Miracle-dz/UniFAR-FTUs huggingface dataset:
Alpha fetoprotein mediates HBx induced carcinogenesis in the hepatocyte cytoplasm

Although tumor‐associated fetal protein AFP has demonstrated utility as a clinical tumor marker, the significance of intracellular AFP is still unclear. The aim of this study was to explore the role of cytoplasmic AFP during HBx induced carcinogenesis, which had not previously been recognized; 614 HCC patients were analyzed for correlation of HBV infection with AFP level, and much higher AFP levels were found in HBsAg positive patients. Tumor tissue specimens from 20 HCC patients were used for analysis of AFP and GADD45α. Analysis of HCC specimens showed that upregulation of cytoplasmic AFP is associated with down‐regulation of GADD45α in neoplastic tissue. Transfected HBx promotes transcription of AFP by acting on the elements in the AFP gene regulatory region. HBx itself did not directly impact transcription of GADD45α. However, the obstruction of RAR signaling by HBx induced elevation of AFP, which led to down‐regulation of GADD45α. Cytoplasmic AFP was able to interact with RAR, disrupting its entrance into the nucleus and binding to the elements in the regulatory region of the GADD45α gene. Knockdown of AFP in siRNA‐transfected AFP positive cell lines was synchronously associated with an incremental increase of RAR binding to DNA, as well as upregulation of GADD45α and it was contrary in AFP gene‐transfected AFP negative cell lines. These results indicate cytoplasmic AFP is not only a histochemical tumor biomarker for human hepatoma but is also an intracellular signal molecule and potential participant in HBx induced hepatocarcinogenesis.
The brain activity related to residual motion vision in a patient with bilateral lesions of V5.

We have used the technique of PET to chart the cortical areas activated by visual motion in the brain of a patient with a severe impairment in the ability to recognize the motion of objects (akinetopsia), following bilateral lesions which have so far been presumed to include area V5. High resolution MRI of her brain showed that the zone occupied by area V5 had indeed been destroyed bilaterally. Positron emission tomography activation images, co-registered to the MRIs, showed three principal regions of the cortex activated by motion. These were located (i) bilaterally in the precuneus of superior parietal cortex (area 7 of Brodmann); (ii) bilaterally in the cuneus (a region considered to represent upper V3); (iii) in the left lingual and fusiform gyri (possibly lower V3 and adjacent areas). In contrast to normal subjects, there was no significant activation of area V1 or V2. The stimuli used for scanning were chosen by prior testing of the patient's visual capacities. The control stimulus was a static random distribution of light squares on a dark background. In the moving stimulus these squares moved coherently, the direction of motion changing periodically between the cardinal directions (left, right, up and down). It was ascertained that the patient could correctly identify these directions. We also found (i) that her occasional errors were always in the direction opposite to the motion presented, so that her identification of axis of motion (i.e. vertical or horizontal) was 100% correct; (ii) that when a few static squares were added to the moving the display her identification of direction fell to chance but her identification of the axis of motion remained 100%; (iii) that when a few squares moving opposite and orthogonal to the predominant direction of motion were incorporated, her performance on both direction and axis fell to chance; (iv) that she was unable to identify motion in oblique directions between the horizontal or vertical axes, always guessing one of the cardinal directions. In accounting for her residual vision in terms of cortex, which remains active, we hypothesize; (i) that the bilateral loss of V5 has affected direction sensitive mechanisms at other sites in the cortex which are interconnected with V5 and (ii) that in consequence her performance on our tests reflects the properties of dynamic orientation selective mechanisms that were also differentially activated by the stimuli used during scanning.
Cyclosporine A-resistant human immunodeficiency virus type 1 mutants demonstrate that Gag encodes the functional target of cyclophilin A

The cellular peptidyl-prolyl isomerase cyclophilin A is incorporated into human immunodeficiency virus type 1 virions via contacts with the proline-rich domain of the Gag polyprotein. Cyclosporine A and nonimmunosuppressive analogs bind with high affinity to cyclophilin A, compete with Gag for binding to cyclophilin A, and prevent incorporation of cyclophilin A into virions; in parallel with the disruption of cyclophilin A incorporation into virions, there is a linear reduction in the initiation of reverse transcription after infection of a T cell. Passage of human immunodeficiency virus type 1 in the presence of the drug selects one of two mutations, either of which alters the proline-rich domain of Gag and is sufficient to confer drug resistance on the cloned wild-type provirus. Neither mutation alters Gag's cyclophilin A-binding properties in vitro, and cyclophilin A incorporation into drug-resistant virions is effectively disrupted by cyclosporine A, indicating that the drug-resistant mutants do not require virion-associated cyclophilin A to initiate infection. That Gag's functional dependence on cyclophilin A can be differentiated genetically from its ability to bind cyclophilin A is further demonstrated by the rescue of a mutation precluding cyclophilin A packaging by a mutation conferring cyclosporine A resistance. These experiments demonstrate that, in addition to its ability to package cyclophilin A into virions, gag encodes the functional target of cyclophilin A.
Coordination of synaptic vesicle trafficking and turnover by the Rab35 signaling network

