Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Although computational approaches have been complementing high-throughput biolog-ical experiments for the identification of functional regions in the human genome,it remains a great challenge to systematically decipher interactions between transcription factors(TFs)and regulatory elements to achieve interpretable annotations of chromatin accessibility across diverse cellular con-texts.To solve this problem,we propose DeepCAGE,a deep learning framework that integrates sequence information and binding statuses of TFs,for the accurate prediction of chromatin acces-sible regions at a genome-wide scale in a variety of cell types.DeepCAGE takes advantage of a den-sely connected deep convolutional neural network architecture to automatically learn sequence signatures of known chromatin accessible regions and then incorporates such features with expres-sion levels and binding activities of human core TFs to predict novel chromatin accessible regions.In a series of systematic comparisons with existing methods,DeepCAGE exhibits superior perfor-mance in not only the classification but also the regression of chromatin accessibility signals.In a detailed analysis of TF activities,DeepCAGE successfully extracts novel binding motifs and mea-sures the contribution of a TF to the regulation with respect to a specific locus in a certain cell type.When applied to whole-genome sequencing data analysis,our method successfully prioritizes puta-tive deleterious variants underlying a human complex trait and thus provides insights into the understanding of disease-associated genetic variants.

Isogenic cells growing in identical environments show cell-to-cell variations because of the stochasticity in gene expression. High levels of variation or noise can disrupt robust gene expression and result in tremendous consequences for cell behaviors. In this work, we showed evidence from single-cell RNA sequencing data analysis that microRNAs (miRNAs) can reduce gene expression noise at the mRNA level in mouse cells. We identified that the miRNA expression level, number of targets, target pool abundance, and miRNA-target interaction strength are the key features contributing to noise repression. miRNAs tend to work together in cooperative subnetworks to repress target noise synergistically in a cell type-specific manner. By building a physical model of post-transcriptional regulation and observing in synthetic gene circuits, we demonstrated that accelerated degradation with elevated transcriptional activation of the miRNA target provides resistance to extrinsic fluctuations. Together, through the integrated analysis of single-cell RNA and miRNA expression profiles, we demonstrated that miRNAs are important post-transcriptional regulators for reducing gene expression noise and conferring robustness to biological processes.

The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis.

Objective To investigate the effect of Bushen-Tongmai decoction on plasma renin activity (PRA), plasma levels of brain natriuretic peptide (BNP) and angiotensinⅡ(AngⅡ) in patients with chronic heart failure. Methods A total of 100 patients with chronic heart failure from January 2011 to December 2013 were randomly divided into a control group and a treatment group, with 50 patients in each group. The patients in the control and treatment groups received conventional treatment and Bushen-Tongmai decoction plus conventional treatment for 8 weeks, respectively. Laboratory measurements including PRA, BNP and AngⅡwere performed before and after treatment.Cardiac function was measured before and after treatment with echocardiography. Results The PRA , plasma levels of BNP and AngⅡ after treatment in the treatment group were significantly decreased than before treatment (treatment group:t=2.990, 4.030, 4.401, all P<0.01);after treatment, there was significant difference in PRA, BNP and AngⅡbetween the treatment group and the control group(t=2.622, 2.863, 3.809, all P<0.05). Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF) by echocardiography in both groups were significantly improved (treatment group:t=9.167, 11.030, 13.273, all P<0.01;control group:t=5.189, 7.626, 6.906, all P<0.01). Improvements of LVESD, LVEDD and LVEF in the treatment group were grater than those in the control group (t=4.037, 2.701, 7.458, all P<0.01). Conclusion Bushen-Tongmai decoction can effectively decrease PRA , plasma levels of BNP, AngⅡ, and improve cardiac function in patients with chronic heart failure.

Medical education of PhD candidates is of great importance to medical personnel training in our country. With the development of society, the progress of science and technology and renewal of knowledge, cultivation of innovative talents and improvement of graduate education quality is priority nowadays. This paper reflects on the progress we’ve made on medical education of PhD candidates. Though efforts have been made to improve the innovative ability of talents in our country gradually, we still need to be more innovative, more consistent and more scientific in the future. According to the state Degree Requirements and our goal of talent training, we should combine courses with scientific research systematically, pay more attention to scientific methodology and academic training, finally form a better training mode of PhD candidates majoring in medical science.

Objective To investigate the effect of reinforcing spleen and kidney method on adriamycin-induced CKD in rats and to explore its possible mechanism.Methods Totally 36 Sprague-Dawley rats were randomly divided into a Adriamycin-induced model group and a control group.The model group was further divided into five groups:the Adriamycin-induced model control group,bennazepril-treated group,and TCM treated low,moderate,and high dose groups.The level of serum creatinine,urea nitrogen,24hours urine protein and urine creatinine were measured at 14,28,42 days after establishing the model rats.And the protein expression of transforming growth factor-β1 (TGF-β1) and cyclin-dependent kinase inhibitor p21cip1 (p21)were detected by immunohistochemistry.Results The proteinuria was observed on the seventh day after injection of adriamycin in adriamycin nephropathy model group,and reached summit on the fourteenth day.Both TCM treated groups and benazepril group reduced the level of urine protein within 24 hours (P＜0.05),the reduction was most remarkable in the TCM high dose group.The expression of p21 and TGF-β1 (p21 288627.66±97021.65,TGF-β1 98405.14± 19216.89) in kidney increased in the model groups,while the TCM treated high dose group (p21 518886.35±6810.89,TGF-β1 222012.95± 50484.73) was significantly lower than the model control group (P＜ 0.05).Conclusion Reinforcing spleen and kidney method could decrease the level of urine protein within 24 hours by regulating the expression of p21 and TGF-β1,so thus to protect renal function and delay progress of kidney disease.

