As confusion mounts over RNA isoforms involved in phenotypic plasticity, aberrant CpG methylation-mediated disruption of alternative splicing is increasingly recognized as a driver of intratumor heterogeneity (ITH). Protease serine 3 (PRSS3), possessing four splice variants (PRSS3-SVs; PRSS3-V1-V4), is an indispensable trypsin that shows paradoxical effects on cancer development. Here, we found that PRSS3 transcripts and their isoforms were divergently expressed in lung cancer, exhibiting opposing functions and clinical outcomes, namely, oncogenic PRSS3-V1 and PRSS3-V2 versus tumor-suppressive PRSS3-V3, by targeting different downstream genes. We identified an intragenic CpG island (iCpGI) in PRSS3. Hypermethylation of iCpGI was mediated by UHRF1/DNMT1 complex interference with the binding of myeloid zinc finger 1 (MZF1) to regulate PRSS3 transcription. The garlic-derived compound diallyl trisulfide cooperated with 5-aza-2'-deoxycytidine to exert antitumor effects in lung adenocarcinoma cells through site-specific iCpGI demethylation specifically allowing MZF1 to upregulate PRSS3-V3 expression. Epigenetic silencing of PRSS3-V3 via iCpGI methylation (iCpGIm) in BALF and tumor tissues was associated with early clinical progression in patients with lung cancer but not in those with squamous cell carcinoma or inflammatory disease. Thus, UHRF1/DNMT1-MZF1 axis-modulated site-specific iCpGIm regulates divergent expression of PRSS3-SVs, conferring nongenetic functional ITH, with implications for early detection of lung cancer and targeted therapies.

OBJECTIVE: To explore the long-term efficacy of allogeneic hematopoietic stem cell transplantation (alloHSCT) in patients with Mucopolysaccharidosis (MPS), which has rarely been reported in China. METHODS: A 18-month-old boy and a 23-month-old girl undergoing alloHSCT for MPS VI and MPS IH Shanghai Children's Medical Center on March 30, 2006 and September 6, 2006 were selected as the study subjects. A busulfan-based myeloablative regimen was used as the conditioning regimen. Peripheral stem cells were respectively collected from a human leucocyte antigen (HLA) matched sibling carrier donor and a HLA 9/10 matched unrelated donor. Both patients were followed up for more than 15 years. The functions of internal organs before and after the transplantation were compared, and child 1 was also compared with his untreated brother and healthy brother. RESULTS: Both children have achieved full donor chimerism after the transplantation, and their enzymatic activities have remained stable. The enzymatic activity of the child 1 was slightly lower than normal but similar to that of his carrier donor, whilst that of the child 2 was normal. Both children have attended schools with good academic performance. Compared with his untreated brother, the respiratory function and hearing of child 1 have significantly improved. However, his orthopedic and cardiac disorders have still remained and required medical intervention. For child 2, her obstructive pulmonary disease was resolved and cognitive development was well preserved after the HSCT. Her heart disease has become stabilized and even improved with time, though her corneal clouding and skeletal malformation still required surgery. CONCLUSION MPS patients can sustain long-term and stable enzymatic activities after successful alloHSCT. Compared with untreated patients, their health can be significantly improved, along with considerably prolonged survival, though the long-term efficacy of HSCT for different organs may vary to a certain extent.
Humans ; Child ; Male ; Female ; Infant ; Child, Preschool ; Graft vs Host Disease/etiology* ; China ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Mucopolysaccharidoses/etiology* ; Busulfan ; Treatment Outcome

The 2 patients were both aged females with medical history of diabetes mellitus. The chief complaints were both hyperpyrexia. Laboratory tests presented markedly elevated white blood cells and C-reactive protein, indicating severe systemic infections. Urine culture confirmed the growth of Escherichia coli. CT scan revealed thickened bladder wall with intraluminal and interstitial collections of gas. After the diagnosis of emphysema cystitis was established, conservative treatments including bladder drainage, strict glycemic control and sensitive antibiotics were administered timely. Both of the 2 patients got fully recovery after standard treatment.

Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatosteatosis.Oridonin(ORI)is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens.In this paper,we showed that ORI exerted significant protective ef-fects against hepatic steatosis,inflammation and fibrosis,which was dependent on LXRα signaling.It is reported that LXRα regulated lipid homeostasis between triglyceride(TG)and phosphatidylethanol-amine(PE)by promoting ATCL and EPT1 expression.Therefore,we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRα-dependent manner,and the results showed the TG reduction and PE elevation.In detail,hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATCL and EPT1 genes,respectively.Taken together,the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRα-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

Objective:To explore the value of different radiomics models based on machine learning in predicting the risk of distant recurrence and metastasis of triple-negative breast cancer after neoadjuvant therapy.Methods:The clinical and imaging data of 150 patients with triple-negative breast cancer (TNBC) confirmed by histopathology were retrospectively analyzed. All patients underwent neoadjuvant chemotherapy and surgical resection from August 2011 to May 2017 in Fudan University Shanghai Cancer Center and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. One hundred and nine patients from Shanghai Fudan University Shanghai Cancer Center were used as the training group, and 41 patients from Ruijin Hospital, Shanghai Jiao Tong University School of Medicine were used as the validation group. The features were extracted from dynamic contrast-enhanced MRI (DCE-MRI) before treatment and were added with time domain features innovatively. Least absolute shrinkage and selection operator cross validation and recursive feature elimination were applied to select features. Six different supervised machine learning algorithms (logistic regression, linear discriminant analysis, k-nearest neighbor, naive bayesian, decision tree, support vector machine) were used to predict the prognosis. ROC curve, accuracy and F1 measure were used to evaluate the performance of the six algorithms, and also verified by the validation group.Results:The support vector machine algorithm had the best predictive effect in the recurrence and metastasis model based on 15 features, with the highest area under curve (training group was 0.917, validation group was 0.859), and the highest accuracy rate (training group was 87.5%, validation group was 82.9%) and the highest F1 measure (training group was 0.800, validation group was 0.741). In addition, of the 15 imaging features, 12 were the time domain features and 3 were spatial features.Conclusion:With the help of the time domain features and machine learning algorithms, radiomics signatures based on preoperative DCE-MRI can help predict the distant prognosis for TNBC after neoadjuvant chemotherapy and provide support for clinical decision making and follow-up management.

Because of the lack of typical clinical manifestations, infection is difficult to be diagnosed in patients with hematological malignancies, resulting in high mortality. Neutrophil CD64 (nCD64) has been used in the early diagnosis of infection for many years and has been proved to be highly sensitive and specific. However, it is rarely used in the diagnosis of hematological malignancies with infection. This paper reviews the main influencing factors and coping methods in the diagnosis of hematological malignancies with infection.

Background/Aims: The risk factors of colorectal stricture associated with ulcerative colitis (UC) carcinogenesis in the long-term disease duration remain unclear. Methods: This study included all UC patients registered from a prospectively maintained database between June 1986 to July 2018. The demographic data, clinical features, and outcomes in patients with dysplasia and stricture were assessed using univariable analysis and multivariate logistic regression models. Results: A total of 246 eligible patients were in-cluded in the analysis. The median follow-up time was 13.0 years (interquartile range [IQR], 9.0 to 16.0). There were 35 cases (14.2%) of colorectal stricture. Patients with stricture had worse clinical outcomes. Stricture formation (odds ratio [OR], 9.350; 95% confidence interval [CI], 2.842 to 30.762), inflammatory polyps (OR, 5.464; 95% CI, 1.692 to 17.638), disease duration of more than 10 years (OR, 3.223; 95% CI, 1.040 to 9.985), and age >40 years at diagnosis (OR, 8.499; 95% CI, 1.903 to 37.956) were significantly associated with high-grade dysplasia or colorectal cancer. In addition, disease duration of more than 5 years (OR, 3.211; 95% CI, 1.168 to 8.881), moderated anemia (OR, 3.373; 95% CI, 1.472 to 7.731), and primary sclerosing cholangitis (OR, 5,842; 95% CI, 1.395 to 24.468) were contributing factors for the development of colorectal stricture. Conclusions Colorectal stricture had the highest risk for malignant transformation.Earlier initiation of colonoscopic surveillance in UC patients with risk factors for stricture should be considered to prevent stricture formation and further malignant transformation.

