Incidence of superficial left hepatic vein and its usability for graft hepatic vein venoplasty in pediatric liver transplantation.

BACKGROUNDS: The anatomy of the left hepatic vein (LHV) is variable; thus, it should be considered for graft hepatic vein (GHV) venoplasty for left lateral section (LLS) and left liver grafts. This study assessed the incidence of superficial LHV (sLHV) branches according to LHV anatomy and its usability for GHV venoplasty in pediatric liver transplantation (LT). METHODS: This study consisted of three parts: (1) anatomical classification of LHV variations and the incidence of sLHV branches; (2) morphometric simulative analysis of GHV reconstruction and (3) clinical application based on LHV anatomy. RESULTS: The LHV anatomy of 248 potential LLS graft donors was classified into four types according to the number and location of GHV openings: one single opening (type 1; n = 186 [75.0%]), two large openings (type 2; n = 35 [14.1%]), one large and one small adjacent opening (type 3; n = 14 [5.6%]), and two large widely-separated openings (type 4; n = 13 [5.2%]). An sLHV branch was identified in 87 of 248 (35.1%) donor livers. Morphometric analysis of simulative GHV venoplasty with an sLHV branch increased GHV diameters by 30% in type 1 LLS grafts and 20% in type 2/3 LLS grafts. An analysis of 50 consecutive patients who underwent pediatric LT showed that the 2-year rates of GHV obstruction were 2.0% with LLS grafts and 0% with left liver grafts. CONCLUSIONS: The GHV orifice can be enlarged through LHV anatomy-based unification venoplasty. Unification venoplasty with an sLHV branch provided sufficient enlargement of the GHV orifice.

A single-center prospective study regarding time to return to activities of daily living after craniotomy for brain tumors.

BACKGROUND: There are few studies on the time to return to activities of daily living (ADL) after craniotomy in patients with brain tumors. This study aimed to investigate the duration before returning to ADLs after craniotomy for brain tumors and present data that can provide information and guidelines on the appropriate time needed. METHODS: Patients (n = 183 of 234) who underwent craniotomy for brain tumors between April 2021 and July 2021 capable of self-care upon discharge were enrolled, and data of 158 were collected. The start time of 85 ADL items was prospectively investigated for 4 months postoperatively, using the self-recording sheet. RESULTS: Over 89% and 87% of the patients performed basic ADL items within a month and instrumental ADL items within 2 months (medians: within 18 days), except for a few. Regarding work, 50% of the patients returned within 4 months. Washing hair with a wound was performed at 18 days of median value, after 4 months of dyeing/perming hair, 6 days of drinking coffee/tea, after 4 months of air travel, and 40 days of complementary and alternative medicine. In patients with infratentorial tumors or surgical problems, return times were much later for various items. CONCLUSIONS: It is possible to provide practical information and guidelines on the duration to return to ADL after craniotomy in brain tumor patients. These study findings also reduce uncertainty about recovery and daily life and help patients return to their daily life at the appropriate time, thereby maintaining function and daily well-being after surgery.

N,N'-Diacetyl-p-phenylenediamine restores microglial phagocytosis and improves cognitive defects in Alzheimer's disease transgenic mice.

As a central feature of neuroinflammation, microglial dysfunction has been increasingly considered a causative factor of neurodegeneration implicating an intertwined pathology with amyloidogenic proteins. Herein, we report the smallest synthetic molecule (N,N'-diacetyl-p-phenylenediamine [DAPPD]), simply composed of a benzene ring with 2 acetamide groups at the para position, known to date as a chemical reagent that is able to promote the phagocytic aptitude of microglia and subsequently ameliorate cognitive defects. Based on our mechanistic investigations in vitro and in vivo, 1) the capability of DAPPD to restore microglial phagocytosis is responsible for diminishing the accumulation of amyloid-ß (Aß) species and significantly improving cognitive function in the brains of 2 types of Alzheimer's disease (AD) transgenic mice, and 2) the rectification of microglial function by DAPPD is a result of its ability to suppress the expression of NLRP3 inflammasome-associated proteins through its impact on the NF-κB pathway. Overall, our in vitro and in vivo investigations on efficacies and molecular-level mechanisms demonstrate the ability of DAPPD to regulate microglial function, suppress neuroinflammation, foster cerebral Aß clearance, and attenuate cognitive deficits in AD transgenic mouse models. Discovery of such antineuroinflammatory compounds signifies the potential in discovering effective therapeutic molecules against AD-associated neurodegeneration.

