Simple Summary In this study, we investigated the potential of TLR4 to improve the treatment of hepatocellular carcinoma (HCC). HCC is a serious health concern worldwide, and finding new ways to combat it is crucial. Our study focused on understanding how TLR4 can enhance the effectiveness of immunotherapy, a treatment approach that harnesses the body’s immune system to fight cancer cells. We demonstrated that targeting TLR4 can stimulate the immune response against HCC cells, leading to their destruction. This exciting finding suggests that TLR4 could serve as a valuable target for developing new therapies for HCC. The implications of this study extend beyond the realm of medical research. If successful, these new strategies could offer renewed hope to HCC patients and potentially improve the overall survival rates. Furthermore, the insights gained from our study may pave the way for similar approaches in treating other types of cancer. In summary, our research highlights the significant role of TLR4 in enhancing immunotherapy for HCC. This knowledge brings us one step closer to developing more effective treatments and improving the lives of cancer patients. Abstract Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.

/pdf/the-role-of-tlr4-in-the-immunotherapy-of-hepatocellular-3ah5avr5.pdf

The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks?

Abstract Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer’s disease (AD) and Parkinson’s disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases. 

The role of cellular senescence in neurodegenerative diseases.

Gender-affirming treatment remains a topic of controversy; of particular concern is whether gender-affirming treatment reduces suicidality. A narrative review was undertaken evaluating suicide-related outcomes following gender-affirming surgery, hormones, and/or puberty blockers. Of the 23 studies that met the inclusion criteria, the majority indicated a reduction in suicidality following gender-affirming treatment; however, the literature to date suffers from a lack of methodological rigor that increases the risk of type I error. There is a need for continued research in suicidality outcomes following gender-affirming treatment that adequately controls for the presence of psychiatric comorbidity and treatment, substance use, and other suicide risk-enhancing and reducing factors. There is also a need for future systematic reviews given the inherent limitations of a narrative review. There may be implications on the informed consent process of gender-affirming treatment given the current lack of methodological robustness of the literature reviewed.

/pdf/suicide-related-outcomes-following-gender-affirming-2hydoy0b.pdf

Suicide-Related Outcomes Following Gender-Affirming Treatment: A Review

Toll-like receptor 4 (TLR4) plays an important role as a key signal-receiving transmembrane protein molecule in the liver, and substances that target the liver exert therapeutic effects via TLR4-related signaling pathways. This article provides a comprehensive review of targeting the TLR4 signaling axis to play an important role in the liver based on endogenous substances. Articles were divided into 5 major types of liver disease, acute liver injury, viral hepatitis, alcoholic and non-alcoholic liver disease, cirrhosis, and liver cancer, to elucidate how various endogenous substances affect the liver via the TLR4 pathway and the important role of the pathway itself in liver-related diseases to discover the potential therapeutic implications of the TLR4-related pathway in the liver. The results indicate that activation of the TLR4-related signaling axis primarily plays a role in promoting disease progression in liver-related diseases, and the TLR4/MyD88/NF-κB axis plays the most dominant role. Therefore, exploring the full effects of drugs targeting the TLR4-related signaling axis in the liver and the new use of old drugs may be a new research direction. 

Role of targeting TLR4 signaling axis in liver-related diseases.

Introduction Oncologists are usually faced with a huge amount of diagnostic and therapeutic data in the process of cancer care. However, they do not have access to the integrated data. This research aimed to present a conceptual model of an oncology information system based on the users' requirements. Methods This study was conducted in 2019 and composed of two phases. Initially, a questionnaire was designed, and clinical experts (n=34) were asked to identify the most important data elements and functional requirements in an oncology information system. In the second phase, conceptual, structural and behavioral diagrams of the system were drawn based on the results of the first phase. These diagrams were also reviewed and validated by five experts. Results Most of the data elements and all functional requirements were found important by the experts. The data elements were related to different phases of cancer care including screening, prevention, diagnosis, treatment, mental care and pain relief, and end-of-life care. Then, conceptual, structural and behavioral diagrams of the system were designed and approved by the experts or revised based on their comments. Conclusion The conceptual model and the diagrams presented in the current study can be used for developing an oncology information system. This system will be able to manage patients' cancer data from screening to the end-of-life care. However, the system needs to be designed and implemented in a real healthcare setting to see how it can meet users' requirements.

