Biomedical subjects

Joaquim Majo

Publications and source records attributed to Joaquim Majo.

7 recordsLinked to original sources

PubMed2025

Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19.

The most common cause of death due to COVID-19 remains respiratory failure. Yet, our understanding of the precise cellular and molecular changes underlying lung alveolar damage is limited. Here, we integrate single cell transcriptomic data of COVID-19 and donor lung tissue with spatial transcriptomic data stratifying histopathological stages of diffuse alveolar damage. We identify changes in cellular composition across progressive damage, including waves of molecularly distinct macrophages and depletion of epithelial and endothelial populations. Predicted markers of pathological states identify immunoregulatory signatures, including IFN-alpha and metallothionein signatures in early damage, and fibrosis-related collagens in late damage. Furthermore, we predict a fibrinolytic shutdown via endothelial upregulation of SERPINE1/PAI-1. Cell-cell interaction analysis revealed macrophage-derived SPP1/osteopontin signalling as a key regulator during early steps of alveolar damage. These results provide a comprehensive, spatially resolved atlas of alveolar damage progression in COVID-19, highlighting the cellular mechanisms underlying pro-inflammatory and pro-fibrotic pathways in severe disease.

COVID-19↗

PubMed2005

Tuberculosis in lung transplant recipients.

BACKGROUND: Post-lung transplant infection is one of the leading causes of morbidity and mortality. The cause and incidence are similar in many series; however, infections such as Mycobacterium tuberculosis are influenced by the epidemiologic situation. The authors present a prospective and observational study to define the incidence, clinical presentation, and course of tuberculosis in a cohort of lung transplant patients at a single center in Spain. METHODS: Between 1990 and 2002, cutaneous delayed-type hypersensitivity testing and pathologic and microbiologic study of explanted lungs were conducted in 187 lung transplant patients. Serial bronchoscopies with transbronchial biopsy and bronchioalveolar lavage were performed during follow-up. The diagnosis of tuberculosis was established only when M. tuberculosis was identified in any sample or when histopathologic study was conclusive. RESULTS: Forty-eight patients were classified as anergic (25.6%) and 61 (32.6%) were classified as having a positive tuberculin skin test. Of the 109 patients, 95 received latent tuberculosis infection prophylaxis. Tuberculosis was diagnosed in 12 patients (6.41%); in six of them, diagnosis was determined from the explanted lungs. The remainder were diagnosed during follow-up. Fever and dyspnea were the most common symptoms. Chest radiographic findings presented an alveolar pattern. All patients responded well to antituberculous therapy; no deaths were attributable to tuberculosis. CONCLUSIONS: In the authors' experience, tuberculosis is not rare in lung transplant patients and can be managed successfully with antituberculous therapy without rifampin. A systematic protocol for diagnosing tuberculosis of the explanted lung is useful for reducing tuberculous complications of the implanted lung.

Adolescent↗

PubMed2005

Clinical significance of hypoxia-inducible factor-1a messenger RNA expression in locally advanced non-small-cell lung cancer after platinum agent and gemcitabine chemotherapy followed by surgery.

Hypoxia-inducible factor-1a (HIF-1a) is a key regulator of the angiogenic cascade. This study analyzed HIF-1a messenger RNA expression levels using real-time quantitative polymerase chain reaction (PCR) in paraffin-embedded surgical specimens from 54 stage IIB-III patients with non-small-cell lung cancer (NSCLC) treated with induction platinum/gemcitabine followed by surgery between September 1998 and December 2002. Radiographic response was observed in 61% of patients. Median survival was 37.8 months. Forty-five patients with complete resection attained a 52-month median survival, whereas 8 patients with incomplete resection had a 12-month median survival, and 1 unresectable patient had a survival of 14 months. No significant differences were observed in overall survival (OS) or event-free survival (EFS) according to HIF-1a expression levels. Patients were divided into quartiles according to HIF-1a gene expression levels. Median EFS for the 13 patients in the lowest quartile has not been reached yet, whereas median EFS for the 13 patients in the top quartile was 9 months (P = 0.192). Similarly, median OS for the 13 patients in the lowest quartile has not been reached yet, whereas median OS for the 13 patients in the top quartile was 52 months (P = 0.297). The cisplatin/gemcitabine combination is highly active in neoadjuvant treatment. Hypoxia-inducible factor-1a expression levels analyzed by real-time quantitative PCR in surgery specimens after platinum/gemcitabine therapy do not correlate with the outcome of patients with stage II/III NSCLC.

