.00 ± 0.85%. The overall survival was 71.78 ± 9.05% at a median follow-up of 42.08 months (range, 2.67–104). Promisingly, the protocol yielded a similar curative effect in both young and adult SAA patients. Conclusions The authors’ data suggest that co-transplantation of HLA-haploidentical HSCs and UC-MSCs may provide an effective and safe treatment for adult SAA.

OBJECTIVE: : To explore the association between napping status and depressive symptoms in urban residents during the coronavirus disease 2019 (COVID-19) epidemic. METHODS: : The survey was embedded in the Wellness Living Laboratory-China (WELL China) cohort study. Health and lifestyle information during the COVID-19 epidemic were obtained via the telephone interview from April 8, 2020 to May 29, 2020. A total of 3075 residents aged 18 to 80 years from Gongshu district of Hangzhou city with complete data were included in the analyses. The World Health Organization-Five Well-being Index (WHO-5) was used to measure depressive symptoms. Multiple logistic regression model was used to assess the association between napping status and depressive symptoms in the participants. RESULTS: : The prevalence of depressive symptoms was 20.6% in the participants during the COVID-19 epidemic. Daytime napping behavior, especially napping time ≤30 min, was associated with a lower risk of prevalent depressive symptoms ( OR=0.61, 95% CI: 0.47–0.79, P

Background The extent of cellular heterogeneity in breast cancer could have potential impact on diagnosis and long-term outcome. However, pathology evaluation is limited to biomarker immunohistochemical staining and morphology of the bulk cancer. Inter-cellular heterogeneity of biomarkers is not usually assessed. As an initial evaluation of the extent of breast cancer cellular heterogeneity, we conducted quantitative and spatial imaging of Estrogen Receptor (ER), Progesterone Receptor (PR), Epidermal Growth Factor Receptor-2 (HER2), Ki67, TP53, CDKN1A (P21/WAF1), CDKN2A (P16INK4A), CD8 and CD20 of a tissue microarray (TMA) representing subtypes defined by St. Gallen surrogate classification. Methods Quantitative, single cell-based imaging was conducted using an Immunofluorescence protein multiplexing platform (MxIF) to study protein co-expression signatures and their spatial localization patterns. The range of MxIF intensity values of each protein marker was compared to the respective IHC score for the TMA core. Extent of heterogeneity in spatial neighborhoods was analyzed using co-occurrence matrix and Diversity Index measures. Results On the 101 cores from 59 cases studied, diverse expression levels and distributions were observed in MxIF measures of ER and PR among the hormonal receptor-positive tumor cores. As expected, Luminal A-like cancers exhibit higher proportions of cell groups that co-express ER and PR, while Luminal B-like (HER2-negative) cancers were composed of ER+, PR- groups. Proliferating cells defined by Ki67 positivity were mainly found in groups with PR-negative cells. Triple-Negative Breast Cancer (TNBC) exhibited the highest proliferative fraction and incidence of abnormal P53 and P16 expression. Among the tumors exhibiting P53 overexpression by immunohistochemistry, a group of TNBC was found with much higher MxIF-measured P53 signal intensity compared to HER2+, Luminal B-like and other TNBC cases. Densities of CD8 and CD20 cells were highest in HER2+ cancers. Spatial analysis demonstrated variability in heterogeneity in cellular neighborhoods in the cancer and the tumor microenvironment. Conclusions Protein marker multiplexing and quantitative image analysis demonstrated marked heterogeneity in protein co-expression signatures and cellular arrangement within each breast cancer subtype. These refined descriptors of biomarker expressions and spatial patterns could be valuable in the development of more informative tools to guide diagnosis and treatment.

The aim of the present study was to evaluate the efficacy and safety of a unipolar focused-RF device used to rejuvenate the middle and lower face and to create an assessment system. This retrospective study comprised 52 patients with mild-to-moderate skin laxity and wrinkles who received 1-3 treatments 1 month apart and were followed up for 1-7 months. At baseline and post-treatment, three blinded observers measured facial contour and lines, analyzed VISIA scores, and assessed the results using Alexiades Comprehensive Grading Scale (ACGS) and Global Aesthetic Improvement Scale (GAIS). Significant improvements were observed (P .05) in facial width (left 5.95%, right 5.66%), nasolabial folds (left 18.98%, right 20.56%), marionette lines (left 18.88%, right 25.80%), and cheek lines (left 3.35%, right 3.05%) and in the scores of wrinkles (15.37%), texture (13.67%), pores (6.48%), and red areas (6.57%) using VISIA. There was an obvious reduction in wrinkles, laxity, erythema/telangiectasia based on ACGS, and 75% improved and 5.8% much improved using GAIS. There was no severe side effect. We suggest that the unipolar focused-RF device is an effective and safe technique for middle and lower face rejuvenation and provides a series of comprehensive assessment methods based on standardized photos using VISIA.

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging negatively stranded enveloped RNA bunyavirus that causes SFTS with a high case fatality rate of up to 30%. Macroautophagy/autophagy is an evolutionarily conserved process involved in the maintenance of host homeostasis, which exhibits anti-viral or pro-viral responses in reaction to different viral challenges. However, the interaction between the bunyavirus SFTSV and the autophagic process is still largely unclear. By establishing various autophagy-deficient cell lines, we found that SFTSV triggered RB1CC1/FIP200-BECN1-ATG5-dependent classical autophagy flux. SFTSV nucleoprotein induced BECN1-dependent autophagy by disrupting the BECN1-BCL2 association. Importantly, SFTSV utilized autophagy for the viral life cycle, which not only assembled in autophagosomes derived from the ERGIC and Golgi complex, but also utilized autophagic vesicles for exocytosis. Taken together, our results suggest a novel virus-autophagy interaction model in which bunyavirus SFTSV induces classical autophagy flux for viral assembly and egress processes, suggesting that autophagy inhibition may be a novel therapy for treating or releasing SFTS.

OBJECTIVE: Surgery is considered a relative contraindication in sarcoma tumor. Because of the unique characteristics of heart, whether surgery is optimally chosen in primary cardiac sarcoma (PCS) is unknown. In this study, we aimed to evaluate the 1-year survival after surgery for PCS. METHODS: Patients with PCS from the Surveillance, Epidemiology, and End Results Database (SEER) between 1975 and 2015 were recruited. The endpoints were defined as 1-year all-cause mortality (ACM) and 1-year cancer-specific mortality (CSM). RESULTS: The study population consisted of 335 patients diagnosed with PCS. The 1-year ACM and CSM were 49.0% and 42.1% respectively. The Kaplan-Meier curves revealed that decreased 1-year ACM&CSM were significantly associated with surgical treatment. Multiple COX regression analysis, surgery, and chemotherapy showed a significantly decreased rate of 1-year ACM and CSM. The adjusted hazard ratio of surgery was significant when the year of diagnosis was ≥2000, patients were aged 0.05). No interaction effects were detected between the variables and surgery (all p for interaction >0.05). CONCLUSION: Surgery should be highly recommended in patients with PCS to improve the 1-year survival rate, especially in younger patients with localized SEER stage and non-chemotherapy management.

