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OBJECTIVE: We aimed to compare clinical features, outcomes, treatments, and to define the predictive factors of complete renal response (CRR) in patients with proliferative and non-proliferative lupus nephritis (LN). METHODS: Patients with systemic lupus erythematosus (SLE) followed between 2014 and 2020 at Hacettepe University Hospitals and who had a kidney biopsy were the subject of the study. One hundered and sixteen patients' kidney biopsies reported as LN were evaluated retrospectively. Clinical characteristics and laboratory values at the time of kidney biopsy, histopathological forms of LN, and renal response (complete or partial) were recorded. We analyzed the association between CRR rates during the 2-year follow-up after induction therapy and the predictive factors for CRR. RESULTS: Of 116 (93 females, 23 males) patients, 95 (81.9%) were in the proliferative group (class III and IV) and 21 (18.1%) were in the non-proliferative group (class II and V). In the proliferative group, the percentage of the patients with elevated basal creatinine levels, median daily proteinuria, anti-double-stranded DNA (dsDNA) positivity, low C3 and C4 levels, the presence of active urinary sediment, and median renal SLE Disease Activity Index (SLEDAI) scores at the time of kidney biopsy were significantly higher than the non-proliferative group. Renal response status during the 2-year follow-up after induction therapy was available for 99 patients. During this time, 70 (70.7%) patients had achieved CRR and time-to-CRR was similar between the proliferative and non-proliferative groups (p = 0.64, log-rank test). The Cox proportional hazards model showed that achievement of CRR was associated with female gender [HR: 2.15 (1.19-3.89 95% CI), p = 0.011], newly diagnosed SLE with renal biopsy [HR: 2.15 (1.26-3.67 95% CI), p = 0.005], hypertension [HR: 0.40 (0.27-0.94 95% CI), p = 0.032], eGFR increase [HR: 1.01 (1.00-1.01 95% CI), p = 0.046], and the presence of active urinary sediment [HR: 0.46 (0.22-0.96 95% CI), p = 0.039]. CONCLUSIONS: Achieving CRR was similar in proliferative and non-proliferative LN patients, although certain laboratory parameters differed at the onset. Our results indicated the importance of kidney biopsy in the decision-making of treatment of SLE patients with renal involvement and that the defined factors associated with CRR achievement help to predict good renal response.
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Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Biópsia , Feminino , Humanos , Rim/patologia , Lúpus Eritematoso Sistêmico/diagnóstico , Nefrite Lúpica/patologia , Masculino , Estudos RetrospectivosRESUMO
Constitutional mismatch repair deficiency (CMMRD) syndrome is characterized by biallelic mutations in a mismatch repair gene and is associated with development of childhood cancers and symptoms resembling neurofibromatosis type 1, like café-au-lait spots. We describe the extremely rare case of a 12-year-old male presenting with several light brown macular lesions on the skin, gastrointestinal diffuse large B-cell lymphoma, adenomatous polyposis throughout the gastrointestinal tract and an intra-abdominal invasive carcinoma derived from upper gastrointestinal system. All neoplasia, as well as normal tissues, showed loss of Msh6 expression with immunohistochemistry. Molecular studies showed pathogenic homozygous p.F1088Sfs*2 mutation in MSH6. Furthermore, signs consistent with immunodeficiency, namely decreased levels of IgG and IgA in the serum, nodular lymphoid hyperplasia and EBV-associated plasma cell proliferation with monotypic kappa light chain expression in the ileum, were also noted. Our case depicts the phenotypic diversity of CMMRD syndrome and emphasizes its association with immunodeficiency, raising awareness to a feature not widely recognized.
