Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

In Vitro Profiling of Commonly Used Post-transplant Immunosuppressants Reveals Distinct Impact on Antiviral T-cell Immunity Towards CMV.

Infectious complications, including widespread human cytomegalovirus (CMV) disease, frequently occur after hematopoietic stem cell and solid organ transplantation due to immunosuppressive treatment causing impairment of T-cell immunity. Therefore, in-depth analysis of the impact of immunosuppressants on antiviral T cells is needed. We analyzed the impact of mTOR inhibitors sirolimus (SIR/S) and everolimus (EVR/E), calcineurin inhibitor tacrolimus (TAC/T), purine synthesis inhibitor mycophenolic acid (MPA/M), glucocorticoid prednisolone (PRE/P) and common double (T+S/E/M/P) and triple (T+S/E/M+P) combinations on antiviral T-cell functionality. T-cell activation and effector molecule production upon antigenic stimulation was impaired in presence of T+P and triple combinations. SIR, EVR and MPA exclusively inhibited T-cell proliferation, TAC inhibited activation and cytokine production and PRE inhibited various aspects of T-cell functionality including cytotoxicity. This was reflected in an in vitro infection model, where elimination of CMV-infected human fibroblasts by CMV-specific T cells was reduced in presence of PRE and all triple combinations. CMV-specific memory T cells were inhibited by TAC and PRE, which was also reflected with double (T+P) and triple combinations. EBV- and SARS-CoV-2-specific T cells were similarly affected. These results highlight the need to optimize immune monitoring to identify patients who may benefit from individually tailored immunosuppression.

Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

Background: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI). Methods: Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics. Results: CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with the other drugs. The MMF-containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with that of the MMF group, although liver transplantation patients have lower NK cell activity and function. Conclusions: Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

Prevalence and factors associated with depression and anxiety in living liver donors: A systematic review and meta-analysis.

OBJECTIVE: This study aimed to systematically review the prevalence and factors associated with depression and anxiety in living liver donors after liver transplantation. METHODS: Five English language electronic databases and four Chinese language electronic databases were searched from inception to February 2023. Two investigators independently extracted the data and assessed the study quality. The pooled prevalence was calculated using STATA software (version 14.0). We performed a narrative review to summarize the factors associated with depression and anxiety in living liver donors after liver transplantation. The protocol of this study was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database, registration number: CRD42021290071. RESULTS: This study included 39 articles involving 18,577 participants. The pooled prevalence was 6.3% [95% confidence interval (CI) (4.1-8.9%)] for depression in living liver donors, and 10.0% [95% CI (4.0-18.1%)] for anxiety. Prevalence of clinically significant depressive or anxiety symptoms was higher (15.7% and 17.4%) compared with disorders (2.7% and 2.2%). The prevalence of depression and anxiety was highest within 3 months post-donation. Specifically, female donors, serious postoperative complications, and recipients' poor health/death have been reported as factors having a negative influence on depression and anxiety. CONCLUSIONS: Collected evidence showed that the overall prevalence of depression or anxiety of living liver donors was high. Therefore, early detection and timely treatment of psychological disorders are crucial to promote positive psychiatric health outcomes and ensure the quality of life of living liver donors.

Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid-derived suppressor cells in hepatocellular carcinoma.

BACKGROUND: Preclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC). METHOD AND RESULTS: Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC. CONCLUSION: Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.

Retroperitoneal Laparoscopic Hepatectomy for a Subcapsular Hepatocellular Carcinoma in Segment VI (Video).

