Cyclophilin A (CyPA), a ubiquitously distributed intracellular protein, is a peptidylprolyl cis-trans-isomerase and the major target of the potent immunosuppressive drug cyclosporin A. Although expressed predominantly as an intracellular molecule, CyPA is secreted by cells in response to inflammatory stimuli and is a potent neutrophil and eosinophil chemoattractant in vitro and in vivo. The mechanisms underlying CyPA-mediated signaling and chemotaxis are unknown. Here, we identified CD147 as a cell surface receptor for CyPA and demonstrated that CD147 is an essential component in the CyPA-initiated signaling cascade that culminates in ERK activation. Both signaling and chemotactic activities of CyPA depended also on the presence of heparans, which served as primary binding sites for CyPA on target cells. The proline 180 and glycine 181 residues in the extracellular domain of CD147 were critical for signaling and chemotactic activities mediated by CD147. Also crucial were active site residues of CyPA, because rotamase-defective CyPA mutants failed to initiate signaling events. These results establish cyclophilins as natural ligands for CD147 and suggest an unusual, rotamase-dependent mechanism of signaling.

Recent data have implicated macrophage inflammatory protein-1␣ (MIP-1␣) in multiple myeloma (MM)-associated osteolysis. However, it is unclear whether the chemokine's effects are direct, to enhance osteolysis, or indirect and mediated through a reduction in tumor burden, or both. It is also unclear whether MIP-1␣ requires other factors such as receptor activator of nuclear factor-B ligand (RANKL) for its effects on bone. In murine 5TGM1 (Radl) myeloma-bearing mice, administration of neutralizing anti-MIP-1␣ antibodies reduced tumor load assessed by monoclonal paraprotein titers, prevented splenomegaly, limited development of osteolytic lesions, and concomitantly reduced tumor growth in bone. IntroductionMurine macrophage inflammatory protein-1␣ (MIP-1␣)/CCL3 is a member of a superfamily of structurally related and secreted low molecular weight cytokines involved in the directed migration (chemotaxis) and activation of cells that have been implicated in inflammation, wound healing, hematopoiesis, and tumorigenesis. [1][2][3][4] MIP-1␣ was originally isolated as a macrophage product with inflammatory and chemotactic properties. 5,6 To date, 4 chemokine subfamilies (CXC [␣], CC [␤], C [␥], and CX 3 C) have been described based on the position of conserved cysteine residues, and MIP-1␣ belongs to the CC subfamily. The 4 classes of chemokines act on different cell types, and members of the CC subfamily including MIP-1␣ promote migration of monocytes/macrophages and T lymphocytes. 1,3,7,8 Multiple myeloma (MM), the second most common adult hematologic malignancy-affecting 14 000 patients in the United States and accounting for 1% to 2% of cancer-related deaths 9 -is associated with severe and progressive bone destruction. The high morbidity and mortality rates associated with this plasma cell malignancy are primarily due to the effects of the unremitting osteolysis and occasional hypercalcemia. 10 There is unequivocal evidence that myeloma-induced bone loss is due to increased osteoclast activity induced by an as yet unidentified locally acting factor(s). 10 MIP-1␣ is expressed and secreted by myeloma cells freshly isolated from patients as well as human myeloma cell lines. 11-14 Levels of MIP-1␣ are elevated in bone marrow plasma of myeloma patients compared with other lymphoid hematologic malignancies and normal controls. 11,12 Gene expression profiling studies also show that MIP-1␣ expression in mononuclear cells isolated from the bone marrow of myeloma patients is several-fold higher than in those from healthy subjects. 14 MIP-1␣ stimulates chemotaxis of human osteoclast precursors 15 and formation of human osteoclast-like cells in vitro. 12,15,16 In nonhuman systems, The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. MIP-1␣ has also been shown to be chemotactic for cells at various stages in osteoclast ontogeny including murine granulocytemacrop...