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Neoplasias Encefálicas , Carcinoma , Infecções por Vírus Epstein-Barr , Linfoma Difuso de Grandes Células B , Síndromes Neoplásicas Hereditárias , Neoplasias Encefálicas/genética , Proliferação de Células , Criança , Neoplasias Colorretais , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico , Herpesvirus Humano 4/genética , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Mutação , Síndromes Neoplásicas Hereditárias/diagnósticoRESUMO
Atypical teratoid rhabdoid tumor (AT/RT) is a rare and aggressive tumor usually occurring at younger ages. Pleomorphic xanthoastrocytomas (PXA) on the other hand are quiescent tumors with benign behavior. AT/RTs arising in the setting of PXA are exceptional. We present the case of a 23-year-old female patient, the fourth in the literature, speculated as having AT/RT arising within a PXA, as demonstrated by the presence of INI1 mutation. The patient presented with a short history of headache, which increased over time, and emerging seizures. She had a contrast-enhancing mass in the left temporal area demonstrated by MRI. Pathological examination demonstrated a dimorphic tumor containing a spindle-pleomorphic component reminiscent of PXA and a rhabdoid component with INI1 loss showing features of AT/RT. Both components shared the same BRAF mutation, supporting their common origin, and hence the case was speculated as an AT/RT arising in the setting of a PXA by secondary genetic change of inactivation of INI1. She had a poor outcome despite surgery and died 8 months after her diagnosis.â©.
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Astrocitoma/patologia , Neoplasias Encefálicas/patologia , Neoplasias Primárias Múltiplas/patologia , Tumor Rabdoide/patologia , Teratoma/patologia , Astrocitoma/genética , Neoplasias Encefálicas/genética , Evolução Fatal , Feminino , Humanos , Mutação , Neoplasias Primárias Múltiplas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Tumor Rabdoide/genética , Teratoma/genética , Adulto JovemRESUMO
BACKGROUND: Primary dysfunction and rejection are more common in donor liver tissues with steatosis. AMP-activated protein kinase (AMPK) assumes organ-protective functions during ischemia. Metformin was used for the activation of AMPK in hepatocytes. The aim of this study is to investigate the effectiveness of metformin administration for the reversal of cold-ischemia-induced damage in hepatosteatosis. MATERIAL AND METHODS: Seven-week-old C7BL56 male-mice (n = 109) were separated into four groups depending on diet type and metformin use. A specific diet model was followed for 10 weeks to induce hepatosteatosis. A group of the animals was administered with metformin for the last four weeks via oral gavage. After resection, the liver tissues were perfused and kept for 0-6-12-24 h in the UW solution. Histopathological examinations were performed, and Western blot was utilized to analyze p-AMPK and AMPK expression levels. RESULTS: Hepatosteatosis decreased significantly with metformin. The steatotic liver group had more prominent pericentral inflammation, necrosis as well as showing a decreased and more delayed AMPK response than the non-fat group. All these alterations could be corrected using metformin. CONCLUSION: Metformin can increase the resistance of livers with hepatosteatosis to cold-ischemia-induced damage, which in turn may pave the way for successful transplantation of fatty living-donor livers.
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Fígado Gorduroso , Transplante de Fígado , Metformina , Soluções para Preservação de Órgãos , Traumatismo por Reperfusão , Masculino , Camundongos , Animais , Humanos , Metformina/farmacologia , Metformina/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Doadores Vivos , Fígado/patologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Glutationa , Rafinose , Alopurinol , Insulina , AdenosinaRESUMO
Placental transmogrification of the lung (PTL) is a rare pulmonary condition characterized by the presence of immature placental villous structures. The etiology and molecular mechanisms underlying this disease remain largely unknown. This functional study aimed to identify the molecular signatures in the pathogenesis of PTL via comprehensive transcriptome analysis. Comparative transcriptomic assessment of PTL tissue and stromal cells showed differential expression of 257 genes in PTL tissue and 189 genes in stromal cells. Notably, several transcription factors and regulators, including FOSB, FOS, JUN, and ATF3, were upregulated in PTL tissue. Additionally, genes associated with the extracellular matrix and connective tissue, such as COL1A1, MMP2, and SPARC, were significantly altered, indicating possible fibrotic changes. Gene set enrichment analysis highlighted the role of vascular development and extracellular matrix organization, and the Activator Protein-1 (AP-1) transcription factor was significantly activated in PTL tissue. Furthermore, the analysis highlighted an overlap of 25 genes between PTL tissue and stromal cells, underscoring the importance of shared molecular pathways in the pathogenesis of PTL. Among the shared genes, JUND, COL4A2, COL6A2, IGFBP5, and IGFBP7 were consistently upregulated, highlighting the possible involvement of AP-1-mediated signaling and fibrotic changes in the pathogenesis of PTL. The present findings pave the way for further research into the molecular mechanisms underlying PTL and offer novel insights for therapeutic interventions. Given the rarity of PTL, these molecular findings represent a significant step forward in our understanding this enigmatic disease.
