RESUMO
"Basal-like" (BL) morphology and the expression of cancer testis antigens (CTA) in breast cancer still have unclear prognostic significance. The aim of our research was to explore correlations of the morphological characteristics and tumor microenvironment in triple-negative breast carcinomas (TNBCs) with multi-MAGE-A CTA expression and to determine their prognostic significance. Clinical records of breast cancer patients who underwent surgery between January 2017 and December 2018 in four major Croatian clinical centers were analyzed. A total of 97 non-metastatic TNBCs with available tissue samples and treatment information were identified. Cancer tissue sections were additionally stained with programmed death-ligand 1 (PD-L1) Ventana (SP142) and multi-MAGE-A (mAb 57B). BL morphology was detected in 47 (49%) TNBCs and was associated with a higher Ki-67 proliferation index and histologic grade. Expression of multi-MAGE-A was observed in 77 (79%) TNBCs and was significantly associated with BL morphology. Lymphocyte-predominant breast cancer (LPBC) status was detected in 11 cases (11.3%) and significantly correlated with the Ki-67 proliferation index, increased number of intratumoral lymphocytes (itTIL), and PD-L1 expression. No impact of BL morphology, multi-MAGE-A expression, histologic type, or LPBC status on disease-free survival was observed. Our data suggest that tumor morphology could help identify patients with potential benefits from CTA-targeting immunotherapy.
Assuntos
Antígenos de Neoplasias , Linfócitos do Interstício Tumoral , Neoplasias de Mama Triplo Negativas , Adulto , Feminino , Humanos , Antígenos de Neoplasias/metabolismo , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Prognóstico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/metabolismo , Microambiente TumoralRESUMO
The calcium-sensing receptor (CaSR) plays a crucial role in maintaining the balance of calcium in the body. Altered signaling through the CaSR has been linked to the development of various tumors, such as colorectal and breast tumors. This retrospective study enrolled 79 patients who underwent surgical removal of invasive breast carcinoma of no special type (NST) to explore the expression of the CaSR in breast cancer. The patients were categorized based on age, tumor size, hormone receptor status, HER2 status, Ki-67 proliferation index, tumor grade, and TNM staging. Immunohistochemistry was conducted on core needle biopsy samples to assess CaSR expression. The results revealed a positive correlation between CaSR expression and tumor size, regardless of the tumor surrogate subtype (p = 0.001). The expression of ER exhibited a negative correlation with CaSR expression (p = 0.033). In contrast, a positive correlation was observed between CaSR expression and the presence of HER2 receptors (p = 0.002). Increased CaSR expression was significantly associated with lymph node involvement and the presence of distant metastasis (p = 0.001 and p = 0.038, respectively). CaSR values were significantly higher in the patients with increased Ki-67 (p = 0.042). Collectively, higher CaSR expression in breast cancer could suggest a poor prognosis and treatment outcome regardless of the breast cancer subtype.
Assuntos
Neoplasias da Mama , Receptores de Detecção de Cálcio , Feminino , Humanos , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Detecção de Cálcio/genética , Receptores de Progesterona/metabolismo , Estudos RetrospectivosRESUMO
The aim of this study was to evaluate selected parameters of redox signaling and inflammation in the granulocytes of COVID-19 patients who recovered and those who died. Upon admission, the patients did not differ in terms of any relevant clinical parameter apart from the percentage of granulocytes, which was 6% higher on average in those patients who died. Granulocytes were isolated from the blood of 15 healthy people and survivors and 15 patients who died within a week, and who were selected post hoc for analysis according to their matching gender and age. They differed only in the lethal outcome, which could not be predicted upon arrival at the hospital. The proteins level (respective ELISA), antioxidant activity (spectrophotometry), and lipid mediators (UPUPLC-MS) were measured in the peripheral blood granulocytes obtained via gradient centrifugation. The levels of Nrf2, HO-1, NFκB, and IL-6 were higher in the granulocytes of COVID-19 patients who died within a week, while the activity of cytoplasmic Cu,Zn-SOD and mitochondrial Mn-SOD and IL-2/IL-10 were lower in comparison to the levels observed in survivors. Furthermore, in the granulocytes of those patients who died, an increase in pro-inflammatory eicosanoids (PGE2 and TXB2), together with elevated cannabinoid receptors 1 and 2 (associated with a decrease in the anti-inflammatory 15d-PGJ2), were found. Hence, this study suggests that by triggering transcription factors, granulocytes activate inflammatory and redox signaling, leading to the production of pro-inflammatory eicosanoids while reducing cellular antioxidant capacity through SOD, thus expressing an altered response to COVID-19, which may result in the onset of systemic oxidative stress, ARDS, and the death of the patient.
