A pan-KRAS degrader for the treatment of KRAS-mutant cancers.

KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting "undruggable" proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

The semi-extended infrapatellar intramedullary nailing of distal tibia fractures: a randomized clinical trial.

BACKGROUND: Malalignment is a common event during the intramedullary nailing (IMN) of distal tibia fractures (DTFs). Although it is reported that the semi-extended IMN techniques such as suprapatellar (SP) and parapatellar (PP) approaches may be superior in preventing malalignment, the application of these techniques is concerning owing to the intra-articular involvement. We thus developed an extra-articular semi-extended infrapatellar (SEIP) approach which utilizes the infrapatellar (IP) space while maintaining the knee in a semi-extended position. However, there are no studies on the safety and efficacy of SEIP in treating DTFs. Therefore, in this study, the SEIP technique was examined, particularly in terms of the potential alignment improvement of DTFs, and this technique was compared with the traditional hyperflexed infrapatellar (HFIP) procedure. MATERIALS AND METHODS: This randomized clinical trial (RCT) compared IMN malalignment while correcting extraarticular and nondisplaced intra-articular DTFs between April 2018 and June 2021 using the HFIP and SEIP techniques at a level I trauma center in China. The study participants were clinically and radiographically examined for at least 12 months of follow-ups. Intraoperative fluoroscopy time, operation time, blood loss, hospitalization duration, functional ankle score, and complications were assessed as well. RESULTS: Among the 88 recruited participants, 45 (51%) underwent traditional HFIP IMN and 43 (49%) underwent SEIP IMN. Malalignment occurred in 9 patients (20.0%) from the HFIP cohort and in 2 patients (4.7%) from the SEIP cohort (P value = 0.030). In addition, the SEIP IMN technique significantly reduced the intraoperative fluoroscopy time, operation time, and improved the postoperative ankle function compared to the HFIP IMN technique. However, the intraoperative blood loss, hospitalization duration, infection, delay union, and nonunion remained the same between the two cohorts. CONCLUSIONS: In summary, we demonstrated that the SEIP IMN provides markedly enhanced alignment of extraarticular and nondisplaced intra-articular DTFs compared to the traditional HFIP IMN procedure. The described technique represents an effective option for IMN of DTFs. LEVEL OF EVIDENCE: Level 2. Trial registration The Chinese Clinical Trial Registry, ChiCTR2100043673. Registered 26 February 2021, retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=122263.

Removing a suprapatellar intramedullary nail via a suprapatellar approach: a retrospective cohort study.

BACKGROUND: Over the last 20 years, suprapatellar (SP) intramedullary nailing has gained considerable attention for treating tibia fractures and is believed to improve fracture alignments, decrease anterior knee pain, and facilitate intraoperative fluoroscopy. However, it is associated with various concerns, including the need to make another infrapatellar (IP) incision to remove the nail. AIMS: This study was aimed at developing a new technique for the removal of SP tibial nails through an SP approach using a cannulated extraction system. The efficiency of the novel SP approach was compared to that of the traditional IP approach for the removal of SP tibial nails. PATIENTS AND METHODS: This was a retrospective cohort study from a prospectively collected clinical registry. The data for 69 consecutive patients who received surgery to remove a previous SP intramedullary nail using an SP approach (n = 30, SP cohort) or an IP approach (n = 39, IP cohort) were analyzed. Intra-operative evaluations included intraoperative blood loss, operation time, and changes in the surgical procedures. At six months follow-up, post-operative Lysholm knee score, visual analog scale (VAS) score, and the active range of motion (ROM) of the affected knee and complications were assessed. RESULTS: Patients in the SP cohort exhibited an increased post-operative Lysholm knee score (ß, 2.6; 95% confidence interval [CI], 0.6 to 4.6; P = 0.012), decreased post-operative VAS score (ß, - 0.7; 95% CI, - 1.1 to - 0.2; P = 0.004), and increased operation time (ß, 9.8 minutes; 95% CI, 5.7 to 14.0 minutes; P < 0.001) compared with those treated with the IP approach after adjustment for baseline characteristics. There were no statistically significant differences in blood loss, post-operative ROM, or complications between the two cohorts. CONCLUSIONS: Compared with the IP technique, the SP approach for the removal of an SP tibial nail was independently associated with an increased post-operative Lysholm knee score and decreased VAS score, although the surgery was longer in duration. The novel technique offers a reliable and minimally invasive option for the removal of an SP tibial nail.

Comparison between infrapatellar and suprapatellar approaches for intramedullary nailing for the fractures of the tibial shaft.

