Quantifying the Impact of Alternative Definitions of Sepsis-Associated Acute Kidney Injury on its Incidence and Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVES: To derive a pooled estimate of the incidence and outcomes of sepsis-associated acute kidney injury (SA-AKI) in ICU patients and to explore the impact of differing definitions of SA-AKI on these estimates. DATA SOURCES: Medline, Medline Epub, EMBASE, and Cochrane CENTRAL between 1990 and 2023. STUDY SELECTION: Randomized clinical trials and prospective cohort studies of adults admitted to the ICU with either sepsis and/or SA-AKI. DATA EXTRACTION: Data were extracted in duplicate. Risk of bias was assessed using adapted standard tools. Data were pooled using a random-effects model. Heterogeneity was assessed by using a single covariate logistic regression model. The primary outcome was the proportion of participants in ICU with sepsis who developed AKI. DATA SYNTHESIS: A total of 189 studies met inclusion criteria. One hundred fifty-four reported an incidence of SA-AKI, including 150,978 participants. The pooled proportion of patients who developed SA-AKI across all definitions was 0.40 (95% CI, 0.37-0.42) and 0.52 (95% CI, 0.48-0.56) when only the Risk Injury Failure Loss End-Stage, Acute Kidney Injury Network, and Improving Global Outcomes definitions were used to define SA-AKI. There was significant variation in the incidence of SA-AKI depending on the definition of AKI used and whether AKI defined by urine output criteria was included; the incidence was lowest when receipt of renal replacement therapy was used to define AKI (0.26; 95% CI, 0.24-0.28), and highest when the Acute Kidney Injury Network score was used (0.57; 95% CI, 0.45-0.69; p < 0.01). Sixty-seven studies including 29,455 participants reported at least one SA-AKI outcome. At final follow-up, the proportion of patients with SA-AKI who had died was 0.48 (95% CI, 0.43-0.53), and the proportion of surviving patients who remained on dialysis was 0.10 (95% CI, 0.04-0.17). CONCLUSIONS: SA-AKI is common in ICU patients with sepsis and carries a high risk of death and persisting kidney impairment. The incidence and outcomes of SA-AKI vary significantly depending on the definition of AKI used.

Extracorporeal membrane oxygenation in children: A brief review.

With the advancement in technology and increasing familiarity, the use of extracorporeal membrane oxygenation (ECMO) has expanded in the past decade. Although ECMO can be lifesaving for critically ill children, it is an invasive therapy associated with complications that may necessitate rehabilitation and long-term follow-up. Paediatric clinicians play an essential role in managing these children, especially after the acute phase of their illness. This review provides an overview of ECMO and will provide a basic understanding of ECMO and its principles.

Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD+ salvage pathway. Since NAD+ plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators. Early optimization of HTS hits afforded compound 12, with a triazolopyridine core, as a lead compound. CYP direct inhibition (DI) was identified as an issue of concern, and was resolved through modulation of lipophilicity to culminate in 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea (21), which showed potent NAMPT activity accompanied with attenuated CYP DI towards multiple CYP isoforms.

Discovery of DS68702229 as a Potent, Orally Available NAMPT (Nicotinamide Phosphoribosyltransferase) Activator.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the nicotinamide adenine dinucleotide (NAD+) salvage pathway. Because NAD+ plays a pivotal role in energy metabolism and boosting NAD+ has positive effects on metabolic regulation, activation of NAMPT is an attractive therapeutic approach for the treatment of various diseases, including type 2 diabetes and obesity. Herein we report the discovery of 1-(2-phenyl-1,3-benzoxazol-6-yl)-3-(pyridin-4-ylmethyl)urea 12c (DS68702229), which was identified as a potent NAMPT activator. Compound 12c activated NAMPT, increased cellular NAD+ levels, and exhibited an excellent pharmacokinetic profile in mice after oral administration. Oral administration of compound 12c to high-fat diet-induced obese mice decreased body weight. These observations indicate that compound 12c is a promising anti-obesity drug candidate.

Granulomatous cholangitis mimicking hilar cholangiocarcinoma: a case report.