Assuntos
Antioxidantes , COVID-19 , Humanos , Granulócitos , Estresse Oxidativo , CentrifugaçãoRESUMO
BACKGROUND: Our objective was to assess the effects of COVID-19 antiepidemic measures and subsequent changes in the function of the health care system on the number of newly diagnosed breast cancers in the Republic of Croatia. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective, population- and registry-based study during 2020. The comparator was the number of patients newly diagnosed with breast cancer during 2017, 2018, and 2019. The outcome was the change in number of newly diagnosed breast cancer cases. RESULTS: The average monthly percent change after the initial lockdown measures were introduced was -11.0% (95% confidence interval - 22.0% to 1.5%), resulting in a 24% reduction of the newly diagnosed breast cancer cases in Croatia during April, May, and June compared with the same period of 2019. However, during 2020, only 1% fewer new cases were detected than in 2019, or 6% fewer than what would be expected based on the linear trend during 2017-2019. CONCLUSION: It seems that national health care system measures for controlling the spread of COVID-19 had a detrimental effect on the number of newly diagnosed breast cancer cases in Croatia during the first lockdown. As it is not plausible to expect an epidemiological change to occur at the same time, this may result in later diagnosis, later initiation of treatment, and less favorable outcomes in the future. However, the effect weakened after the first lockdown and COVID-19 control measures were relaxed, and it has not reoccurred during the second COVID-19 wave. Although the COVID-19 lockdown affected the number of newly diagnosed breast cancers, the oncology health care system has shown resilience and compensated for these effects by the end of 2020. IMPLICATIONS FOR PRACTICE: It is possible to compensate for the adverse effects of COVID-19 pandemic control measures on breast cancer diagnosis relatively promptly, and it is of crucial importance to do it as soon as possible. Moreover, as shown by this study's results on the number of newly diagnosed breast cancer cases during the second wave of the pandemic, these adverse effects are preventable to a non-negligible extent.
Assuntos
Neoplasias da Mama , COVID-19 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Controle de Doenças Transmissíveis , Croácia/epidemiologia , Feminino , Humanos , Pandemias , Sistema de Registros , Estudos Retrospectivos , SARS-CoV-2RESUMO
CIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC-DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45-years-old, range 14-65) superficial CIC-rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next-generation sequencing was positive for CIC-DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC-DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow-up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC-rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC-rearranged sarcomas are aggressive.
Assuntos
Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Sarcoma de Ewing/genética , Sarcoma/genética , Antígeno 12E7/metabolismo , Adolescente , Adulto , Neoplasias Ósseas/patologia , Feminino , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Homeodomínio/metabolismo , Humanos , Imuno-Histoquímica/métodos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
Metastatic involvement of the breast is far less common than primary breast carcinoma, comprising 0.5%-6.6% of all breast malignancies. Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor with higher incidence among men, particularly smokers, strongly associated with asbestos exposure. The epithelioid type of MPM can represent a diagnostic pitfall in this setting, as it shows similar histologic features to primary breast carcinoma as well as other metastatic epithelioid malignancies. We report a rare case of breast metastasis of malignant pleural mesothelioma in a 61-year-old female.
Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurais , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Masculino , Mesotelioma/diagnóstico por imagem , Pessoa de Meia-Idade , Neoplasias Pleurais/diagnóstico por imagemRESUMO
AIMS: Dermal hyperneury is defined as the hypertrophy of small nerves in the dermis. It has been described in a variety of settings. We present a series of nine new cases with a distinctive clinical presentation and review the existing literature. The aim of the study was to summarise the clinical, histopathological and immunohistochemical findings in a case series of dermal hyperneury with unique clinical presentation. METHODS AND RESULTS: Nine cases were identified from the referral practice of one of the authors. Clinical characteristics, including demographic details, were collated. The histopathological features and novel immunohistochemical findings were analysed. Four cases presented with multiple skin lesions. Clinical evaluation revealed no associated syndromic stigmata. The histology in all cases was that of dermal hyperneury. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and RET was supportive of the lack of syndromic association. CONCLUSION: The presentation of dermal hyperneury with multiple cutaneous lesions and no syndromic associations is distinctive, and no study with PTEN and RET immunohistochemistry has previously been reported. Comparisons with recent reports of multiple non-syndromic mucocutaneous neuromas are discussed.
