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Introduction: Transarterial chemoembolization combined with lenvatinib and PD-1 inhibitor (triple therapy) has displayed encouraging clinical outcomes for unresectable hepatocellular carcinoma (uHCC). We aimed to explore the prognostic value of pathological response (PR) in patients with initially uHCC who underwent conversion surgery following triple therapy and identify predictors of major pathological response (MPR). Methods: A total of 76 patients with initially uHCC who underwent conversion surgery following triple therapy were retrospectively analyzed. PR was calculated as the proportion of nonviable tumor cell surface area of the whole tumor bed surface area. MPR was identified when PR was ≥90%. Pathological complete response (pCR) was defined as the absence of viable tumor cells. Results: MPR and pCR were identified in 53 (69.7%) and 25 (32.9%) patients, respectively. The 1- and 2-year overall survival in patients with MPR were significantly higher than in those without MPR (100.0% and 91.3% vs. 67.7% and 19.4%; p < 0.001). The corresponding recurrence-free survival was also improved in patients with MPR compared to those without (75.9% and 50.8% vs. 22.3% and 11.2%; p < 0.001). Similar results were observed among patients with pCR and those without. Patients who achieved MPR without pCR exhibited survival rates comparable to those of patients who achieved pCR. Baseline neutrophil-to-lymphocyte ratio ≥2.6 (p = 0.016) and preoperative alpha-fetoprotein level ≥400 ng/mL (p = 0.015) were independent predictors of MPR. Conclusion: The presence of MPR or pCR could improve prognosis in patients with initially uHCC who underwent conversion surgery following triple therapy. The PR may become a surrogate marker for predicting the prognosis of these patients. Plain Language Summary: The combination of transarterial chemoembolization, lenvatinib, and PD-1 inhibitor is an efficacious conversion therapy for uHCC. In this multicenter retrospective study, we discovered that PR was associated with the prognosis of patients who underwent conversion surgery. Predictors of MPR included neutrophil-to-lymphocyte ratio and alpha-fetoprotein levels. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the effect of adjuvant therapy with different durations in patients with initially unresectable hepatocellular carcinoma (uHCC) after conversion surgery. Methods: This study included 85 patients with initially uHCC who received conversion surgery between May 2019 and November 2022. They were divided into the long duration group (n = 57) and short duration group (n = 28) based on postoperative medication duration. Recurrence-free survival (RFS) and overall survival (OS) were analyzed and compared between the cohorts. Results: No significant difference in RFS or OS was found between the two groups [RFS: hazard ratio (HR) = 0.486; 95% confidence interval (CI), 0.229– 1.034, P = 0.061; OS: HR = 0.377; 95% CI, 0.119– 1.196, P = 0.098]. Patients without major pathologic response (MPR) in the long duration group had better RFS and OS results compared to those in the short duration group (RFS: HR = 0.242; 95% CI, 0.092– 0.634, P = 0.004; OS: HR = 0.264; 95% CI, 0.079– 0.882, P = 0.031). No significant difference was detected in RFS or OS between the two groups in patients with MPR (RFS: HR = 1.250; 95% CI, 0.373– 4.183, P = 0.718; OS: HR = 7.389; 95% CI, 0.147– 372.4, P = 0.317). After propensity score matching, 25 pairs of patients were selected and the results remained consistent. Conclusion: At least 6 months of adjuvant therapy may be beneficial for patients without MPR after conversion surgery. However, in patients with MPR, the effect of adjuvant therapy remains unclear. Further studies are needed to confirm the optimal duration of adjuvant therapy. [ABSTRACT FROM AUTHOR]