BACKGROUND: Hilar biliary stricture caused by isolated fungal infections in immunocompetent patients are considered to be extremely rare and difficult to the diagnose from the outset. CASE PRESENTATION: We report a unique case of granulomatous cholangitis based on isolated biliary fungal infection manifesting as obstructive jaundice and mimicking hilar cholangiocarcinoma in an immunocompetent woman. A 67-year-old Japanese woman was referred to our hospital for obstructive jaundice. She had been followed up for hypochondroplasia by the referring physician. Her total bilirubin level was 5.4 mg/dL. Viral hepatitis screening was found to be negative, and serum IgG4 was within normal limits; however, her CA19-9 level was high. Abdominal computed tomography revealed dilatation of the intrahepatic bile ducts. Abdominal echogram detected a solid mass in the hilar bile duct. Her magnetic resonance cholangiopancreatography has also revealed an abrupt stenosis of the primary biliary confluence with upstream dilatation of the intrahepatic bile ducts. Endoscopic nasobiliary drainage was then performed to improve the obstructive jaundice. Although biliary cytology did not reveal malignant findings, the bile duct in the hilum showed severe stenosis, and hilar cholangiocarcinoma could not be completely excluded. The patient had a developmental disorder based on chondrodystrophy. To avoid excessive surgical stress, such as hepatic lobectomy, we performed resection of the extrahepatic bile duct and Roux-en-Y hepaticojejunostomy reconstruction. Intraoperative frozen sections of the resection margins were determined to be negative for tumor. The resected specimen showed multiple strictures inside the common bile duct, numerous calculi in the lumen, and little free space. The final pathological diagnosis was granulomatous cholangitis due to fungal infection. The patient's postoperative course was deemed uneventful. She was discharged from our hospital 23 days after surgery without antifungal treatment. CONCLUSIONS: For a unique case of granulomatous cholangitis based on isolated biliary fungal infection mimicking hilar cholangiocarcinoma, we were able to avoid excessive invasion and performed appropriate surgical management.

Discovery of a bicyclo[4.3.0]nonane derivative DS88790512 as a potent, selective, and orally bioavailable blocker of transient receptor potential canonical 6 (TRPC6).

In this study, we aimed to synthesize a novel blocker of transient receptor potential canonical 6 (TRPC6). The sp2 carbon atoms of the aminoindane skeleton of the known inhibitor were replaced with sp3 carbon atoms to increase the molecular complexity, measured by fraction sp3 (Fsp3). The representative compound, a bicyclo[4.3.0]nonane derivative DS88790512, inhibited TRPC6 with an IC50 value of 11 nM. Notably, DS88790512 exhibited excellent selectivity against hERG and hNaV1.5 channels, and was identified as an orally bioavailable compound.

Circulating liver-specific microRNAs in cynomolgus monkeys.

Circulating microRNAs (miRNAs) can potentially be used as sensitive and specific biomarkers for tissue injury. However, the usefulness of circulating miRNAs as safety biomarkers in nonclinical toxicological studies using nonhuman primates is debatable owing to the limited information on organ-specific miRNAs. Therefore, a systematic investigation was performed to address this point. We identified organ-specific miRNAs from cynomolgus monkeys by next-generation sequencing analysis, which revealed that miR-122 was only abundant in the liver, whereas miR-192 was abundant in the liver, stomach, intestines, and kidney. The sequences of these miRNAs were identical to their human counterparts. Next, the absolute miR-122 and miR-192 levels were qualified by quantitative reverse transcription polymerase chain reaction (RT-qPCR) to determine the circulating levels of the miRNAs. No significant differences in the levels of circulating miRNAs between sexes were noted, and there was greater interindividual variation in miR-122 (20-fold variation) than in miR-192 (8-fold variation), based on their dynamic ranges. Finally, we evaluated the fluctuation in circulating liver-specific miRNAs in a monkey model of acetaminophen-induced hepatotoxicity. Acetaminophen with L-buthionine-(S,R)-sulfoximine induced hepatotoxicity in all the animals, which was characterized histopathologically by centrilobular necrosis and vacuolation of hepatocytes. Circulating miR-122 and miR-192 levels increased more than ALT levels after 24 h, indicating that circulating miR-122 and miR-192 may serve as sensitive biomarkers for the detection of hepatotoxicity in cynomolgus monkeys. This review describes the fundamental profiles of circulating liver-specific miRNAs in cynomolgus monkeys and focusses on their organ specificity, circulating levels, and fluctuations in drug-induced hepatotoxicity.