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Background. Colchicine has been used in conditions such as periodic febrile illness, acute pericarditis, and gouty arthritis, all having a common hyperinflammatory response as seen in moderate to severe forms of coronavirus disease 2019 (COVID-19). This project was carried out during the rapid surge of cases in New York City, and the goal was to assess the efficacy of colchicine in treating patients with COVID-19. Methods. Patients admitted to two distinct pulmonary oriented floors of the BronxCare Hospital Center were compared. Patients on one floor were given colchicine in addition to standard of care, while control patients from another floor received only standard of care. Patients who had at least two separate timepoint measurements for at least two out of four serum inflammatory markers (C-reactive protein (CRP), D-dimer, ferritin, or lactate dehydrogenase (LDH)) were selected for the final comprehensive analysis. Results. An initial analysis performed on all patients, irrespective of the availability of two timepoint inflammatory markers, revealed a lower mortality (49.1% versus 72.9%, P = 0.002 ), a lower percentage of intubations (52.8% versus 73.6%, P = 0.006 ), and a higher discharge rate (50.9% versus 27.1%, P = 0.002 ), in the patients who received colchicine. Patients in the final comprehensive analysis groups (34 in the colchicine group and 78 in the control group) had a similar prevalence of comorbid medical conditions, except for renal failure, which was higher in the control group (65.3% versus 35.2%, P = 0.015 ). HTN (71.8% versus 52.9%, P = 0.053 ) and DM (51.3% versus 32.4%, P = 0.064 ) were also more prevalent in the control group, although the difference was not statistically significant. Patients who received colchicine had a lower mortality than the control group (47.1% versus 80.8%, P = 0.0003 ), lower rate of intubations (47.1% versus 87.2%, P < 0.0001 ), and a higher discharge rate (52.9% versus 19.2%, P = 0.0003 ). Patients in the colchicine group also showed a more significant decrease in inflammatory markers for D-dimer ( P = 0.037 ), CRP ( P = 0.014 ), and ferritin ( P = 0.012 ). Conclusions. Our study demonstrates that colchicine improved outcomes in patients with COVID-19 receiving standard of care therapy. Future randomized, placebo-controlled clinical trials to assess the potential benefit of colchicine in COVID-19 are warranted.

It is now well established that HIV-1 requires interactions with both CD4 and a chemokine receptor on the host cell surface for efficient infection. The expression of the CCR5 chemokine receptor in human macrophages facilitates HIV-1 entry into these cells, which are considered important in HIV pathogenesis not only as viral reservoirs but also as modulators of altered inflammatory function in HIV disease and AIDS. LPS, a principal constituent of Gram-negative bacterial cell walls, is a potent stimulator of macrophages and has been shown to inhibit HIV infection in this population. We now present evidence that one mechanism by which LPS mediates its inhibitory effect on HIV-1 infection is through a direct and unusually sustained down-regulation of cell-surface CCR5 expression. This LPS-mediated down-regulation of CCR5 expression was independent of de novo protein synthesis and differed from the rapid turnover of these chemokine receptors observed in response to two natural ligands, macrophage-inflammatory protein-1α and -1β. LPS did not act by down-regulating CCR5 mRNA (mRNA levels actually increased slightly after LPS treatment) or by enhancing the degradation of internalized receptor. Rather, the observed failure of LPS-treated macrophages to rapidly restore CCR5 expression at the cell-surface appeared to result from altered recycling of chemokine receptors. Taken together, our results suggest a novel pathway of CCR5 recycling in LPS-stimulated human macrophages that might be targeted to control HIV-1 infection.

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Deep learning models based on medical images play an increasingly important role for cancer outcome prediction. The standard approach involves usage of convolutional neural networks (CNNs) to automatically extract relevant features from the patient’s image and perform a binary classification of the occurrence of a given clinical endpoint. In this work, a 2D-CNN and a 3D-CNN for the binary classification of distant metastasis (DM) occurrence in head and neck cancer patients were extended to perform time-to-event analysis. The newly built CNNs incorporate censoring information and output DM-free probability curves as a function of time for every patient. In total, 1037 patients were used to build and assess the performance of the time-to-event model. Training and validation was based on 294 patients also used in a previous benchmark classification study while for testing 743 patients from three independent cohorts were used. The best network could reproduce the good results from 3-fold cross validation [Harrell’s concordance indices (HCIs) of 0.78, 0.74 and 0.80] in two out of three testing cohorts (HCIs of 0.88, 0.67 and 0.77). Additionally, the capability of the models for patient stratification into high and low-risk groups was investigated, the CNNs being able to significantly stratify all three testing cohorts. Results suggest that image-based deep learning models show good reliability for DM time-to-event analysis and could be used for treatment personalisation.

The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.