INTRODUCTION: This study aimed to compare the outcomes at the clinical and functional levels of suprapatellar (SP) and infrapatellar (IP) approaches for intramedullary nailing in treating tibial shaft fracture. METHODS: Patients who underwent tibial shaft fracture intramedullary nailing by the SP approach or IP approach in a trauma center were retrospectively reviewed. The demographics, intraoperative fluoroscopy time, operation time, blood loss, irrigation volume, postoperative X-ray alignment, and complications of patients were compared between the two groups under different approaches. Lysholm knee score, visual analog score (VAS), and incidence of anterior knee pain (AKP) were assessed 1 year after surgery. RESULTS: The study finally included well-documented 81 patients (38 SP versus 43 IP). The SP group exhibited significantly shorter intraoperative fluoroscopy time than that of the IP group (81.7 ± 14.5 s vs. 122.0 ± 24.3 s, P < 0.001). Both aspects recorded a precise reduction of the fracture: angulation (2.1 ± 1.2° vs 3.1 ± 1.5°, P < 0.05) and translation (0.6 ± 0.8 mm vs 1.4 ± 1.5 mm, P < 0.05) in the coronal plane in the SP group. However, the sagittal plane recorded no such change (P > 0.05). The Lysholm knee score was higher in the SP group than that of the IP group (87 ± 8 vs. 80 ± 15, P < 0.05). The SP group displayed an evidently lower average VAS score than that of the IP approach group (0.3 ± 0.8 vs 1.3 ± 1.4, P < 0.001). Six cases (16%) in the SP group and 16 cases (37%) in the IP group experienced AKP 1-year post-operation (P < 0.05). As far as complications are concerned, neither group showed any significant difference (P > 0.05). CONCLUSION: Compared with the IP approach, the application of intramedullary nailing through the SP approach in treating tibial shaft fractures can effectively shorten the intraoperative fluoroscopy time, correct coronal plane angulation and translation deformity, reduce the incidence of AKP and improve postoperative function.

Development a multi-immunoaffinity column LC-MS-MS method for comprehensive investigation of mycotoxins contamination and co-occurrence in traditional Chinese medicinal materials.

Mycotoxins are poisonous secondary fungal toxic metabolites and harmful to human health. Traditional Chinese medicinal materials (TCMs), including more than two hundred functional foods, are vulnerably bred fungi, causing spoilage and multi-mycotoxins contamination. This study established a simultaneous analytical method by using multi-mycotoxins immunoaffinity column (multi-IAC) and HPLC-MS/MS to evaluate mycotoxins' contamination levels and natural incidence in TCMs. Aflatoxins (AFs, including AFB1, AFB2, AFG1 and AFG2), ochratoxin A (OTA), fumonisins (FB1 and FB2), zearalenone (ZEN), deoxynivalenol (DON) and T-2 toxins in three TCMs or functional foods of Polygalae Radix (PR), Coicis Semen (CS) and Eupolyphaga Steleophaga (ES) were detected. The systematically investigated results of 30 batch AFB1 positive samples revealed co-occurrence and correlation of multi-mycotoxins are significant differences in various matrices. All the samples in this study contain more than 5 mycotoxins. AFB1-AFs, AFB1-FBs, AFB1-DON, and AFB1-T-2 are the most observed co-occurrence, AFB1-OTA is also of concern due to its synergistic toxicity. This study's results can be used to establish guidelines for screening mycotoxin contaminants and limitations on acceptable levels in TCMs. Simultaneously, mycotoxin's correlation results in different matrices can also provide a reference for the standardization of TCM production and processing.

Semi-extended intramedullary nailing of the tibia using an infrapatellar approach: a retrospective cohort study.

