Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Objective To provide evidence for the presence of the lower body fascia chain. Methods Totally 20 cases of Chinese adult femur were selected, and the anatomy was performed to observe the continuity on fascia between periosteal fascia and iliotibial tract (ITT). Judging the generic character and the degree of continuity of them. If there was a significant anatomical continuity between them, the tensile strength of the structure is tested by applying a certain tension to both. Results First, an indirect link between the iliotibial tract and the fibular myofascial fascia was found: in all anatomical lower extremity specimens, the iliotibial bundle (ITT) was structurally connected to the fascial fascia, which was almost inseparable from the fibular fascia. Second, the application of tension to the iliotibial tract (ITT) could cause local movement between the fascia of the calf and the periosteal fascia. Conclusion Iliotibial tract and fibular long muscle fascia are connected firmly. The stability of the connection suggests that it may play a role in the conduction of a certain tension.

ObjectiveTo investigate the effect of imperatorin on liver damage， peroxidative stress and immune response in young rats with type I diabetes induced by streptozotocin （STZ）. MethodsTotally 50 BALB/c juvenile mice were equally divided into healthy control group， model group， model plus+3 mg/kg Imperatorin group， model+6 mg/kg Imperatorin group， and model+12 mg/kg Imperatorin group. Glucose tolerance test was used to detect fasting blood glucose， serum insulin and obesity index of mice in each group. Automatic biochemical analyzer was used to determine serum HDL， LDL， TG， TC content. HE staining was used to observe the degree of liver damage. TUNEL staining was used to observe cell apoptosis. SOD and MDA levels were detected by Kit， Box/Bcl-2， cleaved cas3/cas3， c-Myc expression levels in mitochondria by Western blot， and serum IL-6， TNF-α， IL-1β levels by ELISA. ResultsCompared with the model group， 12 mg/kg Imperatorin significantly reduced fasting blood glucose ［mean difference 5.3 mmol/L， 95% confidence interval （4.5， 6.1） mmol/L］， serum insulin ［mean difference 13.2 μU/L， 95% confidence interval （10.6， 15.8） μU/L］ and obesity index ［average difference 2.3 kg/m²， 95% confidence interval （2.1， 2.5） kg/m²］ all decreased. The content of SOD increased （P<0.05）， while the content of MDA was reduced （P<0.05）. The expression level of Bax/Bcl-2， and cleaved cas3/cas3 was down-regulated （P<0.05）， while the level of c-Myc was up-regulated （P<0.05）， and the content of IL-6， TNF-α and IL-1β was reduced （P<0.05）. ConclusionImperatorin can alleviate the liver damage， peroxidation and immune response in young rats with STZ-induced type I diabetes.

OBJECTIVETo analyze changes in gene amplification in the mitochondrial genome and in the ID4 gene promoter methylation region in patients with chronic aplastic anemia (CAA) suffering from Kidney (Shen) yin deficiency or Kidney yang deficiency.

METHODSBone marrow and oral epithelium samples were collected from CAA patients with Kidney yin deficiency or Kidney yang deficiency (20 cases). Bone marrow samples were collected from 20 healthy volunteers. The mitochondrial genome was amplified by polymerase chain reaction (PCR), and PCR products were used for sequencing and analysis.

RESULTSHigher mutational rates were observed in the ND1-2, ND4-6, and CYTB genes in CAA patients suffering from Kidney yin deficiency. Moreover, the ID4 gene was unmethylated in bone marrow samples from healthy individuals, but was methylated in some CAA patients suffering from Kidney yin deficiency (positive rate, 60%) and Kidney yang deficiency (positive rate, 55%).

CONCLUSIONSThese data supported that gene mutations can alter the expression of respiratory chain enzyme complexes in CAA patients, resulting in energy metabolism impairment and promoting the physiological and pathological processes of hematopoietic failure. Functional impairment of the mitochondrial respiration chain induced by gene mutation may be an important reason for hematopoietic failure in patients with CAA. This change is closely related to maternal inheritance and Kidney yin deficiency. Finally, these data supported the assertion that it is easy to treat disease in patients suffering from yang deficiency and difficult to treat disease in patients suffering from yin deficiency.

Adult ; Anemia, Aplastic ; genetics ; Base Sequence ; Biopsy ; Bone Marrow ; pathology ; Case-Control Studies ; Child ; Chronic Disease ; DNA Methylation ; genetics ; DNA, Mitochondrial ; genetics ; Electrophoresis, Agar Gel ; Female ; Genome, Mitochondrial ; genetics ; Humans ; Inhibitor of Differentiation Proteins ; genetics ; Kidney ; pathology ; Male ; Middle Aged ; Mutation ; genetics ; Polymorphism, Genetic ; Promoter Regions, Genetic ; genetics ; Yin Deficiency ; genetics ; Young Adult

OBJECTIVETo investigate the mRNA and protein expression of nucleostemin (NS) in human esophageal squamous cell carcinoma.