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Perfilação da Expressão Gênica , Fator de Transcrição AP-1 , Humanos , Feminino , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Gravidez , Transcriptoma , Pulmão/patologia , Pulmão/metabolismo , Fibrose/patologia , Fibrose/genética , Placenta/patologia , Placenta/metabolismo , Pneumopatias/genética , Pneumopatias/patologia , Pneumopatias/metabolismoRESUMO
Trastuzumab emtansine (T-DM1) was the first and one of the most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form of cell death. The payload of T-DM1 mediated ICD by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which were lost in resistance. Accordingly, ICD-related gene signatures in pretreatment samples correlated with clinical response to T-DM1-containing therapy, and increased infiltration of antitumor CD8+ T cells in posttreatment samples was correlated with better T-DM1 response. Transforming acidic coiled-coil containing 3 (TACC3) was overexpressed in T-DM1-resistant cells, and T-DM1 responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacologic inhibition of TACC3 restored T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition in vivo elicited ICD in a vaccination assay and potentiated the antitumor efficacy of T-DM1 by inducing dendritic cell maturation and enhancing intratumoral infiltration of cytotoxic T cells. Together, these results illustrate that ICD is a key mechanism of action of T-DM1 that is lost in resistance and that targeting TACC3 can restore T-DM1-mediated ICD and overcome resistance. SIGNIFICANCE: Loss of induction of immunogenic cell death in response to T-DM1 leads to resistance that can be overcome by targeting TACC3, providing an attractive strategy to improve the efficacy of T-DM1.
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Ado-Trastuzumab Emtansina , Neoplasias da Mama , Morte Celular Imunogênica , Proteínas Associadas aos Microtúbulos , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/imunologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Morte Celular Imunogênica/efeitos dos fármacos , Receptor ErbB-2/metabolismo , Ado-Trastuzumab Emtansina/farmacologia , Ado-Trastuzumab Emtansina/uso terapêutico , Animais , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/genética , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Linfócitos T CD8-Positivos/imunologiaRESUMO
Urinary omics has become a powerful tool for elucidating pathophysiology of glomerular diseases. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urine proteomic and metabolomic analysis between recently diagnosed renal AA amyloidosis (AA) and membranous nephropathy (MN) patients. Urine samples of 22 (8 AA, 8 MN and 6 healthy control) patients were analyzed with nLC-MS/MS and GC/MS for proteomic and metabolomic studies, respectively. Pathological specimens were scored for glomerulosclerosis and tubulointerstitial fibrosis grades. Functional enrichment analysis between AA and control groups showed enrichment in cell adhesion related sub-domains. Uromodulin (UMOD) was lower, whereas ribonuclease 1 (RNase1) and α-1-microglobulin/bikunin precursor (AMBP) were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed myo-inositol and urate were higher in AA compared to MN group. A positive correlation was detected between RNase1 and urate independent of eGFR values (r = 0.63, p = 0.01). Enrichment in cell adhesion related domains suggested a possible increased urinary shear stress due to amyloid fibrils. UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be related with systemic inflammation in AA amyloidosis. SIGNIFICANCE: Urinary omics studies have become a standard tool for biomarker studies. However, no urinary omics analysis has been performed yet on renal AA amyloidosis. Here, we performed a comparative urinary omics analysis between recently diagnosed renal AA amyloidosis (AA), membranous nephropathy (MN) patients and healthy controls. Pathological specimens were scored with glomerulosclerosis (G) and tubulointerstitial fibrosis (IF) grades to consolidate the results of the omics studies and correlation analyzes. Functional enrichment analysis showed enrichment in cell adhesion related sub-domains due to downregulation of cadherins; which could be related with increased urinary shear stress due to amyloid deposition and disruption of tissue micro-architecture. In comparative proteomic analyzes UMOD was lower, whereas RNase1 and AMBP were higher in AA compared to MN group. Whereas in metabolomic analyzes; myo-inositol, urate and maltose were higher in AA compared to MN group. Correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03), AMBP-eGFR (r = -0.69, p = 0.003) and between RNase1-Urate independent of eGFR values (r = 0.63, p = 0.01). This study is the first comprehensive urinary omics analysis focusing on renal AA Amyloidosis to the best of our knowledge. Based on physiologic roles and clinicopathologic correlations of the molecules; UMOD, AMBP and myo-inositol were related with tubulointerstitial damage, whereas RNase1 and urate were believed to be increased with systemic inflammation and endothelial damage in AA amyloidosis.
