Miracle-dz/UniFAR-FTUs huggingface dataset:
Conflicting consequences of immunity to cancer versus autoimmunity to neurons: Insights from paraneoplastic disease

Immunologists are well aware that cancer regression and increased patient survival with the use of checkpoint inhibitors, such as ipilimumab, an antibody directed against cytotoxic T‐lymphocyte–associated antigen 4, CTLA‐4 (CD152), is accompanied by concomitant autoimmunity. For over 30 years, a small group of investigators have shown that the rare paraneoplastic syndromes are caused by immunity to shared antigens found on both tumors and on components of the nervous system. In this issue of the European Journal of Immunology, Blachère et al. [Eur. J. Immunol. 2014. 44: 3240–3251] elucidate some of the molecular mechanisms underlying the tolerance to neuronal antigens which share epitopes with oncologic antigens, observed in the context of paraneoplastic syndromes in mice. The presence of the shared tumor antigen on a nonhematopoietic cell underlies the basis for a certain level of tolerance in CD4+ and CD8+ T cells, preventing these cells from attacking the brain, but allowing them to lyse the tumor upon transfer into tumor‐bearing recipient mice. Comparisons between the paraneoplastic syndromes and the new autoimmune conditions seen with antibodies to immune checkpoints at CD152 or at CD279 are likely to illuminate shared mechanisms and solutions to these vexing diseases.
Nasal Carriage of Staphylococcus in Health Care Workers in Benghazi Hospitals

This study was aimed to determine the frequency of staphylococcal nasal carriage of health care workers (HCWs) and antimicrobial susceptibility profile of the isolates in hospitals of Benghazi, Libya. The study was conducted in the period between April 2013 and August 2013 on HCWs from ten hospitals in Benghazi-Libya. Nasal swabs from anterior nares of HCWs were cultured and identified as Staphylococcus aureus (S. aureus), coagulase - negative staphylococci (CoNS) and methicillin-resistant S. aureus (MRSA) by using standard methods. Antimicrobial susceptibility testing was performed on Muller Hinton Agar using disc diffusion method. Of the 472 HCWs, (47.5%) were nasal carriers of S. aureus, (21.4%) for MRSA and (26.1%) for MSSA, (36.4%) of CoNS. The highest carriage rate for S. aureus was in Physician (30.6%) followed by nurses (20.4%), helpers (22.9%) and technicians (10.9%). Almost all of the isolates showed high resistance against penicillin (97.5%) and ampicillin (98.2%). The lowest resistance recorded was for augmentin (14.2%), gentamycin (7.1%), clindamycin (7.5%) ciprofloxacin (3.2%) and vancomycin (2.1%). Most of isolated strains were susceptible to rifampicin (98.9%). The emergence of resistant strains of S.aureus should be prevented by controlling the amount of antibiotics used in and out of hospitals. Also, better control measures of nosocomial infection must be established.
Reprogramming mitochondrial metabolism in macrophages as an anti‐inflammatory signal

Mitochondria are master regulators of metabolism. Mitochondria generate ATP by oxidative phosphorylation using pyruvate (derived from glucose and glycolysis) and fatty acids (FAs), both of which are oxidized in the Krebs cycle, as fuel sources. Mitochondria are also an important source of reactive oxygen species (ROS), creating oxidative stress in various contexts, including in the response to bacterial infection. Recently, complex changes in mitochondrial metabolism have been characterized in mouse macrophages in response to varying stimuli in vitro. In LPS and IFN‐γ‐activated macrophages (M1 macrophages), there is decreased respiration and a broken Krebs cycle, leading to accumulation of succinate and citrate, which act as signals to alter immune function. In IL‐4‐activated macrophages (M2 macrophages), the Krebs cycle and oxidative phosphorylation are intact and fatty acid oxidation (FAO) is also utilized. These metabolic alterations in response to the nature of the stimulus are proving to be determinants of the effector functions of M1 and M2 macrophages. Furthermore, reprogramming of macrophages from M1 to M2 can be achieved by targeting metabolic events. Here, we describe the role that metabolism plays in macrophage function in infection and immunity, and propose that reprogramming with metabolic inhibitors might be a novel therapeutic approach for the treatment of inflammatory diseases.
Integration of linear programming and a watershed-scale hydrologic model for proposing an optimized land-use plan and assessing its impact on soil conservation—A case study of the Nagwan watershed in the Hazaribagh district of Jharkhand, India

