One of the leading therapies for acute lymphoblastic leukemia (ALL) is the chemotherapeutic agent PEGylated E. coli-derived-l-asparaginase (PEG-ASNase). Due to the high risk of dose-limiting liver injury, characterized by clinically elevated levels of hepatic transaminases, PEG-ASNase therapy is generally avoided in adult patients. Our preclinical investigations have indicated that PEG-ASNase-induced liver injury is associated with the release of free fatty acids (FFAs) from white adipose tissue (WAT), suggesting potential lipotoxic effects. However, it remains uncertain whether PEG-ASNase directly induces hepatotoxicity or sensitizes hepatocytes to FFA-induced toxicity. Our results show that PEG-ASNase treatment results in hepatocyte apoptosis and lipid peroxidation. Ex vivo and in vitro studies in mouse and human WAT suggest that PEG-ASNase induces the expression of adipose triglyceride lipase (ATGL), activates the lipase, and stimulates adipose tissue lipolysis, suggesting that the FFAs from WAT may contribute to the observed liver injury. Moreover, treatment with PEG-ASNase sensitizes hepatocytes to FFA-induced lipotoxicity. Mechanistically, our RNA-sequencing (RNA-seq) analyses reveal that PEG-ASNase-induced sensitization to lipotoxicity is accompanied by the induction of Cyp2e1. We demonstrated that this sensitization effect is attenuated by both pharmacological and genetic inhibition of Cyp2e1. Our findings suggest that PEG-ASNase therapy induces WAT lipolysis and sensitizes hepatocytes to hepatic lipotoxicity in a Cyp2e1-dependent manner.

Promoting the international acceptance of clinical studies about traditional Chinese medicine (TCM) interventions is a key strategy for internationalization of TCM. However, the complexities of TCM interventions—in terms of the theories, practice patterns, and components—pose challenges to the design and implementation of clinical studies that are well accepted by the international community. This article summarized the current status of clinical studies about TCM interventions that were published in international journals, explored underlying barriers hindering the international acceptance, and discussed potential strategies for future development.

Promoting the international acceptance of clinical studies about traditional Chinese medicine (TCM) interventions is a key strategy for internationalization of TCM. However, the complexities of TCM interventions—in terms of the theories, practice patterns, and components—pose challenges to the design and implementation of clinical studies that are well accepted by the international community. This article summarized the current status of clinical studies about TCM interventions that were published in international journals, explored underlying barriers hindering the international acceptance, and discussed potential strategies for future development.

Promoting the international acceptance of clinical studies about traditional Chinese medicine (TCM) interventions is a key strategy for internationalization of TCM. However, the complexities of TCM interventions—in terms of the theories, practice patterns, and components—pose challenges to the design and implementation of clinical studies that are well accepted by the international community. This article summarized the current status of clinical studies about TCM interventions that were published in international journals, explored underlying barriers hindering the international acceptance, and discussed potential strategies for future development.

Objective:To explore the indications and effect of surgical treatment of autoimmune pancreatitis.Methods:Clinical data of these 15 patients with autoimmune pancreatitis diagnosed and treated at the Department of General Surgery, the First Hospital of Peking University from 2010 to 2021 were retrospectively analyzed.Results:The main clinical symptoms were obstructive jaundice, abdominal pain, distension and weight loss. The diagnosis of AIP was confirmed by EUS-FNA in 6 patients,among them, 4 did not relapse after oral hormone treatment, 2 did not receive relevant treatment, and 1 developed gastric cancer one year later. Under a suspicion of malignancy, 9 patients underwent surgical laparotomy ,and the diagnosis was established by pathology. There was no recurrence after oral hormone therapy in 1 patient who underwent laparotomy and pancreatic biopsy. One out of the 3 patients with choledochojejunostomy relapsed after 3 years. Of the 5 patients who underwent pancreatectomy, 4 had no obvious recurrence, and 1 had recurrence after 3 years.Conclusions:Untypical autoimmune pancreatitis is likely to be misdiagnosed as pancreatic cancer. For patients with suspicious malignancy, operational management and biopsy may benefit.