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Amiloidose , Glomerulonefrite Membranosa , Nefropatias , Humanos , Glomerulonefrite Membranosa/patologia , Ácido Úrico , Proteômica , Espectrometria de Massas em Tandem , Nefropatias/patologia , Proteinúria , Inflamação , Fibrose , Inositol , Proteína Amiloide A SéricaRESUMO
Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER + ) breast cancer, constituting around 75% of all cases. However, the emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance by blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of the cAMP/PKA/CREB axis and increased expression of the TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on the one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels, in part by cAMP/CREB. These ultimately restore tamoxifen-dependent lipid peroxidation and ferroptotic cell death which are reversed upon chelating Ca2+ or overexpressing GPX4 or xCT. Overexpressing PDE4D reverses LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of tamoxifen sensitization via restoring tamoxifen-dependent ferroptosis upon destabilizing PDE4D, increasing cAMP and Ca2+ levels, thus leading to ROS generation and lipid peroxidation. Our findings reveal LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
Assuntos
Neoplasias da Mama , Cálcio , AMP Cíclico , Resistencia a Medicamentos Antineoplásicos , Ferroptose , RNA Longo não Codificante , Tamoxifeno , Humanos , Tamoxifeno/farmacologia , Tamoxifeno/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Feminino , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , AMP Cíclico/metabolismo , Cálcio/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Animais , Receptores de Estrogênio/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Células MCF-7RESUMO
Hepatocellular cancer (HCC) is a leading cause of cancer-related mortality worldwide, and chronic hepatitis B virus infection (CHB) has been a major risk factor for HCC development. The pathogenesis of HBV-related HCC has been a major focus revealing the interplay of a multitude of intracellular signaling pathways, yet the precise mechanisms and their implementations to clinical practice remain to be elucidated. This study utilizes publicly available transcriptomic data from the livers of CHB patients in order to identify a population with a higher risk of malignant transformation. We report the identification of a novel list of genes (PCM1) which can generate clear transcriptomic sub-groups among HBV-infected livers. PCM1 includes genes related to cell cycle activity and liver cancer development. In addition, markers of inflammation, M1 macrophages and gamma delta T cell infiltration are present within the signature. Genes within PCM1 are also able to differentiate HCC from normal liver, and some genes within the signature are associated with poor prognosis of HCC at the mRNA level. The analysis of the immunohistochemical stainings validated that proteins coded by a group of PCM1 genes were overexpressed in liver cancer, while minimal or no expression was detected in normal liver. Altogether, our findings suggest that PCM1 can be developed into a clinically applicable method to identify CHB patients with a higher risk of HCC development.
