Hasil untuk "Pathology"

D. Schoepp, P. Conn

C. Lucchinetti, W. Brück, Moses Rodriguez et al.

Multiple sclerosis is an inflammatory demyeli‐nating disease of the central nervous system. The hallmark of its pathology is the demyelinated plaque with reactive glial scar formation. However, a detailed analysis of the patterns of demyelination, oligodendroglia cell pathology and the reaction of other tissue components suggests that the pathogenesis of myelin destruction in this disease may be heterogeneous. In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of myelin degradation products in macrophages. When these criteria are used, different patterns of demyelination can be distinguished, including demyelination with relative preservation of oligodendrocytes, myelin destruction with concomitant and complete destruction of oligodendrocytes or primary destruction or disturbance of myelinating cells with secondary demyelination. Furthermore, in some cases a primary selective demyelination may be followed by secondary oligodendrocyte loss in the established lesions. Finally, some extraordinarily severe conditions may result in destructive lesions with loss of myelin, oligodendrocytes, axons and astro‐cytes. This heterogeneity of plaque pathology is discussed in the context of recent experimental models of inflammatory demyelination, which show that different immunological pathways may lead to the formation of demyelinated plaques that reveal the diverse structural aspects described above. Our data indicate, that the demyelinated plaques of multiple sclerosis may reflect a common pathological end point of a variety of different immunological mechanisms of myelin destruction in this disease.

J. Smeitink, L. Heuvel, S. Dimauro

M. Spillantini, M. Goedert

K. Jellinger

A. Husain, A. Husain, N. Siddiqui et al.

Rony Abdi Syahputra, Asriadi, Arnika Gloria Br Sitorus et al.

MicroRNAs are essential post-transcriptional regulators of gene expression, playing dual roles in oncogenesis as either oncogenes or tumour suppressors. Aberrant miRNA expression is a critical factor in cancer progression, influencing tumour development, metastasis, resistance to apoptosis, and therapy evasion. Concurrently, therapeutic peptides have emerged as promising modulators of miRNA activity due to their specificity, low toxicity, and ability to interact with nucleic acids. This review provides of peptide-mediated modulation of miRNA pathways in cancer, emphasising strategies such as degradation of oncogenic miRNAs, stabilization of tumour-suppressive miRNAs, and the targeted delivery of miRNA therapeutics. These methodologies demonstrate the potential to reverse malignant phenotypes by reducing cell proliferation, suppressing metastasis, restoring normal cellular functions, and promoting apoptosis. The integration of peptide-based delivery systems with miRNA-targeted therapies represents a novel paradigm in precision oncology, addressing key challenges related to therapeutic specificity and systemic delivery.

M. Brada

Paul Kleihues and Webster Cavenee, eds, pp 314, IARC Press, Lyon 2000. Price £46.00. ISBN 92 832 24094

Yi Shuai, Bo Chen, Tao Jiang et al.

Abstract Background Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a severe, therapy-refractory condition driven by ferroptotic disruption of jawbone-derived mesenchymal stem cells (MSCs) biology. We dissect this mechanism to validate ferroptosis as a therapeutic target. Methods We first demonstrated that miR-145-3p is mechanistically coupled to ferroptosis and osteogenesis in BRONJ model by gain- and loss-of-function studies. To evaluate therapeutic efficacy under pathologically relevant conditions, we designed three models: (i) Local BRONJ repair model: miR-145-3p-enriched exosomes were encapsulated in an injectable hydrogel scaffold and grafted into necrotic alveolar bone to assess direct BRONJ resolution. After local BRONJ treatment, endogenous MSCs were re-isolated, and both cellular and exosomal miR-145-3p levels were quantified. (ii) Osteoporosis treatment model: The reprogrammed MSCs derived from treated BRONJ rats were then administered intravenously to osteoporotic littermates to evaluate whether these MSCs retain systemic osteogenic competence. (iii) Critical-sized calvarial defect repair model: To further dissect the intrinsic osteogenic capacity, reprogrammed MSCs derived from treated BRONJ rats were fabricated into cell-sheet/HA-TCP “sandwich” constructs and transplanted into calvarial defects. Results BRONJ markedly compromised MSCs viability while elevating hallmarks of ferroptosis that were reversed by the ferroptosis inhibitor. Concomitantly, osteogenic capacity declined, as shown by reduced ALP activity, mineralized nodules, new bone formation and expression of RUNX2 and OCN. Mechanistically, we identified a miR-145-3p/IREB2 regulatory circuit that governs ferroptosis in BRONJ-derived MSCs; exosome-mediated delivery of miR-145-3p reinstated this axis, thereby reactivating the MSCs osteogenesis and driving in situ bone regeneration. Critically, after local BRONJ therapy, the reprogrammed MSCs were (i) infused via tail vein into osteoporotic rats, significantly elevating bone mass, and (ii) engineered into cell-sheet/HA-TCP “sandwich” constructs that achieved robust repair of critical-sized calvarial defects. These data establish exosomal miR-145-3p as a therapeutic that mitigates ferroptosis and restores the osteogenic competence of jawbone-derived MSCs for bone regeneration. Conclusion Collectively, our findings establish the miR-145-3p/IREB2/ferroptosis axis as an important regulator of BRONJ pathology and demonstrate that exosomal delivery of miR-145-3p not only ameliorates localized BRONJ but also substantially reinstates the systemic osteogenic potential of jawbone-derived MSCs, offering a pre-clinical promising strategy to combat both BRONJ and associated bone loss disorders. Graphical Abstract