/pdf/a-conceptual-model-of-an-oncology-information-system-3bxf5g0300.pdf

A Conceptual Model of an Oncology Information System

Authors : Yi-Ting Liu, Pei-Ying Wen Abstract : In order to improve the overall safety of chemotherapy, safety-protecting net was established for the whole process from prescribing by physicians, transcribing by nurses, dispensing by pharmacists to administering by nurses. The information system was used to check and monitor whole process of administration and related sheets were computerized to simplify the paper work.

Establishment and Evaluation of Information System for Chemotherapy Care

Brain cancer is a deadly disease with low survival rates for over 70 % of patients. Therefore, there is a critical need to develop better treatment methods and strategies to improve patient outcomes. In this study, we explored the tumor microenvironment and discovered unique characteristics of microglia to interact with astrocytoma cells and promote proliferation and migration of collisions. The conditioned medium from the collisions expressed cell chemoattraction and anti-inflammatory responses. To further understand the interactions between microglia and astrocytoma cells, we used flow sorting and protein analysis found that the protein alterations were related to biogenesis in the astrocytoma cells and metabolic processes in the microglia. Both types of cells were involved in binding and activity in cell-cell interactions. Using STRING to demonstrate the protein cross-interaction between the cells. Furthermore, PHB and RDX interact with oncogenic proteins, which were significantly expressed in patients with Glioblastoma Multiforme (GBM) and low-grade glioma (LGG) according to GEPIA. To study the role of RDX in chemoattraction, the inhibitor-NSC668394 suppressed collision formation and migration in BV2 cells in vitro by down-regulating F-actin. Additionally, it suppressed macrophage infiltration in infiltrating islands in vivo of intracranial tumor-bearing mice. These findings provide evidence for the role of resident cells in mediating tumor development and invasiveness and suggest that potential interacting molecules may be a strategy for controlling tumor growth by regulating the infiltration of tumor-associated microglia in the brain tumor microenvironment. 

Multi-omics profiling of chemotactic characteristics of brain microglia and astrocytoma.

Purpose: Gender dysphoria is a condition that often leads to significant patient morbidity and mortality. Although gender affirming surgery (GAS) has been offered for more than half a century with clear significant short-term improvement in patient wellbeing, few studies have evaluated the long term durability of these outcomes. This study aims to investigate the long term effect of GAS and patient satisfaction. Methods: Chart review identified 97 patients who were seen for gender dysphoria at a tertiary care center from 1970-1990 with comprehensive preoperative evaluations. These evaluations were used to generate a matched follow-up survey regarding their GAS, appearance, and mental/ social health for standardized outcome measures. Of 97 patients, 15 agreed to participate in the phone interview and survey. Preoperative and postoperative body congruency score (BCS), mental health status, surgical outcomes and patient satisfaction were compared. Results: Both transmasculine and transfeminine groups were more satisfied with their body postoperatively with significantly less dysphoria. BCS for chest, body hair, and voice improved significantly in 40 years postop settings with average scores ranging from 84.2 to 96.2. Body congruency scores for genitals ranged from 67.5 to 79 with free flap phalloplasty showing highest scores. Long term overall BCS was 89.6, compared to that of hormone treatment only scenario (21.2). Improved mental health outcomes persisted following surgery with significantly reduced suicidal ideation and reported resolution of any mental health comorbidity secondary to gender dysphoria. Conclusion: Gender-affirming surgery is a durable treatment that improve overall patient well-being. High patient satisfaction, improved dysphoria, and reduced mental health comorbidities persist decades after GAS without any reported patient regret. 