Patients with Philadelphia chromosome‐like acute lymphoblastic leukaemia (Ph‐like ALL) often face a grim prognosis, with PDGFRB gene fusions being commonly detected in this subgroup. Our study has unveiled a newfound fusion gene, TERF2::PDGFRB, and we have found that patients carrying this fusion gene exhibit sensitivity to dasatinib. Ba/F3 cells harbouring the TERF2::PDGFRB fusion display IL‐3‐independent cell proliferation through activation of the p‐PDGFRB and p‐STAT5 signalling pathways. These cells exhibit reduced apoptosis and demonstrate sensitivity to imatinib in vitro. When transfused into mice, Ba/F3 cells with the TERF2::PDGFRB fusion gene induce tumorigenesis and a shortened lifespan in cell‐derived graft models, but this outcome can be improved with imatinib treatment. In summary, we have identified the novel TERF2::PDGFRB fusion gene, which exhibits oncogenic potential both in vitro and in vivo, making it a potential therapeutic target for tyrosine kinase inhibitors (TKIs). [ABSTRACT FROM AUTHOR]

Introduction: Myeloid tumors typically harbor TP53 mutations, which are linked to a dismal prognosis. There are fewer studies on whether TP53‐mutated acute myeloid leukemia (AML) and myelodysplastic syndrome with excess blasts (MDS‐EB) differ in molecular characteristics and should be considered as separate entities. Methods: Between January 2016 and December 2021, a retrospective analysis was done on a total of 73 newly diagnosed AML patients and 61 MDS‐EB patients from the first affiliated hospital of Soochow University. We described a survival profile and a thorough characterization of newly found TP53‐mutant AML and MDS‐EB and investigated the relationship between these characteristics and overall survival (OS). Results: 38 (31.1%) were mono‐allelic, and 84 (68.9%) were bi‐allelic. There is no significant difference between TP53‐mutated AML and MDS‐EB (median OS 12.9 verse 14.4 months; p =.558). Better overall survival was linked to mono‐allelic TP53 than bi‐allelic TP53(HR = 3.030, CI:1.714–5.354, p <.001). However, the number of TP53 mutations and comutations were not significantly associated with OS. TP53 variant allele frequency cutoff of 50% is significant correlation with OS (HR: 2.177, 95% CI: 1.142–4.148; p =.0063). Conclusion: Our data revealed that allele status and allogeneic hematopoietic stem cell transplant independently affect the prognostic of AML and MDS‐EB patients, with a concordance of molecular features and survival between these two disease entities. Our analysis favors considering TP53‐mutated AML/MDS‐EB as a distinct disorder. [ABSTRACT FROM AUTHOR]

Introduction: The actual rate of conversion surgery and its prognostic advantages remain unclear. This study aimed to assess the outcomes of salvage surgery after conversion therapy with triple therapy (transcatheter arterial chemoembolization [TACE] combined with lenvatinib plus anti-PD-1 antibodies) in patients with initially unresectable hepatocellular carcinoma (uHCC). Methods: Patients with initially uHCC who received at least one cycle of first-line triple therapy and salvage surgery at five major cancer centers in China were included. The primary endpoints were overall survival (OS) and recurrence-free survival (RFS) rates after salvage surgery. The secondary endpoints were perioperative complications, 90-day mortality, and pathological tumor response. Results: Between June 2018 and December 2021, 70 patients diagnosed with uHCC who underwent triple therapy and salvage surgery were analyzed: 39 with Barcelona Clinic Liver Cancer (BCLC) stage C, 22 with BCLC stage B, and 9 with BCLC stage A disease. The median interval between the start of triple therapy and salvage surgery was 4.3 months (range, 1.7–14.2 months). Pathological complete response and major pathological response were observed in 29 (41.4%) and 59 (84.3%) patients, respectively. There were 2 cases of perioperative mortality (4.3%) and 5 cases of severe perioperative complications (7.1%). With a median follow-up of 12.9 months after surgery (range, 0.3–36.8 months), the median OS and RFS were not reached. The 1- and 2-year OS rates were 97.1% and 94.4%, respectively, and the corresponding RFS rates were 68.9% and 54.4%, respectively. Conclusion: First-line combination of TACE, lenvatinib, and anti-PD-1 antibodies provides a better chance of conversion therapy in patients with initially uHCC. Furthermore, salvage surgery after conversion therapy is effective and safe and has the potential to provide excellent long-term survival benefits. [ABSTRACT FROM AUTHOR]

