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In data envelopment analysis (DEA), calculating the distances of decision making units (DMUs) from the weak efficient boundary of a production possibility set (PPS) is a very important subject which has attracted increasing interest of researchers in recent years. The distances of DMUs to the weak efficient boundary of the PPS can be used to evaluate the performance of DMUs, obtain the closest efficient patterns and also assess the sensitivity and stability of efficiency classifications in DEA. The present study proposes some new models which compute the distances of DMUs from the weak efficient boundary of a PPS for both convex and nonconvex PPSs using Hölder norms. In fact, the presented models assist a DMU to improve its performance by an appropriate movement towards the weak efficient boundary. [ABSTRACT FROM AUTHOR]

Evaluating group performance of decision-making units (DMUs) is an application of data envelopment analysis (DEA) and usually provides a measure to compare the frontiers of the production possibility sets (PPSs) corresponding to different groups and the internal inefficiencies of DMUs associated with their group. In this paper, first, a method is presented for obtaining the minimum distance of DMUs from the frontier of the PPS by |⋅|1, which itself can be a very important subject in DEA, and then, for stating an application of these distances, an approach is provided for evaluating group performance of DMUs based on the production ability of the PPSs such that both constant and variable returns to scale assumptions can be used in this method in contrast with some other methods. Therefore, providing the methods for both obtaining the minimum distance of DMUs from the frontier of the PPS and evaluating group performance of DMUs is the most important contribution of this paper. [ABSTRACT FROM AUTHOR]

Data envelopment analysis (DEA) can be used for assessing the relative efficiency of a number of operating units, finding, for each unit, a target operating point lying on the strong efficient frontier. Most DEA models project an inefficient unit onto a most distant target, which makes its attainment more difficult. In this paper, a linear bilevel programming problem for obtaining the closest targets and minimum distance of a unit from the strong efficient frontier by different norms is provided. The idea behind this approach is that closer targets determine less demanding levels of operation for the inputs and outputs of the units to perform efficiently. Finally, it will be shown that the proposed method is an extension of the existing methods. [ABSTRACT FROM AUTHOR]

Efficiency is a basic issue in Data Envelopment Analysis (DEA). There are different types of efficiency in DEA, e.g. Technical Efficiency (TE), Cost Efficiency (CE) and Revenue Efficiency (RE). They may be different in terms of efficiency score values because they use different information obtained from Decision Making Units (DMUs). One of these efficiency types (TE) uses only input and output quantities, another (CE) uses input, output and input cost vectors and still another (RE) uses input, output and output benefit vectors. In real problems, not the cost of each input or the benefit of each output is usually known and accessible, and just the costs (benefits) of some inputs (outputs) of each DMU are known. In this paper, we suggest a method and models to measure the efficiency of DMUs when some input costs and some output benefits are known. The proposed measure is a generalization of TE, CE and RE. This measure is very useful to evaluate the performance of DMUs and uses more information than the other measures. We show that the CCR model to evaluate TE and the minimal cost model to evaluate CE are special cases of the proposed model. Finally we present three examples to compare the proposed measure of efficiency with the other measures of efficiency. [ABSTRACT FROM AUTHOR]