Background Anthracycline‐based chemotherapy (ABC) is one of the standard therapies against breast cancer. However, few guidelines are currently available to optimize the use of ABC. Therefore, the present analysis aimed at determining the profile and treatment patterns of ABC and the association of clinicopathological characteristics with ABC selection. Methods We retrospectively analyzed the data of a nation‐wide multicenter epidemiological study, which collected the medical records of breast cancer patients receiving chemotherapy in different settings from seven geographic regions in China (NCT03047889). Results In total, 3393 patients were included, with 2917 treated with ABC. Among them, 553 (89.8%), 2165 (81.7%), and 814 (25.7%) were subjected to ABC as neoadjuvant, adjuvant, and advanced chemotherapy, respectively. The most frequently used regimens were anthracycline‐taxane‐based combinations for neo‐ and adjuvant chemotherapy, along with taxanes and oral fluorouracils for the palliative stages. In the overall cohort, patients aged < 40 or 40‐65 (p < 0.001), in premenopause (p < 0.001), without comorbidities (p = 0.016), with invasive ductal carcinoma (p= 0.001), high lymph node involvement (p < 0.001), in the pTNM stage II, III, or IV versus stage I (p < 0.001), subjected to mastectomy (p < 0.001) or subjected to sentinel lymph node biopsy combined with axillary lymph node dissection (p = 0.044), or with a decreased disease‐free survival (p < 0.001) were more likely to be recommended to ABC. Conclusion Taken together, ABC remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy. ABC was mainly used as a combination therapy, and the correlation between influencing factors and ABC choice varied during different settings, indicating the preference and different perspectives of medication considered by medical oncologists regarding the use ABC in China., The nation‐wide study revealed that anthracycline‐based chemotherapy (ABC) remained the mainstay of breast cancer treatment, especially in neo and adjuvant therapy, and was predominantly used as a combination therapy. The correlation between clinicopathological characteristics and ABC choice varied at different settings, suggesting the preference and different perspectives of medication regarding the use ABC in China. The real‐world data contribute to guide the selection of the appropriate treatment and maximize the benefit of chemotherapy for patients.

BACKGROUND Advanced breast cancer (ABC) is difficult to treat due to the primary and acquired resistance, which is the main cause of rescue treatment failure. Thus, developing a new rescue treatment strategy for clinicians is a challenge. This study retrospectively collected the medical information of patients with refractory ABC who were treated with bevacizumab at our department to analyze the efficacy and safety of bevacizumab-containing therapy as a new treatment method for refractory ABC. METHODS The complete medical information of patients receiving bevacizumab treatment from November 2017 to November 2020 was collected, and patients' general medical history and disease characteristics were analyzed. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to failure (TTF), overall survival (OS), and safety were also analyzed using SPSS 20.0 statistical software. RESULTS The data of 68 women with refractory ABC who received bevacizumab-containing therapy were collected. The last follow-up examinations were performed on March 31, 2021. The ORR was 41.2% and the DCR was 88.2%. The median PFS, TTF, and OS were 6.0 months [95% confidence interval (CI): 3.4-8.6 months], 4.0 months (95% CI: 3.2-4.8 months), and 26.6 months (95% CI: 10.2-43.0 months), respectively. Treatment was discontinued in 2 patients due to chemo-related adverse reactions. The main adverse events related to bevacizumab were hypertension (7.4%) and bleeding (2 cases, 2.9%), both of which were grade 1. No specific adverse events causing the discontinuation of bevacizumab treatment were observed in the other patients. CONCLUSIONS Among patients with refractory ABC, bevacizumab-containing therapy is feasible and safe, and can be used as a new treatment strategy. However, the question of who can benefit the most from bevacizumab-containing therapy requires further exploration.

To evaluate the clinical value of different combination strategies of high-risk HPV (hr-HPV) testing and Thinprep cytology test (TCT), a cervical cytology test, for cervical cancer screening, especially for high or higher-grade squamous intraepithelial lesion (HSILThe study is a population-based randomized clinical trial. Women aged 35 to 65 years meeting the inclusion criteria were enrolled for the study. At the baseline screening conducted in the first year, the participants were randomly assigned to either cytology test or hr-HPV testing at a ratio of 1∶2. If the paticipants had positive results for the baseline hr-HPV test, they would then undergo either cytology test or colposcopy by random assignment. After 24 months, all participants were called back, and combined screening of cytology test and hr-HPV test were performed. Women who had negative results at baseline screening and who entered and completed the third-year follow-up were selected as the subjects of the study. Based on the aforementioned testing findings, the related data were extracted and four different screening protocols were simulated: 1) combined TCT and hr-HPV screening, with referral for colposcopy when there was positive results for either one of the two; 2) combined TCT and hr-HPV screening, with referral for colposcopy when both tests had positive results at the same time; 3) TCT was done for preliminary screening and those who were found to be positive would then undergo hr-HPV test for triage purpose, with subsequent referral made for colposcopy if the hr-HPV results were positive; 4) hr-HPV was done for preliminary screening and those who were found to be positive would then undergo TCT, with subsequent referral made for colposcopy if TCT results were positive. With the detection of HSILA total of 3102 women were screened, and 2967 women were included in the statistical analysis in this study. Among the 2967 women, 979 were randomized to cytology and 1988 to hr-HPV genotyping. For prescreening, the positive rate of the cytology group was 5.6% (55/979), with of HSILThis randomized clinical trial from Shuangliu District, Chengdu City shows that the sensitivity of hr-HPV testing is better than that of cytology test, and the prevalence of HSIL

Application of differentiation therapy targeting cellular plasticity for the treatment of solid malignancies has been lagging. Nasopharyngeal carcinoma (NPC) is a distinctive cancer with poor differentiation and high prevalence of Epstein-Barr virus (EBV) infection. Here, we show that the expression of EBV latent protein LMP1 induces dedifferentiated and stem-like status with high plasticity through the transcriptional inhibition of CEBPA. Mechanistically, LMP1 upregulates STAT5A and recruits HDAC1/2 to the CEBPA locus to reduce its histone acetylation. HDAC inhibition restored CEBPA expression, reversing cellular dedifferentiation and stem-like status in mouse xenograft models. These findings provide a novel mechanistic epigenetic-based insight into virus-induced cellular plasticity and propose a promising concept of differentiation therapy in solid tumor by using HDAC inhibitors to target cellular plasticity.

Background Patients undergoing cardiac operation are susceptible to anemia. Low hemoglobin concentration is a risk factor for composite adverse events and death after cardiac operation. Here we investigated the association of postoperative nadir hemoglobin with adverse outcomes in patients undergoing on-pump cardiac operation. Methods Adult patients in 2 medical centers were retrospectively analyzed. The primary outcome was postoperative composite adverse events. The secondary outcome was all-cause death in the hospital. Results Of the 8206 patients analyzed, 1628 (19.8%) experienced composite adverse events after operation and 109 (1.3%) died. Patients receiving on-pump cardiac operation with nadir hemoglobin of 9.0 to 9.9 g/L showed a low incidence of composite adverse events (175 of 1423 [12.3%]) and death (5 of 1423 [0.4%]). Compared with nadir hemoglobin at 9.0 to 9.9 g/dL, the relative risk (RR) of composite adverse events increased stepwise as nadir hemoglobin fell below 9.0 g/dL: adjusted RR was 1.44 (95% confidence interval [CI], 1.14-1.83) for 8.5 to 8.9 g/dL, 1.56 (95% CI, 1.23-1.99) for 8.0 to 8.4 g/dL, 1.66 (95% CI, 1.31-2.11) for 7.5 to 7.9 g/dL, 2.22 (95% CI, 1.75-2.83) for 7.0 to 7.4 g/dL, and 4.00 (95% CI, 3.18-5.04) for less than 7 .0 g/dL. Furthermore, the risk of death was significantly higher when nadir hemoglobin was below 7.0 g/dL than when it was 9.0 to 9.9 g/dL (RR, 5.36; 95% CI, 2.20-16.12). Conclusions Compared with the risks when nadir hemoglobin is 9.0 to 9.9 g/dL, the risk of composite adverse events increases when postoperative nadir hemoglobin is below 9.0 g/dL, whereas risk of death increases when nadir hemoglobin is below 7.0 g/dL.