Objective To explore the clinicalpathological characteristics of Lynch syndrome associated ovarian cancer.Methods Totally 260 cases ovarian cancer patients were admitted to Tianjin Medical University General Hospital during Jan.2004 and Jan.2011,among which 10 patients( LS group) belonged to Lynch syndrome associated ovarian cancer according to Amsterdam Ⅱ criteria.One hundred ovarian cancer patients without any family cancer history were enrolled randomizely as control group (sporadic group).Results Lynch syndrome associated ovarian cancer accounted for 3.8％ ( 10/260),the incidence rate of ovarian cancer for female family members of Lynch syndrome was 8.7％ ( 10/115 ).Mean age at time of diagnosis in LS group was (46 ±7) years,significantly earlier than that in sporadic group [ (56 ±11 ) years,P ＜ 0.05 ].There was no statistical difference between two groups in histological type or International Federation of Gynecology and Obstetrics ( FIGO ) stage ( P ＞ 0.05 ).Most of the tissue differentiation in LS group were well or moderate differentiated,there was statistical difference between the two groups(9/10 vs.55％,P ＜0.05).The 3-year and 5-year survival rate in LS group were 87.5％ and 52.5％respectively,compared with 55.4％and 22.7％ in sporadic group(all P＜0.05).Conclusion Compared with sporadic ovarian cancer,Lynch syndrome associated ovarian cancer is more likely present as the clinicalpathological characteristics of early age of onset,serous adenocarcinoma,lower grade and better prognosis.

Objective To investigate and compare the clinical values of routine electrocardiogram and dynamic electrocardiogram in arrhythmia in coronary heart disease diagnosis.Methods 73 patients with coronary heart disease were collected and monitored by routine electrocardiogram and dynamic electrocardiogram,and two groups were e stablished including control group using routine electrocardiogram and observation group using dynamic electrocardiogram.The positive diagnosis rate and the specific diagnosis diresults of arrhythmia in coronary heart disease of both groups were compared.Results The positive diagnosis rate of arrhythmia in coronary heart disease of observation group(75.3％ ) was significantly higher than that of control group(54.8％ ) ( x2 =6.78,P ＜0.05).And the positive diagnosis rate of the observation group was also significantly higher than that of the control group in ventricular premature beats two,triple law,pairs of premature ventricular contractions,atrial premature beats two,triple law,atrial premature beats in pairs,atrioventricular block and paroxysmal ventricular tachycardia( all P ＜ 0.05 ).Conclusion Compared with routine electrocardiogram,the dynamic electrocardiogram in anrnythmia in coronary heart disease diagnosis could obtain higher positive diagnosis rate,and it is worthy of clinical application.

The aim of this study was to investigate the effect of Paris saponin Ⅰ (PS Ⅰ ) on human gastric carcinoma cell growth and apoptosis and to explore the potential mechanisms.The proliferation of SGC7901 cells was monitored by the MTT cell viability assay,while the nuclear morphology of apoptotic cells was assessed by Hoechst 33258 staining.Flow cytometry was performed to analyze the cell cycle progression of propidium iodide (PI)-stained SGC7901 cells and the apoptotic rate of annexin V/PI-stained cells.Western blotting was used to examine the expression of several cell cycle proteins,including cyclin B1 and Cdkl,and the apoptosis-regulated proteins Bcl-2,Bax,cytochrome c,procaspase-9,and procaspase-3.The MTT assay demonstrated that PSⅠ could induce significant doseand time-dependent inhibition of SGC7901 cell proliferation.Marked morphological changes,including condensation of chromatin,nuclear fragmentation and apoptotic bodies were clearly shown on Hoechst 33258 staining.PSⅠ treatment also resulted in the disruption of the cell cycle at G2/M and the induction of apoptosis.Following PSⅠ treatment,the cell cycle-related proteins cyclin B 1 and Cdk1 were downregulated.Expression of the pro-apoptotic protein Bax was increased,while anti-apoptotic protein Bcl-2decreased.PSⅠ treatment resulted in elevated cytoplasmic cytochrome c and activation of the apoptotic proteases caspase-9 and caspase-3.These data indicate that PSⅠ acts as an inhibitor of proliferation in SGC7901 cells by inducing cell cycle arrest and mitochondria-dependent apoptosis.PSⅠ is a potential therapeutic agent against human gastric carcinoma.