Miracle-dz/UniFAR-FTUs huggingface dataset:
Macrocyclic peptides decrease c-Myc protein levels and reduce prostate cancer cell growth

ABSTRACT The oncoprotein c-Myc is often overexpressed in cancer cells, and the stability of this protein has major significance in deciding the fate of a cell. Thus, targeting c-Myc levels is an attractive approach for developing therapeutic agents for cancer treatment. In this study, we report the anti-cancer activity of the macrocyclic peptides [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) and the natural product CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]). [D-Trp]CJ-15,208 reduced c-Myc protein levels in prostate cancer cells and decreased cell proliferation with IC50 values ranging from 2.0 to 16 µM in multiple PC cell lines. [D-Trp]CJ-15,208 induced early and late apoptosis in PC-3 cells following 48 hours treatment, and growth arrest in the G2 cell cycle phase following both 24 and 48 hours treatment. Down regulation of c-Myc in PC-3 cells resulted in loss of sensitivity to [D-Trp]CJ-15,208 treatment, while overexpression of c-Myc in HEK-293 cells imparted sensitivity of these cells to [D-Trp]CJ-15,208 treatment. This macrocyclic tetrapeptide also regulated PP2A by reducing the levels of its phosphorylated form which regulates the stability of cellular c-Myc protein. Thus [D-Trp]CJ-15,208 represents a new lead compound for the potential development of an effective treatment of prostate cancer.
Dexamethasone exacerbates cytotoxic chemotherapy induced lethargy and weight loss in female tumor free mice

ABSTRACT Cytotoxic chemotherapy can induce a systemic inflammatory response which has been proposed to be an underlying mechanism of cancer treatment related fatigue. Dexamethasone, a synthetic glucocorticoid that has potent anti-inflammatory effects, is incorporated into chemotherapy regimens to prevent chemotherapy-induced nausea and vomiting (CINV). The purpose of this study was to determine whether by suppressing cytotoxic chemotherapy-induced inflammation, dexamethasone could ameliorate chemotherapy induced fatigue/lethargy in tumor free mice. The effect of dexamethasone (DEX) on Cytoxan-Adriamycin (CA)-induced inflammation was assessed by measuring circulating levels of IL-1β, TNF-α, IL-6, GCSF, KC, and MCP-1 twenty-four-hours post CA injection. Decline in voluntary wheel running activity (VWRA) from baseline (used as a proxy for fatigue/lethargy), body weight and composition, and food intake were monitored in mice administered four cycles of CA every two weeks with or without DEX. CA increased circulating levels of IL-6, GCSF, KC, and MCP-1 and caused a rapid decline in VWRA and body weight immediately following CA-injection. Although the acute CA-induced decline in VWRA and body weight was not evident in mice administered CA + DEX, DEX alone had a suppressive effect on VWRA, and body weight continued to decline in mice administered both CA and DEX while it returned to baseline in CA-treated mice. CA or DEX alone had no long term impact on VWRA but DEX exacerbated lethargy and weight loss in CA-treated mice. Despite dampening the systemic inflammatory response to chemotherapy, dexamethasone failed to ameliorate acute or long term chemotherapy related fatigue/lethargy. Our pre-clinical findings suggest that supportive therapies like dexamethasone used to acutely control nausea and vomiting in cancer patients may actually contribute to overall symptom burden in cancer patients.
Micro-RNA149 confers taxane resistance to malignant mesothelioma cells via regulation of P-glycoprotein expression

ABSTRACT Multidrug resistance (MDR) represents a major hindrance to the efficacy of cancer chemotherapeutics. While surgical resection, radiation, and chemotherapy can be used to reduce tumor size, the subsequent appearance of drug resistant cells is a frequent problem. One of the main contributors to the development of MDR is increased expression of multi-drug resistant protein 1 (MDR1), also known as P-glycoprotein (P-gp). P-gp is a membrane-associated efflux pump that can efficiently remove internalized taxane-base chemotherapeutics thus preventing drug accumulation and maintaining cellular viability. Consequently, investigation into the molecular mechanisms responsible for regulation of P-gp expression is necessary to facilitate treatment of MDR tumors. Using molecular and biochemical approaches, we identified that the micro-RNA, miRNA149, contributes to the development of MDR within malignant mesothelioma cells by regulating the expression of MDR1.
ATLAS OF BLOOD CELLS

