La falta d’expressió de MICA en pacients amb càncer de bufeta significa un pitjor pronòstic

Antecedents: el càncer de bufeta urinària i de pulmó es troben entre els deu tipus de càncer més comuns en ambdós sexes. El receptor NKG2D i un dels seus lligants, MICA, s’associen amb el tabaquisme i la susceptibilitat de patir malaltia pulmonar obstructiva crònica i càncer de pulmó. Objectiu: esbrinar si el sistema NKG2D-MICA s’associa amb altres càncers epitelials relacionats amb l’hàbit de fumar com el càncer de bufeta. Disseny, Escenari i Participants: 70 casos primaris de càncer de bufeta no múscul invasiu van ser examinats per detectar l’expressió de MICA i CD8 +, CD4 + i la infiltració de cèl·lules NK. La majoria dels pacients (n = 55, 78,6%) eren fumadors actuals o anteriors. Metodologia: la tecnologia de microarrays (TMA) va ser triada per avaluar MICA i l’infiltració tumoral de limfòcits en les mostres de càncer de bufeta. Es varen utilitzar Curves de Kaplan-Meier i l’anàlisi univariant de Cox per avaluar la recaiguda, mortalitat total per càncer i la mortalitat específica per càncer de bufeta. Resultats i limitacions: MICA es va expressar en la majoria dels espècimens de càncer examinats (és a dir, 70%). La recaiguda del càncer de bufeta no es va associar amb l’estat d’expressió de MICA (log rank p = 0,1123). No obstant això, ha existit una associació significativa entre l’expressió de MICA i l’alta mortalitat per càncer de bufeta (HR = 0,25; IC95% = 0,06-0,97). Limfòcits CD4 + i CD8 + es van trobar a la majoria (64%) de les mostres de tumors infiltrants. Les cèl·lules que expressen el receptor NKG2D es van trobar només en el 3% de les mostres. No hi havia cap funció lineal entre les cèl·lules NKG2D +, el nombre o proporció de cèl·lules CD4 + i CD8 + TIL. Conclusions: MICA s’expressa només en una proporció significativa de carcinomes de bufeta. L’expressió de MICA s’associa amb avantatges significatius en la supervivència davant el càncer de bufeta. El sistema NKG2D-MICABackground: Bladder and lung cancer are among the ten most common cancers in both genders. The NKG2D receptor and one of its ligands, MICA, are associated with smoking and susceptibility to both chronic obstructive pulmonary disease and lung cancer. Objective: We hypothesized that NKG2D-MICA system was associated with other smok- ing-related epithelial cancers such as bladder cancer. Design, Setting, and Participants: 70 cases of primary non-muscle invasive bladder cancer were screened for the MICA expression and CD8+, CD4+ and NK cell infiltration. Most patients (n = 55, 78.6%) were current or former smokers. Measurements: Tissue microarray (TMA) technology was chosen to evaluate MICA and tumor infiltrating lymphocytes in samples with confirmed bladder cancer. Kaplan- Meier curves and univariate Cox analysis was used to assess relapse, all-cancer mortality and specific bladder cancer mortality. Results and Limitations: MICA was expressed in most cancer specimens examined (i.e., 70%). Relapse of bladder cancer was not associated with the status of MICA expression (log rank p = 0.1123). Nevertheless, a signifi- cant association existed between high MICA expression and bladder cancer mortality (HR = 0.25; CI95% = 0.06 - 0.97). Tumor infiltrating CD4+ and CD8+ lymphocytes were found in the majority (64%) of samples. Cells expressing the NKG2D receptor were found in only 3% of the samples. There was no linear function between NKG2D+ cells and number or ratio of CD4+ and CD8+ TIL. Conclusions: MICA is expressed in a significant proportion of bladder carci- nomas. MICA expression associates with significant survival advantages in the face of both all-cancer and bladder can- cer. The NKG2D-MICA system could represent a common mechanism involved in the immunopathology and natural history of bladder neoplasms

Plasmalogen enrichment in exosomes secreted by a nematode parasite versus those derived from its mouse host: implications for exosome stability and biology

Extracellular vesicles (EVs) mediate communication between cells and organisms across all 3 kingdoms of life. Several reports have demonstrated that EVs can transfer molecules between phylogenetically diverse species and can be used by parasites to alter the properties of the host environment. Whilst the concept of vesicle secretion and uptake is broad reaching, the molecular composition of these complexes is expected to be diverse based on the physiology and environmental niche of different organisms. Exosomes are one class of EVs originally defined based on their endocytic origin, as these derive from multivesicular bodies that then fuse with the plasma membrane releasing them into the extracellular environment. The term exosome has also been used to describe any small EVs recovered by high-speed ultracentrifugation, irrespective of origin since this is not always well characterized. Here, we use comparative global lipidomic analysis to examine the composition of EVs, which we term exosomes, that are secreted by the gastrointestinal nematode, Heligmosomoides polygyrus, in relation to exosomes secreted by cells of its murine host. Ultra-performance liquid chromatography – tandem mass spectrometry (UPLC-MS/MS) analysis reveals a 9- to 62-fold enrichment of plasmalogens, as well as other classes of ether glycerophospholipids, along with a relative lack of cholesterol and sphingomyelin (SM) in the nematode exosomes compared with those secreted by murine cells. Biophysical analyses of the membrane dynamics of these exosomes demonstrate increased rigidity in those from the nematode, and parallel studies with synthetic vesicles support a role of plasmalogens in stabilizing the membrane structure. These results suggest that nematodes can maintain exosome membrane structure and integrity through increased plasmalogens, compensating for diminished levels of other lipids, including cholesterol and SM. This work also illuminates the prevalence of plasmalogens in some EVs, which has not been widely reported and could have implications for the biochemical or immunomodulatory properties of EVs. Further comparative analyses such as those described here will shed light on diversity in the molecular properties of EVs that enable them to function in cross-species communication

Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae

We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM