Miracle-dz/UniFAR-FTUs huggingface dataset:
Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors

Purpose: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. Experimental Design: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1–30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. Results: No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non–small cell lung cancer (n = 3). Conclusions: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. Clin Cancer Res; 21(11); 2462–70. ©2015 AACR.
A Theory of Nonphysical Suffering and Trust in Hospice Patients

Suffering is a complex, dynamic experience that overarches life experiences and includes physical, social, spiritual, and emotional domains. The purpose of this grounded theory study was to uncover participants' experiences of nonphysical suffering and what was helpful during this time. Eighteen patients who were chronically ill participated in this grounded theory study. Trust was uncovered as a central issue within nonphysical suffering, whereas meaning was the vehicle that enabled the individual to move within the suffering. Participants acknowledged suffering through the identification of various meanings of a situation within their constructed reality and belief system. During individuals' suffering, time was altered and the experience occurred within an expanded present. The individual created an emotional space apart from the meaning of loss within suffering. Trust included the categories of dynamic experience, losing trust, and dealing to regain trust. Participants identified nurse trustworthiness as important for decreasing energy expenditures associated with suffering.
Comparison of tumor density by CT scan based on histologic type in lung cancer patients.

AIM To investigate the differences of tumor density of lung cancer by CT scan based on histopathologic type of cancer cell. METHODS Subjects were lung cancer patients at Dr. Kariadi hospital Semarang between January 2002 and December 2003. Diagnosis was made based on clinical symptoms, histologic examination and lateral chest radiograph, and thorax CT scan. Density of tumor was measured within area which had most enhancements before and after contrast administration. Then, it was followed by transthoraxic fine needle aspiration (TNFNAB) and histopathologic examination. Study design was a cross sectional study. Inclusion criteria were primary lung cancer and exclusion criteria were non lung cancer, metastatic cancer, histopathologic non interpreted. Estimated number of samples was 41 patients. Density value before and after contrast were analyzed using Wilcoxon signed rank test. Difference of tumor density for each type of cancer cell was analyzed using chi-square test with significant level at p < 0.05 and confidence interval of 95%. RESULTS Forty-one patients with lung cancer were enrolled in this study. There were 30 males (73.2%) and 11 females (26.8%). Histopathologic types of cell cancer were epidermoid in 17 patients (14.5%), adenocarcinoma 8 patients (19.5%), large cell 7 patients ( 17.1%), small cell 7 patients ( 17.1%) and undifferentiated cell 2 patients ( 4.5%). Mean of increasing HU before and after contrast in epidermoid carcinoma was 26.8 (10.4) HU, adenocarcinoma 17.2 (7.1) HU, large cell 8.7 (4.5) HU, small cell 9.9(4.1) HU and undifferentiated cell 23.5 (1.5) HU with overall increase of all cancer cell types was 17.3(9.2) HU, p < 0.001. Histopathologic type of non small cell lung carcinoma (NSCLC) with density < 60 HU was found in 30 patients (73.2%) and small cell lung carcinoma with density > 60 HU was found in 5 patient (12.2%), p=0.01. CONCLUSION There was evident increase of density in all histopathologic type of cell cancer, p < 0.0001, with mean of density after contrast administration was 17.2 (7.1). There was significant difference between NSCLC and SCLC group and tumor density > 60 HU and < 60 HU, p=0.01.
Translation And The Nature Of Philosophy A New Theory Of Words

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A New Divergent Type of Eukaryotic Methionine Adenosyltransferase is Present in Multiple Distantly Related Secondary Algal Lineages