Assuntos
Derme/patologia , Neuroma/patologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Neoplasias Cutâneas/patologia , Idoso , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pele/patologia , Dermatopatias/diagnósticoRESUMO
Hemangioma of the small intestine is a rare vascular malformation which mostly presents as occult gastrointestinal bleeding and iron-deficiency anemia. Patients are often asymptomatic except of fatigue due to anemia. Hemangiomas can arise anywhere in the luminal gastrointestinal tract, with jejunum as the most commonly involved site. They are very hard to recognize mostly due to their localization. Video capsule endoscopy and balloon-assisted enteroscopy have very much improved preoperative diagnostics and made major contribution to establishing the diagnosis - which was very difficult in the past and almost all cases were diagnosed during or after the operation. Surgical resection is still the conventional treatment modality, although with the improvement of endoscopic therapeutic interventions (endoscopic mucosal resection, argon-plasma coagulation) there are more therapeutic possibilities.
Assuntos
Anemia Ferropriva , Endoscopia por Cápsula , Hemangioma , Hemorragia Gastrointestinal , Humanos , Intestino DelgadoAssuntos
Dermoscopia/métodos , Melanose/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Diagnóstico Diferencial , Humanos , Melanoma/patologia , Nevo Pigmentado/diagnóstico , Neoplasias Cutâneas/diagnósticoRESUMO
Spiradenocarcinoma is a rare skin adnexal neoplasm with potential for aggressive behavior, classified histologically into low- and high-grade tumors. Morphologically, low-grade tumors are thought to behave more favorably. Limited information is available, however, with only 18 published cases. To study their clinical behavior, histological features, and the diagnostic value of immunohistochemistry, 19 morphologically low-grade spiradenocarcinomas were retrieved and compared with 21 spiradenomas and cylindromas. H&E-stained sections were reviewed, follow-up was obtained, and immunohistochemistry for Ki-67, p53 and, MYB was performed. The tumors were solitary, measuring 0.8-7 cm (median: 2.7 cm), with a predilection for the head and neck of elderly patients (median age: 72 years; range 53-92) without gender bias. Histologically, the tumors were multinodular and located in deep dermis and subcutis. A pre-existing spiradenoma was present in all cases. The malignant component was characterized by expansile growth with loss of the dual cell population, up to moderate cytological atypia and increased mitotic activity (median: 10/10 HPF; range 1-28). Additional findings included squamoid differentiation (n=9), necrosis (n=7), and ulceration (n=5). P53 expression was variable and no significant differences were noted in the benign compared with the malignant parts of the tumors. In contrast, in the malignant components the Ki-67 proliferative index was slightly increased, and MYB expression was lost. Follow-up (median: 67 months; range: 13-132) available for 16 patients (84%) revealed a local recurrence rate of 19% but no metastases or disease-related mortality. In this large study with long-term follow-up, we demonstrate that spiradenocarcinomas with low-grade morphology pursue an indolent course, characterized by local recurrence only. Metastases and disease-related mortality appear to be exceptional. Lack of MYB expression may be useful as an additional aid in the diagnosis of these challenging tumors.
Assuntos
Adenocarcinoma/patologia , Neoplasias de Cabeça e Pescoço/patologia , Proteínas Proto-Oncogênicas c-myb/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias das Glândulas Sudoríparas/patologia , Adenocarcinoma/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Prognóstico , Neoplasias Cutâneas/metabolismo , Neoplasias das Glândulas Sudoríparas/metabolismoRESUMO
OBJECTIVE: The identification of myoepithelial cells (MEC) is a valuable clue in the differential diagnosis of breast lesions. A series of breast lesions with occasional absence of or decrease in the staining for some MEC markers was analyzed for the expression of a novel marker, p40, and results were compared to the p63 staining profile. METHODS: Samples (n = 34) from patients with benign sclerosing lesions (n = 11), ductal carcinoma in situ (n = 13) and adenomyoepithelial lesions (n = 10) and associated normal breast tissues (n = 31) were selected to evaluate the differential expression of p40 and p63 using immunohistochemistry. Triple-negative, cytokeratin 5 (CK5)-expressing invasive breast carcinomas (n = 19) were also assessed for p40 expression. RESULTS: Normal structures showed similar diffuse and strong MEC positivity using p40 and p63 in all 31 cases. The two antibodies performed similarly in all 34 breast lesions acknowledged to present altered expression of MEC markers; focal losses of expression occurred in a parallel fashion. CK5-positive carcinomas expressed p40 more frequently than p63 (18/19 vs. 8/19) and the staining was more marked. CONCLUSIONS: It seems that both antibodies can be used interchangeably for MEC identification, but show differences in the labeling at least in a subset of tumor cells in triple-negative carcinomas.
