Systemic Inflammatory Markers and Clinical Outcomes of Open versus Biportal Endoscopic Transforaminal Lumbar Interbody Fusion.

Purpose: The purpose of this study is to preliminarily assess the change in perioperative systemic inflammatory markers and clinical outcomes between open TLIF and BE-TLIF procedures. Patients and Methods: In total, 38 patients who underwent single-level lumbar fusion surgery (L4-5 or L5-S1) were retrospectively reviewed. 19 patients were treated by the BE-TLIF technique, while the other patients were managed using open TLIF. The perioperative serum C-reactive protein (CRP), neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), and platelet/lymphocyte ratio (PLR) of the two groups were compared to determine if there was a statistical difference. Meanwhile, clinical evaluations were conducted to assess various factors including operative duration, estimated blood loss (EBL), drainage catheter stay, length of hospitalization, visual analogue scale (VAS), and Oswestry disability index (ODI) scores. Results: The perioperative analysis revealed that BE-TLIF cases experienced a longer operative duration than open TLIF cases (open TLIF: 138.63 ± 31.59 min, BE-TLIF: 204.58 ± 49.37 min, p < 0.001). Meanwhile, the EBL showed an increased trend in the BE-TLIF group (260.7 ± 211.9 mL) in comparison with the open TLIF group (200.9 ± 211.9 mL) (p =0.485). In terms of systemic inflammatory markers, the mean postoperative CRP, NLR, LMR, and PLR were lower in the BE-TLIF group than in the open TLIF group, although these differences were not statistically significant (p > 0.05). The VAS and ODI scores in both groups were significantly improved after surgery (p < 0.05). Conclusion: There was no significant difference found between BE-TLIF and open TLIF in terms of systemic inflammatory markers, and clinical outcomes. Overall, BE-TLIF can be considered a viable choice for lumbar canal decompression and interbody fusion for less invasion. It is worth noting that BE-TLIF does have a longer operation time, indicating that there is still potential for further improvement in this technique.

PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes.

The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies.

HBV integrations reshaping genomic structures promote hepatocellular carcinoma.

OBJECTIVE: Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), mostly characterised by HBV integrations, is prevalent worldwide. Previous HBV studies mainly focused on a few hotspot integrations. However, the oncogenic role of the other HBV integrations remains unclear. This study aimed to elucidate HBV integration-induced tumourigenesis further. DESIGN: Here, we illuminated the genomic structures encompassing HBV integrations in 124 HCCs across ages using whole genome sequencing and Nanopore long reads. We classified a repertoire of integration patterns featured by complex genomic rearrangement. We also conducted a clustered regularly interspaced short palindromic repeat (CRISPR)-based gain-of-function genetic screen in mouse hepatocytes. We individually activated each candidate gene in the mouse model to uncover HBV integration-mediated oncogenic aberration that elicits tumourigenesis in mice. RESULTS: These HBV-mediated rearrangements are significantly enriched in a bridge-fusion-bridge pattern and interchromosomal translocations, and frequently led to a wide range of aberrations including driver copy number variations in chr 4q, 5p (TERT), 6q, 8p, 16q, 9p (CDKN2A/B), 17p (TP53) and 13q (RB1), and particularly, ultra-early amplifications in chr8q. Integrated HBV frequently contains complex structures correlated with the translocation distance. Paired breakpoints within each integration event usually exhibit different microhomology, likely mediated by different DNA repair mechanisms. HBV-mediated rearrangements significantly correlated with young age, higher HBV DNA level and TP53 mutations but were less prevalent in the patients subjected to prior antiviral therapies. Finally, we recapitulated the TONSL and TMEM65 amplification in chr8q led by HBV integration using CRISPR/Cas9 editing and demonstrated their tumourigenic potentials. CONCLUSION: HBV integrations extensively reshape genomic structures and promote hepatocarcinogenesis (graphical abstract), which may occur early in a patient's life.

Overlapping lockup lymphaticovenous anastomosis: A useful addition to supermicrosurgery.

