Author Correction: L1 drives IFN in senescent cells and promotes age-associated inflammation.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

L1 drives IFN in senescent cells and promotes age-associated inflammation.

Retrotransposable elements are deleterious at many levels, and the failure of host surveillance systems for these elements can thus have negative consequences. However, the contribution of retrotransposon activity to ageing and age-associated diseases is not known. Here we show that during cellular senescence, L1 (also known as LINE-1) retrotransposable elements become transcriptionally derepressed and activate a type-I interferon (IFN-I) response. The IFN-I response is a phenotype of late senescence and contributes to the maintenance of the senescence-associated secretory phenotype. The IFN-I response is triggered by cytoplasmic L1 cDNA, and is antagonized by inhibitors of the L1 reverse transcriptase. Treatment of aged mice with the nucleoside reverse transcriptase inhibitor lamivudine downregulated IFN-I activation and age-associated inflammation (inflammaging) in several tissues. We propose that the activation of retrotransposons is an important component of sterile inflammation that is a hallmark of ageing, and that L1 reverse transcriptase is a relevant target for the treatment of age-associated disorders.

Pharmacokinetics of Brexpiprazole, Quetiapine, Risperidone, and Its Active Metabolite Paliperidone in a Postpartum Woman and Her Baby.

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

Targeted genetic and small molecule disruption of N-Ras CaaX cleavage alters its localization and oncogenic potential.

Ras GTPases and other CaaX proteins undergo multiple post-translational modifications at their carboxyl-terminus. These events initiate with prenylation of a cysteine and are followed by endoproteolytic removal of the 'aaX' tripeptide and carboxylmethylation. Some CaaX proteins are only subject to prenylation, however, due to the presence of an uncleavable sequence. In this study, uncleavable sequences were used to stage Ras isoforms in a farnesylated and uncleaved state to address the impact of CaaX proteolysis on protein localization and function. This targeted strategy is more specific than those that chemically inhibit the Rce1 CaaX protease or delete the RCE1 gene because global abrogation of CaaX proteolysis impacts the entire CaaX protein proteome and effects cannot be attributed to any specific CaaX protein of the many concurrently affected. With this targeted strategy, clear mislocalization and reduced activity of farnesylated and uncleaved Ras isoforms was observed. In addition, new peptidomimetics based on cleavable Ras CaaX sequences and the uncleavable CAHQ sequence were synthesized and tested as Rce1 inhibitors using in vitro and cell-based assays. Consistently, these non-hydrolyzable peptidomimetic Rce1 inhibitors recapitulate Ras mislocalization effects when modeled on cleavable but not uncleavable CaaX sequences. These findings indicate that a prenylated and uncleavable CaaX sequence, which can be easily applied to a wide range of mammalian CaaX proteins, can be used to probe the specific impact of CaaX proteolysis on CaaX protein properties under conditions of an otherwise normally processed CaaX protein proteome.

Clinical features of pasteurellosis without an animal bite or scratch in comparison with bite/scratch pasteurellosis.

Pasteurellosis is a common zoonotic infection that occurs after an animal bite or scratch (B/S). We compared the clinical features of six patients with non-B/S pasteurellosis with those of 14 patients with B/S infections. Pasteurella multocida was identified with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all six non-B/S infections, whereas 13 of the 14 B/S infections were identified with diagnostic kits. The non-B/S infections were pneumonia (n = 3), skin and soft tissue infections (n = 2), and bacteremia (n = 1). Pneumonia occurred in two patients with underlying pulmonary disease, whereas ventilator-associated pneumonia developed in one patient with cerebral infarction. Pasteurella multocida was isolated from a blood specimen and nasal swab from a patient with liver cirrhosis (Child-Pugh class C) and diabetes. Cellulitis developed in one patient with diabetes and normal-pressure hydrocephalus, who had an open wound following a fall, and in one patient with diabetes and a foot ulcer. Three patients with non-B/S infections had no pet and no episode of recent animal contact. The rate of moderate-to-severe comorbidities was significantly higher in patients with non-B/S infections than in those with B/S infections (100% and 14.3%, respectively, p < 0.001). In conclusion, non-B/S infections can develop in patients with chronic pulmonary disease, invasive mechanical ventilation, or open wounds, or who are immunocompromised, irrespective of obvious animal exposure. In contrast to B/S infections, non-B/S pasteurellosis should be considered opportunistic.

