I2-DMSO-Mediated Construction of 2,3- and 2,4-Disubstituted Pyrimido[1,2-b]indazole Skeletons.

An efficient synthetic method for constructing 2,3- and 2,4-disubstituted pyrimidio[1,2-b]indazole skeletons through I2-DMSO-mediated and substrate-controlled regioselective [4 + 2] cyclization is reported. The reaction conditions are mild, its operation is simple, and the substrate scope is wide. More than 60 pyrimidio[1,2-b]indazole derivatives have been synthesized, providing a new methodology for constructing related molecules and potentially enriching bioactive-molecule libraries.

ROS downregulate TCA activity to modulate energy metabolism via the HIF/miR-34/ACS-PK pathway for lifespan extension in Helicoverpa armigera.

Previous studies have shown that high levels of reactive oxygen species (ROS) and low tricarboxylic acid (TCA) activity in the brain promote pupal diapause, which is characterized by metabolic depression and lifespan extension. However, it is unclear whether ROS are associated with TCA activity. In this study, we demonstrate that ROS downregulate TCA activity and acetyl-CoA and pyruvate levels in the brains of diapause-destined pupae in the moth Helicoverpa armigera, as well as the protein levels of acetyl-CoA synthetase (ACS) and pyruvate kinase (PK), two proteins involved in the biosynthesis of acetyl-CoA and pyruvate, respectively. Interestingly, miR-34, which is highly expressed in the brains of diapause-destined pupae, can respond to ROS signaling. Furthermore, we show that miR-34 can reduce the expression of ACS and PK by directly targeting their mRNAs. Additionally, hypoxia-inducible factor (HIF), a transcription factor, can be activated by ROS and then promotes miR-34 transcription by binding a cis-element in its promoter. Moreover, we observed delayed pupal development after treatment with a ROS activator paraquat and a HIF activator dimethyloxallyl glycine. Taken together, these results suggest that a novel pathway ROS/HIF/miR-34/ACS-PK was found to negatively regulate TCA activity to promote insect diapause for lifespan extension.

FoxO induces pupal diapause by decreasing TGFß signaling.

Diapause is a form of dormancy used widely by insects to survive adverse seasons. Previous studies have demonstrated that forkhead box O (FoxO) is activated during pupal diapause initiation in the moth Helicoverpa armigera. However, it is unclear how FoxO induces diapause. Here, we show that knockout of FoxO causes H. armigera diapause-destined pupae to channel into nondiapause, indicating that FoxO is a master regulator that induces insect diapause. FoxO activates the ubiquitin-proteasome system (UPS) by promoting ubiquitin c (Ubc) expression via directly binding to the Ubc promoter. Activated UPS decreases transforming growth factor beta (TGFß) receptor signaling via ubiquitination to block developmental signaling to induce diapause. This study significantly advances the understanding of insect diapause by uncovering the detailed molecular mechanism of FoxO.

CXCL9 Is a Potential Biomarker of Immune Infiltration Associated With Favorable Prognosis in ER-Negative Breast Cancer.

The chemokine CXCL9 (C-X-C motif chemokine ligand 9) has been reported to be required for antitumour immune responses following immune checkpoint blockade. In this study, we sought to investigate the potential value of CXCL9 according to immune responses in patients with breast cancer (BC). A variety of open-source databases and online tools were used to explore the expression features and prognostic significance of CXCL9 in BC and its correlation with immune-related biomarkers followed by subsequent verification with immunohistochemistry experiments. The CXCL9 mRNA level was found to be significantly higher in BC than in normal tissue and was associated with better survival outcomes in patients with ER-negative tumours. Moreover, CXCL9 is significantly correlated with immune cell infiltration and immune-related biomarkers, including CTLA4, GZMB, LAG3, PDCD1 and HAVCR2. Finally, we performed immunohistochemistry with breast cancer tissue samples and observed that CXCL9 is highly expressed in the ER-negative subgroup and positively correlated with the immune-related factors LAG3, PD1, PDL1 and CTLA4 to varying degrees. These findings suggest that CXCL9 is an underlying biomarker for predicting the status of immune infiltration in ER-negative breast cancer.

A Comparative Study of Intramedullary Nail Strengthened with Auxiliary Locking Plate or Steel Wire in the Treatment of Unstable Trochanteric Fracture of Femur.