BACKGROUND: Lymphaticovenular anastomosis (LVA) is a minimally invasive surgical procedure used to treat lymphedema. This surgical procedure connects the superficial lymphatic vessels to nearby veins to establish lymphatic-venous pathways. One of the most common challenges encountered by lymphatic surgeons when performing LVA is a mismatch in the sizes of the veins and lymphatic vessels, with the effectiveness limited by technical constraints. We conducted a pilot study to evaluate the feasibility of an overlapping lockup anastomosis (OLA) LVA technique to address these problems. METHODS: In this study, we present a novel OLA technique for LVA that addresses the challenges with conventional techniques. The OLA technique was used in 10 lymphedema patients between September 2022 and March 2023 to compare OLA and end-to-end anastomosis. The time required for anastomosis, method of anastomosis, patency rates, and lymphedema volume were evaluated in this study. RESULTS: Of 123 LVAs, 44 were performed using the OLA technique in 10 patients, with indocyanine green lymphangiography revealing unobstructed drainage. A single case of slight fluid leakage occurred, which was resolved by reinforcing the sutures. The average anastomosis time for OLA and the end-to-end technique was 5.55 minutes and 12.1 minutes, respectively. The wounds of the patients healed without infection, and the subjective limb circumference decreased. CONCLUSIONS: The OLA technique could serve as a valuable addition to the current LVA technique, especially for cases with a mismatch in the sizes of the lymphatic vessels and veins. This technique has the potential to promote the broader application of LVA in the treatment and prevention of lymphedema.

YWK-II/APLP2 inhibits TGF-ß signaling by interfering with the TGFBR2-Hsp90 interaction.

Transforming growth factor-ß (TGF-ß) regulates multiple cellular biological processes by activating TGF-ß type I receptors (TGFBR1) and type II receptors (TGFBR2), and Hsp90 stabilizes these receptors through specific interactions. In many malignancies, one of the most deregulated signaling pathways is the TGF-ß signaling pathway, which is often inactivated by mutations or deregulation of TGF-ß type II receptors (TGFBR2). However, the molecular mechanisms are not well understood. In this study, we show that YWK-II/APLP2, an immediately early response gene for TGF-ß signaling, inhibits TGF-ß signaling by promoting the degradation of the TGFBR2 protein. Knockdown of YWK-II/APLP2 increases the TGFBR2 protein level and sensitizes cells to TGF-ß stimulation, while YWK-II/APLP2 overexpression destabilizes TGFBR2 and desensitizes cells to TGF-ß. Mechanistically, YWK-II/APLP2 is associated with TGFBR2 in a TGF-ß activity-dependent manner, binds to Hsp90 to interfere with the interaction between TGFBR2 and Hsp90, and leads to enhanced ubiquitination and degradation of TGFBR2. Taken together, YWK-II/APLP2 is involved in negatively regulating the duration and intensity of TGF-ß/Smad signaling and suggests that aberrantly high expression of YWK-II/APLP2 in malignancies may antagonize the growth inhibition mediated by TGF-ß signaling and play a role in carcinogenesis.

Kinome-wide CRISPR-Cas9 knockout screens revealed PLK1 as a therapeutic target for osteosarcoma.

Osteosarcoma is the most common malignant bone tumor, tending to be aggressive and recurrent. The therapeutic development for treating osteosarcoma has been largely hampered by the lack of effective and specific targets. Using kinome-wide CRISPR-Cas9 knockout screens, we systematically revealed a cohort of kinases essential for the survival and growth of human osteosarcoma cells, in which Polo-like kinase 1 (PLK1) appeared as a specific prominent hit. PLK1 knockout substantially inhibited proliferation of osteosarcoma cells in vitro and the tumor growth of osteosarcoma xenograft in vivo. Volasertib, a potent experimental PLK1 inhibitor, can effectively inhibit the growth of the osteosarcoma cell lines in vitro. It can also disrupt the development of tumors in the patient-derived xenograft (PDX) models in vivo. Furthermore, we confirmed that the mode of action (MoA) of volasertib is primarily mediated by the cell-cycle arrest and apoptosis triggered by DNA damage. As PLK1 inhibitors are entering phase III clinical trials, our findings provide important insights into the efficacy and MoA of the relevant therapeutic approach for combating osteosarcoma.

Arthroscopic reconstruction of the medial patellofemoral ligament in skeletally immature patients using the modified sling procedure: a novel technique for MPFL reconstruction.