ABSTRACT. S‐adenosylmethionine is one of the most important metabolites in living cells and is synthesized in a single reaction catalyzed by methionine adenosyltransferase (MAT). At the sequence and structural level, this enzyme is one of the most conserved proteins known. Here we show that some representatives of three distantly related eukaryotic lineages—dinoflagellates, haptophytes, and euglenids—possess a highly divergent type of MAT, which we call MATX. Even though MATX contains all the sites known to be involved in catalysis and the association of monomers, it also has four insertions throughout the protein that are not observed in other MAT homologs. The phylogenetic distribution and affinities of MATX suggest that it originated in a single eukaryotic lineage and was spread via multiple events of eukaryote‐to‐eukaryote lateral gene transfer. We suggest a tentative model in which the origin of MATX is connected with the progression of secondary endosymbiosis.
Strategies of polyhydroxyalkanoates modification for the medical application in neural regeneration/nerve tissue engineering

Neural regeneration was once considered to be impossible, especially in the central nervous system where neural regeneration comprise the generation of new neurons, glia, axons, myelin, and synapses. Until recently, neural stem cells/neural progenitor cells (NSCs/NPCs) were identified from various areas of brain and brought hopes to the neural repair and regeneration. Tissue engineering has revolutionized the current neural regeneration technology and it has become a pioneering interdisciplinary field in the areas of biomedical research. Polyhydoxyalkanoate (PHA) as one of biodegradable material has been successfully used as tissue engineering materials. It has also been applied in nerve tissue engineering due to the high biocompatibility and low cytotoxicity. Over the past 10 years, different kinds of modification strategies have been undertaken to improve the properties of PHA to fit the requirements from various fields. Several members of PHA family have been attempted for neural regeneration. This article reviewed the recent modification strategies for improving the properties of PHA and highlighted the pioneer applications in neural regeneration.
Histopathological Alterations in The Liver And Lungs of Hoplobatrachus Occipitalis Exposed to Sub Lethal Concentrations of Cadmium

The toxic effects of cadmium on the liver and lungs of H. occipitalis after 28 days was studied. The frog was exposed to 0.25, 0.50, 1.00 and 2.00mg/l cadmium. Cadmium was bioaccumulated in the liver. Bioaccumulation of cadmium increased significantly (p<0.05) with increase in cadmium concentration. There was high accumulation of cadmium in the liver which may alter the levels of various biochemical parameters and cause liver damage. At the end of the study, the liver and lungs of control frog showed normal structural pattern. The major histopathological changes observed in the liver were excessive bile secretion and dilation of sinusoids. These changes may be due to the direct toxic effects of cadmium on the hepatocytes since the liver is the site of detoxification of all types of toxins and chemicals. Histopathological changes in the lungs were pulmonary haemorrhage and distortion of lung structure. These changes could lead to loss of lung elasticity and capacity to carry out gaseous exchange. The results of this study revealed that H. occipitalis manifested histopathological changes in the liver and lungs when exposed to cadmium concentrations. The investigation of histological changes in the organs of amphibians is an accurate way to assess the effects of heavy metals to these amphibian tetrapods in their habitats where they may be exposed owing to anthropogenic activities.
Band-Notched Small Square-Ring Antenna With a Pair of T-Shaped Strips Protruded Inside the Square Ring for UWB Applications

A novel printed monopole antenna with constant gain over a wide bandwidth for ultra wideband applications with desired notch-band characteristic is presented. The proposed antenna consists of a square-ring radiating patch with a pair of T-shaped strips protruded inside the square ring and a coupled T-shaped strip and a ground plane with a protruded strip, which provides a wide us able fractional bandwidth of more than 130% (3.07-14.6 GHz). By using the square-ring radiating patch with a pair of T-shaped strips protruded inside it, the frequency bandstop performance is generated, and we can control its characteristics such as band-notch frequency and its bandwidth by electromagnetically adjusting coupling between a pair of T-shaped strips protruded inside the square ring. The designed antenna has a small size of 12 × 18 mm2, or about 0. 15λ × 0. 25λ at 4.2 GHz, while showing the band-rejection performance in the frequency band of 5.05-5.95 GHz.
Brain metastases from epithelial ovarian cancer: a review of the literature.