Safe use of right lobe living donor livers with moderate steatosis in adult-to-adult living donor liver transplantation: a retrospective study.

Hepatic steatosis (HS) beyond a certain degree can jeopardize living donor (LD) safety, particularly in right lobe (RL) donors, making it a major obstacle for donor pool expansion in adult-to-adult living donor liver transplantation (ALDLT). From July 2004 to June 2016, 58 LDs donated their RLs despite having moderate HS (30%-50% steatosis) determined by intraoperative biopsy at a single center. We performed greedy matching to compare the outcomes of the donors and recipients of this group with those of LDs with no HS. The mean left lobe (LL) HS value in the 58 cases was 20.9 ± 12.4%, which was significantly lower than the mean RL HS value (38.8 ± 6.7%, P < 0.001). The mean ratio of the remnant LL to the total liver volume was 37.8 ± 2.2. No differences were observed in the postoperative liver function and donor and recipient morbidity and mortality rates. The liver regeneration rates in recipients and donors at 1 month, 6 months, and 1 year postoperatively did not differ significantly. The patient and graft survival rates of the recipients showed no differences. The use of well-selected RL grafts with moderate steatosis does not impair graft function, recipient outcomes, or donor safety.

Phenylboronic acid conjugated to doxorubicin nanocomplexes as an anti-cancer drug delivery system in hepatocellular carcinoma.

Anti-cancer strategies using nanocarrier systems have been explored in a variety of cancers; these systems can easily be incorporated into tumors via the enhanced permeability and retention (EPR) effect leading to enhanced anti-tumor activity while reducing systemic toxicity by specific tumor-targeting. The prognosis of hepatocellular carcinoma (HCC) is extremely poor when the condition is diagnosed at the unresectable stage as treatment options are limited. In order to improve the treatment of cancer and the overall anti-cancer effect, polymerized phenylboronic acid conjugated doxorubicin (pPBA-Dox) nanocomplexes were generated, and conjugated doxorubicin, which is conventionally used in HCC. The nanocomplexes exhibited enhanced anti-tumor activity via tumor-specific targeting in the subcutaneous and orthotopic HCC syngeneic mice tumor model, implying that the nanocomplexes facilitate the targeted Dox delivery to liver cancer in which the sialic acid is over-expressed. Therefore, this study provides insight into the novel targeted therapy using the nanocomplexes for the treatment of HCC.

Minimalistic Principles for Designing Small Molecules with Multiple Reactivities against Pathological Factors in Dementia.

Multiple pathogenic elements, including reactive oxygen species, amyloidogenic proteins, and metal ions, are associated with the development of neurodegenerative disorders. We report minimalistic redox-based principles for preparing compact aromatic compounds by derivatizing the phenylene moiety with various functional groups. These molecular agents display enhanced reactivities against multiple targets such as free radicals, metal-free amyloid-ß (Aß), and metal-bound Aß that are implicated in the most common form of dementia, Alzheimer's disease (AD). Mechanistic studies reveal that the redox properties of these reagents are essential for their function. Specifically, they engage in oxidative reactions with metal-free and metal-bound Aß, leading to chemical modifications of the Aß peptides to form covalent adducts that alter the aggregation of Aß. Moreover, the administration of the most promising candidate significantly attenuates the amyloid pathology in the brains of AD transgenic mice and improves their cognitive defects. Our studies demonstrate an efficient and effective redox-based strategy for incorporating multiple functions into simple molecular reagents.

Remote Ischemic Preconditioning and Diazoxide Protect from Hepatic Ischemic Reperfusion Injury by Inhibiting HMGB1-Induced TLR4/MyD88/NF-κB Signaling.