Tumor‐associated macrophages (TAMs) and M2 macrophage polarization have been documented for their implication in various malignancies, but their implication in liver cancer remains to be determined. This study is intended to explore the effect of S100A9 regulated TAMs and macrophage polarization in liver cancer progression. THP‐1 cells were induced to differentiate into M1 and M2 macrophages, which were then cultured in liver cancer cell conditioned culture medium before the M1 and M2 macrophages were identified by measuring biomarkers using real‐time polymerase chain reaction. The differential expressed genes in macrophages in Gene Expression Omnibus (GEO) databases were screened. S100A9 overexpression and knockdown plasmid were transfected into macrophages to determine the effect of S100A9 on M2 macrophage polarization of TAMs and on proliferation ability of liver cancer cells. The proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) abilities of liver cancer co‐cultured with TAMs. M1 and M2 macrophages were successfully induced and liver cancer cell conditioned culture medium can increase polarization of macrophages into M2 macrophages, in which elevated expression of S100A9 was detected. Data in GEO database showed that tumor microenvironment (TME) upregulated S1000A9 expression. Suppression on S1000A9 can significantly suppress M2 macrophage polarization. TAM can provide the necessary microenvironment for liver cancer cells, HepG2 and MHCC97H by increasing cell proliferation, migration, and invasion ability, while suppression on S1000A9 can reverse this expression pattern. Suppression on S100A9 expression can regulate M2 macrophage polarization of TAMs to suppress the progression of liver cancer. [ABSTRACT FROM AUTHOR]

Background. Robotic systems can overcome some limitations of laparoscopic total mesorectal excision (L-TME), thus improving the quality of the surgery. So far, many studies have reported the technical feasibility and short-term oncological results of robotic total mesorectal excision (R-TME) in treating rectal cancer (RC); however, only a few evaluated the survival and long-term oncological outcomes. The following study compared the medium-term oncological data, 3-year overall survival (OS), and disease-free survival (DFS) of L-TME and R-TME in patients with rectal cancer. Methods. In this retrospective study, records of patients (patients with stage I-III rectal cancer) who underwent surgery (127 cases of L-TME and 148 cases of R-TME) at the Gansu Provincial Hospital between June 2016 and March 2018 were included in the analysis. Kaplan-Meier analysis evaluated the 3-year OS and DFS for all patients treated with curative intent. Results. The conversion rate was significantly higher, and the postoperative hospital stay was significantly longer in the L-TME group than in the R-TME group (all P <.05). Major complications were significantly lower in the robotic group (P<.05). The 3-year DFS rate (for all stages) was 74.8% for L-TME and 85.8% for R-TME (P =.021). For disease stage III, the 3-year DFS and OS were significantly higher in the R-TME group (P <.05). Conclusion. R-TME can achieve better oncological outcomes and is more beneficial for RC patients compared with L-TME, especially for those with stage III rectal cancers. Nevertheless, further randomized controlled trials and a longer follow-up period are needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Objective: To study the effect of total flavonoids of Rhizoma Drynariae on the expression of NMDAR1, GluR2 and CAMK II protein in model mice of kidney deficiency induced by exogenous glucocorticoid hydrocortisone and its mechanism. Methods: Kunming (KM) mice were randomly divided into the blank group, the hydrocortisone model group, the anti-brain failure capsule group, the Drynaria total flavonoids group, the Drynaria total flavonoids+ER blocker group, with 15 animals in each group. Except for the blank group, all groups were injected intramuscularly with hydrocortisone (25 mg·kg-1·d-1) to create models. The water maze experiment, new object recognition experiment and platform jump experiment were used to conduct behavioral investigations. HE staining was used to observe the pathological changes of mouse hippocampus, and Western blotting detected the expressions of NMDR1, GluR2 and CAMK II proteins in the hippocampus of mice in each group. Results: The experimental results showed that compared with the model group, the learning and memory ability of the mice in the Drynaria fortunei total flavonoids group was significantly improved, and the difference was statistically significant (P <0.01), the expression of NMDR1 and GluR2 proteins in the hippocampus of the mice was significantly increased (P<0.01), and the level of CAMK II protein significantly decreased (P<0.01). Conclusion: The total flavonoids of Rhizoma Drynariae may enhance the expression of NMDAR1 and GluR2 protein in the brain of hydrocortisone model mice through ER, reduce the expression of CAMK II protein, and alleviate the damage to the brain tissue of the model mice and play a neuroprotective effect. [ABSTRACT FROM AUTHOR]