INTRODUCTION: Hepatocellular carcinoma located in hepatic segment VI/VII or close to the adrenal gland were generally considered challenging for minimally invasive resection. For these individualized patients, this may be overcome by the novel use of a retroperitoneal laparoscopic hepatectomy; however, minimally invasive retroperitoneal liver resection is difficult to perform.1-3 This video article demonstrates a pure retroperitoneal laparoscopic hepatectomy for a subcapsular hepatocellular carcinoma. VIDEO: A 47-year-old male patient with Child-Pugh A liver cirrhosis presented with a small tumor located very close to the adrenal gland next to segment VI of the liver. An enhanced abdominal computed tomographic scan demonstrated a solitary 2.3 × 1.6 cm lesion. Considering the special location of the lesion, a pure retroperitoneal laparoscopic hepatectomy was performed after obtaining the patient's consent. The patient was positioned in the flank position. The procedure was carried out using the balloon technique for a retroperitoneoscopic approach, with the patient in the lateral kidney position. The retroperitoneal space was first accessed through a 12-mm skin incision above the anterior superior iliac spine in the mid-axillary line and was expanded by inflating a glove balloon to 900 mL. A 5 mm port below the 12th rib in the posterior axillary line and a 12 mm port below the 12th rib in the anterior axillary line were placed. Following incision of Gerota's fascia, the dissection plane between the perirenal fat and the anterior renal fascia located at the superomedial side of the kidney was explored. The retroperitoneum behind the liver was fully exposed after the upper pole of the kidney was isolated. After localization of the tumor by intraoperative ultrasonography through the retroperitoneum, the retroperitoneum was dissected directly above the tumor. We used an ultrasonic scalpel to divide the hepatic parenchyma, and a Biclamp for hemostasis. The blood vessel was clamped using titanic clips, and the specimen was extracted using a retrieval bag following resection. A drainage tube was placed after completing meticulous hemostasis. Closure of the retroperitoneum was performed using a conventional suture method. RESULTS: The total operation time was 249 min, with an estimated blood loss of 30 mL. The final histopathological diagnosis showed a 3.0 × 2.2 × 2.0 cm-sized hepatocellular carcinoma. The patient was discharged on postoperative day 6 without any complications. CONCLUSION: Lesions located in segment VI/VII or close to the adrenal gland were generally considered difficult for minimally invasive resection. Under these circumstances, a retroperitoneal laparoscopic hepatectomy might be a more suitable option as it is a safe, effective and complementary approach to standard minimally invasive technology for the resection of small hepatic tumors in these special locations of the liver.

Systematic characterization of chromodomain proteins reveals an H3K9me1/2 reader regulating aging in C. elegans.

The chromatin organization modifier domain (chromodomain) is an evolutionally conserved motif across eukaryotic species. The chromodomain mainly functions as a histone methyl-lysine reader to modulate gene expression, chromatin spatial conformation and genome stability. Mutations or aberrant expression of chromodomain proteins can result in cancer and other human diseases. Here, we systematically tag chromodomain proteins with green fluorescent protein (GFP) using CRISPR/Cas9 technology in C. elegans. By combining ChIP-seq analysis and imaging, we delineate a comprehensive expression and functional map of chromodomain proteins. We then conduct a candidate-based RNAi screening and identify factors that regulate the expression and subcellular localization of the chromodomain proteins. Specifically, we reveal an H3K9me1/2 reader, CEC-5, both by in vitro biochemistry and in vivo ChIP assays. MET-2, an H3K9me1/2 writer, is required for CEC-5 association with heterochromatin. Both MET-2 and CEC-5 are required for the normal lifespan of C. elegans. Furthermore, a forward genetic screening identifies a conserved Arginine124 of CEC-5's chromodomain, which is essential for CEC-5's association with chromatin and life span regulation. Thus, our work will serve as a reference to explore chromodomain functions and regulation in C. elegans and allow potential applications in aging-related human diseases.

Entecavir Combined With Short-term Hepatitis B Immunoglobulin in Preventing Hepatitis B Virus Recurrence in Liver Transplant Recipients.

BACKGROUND: The combination of nucleoside analogs and long-term hepatitis B immunoglobulin (HBIG) is considered to be the standard regimen for preventing hepatitis B virus (HBV) recurrence after liver transplant (LT). However, long-term use of HBIG causes many adverse effects. The aim of this study was to evaluate the effect of nucleoside analogs entecavir combined with short-term HBIG in preventing HBV recurrence after LT. METHODS: This retrospective study assessed the effect a combination of entecavir and short-term HBIG in prophylaxis of HBV recurrence among 56 LT recipients who had undergone the procedure because of HBV-associated liver disease at our center between December 2017 and December 2021. All patients received entecavir treatment combined with HBIG for the prevention of hepatitis B recurrence, and HBIG treatment was withdrawn within 1 month. The patients were followed up to determine levels of hepatitis B surface antigen, antibody to hepatitis B surface antigen (HBsAb), and HBV-DNA and the recurrence rate of HBV. RESULTS: Only 1 patient appeared positive for hepatitis B surface antigen at 2 months post-LT. The overall HBV recurrence rate was 1.8%. The HBsAb titers of all patients gradually decreased over time, with a median of 376.6 IU/L at 1 month post-LT and a median of 13.47 IU/L at 12 months post-LT. During the follow-up period, the HBsAb titer of the preoperative HBV-DNA-positive patients remained at a lower level than that of HBV-DNA-negative patients. CONCLUSIONS: Entecavir combined with short-term HBIG can exert a good effect for the prevention of HBV reinfection post-LT.