The present investigation was an attempt to develop a Spatial Decision Support System (SDSS) for a test Nagwan watershed situated in the Damodar–Barakar catchment in India, the second most seriously eroded area in the world, for not only estimating sediment yields under prevailing resource management systems but also designing a linear programming (LP)-based optimized land-use plan for soil loss reduction in the test watershed. The proposed SDSS was validated on 9 years (1981–1983, 1985–1989, and 1991) of sediment yield data for the test watershed. This showed that the SDSS could mimic the annual dynamics of the total sediment yields at the test watershed outlet with a correlation coefficient of 0.65, model efficiency coefficient of 0.70, mean relative error of −17.97%, and root mean square prediction error of 9.63 t ha−1. It could also be used as an efficient tool for assessing sediment yields from different parts of the test watershed and for designing a linear programming (LP)-based optimized land-use plan for reduced total sediment yields from the test watershed. The LP-based land-use plan proposed no change in the total areas under paddy, corn, and forest land-use types but suggested their re-distribution within the test watershed, thereby leading to not only a reduction in the test watershed's total sediment yield by about 14.61% but also an increase in its paddy and corn crop productivities by 2.80 and 68.14%, respectively. The proposed LP-based land-use plan for the test watershed could thus lead to an enhanced productivity benefit of about Rs 3735 ha−1, in monetary terms, from corn crop cultivation at its optimal locations.
Bacterial communities in urban aerosols collected with wetted-wall cyclonic samplers and seasonal fluctuations of live and culturable airborne bacteria.

Airborne transmission of bacterial pathogens from point sources (e.g., ranches, dairy waste treatment facilities) to areas of food production (farms) has been suspected. Determining the incidence, transport and viability of extremely low levels of pathogens require collection of high volumes of air and characterization of live bacteria from aerosols. We monitored the numbers of culturable bacteria in urban aerosols on 21 separate days during a 9 month period using high volume cyclonic samplers at an elevation of 6 m above ground level. Culturable bacteria in aerosols fluctuated from 3 CFU to 6 million CFU/L of air per hour and correlated significantly with changes in seasonal temperatures, but not with humidity or wind speed. Concentrations of viable bacteria determined by fluorescence staining and flow cytometry correlated significantly with culturable bacteria. Members of the phylum Proteobacteria constituted 98% of the bacterial community, which was characterized using 16S rRNA gene sequencing using DNA from aerosols. Aquabacterium sp. , previously characterized from aquatic environments, represented 63% of all clones and the second most common were Burkholderia sp; these are ubiquitous in nature and some are potential human pathogens. Whole genome amplification prior to sequencing resulted in a substantial decrease in species diversity compared to characterizing culturable bacteria sorted by flow cytometry based on scatter signals. Although 27 isolated colonies were characterized, we were able to culture 38% of bacteria characterized by sequencing. The whole genome amplification method amplified DNA preferentially from Phyllobacterium myrsinacearum, a minor member of the bacterial communities, whereas Variovorax paradoxus dominated the cultured organisms.
Adult thymic epithelial cell (TEC) progenitors and TEC stem cells: Models and mechanisms for TEC development and maintenance

The thymus is the primary lymphoid organ for generating self‐restricted and self‐tolerant functional T cells. Its two distinct anatomical regions, the cortex and the medulla, are involved in positive and negative selection, respectively. Thymic epithelial cells (TECs) constitute the framework of this tissue and function as major stromal components. Extensive studies for more than a decade have revealed how TECs are generated during organogenesis; progenitors specific for medullary TECs (mTECs) and cortical TECs (cTECs) as well as bipotent progenitors for both lineages have been identified, and the signaling pathways required for the development and maturation of mTECs have been elucidated. However, little is known about the initial commitment of mTECs and cTECs during ontogeny, and how regeneration of both lineages is sustained in the postnatal/adult thymus. Recently, stem cell activities in TECs have been demonstrated, and TEC progenitors have been identified in the postnatal thymus. In this review, recent advances in studying the development and maintenance of TECs are summarized, and the possible mechanisms of thymic regeneration and involution are discussed.
Hiatal hernia in a Shar-Pei.

