Miracle-dz/UniFAR-FTUs huggingface dataset:
Autocrine Regulation of Osteoclast Formation and Bone Resorption by IL-1α and TNFα

Bone resorption is regulated by the cytokines within marrow cells that mediate osteoclast formation and activation. IL-1 and TNF induce bone resorption by stimulating the production of osteoclast-like multinucleated cells and by increasing the bone-resorbing activity of formed osteoclasts. This study was designed to detect IL-1 and TNF in osteoclasts in vitro and to determine whether these cytokines up-regulate osteoclast differentiation and bone resorption. The production of IL-1α, -β, and TNFa, β in osteoclasts was examined immunohistochemically and by in situ hybridization. In the co-culture of C57BL/6N mouse bone marrow and MC3T3-G2/PA6 cells, a colony of osteoclasts formed, and IL-1α and TNFa were detected. However, IL-1β and TNF β were not detected. To investigate the role of IL-1α and TNFα from osteoclasts, we enumerated TRAP-positive cells and measured the resorption pit areas in the presence of antibodies against IL-1α and TNFα. The addition of antibodies against IL-1α and TNFα to the co-culture system decreased the number of TRAP-positive colonies at seven days after incubation (anti-IL-1α, 25.0 ± 2.3%; anti-TNFα, 41.7 ± 3.7%; anti-IL-1α + anti-TNFα, 40.5 ± 1.3%; and control, 100%), and the ratio of mononuclear to multinuclear cells had changed (anti-IL-1α, 90:10; anti-TNFα, 75:25; anti-IL-1α+ anti-TNFα, 88:12; and control, 60:40). The total pit areas per dentin slice also decreased with the addition of antibodies (anti-IL-1α, 28,828; anti-TNFα, 49,249; anti-IL-1α + anti-TNFα, 30,685; and control, 303,139 mm2). These results suggest that local production of IL-la and TNFα by osteoclasts is an important mechanism for regulating the osteoclast differentiation and bone resorptive process.
Metabolomic applications in radiation biodosimetry: exploring radiation effects through small molecules

Abstract Purpose: Exposure of the general population to ionizing radiation has increased in the past decades, primarily due to long distance travel and medical procedures. On the other hand, accidental exposures, nuclear accidents, and elevated threats of terrorism with the potential detonation of a radiological dispersal device or improvised nuclear device in a major city, all have led to increased needs for rapid biodosimetry and assessment of exposure to different radiation qualities and scenarios. Metabolomics, the qualitative and quantitative assessment of small molecules in a given biological specimen, has emerged as a promising technology to allow for rapid determination of an individual’s exposure level and metabolic phenotype. Advancements in mass spectrometry techniques have led to untargeted (discovery phase, global assessment) and targeted (quantitative phase) methods not only to identify biomarkers of radiation exposure, but also to assess general perturbations of metabolism with potential long-term consequences, such as cancer, cardiovascular, and pulmonary disease. Conclusions: Metabolomics of radiation exposure has provided a highly informative snapshot of metabolic dysregulation. Biomarkers in easily accessible biofluids and biospecimens (urine, blood, saliva, sebum, fecal material) from mouse, rat, and minipig models, to non-human primates and humans have provided the basis for determination of a radiation signature to assess the need for medical intervention. Here we provide a comprehensive description of the current status of radiation metabolomic studies for the purpose of rapid high-throughput radiation biodosimetry in easily accessible biofluids and discuss future directions of radiation metabolomics research.
3‐(2‐Oxoethylidene)indolin‐2‐one Derivatives Activate Nrf2 and Inhibit NF‐κB: Potential Candidates for Chemoprevention

Induction of cytoprotective phase 2 enzymes through inhibition of Keap1, a repressor of transcription factor Nrf2, is a cancer‐prevention strategy. Compounds that elicit antiinflammatory and cytoprotective effects are promising candidates for chemoprevention. Novel analogues of 1‐methyl‐3‐(2‐oxopropylidene)indolin‐2‐one (‘supercinnamaldehyde’; SCA) were synthesized, and their abilities to induce cytoprotective responses through Nrf2 induction and to suppress inflammatory responses were examined. 1‐Methyl‐3‐(2‐oxo‐2‐phenylethylidene)indolin‐2‐one (6) was identified as the lead compound. The compounds showed induction of Nrf2‐dependent phase 2 enzymes in Keap1+/+ mouse embryonic fibroblasts (MEFs), which was abrogated in Keap1−/− MEFs. The compounds also displayed a suppressive effect on NF‐κB signaling that was at least partly responsible for inhibition of lipopolysaccharideinduced inflammatory responses. These SCA analogues exhibited cytoprotective and anti‐inflammatory activities and may be developed further as chemopreventive agents.
Poorer survival in patients whose explanted hepatocellular carcinoma (HCC) exceeds Milan or UCSF Criteria. An analysis of liver transplantation in HCC in Australia and New Zealand.