METHODSThe mRNA and protein expression of NS were detected in 31 mucosal atypical hyperplasia specimens, 62 esophageal squamous cell carcinoma specimens and the matched normal esophageal mucosa samples by RT-PCR and immunohistochemistry method, respectively.

RESULTSThe positive expression rate of NS protein in normal esophageal mucosa, atypical hyperplasia and esophageal squamous cell carcinoma was 17.7% (11/62), 41.9% (13/31) and 69.4% (43/62), respectively. There was a significant difference among the above three groups (chi2 = 33.676, P < 0.01). The expression levels of NS mRNA in esophageal squamous cell carcinoma (0.971 +/- 0.121) was significantly higher than that in the atypical hyperplasia (0.913 +/- 0.085) and also in the normal esophageal mucosa (0.866 +/- 0.103; F = 14.829, P < 0.01). The expression level of both NS protein and mRNA was positively correlated with histological grade, infiltration depth, and lymph node metastasis (P < 0.05), but not with age, gender or pathological type (P > 0.05).

CONCLUSIONOur results indicate that nucleostemin mRNA and protein are over-expressed in human esophageal squamous cell carcinoma, and it may be related with its oncogenesis.

Carcinoma, Squamous Cell ; metabolism ; pathology ; Carrier Proteins ; biosynthesis ; genetics ; Esophageal Neoplasms ; metabolism ; pathology ; Esophagus ; pathology ; Female ; GTP-Binding Proteins ; Gene Expression Regulation, Neoplastic ; Humans ; Hyperplasia ; Lymphatic Metastasis ; Male ; Middle Aged ; Mucous Membrane ; metabolism ; Neoplasm Invasiveness ; Neoplasm Staging ; Nuclear Proteins ; biosynthesis ; genetics ; Precancerous Conditions ; metabolism ; pathology ; RNA, Messenger ; metabolism

OBJECTIVETo investigate the changes of hair dermal papilla and its regulatory role in the growth cycle of the hair follicles.

METHODSSingle hair follicles were isolated from surgical specimens of human scalp and cultured in Williams E medium. The growth of the hair follicle was measured and the morphology and structure of the dermal papilla in the different growth cycles were observed continuously.

RESULTSThe hair follicle could grow in the medium for 12 days at the average growth rate of 0.2-0.3 mm/day. The flat and round dermal papilla lay at the bottom of the hair bulb in the telogen and anagen stages. In the hair follicle with accelerated growth, the dermal papilla became elongated, loosened, and closely adhered to the hair matrix. In the catagen stage the dermal papilla shrunk, and became separated from the hair matrix. A new hair bulb was regenerated when the hair follicle was transected at a low level. The hair follicle stopped growing after transection at a higher position.

CONCLUSIONThe hair dermal papilla is the essential for hair follicle growth, and plays an important role in regulating the hair growth cycle.

Dermis ; cytology ; growth & development ; Hair ; growth & development ; Hair Follicle ; cytology ; growth & development ; Humans ; Tissue Culture Techniques

Objective To evaluate the efficacy and safety of a fixed dose combination of telmisartan 80 mg plus hydrochlothiazide(HCTZ)12.5 mg(TH)to telmisartan 80 mg(T)in Chinese patients who failed to respond adequately to treatment with T.Method This is a multi-center, randomized, doubleblind, double-dummy clinical study.A total of 699 eligible hypertensive patients entered a one-week screening phase prior to the eight-week open-label T period.At the end of eight weeks,345 patients who failed to respond to T(DBP≥90 mm Hg,1 mm Hg=0.133 kPa)were randomized to receive either TH (175 patients)or T(170 patients)for another eight weeks.Sitting and standing BP were taken 24 hours post-dose and adverse events were documented at visit with 4 weeks interval.Laboratory.ECG and physical examination were performed at screening.at baseline and at the final visit.Results After 8 weekstreatment,(1)The mean trough reduction in sitting diastolic blood pressure(SiDBP)from baseline in TH group was greater than that in T group(10.1 mm Hg vs 7.7 mm Hg,P=0.0017).The mean trough reduction in sitting systolic blood pressure(SiSBP)from baseline was 14.2 mm Hg in TH group and 7.4 mm Hg in T group(P＜0.0001).(2)The mean trough reduction in standing DBP and standing SBP from baseline were significantly greater in TH group(8.7 mm Hg and 12.9 mm Hg)compared those in T group (7.3 mm Hg and 7.0 mmHg,P=0.0350,P＜0.0001).(3)The number and percentage of responders in TH group(129,74.6%)were significantly higher than in T group(100,59.2%,P=0.0016).(4)The incidence of the study drug-related adverse events was similar between TH and T group(3.5%vs.3.6%,P＞0.05).Conclusion TH was more effective than T in patients not responded adequately to T in Chinese hypertensive patients.

OBJECTIVETo analyze the epidemiology of methicillin resistant Staphylococcus aureus (MRSA) in molecular level in burn centre of Shanghai Ruijin hospital.

