The Role of Genetic Sex and Mitochondria in Response to COVID-19 Infection.

The difference between the female and male immune response to COVID-19 infection, and infections in general, is multifactorial. The well-known determiners of the immune response, such as X and Y chromosomes, sex hormones, and microbiota, are functionally interconnected and influence each other in shaping the organism's immunity. We focus our commentary on the interplay between the genetic sex and mitochondria and how this may affect a sex-dependent immune response in COVID-19 infection. Realizing the existence of these interactions may help in designing novel methods or fine-tuning the existing and routine therapies to fight COVID-19 and other infections.

Role of Macrophages and RhoA Pathway in Atherosclerosis.

The development, progression, or stabilization of the atherosclerotic plaque depends on the pro-inflammatory and anti-inflammatory macrophages. The influx of the macrophages and the regulation of macrophage phenotype, inflammatory or anti-inflammatory, are controlled by the small GTPase RhoA and its downstream effectors. Therefore, macrophages and the components of the RhoA pathway are attractive targets for anti-atherosclerotic therapies, which would inhibit macrophage influx and inflammatory phenotype, maintain an anti-inflammatory environment, and promote tissue remodeling and repair. Here, we discuss the recent findings on the role of macrophages and RhoA pathway in the atherosclerotic plaque formation and resolution and the novel therapeutic approaches.

Strongyloides stercoralis in solid organ transplantation: early diagnosis gets the worm.

PURPOSE OF REVIEW: Strongyloidiasis is a parasitic infection affecting millions of people worldwide. Complications of infection are strongly associated with alcoholism, immunosuppression, and organ transplantation. Delayed diagnosis results in hyperinfection syndrome and disseminated strongyloidiasis leading to mortality rates approaching 80%. Early detection, and prevention of infection and transmission are key to diminish this illness. RECENT FINDINGS: In this review, we cover the basic concepts in immunity, immunosuppression, and disorder necessary for understanding the infectious syndromes associated with Strongyloides stercoralis infection. Focused discussion on donor-derived transmission and recipient risk in solid organ transplantation is presented. Current methodology for diagnosis, screening algorithms, and treatment are also reviewed. SUMMARY: Strongyloidiasis complicated by hyperinfection and dissemination remains associated with a poor outcome. The poor outcome pleads for a high level of suspicion and aggressive treatment in at-risk patients. As the population of transplant patients continues to increase, the risk of infection also increases, compelling us to address this highly fatal infectious complication in solid organ transplantation (SOT). Here we review the pathology, immunology, diagnosis, and treatment of strongyloides infection in the immunosuppressed SOT population.

Utilization of Immunotherapy as a Neoadjuvant Therapy for Liver Transplant Recipients with Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is widely recognized as the predominant type of primary liver malignancy. Orthotopic liver transplantation (OLT) has emerged as a highly effective treatment option for unresectable HCC. Immunotherapies as neoadjuvant options are now being actively investigated in the transplant oncology era to enhance outcomes in patients with HCC. Here, we report our experience with patients with HCC who had received Immune Checkpoint Inhibitors (ICPI) prior to curative OLT. Methods: This was a retrospective cohort that included patients with HCC who received ICPI prior to OLT at a single institution from January 2019 to August 2023. Graft rejection was assessed and reported along with the type of ICPI, malignancy treated, and the timing of ICPI in association with OLT. Results: During this cohort period, six patients with HCC underwent OLT after neoadjuvant ICPI. All patients were male with a median age of 61 (interquartile range: 59-64) years at OLT. Etiology associated with HCC was viral (N = 4) or Non-alcoholic steatohepatitis, NASH (N = 2). Tumor focality was multifocal (N = 4) and unifocal (N = 2). Lymphovascular invasion was identified in four patients. No perineural invasion was identified in any of the patients. All patients received ICPI including atezolizumab/bevacizumab (N = 4), nivolumab/ipilimumab (N = 1), and nivolumab as monotherapy (N = 1). All patients received either single or combined liver-directed/locoregional therapy, including transarterial chemoembolization (TACE), Yttrium-90 (Y90), stereotactic body radiotherapy (SBRT), and radiofrequency ablation (RFA). The median washout period was 5 months. All patients responded to ICPI and achieved a safe and successful OLT. All patients received tacrolimus plus mycophenolate as immunosuppressant (IS) therapy post-OLT and one patient received prednisone as additional IS. No patient had clinical evidence of rejection. Conclusions: This cohort emphasizes the success of tumor downstaging by ICPI for OLT when employed as the neoadjuvant therapy strategy. In addition, this study illustrated the importance of timing for the administration of ICPI before OLT. Given the lack of conclusive evidence in this therapeutic area, we believe that our study lays the groundwork for prospective trials to further examine the impact of ICPI prior to OLT.

Factors affecting survival after liver retransplantation: a systematic review and meta-analysis.

