Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APC^min/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Objective:To explore the predictive value of early serum tumor markers (STM) , neutrophil to lymphocyte ratio (NLR) , platelet to lymphocyte ratio (PLR) combination score on the efficacy of gastric cancer immunotherapy.Methods:A total of 76 patients with gastric cancer who received immunotherapy at Second Affiliated Hospital of Shandong First Medical University from January 1, 2020 to June 30, 2022 were selected. Patients' leading STM, NLR, PLR were collected. Optimal cut-off value of NLR and PLR were determined by the receiver operating characteristic (ROC) curve. The clinical efficacy and prognosis of different leading STM, NLR, PLR and combined scores in gastric cancer patients received immunotherapy were analyzed. ROC curve was used to evaluate the predictive efficiency of each index and the combined score. Cox regression model was used to analyze the factors affecting patients' survival.Results:The best truncation value for NLR was 2.75, and the best truncation value for PLR was 175.9. All patients completed at least 2 cycles of immunotherapy, the objective response rate (ORR) was 23.7% (18/76) , and the disease control rate (DCR) was 88.2% (67/76) . There were no significant differences in ORR [ (20.9% (9/43) vs. 27.3% (9/33) ], DCR [83.7% (36/43) vs. 93.9% (31/33) ] between the high NLR group ( n=43) and low NLR group ( n=33) ( χ2=0.42, P=0.519; χ2=1.02, P=0.313) . There were no significant differences in ORR [27.3% (12/44) vs. 18.8% (6/32) ], DCR [81.8% (36/44) vs. 96.9% (31/32) ] between the high PLR group ( n=44) and low PLR group ( n=32) ( χ2=0.75, P=0.388; χ2=2.71, P=0.555) . The ORR for the high combined score group ( n=39) and low combined score group ( n=37) was 17.9% (7/39) and 29.7% (11/37) , respectively, with no statistically significant difference ( χ2=1.46, P=0.230) ; the DCR was 79.5% (31/39) and 97.3% (36/37) , respectively, with a statistically significant difference ( χ2=4.19, P=0.041) . The median progression free survival (PFS) and overall survival (OS) of 76 patients were 8.0 and 12.0 months. The median PFS in the high NLR group and low NLR group was 7.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=7.95, P=0.005) ; the median OS was 12.0 and 14.0 months, respectively, with no statistically significant difference ( χ2=1.04, P=0.307) . The median PFS in the high PLR group and low PLR group was 8.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=3.90, P=0.048) ; the median OS was 13.0 and 13.0 months, respectively, with no significant difference ( χ2=0.02, P=0.896) . The median PFS in the high combined score group and low combined score group was 7.0 and 10.0 months, respectively, with a statistically significant difference ( χ2=13.52, P<0.001) ; the median OS was 12.0 and 14.0 months, respectively, with a statistically significant difference ( χ2=5.02, P=0.025) . ROC curve analysis showed that the area under curve (AUC) of leading STM, NLR, PLR and combined score to predict the efficacy of gastric cancer immunotherapy was 0.662, 0.697, 0.601 and 0.773. Univariate analysis showed that, surgery ( HR=0.59, 95% CI: 0.36-0.95, P=0.031) , leading STM ( HR=0.57, 95% CI: 0.34-0.93, P=0.026) , NLR ( HR=0.54, 95% CI: 0.34-0.87, P=0.011) , combined score ( HR=0.42, 95% CI: 0.26-0.68, P<0.001) were all influencing factors for PFS in gastric cancer patients received immunotherapy; tumor stage ( HR=0.30, 95% CI: 0.12-0.75, P=0.011) , leading STM ( HR=0.28, 95% CI: 0.15-0.50, P<0.001) , combined score ( HR=0.55, 95% CI: 0.31-0.96, P=0.036) were all influencing factors for OS in gastric cancer patients received immunotherapy. Multivariate analysis showed that, leading STM ( HR=0.56, 95% CI: 0.33-0.98, P=0.041) was an independent influencing factor for PFS in gastric cancer patients received immunotherapy; tumor stage ( HR=0.29, 95% CI: 0.11-0.76, P=0.012) , leading STM ( HR=0.32, 95% CI: 0.17-0.58, P<0.001) , combined score ( HR=0.46, 95% CI: 0.25-0.82, P=0.009) were all independent influencing factors for OS in gastric cancer patients received immunotherapy. Conclusion:The combined score of leading STM, NLR and PLR is an independent factor influencing OS in patients receiving immunotherapy for gastric cancer, and can predict the efficacy of immunotherapy for gastric cancer.

