The Hedgehog (Hh) signaling pathway is a critical transduction system regulating cell proliferation, differentiation, and tissue homeostasis during embryonic development. Its aberrant activation is closely associated with the pathogenesis of malignancies such as basal cell carcinoma and medulloblastoma. Although Smoothened (SMO)-targeting inhibitors have received clinical approval, their therapeutic efficacy is limited by acquired resistance mutation and compensatory pathway activation. Glioma-associated oncogene homolog 1 (GLI1), the terminal effector transcription factor of the Hh pathway, has emerged as a promising therapeutic target due to its tumor-specific overexpression and lower propensity for resistance induction. However, GLI1 is classified as an "undruggable" target due to the absence of well-defined ligand-binding pockets, low inhibitory activity, and poor drug-like properties. Currently, no GLI1 inhibitor has entered clinical trials. This review systematically analyzes multidimensional modulation strategies (e.g., allosteric modulation, protein-protein interaction disruption, targeted protein degradation) for targeting transcription factors, based on the structural and functional features of GLI1-DNA interaction combined with recent advances in structural biology and chemical biology, offering new paradigms to overcome therapeutic barriers against undruggable targets.

Chest trauma is one of the most common injuries. Venous thromboembolism (VTE) as a common complication of chest trauma seriously affects the quality of patients′ life and even leads to death. Although there are some consensus and guidelines on the prevention and treatment of VTE at home and abroad, the current literatures lack specificity considering the diagnosis, treatment and prevention of VTE in patients with chest trauma have their own characteristics, especially for those with blunt trauma. Accordingly, China Chest Injury Research Society and editorial board of Chinese Journal of Traumatology organized relevant domestic experts to jointly formulate the Chinese expert consensus on the diagnosis, treatment and prevention of chest trauma venous thromboembolism associated with chest trauma (2022 version). This consensus provides expert recommendations of different levels as academic guidance in terms of the characteristics, clinical manifestations, risk assessment, diagnosis, treatment, and prevention of chest trauma-related VTE, so as to offer a reference for clinical application.

Transglutaminase 2 (TGM2) is a ubiquitous multifunctional protein, which is related to the adhesion of different cells and tumor formation. Previous studies found that TGM2 is involved in the interaction between host cells and viruses, but the effect of TGM2 on the proliferation of influenza virus in cells has not been reported. To explore the effect of TGM2 during H1N1 subtype influenza virus infection, a stable MDCK cell line with TGM2 overexpression and a knockout cell line were constructed. The mRNA and protein expression levels of NP and NS1 as well as the virus titer were measured at 48 hours after pot-infection with H1N1 subtype influenza virus. The results showed that overexpression of TGM2 effectively inhibited the expression of NP and NS1 genes of H1N1 subtype influenza virus, while knockout of TGM2 up-regulated the expression of the NP and NS1 genes, and the expression of the NP at protein level was consistent with that at mRNA level. Virus proliferation curve showed that the titer of H1N1 subtype influenza virus decreased significantly upon TGM2 overexpression. On the contrary, the virus titer in TGM2 knockout cells reached the peak at 48 h, which further proved that TGM2 was involved in the inhibition of H1N1 subtype influenza virus proliferation in MDCK cells. By analyzing the expression of genes downstream of influenza virus response signaling pathway, we found that TGM2 may inhibit the proliferation of H1N1 subtype influenza virus by promoting the activation of JAK-STAT molecular pathway and inhibiting RIG-1 signaling pathway. The above findings are of great significance for revealing the mechanism underlying the interactions between host cells and virus and establishing a genetically engineering cell line for high-yield influenza vaccine production of influenza virus.
Animals ; Cell Proliferation ; Dogs ; Humans ; Influenza A Virus, H1N1 Subtype/genetics* ; Influenza, Human ; Madin Darby Canine Kidney Cells ; Protein Glutamine gamma Glutamyltransferase 2

Objective:To observe the motor capacity of patients early after cardiac surgery using a cardiopulmonary exercise test.Methods:Patients who had performed a cardiopulmonary exercise test within 3 months after cardiac surgery were included in this retrospective study. Patients who took the test within 30 days of the operation formed a discharge group ( n=20), those within 30 to 60 days and 60 to 90 days formed the one month and two month groups ( n=10 for both). The discharge group was further divided into an aortic surgery group ( n=9), a bypass surgery group ( n=6) and a valve surgery group ( n=5) according to their procedure. The exercise capacity of each person was measured in terms of the changes in heart rate and systolic pressure from the resting to the anaerobic threshold stage. Anaerobic threshold, peak oxygen uptake and carbon dioxide ventilation equivalent were also recorded. Results:All of the patients completed the cardiopulmonary exercise test above the anaerobic threshold, and no adverse events such as exercise accidents occurred. At the anaerobic threshold the average heart rate of the discharge group was (8.8±7.1)bpm, significantly lower than the averages of the one month and two months groups: (17.0±5.9) and (18.3±10.5)bpm respectively. The average anaerobic thresholds and peak oxygen uptakes of the 1 month and 2 months groups were not significantly different, but they were all significantly higher than the discharge group′s averages. There were, however, no significant differences among the groups in the average changes in their systolic pressure and carbon dioxide ventilation equivalent. Moreover, the average anaerobic threshold and peak oxygen uptake of the aortic surgery group and the bypass surgery group were significantly lower than the valve surgery group′s averages.Conclusions:Postoperative motor ability after cardiac surgery improves significantly for at least 30 days. Patients who have received aortic or bypass surgery have significantly lower exercise capacity than those after valve surgery.