BACKGROUND Milan and University of California San Francisco (UCSF) Criteria have been used for selection of patients with hepatocellular carcinoma (HCC) for liver transplantation (LTx). The aims of this study were to analyse the results of LTx for HCC in Australia and New Zealand with emphasis on the effects of discordance between pre-LTx radiological and post-LTx pathological staging. METHODS A total of 186 LTx for HCC carried out between July 1985 and August 2003 were included. Patients were categorized according to the Milan and UCSF Criteria. RESULTS The median follow-up was 6.55 years (range 2.96-20.93 years). Pre-LTx factors associated with better survival include tumour size < or = 5 cm, number of tumours < or = 3, staging within Milan and UCSF Criteria and more recent transplantation (1996-2003). In all, 14 patients had a pre-LTx stage outside the Milan but within the UCSF Criteria. One- and 5-year patient survival rates were, respectively, 88% and 74% within the Milan Criteria, and 87% and 73% within the UCSF Criteria. Vascular invasion, capsular invasion, lymph node invasion and pathological stage outside UCSF Criteria were associated with poor outcome. Of patients within the Milan and UCSF Criteria pre-LTx, 24% and 18%, respectively, were outside the same criteria post-LTx. These patients had poorer survival rates. CONCLUSIONS The use of the UCSF Criteria in this cohort increased the number of patients eligible for LTx without compromising 5-year survival rates. Patients whose explant tumours were outside the Milan or UCSF Criteria had poorer outcomes compared with those whose explants remained within these criteria.
A review of radiation countermeasures focusing on injury-specific medicinals and regulatory approval status: part III. Countermeasures under early stages of development along with ‘standard of care’ medicinal and procedures not requiring regulatory approval for use

Abstract Purpose: Terrorist attacks, with their intent to maximize psychological and economic damage as well as inflicting sickness and death on given targeted populations, are an ever-growing worldwide concern in government and public sectors as they become more frequent, violent, and sensational. If given the chance, it is likely that terrorists will use radiological or nuclear weapons. To thwart these sinister efforts, both physical and medical countermeasures against these weapons are currently being researched and developed so that they can be utilized by the first responders, military, and medical providers alike. This is the third article of a three-part series in which we have reviewed additional radiation countermeasures that are currently under early preclinical phases of development using largely animal models and have listed and discussed clinical support measures, including agents used for radiation-induced emesis, as well as countermeasures not requiring Food and Drug Administration approval. Conclusions: Despite the significant progress that has been made in this area during the last several years, additional effort is needed in order to push promising new agents, currently under development, through the regulatory pipeline. This pipeline for new promising drugs appears to be unreasonably slow and cumbersome; possible reasons for this inefficiency are briefly discussed. Significant and continued effort needs to be afforded to this research and development area, as to date, there is no approved radioprotector that can be administered prior to high dose radiation exposure. This represents a very significant, unmet medical need and a significant security issue. A large number of agents with potential to interact with different biological targets are under development. In the next few years, several additional radiation countermeasures will likely receive Food and Drug Administration approval, increasing treatment options for victims exposed to unwanted ionizing irradiation.
Atomistic‐Level Portrayal of Drug–DNA Interplay: A History of Courtships and Meetings Revealed by Molecular Simulations

Simulation techniques play an ever increasing role in drug design by providing an atomistic view of the pathways of drugs to their target sites, thus revealing the determinants behind molecular recognition and binding, pinpointing local and allosteric conformational changes of both drugs and receptors, and unveiling key chemical mechanisms in enzymatic‐like processes. In particular, molecular dynamics simulations, relying on a force field, quantum mechanical, or hybrid description of the system, have been largely employed to unveil mechanistic, kinetic, and thermodynamic aspects of the binding of anticancer drugs to DNA, ultimately contributing to a better understanding of their mechanism of action. Herein we review recent literature, focusing on selected examples from our work, to show how modern computer simulations can be applied to study the mechanism of action of antitumor drugs such as platinum compounds, organic antibiotics, and metal‐based octahedral complexes, which are archetypal examples of the most common classes of DNA binding molecules. We discuss the strengths and limitations of in silico studies in this field, as well as current and future challenges.
Escalating computed tomography angiogram (CTA) grade predicts unresectability and margin status for pancreaticobiliary neoplasms.