Introduction: Acute endurance exercise may induce airway epithelium injury. However, the response of epithelial integrity markers of the airways including club cell secretory protein (CC16) and surfactant protein D (SP-D) to endurance exercise have not been systematically reviewed. Therefore, the aim of this systematic review and meta-analysis was to assess the acute effects of endurance exercise on markers of epithelial integrity of the airways (CC16, SP-D and the CC16/SP-D ratio) in athletes and non-athletes., Methods: A systematic search was performed utilizing PubMed/Medline, EMBASE, Web of Science, and hand searching bibliographies of retrieved articles through to September 2022. Based on the inclusion criteria, articles with available data about the acute effects of endurance exercise on serum or plasma concentrations of CC16, SP-D and CC16/SP-D ratio in athletes and non-athletes were included. Quality assessment of studies and statistical analysis were conducted via Review Manager 5.4 software., Results: The search resulted in 908 publications. Finally, thirteen articles were included in the review. Acute endurance exercise resulted in an increase in CC16 (P = 0.0006, n = 13) and CC16/SP-D ratio (P = 0.005, n = 2) whereas SP-D (P = 0.47, n = 3) did not change significantly. Subgroup analysis revealed that the type (P = 0.003), but not the duration of exercise (P = 0.77) or the environmental temperature (P = 0.06) affected the CC16 response to endurance exercise., Conclusions: Acute endurance exercise increases CC16 and the CC16/SP-D ratio, as markers of epithelial integrity, but not SP-D in athletes and non-athletes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Human immunodeficiency virus (HIV), hepatitis C virus (HCV), and injection drug use are syndemic in the central Appalachian states. In Tennessee (TN), declines in HIV among persons who inject drugs (PWID) stalled, and HCV infection rates increased significantly from 2013-2017. To better target strategies to address the syndemic, county-level socioeconomic, opioid use, access to healthcare, and health factors were modeled to identify indicators predictive of vulnerability to an HIV/HCV outbreak among PWID in TN., Methods: Newly reported chronic HCV cases among persons aged 13-39 years in 2016-2017 were used as a proxy for county-level HIV/HCV vulnerability among TN's 95 counties. Seventy-five publicly available county-level measures from 2016-2017 were collected and reduced through multiple dimension reduction techniques. Negative binomial regression identified indicators associated with HCV which were used to calculate county-level vulnerability to a local HIV/HCV outbreak., Results: Thirteen county-level indicators were identified as strongly predictive of HIV/HCV vulnerability with the statistically significant indicators being percentage of the population aged 20-44 years, per capita income, teen birth rate, percentage of clients in TDMHSAS-funded opioid treatment and recovery, syphilis case rate, and percentage of homes with at least one vehicle. Based on the 13 indicators, we identified the distribution of vulnerability to an HIV/HCV outbreak among TN's counties. Eleven high vulnerability counties were identified, with the preponderance located in east and middle TN., Conclusion: This analysis identified the county-level factors most associated with vulnerability to an HIV/HCV outbreak among PWID in TN. These results, alongside routine surveillance, will guide targeted prevention and linkage to care efforts for the most vulnerable communities., Competing Interests: The authors have declared that no competing interests exist.

The nongenetic mechanisms required to sustain malignant tumor state are poorly understood. During the transition from benign tumors to malignant carcinoma, tumor cells need to repress differentiation and acquire invasive features. Using transcriptional profiling of cancer stem cells from benign tumors and malignant skin squamous cell carcinoma (SCC), we identified the nuclear receptor NR2F2 as uniquely expressed in malignant SCC. Using genetic gain of function and loss of function in vivo, we show that NR2F2 is essential for promoting the malignant tumor state by controlling tumor stemness and maintenance in mouse and human SCC. We demonstrate that NR2F2 promotes tumor cell proliferation, epithelial-mesenchymal transition and invasive features, while repressing tumor differentiation and immune cell infiltration by regulating a common transcriptional program in mouse and human SCCs. Altogether, we identify NR2F2 as a key regulator of malignant cancer stem cell functions that promotes tumor renewal and restricts differentiation to sustain a malignant tumor state., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Eribulin is a non-taxane microtubule dynamics inhibitor that showed a survival benefit versus treatment of physician's choice in a phase III trial enrolling patients with metastatic breast cancer (MBC)., Methods: The E7389-G000-398 trial was designed to provide eribulin to MBC patients pre-treated with anthracylines, taxanes and capecitabine. Patient characteristics, efficacy and safety data were collected prospectively. Efficacy and survival analyses were performed using retrospectively collected data of patients treated at a single institution., Results: One hundred fifty-four patients were enrolled and the median number of previous lines of chemotherapy was 4. The most frequent adverse events were fatigue/asthenia (74%), alopecia (55%), peripheral neuropathy (46%) and neutropenia (43%). Objective response rate (ORR) was 24% in the evaluable population and 14% in patients pre-treated with both taxanes and vinorelbine. In patients with oestrogen receptor (ER)+/human epidermal growth factor receptor 2 (HER2)- MBC, response rate was 29% and 21% with triple-negative disease. Activity was minimal in HER2+ MBC treated with eribulin monotherapy (14% ORR). Median progression-free survival was 3.2 months. Median overall survival was 11.3 months; 77% of patients were alive at 6 months and 43% at 12 months., Conclusion: Eribulin was active in MBC patients with a high tumour burden and predominant visceral disease. Safety profile was similar to what was reported in the phase III trials. Prophylactic granulocyte colony-stimulating factor administration allowed optimal dose intensity and could have contributed to the recorded response rate. Activity is sustained after treatment with taxanes and vinorelbine. The recently investigated combination of eribulin and trastuzumab should lead to higher activity in HER2-positive MBC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1-74) circulates in high concentrations in plasma. CCL14a(1-74) is converted into CCL14a(9-74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12-74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca(2+) concentration mobilization is CCL14a(6-74)<(7-74)<(8-74)<<(9-74) = (10-74)>>(11-74)>>(12-74). The almost identical affinities of CCL14a(7-74), CCL14a(9-74), and CCL14a(10-74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12-74) did reveal antagonistic activity on intracellular Ca(2+) concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr(11) might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9-74) to CCL14a(12-74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11-74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12-74) from CCL14a(11-74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.