Although complete omentectomy is traditionally performed in patients with gastric cancer as part of radical gastrectomy to ensure the elimination of micrometastases, the prognostic value of omentectomy during gastrectomy remains unclear. Retrospective studies have shown that the incidence of metastases in the greater omentum is very low in T1–T3 gastric cancer. Thus radical gastrectomy with D2 lymphadenectomy and preservation of the greater omentum may be a proper curative treatment for gastric cancer patients with T1–T3 tumors. The aim of this article is to describe the design and rationale for this prospective, randomized controlled DRAGON-05 trial, conducted to evaluate the prognostic value of omentum-preserving gastrectomy for patients with T1–T3 gastric cancer. Clinical trial registration: ChiCTR2000040045 (ClinicalTrials.gov)

Background Triple-negative breast cancer (TNBC) is a clinically aggressive disease with abundant variants that cause homologous recombination repair deficiency (HRD). Whether TNBC patients with HRD are sensitive to anthracycline, cyclophosphamide and taxane (ACT), and whether the combination of HRD and tumour immunity can improve the recognition of ACT responders are still unknown. Methods Data from 83 TNBC patients in The Cancer Genome Atlas (TCGA) was used as a discovery cohort to analyse the association between HRD and ACT chemotherapy benefits. The combined effects of HRD and immune activation on ACT chemotherapy were explored at both the genome and the transcriptome levels. Independent cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) were adopted to validate our findings. Results HRD was associated with a longer ACT chemotherapy failure-free interval (FFI) with a hazard ratio of 0.16 (P = 0.004) and improved patient prognosis (P = 0.0063). By analysing both HRD status and ACT response, we identified patients with a distinct TNBC subtype (ACT-S&HR-P) that showed higher tumour lymphocyte infiltration, IFN-γ activity and NK cell levels. Patients with ACT-S&HR-P had significantly elevated immune inhibitor levels and presented immune activation associated with the increased activities of both innate immune cells and adaptive immune cells, which suggested treatment with immune checkpoint blockade as an option for this subtype. Our analysis revealed that the combination of HRD and immune activation enhanced the efficiency of identifying responders to ACT chemotherapy (AUC = 0.91, P = 1.06e−04) and synergistically contributed to the clinical benefits of TNBC patients. A transcriptional HRD signature of ACT response-related prognostic factors was identified and independently validated to be significantly associated with improved survival in the GEO cohort (P = 0.0038) and the METABRIC dataset (P < 0.0001). Conclusions These findings highlight that HR deficiency prolongs FFI and predicts intensified responses in TNBC patients by combining HRD and immune activation, which provides a molecular basis for identifying ACT responders.

Structured abstractLay abstract In this study, we aimed to elucidate the therapeutic mechanism of miRNA (miR)-498 in autophagy and macrophage polarization to M2-like phenotype in esophageal cancer. This study reports lower miR-498 expression in esophageal cancer tissues compared with adjacent normal tissues. According to the experimental results, miR-498 negatively targets MDM2 by binding to its 3′UTR, which leads to attenuated ubiquitination and degradation of ATF3 induced by MDM2. Specifically, overexpressed miR-498 reduces ratio of LC3II (a marker that is commonly utilized to detect cell autophagy) to LC3I and increases p62 (a common cargo receptor for autophagy) accumulation in KYSE-150 cells, and elevates macrophage polarization to M2-like phenotype by depressing MDM2-mediated ATF3 degradation. The present study deepened our understanding of the causes of esophageal cancer and provided at least three novel therapeutic targets for the development of effective targeted therapy for esophageal cancer.

Background Increasing studies have reported that oncogenes regulate components of the immune system, suggesting that this is a mechanism for tumorigenesis. Aurora kinase A (AURKA), a serine/threonine kinase, is involved in cell mitosis and is essential for tumor cell proliferation, metastasis, and drug resistance. However, the mechanism by which AURKA is involved in immune response regulation is unclear. Therefore, this study aimed to investigate the role of AURKA in immune regulation in triple‐negative breast cancer (TNBC). Methods Peripheral blood mononuclear cells (PBMCs) were co‐cultured with TNBC cells. The xCELLigence Real‐Time Cell Analyzer‐MP system was used to detect the killing efficiency of immune cells on TNBC cells. The expression of immune effector molecules was tested by quantitative real‐time polymerase chain reaction (qRT‐PCR) to evaluate immune function. Furthermore, to validate AURKA‐regulated immune response in vivo, 4T1 murine breast cancer cell line with AURKA overexpression or downregulation was engrafted into BALB/c mice. The distribution and proportion of immune cells in tumors were further evaluated by immunohistochemistry and flow cytometry. Results Downregulation of AURKA in TNBC cells increased immune response by activating CD8+ T cell proliferation and activity. Nuclear rather than cytoplasmic AURKA‐derived programmed death‐ligand 1 (PD‐L1) expression was independent of its kinase activity. Mechanistic investigations showed that nuclear AURKA increased PD‐L1 expression via an MYC‐dependent pathway. PD‐L1 overexpression mostly reversed AURKA silencing‐induced expression of immune effector molecules, including interleukin‐ (IL‐2), interferon‐γ (IFN‐γ), and perforin. Moreover, AURKA expression was negatively correlated with the enrichment and activity of tumor‐infiltrating CD8+ T cells in 4T1 engrafted BALB/c mouse model. Conclusions Nuclear AURKA elevated PD‐L1 expression via an MYC‐dependent pathway and contributed to immune evasion in TNBC. Therapies targeting nuclear AURKA may restore immune responses against tumors., The present study showed that nuclear AURKA rather than its kinase activity induced PD‐L1 expression via a MYC‐dependent pathway. In addition, downregulation of AURKA led to increased CD8+ T cell infiltration and activation in vivo. Thus, our data provided evidences for the involvement of AURKA in immune evasion of triple‐negative breast cancer.