A combined axial and paraoesophageal hiatal hernia complicated by splenic involvement was diagnosed in a two-year-old Chinese shar-pei. A circumcostal gastropexy was performed following reduction of the hernia and fundoplication of the cardia The dog recovered well and is asymptomatic six months postoperatively. The literature concerning hiatal hernia in the dog is reviewed and the various surgical techniques described for its management are discussed.
Job strain and ambulatory blood pressure in British general practitioners: A preliminary study

Occupational stress, in particular 'high strain' (defined as high psychological job demands and low job control; Karasek, 1979) has been found to be associated with coronary heart disease and hypertensive risk in a number of occupations. However, despite the large number of studies of GP stress, none have extended this model to British GPs. It was hypothesized that 'high strain' GPs would exhibit heightened levels of cardiovascular arousal compared to 'low strain' GPs, with a carry-over effect into the non-work day. Twenty low strain GPs were compared with seven high strain GPs on ambulatory blood pressure during a work day, work day evening, non-work day and non-work day evening. Work day and non-work day monitoring was counterbalanced. Levels of mental health and job satisfaction were also assessed. High strain GPs' systolic blood pressure and diastolic blood pressure was generally elevated, in particular during the non-work day, compared to their low strain counterparts. No gender differences were found for any of the BP variables. Levels of depression, anxiety and job dissatisfaction were found to be significantly greater for high strain GPs. In terms of GP stress research, these findings are novel; however replication is required with a larger sample.
NF‐κB‐inducing kinase is essential for B‐cell maintenance in mice

NF‐κB‐inducing kinase (NIK) is a key mediator of the noncanonical NF‐κB signaling pathway, which is critical for normal B‐cell development and function. It is well established that the complete deletion of NIK in mice results in defective B cells and impaired secondary lymphoid organogenesis. To address the role of NIK deficiency specifically in B cells, we generated a new mouse strain for the conditional deletion of this kinase. Deletion of NIK during B‐cell development results in a drastic reduction of mature B cells from the transitional 2 stage on, while B‐1 B cells are less affected. Moreover, deletion of NIK in the germinal centers decreases the numbers of germinal center B cells and impairs the ability of NIK‐deficient B cells to develop into class‐switched cells in vivo. This new mouse strain will be helpful for studying the role of NIK in different cell types of the body.
A novel Flt3‐deficient HIS mouse model with selective enhancement of human DC development

Humanized mice harboring human immune systems (HIS) represent a platform to study immune responses against pathogens and to screen vaccine candidates and novel immunotherapeutics. Innate and adaptive immune responses are suboptimal in HIS mice, possibly due to poor reconstitution of human antigen‐presenting cells, including dendritic cells (DCs). DC homeostasis is regulated by cytokine availability, and Flt3‐ligand (Flt3L) is one factor that conditions this process. Mouse myelopoiesis is essentially normal in most current HIS models. As such, developing mouse myeloid cells may limit human DC reconstitution by reducing available Flt3L and by cellular competition for specific “niches. ” To address these issues, we created a novel HIS model that compromises host myeloid cell development via deficiency in the receptor tyrosine kinase Flk2/Flt3. In Balb/c Rag2−/−Il2rg−/−Flt3−/− (BRGF) recipients, human conventional DCs and plasmacytoid DCs develop from hCD34+ precursors and can be specifically boosted with exogenous Flt3L. Human DCs that develop in this context normally respond to TLR stimulation, and improved human DC homeostasis is associated with increased numbers of human NK and T cells. This new HIS‐DC model should provide a means to dissect human DC differentiation and represents a novel platform to screen immune adjuvants and DC targeting therapies.
Update in the medical therapy of Cushing's disease

