Yale Journal of Biology and Medicine最新文献

The participation of the Rho-associated protein kinases (ROCK1 and 2) in the regulation of actin cytoskeleton organization, cell adhesion, motility, and gene expression has been extensively investigated in many tumors of different histology. However, their pathogenic roles in medulloblastoma (MB) remain understudied, demanding a deeper appreciation of their participation in cancer cell dissemination and tumor progression. Herein, we show that ROCK2 is downregulated in MB tumor samples and functionally increases migration of cell lines belonging to the SHH subgroup. A comprehensive comparative bioinformatic scrutiny of differentially expressed genes within a list of ROCK2 candidate substrates, uncovered a network of 21 dysregulated genes from which DYPSL3 (dihydropyrimidinase-related protein 3) denoted a strong positive correlation. Enrichment analysis revealed SHH/RHOA/ROCK2/DYPSL3 as top hub genes and the intersection between two biological processes of most importance in MB: actin cytoskeleton remodeling and neuron development. Of note, evidence shows that both ROCK2 and DYPSL3, interact with RHOA and in many tumor types they act as tumor suppressors, mitigating cell spreading. Alternatively, their impaired activity leads to undifferentiated phenotypes and inappropriate cytoskeletal dynamics affecting cell shape, attachment to the extracellular matrix, and cell movement. In parallel, cell motility is considered a prototypical non-canonical response to SHH mediated by RHOA. Therefore, we propose a model in which the interplay between these pathways may lead to a perturbation of proper cytoskeletal dynamics that underpins cell migration.

Objective: Activating transcription factor 3 (ATF3) has attracted recent scientific attention as a novel mediator of tumor suppression, particularly within the context of cervical cancer (CC). Our prior research demonstrated that ATF3 overexpression induces cell cycle arrest and apoptosis in human papillomavirus (HPV)16- and HPV18-positive CC cells. The present study aims to examine the impact of ATF3 overexpression on the expression levels of p16 and NF-κB, two proteins with pro-tumorigenic roles in HPV-induced CC. Methods: Ca Ski and HeLa cells underwent transfection with pCMV6-AC-IRES-GFP plasmids containing the ATF3 gene. To establish the optimal plasmid DNA quantities for transfection, MTT assay was conducted. Furthermore, fluorescence microscopy and flow cytometric analysis were employed to assess the efficiency of transfection. The expression levels of p16 and NF-κB were evaluated by RT-qPCR and western blotting prior and subsequent to ATF3 overexpression. Results: The overexpression of ATF3 induced a decrease in p16 mRNA levels in both Ca Ski and HeLa cells (p<0.04), along with the concomitant reduction of p16 protein expression within both cellular populations (p<0.005). Additionally, it led to a reduction in NF-κB p65 protein levels in both cell lines (p<0.005), with no discernible impact on its mRNA expression. Conclusion: Given ATF3's demonstrated capability to downregulate p16 and NF-κB, both of which play important pro-tumorigenic roles in HPV-related CC, ATF3 emerges as a promising therapeutic candidate with the potential for application in the treatment of CC.

Stress adaptation is an evolutionarily conserved mechanism that promotes survival in the face of adverse conditions. AMP-activated protein kinase (AMPK) is a highly conserved energy-sensing kinase found in nearly all eukaryotic cells. It maintains energy homeostasis by promoting catabolism and inhibiting anabolism. In the context of cancer, the role of AMPK is controversial. It was initially touted as a tumor suppressor due to its association with Liver Kinase B1 (LKB1) (an upstream regulator and a known tumor suppressor) and ensuing growth-suppressive actions. However, emerging studies across a variety of cancer types unambiguously reveal AMPK's pro-survival and, thus, tumor-promoting activity, especially under cancer-associated stresses such as hypoxia, nutrient deprivation, oxidative stress, matrix detachment, and chemotherapy. In cancer cells, AMPK is activated in response to stress-induced increases in the levels of adenosine monophosphate (AMP), Ca²⁺, or reactive oxygen species (ROS). Upon activation, AMPK engages in metabolic rewiring and crosstalk with signaling molecules to mobilize resources toward survival while compromising proliferation. Here, we posit that AMPK is a non-genetic "reversible switch," allowing cancer cells' phenotype to switch to dormant, stem-like, and drug-resistant states, thereby enabling tumor cell survival, pathological progression, and therapy resistance. This review underscores the critical role of AMPK in driving cancer cell stress resilience and survival, advocating for the strategic use of AMPK inhibitors to improve cancer treatment outcomes.