Impact of radiological and pathological splenic vein involvement in patients with resectable pancreatic body or tail cancer.

PURPOSE: Several studies have reported a negative impact on survival associated with splenic vessel involvement, especially splenic artery (SpA) involvement, in patients diagnosed with pancreatic body or tail cancer. However, there is limited research on splenic vein (SpV) involvement. Therefore, we aimed to elucidate the significance of splenic vessel involvement, especially SpV involvement, in patients with resectable pancreatic body or tail cancer. METHODS: Between January 2007 and December 2021, 116 consecutive patients underwent distal pancreatectomies for pancreatic body or tail cancer. Among them, this study specifically examined 88 patients with resectable pancreatic body or tail cancer to elucidate prognostic factors using a multivariable Cox proportional analysis. The Kaplan-Meier method evaluated the impact of SpV involvement in terms of both radiological and pathological aspects and the efficacy of neoadjuvant therapy. RESULTS: Higher pre-operative carcinoembryonic antigen levels, larger tumour size, pathological SpV invasion, and non-completion of adjuvant therapy were identified as independent poor prognostic factors for overall survival (OS) and recurrence-free survival (RFS). Additionally, patients with radiological SpV encasement had significantly worse prognoses in terms of OS (p = 0.039) and RFS (p < 0.001). The sensitivity and specificity of multidetector-row computed tomography for detecting pathological SpV invasion were 81.0% and 61.2%, respectively. However, the prognostic impact of neoadjuvant therapy could not be determined, regardless of radiological SpV involvement. CONCLUSION: Radiological and pathological SpV involvement is a poor prognostic factor for patients with resectable pancreatic body or tail cancer. New innovative treatments and effective neoadjuvant therapy regimens are required for patients with SpV involvement.

Radiomics-based prediction of nonalcoholic fatty liver disease following pancreatoduodenectomy.

PURPOSE: Predicting nonalcoholic fatty liver disease (NAFLD) following pancreaticoduodenectomy (PD) is challenging, which delays therapeutic intervention and makes its prevention difficult. We conducted this study to assess the potential application of preoperative computed tomography (CT) radiomics for predicting NAFLD. METHODS: The subjects of this retrospective study were 186 patients with PD from a single institution. We extracted the predictors of NAFLD after PD statistically from conventional clinical and radiomic features of the estimated remnant pancreas and whole liver region on preoperative nonenhanced CT images. Based on these predictors, we developed a machine-learning predictive model, which integrated clinical and radiomic features. A comparative model used only clinical features as predictors. RESULTS: The incidence of NAFLD after PD was 43.5%. The variables of the clinicoradiomic model included one shape feature of the pancreas, two texture features of the liver, and sex; the variables of the clinical model were age, sex, and chemoradiotherapy. The accuracy%, precision%, recall%, F1 score, and area under the curve of the two models were 75.0, 72.7, 66.7, 69.6, and 0.80; and 69.6, 68.4, 54.2, 60.5, and 0.69, respectively. CONCLUSIONS: Preoperative CT-derived radiomic features from the pancreatic and liver regions are promising for the prediction of NAFLD post-PD. Using these features enhances the predictive model, enabling earlier intervention for high-risk patients.

Astrotactin 2 (ASTN2) regulates emotional and cognitive functions by affecting neuronal morphogenesis and monoaminergic systems.