Background: Liver retransplantation (reLT) has historically had inferior survival relative to primary liver transplant (LT). To improve outcomes after reLT, researchers have identified factors predicting overall (OS) and/or graft survival (GS) after reLT. This systematic review and random effects meta-analysis sought to summarize this literature to elucidate the strongest independent predictors of post-reLT. Methods: A systematic review was conducted to identify manuscripts reporting factors affecting survival in multivariable Cox proportional hazards analyses. Papers with overlapping cohorts were excluded. Results: All 25 included studies were retrospective, and 15 (60%) were single-center studies. Patients on pre-transplant ventilation (HR, 3.11; 95% CI, 1.56-6.20; p = 0.001) and with high serum creatinine (HR, 1.46; 95% CI, 1.15-1.87; p = 0.002) had the highest mortality risk after reLT. Recipient age, Model for End-Stage Liver Disease score, donor age, and cold ischemia time >12 h also conferred a significant risk of post-reLT death (all p < 0.05). Factors affecting GS included donor age and retransplant interval (the time between LT and reLT; both p < 0.05). OS is significantly higher when the retransplant interval is ≤7 days relative to 8-30 days (p = 0.04). Conclusions: The meta-analysis was complicated by papers utilizing non-standardized cut-off values to group variables, which made between-study comparisons difficult. However, it did identify 7 variables that significantly impact survival after reLT, which could stimulate future research into improving post-reLT outcomes.

Transplant Oncology: An Emerging Discipline of Cancer Treatment.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The applications of oncology, transplant medicine, and surgery are the core of transplant oncology to improve patients' survival and quality of life. The main concept of transplant oncology is to radically cure cancer by removing the diseased organ and replacing it with a healthy one, aiming to improve the survival outcomes and quality of life of cancer patients. Subsequently, it seeks to expand the treatment options and research for hepatobiliary malignancies, which have seen significantly improved survival outcomes after the implementation of liver transplantation (LT). In the case of colorectal cancer (CRC) in the transplant setting, where the liver is the most common site of metastasis of patients who are considered to have unresectable disease, initial studies have shown improved survival for LT treatment compared to palliative therapy interventions. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years beyond Milan criteria in a stepwise manner. However, the outcome improvements and overall patient survival are limited to the specifics of the setting and systematic intervention options. This review aims to illustrate the representative concepts and history of transplant oncology as an emerging discipline for the management of hepatobiliary malignancies, in addition to other emerging concepts, such as the uses of immunotherapy in a peri-transplant setting as well as the use of circulating tumor DNA (ctDNA) for surveillance post-transplantation.

Progress in Combined Liver-lung Transplantation at a Single Center.

Combined liver-lung transplantation is an uncommon, although vital, procedure for patients with simultaneous end-stage lung and liver disease. The utility of lung-liver transplant has been questioned because of initial poor survival outcomes, particularly when compared with liver-alone transplant recipients. Methods: A single-center, retrospective review of the medical records of 19 adult lung-liver transplant recipients was conducted, comparing early recipients (2009-2014) with a recent cohort (2015-2021). Patients were also compared with the center's single lung or liver transplant recipients. Results: Recent lung-liver recipients were older (P = 0.004), had a higher body mass index (P = 0.03), and were less likely to have ascites (P = 0.02), reflecting changes in the etiologies of lung and liver disease. Liver cold ischemia time was longer in the modern cohort (P = 0.004), and patients had a longer posttransplant length of hospitalization (P = 0.048). Overall survival was not statistically different between the 2 eras studied (P = 0.61), although 1-y survival was higher in the more recent group (90.9% versus 62.5%). Overall survival after lung-liver transplant was equivalent to lung-alone recipients and was significantly lower than liver-alone recipients (5-y survival: 52%, 51%, and 75%, respectively). Lung-liver recipient mortality was primarily driven by deaths within 6 mo of transplant due to infection and sepsis. Graft failure was not significantly different (liver: P = 0.06; lung: P = 0.74). Conclusions: The severity of illness in lung-liver recipients combined with the infrequency of the procedure supports its continued use. However, particular attention should be paid to patient selection, immunosuppression, and prophylaxis against infection to ensure proper utilization of scarce donor organs.

Utility of Cell-Free DNA Detection in Transplant Oncology.

Transplant oncology is an emerging field in cancer treatment that applies transplant medicine, surgery, and oncology to improve cancer patient survival and quality of life. A critical concept that must be addressed to ensure the successful application of transplant oncology to patient care is efficient monitoring of tumor burden pre-and post-transplant and transplant rejection. Cell-free DNA (cfDNA) detection has emerged as a vital tool in revolutionizing the management of cancer patients who undergo organ transplantation. The advances in cfDNA technology have provided options to perform a pre-transplant evaluation of minimal residual disease (MRD) and post-transplant evaluation of cancer recurrence and transplant rejection. This review aims to provide a comprehensive overview of the history and emergence of cfDNA technology, its applications to specifically monitor tumor burden at pre-and post-transplant stages, and evaluate transplant rejection.