Comprehensive Analysis of Circulating microRNA Specific to the Liver, Heart, and Skeletal Muscle of Cynomolgus Monkeys.

Circulating microRNAs (miRNAs) could represent sensitive and specific biomarkers for tissue injury. However, their utility as biomarkers in nonclinical toxicological studies using nonhuman primates is limited by a lack of information on their organ specificity and circulating levels under resting condition of the animals. Herein, liver, heart, and skeletal muscle-specific expression patterns of miRNAs were determined in 27 tissues/organs from male and female monkeys (n =2/sex) by next-generation sequencing (NGS) analysis. This analysis revealed organ-specific miRNAs in the liver (miR-122), heart (miR-208a and miR-499a), and skeletal muscle (miR-206). Next, plasma was collected from conscious-naive male and female cynomolgus monkeys (n = 25/sex) to better understand the expressions of organ-specific circulating miRNAs. The absolute values of circulating miRNAs were quantified using a Taqman microRNA assay. MiR-1, miR-133a, and miR-208b showed preferential expression in the heart and skeletal muscles, whereas miR-192 was abundant in the liver, stomach, small intestine, and kidney. These miRNAs had identical sequences to their human counterparts. Six organ-specific miRNAs (miR-1, miR-122, miR-133a, miR-192, miR-206, and miR-499a) could be evaluated quantitatively by quantitative real-time reverse transcription polymerase chain reaction with or without preamplification. No significant sex differences were noted for these circulating miRNAs. For their circulation levels, miR-133a showed more than 900-fold interindividual variation, whereas miR-122 showed only a 20-fold variation. In conclusion, we profiled circulating organ-specific miRNAs for the liver, heart, and skeletal muscle of cynomolgus monkeys.

MicroRNA profiles in a monkey testicular injury model induced by testicular hyperthermia.

To characterize microRNAs (miRNAs) involved in testicular toxicity in cynomolgus monkeys, miRNA profiles were investigated using next-generation sequencing (NGS), microarray and reverse transcription-quantitative real-time-PCR (RT-qPCR) methods. First, to identify organ-specific miRNAs, we compared the expression levels of miRNAs in the testes to those in representative organs (liver, heart, kidney, lung, spleen and small intestine) obtained from naïve mature male and female monkeys (n = 2/sex) using NGS analysis. Consequently, miR-34c-5p, miR-202-5p, miR-449a and miR-508-3p were identified to be testicular-specific miRNAs in cynomolgus monkeys. Next, we investigated miRNA profiles after testicular-hyperthermia (TH) treatment to determine which miRNAs are involved in testicular injury. In this experiment, mature male monkeys were divided into groups with or without TH-treatment (n = 3/group) by immersion of the testes in a water bath at 43 °C for 30 min for 5 consecutive days. As a result, TH treatment induced testicular injury in all animals, which was characterized by decreased numbers of spermatocytes and spermatids. In a microarray analysis of the testis, 11 up-regulated (>2.0 fold) and 13 down-regulated (<0.5 fold) miRNAs were detected compared with those in the control animals. Interestingly, down-regulated miRNAs included two testicular-specific miRNAs, miR-34c-5p and miR-449a, indicating their potential use as biomarkers for testicular toxicity. Furthermore, RT-qPCR analysis revealed decreased expression levels of testicular miR-34b-5p and miR-34c-5p, which are enriched in meiotic cells, reflecting the decrease in pachytene spermatocytes and spermatids after TH treatment. These results provide valuable insights into the mechanism of testicular toxicity and potential translational biomarkers for testicular toxicity. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.

A method for estimating the glomerular filtration rate in conscious monkeys.