BACKGROUND Brain metastases from epithelial ovarian cancer (EOC) are rare. This report is based on a review of the literature. METHODS AND RESULTS This review summarizes the incidence, clinical features, pathophysiology, and diagnostic evaluation of EOC. The section on current treatment includes a thorough evaluation of the literature, highlights controversies over treatment options, and provides insight into novel approaches. Current treatment options include surgical resection, whole-brain radiation therapy (WBRT), stereotactic radiosurgery, and chemotherapy. Corticosteroids and anticonvulsant medications are commonly used for the palliation of mass effects and seizures, respectively. In the reviewed series, a better outcome was seen following surgical resection and WBRT with or without chemotherapy for solitary and resectable brain metastases. CONCLUSION The prognosis for patients with brain metastases from EOC is poor. A better outcome might be obtained using multimodality therapy. Because of the small number of patients included in the reported studies, multicenter clinical trials are needed for further investigation in order to critically evaluate the clear benefit of these treatment options in selected patients.
Genetics and regulation of angiopoietin-like proteins 3 and 4

Purpose of review Lipoprotein lipase activity in a given tissue is the rate limiting step for the uptake of triglyceride-derived fatty acids. Imbalances in the partitioning of fatty acids have major metabolic consequences. Given the central role of lipoprotein lipase in energy metabolism, the discovery of new molecules that affect the activity of lipoprotein lipase holds great potential for novel therapeutic targets. Recent findings Angiopoietin-like proteins 3 and 4 are two members of the angiopoietin-like family of proteins (Angptl). Unique within this family, Angptl3 and 4 inhibit lipoprotein metabolism via their ability to inhibit the activity of lipoprotein lipase. This review highlights recent studies on the biochemistry of Angptl3 and 4 as well as mouse models with selective overexpression of Angptl4 or global knockout of Angptl3, 4, or both. Summary Both angiopoietins and angiopoietin-like proteins share similar domain structures. Angptl3 and 4 are the only two members of this superfamily that inhibit lipoprotein lipase activity. However, Angptl3 and 4 are differentially regulated at multiple levels, suggesting non-redundant functions in vivo. Angptl3 and 4 are proteolytically processed into two halves and are differentially regulated by nuclear receptors. Transgenic overexpression of Angptl4 as well as knockout of Angptl3 or 4 demonstrate that these two proteins play essential roles in lipoprotein metabolism: liver-derived Angptl3 inhibits lipoprotein lipase activity primarily in the fed state, while Angptl4 plays important roles in both fed and fasted states. In addition, Angptl4 regulates the tissue-specific delivery of lipoprotein-derived fatty acids. Angptl4 is thus an endocrine or autocrine/paracarine inhibitor of lipoprotein lipase depending on its sites of expression.
Subjective Clinical Lipoatrophy Assessment Correlates with DEXA-Measured Limb Fat

Abstract Objectives: Although physician- and patient-rated diagnoses of lipoatrophy are currently used as a basis for inclusion into clinical trials, few studies have compared physician- or patient-rated lipoatrophy severity with objective measures. We aim to assess the validity of physician- and patient-rated diagnoses of lipoatrophy by evaluating the correlation between clinical assessments of lipoatrophy and objective fat indices. Methods: This cross-sectional study evaluated the association between clinical lipoatrophy scores and DEXA-measured limb fat (n = 154) and subcutaneous fat mitochondrial DNA (mtDNA) levels (n = 80) in HIV+ individuals. Results: There was a signifi cant negative correlation between DEXA-measured limb fat and lipoatrophy scores generated by either the patients (r = –0.27, p = .008) or the physician (r = –0.48, p < .0001). Also, a signifi cant positive correlation was found between the patient-generated lipoatrophy score and the physician score (r = 0.68, p < .0001). However, there was no correlation between fat mtDNA levels and DEXA-measured limb fat (r = –0.09, p = .42) or between physician- or patient-generated lipoatrophy scores (r = –0.09, p = .43, and r = 0.04, p = .71, respectively). Conclusion: These results suggest that physician- and patient-rated lipoatrophy scores may be useful surrogates for more expensive measures of lipoatrophy, which could be reserved for research studies.
An mRNA Is Capped by a 2', 5' Lariat Catalyzed by a Group I-Like Ribozyme