Astrotactin2 (ASTN2) regulates neuronal migration and synaptic strength through the trafficking and degradation of surface proteins. Deletion of ASTN2 in copy number variants has been identified in patients with schizophrenia, bipolar disorder, and autism spectrum disorder in copy number variant (CNV) analysis. Disruption of ASTN2 is a risk factor for these neurodevelopmental disorders, including schizophrenia, bipolar disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. However, the importance of ASTN2 in physiological functions remains poorly understood. To elucidate the physiological functions of ASTN2, we investigated whether deficiency of ASTN2 affects cognitive and/or emotional behaviors and neurotransmissions using ASTN2-deficient mice. Astn2 knockout (KO) mice produced by CRISPR/Cas9 technique showed no obvious differences in physical characteristics and circadian rhythm. Astn2 KO mice showed increased exploratory activity in a novel environment, social behavior and impulsivity, or decreased despair-, anxiety-like behaviors and exploratory preference for the novel object. Some behavioral abnormalities, such as increased exploratory activity and impulsivity, or decreased exploratory preference were specifically attenuated by risperidone, but not by haloperidol. While, the both drugs did not affect any emotion-related behavioral abnormalities in Astn2 KO mice. Dopamine contents were decreased in the striatum, and serotonin or dopamine turnover were increased in the striatum, nucleus accumbens, and amygdala of Astn2 KO mice. In morphological analyses, thinning of neural cell layers in the hippocampus, reduction of neural cell bodies in the prefrontal cortex, and decrease in spine density and PSD95 protein in both tissues were observed in Astn2 KO mice. The present findings suggest that ASTN2 deficiency develops some emotional or cognitive impairments related to monoaminergic dysfunctions and abnormal neuronal morphogenesis with shrinkage of neuronal soma. ASTN2 protein may contribute to the pathogenic mechanism and symptom onset of mental disorders.

Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.

Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.

Safety and efficacy of neoadjuvant chemotherapy based on our resectability criteria for locally advanced perihilar cholangiocarcinoma.

PURPOSE: Neoadjuvant chemotherapy (NAC) is not commonly used for perihilar cholangiocarcinoma (PHC). This study evaluated the safety and efficacy of NAC for PHC. METHODS: Ninety-one PHC patients without metastases were treated at our department. Patients were classified as resectable (R), borderline resectable (BR), or locally advanced unresectable (LA). Upfront surgery (US) was performed for R-PHC patients without regional lymph node metastases (LNM) or those unable to tolerate NAC. The NAC regimen comprised two courses of gemcitabine-based chemotherapy for advanced PHC: R-PHC with LNM, BR, and LA. RESULTS: US and NAC were performed on 32 and 59 patients, respectively. For US, 31 patients underwent curative intent surgery (upfront-CIS). NAC caused adverse effects in 10/59 (17%), allowed 36/59 (61%) to undergo curative intent surgery (NAC-CIS) without impairing liver function, and spared 23/59 (39%) from undergoing resection (NAC-UR). Overall survival was better in the upfront-CIS and NAC-CIS groups than in the NAC-UR group (MST: 74 vs 57 vs 17 months, p < 0.001). In 59 NAC patients, tumour size response occurred in 11/11 (100%) of R, 22/33 (66.7%) of BR, and 9/15 (60.0%) of LA patients. The un-resection rate was the highest in the LA group (27% [3/11] than in R, 30% [10/33] in BR, and 67% [10/15] in LA, p = 0.039). Multivariate analyses revealed that LA and age were independent risk factors for non-resection after NAC. CONCLUSION: was safe and contributed to improving survival in advanced PHC patients. R-PHC was responsive to NAC, but LA remains a risk factor for non-resection through NAC.

Spleen volume is a predictor of posthepatectomy liver failure and short-term mortality for hepatocellular carcinoma.

BACKGROUND: The study aimed at retrospectively assessing the impact of spleen volume (SpV) on the development of posthepatectomy liver failure (PHLF) in patients who underwent hepatectomy for hepatocellular carcinoma (HCC). METHODS: 152 patients with primary HCC who underwent hepatectomy (sectionectomy or more) were classified into PHLF and non-PHLF groups, and then the relationship between PHLF and SpV was assessed. SpV (cm3) was obtained from preoperative CT and standardized based on the patient's body surface area (BSA, m2). RESULTS: PHLF was observed in 39 (26%) of the 152 cases. SpV/BSA was significantly higher in the PHLF group, and the postoperative 1-year survival rate was significantly worse in the PHLF group than that in the non-PHLF group (p = 0.044). Multivariable analysis revealed SpV/BSA as a significant independent risk factor for PHLF. Using the cut-off value (160 cm3/m2), the 152 cases were divided into small SpV and large SpV groups. The incidence of PHLF was significantly higher in the large SpV group (p = 0.002), the liver failure-related mortality rate was also significantly higher in the large SpV group (p = 0.007), and the 1-year survival rate was significantly worse in the large SpV group (p = 0.035). CONCLUSION: These results suggest SpV as a predictor of PHLF and short-term mortality in patients who underwent hepatectomy for HCC. Moreover, SpV measurement is a simple and potentially useful method for predicting PHLF in patients with HCC.