Remote ischemic preconditioning (RIPC) is known to have a protective effect against hepatic ischemia-reperfusion (IR) injury in animal models. However, the underlying mechanism of action is not clearly understood. This study examined the effectiveness of RIPC in a mouse model of hepatic IR and aimed to clarify the mechanism and relationship of the ATP-sensitive potassium channel (KATP) and HMGB1-induced TLR4/MyD88/NF-κB signaling. C57BL/6 male mice were separated into six groups: (i) sham-operated control, (ii) IR, (iii) RIPC+IR, (iv) RIPC+IR+glyburide (KATP blocker), (v) RIPC+IR+diazoxide (KATP opener), and (vi) RIPC+IR+diazoxide+glyburide groups. Histological changes, including hepatic ischemia injury, were assessed. The levels of circulating liver enzymes and inflammatory cytokines were measured. Levels of apoptotic proteins, proinflammatory factors (TLR4, HMGB1, MyD88, and NF-κB), and IκBα were measured by Western blot and mRNA levels of proinflammatory cytokine factors were determined by RT-PCR. RIPC significantly decreased hepatic ischemic injury, inflammatory cytokine levels, and liver enzymes compared to the corresponding values observed in the IR mouse model. The KATP opener diazoxide + RIPC significantly reduced hepatic IR injury demonstrating an additive effect on protection against hepatic IR injury. The protective effect appeared to be related to the opening of KATP, which inhibited HMGB1-induced TRL4/MyD88/NF-kB signaling.

Cytotoxicity of Human Hepatic Intrasinusoidal CD56bright Natural Killer Cells against Hepatocellular Carcinoma Cells.

Hepatic intrasinusoidal (HI) natural killer (NK) cells from liver perfusate have unique features that are similar to those of liver-resident NK cells. Previously, we have reported that HI CD56bright NK cells effectively degranulate against SNU398 hepatocellular carcinoma (HCC) cells. Thus, the aim of this study was to further investigate the phenotype and function of HI NK cells. We found that HI CD56bright NK cells degranulated much less to Huh7 cells. HI CD56bright NK cells expressed NKG2D, NKp46, TNF-related apoptosis-inducing ligand (TRAIL), and FAS ligand (FASL) at higher levels than CD56dim cells. SNU398 cells expressed more NKG2D ligands and FAS and less PD-L1 than Huh7 cells. Blockade of NKG2D, TRAIL, and FASL significantly reduced the cytotoxicity of HI NK cells against SNU398 cells, but blockade of PD-L1 did not lead to any significant change. However, HI NK cells produced IFN-γ well in response to Huh7 cells. In conclusion, the cytotoxicity of HI CD56bright NK cells was attributed to the expression of NKG2D, TRAIL, and FASL. The results suggest the possible use of HI NK cells for cancer immunotherapy and prescreening of HCC cells to help identify the most effective NK cell therapy recipients.

Outcome of ABO-incompatible adult living-donor liver transplantation for patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Living-donor liver transplantation (LDLT) can simultaneously cure hepatocellular carcinoma (HCC) and underlying liver cirrhosis, improving long-term results in patients with HCC. ABO-incompatible LDLT could expand the living-donor pool, reduce waiting times for deceased-donor liver transplantation, and improve long-term survival for some patients with HCC. METHODS: We retrospectively reviewed the medical records of patients undergoing LDLT for HCC from November 2008 to December 2015 at a single institution in Korea. In total, 165 patients underwent ABO-incompatible and 753 patients underwent ABO-compatible LDLT for HCC. ABO-incompatible recipients underwent desensitization to overcome the ABO blood group barrier, including pretransplant plasma exchange and rituximab administration (300-375 mg/m2 /body surface area). RESULTS: We performed 1:1 propensity score matching and included 165 patients in each group. 82.4% of ABO-incompatible and 83.0% of -compatible LDLT groups had HCC within conventional Milan criteria, respectively, and 92.1% and 92.7% of patients in each group had a Child-Pugh score of A or B. ABO-incompatible and -compatible LDLT groups were followed up for 48.0 and 48.7 months, respectively, with both groups showing comparable recurrence-free survival rates (hazard ratio [HR] 1.14; 95% CI 0.68-1.90; p = 0.630) and overall patient-survival outcomes (HR 1.10; 95% CI 0.60-2.00; p = 0.763). CONCLUSIONS: These findings suggested that ABO-incompatible liver transplantation is a feasible option for patients with HCC, especially for those with compensated cirrhosis with HCC within conventional Milan criteria. LAY SUMMARY: Despite hypothetical immunological concerns that the desensitization protocol for breaking through the ABO blood group barrier might have a negative impact on the recurrence of hepatocellular carcinoma, our experience demonstrated no significant differences in the long-term overall survival and recurrence-free survival rates between patients receiving ABO-compatible or ABO-incompatible liver transplantation. In conclusion, results from our institution indicated that ABO-incompatible living-donor liver transplantation constitutes a potentially feasible option for patients with hepatocellular carcinoma, especially those with compensated cirrhosis with hepatocellular carcinoma within conventional Milan criteria.

Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence.

Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. © 2018 AASLD.

Once-daily, prolonged-release tacrolimus vs twice-daily, immediate-release tacrolimus in de novo living-donor liver transplantation: A Phase 4, randomized, open-label, comparative, single-center study.

Randomized, open-label, comparative, single-center, Phase 4, 24-week study comparing pharmacokinetics (PK), safety, and efficacy of once-daily, prolonged-release tacrolimus (PR-T) with twice-daily, immediate-release tacrolimus (IR-T) in adult de novo living-donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR-T or IR-T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration-time curve over 24 hour (AUC0-24 ). Predefined similarity interval for confidence intervals of ratios: 80%-125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24 ), patient/graft survival, biopsy-confirmed acute rejection (BCAR), treatment-emergent adverse events (TEAEs). One-hundred patients were included (PR-T, n = 50; IR-T, n = 50). Compared with IR-T, 40% and 66% higher mean PR-T daily doses resulted in similar AUC0-24 between formulations on Day 6 (PR-T:IR-T ratio of means 96.8%), and numerically higher AUC0-24 with PR-T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0-24 and C24 , and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR-T vs IR-T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR-T was efficacious; no new safety signals were detected.

Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure.

Acute liver failure (ALF) is a severe life-threatening disease which usually arises in patients with-irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase-1, E-NTPDase1 (CD39) and ecto-5'-nucleotidase, Ecto5'NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)-1α, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF-related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care.

Identification of hypoxia-inducible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury.

Although acute lung injury (ALI) contributes significantly to critical illness, resolution often occurs spontaneously through endogenous pathways. We recently found that mechanical ventilation increases levels of pulmonary adenosine, a signaling molecule known to attenuate lung inflammation. In this study, we hypothesized a contribution of transcriptionally controlled pathways to pulmonary adenosine receptor (ADOR) signaling during ALI. We gained initial insight from microarray analysis of pulmonary epithelia exposed to conditions of cyclic mechanical stretch, a mimic for ventilation-induced lung disease. Surprisingly, these studies revealed a selective induction of the ADORA2B. Using real-time RT-PCR and Western blotting, we confirmed an up to 9-fold induction of the ADORA2B following cyclic mechanical stretch (A549, Calu-3, or human primary alveolar epithelial cells). Studies using ADORA2B promoter constructs identified a prominent region within the ADORA2B promoter conveying stretch responsiveness. This region of the promoter contained a binding site for the transcription factor hypoxia-inducible factor (HIF)-1. Additional studies using site-directed mutagenesis or transcription factor binding assays demonstrated a functional role for HIF-1 in stretch-induced increases of ADORA2B expression. Moreover, studies of ventilator-induced lung injury revealed induction of the ADORA2B during ALI in vivo that was abolished following HIF inhibition or genetic deletion of Hif1a. Together, these studies implicate HIF in the transcriptional control of pulmonary adenosine signaling during ALI.

Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver.

Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild-type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b(-/-) mice. Subsequent studies in mice with Adora2b deletion in different tissues--including vascular endothelia, myeloid cells, and hepatocytes--revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-κB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury.

CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy.

Nucleotide phosphohydrolysis by the ecto-5'-nucleotidase (CD73) is the main source for extracellular generation of adenosine. Extracellular adenosine subsequently signals through four distinct adenosine A receptors (Adora1, Adora2a, Adora2b, or Adora3). Here, we hypothesized a functional role for CD73-dependent generation and concomitant signaling of extracellular adenosine during diabetic nephropathy. CD73 transcript and protein levels were elevated in the kidneys of diabetic mice. Genetic deletion of CD73 was associated with more severe diabetic nephropathy, whereas treatment with soluble nucleotidase was therapeutic. Transcript levels of renal adenosine receptors showed a selective induction of Adora2b during diabetic nephropathy. In a transgenic reporter mouse, Adora2b expression localized to the vasculature and increased after treatment with streptozotocin. Adora2b(-/-) mice experienced more severe diabetic nephropathy, and studies in mice with tissue-specific deletion of Adora2b in tubular epithelia or vascular endothelia implicated endothelial Adora2b signaling in protection from diabetic nephropathy. Finally, treatment with a selective Adora2b agonist (BAY 60-6583) conveyed potent protection from diabetes-associated kidney disease. Taken together, these findings implicate CD73-dependent production of extracellular adenosine and endothelial Adora2b signaling in kidney protection during diabetic nephropathy.

Equilibrative nucleoside transporter (ENT)-1-dependent elevation of extracellular adenosine protects the liver during ischemia and reperfusion.

UNLABELLED: Ischemia and reperfusion-elicited tissue injury contributes to morbidity and mortality of hepatic surgery and during liver transplantation. Previous studies implicated extracellular adenosine signaling in liver protection. Based on the notion that extracellular adenosine signaling is terminated by uptake from the extracellular towards the intracellular compartment by way of equilibrative nucleoside transporters (ENTs), we hypothesized a functional role of ENTs in liver protection from ischemia. During orthotopic liver transplantation in humans, we observed higher expressional levels of ENT1 than ENT2, in conjunction with repression of ENT1 and ENT2 transcript and protein levels following warm ischemia and reperfusion. Treatment with the pharmacologic ENT inhibitor dipyridamole revealed elevations of hepatic adenosine levels and robust liver protection in a murine model of liver ischemia and reperfusion. Studies in gene-targeted mice for Ent1 or Ent2 demonstrated selective protection from liver injury in Ent1(-/-) mice. Treatment with selective adenosine receptor antagonists indicated a contribution of Adora2b receptor signaling in ENT-dependent liver protection. CONCLUSION: These findings implicate ENT1 in liver protection from ischemia and reperfusion injury and suggest ENT inhibitors may be of benefit in the prevention or treatment of ischemic liver injury.

Adora2b adenosine receptor signaling protects during acute kidney injury via inhibition of neutrophil-dependent TNF-α release.

Renal ischemia is among the leading causes of acute kidney injury (AKI). Previous studies have shown that extracellular adenosine is a prominent tissue-protective cue elicited during ischemia, including signaling events through the adenosine receptor 2b (Adora2b). To investigate the functional role of Adora2b signaling in cytokine-mediated inflammatory pathways, we screened wild-type and Adora2b-deficient mice undergoing renal ischemia for expression of a range of inflammatory cytokines. These studies demonstrated a selective and robust increase of TNF-α levels in Adora2b-deficient mice following renal ischemia and reperfusion. Based on these findings, we next sought to understand the contribution of TNF-α on ischemic AKI through a combination of loss- and gain-of-function studies. Loss of TNF-α, through either Ab blockade or study of Tnf-α-deficient animals, resulted in significantly attenuated tissue injury and improved kidney function following renal ischemia. Conversely, transgenic mice with overexpression of TNF-α had significantly pronounced susceptibility to AKI. Furthermore, neutrophil depletion or reconstitution of Adora2b(-/-) mice with Tnf-α-deficient neutrophils rescued their phenotype. In total, these data demonstrate a critical role of adenosine signaling in constraining neutrophil-dependent production of TNF-α and implicate therapies targeting TNF-α in the treatment of ischemic AKI.

Time taken to resume activities of daily living after transsphenoidal surgery for pituitary tumors.