To establish a method for estimating the glomerular filtration rate (GFR) in conscious monkeys, the radiographic contrast medium iodixanol and the standard agent inulin were coadministered as tracers to male cynomolgus monkeys (Macaca fascicularis) as a bolus injection; blood was collected after 60, 90 and 120 min. An equation based on a single-blood-sample method derived from Jacobsson's formula was prepared using the data from healthy and saline- and gentamicin-treated monkeys by a multisample strategy with iodixanol. The GFR using the equation with iodixanol was in agreement with that from the multisample method with inulin or iodixanol. When the GFR decreased to more than 60% of the basal reference level, serum creatinine concentrations tended to increase, whereas serum blood urea nitrogen concentrations fluctuated. The results suggest that the single-sample-blood method with iodixanol is a practical tool for estimating the monkey GFR in a toxicological research setting therefore minimizing animal sufferings.

Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

The development of new immunotherapies to treat the inflammatory mechanisms that sustain atherosclerotic cardiovascular disease (ASCVD) is urgently needed. Herein, we present a path to drug repurposing to identify immunotherapies for ASCVD. The integration of time-of-flight mass cytometry and RNA sequencing identified unique inflammatory signatures in peripheral blood mononuclear cells stimulated with ASCVD plasma. By comparing these inflammatory signatures to large-scale gene expression data from the LINCS L1000 dataset, we identified drugs that could reverse this inflammatory response. Ex vivo screens, using human samples, showed that saracatinib-a phase 2a-ready SRC and ABL inhibitor-reversed the inflammatory responses induced by ASCVD plasma. In Apoe-/- mice, saracatinib reduced atherosclerosis progression by reprogramming reparative macrophages. In a rabbit model of advanced atherosclerosis, saracatinib reduced plaque inflammation measured by [18F] fluorodeoxyglucose positron emission tomography-magnetic resonance imaging. Here we show a systems immunology-driven drug repurposing with a preclinical validation strategy to aid the development of cardiovascular immunotherapies.

Erratum: Publisher Correction: Systems immunology-based drug repurposing framework to target inflammation in atherosclerosis.

[This corrects the article DOI: 10.1038/s44161-023-00278-y.].

Multiparametric Immunoimaging Maps Inflammatory Signatures in Murine Myocardial Infarction Models.

In the past 2 decades, research on atherosclerotic cardiovascular disease has uncovered inflammation to be a key driver of the pathophysiological process. A pressing need therefore exists to quantitatively and longitudinally probe inflammation, in preclinical models and in cardiovascular disease patients, ideally using non-invasive methods and at multiple levels. Here, we developed and employed in vivo multiparametric imaging approaches to investigate the immune response following myocardial infarction. The myocardial infarction models encompassed either transient or permanent left anterior descending coronary artery occlusion in C57BL/6 and Apoe-/-mice. We performed nanotracer-based fluorine magnetic resonance imaging and positron emission tomography (PET) imaging using a CD11b-specific nanobody and a C-C motif chemokine receptor 2-binding probe. We found that immune cell influx in the infarct was more pronounced in the permanent occlusion model. Further, using 18F-fluorothymidine and 18F-fluorodeoxyglucose PET, we detected increased hematopoietic activity after myocardial infarction, with no difference between the models. Finally, we observed persistent systemic inflammation and exacerbated atherosclerosis in Apoe-/- mice, regardless of which infarction model was used. Taken together, we showed the strengths and capabilities of multiparametric imaging in detecting inflammatory activity in cardiovascular disease, which augments the development of clinical readouts.

The role of native T1 values on the evaluation of cardiac manifestation in Japanese Fabry disease patients.