Twin-ribozyme introns are formed by two ribozymes belonging to the group I family and occur in some ribosomal RNA transcripts. The group I-like ribozyme, GIR1, liberates the 5′ end of a homing endonuclease messenger RNA in the slime mold Didymium iridis. We demonstrate that this cleavage occurs by a transesterification reaction with the joining of the first and the third nucleotide of the messenger by a 2′,5′-phosphodiester linkage. Thus, a group I-like ribozyme catalyzes an RNA branching reaction similar to the first step of splicing in group II introns and spliceosomal introns. The resulting short lariat, by forming a protective 5′ cap, might have been useful in a primitive RNA world.
Protection from High Fat Diet-induced Increase in Ceramide in Mice Lacking Plasminogen Activator Inhibitor 1*

Obesity increases the risk for metabolic and cardiovascular disease, and adipose tissue plays a central role in this process. Ceramide, the key intermediate of sphingolipid metabolism, also contributes to obesity-related disorders. We show that a high fat diet increased ceramide levels in the adipose tissues and plasma in C57BL/6J mice via a mechanism that involves an increase in gene expression of enzymes mediating ceramide generation through the de novo pathway (e.g. serine palmitoyltransferase) and via the hydrolysis of sphingomyelin (acid sphingomyelinase and neutral sphingomyelinase). Although the induction of total ceramide in response to the high fat diet was modest, dramatic increases were observed for C16, C18, and C18:1 ceramides. Next, we investigated the relationship of ceramide to plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of plasminogen activation and another key player in obesity. PAI-1 is consistently elevated in obesity and thought to contribute to increased artherothrombotic events and more recently to obesity-mediated insulin resistance. Interestingly, the changes in ceramide were attenuated in mice lacking PAI-1. Mechanistically, mice lacking PAI-1 were protected from diet-induced increase in serine palmitoyltransferase, acid sphingomyelinase, and neutral sphingomyelinase mRNA, providing a mechanistic link for decreased ceramide in PAI-1–/– mice. The decreases in plasma free fatty acids and adipose tumor necrosis factor-α in PAI-1–/– mice may have additionally contributed indirectly to improvements in ceramide profile in these mice. This study has identified a novel link between sphingolipid metabolism and PAI-1 and also suggests that ceramide may be an intermediary molecule linking elevated PAI-1 to insulin resistance.
Src Kinase Is the Connecting Player between Protein Kinase A (PKA) Activation and Hyperpolarization through SLO3 Potassium Channel Regulation in Mouse Sperm*

Background: Membrane potential (Em) hyperpolarization during sperm capacitation is necessary for acrosome reaction. Results: cSrc is activated downstream of PKA, regulating the SLO3 K+ channel and promoting membrane hyperpolarization. Conclusion: Acrosomal responsiveness of mouse sperm depends on cSrc activation of SLO3. Significance: This represents the first evidence of K+ channel regulation in mouse sperm by a tyrosine kinase, affecting Em. Plasma membrane hyperpolarization is crucial for mammalian sperm to acquire acrosomal responsiveness during capacitation. Among the signaling events leading to mammalian sperm capacitation, the immediate activation of protein kinase A plays a pivotal role, promoting the subsequent stimulation of protein tyrosine phosphorylation that associates with fertilizing capacity. We have shown previously that mice deficient in the tyrosine kinase cSrc are infertile and exhibit improper cauda epididymis development. It is therefore not clear whether lack of sperm functionality is due to problems in epididymal maturation or to the absence of cSrc in sperm. To further address this problem, we investigated the kinetics of cSrc activation using anti-Tyr(P)-416-cSrc antibodies that only recognize active cSrc. Our results provide evidence that cSrc is activated downstream of PKA and that inhibition of its activity blocks the capacitation-induced hyperpolarization of the sperm plasma membrane without blocking the increase in tyrosine phosphorylation that accompanies capacitation. In addition, we show that cSrc inhibition also blocks the agonist-induced acrosome reaction and that this inhibition is overcome by pharmacological hyperpolarization. Considering that capacitation-induced hyperpolarization is mediated by SLO3, we evaluated the action of cSrc inhibitors on the heterologously expressed SLO3 channel. Our results indicate that, similar to SLO1 K+ channels, cSrc blockers significantly decreased SLO3-mediated currents. Together, these results are consistent with findings showing that hyperpolarization of the sperm plasma membrane is necessary and sufficient to prepare the sperm for the acrosome reaction and suggest that changes in sperm membrane potential are mediated by cSrc activation.
Overview of Facial Paralysis: Current Concepts