Improved Antitumor Effect of NK Cells Activated by Neutrophils in a Bone Marrow Transplant Model.

The licensing process mediated by inhibitory receptors of the Ly49 C-type lectin superfamily that recognizes self-major histocompatibility complex (MHC) class I in mice is essential for the proper antitumor function of natural killer (NK) cells. Several models for NK cell licensing can be exploited for adoptive immunotherapy for cancer. However, the appropriate adoptive transfer setting to induce efficient graft versus tumor/leukemia effects remains elusive, especially after hematopoietic stem cell transplantation (HSCT). In our previous experiment, we showed that intraperitoneal neutrophil administration with their corresponding NK receptor ligand-activated NK cells using congenic mice without HSCT. In this experiment, we demonstrate enhanced antitumor effects of licensed NK cells induced by weekly intraperitoneal injections of irradiated neutrophil-enriched peripheral blood mononuclear cells (PBMNCs) in recipient mice bearing lymphoma. Bone marrow transplantation was performed using BALB/c mice (H-2d) as the recipient and B10 mice (H-2b) as the donor. The tumor was A20, a BALB/c-derived lymphoma cell line, which was injected subcutaneously into the recipient at the same time as the HSCT. Acute graft versus host disease was not exacerbated in this murine MHC class I mismatched HSCT setting. The intraperitoneal injection of PBMNCs activated a transient licensing of NK subsets expressed Ly49G2, its corresponding NK receptor ligand to H-2d, and reduced A20 tumor growth in the recipient after HSCT. Pathological examination revealed that increased donor-oriented NK1.1+NK cells migrated into the recipient tumors, depending on neutrophil counts in the administered PBMNCs. Collectively, our data reveal a pivotal role of neutrophils in promoting NK cell effector functions and adoptive immunotherapy for cancer.

Extreme Medialized Repair for Challenging Large and Massive Rotator Cuff Tears Reveals Healing and Significant Functional Improvement.

PURPOSE: To evaluate range of motion, muscle strength, clinical outcomes, and radiographic results of the extreme medialized procedure on rotator cuff tears that were initially irreparable. METHODS: From arthroscopic rotator cuff repair cases performed at our institution (June 2017 and August 2020), we retrospectively reviewed cases in which the rotator cuff was (1) unable to be withdrawn to the greater tuberosity, (2) repaired using the extreme medialized procedure, and (3) followed up for a minimum of 2 years. Patients with a history of previous surgery were excluded. Preoperative and postoperative scores were used for clinical evaluation. Imaging evaluation used 2-year postoperative magnetic resonance (MR) images. RESULTS: Sixty-four patients met the criteria; mean age 68.2 ± 7.9 (range 51-82) years; mean follow-up period 26 ± 2 (24-37) months. Tear size: 45 ± 7.1 (30-70) mm in medial to lateral diameters, 40 ± 9.3 (30-60) mm in anteroposterior diameter; suture anchor number: 5.5 ± 1.2 (4-8). The visual analog scale score (50.7 to 11.8), the University of California, Los Angeles, score (12 to 31), constant score (45 to 31), and the American Shoulder and Elbow Surgeons score (53 to 31) at the final follow-up improved compared with preoperative values (all P < .0001). Preoperative and postoperative changes in range of motion also showed improvement in anterior elevation (107° to 151°, P < .0001), abduction (100° to 154°, P < .0001), external rotation (41° to 47°, P = .0238), and internal rotation (L1 to Th10, P < .0001). Muscle strength was also improved in abduction (from 1.9 kg to 5.0 kg, P < .0001) and external rotation (from 3.5 kg to 7.7 kg, P < .0001). MR imaging evaluation revealed 2 cases (3.1%) of retears that fell into type 4 Sugaya classification. CONCLUSIONS: Extremely medialized repair of large and massive tears not able to be repaired using conventional techniques led to improved clinical outcomes compared to preoperative conditions. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

Surgical outcomes of the Frey procedure for chronic pancreatitis: correlation between preoperative characteristics and the histological severity of pancreatic fibrosis.