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BACKGROUND: Molecular biomarkers that predict disease progression can help identify tumor subtypes and shape treatment plans. In this study, we aimed to identify robust biomarkers of prognosis in gastric cancer based on transcriptomic data obtained from primary gastric tumors. METHODS: Microarray, RNA sequencing, and single-cell RNA sequencing-based gene expression data from gastric tumors were obtained from public databases. Freshly frozen gastric tumors (n = 42) and matched FFPE (formalin-fixed, paraffin-embedded) (n = 40) tissues from a Turkish gastric cancer cohort were used for quantitative real-time PCR and immunohistochemistry-based assessments of gene expression, respectively. RESULTS: A novel list of 20 prognostic genes was identified and used for the classification of gastric tumors into two major tumor subgroups with differential stromal gene expression ("Stromal-UP" (SU) and "Stromal-DOWN" (SD)). The SU group had a more mesenchymal profile with an enrichment of extracellular matrix-related gene sets and a poor prognosis compared to the SD group. Expression of the genes within the signature correlated with the expression of mesenchymal markers ex vivo. A higher stromal content in FFPE tissues was associated with shorter overall survival. CONCLUSIONS: A stroma-rich, mesenchymal subgroup among gastric tumors identifies an unfavorable clinical outcome in all cohorts tested.
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Centrosome amplification (CA) is a hallmark of cancer that is strongly associated with highly aggressive disease and worse clinical outcome. Clustering extra centrosomes is a major coping mechanism required for faithful mitosis of cancer cells with CA that would otherwise undergo mitotic catastrophe and cell death. However, its underlying molecular mechanisms have not been fully described. Furthermore, little is known about the processes and players triggering aggressiveness of cells with CA beyond mitosis. Here, we identified Transforming Acidic Coiled-Coil Containing Protein 3 (TACC3) to be overexpressed in tumors with CA, and its high expression is associated with dramatically worse clinical outcome. We demonstrated, for the first time, that TACC3 forms distinct functional interactomes regulating different processes in mitosis and interphase to ensure proliferation and survival of cancer cells with CA. Mitotic TACC3 interacts with the Kinesin Family Member C1 (KIFC1) to cluster extra centrosomes for mitotic progression, and inhibition of this interaction leads to mitotic cell death via multipolar spindle formation. Interphase TACC3 interacts with the nucleosome remodeling and deacetylase (NuRD) complex (HDAC2 and MBD2) in nucleus to inhibit the expression of key tumor suppressors (e.g., p21, p16 and APAF1) driving G1/S progression, and its inhibition blocks these interactions and causes p53-independent G1 arrest and apoptosis. Notably, inducing CA by p53 loss/mutation increases the expression of TACC3 and KIFC1 via FOXM1 and renders cancer cells highly sensitive to TACC3 inhibition. Targeting TACC3 by guide RNAs or small molecule inhibitors strongly inhibits growth of organoids and breast cancer cell line- and patient-derived xenografts with CA by induction of multipolar spindles, mitotic and G1 arrest. Altogether, our results show that TACC3 is a multifunctional driver of highly aggressive breast tumors with CA and that targeting TACC3 is a promising approach to tackle this disease.
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Neoplasias da Mama , Fuso Acromático , Humanos , Feminino , Fuso Acromático/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias da Mama/patologia , Proteína Supressora de Tumor p53/metabolismo , Centrossomo/metabolismo , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismoRESUMO
Resistance to endocrine therapy and CDK4/6 inhibitors, the standard of care (SOC) in estrogen receptor-positive (ER+) breast cancer, greatly reduces patient survival. Therefore, elucidating the mechanisms of sensitivity and resistance to SOC therapy and identifying actionable targets are urgently needed. Here, we show that SOC therapy causes DNA damage and toxic PARP1 trapping upon generation of a functional BRCAness (i.e., BRCA1/2 deficiency) phenotype, leading to increased histone parylation and reduced H3K9 acetylation, resulting in transcriptional blockage and cell death. Mechanistically, SOC therapy downregulates phosphodiesterase 4D (PDE4D), a novel ER target gene in a feedforward loop with ER, resulting in increased cAMP, PKA-dependent phosphorylation of mitochondrial COXIV-I, ROS generation and DNA damage. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Notably, combining SOC with inhibitors of PDE4D, EGFR or PARP1 overcomes SOC resistance irrespective of the BRCA1/2 status, providing actionable targets for restoring SOC efficacy.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Proteína BRCA1/genética , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Receptores de Estrogênio/metabolismo , Proteína BRCA2/genética , Dano ao DNA , Receptores ErbB/genética , Quinase 4 Dependente de CiclinaRESUMO