BACKGROUND AND AIMS The Raptopoulos computed tomography (CT) grading system of pancreaticobiliary cancers was conceived to predict resectability based on tumour involvement of critical vasculature. The aim of the present study was to investigate the relationship between CT grade, resectability, margin status and survival after pancreatic resection. METHODS Patients with presumed pancreaticobiliary malignancy and a pancreas protocol computed tomography angiogram (CTA) who underwent attempted curative resection from October 2001 and August 2008 were identified. The relationship between radiographical involvement of critical vasculature, according to a five-point scale, and ultimate resectability, margin status and survival was assessed. RESULTS Overall, 276 (70.2%) out of 393 patients were resectable. The proportion of patients who were unresectable at laparotomy increased as CT grade escalated; 41/250 (16.4%) CT Grade 0, 16/55 (29.1%) CT Grade 1, 33/55 (60%) CT Grade 2, 27/33 CT Grade 3, P < 0.001. Local invasion or vascular involvement was the reason for unresectability in 14/41, 12/16, 23/33, 16/27 patients with CT Grade 0-3, respectively. A R0 resection was achieved in 84/131 patients with pancreatic adenocarcinoma and varied significantly by CT grade, P= 0.021. Significant predictors of survival were age (P < 0.0001), resectability (P < 0.0001) and diagnosis (P < 0.009). CONCLUSIONS Escalating Raptopoulos CT grade is correlated with increasing probability of unresectability and R1 resection.
Assessment of squalene eligibility in bettering some maternal and fetal disorders instigated by gamma irradiation of rats at mid gestation

Abstract Purpose: Squalene is an eminent vital part of the synthesis of steroid hormones in the body as well as the first specific intermediate in cholesterol biosynthesis that plays an essential role in normal embryogenesis. The present work was designed to test the maternal and embryonic response to the modulating capacity of squalene (0.4 ml/kg/d), when supplemented to rats from days 1 to 18 of pregnancy, against the damaging consequences induced by maternal subjection to 3 Gy gamma irradiation on day 10 post-conception. Materials and methods: The experimental protocol comprised of four different pregnant groups, namely: (1) control, (2) squalene supplemented, (3) irradiated and (4) squalene supplemented + irradiated. Results: It has been detected that radiation has increased the maternal blood lactate dehydrogenase (as a marker of tissue injury), cholesterol, triglycerides, estradiol and progesterone and has also provoked the oxidative stress that has been demonstrated by the increased malondialdehyde (MDA) and the decreased glutathione (GSH) and superoxide dismutase (SOD). These maternal changes were associated with high embryonic lethality, growth retardation, severe developmental abnormalities and defective neural tube closure expressed by exencephaly. However, squalene treatment has significantly improved the radiation imposed maternal variations and reduced the embryonic mortality, although it has not been able to attenuate the embryonic neural tube defects. Conclusions: It has been presumed that the maternal mid-gestational irradiation (day 10) has affected the fetal nervous system development with concomitant maternal oxidative stress, hyperlipidemia, and increased progesterone and estradiol levels. Squalene uptake has improved the maternal variations and reduced the embryonic mortality while could not stop or improve the embryonic neural tube defects imposed by radiation at this exact radiation timing.
Accuracy of intraoperative consultation in lesions of the salivary glands: analysis of 748 cases