ABSTRACT Rab35 and the Rab35 network of GAPs, GEFs, and effectors are important regulators of membrane trafficking for a variety of cellular processes, from cytokinesis and phagocytosis to neurite outgrowth. In the past five years, components of this signaling network have also been implicated as critical mediators of synaptic vesicle (SV) recycling and protein homeostasis. Recent studies by several groups, including our own, have demonstrated that Rab35-mediated endosomal sorting is required for the degradation of SV proteins via the ESCRT pathway, thereby eliminating old or damaged proteins from the SV pool. This sorting process is regulated by Rab35 activation in response to neuronal activity, and potentially by an antagonistic signaling relationship between Rab35 and the small GTPase Arf6 that directs SVs into distinct recycling pathways depending on neuronal activity levels. Furthermore, mutations in genes encoding Rab35 regulatory proteins are emerging as causative factors in human neurologic and neurodegenerative diseases, consistent with their important roles in synaptic and neuronal health. Here, we review these recent findings and offer our perspective on how the Rab35 signaling network functions to maintain neurotransmission and synaptic fitness.
Direct intramuscular fetal or maternal antenatal corticosteroid therapy: short-time effects on fetal behavior and oxygenation: a comparative study

Abstract Objective: To compare the effects of antenatal administration of corticosteroids used in two different regimens, on fetal biophysical profile (BPP), baseline fetal heart rate (BFHR), nonstress test (NST) and perinatal outcomes. Study design: We evaluated the effects of single direct intramuscular (i.m.) fetal dose of dexamethasone (4 mg/kg), or four doses of 6 mg dexamethasone given to the mother 12 hours apart on the parameters of fetal BPP 0–4 hours before and after antenatal contraction stress (ACST). We evaluated two groups of 41 fetuses in the 31st gestation week at risk of fetal hypoxia at the Department of Gynecology/Obstetrics, Clinical Center of Serbia in 2013. Results: In fetal ACST group, we found significantly different changes in fetal breathing movement before (D0-f) and after therapy (D1-f), p = 0.019 (−11.75; −1.12), 95% confidence interval (CI), as well as in the maternal ACST group, p = 0.001; (−11.75; −1.12), 95% CI. We found significant difference between BPP 0-m and BPP1-m in the maternal group, p = 0.000. Neonatal asphyxia occurred more often with the increased frequency of fetal breath movements after both ACST (p = 0.04 versus p = 0.07). Conclusion: Fetal ACST results in increased fetal breathing movements. Maternal ACST can result in changes to BPP. The increase in fetal breathing movements determinates neonatal asphyxia regardless of the ACST.
Biochemistry students' ideas about how an enzyme interacts with a substrate

Enzyme‐substrate interactions are a fundamental concept of biochemistry that is built upon throughout multiple biochemistry courses. Central to understanding enzyme‐substrate interactions is specific knowledge of exactly how an enzyme and substrate interact. Within this narrower topic, students must understand the various binding sites on an enzyme and be able to reason from simplistic lock and key or induced fit models to the more complex energetics model of transition state theory. Learning to understand these many facets of enzyme‐substrate interactions and reasoning from multiple models present challenges where students incorrectly make connections between concepts or make no connection at all. This study investigated biochemistry students' understanding of enzyme‐substrate interactions through the use of clinical interviews and a national administration (N = 707) of the Enzyme–Substrate Interactions Concept Inventory. Findings include misconceptions regarding the nature of enzyme‐substrate interactions, naïve ideas about the active site, a lack of energetically driven interactions, and an incomplete understanding of the specificity pocket. © 2015 by the International Union of Biochemistry and Molecular Biology, 43(4):213–222, 2015.
Kinetic model optimization for characterizing tumour physiology by dynamic contrast-enhanced near-infrared spectroscopy