Assuntos
Adenomioepitelioma/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/genética , Mama/metabolismo , Doenças Mamárias/metabolismo , Carcinoma Intraductal não Infiltrante/metabolismo , Diagnóstico Diferencial , Células Epiteliais/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
BACKGROUND: Multiple BAP1 negative melanocytic neoplasms are a hallmark of familial cancer susceptibility syndrome caused by BAP1 germline mutation. The syndrome is characterized by increased incidence of renal cell carcinoma, mesothelioma, cholangiocarcinoma, cutaneous and uveal melanoma and some other neoplasms. METHODS: We report histomorphologic characteristics of six cutaneous melanocytic neoplasms with loss of BAP1 expression in two members of a family with BAP1-associated cancer susceptibility syndrome. RESULTS: The neoplasms were dermal melanocytic nevi characterized by a proliferation of large epithelioid (spitzoid) melanocytes, and adipocytic metaplasia. Nuclear pseudoinclusions and multinucleated melanocytes were present in most neoplasms. In two of the cases, a nodular melanoma was found associated with a dermal nevus. None of the melanomas recurred or metastasized after 6 and 3 years of follow up. CONCLUSIONS: We report two new cases of melanoma arising in a BAP1-deficient melanocytic nevus in the setting of familial tumor predisposition syndrome. Adipocytic metaplasia and nuclear pseudoinclusions may be additional morphologic clues to a BAP1-deficient nevus. It remains to be seen whether these features are more common in familial than sporadic lesions.
Assuntos
Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Síndromes Neoplásicas Hereditárias/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/patologia , Colangiocarcinoma/epidemiologia , Colangiocarcinoma/patologia , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Masculino , Melanoma/epidemiologia , Melanoma/genética , Mesotelioma/epidemiologia , Mesotelioma/patologia , Pessoa de Meia-Idade , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Neoplasias Cutâneas/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/epidemiologia , Neoplasias Uveais/patologia , Melanoma Maligno CutâneoRESUMO
AIMS: Syringomatous tumour of the nipple and low-grade adenosquamous carcinoma (LGAdSC) of the breast are regarded as distinct entities. To clarify the nature of these two lesions, we compared the expression of different lineage/differentiation markers in 12 syringomatous tumours of the nipple, nine LGAdSCs, and normal breast epithelium. METHODS AND RESULTS: Using triple immunofluorescence labelling and quantitative RT-PCR for keratins, p63, and smooth muscle actin, we demonstrated that syringomatous tumour and LGAdSC contain p63+/K5/14+ tumour cells, K10+ squamous cells, and K8/18+ glandular cells, with intermediary cells being found in both lineages. Identical p63+/K5/14+ cells were also found in the normal breast duct epithelium. CONCLUSIONS: Our data provide evidence that syringomatous tumour of the nipple and LGAdSC are identical or nearly identical lesions. They contain p63+/K5/14+ cells as the key cells from which the K10+ squamous lineage and the K8/18+ glandular lineage arise. On the basis of our findings in normal breast tissue and associated benign lesions, we suggest that p63+/K5/14+ cells of the normal breast duct epithelium or early related cells might play a key role in the neoplastic transformation of both syringomatous tumour and LGAdSC. We propose that the differentiation patterns found in both lesions reflect the early ontogenetic stages of the normal breast epithelium.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/patologia , Carcinoma Adenoescamoso/patologia , Mamilos/patologia , Siringoma/patologia , Diferenciação Celular , Feminino , Humanos , Imuno-Histoquímica , Gradação de Tumores , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVES: PRAME (PReferentially expressed Antigen in MElanoma) is a carcinoma testis antigen expressed in numerous tumour types. The aim of this study was to assess PRAME expression in different surrogate subtypes of breast carcinoma and its correlation with other prognostic factors. MATERIAL AND METHODS: A total of 220 cases of invasive breast carcinoma were selected and categorized according to ER, PgR, HER2 status, and Ki67 proliferation index in luminal A like, luminal B HER2+ like, luminal B HER2- negative like, HER2 positive like and triple-negative or basal-like. All cases were examined for PRAME expression by immunohistochemistry (IHC). RESULTS: A PRAME-high profile was detected in 53 (24,1 %) of all examined breast carcinoma samples. A significantly higher expression of PRAME was detected in HER2-positive carcinomas (50 %) and TN breast carcinomas (40,54 %) compared to ER-positive (luminal-like) subtype of breast carcinomas (3,38 % luminal A and 15,38 % luminal B). Percentage of PRAME positive tumour cells showed positive correlation with tumor size, Ki67 proliferation index, HER2 status, nuclear grade, TILs and presence of metastasis, and negative correlation with ER status and disease-free survival (DFS). CONCLUSION: Our study showed that HER2 positive and TN breast carcinomas more commonly express PRAME than ER positive carcinomas and that PRAME expression shows positive correlation with certain prognostic factors, however PRAME wasn't revealed as an independent prognostic factor in our study. The importance of PRAME expression in breast carcinoma lies in its potential use as an immunotherapeutic target, particularly in patients with limited therapeutic options.