PURPOSE: The semi-extended tibial intramedullary nailing method would enable easier and improved reductions for tibial fractures as well as facilitate fluoroscopic imaging; however, its in-articular nature remains controversial. The aim of this study was to compare the clinical and functional outcomes of the semi-extended infrapatellar (SEIP) approach and hyper-flexed infrapatellar (HFIP) approach for intramedullary nailing to treat tibial shaft fractures. METHODS: This study involved the retrospective analysis of the medical records of patients with tibial shaft fractures that were fixed through either the SEIP approach or the HFIP approach of intramedullary nailing and who were admitted to a level 1 trauma centre. The minimum patient follow-up period was 12 months and the clinical and functional outcomes were estimated at the 12-month visit. RESULTS: Of the 80 patients whose medical records were analyzed, 40 (50%) underwent SEIP nailing and the remaining 40 (50%) underwent the traditional HFIP nailing. Compared with the HFIP group, patients in the SEIP group had a higher Lysholm knee score (median, 92 [interquartile range, 88-95] vs median, 88 [interquartile range, 81-92]; p = .01), a shorter intra-operative fluoroscopy time (median, 93 [interquartile range, 78-105] s, vs median, 136 [interquartile range, 110-157] s; p < .001), and operation time (mean, 88.1 [SD, 17.8] min vs mean, 98.7 [SD, 19.3] min; p = .01). The VAS score was significantly lower in the SEIP group (median, 0; interquartile range, 0-0) than in the HFIP group (median, 0; interquartile range, 0-2) (p = .03). There were two cases (5%) in the SEIP group and 10 cases (25%) in the HFIP group of moderate AKP (p = .03). Meanwhile, there was no significant difference in malalignment, nonunion, delayed union, infection, and other complications, as well as SF-36 physical and mental scores. CONCLUSION: We found that the SEIP approach to tibia intramedullary nailing was superior to the HFIP approach based on the intra-operative and post-operative outcomes. Thus, this novel technique provides an infrapatellar option for semi-extended tibial nailing.

A comparison of the use of a suprapatellar Chinese Aircraft-shaped Sleeve System versus suprapatellar intramedullary nailing for tibial shaft fractures: Outcomes over a one-year follow-up.

INTRODUCTION: This study aimed to investigate the effectiveness and safety of the Chinese Aircraft-shaped Sleeve (CASS) system on the clinical outcomes of tibial intermedullary nailing using a suprapatellar approach for the treatment of tibial fractures in a cohort of adult Chinese patients over a minimum one-year follow-up. METHODS: After institutional review board approval, skeletally mature patients with Orthopaedic Trauma Association (OTA) type 42 tibial shaft fractures were randomized into either a SP approach using CASS group or a conventional SP approach group after informed consent was obtained. The operations were performed by a single senior orthopaedic surgeon according to group assignments. A group of 33 patients were treated using the CASS system and the other group of 34 patients were treated using a conventional SP approach. Both groups fully complied with research requirements and completed 12 months of follow-up. Magnetic resonance images (MRI) were obtained for the evaluation of the patellofemoral joint (PFJ) and residual debris preoperatively, as well as one week and 12 months postoperatively. Radiographs were used to assess alignment and union, visual analog scores (VAS) were used to assess anterior knee pain, and range of motion (ROM) and the Lysholm knee scoring scales were used for evaluating the operated knee at the 12-month follow-up. RESULTS: Differences in cartilage lesion changes observed by MRI between the two groups were statistically significant (P = 0.030 at 1 week postoperatively; P = 0.025 at 12 months postoperatively). No significant differences were evident with respect to debris residue, malalignments, nonunion, VAS, ROM and Lysholm knee scoring scale with the exception of stair climbing (P = 0.02). CONCLUSION: Based on the data of this one-year clinical follow-up study, the SP approach using the CASS system offers the potential to benefit patients suffering from tibial shaft fractures, who will be treated with intramedullary nailing especially for smaller patients.

Application of the Chinese Aircraft-shaped Sleeve system in the treatment of tibial shaft fractures using a suprapatellar approach for tibial intramedullary nailing: a randomised controlled trial.

BACKGROUND: The use of the suprapatellar approach for intramedullary nailing has recently become popular for the treatment of tibial fractures. This study aimed to investigate the effectiveness of using the Chinese Aircraft-shaped Sleeve (CASS) system on the clinical outcomes of tibial intermedullary nailing using a suprapatellar approach for the treatment of tibial fractures in a cohort of adult Chinese patients. METHODS: Magnetic resonance images (MRI) of the knee joints of 212 healthy adults with normal lower limb function from May 2011 to May 2015 were obtained from a level I Chinese regional trauma centre. Sixty inpatients at the same trauma centre who underwent treatment for tibial shaft fractures from June 2015 to June 2018 were enrolled. Tibial intramedullary nailing fixation of tibial shaft fractures via the suprapatellar approach was performed with either a CASS system or a conventional sleeve. The measurements of patellofemoral joint anatomy, the surgical time, the assessments of the patellofemoral joint cartilage conditions, and information of residual debris based on arthroscopic analysis were subsequently collected. RESULTS: The mean patellar angle (PA), sulcus angle (SA), sulcus width (SW) and sulcus depth (SD) were 135.40 ± 6.20°, 142.37 ± 5.33°, 33.37 ± 2.73 mm, and 4.29 ± 0.63 mm, respectively. The surgical time until entry reaming commencement and the irrigation time were significantly lower in the CASS group (P < 0.001). The difference in cartilage damage rate between groups was statistically significant (P = 0.031); the difference in residual debris conditions was not statistically significant (P = 0.1967). CONCLUSION: The use of the CASS system could improve clinical outcomes of intramedullary nailing via suprapatellar approach for patients with a small patellofemoral joint space.