Dynamic contrast-enhanced (DCE) methods are widely used with magnetic resonance imaging and computed tomography to assess the vascular characteristics of tumours since these properties can affect the response to radiotherapy and chemotherapy. In contrast, there have been far fewer studies using optical-based applications despite the advantages of low cost and safety. This study investigated an appropriate kinetic model for optical applications to characterize tumour haemodynamics (blood flow, F, blood volume, Vb, and vascular heterogeneity) and vascular leakage (permeability surface-area product, PS). DCE data were acquired with two dyes, indocyanine green (ICG) and 800 CW carboxylate (IRDcbx), from a human colon tumour xenograph model in rats. Due to the smaller molecular weight of IRDcbx (1166 Da) compared to albumin-bound ICG (67 kDa), PS of IRDcbx was significantly larger; however, no significant differences in F and Vb were found between the dyes as expected. Error analysis demonstrated that all parameters could be estimated with an uncertainty less than 5% due to the high temporal resolution and signal-to-noise ratio of the optical measurements. The next step is to adapt this approach to optical imaging to generate haemodynamics and permeability maps, which should enhance the clinical interest in optics for treatment monitoring.
Impact of adding Level II and III trauma centers on volume and disease severity at a nearby Level I trauma center

BACKGROUND As emergency care becomes increasingly regionalized, systems planners must determine how system expansion impacts existing system assets. We hypothesized that accrediting new Level II and III trauma centers impacted the trauma patient census and severity at a nearby Level I trauma center and estimated the magnitude of the impact. METHODS We conducted an interrupted time series analysis using monthly patient counts during the past 10 years for five trauma centers located near one another in Pennsylvania. The Level I center (TC-A) operated for the entire period. A Level II center 39 miles away was accredited after 70 months (TC-B), one Level III center 46 miles away was accredited after 95 months but lost accreditation after 11 months (TC-C), and two other Level III centers 40 miles and 45 miles away were accredited after 107 months (TC-D and TC-E). RESULTS Monthly patient volume at the Level I center, which increased gradually over the study and summed to 25,120 patients, decreased by 10.8% (p < 0.05) when TC-B was accredited and decreased by an additional 12.9% (p < 0.05) when TC-D and TC-E were accredited simultaneously. No change stemmed from temporarily accrediting TC-C. Ultimately, the Level I center treated 1,903 fewer patients than expected over 51 months, an 11.9% volume reduction, and patient severity remained consistent but mortality decreased. CONCLUSION Accrediting Level II and Level III trauma centers reduced patient volume and reduced overall mortality at a nearby Level I center. Strategic planning of statewide trauma systems can help balance rapid access to care with maintenance of adequate annual patient volumes of critically injured patients. LEVEL OF EVIDENCE Epidemiologic study, Level IV.
In Vitro and In Vivo Suppression of Osteoclast Function by Adenovirus Vector–Induced csk Gene

The proto‐oncogene c‐src, which encodes a non–receptor‐type tyrosine kinase c‐Src, has been shown to be essential for osteoclastic bone resorption by the finding that the targeted disruption of the c‐src gene induced osteopetrosis in mice. The csk (C‐terminal Src family kinase) gene encodes a cytoplasmic protein‐tyrosine kinase that specifically phosphorylates the negative regulatory site of c‐Src (Tyr‐527), thereby inhibiting its kinase activity. To regulate osteoclast function by modulating the kinase activity of c‐Src, we constructed an adenovirus vector that carries this gene. The recombinant adenovirus vector carrying csk cDNA induced Csk expression in mouse osteoclast‐like cells formed in vitro and clearly reduced c‐Src kinase activity in a dose‐dependent manner. The expression of Csk caused cytoskeletal disorganization of osteoclast‐like cells and strongly suppressed pit‐forming activity of the cells in vitro. In addition, the viral vector carrying csk gene dramatically suppressed interleukin‐1α–induced bone resorption in vivo. Conversely, kinase‐inactive Csk caused an increase in c‐Src kinase activity and bone resorbing activity of the cells both in vitro and in vivo, acting as a dominant negative molecule against intrinsic Csk. These findings indicate that the inhibition of c‐Src activity by adenovirus vector‐mediated csk expression offers an efficient means for inhibiting pathological bone resorption by suppressing osteoclast function.
Diagnosis of functional kidney failure of cirrhosis with Doppler sonography: Prognostic value of resistive index