Human Leucocyte Antigen-Matching Can Improve Long Term Outcome of Renal Allografts from Donors Older Than 75 Years.

BACKGROUND: Renal transplantation is the therapy of choice for kidney failure. The Eurotransplant Senior Program (ESP) has been established to allocate kidneys ≥65 years to recipients of the same age group considered a regional allocation with short cold ischemia (CIT) but not human-leukocyte-antigen (HLA)-matching. The acceptance of organs aged ≥75 years is also still controversial within the ESP. METHODS: In a multicenter approach, 179 kidney grafts ≥75 years (mean donor age 78 years) that were transplanted in 174 patients in 5 German transplant centers were analyzed. The primary focus of the analysis was long-term outcome of the grafts and the impact of CIT, HLA matching, and recipient related risk factors. RESULTS: The mean graft survival was 59 months (median 67 months) with a mean donor age of 78.3 ± 2.9 years. Grafts with 0 to 3 HLA-mismatches had a significantly better overall graft survival compared to grafts with ≥4 mismatches (69 months vs 54 months; P = .008). The mean CIT was short (11.9 ± 5.3 hours) and had no impact on graft survival. CONCLUSION: Recipients receiving a kidney graft from donors aged ≥75 years can benefit from nearly 5 years of survival with a functioning graft. Even minimal HLA matching may improve long term allograft survival.

Involvement of endoplasmic reticulum stress in rifampicin-induced liver injury.

Rifampicin is a first-line antituberculosis drug. Hepatocyte toxicity caused by rifampicin is a significant clinical problem. However, the specific mechanism by which rifampicin causes liver injury is still poorly understood. Endoplasmic reticulum (ER) stress can have both protective and proapoptotic effects on an organism, depending on the environmental state of the organism. While causing cholestasis and oxidative stress in the liver, rifampicin also activates ER stress in different ways, including bile acid accumulation and cytochrome p450 (CYP) enzyme-induced toxic drug metabolites via pregnane X receptor (PXR). The short-term stress response helps the organism resist toxicity, but when persisting, the response aggravates liver damage. Therefore, ER stress may be closely related to the "adaptive" mechanism and the apoptotic toxicity of rifampicin. This article reviews the functional characteristics of ER stress and its potentially pathogenic role in liver injury caused by rifampicin.

Incidence of Ischemia Reperfusion Injury Related Biliary Complications in Liver Transplantation: Effect of Different Types of Donors.

Liver transplantation from donors after circulatory death (DCD) is associated with considerable rates of primary nonfunction and ischemic-type biliary lesions. Compared with donation was after brain death (DBD), the biggest disadvantage of DCD is warm ischemia injury in the procurement stage. Donation after brain death followed by circulatory death (DBCD) is a unique practice in China. Such donors should donate according to the DCD procedure, that is, remove life support and donate after cardiac arrest. We retrospectively analyzed donor and recipient characteristics with preoperative and postoperative parameters according to 3 donation types to comprehensively describe incidence of ischemia reperfusion injury (IRI) related biliary complications among different donor type adult liver transplantation recipients. A total of 50 patients were included in this study (DBD group n = 17, DCD group n = 26, DBCD group n = 7). Only 1 patient, whose donor type was DBCD was diagnosed with ischemic-type biliary lesions demonstrated cast and retrograde ascending cholangitis. Rates of primary graft non-function (DBD n = 1, 5.9%; DCD n = 2, 7.7%; DBCD, 0%; P = .546) were similar and total biliary complications (DBD n = 1, 5.9%; DCD n = 1, 3.8%; DBCD N = 2, 28.6%; P = .042) were different. No differences were found regarding development of postreperfusion syndrome or coagulopathy in 3 groups. Compared with standard DBD donor, the clinical outcome of DCD donor liver transplantation was satisfactory, with no increase in the incidence of IRI, and, no difference in the incidence of ischemic bile duct complications. This work was carried out in compliance with the Helsinki Congress and the Declaration of Istanbul.

Panoramic comparison between NK cells in healthy and cancerous liver through single-cell RNA sequencing.