Effects of arecoline and calcium ion on the permeability of dysplastic oral epithelia model in vitro / 口腔疾病防治

Objective @# To study the effects of arecolineand Calcium ion (Ca 2+) on the permeability of dysplastic oral epithelia model in vitro.@*Methods@#To establish the dysplastic oral epithelia model in vitro by culturing oral keratinocyte(DOK) and harvesting a DOK cell monolayer. The models were divided into control group, arecoline group and "Ca 2++ arecoline" group. The values of Lucifer Yellow Papp were used to estimate the permeability changes of models after treatedwith arecoline and Ca 2+. @*Results @# In arecoline group, the lucifer yellow Papp values of each subgroup were higher than that of control group (P < 0.05), and the values increased as arecoline concentration elevated and time lasted (P < 0.05). When the "Ca 2++ arecoline" group were pretreated with Ca 2+, the values of subgroup "10 μg/mL" was lower than that of the corresponding arecoline group (P > 0.05). However, the value of subgroup "4 h 10 μg/mL" of "Ca 2++ arecoline" group had no statistical difference with that of control group (P > 0.05), while the other subgroups were increased (P < 0.05); Besides, these values in "Ca 2++ arecoline" group were increased as the arecoline concentration elevated and time lasted too (P < 0.05).@*Conclusion@#Intervention of arecoline contributes to the increase of permeability of DOK cell monolayer model, which maybe an important reason for the cancerization of dysplastic oral epithelia, however Ca 2+might weaken these effects of arecoline in the process.

Involvement of the Hippo pathway in regeneration and fibrogenesis after ischaemic acute kidney injury: YAP is the key effector.

Renal tubule cells can recover after they undergo AKI (acute kidney injury). An incomplete repair of renal tubules can result in progressive fibrotic CKD (chronic kidney disease). Studies have revealed the relationship between tubular epithelial cells and kidney fibrogenesis. However, the underlying mechanism remains unclear. Hippo pathway components were evaluated in complete/incomplete repair of I/R (ischaemia/reperfusion) AKI rat models, HK-2 cells and AKI human renal biopsy samples. We found that the expression levels of the Hippo pathway components changed dynamically during kidney regeneration and fibrogenesis in rat models of I/R-induced AKI and human renal biopsy samples. The transcription cofactor YAP (Yes-associated protein) might be a key effector of renal regeneration and fibrogenesis. Our results showed further that YAP might elicit both beneficial and detrimental effects on I/R AKI. After I/R injury occurred, YAP could promote the repair of the injured epithelia. The constant YAP increase and activation might be related to interstitial fibrosis and abnormal renal tubule differentiation. These results indicate that the proper modulation of the Hippo pathway, specifically the transcription cofactor YAP, during repair might be a potent therapeutic target in AKI-CKD transition after I/R injury.

Betel-quid dependence and oral potentially malignant disorders in six Asian countries.

BACKGROUND: Despite gradual understanding of the multidimensional health consequences of betel-quid chewing, information on the effects of dependent use is scant. AIMS: To investigate the 12-month prevalence patterns of betel-quid dependence in six Asian populations and the impact of this dependence on oral potentially malignant disorders (OPMD). METHOD: A multistage random sample of 8922 participants was recruited from Taiwan, mainland China, Indonesia, Malaysia, Sri Lanka and Nepal. Participants were evaluated for betel-quid dependency using DSM-IV and ICD-10 criteria and assessed clinically for oral mucosal lesions. RESULTS: The 12-month prevalence of dependence was 2.8-39.2% across the six Asian samples, and 20.9-99.6% of those who chewed betel-quid were betel-quid dependent. Men dominated the prevalence among the east Asian samples and women dominated the prevalence in south-east Asian samples. 'Time spent chewing' and 'craving' were the central dependence domains endorsed by the Chinese and southern/south-east Asian samples respectively, whereas the Nepalese samples endorsed 'tolerance' and 'withdrawal'. Dependency was linked to age, gender, schooling years, drinking, smoking, tobacco-added betel-quid use and environmental accessibility of betel-quid. Compared with non-users, those with betel-quid dependency had higher pre-neoplastic risks (adjusted odds ratios 8.0-51.3) than people with non-dependent betel-quid use (adjusted odds ratio 4.5-5.9) in the six Asian populations. CONCLUSIONS: By elucidating differences in domain-level symptoms of betel-quid dependency and individual and environmental factors, this study draws attention to the population-level psychiatric problems of betel-quid chewing that undermine health consequences for OPMD in six Asian communities.