To observe the safety of donor NK cell infusions in the settings of hematopoietic stem cell transplantation and after consolidation chemotherapy in elderly patients with acute myeloid leukemia (AML).Forty patients with AML were included, in which 21 patients aged over 60 years were at the stage of complete remission (CR) and 19 patients that received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mononucleated cells were isolated from peripheral blood from the donors (for allo-HSCT) or healthy immediate family members (elderly AML). The cells were seeded into the flasks pre-coated with NK cell specific activators, and expanded in media containing recombinant human IL-15 and IL-2 for 14 days. The cells were transfused intravenously after the identification of quality control. Trypan blue exclusion test was used for the determination of cell viability and counting. Flow cytometry analysis was performed to assess the surface antigenic profile. Seventy-eight infusions of the cell products were received by the elderly patients with AML after consolidation chemotherapy, 11 infusions were received by the patients during allo-HSCT and 32 infusions 3 moths after transplantation. The safety of cell therapy, body temperature, blood pressure and other indexes were observe during and 48 hours after cell transfusion. Meanwhile, the occurrence and severity of acute graft-versus-host disease (GVHD) were documented.Flow cytometry analysis showed that the proportion of NK cells (CD3NK cell products with a high-purity could be obtained by ex vivo expansion with this protocol. The transfusion of these expanded cells is generally safe in the elderly patients with AML that have received chemotherapy or patients that received hematopoietic stem cell transplantation.NK细胞预防移植复发及治疗老年白血病临床安全性观察.观察急性髓性白血病（AML）患者异基因造血干细胞移植（allo-HSCT）时、移植后及老年AML患者巩固化疗后，供者NK细胞输注的安全性。.入组40例AML患者，其中年龄60岁AML完全缓解（CR）患者21 例，allo-HSCT患者19例。采集健康直系亲属或供者外周血，密度梯度离心法分离单个核细胞，将细胞接种于NK细胞激活剂包被的培养瓶中，以重组人IL-15及IL-2细胞因子组合，优势扩增人NK细胞14 d。质检合格后进行静脉输注。台盼蓝拒染法计数细胞总数和活力，流式细胞术分析免疫细胞表型。AML患者巩固化疗后接受NK细胞输注，共78次；allo-HSCT患者移植时输注NK细胞11次，移植后3个月内输注NK细胞共32次。输注期间及之后48 h，记录患者体温、血压等，以观察细胞治疗的急性毒性，并记录急性移植物抗宿主病（GVHD）发生情况。.免疫表型分析显示，细胞扩增前外周血中NK细胞（CD3-CD56+）占单个核细胞的比例为（14.10±4.22）%（n=121），培养14 d后CD3-CD56+ 细胞比例为（87.29±8.75）%（n=121），NK细胞增殖倍数为 753.47±140.13倍（n=121）。NK细胞输注量为每次（7.58± 2.50）×10采用该体系可获得高纯度的NK细胞，用于白血病造血干细胞移植及老年AML患者，细胞输注是安全的。.

To investigate the clinical characteristics, etiology, therapy and outcome of hyperthyroidism after allogeneic hematopoietic stem cell transplantation (HSCT).The clinical data of 7 patients who experienced hyperthyroidism were retrospectively analyzed in our hospital.These 7 patients (5 males, 2 females) suffered hyperthyroidism after HSCT. All patients did not apply the pretreatment regimen containing total body irradiation (TBI). The median age was 25 years old, only one child. Six patients underwent haploidentical HSCT except one patient after unrelated HSCT. The median time of hyperthyroidism occurrence was 20 months. Two patients experienced chronic graft versus host disease (GVHD) when hyperthyroidism occurred and were treated successfully with glucocorticoid, however one patient suffered hypothyroidism 3 months later and needed long-term oral levothyroxine maintenance. One patient developed hypothyroidism post treatment ofHyperthyroidism is a rare complication after HSCT but may affect healthy and lead to lower quality of life. Routine thyroid function monitoring should be recommended after HSCT. Treatment of hyperthyroidism should be given according to the pathogeny.异基因造血干细胞移植术后并发甲状腺功能亢进的临床分析.探讨异基因造血干细胞移植术后并发甲状腺功能亢进的临床特点、发病机制、治疗及预后情况.回顾性分析中国人民解放军空军特色医学中心7例异基因造血干细胞移植术后并发甲状腺功能亢进患者的临床资料.7例患者中，男5例，女2例，中位年龄为25（7-32）岁，儿童1例，其余6例为成人，急性白血病3例，慢性粒细胞白血病1例，骨髓增生异常综合征1例，重型再生障碍性贫血2例。6例患者接受单倍体相合造血干细胞移植，1例接受无关供者全相合造血干细胞移植。所有患者均未应用含全身照射（TBI）的预处理方案，发生甲状腺功能亢进中位时间为20（9-25）个月。2例患者在诊断甲亢时合并慢性移植物抗宿主病，经激素及抗排异治疗后，甲亢得到控制，但其中1例在3个月后出现甲状腺功能减退症状，需要长期口服左甲状腺素维持。1例应用异基因造血干细胞移植术后甲状腺功能亢进是少见并发症，但严重影响患者生活质量，移植后长期存活患者需定期监测甲状腺功能，治疗上需根据引起甲状腺功能亢进的原因进行.

To analyze the clinical characteristics of SAA patients with post-transplantation lymphoproliferative disease (PTLD) after allogeneic hematopoietic stem cell transplantation, and to improve diagnosis and treatment of PTLD.The clinical data of 192 patients with SAA patients who underwent HSCT in a single center from September 2010 to September 2017 were analyzed retrospectively. All patients were received antithymocyte globulin（ATG） conditioning regimen and mesenchymal stem cell(MSC) infusion.Among 192 cases, PTLD occurred in 14 cases, the incidence was 7.29％， 9 of them were diagnosed by pathology， and 5 were diagnosed clinically. EBV infection occurred with a median time of 72（35-168） days, Viral load higher than 1×10The incidence of PTLD after HSCT with SAA who used ATG and MSC in conditioning regimen closely relates to EBV infection, age of patients≤12 years, HLA-mismatch in URD-HSCT, grade II to IV GVHD. Rituximab combined with RIS may reduce the incidence of PTLD, combined EBV-CTL and chemotherapy may be the useful and most important treatment for PTLD.重型再生障碍性贫血患者造血干细胞移植治疗后淋巴组织增殖性疾病的临床分析.分析重型再生障碍性贫血(SAA)患者造血干细胞移植（HSCT）后淋巴组织增殖性疾病(PTLD)的临床特征,以提高对PTLD的诊疗水平.回顾分析2010年9月至2017年9月在单中心行HSCT的192例SAA患者的临床资料，分析PTLD的有效预警和治疗方法。本组患者预处理方案中均含有ATG并接受间充质干细胞（MSC）输注.192例SAA患者HSCT移植后有14例并发了EBV+ PTLD，总体发生率为7.29%，其中临床诊断5例，病理诊断9例，移植后PTLD发生中位时间72(35-168)d,所有PTLD均发生了EBV感染，且EBV高载量大于1×10SAA患者接受预处理含有ATG和MSC的HSCT后PTLD发生与EBV高拷贝密切相关，年龄≤12岁儿童、非血缘HSCT中供者为HLA不全相合的移植及合并有II度以上aGVHD者移植后PTLD高发； RIS/RTX抢先治疗有效，疗效不佳患者及时应用CTL及联合化疗是控制病情有效及重要方法.