BACKGROUND: Patellar dislocation is common in young people. Although isolated anatomic double-bundle reconstruction of the MPFL is a common and effective surgical treatment for patellofemoral instability, concerns about the risk of injury to the epiphysis remain. METHODS: A total of 21 children and adolescents (9 males, 12 females; mean age: 10.7 years; range: 8 to 13 years) with recurrent patella dislocation or symptomatic instability following a primary dislocation were enrolled in the study. In all patients, double-bundle medial patellofemoral ligament (MPFL) reconstruction and femoral sling procedure were performed under arthroscopy, using an anterior half peroneus longus tendon (AHPLT) autograft. Functional outcomes were evaluated preoperatively and during follow-ups based on Kujala and Lysholm scores. Radiological examinations including radiographs, 3D-CT, and MRI were performed pre- and post-operatively. RESULTS: Among two-year postoperative follow-up (range: 24-42 months) showed significant improvement in functional scores (p < 0.01). The Lysholm score increased from 68 (44.5) to 100 (0) and the Kujala score increased from 26 (34.5) to 100 (2) The patellar tilt angel improved significantly (p < 0.01) from 24.3° ± 10.4 preoperatively to 11.9° ± 7.0 postoperatively. MRIs performed 6- and 12-months post operation did not show any signs of dysfunction of the reconstructed MPFL or cartilage degeneration. STUDY DESIGN: Case Series; Level of evidence, 4. CONCLUSION: Arthroscopic reconstruction of the MPFL using the modified sling procedure is an effective procedure for the treatment of patellar instability in skeletally immature patients.

Combining single-cell transcriptomics and CellTagging to identify differentiation trajectories of human adipose-derived mesenchymal stem cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) have attracted great attention in the application of cell-based therapy because of their pluripotent differentiation and immunomodulatory ability. Due to the limited number of MSCs isolated from donor tissues, a large number of MSCs need to be expanded in a traditional two-dimensional cell culture device to obtain a sufficient therapeutic amount. However, long-term cultivation of MSCs in vitro has been proven to reduce their differentiation potential and change their immunomodulatory characteristics. We aimed to explore the cellular heterogeneity and differentiation potential of different MSCs expanded in vitro and reconstruct the complex cloning track of cells in the process of differentiation. METHODS: Single cell transcriptome sequencing was combined with 'CellTagging', which is a composite barcode indexing method that can capture the cloning history and cell identity in parallel to track the differentiation process of the same cell over time. RESULTS: Through the single-cell transcriptome and CellTagging, we found that the heterogeneity of human adipose tissue derived stem cells (hADSCs) in the early stage of culture was very limited. With the passage, the cells spontaneously differentiated during the process of division and proliferation, and the heterogeneity of the cells increased. By tracing the differentiation track of cells, we found most cells have the potential for multidirectional differentiation, while a few cells have the potential for unidirectional differentiation. One subpopulation of hADSCs with the specific osteoblast differentiation potential was traced from the early stage to the late stage, which indicates that the differentiation trajectories of the cells are determined in the early stages of lineage transformation. Further, considering that all genes related to osteogenic differentiation have not yet been determined, we identified that there are some genes that are highly expressed specifically in the hADSC subsets that can successfully differentiate into osteoblasts, such as Serpin Family E Member 2 (SERPINE2), Secreted Frizzled Related Protein 1 (SFRP1), Keratin 7 (KRT7), Peptidase Inhibitor 16 (PI16), and Carboxypeptidase E (CPE), which may be key regulatory genes for osteogenic induction, and finally proved that the SERPINE2 gene can promote the osteogenic process. CONCLUSION: The results of this study contribute toward the exploration of the heterogeneity of hADSCs and improving our understanding of the influence of heterogeneity on the differentiation potential of cells. Through this study, we found that the SERPINE2 gene plays a decisive role in the osteogenic differentiation of hADSCs, which lays a foundation for establishing a more novel and complete induction system.

[Kirschner wire retractor-assisted reduction and inverted insertion of elastic nail in the treatment of children's irreducible subradial 1/3 fractures].

OBJECTIVE: To explore the clinical effect of Kirschner wire retractor-assisted reduction and inverted insertion of elastic nail in the treatment of children's irreducible subradial 1/3 fractures. METHODS: A total of 34 children with irreducible subradial 1/3 fractures treated by surgery from August 2016 to December 2020 were retrospective analyzed. Among them, 16 cases underwent Kirschner wire retractor-assisted closed reduction and percutaneous elastic intramedullary nailing with inverted insertion(observation group), 10 males and 6 females, aged from 4 to 10 years old with an average of(6.0±0.4)years;18 cases underwent open reduction and plate internal fixation (control group), 11 males and 7 females, the age from 3 to 10 years with an average of(7.0±0.5) years. The operation time, intraoperative blood loss, hospital stay, incision length, fracture healing time and complications of the two groups were observed and the wrist function was evaluated by Cooney wrist joint score. RESULTS: All patients were followed up for 3-12 years old with an average of (11.40±0.48) months in the observation group and 4-13 months with an average of (11.50±0.39) months in the control group. Bone healing was achieved in all patients, and there was no incision infection in both groups. The operation time, intraoperative blood loss, hospital stay and incision length in observation groups were lower than those of control group (P<0.05). There was no significant difference in the fracture healing time between two groups(P>0.05). There was no significant difference in postoperative healing and recovery of wrist function between groups(P>0.05). CONCLUSION: Compared with open reduction and plate internal fixation, Kirschner wire retractor-assisted reduction and percutaneous elastic intramedullary nail fixation for irreducible subradial radial 1/3 fractures has the advantages of less trauma, shorter operation time, less blood loss, and satisfactory short-term clinical results.