Assuntos
Neoplasias da Mama , Carcinoma , Humanos , Feminino , Prognóstico , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia , Receptores de Progesterona/metabolismo , Biomarcadores Tumorais/metabolismo , Antígenos de NeoplasiasRESUMO
BACKGROUND: Helsmoortel-Van der Aa syndrome is a neurodevelopmental disorder in which patients present with autism, intellectual disability, and frequent extra-neurological features such as feeding and gastrointestinal problems, visual impairments, and cardiac abnormalities. All patients exhibit heterozygous de novo nonsense or frameshift stop mutations in the Activity-Dependent Neuroprotective Protein (ADNP) gene, accounting for a prevalence of 0.2% of all autism cases worldwide. ADNP fulfills an essential chromatin remodeling function during brain development. In this study, we investigated the cerebellum of a died 6-year-old male patient with the c.1676dupA/p.His559Glnfs*3 ADNP mutation. RESULTS: The clinical presentation of the patient was representative of the Helsmoortel-Van der Aa syndrome. During his lifespan, he underwent two liver transplantations after which the child died because of multiple organ failure. An autopsy was performed, and various tissue samples were taken for further analysis. We performed a molecular characterization of the cerebellum, a brain region involved in motor coordination, known for its highest ADNP expression and compared it to an age-matched control subject. Importantly, epigenome-wide analysis of the ADNP cerebellum identified CpG methylation differences and expression of multiple pathways causing neurodevelopmental delay. Interestingly, transcription factor motif enrichment analysis of differentially methylated genes showed that the ADNP binding motif was the most significantly enriched. RNA sequencing of the autopsy brain further identified downregulation of the WNT signaling pathway and autophagy defects as possible causes of neurodevelopmental delay. Ultimately, label-free quantification mass spectrometry identified differentially expressed proteins involved in mitochondrial stress and sirtuin signaling pathways amongst others. Protein-protein interaction analysis further revealed a network including chromatin remodelers (ADNP, SMARCC2, HDAC2 and YY1), autophagy-related proteins (LAMP1, BECN1 and LC3) as well as a key histone deacetylating enzyme SIRT1, involved in mitochondrial energy metabolism. The protein interaction of ADNP with SIRT1 was further biochemically validated through the microtubule-end binding proteins EB1/EB3 by direct co-immunoprecipitation in mouse cerebellum, suggesting important mito-epigenetic crosstalk between chromatin remodeling and mitochondrial energy metabolism linked to autophagy stress responses. This is further supported by mitochondrial activity assays and stainings in patient-derived fibroblasts which suggest mitochondrial dysfunctions in the ADNP deficient human brain. CONCLUSION: This study forms the baseline clinical and molecular characterization of an ADNP autopsy cerebellum, providing novel insights in the disease mechanisms of the Helsmoortel-Van der Aa syndrome. By combining multi-omic and biochemical approaches, we identified a novel SIRT1-EB1/EB3-ADNP protein complex which may contribute to autophagic flux alterations and impaired mitochondrial metabolism in the Helsmoortel-Van der Aa syndrome and holds promise as a new therapeutic target.