Objective To establish a non-venous bypass orthotopic liver transplantation model in Bama miniature pigs with high repeatability and stability. Methods Twelve Bama miniature pigs were randomly divided into the donor group (n=6) and recipient group (n=6). Pigs underwent non-venous bypass orthotopic liver transplantation. The time of anhepatic phase during operation was shortened, blood pressure during anhepatic phase was stably maintained, and management of anesthesia and body fluid during operation were strengthened. The operation time, anhepatic phase and survival status of the recipients were observed and recorded. The intraoperative heart rate, mean arterial pressure (MAP) and changes in arterial blood gas analysis were monitored. The perioperative liver function was evaluated. Results Among 6 Bama miniature pigs, 1 died from transplantation failure intraoperatively. The operation time of the remaining 5 pigs was (247±27) min and the time of anhepatic phase was (46±4) min. Three animals survived for more than 2 weeks. Compared with the preanhepatic phase, the heart rate of the animals was significantly faster, MAP was considerably reduced to (46±6) mmHg, blood pH value, base excess (BE) and HCO₃^- level were all significantly decreased and serum level of K⁺ was significantly elevated during the anhepatic phase (all P < 0.05). In the neohepatic phase, MAP of Bama miniature pigs was significantly increased, heart rate was dramatically slower.Blood pH value, BE, HCO₃^- level were significantly increased and serum level of K⁺ was significantly declined (all P < 0.05). During abdominal closure, MAP, blood gas indexes and serum level of K⁺ were almost recovered to those in the preanhepatic phase. Compared with preoperative levels, the levels of alanine aminotransferase(ALT), aspartate aminotransferase(AST), lactate dehydrogenase(LDH)and alkaline phosphatase(ALP)were significantly increased after operation (all P < 0.05), the change in AST was the most obvious, and it gradually decreased at postoperative 2 d. The level of γ-gutamyl transferase(GGT) did not significantly elevated. The level of total bilirubin (TB) was evidently elevated at postoperative 5 d. Compared with the preoperative levels, the levels of total protein (TP) and albumin (ALB) were significantly decreased after operation (both P < 0.05), and began to gradually increase at postoperative 1 d. Conclusions The non-venous bypass orthotopic liver transplantation model of Bama miniature pig is convenient, with highly reproducible and survival rate, which can be utilized as a standardized liver transplantation model.

Objective To investigate the clinical application of enteroscopies in China, and to further provide evidence for popularization and promotion of enteroscopies. Methods The survey was designed between January 1st , 2017 and July 31th , 2017 with pre-survey in Guangdong Province between May 1st , 2017 and July 31st , 2017. It was conducted in Chinese mainland between August 30th , 2017 and December 30th , 2017. Data were collected through the online survey and reality survey at 385 hospitals. A total of 373 hospitals gave feedbacks and 7 hospitals were unqualified for further analysis after data checking, so 366 hospitals were included for final analysis, with a responding rate of 95. 1％. Information on practice status of hospitals with enteroscopies and enteroscopists were collected. The chi-squared test was used for comparison of data between eastern and central and western regions. Results The hospitals owning enteroscopies accounted for 47. 0％ ( 172/366 ) , 154/172 ( 89. 5％) were tertiary referral hospitals, 112/172 ( 65. 1％) established enteroscopy units, and 84/172 ( 48. 8％) owned X-ray exclusive for enteroscopy. The proportion of enteroscopists with senior title was 40. 3％ (50/124), female enteroscopists accounted for 42. 7％ ( 53/124 ) . Most enteroscopists aged 31-40 ( 50. 8％) and 41-50 years ( 27. 4％) . 43. 0％ ( 74/172) hospitals employed only 1-2 enteroscopists. The diagnostic cases per year were less than 50 cases in 51. 2％ hospitals ( 88/172) . The therapeutic cases per year were less than 10 cases in 51. 7％hospitals ( 89/172 ) . Nineteen of 124 ( 15. 3％) of enteroscopists didn' t receive standard training. The number of hospitals performing enteroscopies in eastern regions was higher than that in central and western regions [111(51. 6％) VS 61(40. 4％), P=0. 034]. The training background of enteroscopists in eastern regions was better than that in central and western regions. Untrained endoscopists accounted for 10. 5％ in eastern regions, while those accounted for 22. 9％ in central and western regions with significant difference ( P=0. 031 ) . Conclusion Low number of patients treated and shortage of enteroscopists are obvious in Chinese mainland, especially in central and western regions. Standard training of enteroscopists is impending.

Sepsis-induced cardiac dysfunction is a serious complication of sepsis with no effective treatment. AMP-activated protein kinase (AMPK) is a regulator for energy metabolism in cells and plays a key role in the energy balance. Recent studies have shown that AMPK exerted a protective effect on sepsis-induced cardiac dysfunction, which was related to the regulation of inflammation, endothelial cells injury, energy metabolism, myocardial cells apoptosis and autophagy. Therefore, AMPK is a therapeutic target for sepsis-induced cardiac dysfunction.
AMP-Activated Protein Kinases ; metabolism ; Apoptosis ; Autophagy ; Heart Diseases ; enzymology ; etiology ; Humans ; Sepsis ; complications