Monocyte infiltration into inflammatory sites is generally preceded by neutrophils. We show here that neutrophils may support this process by activation of CCL15, a human chemokine circulating in blood plasma. Neutrophils were found to release CCL15 proteolytic activity in the course of hemofiltration of blood from renal insufficiency patients. Processing of CCL15 immunoreactivity (IR) in the pericellular space is suggested by a lack of proteolytic activity in blood and blood filtrate, but a shift of the retention time (t(R)) of CCL15-IR, detected by chromatographic separation of CCL15-IR in blood and hemofiltrate. CCL15 molecules with N-terminal deletions of 23 (delta23) and 26 (delta26) aa were identified as main proteolytic products in hemofiltrate. Neutrophil cathepsin G was identified as the principal protease to produce delta23 and delta26 CCL15. Also, elastase displays CCL15 proteolytic activity and produces a delta21 isoform. Compared with full-length CCL15, delta23 and delta26 isoforms displayed a significantly increased potency to induce calcium fluxes and chemotactic activity on monocytes and to induce adhesiveness of mononuclear cells to fibronectin. Thus, our findings indicate that activation of monocytes by neutrophils is at least in part induced by quantum proteolytic processing of circulating or endothelium-bound CCL15 by neutrophil cathepsin G.

We have previously isolated from human hemofiltrate an N-terminally truncated form of the hemofiltrate CC chemokine 1 (HCC-1), and characterized HCC-1[9-74] as a strong agonist of CCR1, CCR5, and to a lower extent CCR3. In this study, we show that conditioned media from human tumor cell lines PC-3 and 143B contain proteolytic activities that convert HCC-1 into the [9-74] form. This activity was fully inhibited by inhibitors of urokinase-type plasminogen activator (uPA), including PA inhibitor-1, an anti-uPA mAb, and amiloride. Pure preparations of uPA processed HCC-1 with high efficiency, without further degrading HCC-1[9-74]. Plasmin could also generate HCC-1[9-74], but degraded the active product as well. The kinetics of HCC-1 cleavage by uPA and plasmin (Michaelis constant, K(m), of 0.76 +/- 0.4 microM for uPA, and 0.096 +/- 0.05 microM for plasmin; catalytic rate constant, k(cat): 3.36 +/- 0.96 s(-1) for uPA and 6 +/- 3.6 s(-1) for plasmin) are fully compatible with a role in vivo. The activation of an abundant inactive precursor into a broad-spectrum chemokine by uPA and plasmin directly links the production of uPA by numerous tumors and their ability to recruit mononuclear leukocytes, without the need for the transcriptional activation of chemokine genes.

1. Neuropeptides FF (NPFF) and AF (NPAF) are involved in pain modulation and opioid tolerance. These peptides were known to act through uncharacterized G protein-coupled receptors (GPCR). We describe here, using an aequorin-based assay as screening tool, that an orphan GPCR, previously designated HLWAR77, is a functional high affinity receptor for NPFF and related peptides. This receptor is further designated as NPFFR. 2. Binding experiments were performed with a new radioiodinated probe, [(125)I]-EYF, derived from the EFW-NPSF sequence of the rat NPFF precursor. Chinese hamster ovary (CHO) cell membranes expressing NPFFR bound [(125)I]-EYF with a K(d) of 0.06 nM. Various NPFF analogues and related peptides inhibited [(125)I]-EYF specific binding with the following rank order (K(i)): human NPAF (0.22 nM), SQA-NPFF (0.29 nM), NPFF (0.30 nM), 1DMe (0.31 nM), EYW-NPSF (0.32 nM), QFW-NPSF (0.35 nM), 3D (1.12 nM), Met-enk-RF-NH(2) (3.25 nM), FMRF-NH(2) (10.5 nM) and NPSF (12.1 nM). 3. The stimulatory activity of the same set of peptides was measured by a functional assay based on the co-expression of NPFFR, G(alpha 16) and apoaequorin. The rank order of potency was consistent with the results of the binding assay. 4. Membranes from NPFFR expressing CHO cells bound GTP gamma[(35)S] in the presence of SQA-NPFF. This functional response was prevented by pertussis toxin treatment, demonstrating the involvement of G(i) family members. 5. SQA-NPFF inhibited forskolin induced cyclic AMP accumulation in recombinant CHO cells in a dose dependent manner. This response was abolished as well by pertussis toxin pre-treatment. 6. RT -- PCR analysis of human tissues mRNA revealed that expression of NPFFR was mainly detected in placenta, thymus and at lower levels in pituitary gland, spleen and testis.