Aged↗

PubMed2004

BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer.

Lung cancer is the most common cancer, with dismal outcome. Treatment approaches, including cisplatin-based chemotherapy and surgery, are currently based on the clinical classification of the tumor, without genetic assessment for predicting differential chemosensitivity. BRCA1 plays a central role in DNA repair, and decreased BRCA1 mRNA expression in the human breast cancer HCC1937 cell line caused cisplatin hypersensitivity, but the relation between BRCA1 and survival in lung cancer patients has never been examined. We used real-time quantitative polymerase chain reaction to determine BRCA1 mRNA levels in 55 surgically resected tumors of non-small-cell lung cancer patients who had received neoadjuvant gemcitabine/cisplatin chemotherapy, and divided the gene expression values into quartiles. When results were correlated with outcome, two cut-offs were observed; patients with levels <0.61 had better outcome, and those >2.45 had poorer outcome. Median survival was not reached for the 15 patients in the bottom quartile, whereas for the 28 in the two middle quartiles, it was 37.8 months (95% CI, 10.6-65), and for the 12 patients in the top quartile, it was 12.7 months (95% CI, 0.28-28.8) (P=0.01). Moreover, when patients were stratified by pathologic stage, those in the bottom quartile had a decreased risk of death (HR=0.206; 95% CI, 0.05-0.83; P=0.026) compared with those in the top quartile, and those in the two middle quartiles also had a decreased risk of death (HR=0.294; 95% CI, 0.10-0.83; P=0.020) compared with those in the top quartile. BRCA1 expression is potentially an important tool for use in cancer management and should be assessed for predicting differential chemosensitivity and tailoring chemotherapy in lung cancer.

Aged↗

PubMed2004

Gene expression as a predictive marker of outcome in stage IIB-IIIA-IIIB non-small cell lung cancer after induction gemcitabine-based chemotherapy followed by resectional surgery.

PURPOSE: The first suggestions of a relationship between gene mRNA expression and differential sensitivity to gemcitabine/cisplatin are now emerging. ERCC1, RRM1, and XPD are involved in the nucleotide excision repair pathways, and tumor up-regulation of these genes leads to chemotherapy failure. In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery. EXPERIMENTAL DESIGN: ERCC1, RRM1, and XPD expression was quantified using real-time quantitative reverse transcription-PCR. RESULTS: A good correlation was found between mRNA expression levels of the three genes. For RRM1 levels, patients in the bottom quartile had a decreased risk of death compared with those in the top quartile (risk ratio = 0.30; P = 0.033). Median survival for the 17 patients in the bottom quartile was 52 months, whereas for the 15 in the top quartile, it was 26 months (P = 0.018). When the characteristics of these 17 patients were compared with all of the other 50 patients, no differences in initial staging were observed. However, the 17 patients in the bottom quartile had better outcomes, including more radiographic responses (65% versus 54%; P = 0.24), complete resections (94% versus 72%; P = 0.03), lobectomies (71% versus 34%; P = 0.004), and pathological complete responses (29% versus 0%; P = 0.00001). CONCLUSIONS: Patients with RRM1 levels in the bottom quartile benefited significantly from gemcitabine/cisplatin neoadjuvant chemotherapy, leading us to conclude that RRM1 mRNA levels should be additionally validated to proceed with tailored chemotherapy.

Aged↗

PubMed2002

Inflammation of the airways and lung parenchyma in COPD: role of T cells.