PURPOSE: To evaluate the efficacy of the Frey procedure and clarify the relationship between preoperative characteristics and the histological severity of chronic pancreatitis (CP). METHODS: Thirty patients who underwent the Frey procedure for CP between January, 2002 and December, 2020, at our hospital, were enrolled in this study. The specimen cored out of the pancreatic head was assessed for CP severity. We evaluated preoperative status and surgical outcomes according to CP severity. RESULTS: Long-term pain relief was achieved in all 26 patients with sustained long-term follow-up, with complete pain relief attained in 19 (63%). Albumin levels were significantly higher 1 year postoperatively than preoperatively (p = 0.038). Histological fibrosis was assessed in the 26 patients as follows: normal (n = 4; 15%), mild (n = 8; 31%), moderate (n = 2; 8%), and severe (n = 12; 46%). These patients were divided into two groups according to the severity of fibrosis: normal/mild (n = 12) and moderate/severe (n = 14). The rates of diffuse calcification on preoperative computed tomography (CT) (71% vs. 17%, p = 0.008) and islet atrophy on insulin immunohistochemistry (100% vs. 33%, p < 0.001) were significantly higher in the moderate/severe group than in the normal/mild group. CONCLUSION: The Frey procedure can achieve good pain relief and improve nutritional status. The severity of fibrosis can be predicted based on the extent of calcification on preoperative imaging studies.

Anterior versus posterior radical antegrade modular pancreatosplenectomy for pancreatic body and tail cancer: an inverse probability of treatment weighting with survival analysis.

PURPOSE: Radical antegrade modular pancreatosplenectomy (RAMPS) is a standard procedure for patients with pancreatic body and tail cancer. There are two types of RAMPS: anterior and posterior, but their indications and surgical outcomes remain unclear. We compared the surgical outcomes, postoperative course, and prognosis between anterior and posterior RAMPS. METHODS: Between 2007 and 2020, 105 consecutive patients who underwent RAMPS for pancreatic body and tail cancers were divided into an anterior RAMPS group (n = 30) and a posterior RAMPS group (n = 75). To adjust for differences in preoperative characteristics and intraoperative procedures, an inverse probability of treatment weighting (IPTW) analysis was done, using propensity scores. RESULTS: After IPTW adjustment, the postoperative body temperature of the posterior RAMPS group and the amount of drain discharge in the anterior RAMPS group were significantly lower, from postoperative days (PODs) 1 to 3, but there were no differences in postoperative complications, recurrence patterns, or prognosis between the two groups. Regarding the diagnostic ability of multidetector-row computed tomography (MD-CT) for direct tumor involvement of the left adrenal gland, the sensitivity and specificity were 100% and 90.0%, respectively. CONCLUSION: Pancreatic body and tail cancer without apparent preoperative direct tumor involvement of the left adrenal gland on MD-CT may be sufficient indication for anterior RAMPS.

Extrapancreatic extension is a better adverse prognostic factor than tumor size in patients with localized pancreatic ductal adenocarcinoma treated with chemoradiotherapy - comparison of T category between the American Joint Committee on Cancer and Japan Pancreas Society.

BACKGROUND: T category classification for pancreatic ductal adenocarcinoma (PDAC) in the Classification of Pancreatic Cancer by the Japan Pancreas Society (JPS) is quite different from that of the American Joint Committee on Cancer (AJCC). The JPS classification focuses on extrapancreatic extension, while the AJCC focuses mainly on tumor size. This study aimed at identifying prognostic factors in PDAC patients undergoing chemoradiotherapy (CRT) by comparing the differences of T categories in these two classifications. METHODS: This retrospective study involved 344 PDAC patients who underwent CRT from 2005 to 2019 and their T-category variables were re-evaluated on computed tomography (CT) images. Disease-specific survival (DSS) was compared based on the JPS and AJCC T categories, while multivariate analysis was performed to identify prognostic factors. RESULTS: Based on the AJCC, 5-year DSS of T3 was better than those of T1 and T2 (57.1% vs. 47.7% and 37.4%). In multivariate analysis, performance status, CEA, the involvement of superior mesenteric vein and superior mesenteric artery, the JPS stage before CRT, and regimen of chemotherapy were identified as independent prognostic factors. CONCLUSIONS: In localized PDAC patients treated with chemoradiotherapy, extrapancreatic extension, as while as biological, conditional and therapeutic factors, is a better prognostic factor than tumor size.