Itstructional Course LeLtures. Volume XVI. 1959. American Academy of Orthopaedic Surgeons. Editor Fred C. Reynolds, M.D. (Pp. 335; illustrated. £6.) St. Louis, Missouri: C. V. Mosby Company. 1959. This is the sixteenth volume of selected lectures given at the instructional -courses sponsored by the American Academy of Orthopaedic Surgery. The publication of these lectures, inaugurated by Dr. J. E. M. Thomson, was assured of success from the beginning of 1943. This volume includes a symposium on injuries to athletes, selected lectures on the hand, foot, and knee, unequal extremities, and the spine, with a section on fractures largely devoted to the use of a prosthesis for the treatment of fresh fractures of the femoral neck. The editor has chosen subjects of contemporary interest, and each lecture is of sutficient importance to be read as an entity, for the volumes are not intended to form a textbook. The treatment of claw hand is described, use being made of various tendon transfers developed by Bunnell, Fowler, and others for paralytic conditions. For Dupuytren's contracture subcutaneous fasciotomy under local analgesia is favoured. The conservative and operative treatment of club foot is discussed. " Medial release" is advised when failure of closed methods is recognized, and this is advocated between the ages of 31 and 5{. The long article on the role of subtalar fusion in the treatment of valgus deformity of the foot is full of information. The author uses bone grafts, holding that this procedure is useful for the growing child to maintain an arch while the foot develops, and he appreciates that triple arthrodesis is required in some feet later. A lecture on electromyography in orthopaedic surgery should be read. The symposium on the treatment of fresh fractures of the neck of the femur reports the experience at eight clinics. with an excellent summary by Dr. J. E. NI. Thomson. Stewart has experience of 300 and Moore of 135 operations for fresh fracture using a prosthesis. The general feeling appears to be that results are encouraging, particularly when Moore's vitallium prosthesis is employed, but that experience is still instilficient to advocate definite indications for the procedure. The 260 excellent illustrations are well chosen from radiographs, photographs, and line drawings. These lectures will be invaluable to the postgraduate student.
A MC tool for CT-based calculations of dose delivery and activation in proton therapy

The feasibility and value of offline PET/CT imaging for in-vivo, non-invasive verification of proton beam delivery is currently under investigation at Massachusetts General Hospital, Boston. Within this project we have developed a Monte Carlo framework for CT-based calculation of dose and irradiation induced positron emitter distributions using the FLUKA Monte Carlo code. Particle transport in the patient is performed on the CT grid, taking into account realistic tissue composition as well as the correlation between CT numbers and stopping power ratio to water as used by the commercial treatment planning system (XiO, Computerized Medical System Inc.). Positron emitter production is computed by combining during runtime proton fluence with experimental and evaluated cross-sections for all the major reaction channels yielding measurable tissue activation. In this paper we describe our dedicated implementation which might be easily generalised for use in other proton therapy centres or extended to include further activation reaction channels, provided that initial beam information or experimental cross sections are known. Further, we present clinical examples for calculation of delivered dose and irradiation induced PET activation.
The "Emphatic Narrative": A New Tool for Obesity Treatment

The historical change in the role of the nutritionist has been from that of mainly treating malnourishment to that of mainly treating chronic disease and health promotion. Dietary intervention may be both cost-effective and acceptable for patients. It is clear that behavioral changes such as change in diet, loss of weight, physical activity, and smoking cessation positively affect health outcomes; however, it is not yet clear as how to achieve and maintain those changes. The professional challenge is not only to teach patients what to eat but also to persuade them to change their dietary habits on a long-term basis. Nitche, as quoted by Frankl, best described this idea by saying: ‘‘One should have reasonably good ‘why’ to overcome the many difficulties of the ‘how. ’ ’’ The ‘‘empathic narrative’’ allows the patient to internalize and accept the need to change, and it also emphasizes the reason why. This step is crucial in overcoming the many obstacles to change that we are so familiar with in the field of changing eating habit and disorders.
Natural killer inhibitory receptor expression associated with treatment failure and interleukin‐28B genotype in patients with chronic hepatitis C