To analyze the prognostic factors of haplo-HSCT combined with MSC in the treatment of SAA.127 SAA patients who had undergone haplo-HSCT with co-infusion of MSC in our center from January 2014 to August 2019 were analyzed retrospectively. Median age was 11 (1-37) years, and median follow-up time was 39.8 (1-74) months.The median time for neutrophil and platelet engraftment was 14 d and 18 d respectively. The cumulative incidences of grade III-IV aGVHD was 4.4%±1.9% at day +100. The 2-year cumulative incidence of extensive cGVHD was 8.3%± 2.7%. The estimated 3-year OS was 86.1%±3.1%. Univariate analysis showed that high-dose CD34In the haplo-HSCT of SAA, the prognosis of children patients is better than that of adults patients. More CD34单倍体造血干细胞移植联合间充质干细胞治疗重型再生障碍性贫血.分析单倍体造血干细胞移植（haplo-HSCT）联合间充质干细胞治疗重型再生障碍性贫血（SAA）预后的影响因素.回顾性分析2014年1月至2019年8月在空军特色医学中心接受haplo-HSCT联合间充质干细胞输注治疗的SAA患者共127例，中位年龄11（1-37）岁，中位随访时间为39.8（1-74）个月.粒系和血小板的平均植入时间分别为14和18 d。+100 d III-IV度急性移植物抗宿主病（aGVHD）的累积发生率为4.4%±1.9%，2年广泛性慢性移植物抗宿主病（cGVHD）的累积发生率为8.3%±2.7%，3年总体生存（OS）为86.1%±3.1%。单因素分析结果显示：高剂量的CD34在SAA的haplo-HSCT中，儿童患者的预后明显优于成人，输注较多的CD34

Abnormal co-occurrence medical visit behavior is a form of medical insurance fraud. Specifically, an organized gang of fraudsters hold multiple medical insurance cards and purchase similar drugs frequently at the same time and the same location in order to siphon off medical insurance funds. Conventional identification methods to identify such behaviors rely mainly on manual auditing, making it difficult to satisfy the needs of identifying the small number of fraudulent behaviors in the large-scale medical data. On the other hand, the existing single-view bi-clustering algorithms only consider the features of the time-location dimension while neglecting the similarities in prescriptions and neglecting the fact that fraudsters may belong to multiple gangs. Therefore, in this paper, we present a multi-view bi-clustering method for identifying abnormal co-occurrence medical visit behavioral patterns, which performs cluster analysis simultaneously on the large-scale, complex and diverse visiting record dimension and prescription dimension to identify bi-clusters with similar time-location features. The proposed method constructs a matrix view of patients and visit records as well as a matrix view of patients and prescriptions, while decomposing multiple data matrices into sparse row and column vectors to obtain a consistent patient population across views. Subsequently the proposed method identifies the corresponding abnormal co-occurrence medical visit behavior and may greatly facilitate the safe operations and the sustainability of medical insurance funds. The experimental results show that our proposed method leads to more efficient and more accurate identifications of abnormal co-occurrence medical visit behavior, demonstrating its high efficiency and effectiveness.

Re-biopsy of metastasis in advanced breast cancer (ABC) has become an international convention to assist the diagnosis and evaluation of tumor heterogeneity. This study aimed to detect diagnostic diversity and inconsistencies among estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression levels between primary and metastatic lesions.We conducted a retrospective analysis of 1670 cases of ABC patients who had undergone at least one lesion re-biopsy from January 2010 to December 2018. The pathological diagnosis of biopsies, distribution of biopsy sites, and severe puncture complications at each site were collected. In addition, the inconsistency rates and related factors of ER, PR, and HER2 expression between primary and metastatic lesions were analyzed fully considering patients' demographic profiles and disease characteristics.In total, 1670 cases of breast cancer (BC) patients diagnosed by pathology underwent one to four biopsies of recurrences or metastases in different sites or at different stages during the rescue treatment, producing 2019 histopathological specimens which were analyzed in the study. Pathological diagnosis showed that eight patients had benign pathological diagnoses, 11 patients had second primary malignant tumors but without recurrences of breast cancer, and 17 patients had pathologically confirmed breast cancer recurrences combined with second primary cancer. In 1173 patients who presented ER, PR, and HER2 expressions in primary and metastatic lesions, the inconsistency rates of ER, PR, and HER2 were 17.5% (205/1173), 31.3% (367/1173), and 13.9% (163/1173), respectively. The multivariate analysis showed that the age at the onset of breast cancer or adjuvant endocrine therapy was an independent factor affecting changes in PR expression level. Except one liver puncture with local hemorrhage and two lung punctures with hemopneumothorax, no other severe puncture complications occurred in 1950 non-surgical rebiopsies.The pathological diagnosis of metastasis re-biopsy of ABC was diverse, and the ER, PR, and HER2 expression levels were inconsistent between primary and metastatic lesions. Therefore, more attention should be paid to perform biopsies of relapsed and metastatic breast cancers routinely in clinical practice.

ObjectiveThis meta-analysis aimed to reach a summarised estimate of distress prevalence screened by Distress Thermometer (DT) among patients with breast cancer and compare different pooled prevalence estimated between different subgroups.MethodsTwo independent interviewers conducted a systematic search from PubMed, EMBASE, Ovid and Cochrane Library and checked related reviews and meta-analyses for eligible studies. The studies that identified distress of patients with breast cancer with DT were included. After extracting demographic characteristics and distress prevalence, the pooled analysis and the forest plot were completed by using STATA V.12.0 software. We conducted a subgroup analysis based on demographic and methodological characteristics of the studies. The publication bias was estimated by funnel plot.ResultsSeventeen studies describing 3870 patients with breast cancer were included in this meta-analysis. The distress prevalence of patients with breast cancer varied from 25.3% to 71.7% among these studies. The pooled distress prevalence was 50% (95% CI 49% to 52%) for the overall sample. The pooled distress prevalence rates in DT ≥7, DT ≥5 and DT ≥4 subgroups were 37% (95% CI 35% to 40%), 45% (95% CI 40% to 49%) and 62% (95% CI 60% to 65%), respectively. The distress prevalence had statistically significant differences between subgroups, which were differentiated by the initial time of distress identified, papers’ publication time, patients’ average age and country. There was no publication bias among the included studies.ConclusionThe distress prevalence was high among patients with breast cancer. Routine and timely screening of distress for patients with breast cancer is of great significance in oncology management.

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease characterized by progressive wasting of skeletal muscles. The neuromuscular junction (NMJ) is a synapse between motor neurons and skeletal muscle fibers, critical for the control of muscle contraction. The NMJ decline is observed in DMD patients, but the mechanism is unclear. LRP4 serves as a receptor for agrin, a proteoglycan secreted by motor neurons to induce NMJ, and plays a critical role in NMJ formation and maintenance. Interestingly, we found that protein levels of LRP4 were reduced both in muscles of the DMD patients and DMD model mdx mice. We explored whether increasing LRP4 is beneficial for DMD and crossed muscle-specific LRP4 transgenic mice with mdx mice (mdx; HSA-LRP4). The LRP4 transgene increased muscle strength, together with improved neuromuscular transmission in mdx mice. Furthermore, we found the LRP4 expression mitigated NMJ fragments and denervation in mdx mice. Mechanically, we showed that overexpression of LRP4 increased the activity of MuSK and expression of dystrophin-associated glycoprotein complex proteins in the mdx mice. Overall, our findings suggest that increasing LRP4 improves both function and structure of NMJ in the mdx mice and Agrin signaling might serve as a new therapeutic strategy in DMD.

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain.