Immunogenic cell death (ICD), an immune-priming form of cell death, has been shown to be induced by several different anti-cancer therapies. Despite being the first and one of the most successful antibody-drug conjugates (ADCs) approved for refractory HER2-positive breast cancer, little is known if response and resistance to trastuzumab emtansine (T-DM1) involves ICD modulation that can be leveraged to enhance T-DM1 response. Here, we report that T-DM1 induces spindle assembly checkpoint (SAC)-dependent ICD in sensitive cells by inducing eIF2α phosphorylation, surface exposure of calreticulin, ATP and HMGB1 release, and secretion of ICD-related cytokines, all of which are lost in resistance. Accordingly, an ICD-related gene signature correlates with clinical response to T-DM1-containing therapy. We found that transforming acidic coiled-coil containing 3 (TACC3) is overexpressed in T-DM1 resistant cells, and that T-DM1 responsive patients have reduced TACC3 protein while the non-responders exhibited increased TACC3 expression during T-DM1 treatment. Notably, genetic or pharmacological inhibition of TACC3 revives T-DM1-induced SAC activation and induction of ICD markers in vitro. Finally, TACC3 inhibition elicits ICD in vivo shown by vaccination assay, and it potentiates T-DM1 by inducing dendritic cell (DC) maturation and enhancing infiltration of cytotoxic T cells in the human HER2-overexpressing MMTV.f.huHER2#5 (Fo5) transgenic model. Together, our results show that ICD is a key mechanism of action of T-DM1 which is lost in resistance, and that targeting TACC3 restores T-DM1-mediated ICD and overcomes resistance.
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Tamoxifen has been the mainstay therapy to treat early, locally advanced, and metastatic estrogen receptor-positive (ER+) breast cancer, constituting around 75% of all cases. However, emergence of resistance is common, necessitating the identification of novel therapeutic targets. Here, we demonstrated that long-noncoding RNA LINC00152 confers tamoxifen resistance via blocking tamoxifen-induced ferroptosis, an iron-mediated cell death. Mechanistically, inhibiting LINC00152 reduces the mRNA stability of phosphodiesterase 4D (PDE4D), leading to activation of cAMP/PKA/CREB axis and increased expression of TRPC1 Ca2+ channel. This causes cytosolic Ca2+ overload and generation of reactive oxygen species (ROS) that is, on one hand, accompanied by downregulation of FTH1, a member of the iron sequestration unit, thus increasing intracellular Fe2+ levels; and on the other hand, inhibition of the peroxidase activity upon reduced GPX4 and xCT levels. These ultimately induce lipid peroxidation and ferroptotic cell death in combination with tamoxifen. Overexpressing PDE4D rescues LINC00152 inhibition-mediated tamoxifen sensitization by de-activating the cAMP/Ca2+/ferroptosis axis. Importantly, high LINC00152 expression is significantly correlated with high PDE4D/low ferroptosis and worse survival in multiple cohorts of tamoxifen- or tamoxifen-containing endocrine therapy-treated ER+ breast cancer patients. Overall, we identified LINC00152 inhibition as a novel mechanism of ferroptosis induction and tamoxifen sensitization, thereby revealing LINC00152 and its effectors as actionable therapeutic targets to improve clinical outcome in refractory ER+ breast cancer.
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Replacing equipment and software can improve efficiency and allow updates to laboratory procedures, but has the potential to introduce changes in established values for a laboratory. Replacement of an electron microscope (EM), fitted with an updated digital camera, and use of new software for imaging and analysis prompted this QA study to ensure that new equipment, imaging, and measurement of the glomerular basement membrane (GBM) produced data consistent with the laboratory's established range of normal width. GBM measurements from 14 randomly selected human renal biopsies were compared using five different approaches. Original measurements of GBMs obtained on the laboratory's previous EM were compared to images collected on the new microscope with measurements performed using new software, as well as the original images and the new images measured using a separate software method as a control. The widths obtained by five approaches were compared to each other. While measurements showed minor variability between the approaches, significant difference in GBM width was noted in three of the paired comparisons. In some cases, these differences suggested slight diagnostic changes. Evaluation of new equipment, software, and techniques is important for a laboratory's quality assurance. While new equipment and/or procedures can introduce errors in test outcomes, we found that different EMs, cameras, and software made slight differences in our laboratory's values for kidney GBM width. However, a few cases showed enough difference in GBM width to suggest a change in diagnosis, illustrating the necessity of calibration adjustments in the setting of new equipment and software.