Natural killer (NK) cells constitute a first line of defense against viral infections; their function is governed by the integration of signals from multiple activating and inhibitory surface receptors. We hypothesized that because NKs become rapidly activated by cytokines, response to anti‐hepatitis C virus (HCV) therapy would be predicted by the phenotype and function of NKs. We used a cohort of 101 patients (55 African, 46 Caucasian‐American) who received pegylated‐interferon (IFN) and ribavirin for 48 weeks. Multiparameter FACS analysis was used to examine relative expression of 14 different inhibitory/activating receptors. Interleukin (IL)‐28B genotyping (rs12979860) was also performed. Pretreatment levels of inhibitory receptors CD158a, CD158b, and CD158e were higher in patients who demonstrated poor viral decline within the first 28 days of therapy. Higher expression levels of inhibitory receptors NKG2A, CD158b, and CD158e were demonstrable in patients who failed to achieve sustained virologic response (SVR). Patients carrying the IL‐28B T allele had higher NKG2A expression on effector NKs. We created a mathematical regression model incorporating race, viral level, and two inhibitory receptors. The area‐under‐the curve was 0.88, which is highly predictive of SVR. Moreover, the model performed complementarily with IL‐28B across the CC, CT, and TT genotypes. Purified NKG2Aneg NKs treated with pegylated‐IFN‐α for 4 hours demonstrated higher levels of IFN‐γ‐inducible protein‐10 (IP‐10) and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) compared with their NKG2Apos counterparts. Conclusions: These results provide novel insights into the associations of NK phenotype with IL‐28B genotype and gene expression patterns, as well as the role of NKs in mediating IFN‐induced viral clearance of chronic HCV infection. (HEPATOLOGY 2011;)
Kinetics of inhibition of acetylcholinesterase in the presence of acetonitrile

The hydrolysis of acetylthiocholine by acetylcholinesterase from Electrophorus electricus was investigated in the presence of the inhibitors tacrine, gallamine and compound 1. The interaction of the enzyme with the substrate and the inhibitors was characterized by the parameters KI, α′, b or β, Km and Vmax, which were determined directly and simultaneously from nonlinear Michaelis–Menten plots. Tacrine was shown to act as a mixed‐type inhibitor with a strong noncompetitive component (α′ ≈ 1) and to completely block deacylation of the acyl‐enzyme. In contrast, acetylcholinesterase inhibition by gallamine followed the ‘steric blockade hypothesis’, i.e. only substrate association to as well as substrate/product dissociation from the active site were reduced in the presence of the inhibitor. The relative efficiency of the acetylcholinesterase–gallamine complex for the catalysis of substrate conversion was determined to be 1.7–25% of that of the free enzyme. Substrate hydrolysis and the inhibition of acetylcholinesterase were also investigated in the presence of 6% acetonitrile, and a competitive pseudo‐inhibition was observed for acetonitrile (KI = 0.25 m). The interaction of acetylcholinesterase with acetonitrile and tacrine or gallamine resulted in a seven‐ to 10‐fold increase in the KI values, whereas the principal mode of inhibition was not affected by the organic solvent. The determination of the inhibitory parameters of compound 1 in the presence of acetonitrile revealed that the substance acts as a hyperbolic mixed‐type inhibitor of acetylcholinesterase. The complex formed by the enzyme and the inhibitor still catalysed product formation with 8.7–9.6% relative efficiency.
MicroRNA‐29b suppresses tumor angiogenesis, invasion, and metastasis by regulating matrix metalloproteinase 2 expression

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent intrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. We previously found that microRNA‐29b (miR‐29b) down‐regulation was significantly associated with poor recurrence‐free survival of HCC patients. Therefore, the role of miR‐29b in tumor angiogenesis, invasion, and metastasis was further investigated in this study using in vitro capillary tube formation and transwell assays, in vivo subcutaneous and orthotopic xenograft mouse models, and Matrigel plug assay, and human HCC samples. Both gain‐ and loss‐of‐function studies showed that miR‐29b dramatically suppressed the ability of HCC cells to promote capillary tube formation of endothelial cells and to invade extracellular matrix gel in vitro. Using mouse models, we revealed that tumors derived from miR‐29b‐expressed HCC cells displayed significant reduction in microvessel density and in intrahepatic metastatic capacity compared with those from the control group. Subsequent investigations revealed that matrix metalloproteinase‐2 (MMP‐2) was a direct target of miR‐29b. The blocking of MMP‐2 by neutralizing antibody or RNA interference phenocopied the antiangiogenesis and antiinvasion effects of miR‐29b, whereas introduction of MMP‐2 antagonized the function of miR‐29b. We further disclosed that miR‐29b exerted its antiangiogenesis function, at least partly, by suppressing MMP‐2 expression in tumor cells and, in turn, impairing vascular endothelial growth factor receptor 2‐signaling in endothelial cells. Consistently, in human HCC tissues and mouse xenograft tumors miR‐29b level was inversely correlated with MMP‐2 expression, as well as tumor angiogenesis, venous invasion, and metastasis. Conclusion: miR‐29b deregulation contributes to angiogenesis, invasion, and metastasis of HCC. Restoration of miR‐29b represents a promising new strategy in anti‐HCC therapy. (HEPATOLOGY 2011;)
Bulk pancreatic cancer cells can convert into cancer stem cells(CSCs) in vitro and 2 compounds can target these CSCs