OBJECTIVE: To compare the clinical outcomes of unstable femoral trochanteric fracture treated by proximal femoral intramedullary nail enhanced with lateral locking plate versus cerclage steel wire. METHODS: A retrospective study was conducted on 83 patients who received open reduction and internal fixation with proximal femoral intramedullary nail combined with lateral enhanced fixations for unstable femoral trochanteric fractures from March 2015 to January 2017 in our hospital. Of these patients, 39 received the lateral enhanced fixation with locking plate, while the remaining 44 had cerclage wire as additional fixation. The clinical data were compared between the two groups. RESULTS: All the patients in the study had surgical procedures performed smoothly. Although the plate group had significantly longer operation times and significantly higher hospitalization expenses than the wire group (P < 0.05), no statistically significant differences in intraoperative blood loss and hospital stay were proved between the groups (P > 0.05). The follow-up period lasted for 12-24 months with an average of (16.81 ± 2.92) months. The plate group returned to full-weight bearing significantly earlier than the wire group (P < 0.05). The Harris Hip Score (HHS) significantly increased in both groups over time postoperatively (P < 0.05). The plate group achieved a higher HHS than the wire group, which was statistically significant at 3 months (P < 0.05), whereas it became insignificant at 6 and 12 months postoperatively (P > 0.05). Regarding radiographic assessment, an excellent rate of fracture reduction was proved in 71.79% of the plate group, compared to 45.45% of the wire group, which was statistically significant (P < 0.05). In addition, fracture healing was achieved significantly earlier in the plate group than the wire group (P < 0.05); nevertheless, no statistically significant difference was noted in neck-shaft angle at the latest follow-up between the two groups (P > 0.05). At the latest follow-up, two cases of implant loosening and two cases of coxa varus were found in the plate group, while one case of femoral head necrosis and three cases of coxa varus were revealed by radiographs in the wire group. CONCLUSION: The cerclage wire has benefits of saving time and operation costs; however, the locking plate has the advantages of improving fracture reduction quality, shortening time to full weight bearing and fracture healing, and improving hip function recovery due to the lateral additional fixations to proximal femoral intramedullary nail for unstable trochanteric fractures.

SuperPATH Minimally Invasive Approach to Total Hip Arthroplasty of Femoral Neck Fractures in the Elderly: Preliminary Clinical Results.

OBJECTIVE: To investigate the clinical efficacy and advantages of the SuperPATH minimally invasive approach to total hip arthroplasty in the treatment of femoral neck fractures in the elderly. METHODS: From January 2016 to September 2018, 110 cases of elderly patients with femoral neck fractures were included in the present study. According to the method of operation, the patients were divided into two groups for comparison. There were 55 cases of the SuperPATH minimally invasive approach to total hip arthroplasty and 55 cases with the conventional posterolateral approach to total hip arthroplasty. The operation time, the length of incision, the amount of operative blood loss, the hospitalization time, and the hospitalization cost were compared between the two groups. The position of total hip prosthesis was observed during the follow-up period. All patients were evaluated for the degree of hip joint pain and the function of the hip joint using the visual analog score (VAS) and the Harris score at 1 week, 1 month, 3 months, 6 months, and 12 months after the operation. RESULTS: All patients were followed up for at least 12 months. The operation time was 108.58 ± 15.87 min in the SuperPATH group and 102.51 ± 19.61 min in the conventional group. The length of incision was 6.65 ± 1.53 cm in the SuperPATH group and 17.08 ± 1.40 cm in the conventional group. The amount of operative blood loss was 147.51 ± 28.84 mL in the SuperPATH group and 170.22 ± 25.34 mL in the conventional group. The hospitalization time was 10.05 ± 2.52 days in the SuperPATH group and 13.36 ± 3.39 days in the conventional group. The hospitalization cost was 6871.78 ± 141.63 dollars in the SuperPATH group and 7791.09 ± 184.88 dollars in the conventional group. Compared with the conventional group, the SuperPATH group had shorter incision length, less blood loss, shorter hospitalization time, and lower hospitalization cost. There was significant difference between the two groups (P < 0.05). In the two groups, there were no complications such as infection, lower extremity venous thrombosis, prosthesis loosening, periprosthetic fracture, and dislocation during the follow-up period. The VAS score was 4.45 ± 0.94 in the SuperPATH group and 4.89 ± 0.79 in the conventional group at 1 week after the operation. There was significant difference between the two groups (P < 0.05). The Harris score was 75.36 ± 3.36 and 80.25 ± 3.09 in the SuperPATH group and 68.80 ± 3.25 and 77.35 ± 3.77 in the conventional group at 1 week and 1 month after the operation, respectively. There was significant difference between the two groups (P < 0.05). In the analysis of the operation time, the VAS score at 1 month, 3 months, 6 months, and 12 months after the operation, and the Harris score at 3 months, 6 months, and 12 months after surgery, there was no significant difference between the two groups (P > 0.05). CONCLUSION: The SuperPATH minimally invasive approach to total hip arthroplasty is an ideal method for the treatment of femoral neck fractures in the elderly. This method has the advantages of the relatively simple operation, short incision, less blood loss, and less trauma. The patients had short hospitalization times, low hospitalization costs, and good recovery of hip joint function.