Purpose of review Recently developed agents treat Cushing's disease by inhibiting ACTH secretion from corticotrope tumors or antagonizing cortisol action. Recent findings The dopamine agonist cabergoline and the somatostatin agonist pasireotide target ACTH secretion. Each has low rates of normalization of urine-free cortisol (UFC), about 40% at doses of 1–7 mg weekly and 20% at doses of 600 or 900 &mgr;g twice daily, respectively. Cabergoline, an oral agent, has a relatively benign side-effect profile, primarily asthenia. Small trials suggest that combination therapy with ketoconazole increases effectiveness. Pasireotide, a parenteral agent, is associated with types and rates of adverse events similar to those seen with other somatostatin agonists (diarrhea, nausea, cholelithiasis), except for glucose intolerance, which occurs more frequently (∼ 75%). It may be most effective when UFC is less than two-fold normal. A few case reports suggest that pasireotide or cabergoline may control tumor size and ACTH secretion from macroadenomas. Retinoic acid must be evaluated further. The glucocorticoid antagonist mifepristone ameliorates glucose intolerance but may not normalize other Cushingoid features. Summary These novel approaches provide options for treatment of patients in whom surgery has failed or is not possible, and those who decline adrenalectomy or radiation therapy.
Lactate at the crossroads of metabolism, inflammation, and autoimmunity

For a long time after its discovery at the beginning of the 20th century, lactate was considered a waste product of cellular metabolism. Starting in the early ‘90s, however, lactate has begun to be recognized as an active molecule capable of modulating the immune response. Inflammatory sites, including in rheumatoid arthritis (RA) synovitis, are characterized by the accumulation of lactate, which is partly responsible for the establishment of an acidic environment. We have recently reported that T cells sense lactate via the expression of specific transporters, leading to inhibition of their motility. Importantly, this “stop migration signal” is dependent upon lactate's interference with intracellular metabolic pathways, specifically glycolysis. Furthermore, lactate promotes the switch of CD4+ T cells to an IL‐17+ subset, and reduces the cytolytic capacity of CD8+ T cells. These phenomena might be responsible for the formation of ectopic lymphoid structures and autoantibody production in inflammatory sites such as in RA synovitis, Sjogren syndrome salivary glands, and multiple sclerosis plaques. Here, we review the roles of lactate in the modulation of the inflammatory immune response.
Lack of correlation between ABL‐BCR expression and response to interferon‐α in chronic myeloid leukaemia

Interferon‐α (IFN‐α) is useful in the treatment of Philadelphia (Ph)‐positive chronic myeloid leukaemia (CML). There is, however, a marked heterogeneity among CML patients in relation to their response to IFN‐α treatment, the reasons for which are unknown. Since the reciprocal ABL‐BCR gene is transcriptionally active in only a proportion of CML patients, it has been suggested that response to IFN‐α may correlate with ABL‐BCR expression. In the present study we have tested 209 Ph‐positive CML patients for expression of ABL‐BCR, BCR‐ABL and the normal BCR and ABL genes by reverse transcriptase/polymerase chain reaction (RT/PCR). Whereas BCR‐ABL, BCR and ABL transcripts were detected in all the patients, ABL‐BCR expression was observed in 59% of the cases. A group of 105 patients within this series was treated with IFN‐α: 33% achieved a complete or major cytogenetic response (<35% Ph‐positive metaphases) and the remaining 67% showed minimal or no response to IFN‐α. The proportions of patients who were ABL‐BCR positive (63%) and ABL‐BCR negative (37%) were the same for good responders and poor responders, suggesting that there is no correlation between ABL‐BCR expression and cytogenetic response to IFN‐α in CML.
I.V. BOLUS ADMINISTRATION OF SUBCONVULSIVE DOSES OF LIGNOCAINE TO CONSCIOUS SHEEP: RELATIONSHIPS BETWEEN MYOCARDIAL PHARMACOKINETICS AND PHARMACODYNAMICS