QS37. Long Term Outcomes After Gender Affirming Surgery: 40 Year Follow Up Study

Background Gender dysphoria is a condition that often leads to significant patient morbidity and mortality. Although gender-affirming surgery (GAS) has been offered for more than half a century with clear significant short-term improvement in patient well-being, few studies have evaluated the long-term durability of these outcomes. Methods Chart review identified 97 patients who were seen for gender dysphoria at a tertiary care center from 1970 to 1990 with comprehensive preoperative evaluations. These evaluations were used to generate a matched follow-up survey regarding their GAS, appearance, and mental/social health for standardized outcome measures. Of 97 patients, 15 agreed to participate in the phone interview and survey. Preoperative and postoperative body congruency score, mental health status, surgical outcomes, and patient satisfaction were compared. Results Both transmasculine and transfeminine groups were more satisfied with their body postoperatively with significantly less dysphoria. Body congruency score for chest, body hair, and voice improved significantly in 40 years' postoperative settings, with average scores ranging from 84.2 to 96.2. Body congruency scores for genitals ranged from 67.5 to 79 with free flap phalloplasty showing highest scores. Long-term overall body congruency score was 89.6. Improved mental health outcomes persisted following surgery with significantly reduced suicidal ideation and reported resolution of any mental health comorbidity secondary to gender dysphoria. Conclusion Gender-affirming surgery is a durable treatment that improves overall patient well-being. High patient satisfaction, improved dysphoria, and reduced mental health comorbidities persist decades after GAS without any reported patient regret.

Long-term Outcomes After Gender-Affirming Surgery

Chronic inflammation caused by liver damage or infection plays an important role in the development and progression of hepatocellular carcinoma (HCC). The activation of Toll-like receptors 4 (TLR4) is involved in HCC tumorigenesis. Moreover, high TLR4 expression in HCC has been linked to poor prognosis. Although the expression of TLR4 in HCC is relatively low compared to hematopoietic cells, it is important to explore the molecular mechanism leading to the elevation of TLR4 in HCC. In this study, we aimed to investigate the positive regulating loop for TLR4 expression in HCC in response to chronic inflammation. Our results confirm that the mRNA expression of TLR4 and proinflammatory cytokines, including interleukin 6 (IL6) and C-C motif chemokine ligand 2 (CCL2), positively correlate in human HCC samples. High TLR4 expression in HCC is more susceptible to lipopolysaccharide (LPS); TLR4 activation in HCC provides growth and survival advantages and thus promotes tumorigenesis. It has been shown that the LIN28/let-7 microRNA (miRNA) axis is a downstream effector of the TLR4 signal pathway, and let-7 miRNA is a potential post-transcriptional regulator for TLR4. Thus, we investigated the correlation between TLR4 and LIN28A mRNA and let-7g miRNA in HCC clinical samples and found that the expression of TLR4 was positively correlated with LIN28A and negatively correlated with let-7g miRNA. Moreover, by culturing PLC/PRF5 (PLC5) HCC cells in low-dose LPS-containing medium to mimic chronic inflammation for persistent TLR4 activation, the mRNA and protein levels of TLR4 and LIN28A were elevated, and let-7g miRNA was decreased. Furthermore, the 3’ untranslated region (3’UTR) of TLR4 mRNA was shown to be the target of let-7g miRNA, suggesting that inhibition of let-7g miRNA is able to increase TLR4 mRNA. While parental PLC5 cells have a low susceptibility to LPS-induced cell growth, long-term LPS exposure for PLC5 cells leads to increased proliferation, cytokine expression and stemness properties. In conclusion, our studies demonstrate positive feedback regulation for chronic TLR4 activation in the modulation of TLR4 expression level through the LIN28A/let-7g pathway in HCC and suggest a connection between chronic inflammation and TLR4 expression level in HCC for promoting tumorigenesis.

/pdf/persistent-tlr4-activation-promotes-hepatocellular-carcinoma-29e9cm57.pdf

Persistent TLR4 Activation Promotes Hepatocellular Carcinoma Growth through Positive Feedback Regulation by LIN28A/Let-7g miRNA

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