Time‐velocity wave‐form analysis of Doppler signals from small intrarenal arteries allows estimation of intrarenal arteriolar vascular resistance. Among the various indexes proposed, the resistive index is the most widely used for this estimation. To investigate whether the resistive index is useful in the diagnosis of functional kidney failure and prediction of survival in cirrhotic patients with ascites, we measured resistive index, kidney and liver function and plasma levels of renin, aldosterone and antidiuretic hormone in 10 healthy subjects, 12 patients with compensated cirrhosis and 32 patients with cirrhosis and ascites (17 with kidney failure). A total of 28 clinical and laboratory variables were analyzed for prognostic value. Resistive index was significantly increased in patients with kidney failure (0.74 ± 0.01) compared with those in the other three groups (0.64 ± 0.01, 0.64 ± 0.02 and 0.67 ± 0.01) and correlated significantly with glomerular filtration rate, arterial pressure, plasma renin activity and free water clearance in the cirrhotic patients. The sensitivity and specificity of the resistive index in detecting kidney failure in patients with ascites were 71% and 80%, respectively. Nine variables were correlated with survival in the univariate analysis, including resistive index, age, hepatomegaly, blood urea nitrogen, serum creatinine, plasma sodium concentration, glomerular filtration rate, plasma renin activity and plasma concentration of antidiuretic hormone. Multivariate analysis disclosed only three independent predictors of survival: plasma renin activity, plasma concentration of antidiuretic hormone and serum sodium concentration. In conclusion, resistive index is a sensitive method to assess intrarenal hemodynamics in patients with cirrhosis and ascites. It also has predictive value for survival in these patients. (Hepatology 1994;20:839–844).
Neurogenesis in the human hippocampus and its relevance to temporal lobe epilepsies

Ample evidence points to the dentate gyrus as anatomical region for persistent neurogenesis in the adult mammalian brain. This has been confirmed in a variety of animal models under physiological as well as pathophysiological conditions. Notwithstanding, similar experiments are difficult to perform in humans. Postmortem studies demonstrated persisting neurogenesis in the elderly human brain. In addition, neural precursor cells can be isolated from surgical specimens obtained from patients with intractable temporal lobe epilepsy (TLE) and propagated or differentiated into neuronal and glial lineages. It remains a controversial issue, whether epileptic seizures have an effect on or even increase hippocampal neurogenesis in humans. Recent data support the notion that seizures induce neurogenesis in young patients, whereas the capacity of neuronal recruitment and proliferation decreases with age. Animal models of TLE further indicate that these newly generated neurons integrate into epileptogenic networks and contribute to increased seizure susceptibility. However, pathomorphological disturbances within the epileptic hippocampus, such as granule cell dispersion (GCD), may not directly result from compromised neurogenesis. Still, the majority of adult TLE patients present with significant dentate granule cell loss at an end stage of the disease, which relates to severe memory and learning disabilities. In conclusion, surgical specimens obtained from TLE patients represent an important tool to study mechanisms of stem cell recruitment, proliferation and differentiation in the human brain. In addition, increasing availability of surgical specimens opens new avenues to systematically explore disease pathomechanisms in chronic epilepsies.
Lapatinib inhibits stem/progenitor proliferation in preclinical in vitro models of ductal carcinoma in situ (DCIS)

Breast-conserving surgery for ductal carcinoma in situ (DCIS) is often combined with irradiation, reducing recurrence rates to 20% within 10 years; however, there is no change in overall survival. Evidence in the invasive breast indicates that breast cancer stem cells (CSCs) are radiotherapy-resistant and are capable of re-initiating a tumor recurrence; hence, targeting CSCs in high risk DCIS patient may improve survival. HER2 is overexpressed in 20% of DCIS and is known to be highly active in breast CSCs; we therefore investigated the effect of Lapatinib on DCIS CSC activity using 2 in vitro culture systems. Two DCIS cell lines DCIS.com (HER2 normal) and SUM225 (HER2 overexpressed) as well as DCIS cells from patient samples (n = 18) were cultured as mammospheres to assess CSC activity and in differentiated 3D-matrigel culture to determine effects within the non-CSCs. Mammosphere formation was reduced regardless of HER2 status, although this was more marked within the HER2-positive samples. When grown as differentiated DCIS acini in 3D-matrigel culture, Lapatinib only reduced acini size in the HER2-positive samples via decreased proliferation. Further investigation revealed lapatinib did not reduce self-renewal activity in the CSC population, but their proliferation was decreased regardless of HER2 status. In conclusion we show Lapatinib can reduce DCIS CSC activity, suggesting that the use of Lapatinib in high-risk DCIS patients has the potential to reduce recurrence and the progression of DCIS to invasive disease.
Treatment of Proteinuria with Lercanidipine Associated with Renin-Angiotensin Axis-Blocking Drugs

Objective. Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. Design and Methods. The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 ± 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. Results. BP significantly decreases from 152 ± 15/86 ± 11 mmHg to 135 ± 12/77 ± 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 ± 48 to 192 ± 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 ± 77 to 134 ± 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 ± 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. Conclusions. Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.