METTL3 preferentially enhances non-m6A translation of epigenetic factors and promotes tumourigenesis.

METTL3 encodes the predominant catalytic enzyme to promote m6A methylation in nucleus. Recently, accumulating evidence has shown the expression of METTL3 in cytoplasm, but its function is not fully understood. Here we demonstrated an m6A-independent mechanism for METTL3 to promote tumour progression. In gastric cancer, METTL3 could not only facilitate cancer progression via m6A modification, but also bind to numerous non-m6A-modified mRNAs, suggesting an unexpected role of METTL3. Mechanistically, cytoplasm-anchored METTL3 interacted with PABPC1 to stabilize its association with cap-binding complex eIF4F, which preferentially promoted the translation of epigenetic factors without m6A modification. Clinical investigation showed that cytoplasmic distributed METTL3 was highly correlated with gastric cancer progression, and this finding could be expanded to prostate cancer. Therefore, the cytoplasmic METTL3 enhances the translation of epigenetic mRNAs, thus serving as an oncogenic driver in cancer progression, and METTL3 subcellular distribution can assist diagnosis and predict prognosis for patients with cancer.

Perioperative Protocol of Ankle Fracture and Distal Radius Fracture Based on Enhanced Recovery after Surgery Program: A Multicenter Prospective Clinical Controlled study.

Background: The enhanced recovery after surgery (ERAS) program is aimed to shorten patients' recovery process and improve clinical outcomes. This study aimed to compare the outcomes between the ERAS program and the traditional pathway among patients with ankle fracture and distal radius fracture. Methods: This is a multicenter prospective clinical controlled study consisting of 323 consecutive adults with ankle fracture from 12 centers and 323 consecutive adults with distal radial fracture from 13 centers scheduled for open reduction and internal fixation between January 2017 and December 2018. According to the perioperative protocol, patients were divided into two groups: the ERAS group and the traditional group. The primary outcome was the patients' satisfaction of the whole treatment on discharge and at 6 months postoperatively. The secondary outcomes include delapsed time between admission and surgery, length of hospital stay, postoperative complications, functional score, and the MOS item short form health survey-36. Results: Data describing 772 patients with ankle fracture and 658 patients with distal radius fracture were collected, of which 323 patients with ankle fracture and 323 patients with distal radial fracture were included for analysis. The patients in the ERAS group showed higher satisfaction levels on discharge and at 6 months postoperatively than in the traditional group (P < 0.001). In the subgroup analysis, patients with distal radial fracture in the ERAS group were more satisfied with the treatment (P=0.001). Furthermore, patients with ankle fracture had less time in bed (P < 0.001) and shorter hospital stay (P < 0.001) and patients with distal radial fracture received surgery quickly after being admitted into the ward in the ERAS group than in the traditional group (P=0.001). Conclusions: Perioperative protocol based on the ERAS program was associated with high satisfaction levels, less time in bed, and short hospital stay without increased complication rate and decreased functional outcomes.

RING finger 138 deregulation distorts NF-кB signaling and facilities colitis switch to aggressive malignancy.

Prolonged activation of nuclear factor (NF)-кB signaling significantly contributes to the development of colorectal cancer (CRC). New therapeutic opportunities are emerging from targeting this distorted cell signaling transduction. Here, we discovered the critical role of RING finger 138 (RNF138) in CRC tumorigenesis through regulating the NF-кB signaling, which is independent of its Ubiquitin-E3 ligase activity involved in DNA damage response. RNF138-/- mice were hyper-susceptible to the switch from colitis to aggressive malignancy, which coincided with sustained aberrant NF-кB signaling in the colonic cells. Furthermore, RNF138 suppresses the activation of NF-кB signaling pathway through preventing the translocation of NIK and IKK-Beta Binding Protein (NIBP) to the cytoplasm, which requires the ubiquitin interaction motif (UIM) domain. More importantly, we uncovered a significant correlation between poor prognosis and the downregulation of RNF138 associated with reinforced NF-кB signaling in clinical settings, raising the possibility of RNF138 dysregulation as an indicator for the therapeutic intervention targeting NF-кB signaling. Using the xenograft models built upon either RNF138-dificient CRC cells or the cells derived from the RNF138-dysregulated CRC patients, we demonstrated that the inhibition of NF-кB signaling effectively hampered tumor growth. Overall, our work defined the pathogenic role of aberrant NF-кB signaling due to RNF138 downregulation in the cascade events from the colitis switch to colonic neoplastic transformation and progression, and also highlights the possibility of targeting the NF-кB signaling in treating specific subtypes of CRC indicated by RNF138-ablation.