ABSTRACT Increasing evidence has confirmed the existence of cancer stem cells (CSCs) in both hematological malignancies and solid tumors. However, the origin of CSCs is still uncertain, and few agents have been capable of eliminating CSCs till now. The aim of this study was to investigate whether bulk pancreatic cancer cells could convert into CSCs under certain conditions and explore whether metformin and curcumin can kill pancreatic CSCs. Aspc1, Bxpc3 and Panc1 pancreatic cancer cells were cultured in stem cell culture medium (serum-free Dulbecco's modified Eagle medium/Nutrient Mixture F-12 containing basic fibroblast growth factor, epidermal growth factor, B27 and insulin) for 5 days and it was found that all the pancreatic cancer cells aggregated into spheres and expressed pancreatic cancer stem cell surface markers. Then characteristics of Panc1 sphere cells were analyzed and cytotoxicity assays were performed. The results show that Panc1 sphere cells exhibited CSC characteristics and were more resistant to conventional chemotherapy and more sensitive to metformin and curcumin than their parent cells. These findings suggested that bulk pancreatic cancer cells could acquire CSC characteristics under certain conditions, which may support the “yin-yang” model of CSCs (interconversion between bulk cancer cells and CSCs). These results also showed that metformin and curcumin could be candidate drugs for targeting pancreatic CSCs.
Contributors to Screening Positive for Mental Illness in Lebanon's Shatila Palestinian Refugee Camp

Abstract This study evaluates contributors to the mental health status of Palestinians, Syrians, and nonrefugee residents of Lebanon's Shatila Refugee Camp. Primary health care clinic patients in Shatila were screened for mental illness between 2012 and 2013 using the K6, the Primary Care Posttraumatic Stress Disorder (PTSD), and the Modified Mini International Neuropsychiatric Interview. Logistic regressions enabled the consideration of potential contributors to participants' positive mental illness screens. The sample (n = 254) included 63.4% Palestinians, 18.5% Syrians, and 18.1% nonrefugees. People lived in the camp for 21.1 years (±17), 63% had stable housing and 78% had war event exposure. Mental illness prevalence was 51.6% in total (34.8% serious mental illness [SMI] alone, 5.1% PTSD alone, 11.4% comorbid SMI/PTSD, and 0.08% comorbid psychotic spectrum disorder SMI/PTSD). For Palestinians and nonrefugees, respectively, stable housing accounted for a 79% and a 98% reduction in positive SMI screen risk. For Syrians, access to paid employment accounted for a 66% risk reduction. Stable living situations and economically productive employment for those trapped in a refugee situation, even in the face of war trauma, seem most important for ensuring reduced mental disorder risk.
APOBEC3A damages the cellular genome during DNA replication

ABSTRACT The human APOBEC3 family of DNA-cytosine deaminases comprises 7 members (A3A-A3H) that act on single-stranded DNA (ssDNA). The APOBEC3 proteins function within the innate immune system by mutating DNA of viral genomes and retroelements to restrict infection and retrotransposition. Recent evidence suggests that APOBEC3 enzymes can also cause damage to the cellular genome. Mutational patterns consistent with APOBEC3 activity have been identified by bioinformatic analysis of tumor genome sequences. These mutational signatures include clusters of base substitutions that are proposed to occur due to APOBEC3 deamination. It has been suggested that transiently exposed ssDNA segments provide substrate for APOBEC3 deamination leading to mutation signatures within the genome. However, the mechanisms that produce single-stranded substrates for APOBEC3 deamination in mammalian cells have not been demonstrated. We investigated ssDNA at replication forks as a substrate for APOBEC3 deamination. We found that APOBEC3A (A3A) expression leads to DNA damage in replicating cells but this is reduced in quiescent cells. Upon A3A expression, cycling cells activate the DNA replication checkpoint and undergo cell cycle arrest. Additionally, we find that replication stress leaves cells vulnerable to A3A-induced DNA damage. We propose a model to explain A3A-induced damage to the cellular genome in which cytosine deamination at replication forks and other ssDNA substrates results in mutations and DNA breaks. This model highlights the risk of mutagenesis by A3A expression in replicating progenitor cells, and supports the emerging hypothesis that APOBEC3 enzymes contribute to genome instability in human tumors.
Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion

ABSTRACT Estrogen receptor alpha (ERα) has been implicated in several cell cycle regulatory events and is an important predictive marker of disease outcome in breast cancer patients. Here, we aimed to elucidate the mechanism through which ERα influences proliferation in breast cancer cells. Our results show that ERα protein is cell cycle-regulated in human breast cancer cells and that the presence of 17-β-estradiol (E2) in the culture medium shortened the cell cycle significantly (by 4.5 hours, P < 0.05) compared with unliganded conditions. The alterations in cell cycle duration were observed in the S and G2/M phases, whereas the G1 phase was indistinguishable under liganded and unliganded conditions. In addition, ERα knockdown in MCF-7 cells accelerated mitotic exit, whereas transfection of ERα-negative MDA-MB-231 cells with exogenous ERα significantly shortened the S and G2/M phases (by 9.1 hours, P < 0.05) compared with parental cells. Finally, treatment of MCF-7 cells with antiestrogens revealed that tamoxifen yields a slower cell cycle progression through the S and G2/M phases than fulvestrant does, presumably because of the destabilizing effect of fulvestrant on ERα protein. Together, these results show that ERα modulates breast cancer cell proliferation by regulating events during the S and G2/M phases of the cell cycle in a ligand-dependent fashion. These results provide the rationale for an effective treatment strategy that includes a cell cycle inhibitor in combination with a drug that lowers estrogen levels, such as an aromatase inhibitor, and an antiestrogen that does not result in the degradation of ERα, such as tamoxifen.
A new and efficient method for inhibition of RNA viruses by DNA interference

We report here a new method for inhibition of RNA viruses induced by dsDNA. We demonstrated that both long dsDNA molecules and short interfering DNA with a sequence complementary to that of viral RNA inhibited tobacco mosaic virus expression and prevented virus spread. Also, the expression of the HIV‐1 gp41 gene in HeLa cells was inhibited by complementary short interfering DNA. We showed that Dicer processed dsDNA, which suggests activation of the cellular machinery involved in silencing of RNA. For the silencing of viral RNA effected with dsDNA, we coined the term DNA interference technology.
Group Cognitive Behavior Therapy or Social Skills Training for Individuals With a Recent Onset of Psychosis?: Results of a Randomized Controlled Trial

This study aimed at determining the effectiveness of group cognitive behavior therapy (CBT) for recent onset psychosis in comparison with a recognized intervention for individuals with severe mental illness–social skills training. One hundred twenty-nine participants took part in a single-blind randomized controlled trial with repeated measures (baseline, 3 months, and 9 months). Participants were randomized to 1 of 3 conditions: group CBT, group social skills training for symptom management, or a wait-list control group. Both interventions were delivered by mental health staff with minimal training. Both treatments resulted in improvements on positive and negative symptoms compared with the wait-list control group, with the CBT group having significant effects over time on overall symptoms, and post-treatment effects on self-esteem, and active coping skills compared with the wait-list control group and lower drop-out rates than the skills training group. Therapist fidelity was adequate for both treatment conditions. Group CBT for psychosis is a promising intervention for individuals with recent onset of psychosis and their mental health professionals.
Treatment With Anti‐γ‐Glutamyl Transpeptidase Antibody Attenuates Osteolysis in Collagen‐Induced Arthritis Mice

The effectiveness of a new antibody treatment on arthritis‐associated osteolysis was studied by using CIA mice. GGT, a newly identified bone‐resorbing factor, was upregulated in arthritic joints. We generated monoclonal antibodies against GGT and injected them into CIA mice. Mice treated with antibodies showed a reduction in osteoclast number and bone erosion.