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Membrana Basal Glomerular , Laboratórios , Calibragem , Elétrons , Humanos , Rim , Microscopia EletrônicaRESUMO
OBJECTIVE: High-grade serous ovarian carcinoma (HGSC) is one of the major tumors of the gynecological system with a poor survival rate and variable microscopic appearance. It was suggested that SET (solid, pseudo-endometrioid and transitional-like) morphology in ovarian HGSC is predictably associated with BRCA deficiencies. In this study, we investigated the microscopic patterns and some immunohistochemical markers predicting the prognosis of serous carcinoma. MATERIAL AND METHOD: We re-evaluated 305 HGSC ovarian resections morphologically and calculated the SET morphology percentages for each case. Morphological and immunohistochemical data correlated with the survival and post-treatment disease progression data. RESULTS: The median age at diagnosis was 57 years and the median follow-up period was 3.1 years. The median overall survival (OS) of ovarian carcinoma in SET-predominant tumors (n=60) was 81 months, while for tumors with SET non-dominant morphology (n=63) and non-SET morphology (n=182) it was 59.7 and 44.7 months, respectively. CONCLUSION: Predominant (more than 50%) SET morphology was significantly associated with increased survival rates of HGSC. Immunohistochemically, p53, ERCC1, ER, and PR antibodies were applied and only PR antibody positivity was found to be associated with borderline statistical significance for increased survival rates. Our results suggest that SET morphology may be a potential predictive and prognostic marker in managing the treatment strategies of HGSC.
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Cistadenocarcinoma Seroso , Neoplasias Ovarianas , Biomarcadores Tumorais , Cistadenocarcinoma Seroso/patologia , Feminino , Humanos , Gradação de Tumores , Neoplasias Ovarianas/patologia , Prognóstico , Receptores de ProgesteronaRESUMO
Gastric carcinomas consist of a heterogeneous group of neoplasms with broad cytological and architectural variations. Gastric carcinomas with lymphoid stroma show poor correlation between their histomorphology and biological behavior. This contrast causes a need for more detailed analysis and molecular exploration of lymphoid stroma-rich gastric carcinomas with medullary like features and lack of glandular differentiation. In this study, we performed a detailed retrospective analysis of 53 gastric carcinomas among 654 gastric tumors from surgical resection specimens, all of which had no prominent glandular differentiation. Morphological and clinical data were compared with immunohistochemistry (MLH1, PMS2, MSH2 and MSH6 for mismatch repair mechanism deficiency; CD2, CD8 and CD163 for immune infiltration; and PD-1, PD-L1, LMP-1, ERBB2 and ki-67) besides EBER in situ hybridization and molecular studies (PCR based microsatellite instability and BRAF V600E mutation analysis). Morphological, immunohistochemical and molecular findings lead us to classify lymphoid stroma-rich advanced gastric carcinomas (n = 40/53) into two distinct entities originating from two different pathogenetic pathway: one is gastric carcinomas revealing predominantly medullary type morphology with defective DNA mismatch repair mechanism (n = 30/53) and the other is EBV associated carcinomas (n = 10/53). In addition, we suggest that biomarker based classification algorithms besides morphological evaluation are necessary to identify these two entities. Distinguishing these entities is crucial to apply different treatment strategies, including alternative treatments such as immunotherapy.