Plants have evolved elaborate signaling networks, believed to be necessitated by the diversity and complexity of their morphology, developmental and reproductive strategies, and the need to cope with an ever-changing environment from which they are rooted and cannot escape. Their receptor-like kinase superfamilies, with members numbering in the hundreds to more than a thousand, exemplify how plants have evolved their signaling versatility. FERONIA (FER) receptor kinase from model Arabidopsis is a member of the Malectin-domain receptor kinase family conserved among plants. FER has a perplexingly broad functional range, impacting growth to reproduction throughout the plant life cycle, and survival when encountering biotic and abiotic stressors from the environment, such as pathogens and climatic adversity. Efforts to understand FER signaling have brought to light novel signaling strategies at the continuum of the plant cell wall and plasma membrane, and a network of cytoplasmic and nuclear pathways that together support its biological roles. The discussion here focuses on the cell surface mechanisms, including a sugar-peptide interaction-driven liquid-liquid phase separation process along the cell wall-plasma membrane interface and a plasma membrane-linked signaling node comprised of FER, a glycosylphosphatidylinositol-anchored protein, the RHO GTPase molecular switch and a generator for reactive oxygen species (ROS). The emerging recognition of how the broader FER-related receptor kinase family could impact plant wellness and agricultural productivity is also discussed.

Monkeypox (Mpox) has once again been designated a Public Health Emergency of International Concern (PHEIC) as of August, 2024. The severity of the disease is underscored by its significant mortality rate, and unfortunately, there are no targeted therapeutics currently available for this viral infection. Management relies on preventive measures and the use of existing smallpox vaccines due to their genetic similarity to the Mpox virus. Diagnosing a disease is a critical aspect of managing any health condition, and for a highly contagious viral infection like Mpox, it is essential to employ a specific and sensitive diagnostic approach. The lack of adequate diagnostic facilities in laboratories poses a significant challenge, hindering accurate diagnoses and the identification of underlying etiologies, particularly in low-resource settings. Current serology-based diagnostic tests lack specificity for the Mpox virus, leading to cross-reactivity with other orthopoxviruses. With the emergence of new viral variants, molecular and genomic diagnostic methods are far more reliable for accurately confirming Mpox infections. This review focuses on current diagnostic methods approved worldwide and the future challenges that need to be addressed to effectively control and mitigate the spread of Mpox.

Chikungunya virus infection (CHIKV) increases the risk of persistent arthralgia; however, there is no consistent evidence regarding prognostic biomarkers of progression to chronic arthropathy. This systematic review provides an overview of currently available literature about the potential role of the acute immunologic response in predicting long-term joint pain in patients with a diagnosis of CHIKV. We searched for observational studies using the terms "chikungunya," "cytokines," "biomarkers," and "joint pain" in PubMed/MEDLINE, LILACS, Cochrane Library Plus, and SCOPUS databases, restricting to articles published in English and up to April 2024. PROSPERO registration number: CRD42021279400. Thirty-eight studies were selected for qualitative synthesis with a maximum duration from diagnosis to clinical evaluation of 60 months. The sample sizes ranged from 8 to 346 participants (age range: 0-90 years). We identified an immunologic profile during the acute phase of CHIKV that includes increased levels of proinflammatory cytokines (IFN-α, IFN-γ, IL-2R, IL-6, IL-7, and IL-8), anti-inflammatory cytokines (IL-1Ra and IL-4), chemokines (MCP-1, MIG, and IP-10) and growth factors (VEGF and G-CSF). Only one out of two studies reported differences in cytokine levels during the acute phase, predicting persistent joint pain at 20 months of follow-up. Also, persistence of anti-CHIKV IgG seemed to be a potential prognostic marker. The evidence suggests the existence of an inflammatory response in the acute phase of CHIKV that persists during its chronic phase; however, there is no unequivocal candidate set of biomarkers of progression toward long-term articular sequelae.