A smoking-induced inflammatory reaction in the airways and lung parenchyma, comprised mainly of neutrophils and alveolar macrophages, has long been accepted to be the major cause of COPD in smokers. Recent reports have underlined the role of the T lymphocyte as a potentially important factor in the inflammatory process leading to COPD. It has been found that, in the airways and the lung parenchyma, the presence of T cells, predominantly CD8+ T cells, can distinguish between smokers with and without COPD. In addition to T cells, other inflammatory cell types such as neutrophils and macrophages are probably essential in the initial inflammatory process leading to the breakdown of lung tissue, perhaps producing peptides eventually recognized by T cells as antigenic. This would provide an explanation for the T-cell inflammation. Once activated, T cells are present in the lung, and their effector functions would include the attraction and enhancement of the inflammatory function in other inflammatory cells like neutrophils and macrophages. It seems likely that, only when all inflammatory cell types (ie, CD4+, CD8+, neutrophils, and macrophages) are present in the lung, the airways remodeling and parenchymal destruction characteristic of COPD will ensue. If T cells are responsible for the lung injury and progression of COPD, it would resemble a response to an antigenic stimulus originating in the lung. If that were the case, COPD could be considered to be an autoimmune disease triggered by smoking.

Animals↗

PubMed2000

Serum concentrations of laminin-P1 in thrombotic microangiopathy: usefulness as an index of activity and prognostic value.

Laminin is the main noncollagenous constituent of the basement membrane, and its serum levels could reflect the metabolic changes that occur in the basement membrane. Severe endothelial injury with thickening of basement membrane is a characteristic feature of thrombotic microangiopathy (TMA). With this background, the aim of the study was to investigate in a prospective way (1) the relationship among serum Lam-P1, the extent of renal histopathologic lesions, and the biochemical parameters commonly used as markers of TMA activity, and (2) the usefulness of serum Lam-P1 concentrations as a renal outcome prognostic index. To this end, 18 consecutive patients with active biopsy-proven TMA with renal involvement were studied. One hundred and twenty-one healthy control subjects, 20 patients with systemic scleroderma without renal involvement, and 35 patients with systemic lupus erythematosus (20 without nephropathy and 15 with diffuse proliferative type 4 lupus nephritis) were used as control groups. In addition, to analyze the influence of either renal failure or hemodialysis therapy on serum Lam-P1 levels, 91 patients on regular hemodialysis therapy and 81 patients with predialysis chronic renal failure of different etiologies were included in the study. Serum Lam-P1 was determined by RIA at admission, on days 10 and 30 of follow-up in all patients, and after 6 and 12 mo of follow-up in all surviving patients. Serum lactate dehydrogenase, haptoglobin, platelet count, hemoglobin, and serum creatinine were determined as markers of endothelial dysfunction and hemolysis. At admission, serum levels of Lam-P1 were significantly higher in patients with TMA than in healthy control subjects (3.39 +/- 0.56 U/ml versus 1.40 +/- 0.18 U/ml; P < 0.0001). In addition, patients with TMA had significantly higher serum Lam-P1 levels than the other groups included in the study. At the first control, Lam-P1 correlated with lactate dehydrogenase (P = 0.006) and hemoglobin (P = 0.002). During follow-up, platelet count and hemolysis indicators normalized in all patients, while serum Lam-P1 decreased only in patients with renal function recovery. In multivariate analysis, serum creatinine and Lam-P1 at day 10 were the only independent predictors of renal outcome (r2 = 0.94; P < 0.0001) and also correlated with indices of histopathologic damage (P < 0.001). Serum Lam-P1 normalized in all patients with chronic renal failure in the samples obtained at 6 and 12 mo of regular hemodialysis after solving active TMA, thus suggesting that histopathologic lesions, but not renal function itself, would be mainly responsible for the high Lam-P1 serum concentrations detected in TMA. In conclusion, serum Lam-P1 concentrations are increased in patients with active TMA. Furthermore, patients with poor renal outcome show a prolonged increase of serum Lam-P1 that is related to the extent of renal histologic lesions. Unlike the biochemical markers of hemolysis commonly used to assess TMA activity, the sequential determination of serum Lam-P1 provides valuable information about long-term renal prognosis in patients with TMA.

Adult↗