Platinum is recommended in combination with gemcitabine in the treatment of metastatic triple-negative breast cancer (mTNBC). We conduct a randomized phase 3, controlled, open-label trial to compare nab-paclitaxel/cisplatin (AP) with gemcitabine/cisplatin (GP) in mTNBC patients (ClinicalTrials.gov NCT02546934). 254 patients with untreated mTNBC randomly receive AP (nab-paclitaxel 125 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) or GP (gemcitabine 1250 mg/m² on day 1, 8 and cisplatin 75 mg/m² on day 1) intravenously every 3 weeks until progression disease, intolerable toxicity or withdrawal of consent. The primary endpoint is progression-free survival (PFS); secondary endpoints are objective response rate (ORR), safety and overall survival (OS). The trial has met pre-specified endpoints. The median PFS is 9.8 months with AP as compared to 7.4 months with GP (stratified HR, 0.67; 95% CI, 0.50–0.88; P = 0.004). AP significantly increases ORR (81.1% vs. 56.3%, P P = 0.010) to GP. Of grade 3 or 4 adverse events, a significantly higher incidence of neuropathy in AP and thrombocytopenia in GP is noted. These findings warrant further assessment of adding novel agents to the nab-paclitaxel/platinum backbone due to its high potency for patients with mTNBC.

Missed abortion is one of the common obstetrical and gynecological complications, angiogenesis is the most important factor in fetal and placental development. However, the definite etiology and pathogenesis are not fully understood.The mRNA levels of p53, MDM2, VEGF, and HIF-lα were detected in 60 villous samples of missed abortion patients and 64 healthy controls by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Immunohistochemistry was used to explore the expression and correlation of p53, MDM2, VEGF, and HIF-lα in villous tissues. Furthermore, we upregulated MDM2 expression in JEG-3 and BeWo cells under hypoxia, combined with Nutlin3, the cell cycle was determined using flow cytometry and the expressions of p53, MDM2, VEGF, and HIF-1α were determined by qRT-PCR and western blot.qRT-PCR demonstrated that the expressions of p53, MDM2, and HIF-1α were significantly increased and VEGF was decreased in missed abortion group compared with normal pregnancies. Correlation analysis found that p53 was positively correlated with MDM2 and HIF-1α, and negatively correlated with VEGF in missed abortion group. After administration of Nutlin3, overexpression of MDM2 could arrest cell cycle in G1 phase and reduce the proportion of S phase. The expression of p53 and MDM2 of JEG-3 cells and BeWo cells which transfected with pcDNA3.1-MDM2 plasmid were markedly increased after Nutlin3 addition under hypoxic conditions, while the expression of VEGF and HIF-1α decreased.Our data indicated that during the development of villi in early pregnancy, p53-MDM2 signaling regulate cell cycle and angiogenesis through interaction with HIF-1α and VEGF, which may be a crucial factor affecting pregnancy outcomes.

Summary Background Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. Methods This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18–70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1–14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. Findings Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7–not reached]) than with lapatinib plus capecitabine (6·8 months [5·4–8·1]; hazard ratio 0·39 [95% CI 0·27–0·56]; one-sided p Interpretation Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. Funding Jiangsu Hengrui Medicine and National Key R&D Program of China. Translations For the Chinese translation of the abstract see Supplementary Materials section.

Background: Topical agents are still the mainstay for the treatment of mild-to-moderate plaque psoriasis, in which fixed combinations play an important role. Tazarotene/betamethasone dipropionate (Taz/BD) cream is a novel fixed combination approved for treating plaque psoriasis in China, but its efficacy and safety have not been verified in a real-world environment. Objectives: The primary objective was to investigate the efficacy and safety of Taz/BD cream in treating plaque psoriasis. The secondary objectives were to assess its relapse after discontinuation and the efficacy and safety profiles during retreatment. Methods: A prospective, multicenter, large-scale observational study was conducted. Adult patients with chronic plaque psoriasis involving Results: In total, 2,299 eligible patients were enrolled, and 2,095 patients (91.1%) completed the 4-week study. The mean PASI improvement at week 4 was 53.7%, and the PASI 50/75 response rates were 62.5 and 26.8%, respectively. The mean PASI reduction in plaque induration, desquamation and erythema were 58.3, 61.0 and 40.0%, respectively (p < 0.001). Adverse reactions occurred in 445 patients (20.8%) at week 4. The most frequently reported adverse reactions were local skin irritation, including pruritus (10%), pain (6.7%), erythema (6.1%) and desquamation (1.8%). During the post-treatment period, 47 patients (24.0%) relapsed within 8 weeks after drug discontinuation. Forty-five patients were retreated for another 4 weeks, and the PASI 50/75 response rates were 72.7 and 40.9%, respectively. There were no unexpected safety signals during retreatment. Conclusion: Taz/BD cream is effective and well tolerated in treating mild-to-moderate plaque psoriasis under near real-world conditions and demonstrates efficacy and safety during retreatment.

Pseudomonas aeruginosa is the main conditional pathogen of immunodeficiency individuals. The mechanisms governing immune response to P. aeruginosa infection by macrophages remain incompletely defined. Herein, we demonstrate that protein tyrosine phosphatase-1B (PTP1B) is a critical negative regulator of P. aeruginosa infection response by macrophages. PTP1B-deficient macrophages display greatly enhanced bacterial phagocytosis and killing, accompanied by increased lysosome formation during P. aeruginosa infection. We also found that PTP1B repressed nitric oxide (NO) production and nitric oxide synthase (iNOS) induction following P. aeruginosa infection. PTP1B deficiency tended to upregulate the production of TRIF-interferon (IFN) pathway cytokines and chemokines, including IFN-β and interferon γ-inducible protein 10 (CXCL10, IP-10). Unexpectedly, the phosphorylation level of STAT1 was not regulated by PTP1B. In vivo experiments also confirmed that the regulatory function of PTP1B was not dependent on STAT1. These findings demonstrate that STAT1 is dispensable for negative regulation of P. aeruginosa clearance by macrophages.

Interaction between tumor cells and immune cells determined highly heterogeneous microenvironments across patients, leading to substantial variation in clinical benefits from immunotherapy. Somatic gene mutations were found not only to elicit adaptive immunity but also to influence the composition of tumor immune microenvironment and various processes of antitumor immunity. However, due to an incomplete view of associations between gene mutations and immunophenotypes, how tumor cells shape the immune microenvironment and further determine the clinical benefit of immunotherapy is still unclear. To address this, we proposed a computational approach, inference of mutation effect on immunophenotype by integrated gene set enrichment analysis (MEIGSEA), for tracing back the genomic factor responsible for differences in immunophenotypes. MEIGSEA was demonstrated to accurately identify the previous confirmed immune-associated gene mutations, and systematic evaluation in simulation data further supported its performance. We used MEIGSEA to investigate the influence of driver gene mutations on the infiltration of 22 immune cell types across 19 cancers from The Cancer Genome Atlas. The top associated gene mutations with infiltration of CD8 T cells, such as CASP8, KRAS and EGFR, also showed extensive impact on other immune components; meanwhile, immune effector cells shared critical gene mutations that collaboratively contribute to shaping distinct tumor immune microenvironment. Furthermore, we highlighted the predictive capacity of gene mutations that are positively associated with CD8 T cells for the clinical benefit of immunotherapy. Taken together, we present a computational framework to help illustrate the potential of somatic gene mutations in shaping the tumor immune microenvironment.

The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease specific mechanisms due to a paucity of animal models. Here, we generated homozygous (Slc25a32Y174C/Y174C and Slc25a32K235R/K235R) and compound heterozygous (Slc25a32Y174C/K235R) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out (Slc25a32-/-) mouse was also generated. The Slc25a32K235R/K235R and Slc25a32Y174C/K235R mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32-/- mice die in utero with NTDs. All Slc25a32 mutations did not hinder the mitochondrial uptake of folates but specifically blocked the uptake of flavin adenine dinucleotide (FAD). A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid β-oxidation and amino acid metabolism impaired, Slc25a32-/- embryos still had a subunit of glycine cleavage system–dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulated. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32-/- embryos. The Slc25a32K235R/K235R mice had no glycine oxidation defect but had another formate donor-choline metabolism interrupted and mitochondrial folates deficient. Formate supplementation increased mitochondrial folates amounts of mice, but this effect was not restricted to the Slc25a32 mutant mice. In summary, we established novel animal models, which enabled us to better understand the function of SLC25A32 and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.

Background The optimal locoregional treatment for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is unclear. This study aimed to investigate the efficacy of Gamma knife radiosurgery (GKR) versus transcatheter arterial chemoembolization (TACE) in HCC patients with PVTT. Methods This retrospective study included 544 HCC patients with PVTT (GKR, 202; TACE, 342). Propensity score matching (PSM) analysis identified 171 matched pairs of patients. The primary endpoint was overall survival (OS). Results Before PSM, the GKR group exhibited longer median OS (mOS) than the TACE group (17.2 vs. 8.0 months, p p p = 0.001; 14.5 vs. 6.5 months, p = 0.001, respectively) and comparable OS for patients with PVTT I. After PSM, the GKR group had also a longer mOS than the TACE group (15.8 vs. 10.4 months, p p Conclusions GKR was associated better OS than TACE in HCC patients with PVTT, especially for patients with PVTT II-IV. Clinical Trials Registration The study was registered in the Chinese Clinical Trials Registry under the registration number ChiCTR2100051057.

Shigella flexneri serotype 2a2 (II:9;10) is the most prevalent strain in causing bacillary dysentery in developing countries. Chemical modifications such as glucosylation, O-acetylation, and phosphoethanolamine modifications of lipopolysaccharide (LPS) O antigen (Oag) contribute to the emergence of various serotypes. Sf6 is a Shigella-specific bacteriophage that infects only a limited range of S. flexneri serotypes [X, Y]. LPS Oag is the primary receptor for bacteriophage Sf6 where it uses its tailspike protein (TSP) in binding and hydrolysing LPS Oags. Sf6TSP has recently been shown to be capable of hydrolysing the LPS Oag of Type II strains, albeit modestly. Phage therapy has regained attention in recent years as an alternative therapeutic approach. Therefore, this study aimed to expand the host range of Sf6 to the prevalent S. flexneri serotype 2a2 strain. We discovered a new lytic Sf6 host range mutant that is capable of infecting S. flexneri serotype 2a2 and identified residues in Sf6TSP that may potentially be involved in binding and hydrolysing serotype 2a2 LPS Oag. This work increased the limited Shigella-specific bacteriophage collection and may be useful in the future for phage therapy and/or biocontrolling of S. flexneri in contaminated food and water.

Rationale: Statin, the most widely used medication in lowering cholesterol, is also associated with increased risk of type 2 diabetes, but its molecular basis remains unclear. Methods: Mice were injected intraperitoneally with statins alone or in combination with sirtuin (Sirt) 6 activator, and blood glucose levels were measured. Liver tissues from patients with statin use were analyzed for the expression of Sirt6. Results: Statin treatment up-regulated the hepatic expression of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, which was prevented by Sirt6 overexpression. Mechanistically, statin directly repressed Sirt6 expression by induction of microRNA (miR)-495, a novel inhibitor of Sirt6. Pathway analysis for predicted target genes of miR-495 recognized forkhead box protein (Fox)O1 as a key downstream signaling of Sirt6. Statin treatment increased the acetylation and protein stability of FoxO1, which was suppressed by Sirt6 overexpression. Inhibiting miR-495 recovered Sirt6 levels, blocking the ability of statin to increase FoxO1 mediated gluconeogenesis, and thus confirming the role of the miR-495/Sirt6/FoxO1 pathway in controlling gluconeogenesis. Moreover, the Sirt6 activator MDL801 prevented gluconeogenesis and hyperglycemia induced by statin in mice. Equally noteworthy was that human liver tissues obtained from statin users showed a significant decrease in Sirt6 protein levels compared to those of non-users. Conclusion: Statin induces miR-495 to suppress Sirt6 expression, which leads to enhancement of FoxO1-mediated hepatic gluconeogenesis. Thus, Sirt6 activation may offer a promising strategy for preventing statin-induced hyperglycemia.

Introduction Previous studies of herpes zoster (HZ) have focused on acute patient manifestations and the most common sequela, postherpetic neuralgia (PHN), both serving to disrupt brain dynamics. Although the majority of such patients gradually recover, without lingering severe pain, little is known about life situations of those who recuperate or the brain dynamics. Our goal was to determine whether default mode network (DMN) dynamics of the recuperative population normalize to the level of healthy individuals. Methods For this purpose, we conducted resting‐state functional magnetic resonance imaging (fMRI) studies in 30 patients recuperating from HZ (RHZ group) and 30 healthy controls (HC group). Independent component analysis (ICA) was initially undertaken in both groups to extract DMN components. DMN spatial maps and within‐DMN functional connectivity were then compared by group and then correlated with clinical variables. Results Relative to controls, DMN spatial maps of recuperating patients showed higher connectivity in middle frontal gyrus (MFG), right/left medial temporal regions of cortex (RMTC/LMTC), right parietal lobe, and parahippocampal gyrus. The RHZ (vs HC) group also demonstrated significant augmentation of within‐DMN connectivity, including that of LMTC‐MFG and LMTC‐posterior cingulate cortex (PCC). Furthermore, the intensity of LMTC‐MFG connectivity correlated significantly with scoring of pain‐induced emotions and life quality. Conclusion Findings of this preliminary study indicate that a disrupted dissociative pattern of DMN persists in patients recuperating from HZ, relative to healthy controls. We have thus provisionally established the brain mechanisms accounting for major outcomes of HZ, offering heuristic cues for future research on HZ transition states., It is the first time to demonstrate that a disrupted dissociation pattern of DMN still exists in recuperative herpes zoster patients compared with healthy controls even the rash disappeared and pain was relieved. This study could provide heuristic cues for future research about herpes zoster transition mechanism.

Undifferentiation is a key feature of nasopharyngeal carcinoma (NPC), which presents as a unique opportunity for intervention by differentiation therapy. In this study, we found that SOX1 inhibited proliferation, promoted differentiation, and induced senescence of NPC cells, which depended on its transcriptional function. RNA-Seq-profiling analysis showed that multiple undifferentiated markers of keratin family, including KRT5, KRT13, and KRT19, were reduced in SOX1 overexpressed NPC cells. Interestingly, gene ontology (GO) analysis revealed genes in SOX1 overexpressed cells were enriched in extracellular functions. The data of LC/MS untargeted metabolomics showed that the content of retinoids in SOX1 overexpressed cells and culture medium was both higher than that in the control group. Subsequently, we screened mRNA level of genes in retinoic acid (RA) signaling or metabolic pathway and found that the expression of UDP-glucuronosyltransferases was significantly decreased. Furtherly, UGT2B7 could rescue the differentiation induced by SOX1 overexpression. Inhibition of UGTs by demethylzeylasteral (T-96) could mimic SOX1 to promote the differentiation of NPC cells. Thus, we described a mechanism by which SOX1 regulated the differentiation of NPC cells by activating retinoid metabolic pathway, providing a potential target for differentiation therapy of NPC.