Myeloid Ikaros-SIRT1 signaling axis regulates hepatic inflammation and pyroptosis in ischemia-stressed mouse and human liver.

BACKGROUND & AIMS: Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied. METHODS: We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros-SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1-knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression). RESULTS: In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis - induced by canonical inflammasome signaling in BMM cultures - was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers. CONCLUSION: These findings identify the Ikaros-SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers. LAY SUMMARY: This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros-SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans.

Safety and Efficacy of Bis-Glyceryl Ascorbate as Prophylaxis for Hand-Foot Skin Reaction: A Single-Arm, Open-Label Phase I/II Study (DGA Study).

BACKGROUND: Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR. METHODS: A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint. RESULTS: Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%). CONCLUSION: DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051).

A 3-Decade, Single-Center Experience of Liver Transplantation for Cholangiocarcinoma: Impact of Era, Tumor Size, Location, and Neoadjuvant Therapy.

Liver transplantation (LT) for cholangiocarcinoma (CCA) remains limited to a small number of centers. Although the role of neoadjuvant therapy (NAT) has been explored over time, an in-depth analysis of NAT strategies remains limited. Furthermore, controversy exists regarding acceptable tumor size during patient selection for LT. This study explores the impact of era, tumor size, and NAT strategy on LT outcomes for CCA. We conducted a retrospective review of 53 patients with CCA treated with LT from 1985 to 2019; 19 hilar CCA (hCCA) and 30 intrahepatic CCA (iCCA) were included. The relative contributions of varying NAT (neoadjuvant chemotherapy [NAC], neoadjuvant local therapy [NALT], and combined NAC and NALT [NACLT]) as well as the implication of tumor size and era were analyzed. The primary endpoint was overall survival (OS). Compared with the old era (1985-2007), 5-year OS in patients who underwent LT in the recent era (2008-2019) showed a superior trend. The 5-year OS from initial treatment in patients receiving NACLT for hCCA and iCCA were 88% and 100% versus 9% and 41% in patients without it, respectively (P = 0.01 for hCCA; P = 0.02 for iCCA), whereas NAC or NALT alone did not show significant differences in OS versus no NAT (P > 0.05). Although 33 patients had large-size tumors (hCCA ≥ 30 mm, n = 12, or iCCA ≥ 50 mm, n = 21), tumor size had no impact on survival outcomes. Outcomes of LT for CCA seem to have improved over time. Multimodal NAT is associated with improved survival in LT for both iCCA and hCCA regardless of tumor size.

Low-dose aspirin confers protection against acute cellular allograft rejection after primary liver transplantation.

This study investigated the effect of low-dose aspirin in primary adult liver transplantation (LT) on acute cellular rejection (ACR) as well as arterial patency rates. The use of low-dose aspirin after LT is practiced by many transplant centers to minimize the risk of hepatic artery thrombosis (HAT), although solid recommendations do not exist. However, aspirin also possesses potent anti-inflammatory properties and might mitigate inflammatory processes after LT, such as rejection. Therefore, we hypothesized that the use of aspirin after LT has a protective effect against ACR. This is an international, multicenter cohort study of primary adult deceased donor LT. The study included 17 high-volume LT centers and covered the 3-year period from 2013 to 2015 to allow a minimum 5-year follow-up. In this cohort of 2365 patients, prophylactic antiplatelet therapy with low-dose aspirin was administered in 1436 recipients (61%). The 1-year rejection-free survival rate was 89% in the aspirin group versus 82% in the no-aspirin group (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.63-0.94; p = 0.01). The 1-year primary arterial patency rates were 99% in the aspirin group and 96% in the no-aspirin group with an HR of 0.23 (95% CI, 0.13-0.40; p < 0.001). Low-dose aspirin was associated with a lower risk of ACR and HAT after LT, especially in the first vulnerable year after transplantation. Therefore, low-dose aspirin use after primary LT should be evaluated to protect the liver graft from ACR and to maintain arterial patency.