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Carcinoma , Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Carcinoma/genética , Reparo de Erro de Pareamento de DNA , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4/genética , Humanos , Instabilidade de Microssatélites , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genéticaRESUMO
INTRODUCTION: Patients with AA amyloidosis may present with acute kidney injury that progresses to end-stage kidney disease in a short period of time. Acute allergic tubulointerstitial nephritis (aTIN) is a frequent cause of acute kidney injury in patients with AA amyloidosis. Although aTIN has a favorable prognosis in the general population, the course of aTIN in patients with AA amyloidosis was not previously reported. In this retrospective study, we determined the prognosis of aTIN superimposed on AA amyloidosis. METHODS: Thirty-two patients with combined pathological diagnosis of AA amyloidosis + aTIN and 32 patients with isolated aTIN were compared in terms of 1-year renal functions after the biopsies were performed with an indication of acute kidney injury. Baseline renal functions and number of patients requiring hemodialysis at the time of biopsy was similar in both groups. RESULTS: At the end of the 12-month follow-up period, 29 of 32 patients in the amyloidosis + aTIN group and 1 of 32 patients in the isolated aTIN group required dialysis. Most of these patients with AA amyloidosis had completely normal renal function before the episode of acute kidney injury and had clear exposures to drugs associated with aTIN. CONCLUSION: In contrary to the patients without AA amyloidosis, patients with AA amyloidosis have extremely high risk of permanent renal failure in case of development of aTIN. Great caution should be exercised in prescribing drugs that are associated with aTIN, in patients with AA amyloidosis.
Assuntos
Amiloidose , Nefrite Intersticial , Amiloidose/complicações , Humanos , Nefrite Intersticial/patologia , Prognóstico , Diálise Renal , Estudos Retrospectivos , Proteína Amiloide A SéricaRESUMO
BACKGROUND: Placental transmogrification of the lung (PTL) is a clinical spectrum varying from asymptomatic to severe pulmonary impairment; such as recurrent pneumothorax, bronchopneumonia, respiratory distress syndrome and chronic obstructive airway disease. PTL usually presents as a bullous lesion, and rarely can appear in nodule or cyst formation on chest imaging. PTL with giant bullous emphysema has a male preference, is more commonly unilateral and mostly affects one lobe, but can rarely involve more than one lobe. CASE: Here we report a 13-year-old boy presenting with bullous emphysema and coexisting with a borderline testicular tumor. He had no complaints of cough, sputum, or shortness of breath. He had a past medical history of pneumonia five years ago. In order to elucidate the underlying lung pathology, a wedge lung biopsy was performed and the patient was diagnosed with PTL. Scrotum ultrasonography was performed because of hydrocele in both testes, and bilateral epididymal cysts with papillary solid projections were reported. Pathological examination of the epididymal tumor revealed a `Mullerian type borderline epithelial neoplasm` which is an analogue of the ovarian serous borderline tumor. CONCLUSIONS: In conclusion, we reported the youngest PTL case in the literature, a rare disease with unknown pathophysiology, presenting as bullous emphysema and coincidental Mullerian type borderline epithelial neoplasm. It is important to diagnose placental transmogrification of the lung in a child with bullous emphysema because compared to other cystic lung diseases it is a benign disease and if no additional malignity exists, lobectomy or pneumonectomy is the cure for the disease.
Assuntos
Enfisema , Neoplasias Epiteliais e Glandulares , Enfisema Pulmonar , Criança , Masculino , Feminino , Humanos , Gravidez , Adolescente , Placenta/patologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/diagnóstico por imagem , Pulmão/patologia , Enfisema/patologia , Neoplasias Epiteliais e Glandulares/patologiaRESUMO
Cancer immunotherapy is rapidly changing the treatment paradigm in oncology, and immune checkpoint inhibitors (ICPIs) have been used successfully in a variety of cancer types. Specific side effects termed immune-related adverse events (irAEs) have now been described in various organ systems, including the kidney. Renal complications have rarely been reported compared with other irAEs and mostly consist of acute interstitial nephritis. Only rare cases of ICPI-related glomerulonephritis have been described. Herein, we report the case of an adult patient treated with pembrolizumab (anti-PD-1) for squamous cell carcinoma (SCC), who developed infectious enterocolitis, and ANCA-related with diffuse necrotizing crescentic glomerulonephritis, both conditions potentially linked to treatment with pembrolizumab.