Assuntos
Transtorno Autístico , Deficiência Intelectual , Masculino , Criança , Animais , Camundongos , Humanos , Deficiência Intelectual/genética , Transtorno Autístico/genética , Sirtuína 1/genética , Sirtuína 1/metabolismo , Genes Mitocondriais , Proteínas de Homeodomínio/genética , Cerebelo/metabolismo , Autopsia , Metilação , Proteínas do Tecido Nervoso/metabolismo , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
It is well known that oxidative stress and lipid peroxidation (LPO) play a role in physiology and pathology. The most studied LPO product with pleiotropic capabilities is 4-hydroxynonenal (4-HNE). It is considered as an important mediator of cellular signaling processes and a second messenger of reactive oxygen species. The effects of 4-HNE are mainly attributed to its adduction with proteins. Whereas the Michael adducts thus formed are preferred in an order of potency of cysteine > histidine > lysine over Schiff base formation, it is not known which proteins are the preferred targets for 4-HNE under what physiological or pathological conditions. In this review, we briefly discuss the methods used to identify 4-HNE-protein adducts, the progress of mass spectrometry in deciphering the specific protein targets, and their biological relevance, focusing on the role of 4-HNE protein adducts in the adaptive response through modulation of the NRF2/KEAP1 pathway and ferroptosis.
RESUMO
This study aimed to explore the potential of multi-phase dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) radiomics for classifying breast cancer surrogate subtypes. This retrospective study analyzed 360 breast cancers from 319 patients who underwent pretreatment DCE-MRI between January 2015 and January 2019. The cohort consisted of 33 triple-negative, 26 human epidermal growth factor receptor 2 (HER2)-positive, 109 luminal A-like, 144 luminal B-like HER2-negative, and 48 luminal B-like HER2-positive lesions. A total of 1781 radiomic features were extracted from manually segmented breast cancers in each DCE-MRI sequence. The model was internally validated and selected using ten times repeated five-fold cross-validation on the primary cohort, with further evaluation using a validation cohort. The most successful models were logistic regression models applied to the third post-contrast subtraction images. These models exhibited the highest area under the curve (AUC) for discriminating between luminal A like vs. others (AUC: 0.78), luminal B-like HER2 negative vs. others (AUC: 0.57), luminal B-like HER2 positive vs. others (AUC: 0.60), HER2 positive vs. others (AUC: 0.81), and triple negative vs. others (AUC: 0.83). In conclusion, the radiomic features extracted from multi-phase DCE-MRI are promising for discriminating between breast cancer subtypes. The best-performing models relied on tissue changes observed during the mid-stage of the imaging process.
RESUMO
This study aimed to evaluate the performance of multiparametric breast magnetic resonance imaging (mpMRI) for predicting response to neoadjuvant chemotherapy (NAC) in patients with luminal B subtype breast cancer. The prospective study included thirty-five patients treated with NAC for both early and locally advanced breast cancer of the luminal B subtype at the University Hospital Centre Zagreb between January 2015 and December 2018. All patients underwent breast mpMRI before and after two cycles of NAC. Evaluation of mpMRI examinations included analysis of both morphological (shape, margins, and pattern of enhancement) and kinetic characteristics (initial signal increase and post-initial behavior of the time-signal intensity curve), which were additionally interpreted with a Göttingen score (GS). Histopathological analysis of surgical specimens included grading the tumor response based on the residual cancer burden (RCB) grading system and revealed 29 NAC responders (RCB-0 (pCR), I, II) and 6 NAC non-responders (RCB-III). Changes in GS were compared with RCB classes. A lack of GS decrease after the second cycle of NAC is associated with RCB class and non-responders to NAC.
RESUMO
Introduction: Interleukin 17 (IL-17) has a key role in inflammatory responses. Increased serum concentrations of IL-17 have been reported in patients with different types of cancer. Some studies suggest antitumor activity of IL-17 while others speak in favor of its association with poorer prognosis. The lack of data on IL-17 behavior in vivo hinders the efforts to clarify the exact role of IL-17 in breast cancer patients and precludes the usage of IL-17 as potential therapeutic target. Methods: The study included 118 patients with early invasive breast cancer. The serum concentration of IL-17A was measured before surgery and during adjuvant treatment and compared with healthy controls. The correlation of serum IL-17A concentration and different clinical and pathological parameters, including IL-17A expression in the corresponding tumor tissue samples, was analyzed. Results: Significantly higher serum concentrations of IL-17A were found in women with early breast cancer before surgery, but also during adjuvant treatment in comparison to healthy controls. No significant correlation to tumor tissue IL-17A expression was observed. There was a significant postoperative decrease of serum IL-17A concentrations even in patients with relatively lower preoperative values. A significant negative correlation was found between serum IL-17A concentrations and the tumor estrogen receptor expression. Conclusion: The results suggest that the immune response in early breast cancer is mediated by IL-17A, particularly in triple-negative breast cancer. IL-17A-mediated inflammatory response subsides postoperatively, but IL-17A concentrations remain elevated compared to the values in healthy controls, even after the removal of the tumor.