Postoperative management after transsphenoidal surgery (TSS) is important; however, the guidelines for resuming daily activities after TSS are insufficient. This study aimed to examine the time to return to activities of daily living (ADL) after TSS for pituitary tumors. A 4-month prospective data collection was completed for 114 of 117 patients who underwent TSS for pituitary tumors from April to July 2021. The time when the patient returned to ADL after surgery was measured using the self-recording sheet. More than 97% and 92% of the patients returned within 1 month (median: within 7 days) for the elements of basic ADL and within 2 months (median: within 15 days) for the elements of instrumental ADL, excluding a few. Notably, 73.3% of patients returned to work within 4 months. The median time for the activities included 64 days for washing hair head down, 44 days for blowing nose, 59 days for lifting heavy objects, and 102 days for sexual activity. For patients who received extended-TSS or had postoperative problems, the time to return was delayed. Based on these results, it will be possible to provide practical information and guidelines on the time to return to ADL after TSS in pituitary tumor patients.

Cytotoxicity of Human Hepatic Intrasinusoidal Gamma/Delta T Cells Depends on Phospho-antigen and NK Receptor Signaling.

BACKGROUND/AIM: We previously showed that human hepatic intrasinusoidal (HI) natural killer (NK) T cells selectively eliminate hepatocellular carcinoma (HCC) cell lines. In this study, we investigated the underlying mechanisms on how HI γδ T cells, expanded with zoledronate, exhibit a superior cytotoxic effect on HI NK-resistant Huh7 HCC cells. MATERIALS AND METHODS: γδ T cells were obtained from living liver transplant donors or from peripheral blood mononuclear cells (PBMC) of healthy volunteers and were expanded in the presence of IL-2, IL-15, and zoledronate for 2 weeks. Cytotoxicity was measured using the lactate dehydrogenase (LDH) assay in vitro and by flow cytometry using carboxyfluorescein succinimidyl ester (CFSE) in vivo. RESULTS: The cytotoxicity of expanded HI γδ T cells against Huh7 cells was associated with a higher pyrophosphate expression in Huh7 cells compared to SNU398 cells. In contrast, the cytotoxicity of HI γδ T cells against SNU398 cells depended on NKG2D. HI γδ T cells expressed less PD-1 than PB γδ T cells. The cytotoxicity of HI γδ T cells against Du145 and PC3 prostate cancer cells was also associated with pyrophosphate expression in these cells, as well as NKG2D and DNAM-1. CONCLUSION: The expression levels of phospho-antigen in tumor cells determined the cytotoxicity of HI γδ T cells, although the NK activating receptors, death ligands, and immune checkpoint molecules also contribute to their cytotoxicity. γδ T cells are attractive candidates for cancer immune cell therapy.

Different antibody responses between liver and kidney transplant recipients elicited by third doses of COVID-19 mRNA vaccines.

Background: Solid organ transplant recipients exhibit decreased antibody responses, mainly due to their weakened immune systems. However, data are limited on antibody responses after the primary series of coronavirus disease 2019 (COVID-19) vaccines among recipients of various solid organ transplant types. Thus, we compared the antibody responses after three COVID-19 vaccine doses between liver transplant (LT) and kidney transplant (KT) recipients. Methods: We prospectively enrolled solid organ transplant recipients who received three COVID-19 vaccine doses from June 2021 to February 2022 and measured S1-specific immunoglobulin G antibodies using an enzyme-linked immunosorbent assay. Results: Seventy-six LT and 17 KT recipients were included in the final analysis. KT recipients showed consistently lower antibody responses even after the third vaccine dose (86.2% vs. 52.9%, P=0.008) and lower antibody titers (median, 423.0 IU/mL [interquartile range, 99.6-2,057 IU/mL] vs. 19.7 IU/mL [interquartile range, 6.9-339.4 IU/mL]; P=0.006) than were observed in LT recipients. Mycophenolic acid was a significant risk factor for a seropositive antibody response after the third vaccine dose in the multivariable analysis (odds ratio, 0.06; 95% confidence interval, 0.00-0.39; P=0.02). Conclusions: We found a weaker antibody response despite the completion of the primary series of COVID-19 vaccines in KT recipients than in LT recipients. Mycophenolic acid use in KT recipients might be the main contributor to this observation.