Utilization of Immunotherapy for the Treatment of Hepatocellular Carcinoma in the Peri-Transplant Setting: Transplant Oncology View.

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related deaths and accounts for over eighty percent of primary liver cancers worldwide. Surgical resection and radiofrequency ablation in small tumors are included in the treatment options for HCC patients with good liver function profiles. According to the Milan Criteria, only a small portion of HCC patients are eligible for liver transplantation due to advanced-stage disease and large tumor size preventing/delaying organ allocation. Recently, the use of anti-programmed cell death protein 1 and programmed cell death ligand 1 (PD-1 and PD-L1) checkpoint inhibitors in the treatment of cancers have evolved rapidly and these therapies have been approved for the treatment of HCC. Immune checkpoint inhibitors have resulted in good clinical outcomes in pre-and post-transplant HCC patients, although, some reports showed that certain recipients may face rejection and graft loss. In this review, we aim to illustrate and summarize the utilization of immune checkpoint inhibitor therapies in pre-and post-liver transplants for HCC patients and discuss the assessment of immune checkpoint inhibitor regulators that might determine liver transplant outcomes.

Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation.

BACKGROUND: Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS: Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS: Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ . CONCLUSIONS: Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

Transplant Oncology: An Evolving Field in Cancer Care.

Transplant oncology is an emerging concept of cancer treatment with a promising prospective outcome. The application of oncology, transplant medicine, and surgery to improve patients' survival and quality of life is the core of transplant oncology. Hepatobiliary malignancies have been treated by liver transplantation (LT) with significant improved outcome. In addition, as the liver is the most common site of metastasis for colorectal cancer (CRC), patients with CRC who have stable unresectable liver metastases are good candidates for LT, and initial studies have shown improved survival compared to palliative systemic therapy. The indications of LT for hepatobiliary malignancies have been slowly expanded over the years in a stepwise manner; however, they have only been shown to improve patient survival in the setting of limited systemic therapy options. This review illustrates the concept and history of transplant oncology as an evolving field for the management of hepatocellular carcinoma, intrahepatic biliary cancer, and liver-only metastasis of non-hepatobiliary carcinoma. The utility of immunotherapy in the transplant setting is discussed as well as the feasibility of using circulating tumor DNA for surveillance post-transplantation.

Siponimod (Mayzent) Downregulates RhoA and Cell Surface Expression of the S1P1 and CX3CR1 Receptors in Mouse RAW 264.7 Macrophages.

The Siponimod (Mayzent) is a newly developed drug, similar to Fingolimod (FTY720) but with fewer side effects, approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS). The therapeutic effect of siponimod and FTY720 in MS relies on their inhibitory effect on the sphingosine 1-phosphate (S1P) signaling. These drugs bind to the S1P receptors and block the CCL2 chemokine pathway that is responsible for the exit of the immune cells from the lymphoid organs, and circulation, thus preventing immune cell-dependent injury to the nervous system. We recently found that FTY720 beside its effect on the S1P pathway also blocks the RhoA pathway, which is involved in the actin cytoskeleton-related function of macrophages, such as expression/recycling of fractalkine (CX3CL1) receptors (CX3CR1), which direct macrophages to the transplanted organs during the development of the long-term (chronic) rejection. Here we tested the effects of siponimod on the RhoA pathway and the expression of the S1P1 and CX3CR1 receptors in mouse RAW 264.7 macrophages. We found that siponimod downregulates the expression of RhoA protein and decreases the cell surface expression of S1P1 and CX3CR1 receptors. This newly discovered crosstalk between S1P and RhoA/CX3CR1 pathways may help in the development of novel anti-chronic rejection therapies in clinical transplantation.

The Macrophages and Intestinal Symbiosis.

The human intestinal tract is inhabited by trillions of microorganisms and houses the largest pool of macrophages in the human body. Being a part of the innate immune system, the macrophages, the professional phagocytes, vigorously respond to the microbial and dietary antigens present in the intestine. Because such a robust immune response poses the danger to the survival of the non-harmful and beneficial gut microbiota, the macrophages developed mechanisms of recognition and hyposensitivity toward the non-harmful/beneficial inhabitants of the gut. We will discuss the evolution and identity of some of these mechanisms in the following chapter.

RhoA Pathway and Actin Regulation of the Golgi/Centriole Complex.

In vertebrate cells, the Golgi apparatus is located in close proximity to the centriole. The architecture of the Golgi/centriole complex depends on a multitude of factors, including the actin filament cytoskeleton. In turn, both the Golgi and centriole act as the actin nucleation centers. Actin organization and polymerization also depend on the small GTPase RhoA pathway. In this chapter, we summarize the most current knowledge on how the genetic, magnetic, or pharmacologic interference with RhoA pathway and actin cytoskeleton directly or indirectly affects architecture, structure, and function of the Golgi/centriole complex.