Aims: T1 mapping in cardiac magnetic resonance imaging enables us to distinguish various myocardial diseases showing left ventricular hypertrophy. Fabry disease is a lysosomal storage disorder causing the accumulation of glycosphingolipids into various organs, including the heart, which can be detected by native T1 values in T1 mapping. However, there is no report for the systematic evaluation of native T1 values in Fabry disease in Japan. Methods and results: We analyzed native T1 values of 30 Fabry disease patients (14 males and 16 females) obtained by 3-T cardiac magnetic resonance imaging. Averaged T1 values were significantly lower in male patients (septal T1: 1149.5 ± 63.3 ms; total T1: 1145.1 ± 59.5 ms) than in female patients (septal T1: 1210.5 ± 45.5 ms; total T1: 1198.8 ± 51.8 ms) (p < 0.01). We compared the native T1 values of Fabry disease patients with those obtained from 15 hypertrophic cardiomyopathy patients (9 males and 6 females). Native T1 values effectively differentiate Fabry disease from hypertrophic cardiomyopathy (septal T1: sensitivity 93.3% and specificity 80.0%; total T1: sensitivity 86.7% and specificity 73.3%). In addition, native T1 values had a significant negative correlation with the left ventricular mass index in male patients at the pre-hypertrophic stage (p < 0.05). In male and female patients without late-gadolinium enhancement, native T1 values also had a significant negative correlation with the left ventricular mass index (p < 0.05). Conclusion: These results suggest that native T1 values can be used to discriminate Fabry disease from hypertrophic cardiomyopathy and can reflect the accumulation of glycosphingolipids in cardiomyocytes.

Systematically evaluating DOTATATE and FDG as PET immuno-imaging tracers of cardiovascular inflammation.

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [18F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [64Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [68Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [64Cu]Cu-DOTATATE and [18F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [64Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUVmax 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUVmax 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUVmax 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [18F]F-FDG PET. In atherosclerotic mice, [64Cu]Cu-DOTATATE PET aortic signal, but not [18F]F-FDG PET, was higher compared to controls (SUVmax 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [64Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [18F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [68Ga]Ga-DOTATATE and [18F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [68Ga]Ga-DOTATATE and [18F]F-FDG in atherosclerotic (SUVmax 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUVmax 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [18F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [18F]F-FDG.

Pathology of the first autopsy case diagnosed as mucolipidosis type III α/ß suggesting autophagic dysfunction.

Mucolipidosis type III (MLIII) is a mild form of Mucolipidosis type II (MLII, I-cell disease) of late onset, of which almost no pathological study has been reported, as it is a very rare disease. We encountered the case of a 23-year-old man of Japanese and Caucasian mixed parentage diagnosed with MLIII by enzyme assay and genotyping. He died suddenly due to severe dilated cardiomyopathy. On the day after his death, autopsy was performed, and accumulation of Luxol Fast Blue (LFB) positive material was found to be most severe in the neuronal cells of dorsal root ganglions (DRG). Electromicroscopic DRG revealed the neuronal cytoplasm was filled with a zebra-body-like membranous matrix. We tried immunohistochemistry to investigate the mechanism of such accumulation in the DRG that resulted in double positive anti-ubiquitin antibody (FK-2) and anti-LC3 antibody (as specific marker for autophagy) staining, and speculated activating of autophagosome pathway, and 'zebra-body' should be suspected as dysfunctional autophagosome. We also detected foamy cell proliferation in the dura mater, Auerbach's plexus (peripheral nervous system), podocytes of almost all glomeruli, cartilage tissue in lumbar discs, and in cardiac muscle. We tried FK-2 and anti-LC3 antibody staining also for the podocytes, the area with the most marked proliferation of foamy cells, but the result was negative. This led us to speculate that these pathological findings, namely, accumulation of LFB-positive material and foamy fibroblast proliferation, might be the forms of dysfunctional autophagosome at various stages of development. This pathological study of MLIII supports the theory that MLIII is a mild type of MLII because of the close similarity of their pathological findings.

A retrospective analysis of antimicrobial resistance in pathogenic Escherichia coli and Salmonella spp. isolates from poultry in Uganda.

There are increasing reports of antimicrobial treatment failures for bacterial diseases of poultry in Uganda. The paucity of data on antimicrobial resistance (AMR) of pathogenic bacteria in Uganda is a major setback to AMR control. This study investigated the occurrence of fowl typhoid, colibacillosis, and AMR in associated pathogens from 2012 to 2018. Laboratory records from the Central Diagnostic Laboratory (CDL), a National Veterinary Diagnostic Facility located at Makerere University, were reviewed. Archived isolates of the causative bacteria for the two diseases were also evaluated for AMR. The frequencies of the two disease conditions, their clinical and necropsy presentations and the demographic data of the diagnostic samples were summarized from the records. Archived bacterial isolates were revived before antimicrobial susceptibility testing. This was done on Mueller Hinton agar using the disk diffusion method, against 16 antimicrobials of medical and veterinary importance according to the Clinical Laboratory Standards Institute guidelines. A total of 697 poultry cases were presented for bacteriological investigations in the review period. Colibacillosis and salmonellosis had prevalence rates of 39.7% (277/697) and 16.2% (113/697), respectively. A total of 63 and 92 isolates of Escherichia coli and Salmonella spp., respectively, were archived but 43 (68.3%) E. coli and 47 (51.1%) Salmonella spp. isolates were recovered and evaluated for AMR. Multidrug resistance was more frequent in E. coli (38; 88.4%) than salmonellae (25; 53.2%), (p < 0.001). The high prevalence of colibacillosis, salmonellosis and the AMR of associated pathogens warrants immediate institution of appropriate disease control measures.