As the search for effective treatments for COVID-19 continues, the high mortality rate among critically ill patients in Intensive Care Units (ICU) presents a profound challenge. This study explores the potential benefits of traditional Chinese medicine (TCM) as a supplementary treatment for severe COVID-19. A total of 110 critically ill COVID-19 patients at the Intensive Care Unit (ICU) of Vulcan Hill Hospital between Feb., 2020, and April, 2020 (Wuhan, China) participated in this observational study. All patients received standard supportive care protocols, with a subset of 81 also receiving TCM as an adjunct treatment. Clinical characteristics during the treatment period and the clinical outcome of each patient were closely monitored and analysed. Our findings indicated that the TCM group exhibited a significantly lower mortality rate compared with the non-TCM group (16 of 81 vs 24 of 29; 0.3 vs 2.3 person/month). In the adjusted Cox proportional hazards models, TCM treatment was associated with improved survival odds (P < 0.001). Furthermore, the analysis also revealed that TCM treatment could partially mitigate inflammatory responses, as evidenced by the reduced levels of proinflammatory cytokines, and contribute to the recovery of multiple organic functions, thereby potentially increasing the survival rate of critically ill COVID-19 patients.
Humans ; COVID-19 ; Medicine, Chinese Traditional ; SARS-CoV-2 ; Critical Illness ; Treatment Outcome

Objective:To investigate the clinical features, molecular etiology, and treatment of a family with Treacher Collins Syndrome 2 (TCS2).Methods:Information of the proband (female, 8 years old) including medical history and family history was collected. Physical examination and examinations concerning laboratory, audiology, and radiology were performed on the proband. Physical examination was also performed on the family members. Genomic DNA of proband was extracted for whole exome sequencing, and then the genomic DNA of family members was extracted for Sanger sequencing. POLR1D and TCS2 related literatures published before August 31,2023 were searched and sifted in PubMed and CKNI databases. The clinical characteristics of TCS2 were summarized. Results:The proband had poor hearing since childhood, with pure tone audiometry indicating conductive hearing loss. She had a smaller jaw, bilateral preauricular fistulas and cup-shaped ear deformities. Temporal bone CT scan revealed deformities in the left external ear canal, bilateral middle ear and inner ear. A bone-conduction hearing aid device was surgically implanted, resulting in restoration of almost normal hearing levels. The proband′s mother also had a slightly smaller jaw. Genetic analysis revealed a novel heterozygous variant NM_015972.4:c.38_47del in the POLR1D gene in the proband, which was inherited from her mother. A review of the literature revealed no clear evidence of genotype-phenotype correlation in TCS2. Conclusions:Molecular diagnosis plays a vital role in the diagnosis of TCS2. Patients with normal facial phenotype may be carriers of pathogenic variants in the POLR1D gene and have the risk of passing it to the offsprings with complete penetrance. Proper bone conductive hearing devices can improve the quality of life of TCS2 patients.