OBJECTIVE: NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells. However, the developmental progression, transcriptomic landscape, and functional subtypes of liver NK cells are not well defined. Hepatocellular carcinoma (HCC) accounts for approximately 80% of primary liver cancer worldwide, yet the biological characteristics of NK cells in the HCC environment are unclear. Therefore, we aimed to determine these cells' roles in tumorigenesis and prognosis. METHODS: We compared the single-cell RNA sequencing profiles of NK cells purified from blood (n = 1), healthy liver tissues (n = 3), HCC tumor tissues (n = 4), and peritumor liver tissues (n = 1) to identify NK cell subsets. Furthermore, we performed bioinformatics analysis by using The Cancer Genome Atlas (TCGA) data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC. RESULTS: Transcriptomic analysis revealed 5 NK cell subsets (L1-NK-CD56bright, L2-NK-CD56dim, L3-NK-HLA, L4-LrNK-FCGR3A, and L5-LrNK-XCL1) in the healthy liver tissues. However, the transitional L3 subset and the CXCR6+CD16+ L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues. Furthermore, 4 common prognosis-associated genes (RHOB, TALDO1, HLA-DPA1, and TKT) were significantly overexpressed in the paired tumor tissue and blood. CONCLUSIONS: Our study revealed 5 specific subsets of NK cells in healthy human liver tissues. However, only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues. The cytotoxic NK cell subsets were absent in HCC tissues. Furthermore, we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.

Risk factors of perioperative complications and management with enhanced recovery after primary surgery in women with epithelial ovarian carcinoma in a single center.

The present study aimed to evaluate the postoperative complications and the impact of an enhanced recovery programme in patients who underwent primary surgery (including extensive upper abdominal surgery) for epithelial ovarian carcinoma (EOC). All patients with stage I-IV ovarian carcinoma who underwent primary surgery were identified, and postoperative complications were evaluated and graded according to the Clavien-Dindo classification. Of 161 patients, 46 (28.57%) underwent surgical staging, 27 (16.77%) standard cytoreduction, 12 (7.45%) en bloc debulking and 76 (47.20%) extraradical debulking. A total of 157 patients (97.52%) achieved optimal tumor reduction (<1 cm). The mean postoperative hospitalization time was 17.33±11.29 days after completion of the initial postoperative chemotherapy (IPC), and the IPC interval was 16.22±10.09 days. A total of 13 patients (8.07%) had grade 3 complications (9 with wound dehiscence, 3 with digestive tract leakage and 1 with a bladder fistula). A total of 2 patients (1.24%) had grade 4-5 complications [1 patient with severe pneumonia returned to the intensive care unit (ICU) for tracheotomy and respiration rehabilitation; the other patient died of septicemia on day 19]. The multivariate analysis of the preoperative factors revealed that a human epididymis protein 4 (HE4) level of ≥717 pM (P=0.015) and Federation International of Gynecology and Obstetrics (FIGO) stage IV (P=0.004; compared with stage IIIC) were associated with grade 3-5 complications. The bootstrap analysis revealed that a cancer antigen 125 (CA125) level of ≥1,012 U/ml (P=0.034), a HE4 level of ≥717 pM (P=0.007) and FIGO stage IV (P=0.002; compared with stage IIIC) were significantly associated with grade 3-5 complications. Meanwhile, the multivariate analysis of the postoperative factors did not reveal any risk factors associated with grade 3-5 complications; the bootstrap analysis revealed that only transfer to the ICU after surgery (P=0.026) was significantly associated with grade 3-5 complications. In conclusion, the study found that application of enhanced recovery after surgery protocols is feasible in patients with EOC, especially in those undergoing advanced extensive upper abdominal surgery, and CA125, HE4 and FIGO stage IV were related with the occurrence of adverse perioperative outcomes.

Combined Targeting of AKT and mTOR Inhibits Tumor Formation of EpCAM+ and CD90+ Human Hepatocellular Carcinoma Cells in an Orthotopic Mouse Model.

The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In this study, we demonstrate that combined treatment with AKT and mTOR inhibitors-i.e., MK2206 and RAD001-results in a synergistic reduction in proliferation of EpCAM+ and CD90+ HCC cells cultured either as adherent cells or as tumoroids in vitro. In addition, tumor growth was reduced by combined treatment with AKT and mTOR inhibitors in an orthotopic xenograft mouse model of an EpCAM+ HCC cell line (Huh7) and primary patient-derived EpCAM+ HCC cells (HCC1) as well as a CD90+ HCC-related cell line (SK-HEP1) in vivo. However, during AKT/mTOR treatment, outgrowth of therapy-resistant tumors was observed in all mice analyzed within a few weeks. Resistance was associated in most cases with restoration of AKT signaling in the tumors, intrahepatic metastases and distant metastases. In addition, an upregulation of the p38 MAPK pathway was identified in the AKT/mTOR inhibitor-resistant tumor cells by kinome profiling. The development of resistant cells during AKT/mTOR therapy was further analyzed by red-green-blue (RGB) marking of HCC cells, which revealed an outgrowth of a large number of Huh7 cells over a period of 6 months. In summary, our data demonstrate that combined treatment with AKT and mTOR inhibitors exhibits synergistic effects on proliferation of EpCAM+ as well as CD90+ HCC cells in vitro. However, the fast development of large numbers of resistant clones under AKT/mTOR therapy observed in vitro and in the orthotopic xenotransplantation mouse model in vivo strongly suggests that this therapy alone will not be sufficient to eliminate EpCAM+ or CD90+ cancer stem cells from HCC patients.