Introduction: Lesions of the salivary glands are uncommon, representing 2% to 6.5% of all neoplasms of head and neck, and because of the difference in treatment between them, an accurate diagnosis is essential. The cytological study by fine-needle aspiration (FNA) biopsy is a highly accurate method used to diagnose lesions of the salivary glands. Intraoperative consultation (IOC), in its turn, is a test that provides diagnosis during surgery, aiming to differentiate malignant from benign lesions and to enable the most appropriate surgical approach. Objective: To evaluate the accuracy of IOC in salivary gland lesions. Material and methods: A survey was conducted in the database of Instituto Nacional de Câncer (Inca) into IOC for diagnosis of salivary gland lesions from January 2001 to December 2012, and found 748 cases. Diagnosis made at IOC (IOCD) was compared with the gold standard histopathological diagnosis and classified into: 1) consenting; 2) discordant; and 3) indeterminate. From these data, sensitivity, specificity and accuracy were calculated. Results: Among the 748 IOCs, results were concordant in 656 cases (88%), discordant in 56 (7%), and indeterminate in 36 (5%). Sensitivity was 78%, specificity 99% and accuracy 92%. Conclusion: Our results indicate that IOC in salivary gland lesions is highly accurate and can contribute to the surgical approach.
Comparative genomics of the mesophilic cellulosome‐producing Clostridium cellulovorans and its application to biofuel production via consolidated bioprocessing

Clostridium cellulovorans is an anaerobic, mesophilic bacterium that efficiently degrades native substrates in soft biomass such as corn fibre and rice straw by producing an extracellular enzyme complex called the cellulosomes. By examining genome sequences from multiple Clostridium species, comparative genomics offers new insight into genome evolution and the way natural selection moulds functional DNA sequence evolution. Recently, we reported the whole genome sequence of C. cellulovorans. A total of 57 cellulosomal genes were found in the C. cellulovorans genome and coded for not only carbohydrate‐active enzymes but also lipase, peptidase and proteinase inhibitors, in addition to two novel genes encoding scaffolding proteins CbpB and CbpC. Interestingly, the genome size of C. cellulovorans was about 1 Mbp larger than that of other cellulosome‐producing clostridia: mesophilic C. cellulolyticum and thermophilic C. thermocellum. Since the C. cellulovorans genome included not only cellulosomal genes but also a large number of genes encoding non‐cellulosomal enzymes, the genome expansion of C. cellulovorans included genes more related to degradation of polysaccharides, such as hemicelluloses and pectins, than to cellulose. In this review, we propose a strategy for industrial applications such as biofuel production using enhanced mesophilic cellulosome‐ and solvent‐producing clostridia.
The Application of an Exercise and Wellness Program for Cancer Patients: A Preliminary Outcomes Report

The effects of a 10-week outpatient wellness program on fitness, strength, and quality of life were tested in 20 cancer patients (age 50±12 yrs; length of cancer 1.18±0.6 yrs). Cancers included carcinoma, lymphoma, and leukemia (n = 17, 1, and 2, respectively). Patients were selected from physician referral based on Karnofsky rating and all had undergone radiation and/or chemotherapy. The program consisted of aerobic machines, progressive strength training, and flexibility/relaxation twice a week under supervision. Patients filled out a modified Rotterdam quality-of-life survey afterward. Data were analyzed via Student t-test, and multiple analyses were corrected via Dunn's procedure. Results showed improvements in both endurance and strength, including time on aerobic machines and MET levels, and strength gains in upper and lower body stations. The Rotterdam survey revealed improvements in all psychosocial areas. Results show that cancer patients can achieve significant gains in strength, aerobic capacity, and quality of life from a 10-week exercise program.
The Measurement of Moral Judgment

This two-volume set is a result of more than 30 years of pioneering work by the late Lawrence Kohlberg, professor of human development at the Graduate School of Education, Harvard University. With collaborator Anne Colby, director of the Henry A. Murray Research Center at Radcliffe College, Kohlberg presents the "Standard Issue Moral Judgment Interview and Scoring System," its theoretical assumptions, and supporting empirical data. This scoring system is an attempt to use clear and concrete criteria to assess an individual's state of moral development objectively and reliably. Essentially, a subject is presented with a set of hypothetical moral dilemmas (eg, "Should Heinz steal a drug to save his dying wife when the only druggist with the drug asks a price that Heinz cannot pay? "); then the subject explains what course of action should be taken and why. Through the use of intensive probing, the examiner attempts to elicit the most
Biplanar Medial Open-Wedge High Tibial Osteotomy for Medial Compartment Osteoarthritis of the Knee: A Novel Technique and Follow-Up

We describe a biplanar open-wedge high tibial osteotomy—a modification of the technique described by Puddu et al and its results. High tibial osteotomy to correct the varus knee became popular after Coventry reported favorable outcomes. Twenty-five patients were treated with this technique for medial compartment osteoarthritis of the knee from 1999 to 2005. There was significant improvement in Knee Society score and function as well as in hospital for Special Surgery score. There was no significant increase in posterior tibial slope angle. In this article, the authors review the literature and discuss the technique and experience with this method.
External validation of a pre-operative nomogram predicting peri-operative mortality risk after liver resections for malignancy.