Hemofiltrate CC chemokine (HCC)-1 is a recently described human chemokine that is constitutively expressed in numerous tissues and is present at high concentrations in normal plasma. Using a cell line expressing CC chemokine receptor (CCR)5 as a bioassay, we isolated from human hemofiltrate an HCC-1 variant lacking the first eight amino acids. HCC-1[9-74] was a potent agonist of CCR1, CCR3, and CCR5 and promoted calcium flux and chemotaxis of T lymphoblasts, monocytes, and eosinophils. It also blocked entry of HIV-1 strains using CCR5 as coreceptor. Limited tryptic digestion of HCC-1 generated the active variant. Conditioned media from several tumor cell lines activated HCC-1 with a high efficiency, and this activity could be inhibited by serine protease inhibitors. Our results indicate that HCC-1 represents a nonfunctional precursor that can be rapidly converted to the active chemokine by proteolytic processing. This process represents an additional mechanism by which tumor cells might generate chemoattractant molecules and recruit inflammatory cells. It might also affect HIV-1 replication in infected individuals and play an important role in AIDS pathogenesis.

CCR5 is a functional receptor for MIP-1alpha, MIP-1beta, RANTES (regulated on activation normal T cell expressed), MCP-2, and MCP-4 and constitutes the main coreceptor for macrophage tropic human and simian immunodeficiency viruses. By using CCR5-CCR2b chimeras, we have shown previously that the second extracellular loop of CCR5 is the major determinant for chemokine binding specificity, whereas the amino-terminal domain plays a major role for human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus coreceptor function. In the present work, by using a panel of truncation and alanine-scanning mutants, we investigated the role of specific residues in the CCR5 amino-terminal domain for chemokine binding, functional response to chemokines, HIV-1 gp120 binding, and coreceptor function. Truncation of the amino-terminal domain resulted in a progressive decrease of the binding affinity for chemokines, which correlated with a similar drop in functional responsiveness. Mutants lacking residues 2-13 exhibited fairly weak responses to high concentrations (500 nM) of RANTES or MIP-1beta. Truncated mutants also exhibited a reduction in the binding affinity for R5 Env proteins and coreceptor activity. Deletion of 4 or 12 residues resulted in a 50 or 80% decrease in coreceptor function, respectively. Alanine-scanning mutagenesis identified several charged and aromatic residues (Asp-2, Tyr-3, Tyr-10, Asp-11, and Glu-18) that played an important role in both chemokine and Env high affinity binding. The overlapping binding site of chemokines and gp120 on the CCR5 amino terminus, as well as the involvement of these residues in the epitopes of monoclonal antibodies, suggests that these regions are particularly exposed at the receptor surface.