The SNAPc complex mediates starvation-induced trans-splicing in Caenorhabditis elegans.

Dietary restriction usually suppresses biosynthesis but activates catabolic pathways in animals. However, the short-term starvation enhances biosynthetic activities and promotes ribosomal biogenesis in adult Caenorhabditis elegans. The mechanism underlying the processes remains largely unknown. Here, we find that the short-term starvation enhances the SL1 trans-splicing of translation-related genes in adult C. elegans by transcriptome analysis. The small nuclear RNA-activating protein complex (SNAPc) promotes SL RNA production and mediates starvation-induced trans-splicing. TOFU-5, a core factor in the upstream sequence transcription complex (USTC) essential for piRNA production, is also involved in the starvation-induced trans-splicing processes. Knocking down components of the SNAPc complex and tofu-5 extends worm survival under starvation conditions. Taken together, our study highlights the importance of SL trans-splicing in the nutrition response and reveals a mechanism of the survival regulation by food deprivation via SNAPc and TOFU-5.

Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation.

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.

Early Everolimus-Facilitated Reduced Tacrolimus in Liver Transplantation: Results From the Randomized HEPHAISTOS Trial.

Everolimus-facilitated reduced-exposure tacrolimus (EVR + rTAC) at 30 days after liver transplantation (LT) has shown advantages in renal preservation. This study evaluated the effects of early initiation of EVR + rTAC in de novo LT recipients (LTRs). In HEPHAISTOS (NCT01551212, EudraCT 2011-003118-17), a 12-month, multicenter, controlled study, LTRs were randomly assigned at 7 to 21 days after LT to receive EVR + rTAC or standard-exposure tacrolimus (sTAC) with steroids. The primary objective was to demonstrate superior renal function (assessed by estimated glomerular filtration rate [eGFR]) with EVR + rTAC versus sTAC at month 12 in the full analysis set (FAS). Other assessments at month 12 included the evaluation of renal function in compliance set and on-treatment (OT) patients, efficacy (composite endpoint of graft loss, death, or treated biopsy-proven acute rejection [tBPAR] and individual components) in FAS, and safety. In total, 333 patients (EVR + rTAC, 169; sTAC, 164) were included in the FAS. A high proportion of patients was nonadherent in maintaining tacrolimus trough levels (EVR + rTAC, 36.1%; sTAC, 34.7%). At month 12, the adjusted least square mean eGFR was numerically higher with EVR + rTAC versus sTAC (76.2 versus 72.1 mL/minute/1.73 m2 , difference: 4.1 mL/minute/1.73 m2 ; P = 0.097). A significant difference of 8.3 mL/minute/1.73 m2 (P = 0.03) favoring EVR + rTAC was noted in the compliance set. Incidence of composite efficacy endpoint (7.7% versus 7.9%) and tBPAR (7.1% versus 5.5%) at month 12 as well as incidence of treatment-emergent adverse events (AEs) and serious AEs were comparable between groups. A lower proportion of patients discontinued EVR + rTAC than sTAC treatment (27.2% versus 34.1%). Early use of everolimus in combination with rTAC showed comparable efficacy, safety, and well-preserved renal function versus sTAC therapy at month 12. Of note, renal function was significantly enhanced in the compliance set.

Liver Transplantation Reverses Hepatic Myelopathy in Hepatitis B-Related Decompensated Liver Cirrhosis: Case Report and Review of the Literature.

Severe neurologic complications after chronic liver disease greatly affect the patient's quality of life. Hepatic myelopathy (HM) is a rare but devastating disease, in chronic liver disease. The limbs of patients with HM show slowly progressive symmetrical spastic paralysis without sensory loss. Management of this severe neurologic complication is challenging. These patients often require timely and effective clinical intervention. Although liver transplantation is one of the effective treatments for HM, the prognosis of these patients remains poor, many of them spend their lives in wheelchairs. Here, we report a patient with HM after hepatitis B virus related decompensated liver cirrhosis who recovered well after liver transplant. This work was carried out in compliance with the Helsinki Congress and the Declaration of Istanbul.