Mini-organs with big impact: Organoids in liver cancer studies.

Hepatocellular carcinoma, the most common primary liver cancer and a leading cause of death, is a difficult disease to treat due to its heterogeneous nature. Traditional models, such as 2D culture and patient-derived xenografts, have not proven effective. However, the development of 3D culture techniques, such as organoids, which can mimic the tumor microenvironment (TME) and preserve heterogeneity and pathophysiological properties of tumor cells, offers new opportunities for treatment and research. Organoids also have the potential for biomarker detection and personalized medication, as well as genome editing using CRISPR/Cas9 to study the behavior of certain genes and therapeutic interventions. This review explores to-the-date development of organoids with a focus on TME modeling in 3D organoid cultures. Further, it discusses gene editing using CRISPR/Cas9 in organoids, the challenges faced, and the prospects in the field of organoids.

Investigating Oxidative Stress Levels in Pregnant Patients Infected with Hepatitis C Virus and Bacterial Vaginosis for Better Treatment Option.

Objectives: Hepatitis C virus (HCV) and bacterial vaginosis (BV) coinfection generate sustained inflammation with bulk production of reactive oxygen species. They have the potency to cause hepatocellular carcinoma, vaginal apoptosis, disturb pregnancy, and influence drug treatment and follow-up. This case-control study aimed to compare the redox status in HCV and BV coinfection with respect to BV mono-infection among pregnant females (PFs). Methods: Blood samples and vaginal secretions were drawn from 75 PFs divided into three groups: coinfection (n = 25), monoinfection (n = 25), and control PFs (n = 25) who are presumed healthy subjects. Blood samples were analyzed for HCV detection based on conserved 5' untranslated region via real-time polymerase chain reaction and hematological parameters. Markers of oxidative stress (malondialdehyde and peroxidase) and antioxidants (catalase and superoxide dismutase) were checked in plasma as well as vaginal secretions of patients among all three groups. Results: Hematological analysis reveals that hemoglobin levels, platelets, and lymphocytes decreased significantly (p < 0.050) among the coinfection followed by mono-infection group compared to the control group. Moreover, the higher isolation frequency of pathogenic bacteria (Acinetobacter spp.) and Nugent score trend was observed among the coinfection group. Antioxidant levels were significantly lower (p < 0.050) among the vaginal secretions and blood plasma of patients having coinfection with respect to the mono-infection and control groups. While oxidative stress marker was significantly highest (p < 0.050) among vaginal secretions and blood plasma of coinfection followed by mono-infection and control group. These results validate that overall redox severity was more among the coinfection compared to the mono-infection and control groups. Conclusions: Redox indexes should be considered in early diagnosis and treatment of HCV and BV coinfection which may also facilitate the better treatment of hepatocellular carcinoma and vaginal apoptosis.

Aberrant B-Cell Activation in Systemic Lupus Erythematosus.

Background: B lymphocytes (B cells) are essential in humoral response, and their activation is an important first step for the production of antibodies. However, aberrant B-cell activation is common in the development and progression of autoimmune diseases including systemic lupus erythematosus (SLE), which is characterized by the generation of superfluous autoantibodies. SLE exhibits clinical manifestation such as excessive inflammation and tissue damage. This review aims to summarize the recent emerging studies on aberrant B-cell activation and the associated concurrent therapeutic targets in SLE. Summary: Aberrant B-cell activation is closely associated with the pathogenesis of SLE. Among a variety of mechanisms, dysregulations of B-cell receptor (BCR), toll-like receptor (TLR), and B-cell activating factor receptor (BAFF-R) pathways are the common and dominating factors involved in aberrant B-cell activation. These aberrant signaling transductions play diverse and integrated roles in the development and the pathogenesis of SLE. Therapies targeting aberrant B-cell activation have shown promising efficacy in achieving the clinical alleviation of SLE, suggesting the discovery of new drug targets from these aberrant signaling pathways is imminent. Here, an integrated survey or review of published high-throughput sequencing database covering RNAs of B cells from SLE versus criteria-matched healthy controls highlights that reported signaling molecules in BCR pathway (VAV2, PLC-γ2), TLR pathway (TLR9, P105, IRF7, TAB1), and BAFF-R pathway (SDF-1α) are attitudinally upregulated in SLE patients. This review thus suggests the concurrent and future therapeutic targets and potential biomarkers in both basic and clinical studies of SLE. Key Messages: This review focuses on core B-cell signaling pathways, discussing the progress in the role of aberrant B-cell activation during the pathogenesis of SLE. This review also highlights the signaling molecules from published studies and database for the possible prevention and treatment targets serving the future clinical treatments of SLE.

B cell receptor (BCR) guided mechanotransduction: Critical hypothesis to instruct SARS-CoV-2 specific B cells to trigger proximal signalling and antibody reshaping.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19, has spread around the globe with remarkable consequences for the health of millions of people. Despite the approval of mRNA vaccines to prevent the spread of infection, long-term immunity must still be monitored. Targeting and modifying virus receptor binding regions to activate B cell receptors (BCRs) is a promising way to develop long-term immunity against SARS-CoV-2. After the interaction of antigens, BCRs undergo series of signal transduction events through phosphorylation of immune receptor tyrosine activation motifs (ITAMs) to produce neutralizing antibodies against pathogens. BCRs intricate entity displays remarkable capability to translate the external mechanosensing cues to reshape the immune mechanism. However, potential investigations suggesting how SARS-CoV-2 specific B cells respond to mechanosensing cues remain obscure. This study proposes a sophisticated hypothesis explaining how B cells isolated from the CP of SARS-CoV-2 infected patients may undergo a triggered series of B cell activation, BCR dynamics, proximal signalling, and antibody production on PDMS-embedded in-vitro antigen-presenting structures (APCs). These studies could provide detailed insights in the future for the development of structural and therapeutic entanglements to fight against pathogens.

Structural and immunogenomic insights into B-cell receptor activation.

B cells express B-cell receptors (BCRs) which recognize antigen to trigger signaling cascades for B-cell activation and subsequent antibody production. BCR activation has a crucial influence on B-cell fate. How BCR is activated upon encountering antigen remains to be solved, although tremendous progresses have been achieved in the past few years. Here, we summarize the models that have been proposed to explain BCR activation, including the cross-linking model, the conformation-induced oligomerization model, the dissociation activation model, and the conformational change model. Especially, we elucidate the partially resolved structures of antibodies and/or BCRs by far and discusse how these current structural and further immunogenomic messages and more importantly the future studies may shed light on the explanation of BCR activation and the relevant diseases in the case of dysregulation.

B cell mechanosensing: A mechanistic overview.

B cells are essential to the adaptive immune system for providing the humoral immunity against cohorts of pathogens. The presentation of antigen to the B cell receptor (BCR) leads to the initiation of B cell activation, which is a process sensitive to the stiffness features of the substrates presenting the antigens. Mechanosensing of the B cells, potentiated through BCR signaling and the adhesion molecules, efficiently regulates B cell activation, proliferation and subsequent antibody responses. Defects in sensing of the antigen-presenting substrates can lead to the activation of autoreactive B cells in autoimmune diseases. The use of high-resolution, high-speed live-cell imaging along with the sophisticated biophysical materials, has uncovered the mechanisms underlying the initiation of B cell activation within seconds of its engagement with the antigen presenting substrates. In this chapter, we reviewed studies that have contributed to uncover the molecular mechanisms of B cell mechanosensing during the initiation of B cell activation.