METHODSThe vicissitude of Staphylococcus aureus in the burn centre from 2003 to 2005 was analyzed with software WHONET5. Multiprimer random amplified polymorphic DNA(RAPD) was used to analyze the homology of 17 MRSA strains.

RESULTSRAPD analysis (primer ERIC2 and RAPD7) showed that all 17 MRSA strains were identical (Burn-A type).

CONCLUSIONMRSA with same RAPD type is prevalent in our burn centre for many years, so emphasis should be laid on the anti-infection therapy and its cross infection control. Staphylococcus aureus;

Burn Units ; Humans ; Methicillin-Resistant Staphylococcus aureus ; drug effects ; genetics ; isolation & purification ; Microbial Sensitivity Tests ; Random Amplified Polymorphic DNA Technique ; Sequence Homology ; Staphylococcal Infections ; drug therapy ; microbiology

UNLABELLEDOBJECTIVE To study the clinicopathologic features, radiologic findings, treatment modalities and prognosis of dysembryoplastic neuroepithelial tumor (DNT).

METHODSThe clinical features, histopathologic findings, immunohistochemistry and electron microscopy of 18 cases of DNT were analyzed. Results Among the 18 cases studied, 14 were males and 4 females. The age of these patients ranged from 3 to 46 (mean age = 22. 8 years). Partial seizure was the main presenting symptom in all patients. The history of epilepsy could be as long as 17 years. On magnetic resonance imaging (MRI) study, the tumor was hypodense on T1 and hyperdense on T2. There was neither edema nor mass effect. All but 2 cases were supratentorial and intracortical in location. Ten cases were treated by complete surgical excision and the remaining 8 tumors were partially excised. In the 14 patients with follow-up data available, 13 survived for 1.4 to 11 years after the operation (with more than 10 years survival observed in 2 patients). The average survival period was 5.5 years. None of the cases showed tumor recurrence after operation. Histologically, all tumors demonstrated a multinodular architecture and were intracortical in location, sometimes with extension into the white matter. The characteristic "glioneuronal constituent" was an essential feature for making the diagnosis of DNT. The tumor was formed by an admixture of oligodendrocyte-like cells, mature neurons and astrocytes, with obvious microcystic changes. These neurons were often dispersed singly in the mucoid matrix. In most cases, the foci of cortical dysplasia were found in adjacent areas. Immunohistochemical study demonstrated positivity for synaptophysin, neurofilament and S-100 protein in the neurons and some oligodendrocyte-like cells. The staining of glial fibrillary acidic protein in the oligodendrocyte-like cells was negative. Electron microscopy showed early neuronal, astrocytic and oligodendroglial differentiation of the oligodendrocyte-like cells.

CONCLUSIONSDNT is a benign tumor (corresponding to WHO grade I) that can be cured by surgical excision, despite sometimes incomplete tumor removal. A correct diagnosis of this entity requires thorough understanding of the clinical, radiologic, histologic and immunohistochemical features.

Adolescent ; Adult ; Brain Neoplasms ; metabolism ; pathology ; surgery ; Cerebral Cortex ; pathology ; surgery ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Male ; Middle Aged ; Neoplasms, Neuroepithelial ; metabolism ; pathology ; surgery ; Neurofilament Proteins ; metabolism ; Oligodendroglia ; pathology ; ultrastructure ; S100 Proteins ; metabolism ; Survival Rate ; Synaptophysin ; metabolism

AIMTo investigate the neural network and cellular mechanisms of hippocampal epileptogenesis contralateral or ipsilateral to the side of acute tetanization (60 Hz, 2 s, 0.4 - 0.6 mA) of the posterior dorsal hippocampus (ATPDH).

METHODS10 trains of the ATPDH were administered into the CA1 basal dendritic region of the right hemisphere at an interval of 10 minutes.

RESULTS(1) The firing rate of CA1 single neuron in the right or the left hippocampus was inhibited respectively after the ATPDH, and the effects weakened gradually while the trains of the ATPDH increased. The inhibited firing rate and the transformed firing pattern from tonic one to clonic one were more obvious at the side contralateral to the stimulation (62.94% +/- 3.68%, 36.61% +/- 3.14%, P < 0.01). (2) Synchronous primary afterdischarges of depth EEG and single unit discharges were more commonly observed at the side ipsilateral to the ATPDH (P < 0.01). (3) Primary or secondary hippocampal network afterdischarges at high frequency were only found in CA1 region ipsilateral to the ATPDH. (4) Secondary afterdischarges of CA3 basal dendritic neural network were completely synchronized with those of subicular single neuron, which reoccurred and persisted several hours.

CONCLUSIONIt is possible that post-inhibition bursting of single neuron and recurrent network seizures in the hippocampus contralateral to the artificial focus be the important manifestation of the formation of "epileptic networks" across from one hemisphere to another.

Animals ; Electric Stimulation ; Hippocampus ; physiology ; Male ; Neural Pathways ; physiology ; Rats ; Rats, Sprague-Dawley ; Seizures ; etiology