CCR5 was first characterized as a receptor for MIP-1alpha, MIP-1beta, and RANTES, and was rapidly shown to be the main coreceptor for M-tropic human immunodeficiency virus (HIV)-1 strains and simian immunodeficiency virus (SIV). Chemokines constitute a rapidly growing family of proteins and receptor-chemokine interactions are known to be promiscuous and redundant. We have therefore tested whether other CC-chemokines could bind to and activate CCR5. All CC-chemokines currently available were tested for their ability to compete with [(125)I]-MIP-1beta binding on a stable cell line expressing recombinant CCR5, and/or to induce a functional response in these cells. We found that in addition to MIP-1beta, MIP-1alpha, and RANTES, five other CC-chemokines could compete for [(125)I]-MIP-1beta binding: MCP-2, MCP-3, MCP-4, MCP-1, and eotaxin binding was characterized by IC(50) values of 0.22, 2.14, 5.89, 29.9, and 21.7 nmol/L, respectively. Among these ligands, MCP-3 had the remarkable property of binding CCR5 with high affinity without eliciting a functional response, MCP-3 could also inhibit the activation of CCR5 by MIP-1beta and may therefore be considered as a natural antagonist for CCR5. It was unable to induce significant endocytosis of the receptor. Chemokines that could compete with high affinity for MIP-1beta binding could also compete for monomeric gp120 binding, although with variable potencies; maximal gp120 binding inhibition was 80% for MCP-2, but only 30% for MIP-1beta. MCP-3 could compete efficiently for gp120 binding but was, however, found to be a weak inhibitor of HIV infection, probably as a consequence of its inability to downregulate the receptor.

CCR5 is the major coreceptor for macrophage-tropic human immunodeficiency virus type I (HIV-1). For most G-protein-coupled receptors that have been tested so far, the disulfide bonds linking together the extracellular loops (ECL) are required for maintaining the structural integrity necessary for ligand binding and receptor activation. A natural mutation affecting Cys20, which is thought to form a disulfide bond with Cys269, has been described in various human populations, although the consequences of this mutation for CCR5 function are not known. Using site-directed mutagenesis, we mutated the four extracellular cysteines of CCR5 singly or in combination to investigate their role in maintaining the structural conformation of the receptor, its ligand binding and signal transduction properties, and its ability to function as a viral coreceptor. Alanine substitution of any single Cys residue reduced surface expression levels by 40-70%. However, mutation of Cys101 or Cys178, predicted to link ECL1 and ECL2 of the receptor, abolished recognition of CCR5 by a panel of conformation sensitive anti-CCR5 antibodies. The effects of the mutations on receptor expression and conformation were partially temperature-sensitive, with partial restoration of receptor expression and conformation achieved by incubating cells at 32 degrees C. All cysteine mutants were unable to bind detectable levels of MIP-1beta, and did not respond functionally to CCR5 agonists. Surprisingly, all cysteine mutants did support infection by R5 strains of HIV, though at reduced levels. These results indicate that both disulfide bonds of CCR5 are necessary for maintaining the structural integrity of the receptor necessary for ligand binding and signaling. Env binding and the mechanisms of HIV entry appear much less sensitive to alterations of CCR5 conformation.

The chemokine receptor CCR5 is the major coreceptor for R5 human immunodeficiency virus type-1 strains. We mapped the epitope specificities of 18 CCR5 monoclonal antibodies (mAbs) to identify domains of CCR5 required for chemokine binding, gp120 binding, and for inducing conformational changes in Env that lead to membrane fusion. We identified mAbs that bound to N-terminal epitopes, extracellular loop 2 (ECL2) epitopes, and multidomain (MD) epitopes composed of more than one single extracellular domain. N-terminal mAbs recognized specific residues that span the first 13 amino acids of CCR5, while nearly all ECL2 mAbs recognized residues Tyr-184 to Phe-189. In addition, all MD epitopes involved ECL2, including at least residues Lys-171 and Glu-172. We found that ECL2-specific mAbs were more efficient than NH2- or MD-antibodies in blocking RANTES or MIP-1beta binding. By contrast, N-terminal mAbs blocked gp120-CCR5 binding more effectively than ECL2 mAbs. Surprisingly, ECL2 mAbs were more potent inhibitors of viral infection than N-terminal mAbs. Thus, the ability to block virus infection did not correlate with the ability to block gp120 binding. Together, these results imply that chemokines and Env bind to distinct but overlapping sites in CCR5, and suggest that the N-terminal domain of CCR5 is more important for gp120 binding while the extracellular loops are more important for inducing conformational changes in Env that lead to membrane fusion and virus infection. Measurements of individual antibody affinities coupled with kinetic analysis of equilibrium binding states also suggested that there are multiple conformational states of CCR5. A previously described mAb, 2D7, was unique in its ability to effectively block both chemokine and Env binding as well as coreceptor activity. 2D7 bound to a unique antigenic determinant in the first half of ECL2 and recognized a far greater proportion of cell surface CCR5 molecules than the other mAbs examined. Thus, the epitope recognized by 2D7 may represent a particularly attractive target for CCR5 antagonists.