Datopotamab Deruxtecan, a Novel TROP2-directed Antibody-drug Conjugate, Demonstrates Potent Antitumor Activity by Efficient Drug Delivery to Tumor Cells.

Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.

Prognostic factors for the late onset Pompe disease with enzyme replacement therapy: from our experience of 4 cases including an autopsy case.

We report 4 cases of late onset glycogen storage disease type II (GSD II) or Pompe disease (OMIM #232300), under enzyme replacement therapy (ERT) with recombinant human acid alpha glucosidase (rh-GAA, OMIM *606800). In these 4 cases, we focused on the case of a 28-years-old man, whose condition at the ERT starting was the worst and resulted in poor prognosis. The autopsy was done under his family's permission, and revealed severe accumulation of glycogen in his muscle, especially diaphragm or iliopsoas, and pulmonary veno-occlusive disease (PVOD) which resulted in severe pulmonary hypertension (PH). This is the first report of PVOD as the cause of PH in Pompe disease. We studied this case comparing to another 3 cases of late onset Pompe disease under the same course of ERT in our hospital, and the average data of the group of late onset Pompe disease with severe pulmonary insufficiency receiving ERT, supposed that low score of the body mass index (BMI) on the baseline, the presence of specific genotype (p.R600C), and signs of pulmonary dysfunction suggesting PH (tachypnea, ultrasound cardiography data) were factors that influenced the prognosis. For a better prognosis in the late onset Pompe disease, an early diagnosis for the early start of ERT before the onset of respiratory failure should be important, and the deliberate management and care should be needed even after the ERT start, especially for severe cases including pulmonary dysfunction.

Characteristics of the Electrocardiogram in Japanese Fabry Patients Under Long-Term Enzyme Replacement Therapy.

Objective: An electrocardiogram (ECG) is an important tool for demonstrating cardiac manifestations in various heart diseases. The present study clarified the characteristics of ECG parameters in Japanese Fabry patients under long-term enzyme replacement therapy (ERT). Methods: We analyzed the ECGs of 40 Fabry patients (male, n = 17; female, n = 23) before and after treatment with ERT. To evaluate the atrio-ventricular conduction, the PQ interval, corrected PQ and PQ minus P-wave in lead II (Pend-Q) were calculated. The QRS duration, QTc, Sokolow-Lyon index, and strain pattern were also examined. Results: At the baseline, the shortening of the PQ interval, corrected PQ and Pend-Q was identified in 7.5, 25.0, and 47.5% of cases, respectively. The prolongation of QRS duration and QTc was found in 7.5 and 40.0% of cases, respectively. The strain pattern was mainly identified in female patients, irrespective of left ventricular hypertrophy (LVH). During long-term ERT, the PQ interval, corrected PQ and Pend-Q did not change significantly. The QRS duration was significantly prolonged in both genders, whereas the QTc was significantly prolonged only in male patients. A subgroup analysis revealed that the prolongation of the QRS duration and QTc only occurred in male patients with LVH and only occurred in female patients with the classical type mutation. The prevalence of the strain was significantly increased only in male patients with LVH. Conclusions: These results suggest that the shortening of the Pend-Q is a specific finding in Japanese Fabry patients, and the strain pattern without LVH in female patients can be considered Fabry disease. During long-term ERT, prolongation of the QRS duration and QTc can indicate the progression of myocardial damage in male patients with LVH and in female patients with the classical type mutation.