The evidence of combining neoadjuvant chemotherapy with targeted therapy for patients with locally advanced gastric cancer is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of S-1, oxaliplatin and apatinib (SOXA) in patients with locally advanced gastric adenocarcinoma.Treatment-naïve patients received three preoperative cycles of S-1 (80-120 mg/day on days 1-14) and oxaliplatin (130 mg/mOf 29 patients included, median age was 60 (range, 43-73) years; 20 (69.0%) were male. The pRR was 89.7% (95% confidence interval [CI], 72.7%-97.8%; 26 of 29 patients; P 0.001) with 28 patients treated with surgery. All 29 patients were available for preoperative response evaluation, achieving an objective response rate of 79.3% (95% CI, 60.3%-92.0%) and a disease control rate of 96.6% (95% CI, 82.2%-99.9%). The margin-free resection rate was 96.6% (95% CI, 82.2%-99.9%). The pathologic complete response rate was 13.8% (95%CI, 1.2%-26.3%). Downstaging of overall TNM stage was observed in 16 (55.2%) patients. During neoadjuvant therapy, 10 (34.5%) patients had grade ≥III adverse events. No treatment-related death occurred. Surgery-related complications were observed in 12 of 28 (42.9%) patients.SOXA followed by surgery in patients with locally advanced gastric adenocarcinoma showed favourable activity and manageable safety. A randomised controlled trial in locally advanced gastric or oesophagogastric junction adenocarcinoma is ongoing (ClinicalTrials.gov: NCT04208347).

Summary: Background: Endoscopic submucosal dissection (ESD) has gained more popularity in the treatment of early gastric cancer (EGC). Although there is a lack of confirmed evidence for the feasibility of ESD for undifferentiated EGC. The aim of the study was to investigate the feasibility of ESD with expanded indications for undifferentiated EGC patients. Methods: Data from patients with undifferentiated EGC (including signet-ring cell carcinoma, mucinous adenocarcinoma, mixed adenocarcinoma, and poorly differentiated adenocarcinoma) who underwent radical surgical resection were retrospectively reviewed. The relationship between the clinical parameters and the incidence of lymph node metastasis (LNM) was investigated. Results: A total of 517 patients were included in this study. The results showed that LNM was significantly associated with ulceration, tumor size, depth of invasion, lymphatic invasion, vascular invasion, and perineural invasion. Multivariate stepwise logistic regression analysis revealed that tumor size (OR = 1.61, 95% CI = 1.03–2.52, P = 0.0367), depth of tumor invasion (OR = 2.77, 95% CI = 1.66–4.63, P = 0.0001), and lymphatic invasion (OR = 14.74, 95% CI = 1.58–137.36, P = 0.0182) were independent risk factors for LNM. In the patients who would be included under the new proposed guidelines for ESD, including men with mucosal tumors ≤2 cm and without ulceration or lymphatic or venous infiltration, LNM was present in 11.9% (14/118). Conclusion: Caution to be exercised in expanding application of ESD should be carefully weighed in undifferentiated EGC. Keywords: Early gastric cancer, Endoscopic submucosal dissection, Expanded indication, Lymph node metastasis

There is an increasing demand for effective noninvasive diagnosis against common pulmonary diseases, which are rising sharply due to the serious air pollution. Human neutrophil elastase (HNE), a typical protease highly involved in pulmonary inflammatory diseases and lung cancer, is a potential predictor for disease progression. Currently, few of the HNE-targeting probes are applicable in vivo due to the limitation in sensitivity and biocompatibility. Herein, we reported the achievement of in vitro detection and in vivo imaging of HNE by incorporating the HNE-specific peptide substrate, quantum dots (QDs), and organic dyes into the fluorescence resonance energy transfer (FRET) system. The refined nanoprobe, termed QDP, could specifically measure the HNE with excellent sensitivity of 7.15 pM in aqueous solution and successfully image the endogenous and exogenous HNE in living cells. In addition, this nanoprobe enabled HNE imaging in mouse models of lung cancer and acute lung injury, and the HNE activity at high temporal and spatial resolution was continuously monitored. Most importantly, QDP successfully discriminated the serums of patients with lung diseases from those of the healthy controls based on the HNE activity determination. Overall, this study demonstrates the advantages of a FRET-system-based nanoprobe in imaging performance and provides an applicable tool for in vivo HNE detection and pulmonary disease diagnosis.

The availability of blood transfusion has been a recurrent concern for medical institutions and patients. Efficient management of this resource represents an important challenge for many hospitals. Likewise, rapid reaction during transfusion decisions and planning is a critical factor to maximize patient care. This paper proposes a novel strategy for predicting the blood transfusion need, based on available information, by means of Restricted Boltzmann Machines (RBM). By extracting and analyzing high-level features from 4831 patient records, RBM can deal with complex patterns recognition, helping supervised classifiers in the task of automatic identification of blood transfusion requirements. Results show that a successfully classification is obtained (96.85%), based only on available information from the patient records.

We reported a novel function of recombinant human thrombopoietin (TPO) in increasing hematopoietic stem and progenitor cell (HSPC) homing to the bone marrow (BM). Single doses of TPO treatment to the recipients immediately after BM transplantation showed significantly improved homing of HSPCs to the BM, which subsequently resulted in enhanced short‐ and long‐term engraftment of HSPCs in mice. We found that TPO could downregulate the expression and secretion of matrix metalloproteinase 9 in BM cells. As a result, SDF‐1α level was increased in the BM niche. Blocking the interaction of SDF‐1α and CXCR4 on HSPCs by using AMD3100 could significantly reverse the TPO‐enhanced HSPC homing effect. More importantly, a single dose of TPO remarkably promoted human HSPC homing and subsequent engraftment to the BM of nonobese diabetic/severe combined immunodeficiency mice. We then performed a clinical trial to evaluate the effect of TPO treatment in patients receiving haploidentical BM and mobilized peripheral blood transplantation. Surprisingly, single doses of TPO treatment to patients followed by hematopoietic stem cell transplantation significantly improved platelet engraftment in the cohort of patients with severe aplastic anemia (SAA). The mean volume of platelet and red blood cell transfusion was remarkably reduced in the cohort of patients with SAA or hematological malignancies receiving TPO treatment. Thus, our data provide a simple, feasible, and efficient approach to improve clinical outcomes in patients with allogenic hematopoietic stem cell transplantation. The clinical trial was registered in the Chinese Clinical Trial Registry website (http://www.chictr.org.cn) as ChiCTR‐OIN‐1701083., We reported a novel function of recombinant human thrombopoietin (TPO) in increasing hematopoietic stem and progenitor cell (HSPC) homing to the bone marrow (BM), which subsequently resulted in enhanced long‐term engraftment of HSPCs in mice. Notably, single doses of TPO treatment to patients followed by HSCT improved clinical outcomes, especially in patients with severe aplastic anemia.