Purpose: To report a case of cystoid macular edema (CME) secondary to immune recovery uveitis (IRU) in a patient with previous history of cytomegalovirus (CMV) retinitis and leukemia, which was successfully treated with tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist. Method: The clinical records of the case were reviewed, focusing on demographics, image findings, and clinical course. Results: A 17-year-old female with a past medical history of T-cell acute lymphoblastic leukemia (T-ALL) undergoing chemotherapy for two years presented with active CMV retinitis. She was successfully treated with intravitreal foscarnet injections and systemic ganciclovir. After 5 months of systemic valganciclovir maintenance and following cessation of chemotherapy, the patient developed bilateral CME and vasculitis, and was diagnosed with IRU. CME management was challenging due to a history of bilateral avascular necrosis of the femoral head resulting from prolonged systemic corticosteroid use. Two cycles of monthly TCZ infusions were administered at the dosage of 8mg/kg. Subsequently, the CME and retinal vasculitis resolved significantly without any evidence of inflammation in the anterior chamber and vitreous. Conclusion: The index case report demonstrated the safety and efficacy of the IL-6 receptor antagonist TCZ in treating CME associated with IRU in a non-HIV CMV retinitis patient.

Alkhumra fever is a viral disease caused by the Alkhumra hemorrhagic fever virus (AHFV). It belongs to family Flaviviridae, genus Flavivirus. AHFV is primarily transmitted to humans through the bite of infected ticks, for example, Hyalomma. This disease was first identified in the Kingdom of Saudi Arabia (KSA) in 1995 and then reported in other countries of the Arabian Peninsula and the Middle East. The AHFV genome consists of a positive-sense, single-stranded RNA molecule of approximately 10.2 kilobases (kb) in length. The Open Reading Frame (ORF) encodes a polyprotein precursor that is processed by viral and host proteases to yield individual viral proteins. The polyprotein precursor is cleaved by viral proteases and host signal peptidases into three structural and seven non-structural proteins. AHFV can cause a range of clinical manifestations, from mild flu-like symptoms to severe hemorrhagic fever. In this review, we focus on insightful understanding of molecular biology, pathogenesis, and their potential therapeutic targets for AHFV.

Patients with prior SARS-CoV-2 infections can develop chronic symptoms; this clinical presentation has been called post-acute sequelae of SARS-CoV-2 infection, post-COVID condition, and long COVID. It can develop in both outpatient cases and in hospital cases; the frequency depends on the severity of infection and comorbidity. Many of these patients have exercise limitation when tested using cardiopulmonary exercise tests. The potential explanations for reduced exercise capacity include cardiac limitations, respiratory limitations, skeletal muscle weakness, deconditioning, and limiting symptoms out of proportion to any measured physiological limitation, and many patients have more than one explanation for the exercise limitation. Since these patients may have required prolonged hospitalization, deconditioning has been considered a potential explanation for their post-hospitalization limitations. Patients with deconditioning have a low oxygen uptake per minute (VO₂) maximum with no obvious cardiac or respiratory limitation, but some do have measurable muscle weakness. One complex study reported that these patients had a high proportion of high-fatigable glycolytic fibers, reduced mitochondrial function, atrophic fibers, and focal necrosis in skeletal muscle. Some post-COVID patients have chronic fatigue and post-exertional malaise and meet the clinical criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Most patients with post-COVID syndrome do improve with conventional cardiopulmonary rehabilitation. However, patients with post-exertional malaise need special attention to their exercise programs and careful monitoring for adverse effects. In summary, patients with long COVID can have complex presentations with a broad range of symptoms and several possible exercise limitations. Their rehabilitation program should be based on their physical capacity and their symptom profile.