AIM A pre-operative nomogram using a population-based database to predict peri-operative mortality risk after liver resections for malignancy has recently been developed. The aim of the present study was to perform an external validation of the nomogram using data from a high volume institution. METHODS The National Inpatient Sample (NIS) database (2000-2004) was used initially to construct the nomogram. The dataset for external validation was obtained from a high volume centre specializing in hepatobiliary surgery. Validation was performed using calibration plots and concordance index. RESULTS A total of 794 patients who underwent liver resection from the years 2000-2010 at the external institute were included in the validation set with an observed mortality rate of 1.6%. The mean total points for this sample of patients was 124.9 [standard error (SE) 1.8, range 0-383] which translates to a nomogram predicted mortality rate of 1.5%, similar to the actual observed overall mortality rate. The nomogram concordance index was 0.65 [95% confidence interval (CI) 0.46-0.82] and calibration plots stratified by quartiles revealed good agreement between the predicted and observed mortality rates. CONCLUSIONS The present study provides an external validation of the pre-operative nomogram to predict the risk of peri-operative mortality after liver resection for malignancy.
Small‐Molecule CD4 Mimics Containing Mono‐cyclohexyl Moieties as HIV Entry Inhibitors

CD4 mimics are small molecules that inhibit the protein–protein interaction between gp120 and CD4, which is a key interaction for the entry of human immunodeficiency virus (HIV) into host immune cells. In the present study, mono‐cyclohexyl‐type CD4 mimics were designed to form hydrophobic and electrostatic interactions with Val430 and Asp368 located in the entrance of the Phe43 cavity of gp120, the interaction site of CD4. YIR‐329, a novel 1‐azaspiro[5.5]undecane derivative with a cyclohexyl ring attached to the piperidine ring, exhibited only slightly weaker anti‐HIV activity than a previously described lead HAR‐171, and modeling results indicated the formation of advantageous interactions by the para‐chlorophenyl moiety of YIR‐329. To introduce an electrostatic interaction with Asp368, derivatives with a guanidino group on the piperidine nitrogen atom were synthesized. Mono‐cyclohexyl‐type CD4 mimics with a guanidino group, such as YIR‐819 (N1‐(4‐chlorophenyl)‐N2‐(1‐(2‐(N‐(amidino)glycinamide)ethyl)‐2‐cyclohexylpiperidin‐4‐yl)oxalamide) and YIR‐821 (1‐(2‐(5‐guanidinovaleramide)ethyl derivative of YIR‐819), were identified that exhibit approximately fivefold more potent anti‐HIV activity than YIR‐329. In combination with a neutralizing antibody, their anti‐HIV activities were augmenting. Modeling results suggest that these compounds interact effectively with Val430 and either Asp368 or Asp474 in the gp120 Phe43 cavity. YIR‐819 and YIR‐821 represent useful lead compounds for the further development of HIV‐1 entry inhibitors and could potentially be useful for co‐administration with neutralizing antibodies for the treatment of HIV infection and AIDS.
Torsion of the gallbladder: a systematic review.

BACKGROUND Gallbladder torsion is a rare disease, predominantly affecting elderly women. It is an important differential in the acute surgical abdomen. METHODS A total of 324 published case reports of torsion of the gallbladder were reviewed. Features in diagnostic imaging suggestive of torsion were reviewed and summarized. RESULTS Gallbladder torsion is primarily a disease of elderly people; the median age at presentation is 77 years. It is more common amongst women, occurring at a female : male ratio of 4 : 1, although not in childhood, when it occurs at a male : female ratio of 2.5 : 1. CONCLUSIONS Improved imaging techniques within the last 20 years have enabled the preoperative diagnosis of one quarter of patients with gallbladder torsion. With prompt surgical intervention, the condition has an excellent prognosis.