Anastasya Cornelya Irawan, Muhammad Agus Muljanto

Penelitian ini bertujuan untuk menganalisis ketimpangan pembangunan antarwilayah di Provinsi Jawa Timur pada tahun 2019–2023 secara spasial berdasarkan pendekatan Tipologi Klassen. Selain itu, penelitian ini juga mengkaji pengaruh Produk Domestik Regional Bruto (PDRB) per kapita dan Laju Pertumbuhan Ekonomi (LPE) terhadap klasifikasi wilayah, serta hubungan ketimpangan pembangunan dengan capaian Indeks Pembangunan Manusia (IPM) dan tingkat kemiskinan. Metode penelitian yang digunakan adalah metode kuantitatif dengan pendekatan deskriptif-spasial. Data yang digunakan merupakan data sekunder yang diperoleh dari Badan Pusat Statistik (BPS), berupa data PDRB per kapita, LPE, IPM, dan tingkat kemiskinan kabupaten/ kota di Jawa Timur selama lima tahun. Analisis data dilakukan dengan menggunakan klasifikasi Tipologi Klassen untuk menentukan pembagian kuadran wilayah (Kuadran I–IV). Hasil penelitian menunjukkan bahwa sebagian besar wilayah berada pada Kuadran III (wilayah potensial untuk berkembang) dan Kuadran IV (wilayah relatif tertinggal). Wilayah-wilayah dalam Kuadran IV umumnya memiliki nilai IPM dan pendapatan per kapita yang rendah serta tingkat kemiskinan yang tinggi, seperti Kabupaten Sampang, Bangkalan, Sumenep, dan Bondowoso. Sebaliknya, wilayah Kuadran I seperti Kota Surabaya dan Kabupaten Gresik menunjukkan capaian IPM tinggi dan angka kemiskinan rendah. Temuan ini memperkuat teori Cumulative Causation oleh Myrdal yang menyatakan bahwa tanpa intervensi, wilayah maju akan semakin maju dan wilayah tertinggal akan semakin tertinggal. Oleh karena itu, diperlukan kebijakan pembangunan berbasis wilayah yang lebih adil untuk mengurangi kesenjangan dan meningkatkan kesejahteraan masyarakat secara merata.

M. Norenberg, Jon Smith, A. Marcillo

M. Vercellino, F. Plano, B. Votta et al.

J. Raber, Yadong Huang, J. Ashford

Cecilia Benazzato, Fernando Lojudice, Felizia Pöehlchen et al.

Abstract Zika virus (ZIKV) infection was first reported in 2015 in Brazil as causing microcephaly and other developmental abnormalities in newborns, leading to the identification of Congenital Zika Syndrome (CZS). Viral infections have been considered an environmental risk factor for neurodevelopmental disorders outcome, such as Autism Spectrum Disorder (ASD). Moreover, not only the infection per se, but maternal immune system activation during pregnancy, has been linked to fetal neurodevelopmental disorders. To understand the impact of ZIKV vertical infection on brain development, we derived induced pluripotent stem cells (iPSC) from Brazilian children born with CZS, some of the patients also being diagnosed with ASD. Comparing iPSC-derived neurons from CZS with a control group, we found lower levels of pre- and postsynaptic proteins and reduced functional synapses by puncta co-localization. Furthermore, neurons and astrocytes derived from the CZS group showed decreased glutamate levels. Additionally, the CZS group exhibited elevated levels of cytokine production, one of which being IL-6, already associated with the ASD phenotype. These preliminary findings suggest that ZIKV vertical infection may cause long-lasting disruptions in brain development during fetal stages, even in the absence of the virus after birth. These disruptions could contribute to neurodevelopmental disorders manifestations such as ASD. Our study contributes with novel knowledge of the CZS outcomes and paves the way for clinical validation and the development of potential interventions to mitigate the impact of ZIKV vertical infection on neurodevelopment.

Raphael Boldt

A partir de uma abordagem criminológico-crítica que se projeta desde o trabalho pioneiro dos frankfurtianos (Rusche e Kirchheimer), o presente artigo analisa os principais reflexos no campo do controle penal decorrentes do capitalismo de vigilância, reconfiguração produzida pela chamada revolução digital, compreendida como mais uma das etapas da modernidade, consistente, sobretudo, na glorificação das novas tecnologias, ideologia que autoriza a emergência das novas fronteiras e conquistas da técnica moderna.

A. Kertesz, P. Mcmonagle, M. Blair et al.

J. Hogg, W. Timens

N. Maclachlan, C. Drew, K. Darpel et al.

M. Pearson, R. Beever, B. Boine et al.

S. Pai, W. Westra