We have studied relationships between the time-courses of lignocaine concentrations in arterial and coronary sinus blood and myocardial tissue, and negative inotropic effects on the myocardium, after i.v. bolus administration of 50-, 75- or 100-mg doses of lignocaine to conscious, chronically instrumented sheep. Peak arterial and coronary sinus blood lignocaine concentrations occurred 26-38 s before and 29-78 s after the maximum decreases in myocardial contractility, respectively. Peak myocardial concentrations occurred simultaneously with the maximum decreases in myocardial contractility, except for the 100-mg doses. Anti-clockwise hysteresis occurred only between arterial blood lignocaine concentrations and the negative inotropic effect. It was concluded that, after short-term i.v. administration, only the myocardial concentrations of lignocaine were in pseudoequilibrium with the negative inotropic effects of the lignocaine on the myocardium.
Comparing outcomes of stereotactic body radiotherapy with intensity-modulated radiotherapy for patients with locally advanced unresectable pancreatic cancer

Objectives Survival in patients with locally advanced unresectable pancreatic cancer (LAUPC) is poor, and local recurrence continues to be a major problem in the management of this disease. Radiotherapy (RT) using different RT techniques, including intensity-modulated radiotherapy (IMRT) and stereotactic body radiation therapy (SBRT), may lead to different clinical outcomes for patients with LAUPC. Here, we compared SBRT with IMRT for patients with LAUPC with respect to survival rate, local control (LC) rate, and toxicity-related dose distribution. Materials and methods This retrospective study from March 2007 to March 2011 included 41 patients with LAUPC who were divided into two groups, with 20 patients receiving SBRT and 21 patients receiving IMRT. The median follow-up time was 16 months. Results For the IMRT and SBRT groups, the median survival times were 13 and 20 months, and 1-year overall survival (OS) rates were 70.7 and 80.0%, respectively. There was no difference in OS between the two RT techniques. RT with SBRT showed significantly better local disease-free survival than IMRT for patients with LAUPC. Tobacco use had a borderline effect on LC. Thus, further statistical analysis showed that patients who used tobacco had better LC after receiving SBRT than IMRT. Conclusion SBRT improved LC for LAUPC patients and had similar radiation toxicity compared with IMRT. Further study is required to define the effects of administered radiation dose and fractionation, as well as to further expand the sample size, to use a prospective study, and to observe the long-term efficacy of these techniques.
Detailed characterization of human Mycobacterium tuberculosis specific HLA‐E restricted CD8+ T cells

HLA‐E presented antigens are interesting targets for vaccination given HLA‐Es’ essentially monomorphic nature. We have shown previously that Mycobacterium tuberculosis (Mtb) peptides are presented by HLA‐E to CD8+ effector T cells, but the precise phenotype and functional capacity of these cells remains poorly characterized. We have developed and utilized in this study a new protocol combining HLA‐E tetramer with intracellular staining for cytokines, transcription factors and cytotoxic molecules to characterize these cells in depth. We confirm in this study the significantly increased ex vivo frequency of Mtb‐peptide/HLA‐E‐TM+ CD8+ T cells in the circulation of patients with active tuberculosis (TB). HLA‐E restricted CD8+ T cells from TB patients produced more IL‐13 than cells from controls or subjects with latent tuberculosis infection (LTBI). Compared to total CD8+ T cells, HLA‐E restricted cells produced more IFNγ, IL‐4, IL‐10, and granulysin but less granzyme‐A. Moreover, compared to “classical” Mtb specific HLA‐A2 restricted CD8+ T cells, HLA‐E restricted CD8+ T cells produced less TNFα and perforin, but more IL‐4. In conclusion, HLA‐E restricted‐ Mtb specific cells can produce Th2 cytokines directly.