Objective To discuss the safety and the application of the self-designed multifunctional inflatable pelvis and hip-joint fixator (MIPHF) in damage control in pelvic fracture patients.Methods The MIPHF was subjected to pressure test and quality inspection.From September 2016 to June 2017,61 pelvic-fracture patients were treated with our self-designed MIPHF as pre-hospital first-aid care according to the concept of damage control orthopedics (DCO) (MIPHF group).The control group consisted of 69 pelvic-fracture patients who had not received pre-hospital first-aid care with the self-designed MIPHF from December 2015 to August 2016.There were no statistically significant differences between the two groups in gender,age,types of pelvic fracture,and preoperative injure severity score (ISS).The study compared the two groups for the case fatality rate,volume of blood transfused during surgeries,early complication rates,fracture reduction (Matta standards),and long-term efficacy (Cole scores).Results The pressure test showed that the MIPHF had a good fixation effect on the pelvis.And the quality inspection showed that the material used for the MIPHF was in line with national standards and the safety was guaranteed.The MIPHF group had 1 death (1.6％) and the control group had 8 deaths (11.6％),which was a significant difference (x2=4.979,P=0.026).All survival patients in both groups were followed up.The MIPHF group (61 cases) received 3.0 to 18.0 months follow-up,with an average of 9.0 months.And the control group (69 cases) had 18.0 to 30.0 months follow-up,with an average of 21.9 months.In the MIPHF group,23 cases were treated conservatively,and 37 cases were treated with surgery.Among them,3 cases were fixed with external fixator,20 cases with anterior open reduction and internal fixation,9 cases with posterior open reduction and internal fixation,and 5 cases with combined anterior and posterior fixation.The timing of surgery was 1 to 20 days after injury,with an average of 4.1 days.The volume of blood transfused in the MIPHF group during surgery was 200 to 1500 ml,with an average of 628.6 ml.In the control group,27 patients were treated conservatively,and 42 patients were treated with surgery.Among them,2 cases were fixed with external fixator,24 cases with anterior open reduction and internal fixation,10 cases with posterior open reduction and internal fixation,and 6 cases with combined anterior and posterior fixation.The timing of surgery was 1 to 15 days after injury,with an average of 3.l days.The volume of blood transfused in the control group during surgery was 200 to 4000 ml,with an average of 1 707.1 ml.There was a significant difference between the two groups in intraoperative blood transfusion(Z=-2.330,P=0.020).The MIPHF group had 10 (16.4％) cases of early serious complications and the control group had 22 (31.9％) cases,which had a significant difference (x2=4.187,P=0.041).According to the criteria proposed by Matta et al.,the good rate of results for treating fractures was 82.0％ in the MIPHF group and 60.9％ in the control group,which got a significant difference (x2=6.967,P=0.008).The MIPHF group and the control group also differed significantly in their mean long-term Cole scores (27.2±4.0 versus 25.1 ±5.6,t=2.457,P=0.015).Conclusion MIPHF,which reflects the DCO concept,may be recommended as pre-hospital first-aid care for patients with pelvic fracture because it can lessen bleeding and prevent secondary pelvic injury,thus reduce case fatality rate and the incidence of complications.It can also improve the success rate of treating pelvic fracture,which will positively affect long-term outcomes.

Huacao Community Health Service Center has established an integrated chronic kidney disease (CKD) management system since 2015,which greatly improved CKD management in the community.From September 2016 to August 2017,4084 residents were screened by the family doctor team,975 were suspected to have CKD (23.87％),among whom 202 (20.72％) were referred to district CKD treatment center,and 197 (97.52％) were confirmed as CKD.The detection rate of suspected CKD among patients with hypertension and diabetes mellitus was the highest,which was much higher than that among outpatients and those with routine health check up.It is suggested that the integrated management of CKD should be widely implemented to cope with the prevalence of CKD,particularly for those with hypertension and diabetes.

Objective To observe the alteration and clinical significances of blood coagulation indicators in patients with lymphoplasmacytic lymphoma (LPL). Methods Twenty patients who were newly diagnosed LPL in the First People's Hospital of Changzhou from January 2008 to October 2017 and twenty healthy controls were studied. The patients were treated by chemotherapy, plasma exchange, supplement of coagulation factor or other supportive therapy. The parameters of prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), D-dimer (D-D), and platelet count (Plt) were detected in LPL group and healthy controls. Results The levels of PT and APTT in LPL group were dramatically higher than those in control group [(12.9±1.2) s vs. (11.6±0.9) s, (41.7±9.8) s vs. (24.7±2.9) s], and the level of Plt in LPL group was lower than that in control group [112×109/L (3×109/L - 379×109/L) vs. 210×109/L (170×109/L - 271×109/L)], and the differences were statistically significant (all P< 0.05). There were no significant differences in FIB, TT and D-D levels between LPL group and control group (all P ＞0.05). There were no statistical differences in PT, APTT, FIB, TT, D-D and Plt levels among LPL patients with different types of immunoglobins (all P ＞ 0.05). After treatment, all the coagulation abnormalities got relieved and no patient died of hemorrhage or thrombosis. Conclusions The LPL patients have coagulation disorders and hypercoagulability, and this is independent of the type of immunoglobulin. Clinical attention should be paid to monitoring coagulation indicators to prevent the occurrence of adverse reactions.