Objective:To explore the clinical effects of parallel combined flow-through perforator flaps in the treatment of circular hot crush injuries in limbs with blood supply disorder.Methods:The study was a retrospective observational study. From April 2016 to December 2022, 4 cases with circular hot crush injuries in limbs with blood supply disorder were admitted to the Department of Burns and Plastic Surgery of the 988 th Hospital of Joint Logistics Support Force of PLA, including 3 males and 1 female, aged from 24 to 48 years. Among them, 2 cases were injured in the calf and 2 cases were injured in the forearm. After emergency debridement, the area of skin and soft tissue defects was from 20 cm×20 cm to 44 cm×20 cm. The patients had defects in tibialis anterior and posterior tibial arteries with a length of 13 to 18 cm, and in ulnar and radial arteries with a length of 9 to 12 cm. Flaps were designed and cut, including a flow-through anterolateral thigh perforator flap with area of 20 cm×9 cm to 24 cm×21 cm carrying the descending branch of the lateral circumflex femoral artery and the accompanying veins of 8 to 18 cm in length; and a flow-through posterior tibial artery perforator flap with area of 21 cm×13 cm and 20 cm×14 cm carrying the posterior tibial artery, the accompanying veins with a length of 14 and 17 cm respectively, and the great saphenous vein with a length of 22 and 21 cm. The circular hot crush injury wounds in the calf with blood supply disorder were repaired by a parallel combination of flow-through posterior tibial artery perforator flap and flow-through anterolateral thigh perforator flap, and the circular hot crush injury wounds in the forearm with blood supply disorder were repaired by a parallel combination of bilateral flow-through anterolateral thigh perforator flap, and the injured main vessels were reconstructed. The donor site wounds of flap were closed directly or treated with split-thickness skin grafts from abdomen. After surgery, the blood supply and survival of the flap and distal affected limb, the healing of wounds in the donor and recipient sites, the survival of the skin graft in the flap donor site were observed. During follow-up, the condition of flaps, the appearance, blood supply, and function of affected limbs were observed. At the last follow-up, the foot and ankle functions were evaluated according to the scoring standards of American Orthopedic Foot and Ankle Association, and the wrist and hand function was evaluated according to the trial standard of replantation of amputated upper limb function assessment of the Hand Surgery of Chinese Medical Association. Results:The flaps and distal affected limbs of 4 patients had good blood circulation and successfully survived after surgery. The wounds of 3 cases successfully healed, while one patient with circular hot crush injury in the forearm experienced exudation in the recipient site in the later stage, and the wound healed after re-expansion and suturing. The donor site wounds healed smoothly, and the skin grafts successfully survived. During follow-up of 12 to 24 months after surgery, the flaps were slightly swollen, the limbs had good appearance, normal blood circulation, and fine functional recovery. At the last follow-up, the foot and ankle function of 2 patients with circular hot crush injuries in the calf was evaluated as good in 1 case and commonly in 1 case; the wrist and hand function of 2 patients with circular hot crush injuries in the forearm was evaluated as excellent in 1 case and good in 1 case.Conclusions:The parallel combined flow-through perforator flap can reconstruct the damaged main blood vessels and repair the wound at the same time. It can not only effectively save the limb, but also restore part of the function of the affected limb. It is one of the effective methods to treat the circular hot crush injuries in limbs with blood supply disorder.

Background::There is a need for effective and safe therapies for psoriasis that provide sustained benefits. The aim of this study was to assess the efficacy and safety of tildrakizumab, an anti-interleukin-23p19 monoclonal antibody, for treating moderate-to-severe plaque psoriasis in Chinese patients.Methods::In this multi-center, double-blind, phase III trial, patients with moderate-to-severe plaque psoriasis were enrolled and randomly assigned (1:1) to receive subcutaneous tildrakizumab 100 mg or placebo at weeks 0 and 4. Patients initially assigned to placebo were switched to receive tildrakizumab at weeks 12, 16, and every 12 weeks thereafter. Patients in the tildrakizumab group continued with tildrakizumab at week 16, and every 12 weeks until week 52. The primary endpoint was the Psoriasis Area and Severity Index (PASI 75) response rate at week 12.Results::At week 12, tildrakizumab demonstrated significantly higher PASI 75 response rates (66.4% [73/110] vs. 12.7% [14/110]; difference, 51.4% [95% confidence interval (CI), 40.72, 62.13]; P <0.001) and Physician’s Global Assessment (60.9% [67/110] vs. 10.0% [11/110]; difference, 49.1% [95% CI, 38.64, 59.62]; P <0.001) compared to placebo. PASI 75 response continued to improve over time in both tildrakizumab and placebo-switching to tildrakizumab groups, reaching maximal efficacy after 28 weeks (86.8% [92/106] vs. 82.4% [89/108]) and maintained up to 52 weeks (91.3% [95/104] vs. 87.4% [90/103]). Most treatment-emergent adverse events were mild and not related to tildrakizumab. Conclusion::Tildrakizumab demonstrated durable efficacy through week 52 and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.Trial registration::ClinicalTrials.gov, NCT05108766.