Regional Injury Classification and Treatment of Open Pelvic Fractures.

OBJECTIVES: To propose the regional injury classification of open pelvic fracture and summarize the characteristics of its treatment. METHODS: Clinical data for 67 open pelvic fractures treated from January 2001 to December 2017 were retrospectively analyzed. There were 48 male and 19 female patients. The patients were aged from 12 to 68 years old, and their pelvic fractures were categorized according to Tile classification (type A: 23 cases; type B: 19 cases; type C: 25 cases). Main injury distribution: pubic perineum, 29 cases; ilioinguinal, 20 cases; and sacroiliac, 7 cases. There were 5 cases of ilioinguinal-perineum and 6 cases of sacroiliac-perineum injury. Based on the region of the injury, the mortality and combined injury of each group were observed. The relationship between regional injury groups and death was examined. RESULTS: Following active treatment, 28 patients died. The mortality rate was 41.8% (28/67), with 39 patients surviving. The average follow-up time was 6 months (3 months to 1 year after discharge). Majeed pelvic fracture score: the score was excellent in 12 cases, good in 14 cases, fair in 9 cases, and poor in 4 cases; there was an excellent and good rate of 66.7%. Open pelvic fracture regional injury classification includes: the perineal type (type I); the ilioinguinal type (type II); the sacroiliac type (type III); and the composite type (type IV). All types were independent of each other, and the mortality of open pelvic fractures was positively correlated with this classification, with a correlation coefficient of 0.620 (P = 0.001 < 0.05; the difference was statistically significant). In this study, cystourethral injury, anorectal injury, and infection were the main combined injuries of type I. The type II and III injuries were mainly iliac vascular injuries. The main combined injuries of type IV were infection, injury of ilium vessels and its branches. There was a statistical difference among the combined injuries of each subtype (P = 0.001 < 0.05). CONCLUSIONS: The criteria for regional classification were clear, the mortality of the four subtypes increased gradually, and the incidence of combined injury of each subtype varied. Each subtype had different therapeutic characteristics.

In Situ Reduction and Fixation of the Anterior Medial Fenestration Approach for Femoral Head Fracture.

OBJECTIVE: To investigate the feasibility and clinical application of the anterior medial fenestration approach in the treatment of Pipkin type I and II femoral head fractures. METHODS: The hips of two anti-corrosion adult specimens treated with formalin were dissected and the anatomical structures and directional characteristics of the anterior medial main muscles, ligaments, blood vessels, and nerves were observed. The anterior medial fenestration approach was performed on bilateral hips of four fresh frozen specimens to determine the required pulling direction of the stripped muscles and ligaments during surgery. In addition, the vascular and nerve traction protection directions exposed in the approach were observed and analyzed. The feasibility of this approach was assessed, and the operative approach and critical anatomical depth were measured. We retrospectively analyzed 12 patients with Pipkin type I and II femoral head fractures who underwent in situ reduction and fixation by anterior medial fenestration in our hospital from February 2016 to April 2018. The study group included 3 men and 9 women aged 37-59 years (mean, 48.50 years). There were 8 cases of Pipkin type I and 4 cases of Pipkin type II. The operation time, blood loss, fracture healing time, last Thompson-Epstein evaluation, and Harris score were recorded. RESULTS: A total of 8 fresh frozen specimens from 4 bilateral hips were exposed by anterior medial fenestration. The upper boundary of observation fenestration was the pubic body (anterior acetabulum), and the outer upper boundary was the iliacus and the psoas muscle. The lateral boundary was the rectus femoris and the femoral vessels, while the lower boundary was the transverse branch of the medial femoral circumflex artery and vein. The medial boundary was the pubis muscle, the short adductor muscle, and the long adductor muscle. The pubofemoral and iliofemoral ligaments were observed during fenestration. By cutting open the joint capsule and moving the hip joint, the four quadrants of the femoral head can be exposed. Twelve patients with femoral head fractures who were treated with anterior medial fenestration underwent in situ reduction and fixation. The operation time was 96.25-118.75 min (median, 100 min), and the blood loss was 115.00 ± 22.76 mL. The follow-up time was 18.58 ± 4.48 months, and the fracture healing time was 144.17 ± 14.53 days. The last Thompson-Epstein evaluation was excellent in 6 cases, good in 4 cases, and fair in 2 cases; the excellent and good rate was 83.33%. Finally, the last Harris score was 85.08 ± 5.73 points. CONCLUSIONS: The upper and lower boundaries, inner and outer boundaries, and rear anatomical structure of the anterior medial fenestration approach were defined. The movable hip joint can expose the four quadrants in front of the femoral head in this fenestration. Anterior medial fenestration in situ reduction and fixation surgery is feasible and safe for the treatment of Pipkin type I and II femoral head fractures.