Betel-quid and oral submucous fibrosis: a cross-sectional study in Hunan province, China.

BACKGROUND: The development of betel-quid (BQ) processing industry in Hunan has increased the usage of this substance and may produce significant health consequences. However, the update data for the prevalence of BQ chewing and its effect on oral submucous fibrosis (OSF) are limited. METHODS: A population-based survey was conducted to investigate the prevalence of BQ chewing and OSF in Hunan. A questionnaire interview and an oral examination were conducted. A multivariate logistic regression model was used to study the effect of socio-demographic characteristics on area-specific behaviors of BQ chewing. RESULTS: A total of 2356 subjects participated in this survey, with a 78.5% of response rate. The lifetime prevalence of BQ chewing was 16.2% (2.9% for ex-chewers and 13.3% for current-chewers). The findings from multivariate logistic regression model showed that a higher prevalence of this habit was among individuals who were males, urban residents, 15-49 years old, educated for 9-12 years, smokers, and drinkers. Male chewers occupied a fairly higher percentage of the combined use of tobacco and/or alcohol (86.1-87.5%) than the non-chewers (50.6-56.7%). The overall prevalence of OSF was 1.0%. Compared with the subjects without OSF (1.7-23.2%), a significantly higher proportion of OSF patients were a current-chewer (62.3% in men and 100.0% in women). CONCLUSIONS: BQ chewing is a vital risk factor for OSF in Hunan. A high prevalence of BQ chewing found among the younger cohort (15-49 years old) is an urgent warning for this oral premalignant disorder.

(3R,6R,12R,20S,24R)-20,24-Ep-oxy-dammarane-3,6,12,25-tetra-ol.

In the title compound, C(30)H(52)O(5), the three six-membered rings are in chair conformations, the five-membered ring is in an envelope form and the tetra-hydro-furan ring has a conformation inter-mediate between half-chair and sofa. Intra-molecular O-H⋯O hydrogen bonds may influence the conformation of the mol-ecule. In the crystal, mol-ecules are linked by inter-molecular O-H⋯O hydrogen bonds, forming a three-dimensional network.

[Epidemiological study of betel nut chewing among elementary and middle school students in Loudi city, Hunan province].

OBJECTIVE: To investigate the prevalence of betel nut chewing and oral submucous fibrosis (OSF) among elementary and middle school students in Loudi city, Hunan province. METHODS: According to the standard of the third national oral health epidemiological investigation, the subjects were selected through a two-stage random sampling procedure. A face to face questionnaire survey was conducted among students by random sampling from 6 schools, and oral examination was performed to find the prevalence of OSF. RESULTS: Of the 4087 eligible students, 4019 students participated in the survey(98.3%). Among the 4019 students, there were 498 betel nut chewers, the prevalence of betel nut chewing was 12.4%, which was much higher in male than in female students (437/2073, 21.1% vs 61/1946, 3.1%, P < 0.05). The proportion of students who were chewing areca nuts increased with increasing grades (P < 0.05). The prevalence was highest in senior schools (229/1077, 21.3%)and lowest in elementary schools (126/1983, 6.4%). Most students who were chewing areca nuts in elementary school obtained betel nuts from their parents (61/126, 48.4%), but most middle school betel nut chewers obtained betel nuts from their friends (88/143, 61.5% and 165/229, 72.1%). Five OSF cases (0.12%) were diagnosed among the 4019 students, all of them were male senior school students. CONCLUSIONS: Betel nut chewing was common and OSF cases were found among elementary and middle school students in Loudi city. There were more male than female students who were chewing betel nut.

[Effect of arecoline on the differentiation of myofibroblasts of oral mucosa].

OBJECTIVE: To investigate the origin of myofibroblasts in oral submucous fibrosis. METHODS: The oral keratinocytes and fibroblasts were isolated and cultured. The expression of the alpha-smooth muscle actin in the fibroblasts was examined by immunohistochemistry and reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: No difference was found in expression of alpha-smooth muscle actin between the fibroblasts that were directly stimulated by arecoline and the control. The expression of alpha-smooth muscle actin in the keratinocyte and fibroblast-cocultured group was higher than in the control group, and higher in fibroblasts cocultured with keratinocytes preprocessed by arecoline than in fibroblasts cocultured with keratinocytes without preprocessed by arecoline. CONCLUSIONS: The differentiation of myofibroblasts from fibroblasts in oral submucous fibrosis might be induced by the interaction of arecoline and keratinocyte.