Objective To study the causes of two Chinese families with Branchio-oto syndrome.Methods The clinical data of two families were collected,and the pathogenic genes and variants of Branchio-oto syndrome were screened and verified by whole exome sequencing and Sanger sequencing.Results Two proband patients were diagnosed with Branchio-oto syndrome.Proband 1 presented with preauricular and anterior cervical fistulas,as well as congenital severe sensorineural hearing loss.On the other hand,proband 2 displayed a preauricular fistula and an anterior cervical cyst.At the age of 5,progressive deterioration of binaural hearing was observed,leadingtothe cur-rent diagnosis of severe mixed deafness.Genetic analysis showed that proband 1 and 2 carried nonsense variants of EYA1 gene:NM_000503.6:c.1408G＞T(p.Glu470Ter),and c.889C＞T(p.Arg297Ter).According to the guide-lines of the American College of Medical Genetics and Genomics(ACMG),the above variants were rated as patho-genic variants.After reviewing the literature,the c.1408G＞T variant had not been previously reported,and the c.889C＞T is a known variant.Conclusion The variants c.1408G＞T(p.Glu470Ter)and c.889C＞T(p.Arg297Ter)of EYA1 gene are the cause of these two families with Branchio-oto syndrome.The first report of c.1408G＞T broadens the mutational spectrum of EYA1 gene and provids a clinical reference for the diagnosis of Branchio-oto syndrome.

Objective To explore the efficacy and safety of platelet-derived growth factor(PDGF)combined with allograft bone transplantation in the treatment of spinal tuberculosis.Methods A total of 177 patients with lumbar tuberculosis admitted to the 4th People's Hospital of Qinghai Province from August 2018 to August 2023 were selected as the research subjects.Patients were divided into control group(n=49)and observation group(n=128)based on the source of the transplanted bone.All patients underwent at least 2 weeks of standard quadruple anti-tuberculosis chemotherapy before surgery.Patients in the control group received PDGF combined with autograft bone transplantation,while patients in the observation group received PDGF combined with allograft bone transplantation.The surgical duration,intraoperative blood loss,and length of hospital stay of patients in the two groups were recorded;the erythrocyte sedimentation rate(ESR)and serum C-reactive protein(CRP)levels of patients in the two groups were compared before surgery and at 1,3,6 months after surgery.Preoperative CT and magnetic resonance imaging(MRI)examinations were performed,and postoperative CT and MRI were performed after bone fusion was completed to compare the changes in Cobb angle before and after surgery.The visual analogue scale(VAS)was used to assess the pain degree in the lumbar region before surgery and at 1,3,6 months after surgery.The VAS scores of patients in the two groups,VAS scores of male patients in the two groups,and VAS scores of female patients in the two groups were compared before and after surgery,respectively.Results There was no statistically significant difference in surgical duration and length of hospital stay between the observation group and the control group(P＞0.05).The intraoperative blood loss of patients in the observation group was significantly less than that in the control group(P＜0.05).There was no statistically significant difference in Cobb angle before and after surgery between the two groups(P＞0.05).The postoperative Cobb angle significantly decreased in both groups when compared to preoperative values(P＜0.05).The VAS scores of patients in both groups decreased sequentially before surgery and at 1,3,6 months after surgery,with statistically significant differences in intra-group pairwise comparisons(P＜0.05).The VAS scores of male patients in both groups decreased sequentially before surgery and at 1,3,6 months after surgery,with statistically significant differences in intra-group pairwise comparisons(P＜0.05).The VAS scores of female patients in both groups also decreased sequentially before surgery and at 1,3,6 months after surgery,with statistically significant differences in intra-group pairwise comparisons(P＜0.05).There was no statistically significant difference in VAS scores between the observation group and the control group before surgery and at 1,6 months after surgery(P＞0.05);the VAS score of patients in the observation group was significantly lower than that in