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

Objective:To investigate the clinicopathological characteristics and treatment strategies of undifferentiated carcinoma with osteoclast-like giant cells of pancreas (UCOGCP).Methods:The retrospective and descriptive study was conducted. The clinicopathological data of 5 patients with UCOGCP who were admitted to Peking University First Hospital from January 2004 to January 2019 were collected. There were 1 male and 4 females, aged from 33 to 71 years, with a median age of 56 years. Patients underwent preoperative laboratory test, imaging and histopatho-logical examinations. Patients with pancreatic head tumors underwent pancreaticoduodenectomy, and those with tumors in the body or tail of pancreas underwent distal pancreatectomy combined with splenectomy. All patients underwent standard lymph node dissection. Postoperative adjuvant therapy was individually decided by a multidisciplinary team. Observation indicators: (1) preopera-tive examination and treatment; (2) postoperative histopathological situations; (3) follow-up. Follow-up using outpatient examination and telephone interview was performed to detect tumor recurrence of patients up to January 2020. Measurement data with normal distribution were represented as Mean± SD. Measurement data with skewed distribution were described as M (range). Count data were described as absolute numbers. Results:(1) Preoperative examination and treatment: of the 5 UCOGCP patients, CA19-9 was elevated as 65.43 U/mL in only 1 patient preoperatively, while the CA19-9 was normal in other 4 patients. Four patients showed a solid cystic mass on preoperative contrast-enhanced computed tomography (CT) scan, and 1 patient showed a delayed peripheral enhancement of the solid tumor with central necrosis. The magnetic resonance imaging (MRI) scan showed hypointense signals on T1, T2 and weighted diffusion sequences in all 5 patients. Three of the 5 patients were resectable according to imaging data, 1 patient had locally advanced tumor, infiltrating the transverse colon, stomach, and partial small intestine, with the portal vein thrombus, and 1 patient had pancreatic head tumor with a liver metastatic lesion of 0.4 cm diameter which was detected on position emission tomography CT and was diagnosed as UCOGCP by endoscopic ultrasound-guided fine-needle aspiration biopsy. All patients underwent radical resection. Of the 3 patients with resectable tumors, 2 patients underwent pancreaticoduo-denectomy and 1 patient underwent distal pancreatectomy combined with splenectomy. One patient with locally advanced tumor in the body and tail of pancreas underwent distal pancreatectomy + transverse colostomy + partial gastrectomy + portal vein thrombectomy, and 1 patient with pancreatic head tumor and liver metastasis underwent pancreatoduodenectomy combined with left lateral hepatectomy. Of the 5 patients, 2 received postoperative adjuvant chemotherapy with single-agent gemcitabine, 1 received albumin-paclitaxel+gemcitabine combination chemotherapy, 1 received S1 as single agent chemotherapy, and 1 did not receive adjuvant chemotherapy. (2) Postoperative histopathological situations: of the 5 patients, 4 cases showed a cystic solid appearance of gross specimens, and 1 case had a solid appearance with central hemorrhagic necrosis. The tumor diameter was 5.2 cm(range, 2.0?14.0 cm). All the 5 patients achieved negative margins. Of the 5 patients, there was 1 case with portal vein invasion, 2 cases with vascular invasion, 3 cases with perineural invasion, and 2 cases with regional lymph node metastasis. One patient may had multiple tumor invasion and metastasis. Four of 5 patients had paraffin specimens available for immuno-histochemical staining. Four patients were positive for both CD68 and vimentin stains, while 3 patients were positive for programmed death ligand-1 (PD-L1), including 2 samples with 5% positive cells and 1 sample with 25% positive cells. Postoperative pathological examination showed a large number of spindle histiocytoid sarcoma cells scattered with osteoclast like giant cells and pleomorphic carcinoma giant cells. The tumor mutation burden in the 4 patients was 3.23 Muts/Mb(range, 2.61?21.77 Muts/Mb). Microsatellite status was stable in 4 patients. The next generation sequencing of 4 patients showed that all patients had KRAS mutation which was the most frequently mutation in pancreatic ductal adenocarcinoma. Of the 4 patients, 1 case had germline pathogenic mutation in TP53, 1case had somatic mutation in TP53, 1 case had somatic mutation in TP53, BLM, CDKN2A, and 1 case had somatic mutation in ARID1A. (3) Follow-up: 5 patients were followed up for 14?173 months, with a median follow-up time of 46 months. During the follow-up, 4 patients achieved disease-free survival and 1 patient had local recurrence at postoperative 11 months.Conclusions:UCOGCP is a rare variant of pancreatic tumor that exhibits a cystic solid mass in imaging examinations. High expression of PD-L1 is common in UCOGCP. The prognosis for UCOGCP is favorable following radical surgery. Patients may benefit from extended radical surgery even if the tumor has locally progression or distant metastasis.

The prevalence of obesity-associated conditions raises new challenges in clinical medication. Although altered expression of drug-metabolizing enzymes (DMEs) has been shown in obesity, the impacts of obese levels (overweight, obesity, and severe obesity) on the expression of DMEs have not been elucidated. Especially, limited information is available on whether parental obese levels affect ontogenic expression of DMEs in children. Here, a high-fat diet (HFD) and three feeding durations were used to mimic different obese levels in C57BL/6 mice. The hepatic expression of five nuclear receptors (NRs) and nine DMEs was examined. In general, a trend of induced expression of NRs and DMEs (except for and ) was observed in HFD groups compared to low-fat diet (LFD) groups. Differential effects of HFD on the hepatic expression of DMEs were found in adult mice at different obese levels. Family-based dietary style of an HFD altered the ontogenic expression of DMEs in the offspring older than 15 days. Furthermore, obese levels of parental mice affected the hepatic expression of DMEs in offspring. Overall, the results indicate that obese levels affected expression of the DMEs in adult individuals and that of their children. Drug dosage might need to be optimized based on the obese levels.

The pregnane X receptor(PXR)is a ligand activated nuclear receptor that is highly expressed in the liver and regulates many cellular functions including drug metabolism,endobiotic metabolism,oxidative stress response,apoptosis,inflammation,cell proliferation and regeneration.PXR activation promotes drug-induced liver injury(DILI)through its ability to increase the expression of phase I and phase Ⅱ drug metabolizing enzymes.The PXR also increases lipid synthesis and fatty acid uptake into the liver,leading to lipid accumulation and steatosis.In recent years,PXR has been explored as an important target in DILI and liver diseases.This review will highlight the roles of PXR in modulating DILI.PXR polymorphisms that have been associated with DILI will also be discussed.

Isoniazid (INH) is highly effective for the management of tuberculosis. However, it can cause liver injury and even liver failure. INH metabolism has been thought to be associated with INH-induced liver injury. This review summarized the metabolic pathways of INH and discussed their associations with INH-induced liver injury.