Facial paralysis represents the end result of a wide array of disorders and heterogeneous etiologies, including congenital, traumatic, infectious, neoplastic, and metabolic causes. Thus, facial palsy has a diverse range of presentations, from transient unilateral paresis to devastating permanent bilateral paralysis. Although not life-threatening, facial paralysis remains relatively common and can have truly severe effects on one's quality of life, with important ramifications in terms of psychological impact and physiologic burden. Prognosis and outcomes for patients with facial paralysis are highly dependent on the etiologic nature of the weakness as well as the treatment offered to the patient. Facial plastic surgeons are often asked to manage the sequelae of long-standing facial paralysis. It is important, however, for any practitioner who assists this population to have a sophisticated understanding of the common etiologies and initial management of facial paralysis. This article reviews the more common causes of facial paralysis and discusses relevant early treatment strategies.
Tuberculosis in the HIV / AIDS era: interactions, impacts and solutions.

Tuberculosis (TB) is a health problem of global significance, with 2 billion people infected with the tubercle bacillus and 8 million new cases each year, of which approximately 2.5 million die. TB accounts for an estimated 7% of all avoidable adult deaths worldwide. In 1995, there were an estimated 1.5 million new cases of TB in sub-Saharan Africa; the annual caseload is projected to grow to 2.1 million by 2000. The growth in population and poverty, as well as the HIV/AIDS epidemic, are behind the rise in TB cases. Countries with high rates of HIV infection have reported far faster increases in cases than those with low rates of infection, rates of HIV infection among TB patients are much higher than the rate of infection in the general population, and TB has become the most important opportunistic disease and one of the most important causes of death among HIV-positive patients in Africa. The link between the HIV/AIDS and TB epidemics, how TB makes HIV both a public and individual health problem, challenges for health services, TB treatment, the delivery of care, prevention, developing an effective response, and a future research agenda are discussed.
Polyamines and Root Formation in Mung Bean Hypocotyl Cuttings : II. Incorporation of Precursors into Polyamines.

The incorporation of [(14)C]arginine and [(14)C]ornithine into various polyamines was studied in mung bean (Vigna radiata [L.] Wilczek) hypocotyl cuttings with respect to the effect of indole-3-butyric acid on adventitious root formation.Both [(14)C]arginine and [(14)C]ornithine are rapidly incorporated into putrescine, spermidine, and spermine, with similar kinetics, during 5- to 24-hour incubation periods. The incorporation of arginine into putrescine is generally higher than that of ornithine. The biosynthesis of putrescine and spermidine from the precursors, in the hypocotyls, is closely related to the pattern of root formation: a first peak at 0 to 24 hours corresponding to the period of root primordia development, and a second peak of putrescine biosynthesis at 48 to 72 hours corresponding to root growth and elongation. Indole-3-butyric acid considerably enhances putrescine biosynthesis in both phases, resulting in an increase of the putrescine/spermidine ratio.It is concluded that the promotive effect of indole-3-butyric acid on putrescine biosynthesis, from both arginine and ornithine, supports the hypothesis that auxin-induced root formation may require the promotion of polyamine biosynthesis.