the control group at 3 months after surgery(P＜0.05).There was no statistically significant difference in VAS scores between male patients in the observation group and male patients in the control group before surgery and at 1,3,6 months after surgery(P＞0.05);the VAS score of male patients in the observation group was significantly lower than that in the control group at 3 months after surgery(P＜0.05).There was no statistically significant difference in VAS scores between female patients in the observation group and female patients in the control group before surgery and at 1,6 months after surgery(P＞0.05);the VAS score of female patients in the observation group was significantly lower than that in the control group at 3 months after surgery(P＜0.05).The ESR of patients in both groups decreased sequentially before surgery and at 1,3,6 months after surgery,with statistically significant differences in intra-group pairwise comparisons(P＜0.05).The serum CRP levels of patients in both groups also decreased sequentially before surgery and at 1,3,6 months after surgery,with statistically significant differences in intra-group pairwise comparisons(P＜0.05).There was no statistically significant difference in ESR between the observation group and the control group before surgery and at 1,3,6 months after surgery(P＞0.05).There was no statistically significant difference in serum CRP level between the observation group and the control group before surgery and at 1,6 months after surgery(P＞0.05);the serum CRP level of patients in the observation group was significantly higher than that in the control group at 3 months after surgery(P＜0.05).Conclusion The effect of PDGF combined with allograft bone transplantation in the treatment of spinal tuberculosis is comparable to that of autograft bone transplantation,but PDGF combined with allograft bone transplantation can significantly reduce postoperative pain degree,improve patient comfort,avoid additional damage caused by autograft bone transplantation,and reduce the physical burden on patients.It can be considered a safe and reliable surgical method for bone grafting in lumbar tuberculosis surgery.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To investigate the distribution and antimicrobial resistance profiles of the common pathogens isolated from urine from 2015 to 2021 in the CHINET Antimicrobial Resistance Surveillance Program.Methods The bacterial strains were isolated from urine and identified routinely in 51 hospitals across China in the CHINET Antimicrobial Resistance Surveillance Program from 2015 to 2021.Antimicrobial susceptibility was determined by Kirby-Bauer method,automatic microbiological analysis system and E-test according to the unified protocol.Results A total of 261 893 nonduplicate strains were isolated from urine specimen from 2015 to 2021,of which gram-positive bacteria accounted for 23.8％(62 219/261 893),and gram-negative bacteria 76.2％(199 674/261 893).The most common species were E.coli(46.7％),E.faecium(10.4％),K.pneumoniae(9.8％),E.faecalis(8.7％),P.mirabilis(3.5％),P.aeruginosa(3.4％),SS.agalactiae(2.6％),and E.cloacae(2.1％).The strains were more frequently isolated from inpatients versus outpatients and emergency patients,from females versus males,and from adults versus children.The prevalence of ESBLs-producing strains in E.coli,K.pneumoniae and P.mirabilis was 53.2％,52.8％and 37.0％,respectively.The prevalence of carbapenem-resistant strains in E.coli,K.pneumoniae,P.aeruginosa and A.baumannii was 1.7％,18.5％,16.4％,and 40.3％,respectively.Lower than 10％of the E.faecalis isolates were resistant to ampicillin,nitrofurantoin,linezolid,vancomycin,teicoplanin and fosfomycin.More than 90％of the E.faecium isolates were ressitant to ampicillin,levofloxacin and erythromycin.The percentage of strains resistant to vancomycin,linezolid or teicoplanin was＜2％.The E.coli,K.pneumoniae,P.aeruginosa and A.baumannii strains isolated from ICU inpatients showed significantly higher resistance rates than the corresponding strains isolated from outpatients and non-ICU inpatients.Conclusions E.coli,Enterococcus and K.pneumoniae are the most common pathogens in urinary tract infection.The bacterial species and antimicrobial resistance of urinary isolates vary with different populations.More attention should be paid to antimicrobial resistance surveillance and reduce the irrational use of antimicrobial agents.