How progenitor cells can attain a distinct differentiated cell identity is a challenging problem given the fluctuating signaling environment in which cells exist and that critical transcription factors are often not unique to a differentiation process. Here, we test the hypothesis that a unique differentiated cell identity can result from a core component of the differentiated state doubling up as a signaling protein that also drives differentiation. Using live single-cell imaging in the adipocyte differentiation system, we show that progenitor fat cells (preadipocytes) can only commit to terminally differentiate after up-regulating FABP4, a lipid buffer that is highly enriched in mature adipocytes. Upon induction of adipogenesis in mouse preadipocyte cells, we show that after a long delay, cells first abruptly start to engage a positive feedback between CEBPA and PPARG before then engaging, after a second delay, a positive feedback between FABP4 and PPARG. These sequential positive feedbacks both need to engage in order to drive PPARG levels past the threshold for irreversible differentiation. In the last step before commitment, PPARG transcriptionally increases FABP4 expression while fatty acid-loaded FABP4 increases PPARG activity. Together, our study suggests a control principle for robust cell identity whereby a core component of the differentiated state also promotes differentiation from its own progenitor state. How can progenitor cells attain a distinct differentiated cell identity, given the fluctuating signaling environment and redundancy of critical transcription factors? This study identifies a control principle whereby progenitor cells induced to differentiate can reach the desired distinct differentiated cell fate despite the possibility of many alternative fates en route. [ABSTRACT FROM AUTHOR]

Background and Aims: Natural killer (NK) cells play an important role in biliary atresia (BA) pathogenesis; human poliovirus receptor (PVR) is an important NK‐cell modulator. Here, we explored the role of PVR in BA pathogenesis. Methods: Poliovirus receptor expression and NK cell‐associated genes were detected in human BA samples and a rotavirus‐induced BA mouse model using quantitative PCR and immunofluorescence staining. Chemically modified small interfering RNA silenced PVR expression in the BA model, and its effects on the population and function of intrahepatic NK cells were investigated using flow cytometry (FCM). The effects of PVR overexpression and knockdown on proliferation, apoptosis and NK‐cell‐mediated lysis of cultured human cholangiocytes were analysed using FCM and cell viability assays. Serum PVR, high‐mobility group box 1 (HMGB1), and interleukin‐1beta (IL‐1beta) levels were measured in a cohort of 50 patients using ELISA. Results: Poliovirus receptor expression was upregulated in the biliary epithelium of BA patients and BA model and was positively correlated with the population and activation of intrahepatic NK cells. Silencing of PVR expression impaired the cytotoxicity of NK cells, reduced inflammation and protected mice from rotavirus‐induced BA. Activation of the TLR3‐IRF3 signalling pathway induced PVR expression in cultured cholangiocytes. PVR overexpression promoted proliferation and inhibited the apoptosis of cholangiocytes but exacerbated NK cell‐mediated cholangiocyte lysis. Serum PVR levels were elevated in BA patients and were positively correlated with HMGB1 and IL‐1beta levels. Conclusions: Poliovirus receptor contributes to BA pathogenesis by regulating NK cell‐mediated bile duct injury; PVR has the value as a biomarker of BA. [ABSTRACT FROM AUTHOR]