AHR mediates the aflatoxin B1 toxicity associated with hepatocellular carcinoma.

Aflatoxin exposure is a crucial factor in promoting the development of primary hepatocellular carcinoma (HCC) in individuals infected with the hepatitis virus. However, the molecular pathways leading to its bioactivation and subsequent toxicity in hepatocytes have not been well-defined. Here, we carried out a genome-wide CRISPR-Cas9 genetic screen to identify aflatoxin B1 (AFB1) targets. Among the most significant hits was the aryl hydrocarbon receptor (AHR), a ligand-binding transcription factor regulating cell metabolism, differentiation, and immunity. AHR-deficient cells tolerated high concentrations of AFB1, in which AFB1 adduct formation was significantly decreased. AFB1 triggered AHR nuclear translocation by directly binding to its N-terminus. Furthermore, AHR mediated the expression of P450 induced by AFB1. AHR expression was also elevated in primary tumor sections obtained from AFB1-HCC patients, which paralleled the upregulation of PD-L1, a clinically relevant immune regulator. Finally, anti-PD-L1 therapy exhibited greater efficacy in HCC xenografts derived from cells with ectopic expression of AHR. These results demonstrated that AHR was required for the AFB1 toxicity associated with HCC, and implicate the immunosuppressive regimen of anti-PD-L1 as a therapeutic option for the treatment of AFB1-associated HCCs.

Identification of pathogenic variants in cancer genes using base editing screens with editing efficiency correction.

BACKGROUND: Millions of nucleotide variants are identified through cancer genome sequencing and it is clinically important to identify the pathogenic variants among them. By introducing base substitutions at guide RNA target regions in the genome, CRISPR-Cas9-based base editors provide the possibility for evaluating a large number of variants in their genomic context. However, the variability in editing efficiency and the complexity of outcome mapping are two existing problems for assigning guide RNA effects to variants in base editing screens. RESULTS: To improve the identification of pathogenic variants, we develop a framework to combine base editing screens with sgRNA efficiency and outcome mapping. We apply the method to evaluate more than 9000 variants across all the exons of BRCA1 and BRCA2 genes. Our efficiency-corrected scoring model identifies 910 loss-of-function variants for BRCA1/2, including 151 variants in the noncoding part of the genes such as the 5' untranslated regions. Many of them are identified in cancer patients and are reported as "benign/likely benign" or "variants of uncertain significance" by clinicians. Our data suggest a need to re-evaluate their clinical significance, which may be helpful for risk assessment and treatment of breast and ovarian cancer. CONCLUSIONS: Our results suggest that base editing screens with efficiency correction is a powerful strategy to identify pathogenic variants in a high-throughput manner. Applying this strategy to assess variants in both coding and noncoding regions of the genome could have a direct impact on the interpretation of cancer variants.

A CRISPR knockout negative screen reveals synergy between CDKs inhibitor and metformin in the treatment of human cancer in vitro and in vivo.

Laboratory research and pharmacoepidemiology provide support for metformin as a potential antitumor agent. However, the lack of a clear understanding of the indications of metformin limits its efficacy. Here, we performed a genome-wide CRISPR knockout negative screen to identify potential targets that might synergize with metformin. Next-generation sequencing of pooled genomic DNAs isolated from surviving cells after 18 days of metformin treatment (T18) compared to those of the untreated cells at day 0 (T0) yielded candidate genes. Knockdown of a group of cyclin-dependent kinases (CDKs), including CDK1, CDK4, and CDK6, confirmed the results of the screen. Combination treatment of the CDKs inhibitor abemaciclib with metformin profoundly inhibited tumor viability in vitro and in vivo. Although cell cycle parameters were not further altered under the combination treatment, investigation of the metabolome revealed significant changes in cell metabolism, especially with regard to fatty acid oxidation, the tricarboxylic acid cycle and aspartate metabolism. Such changes appeared to be mediated through inhibition of the mTOR pathway. Collectively, our study suggests that the combination of CDKs inhibitor with metformin could be recognized as a potential therapy in future clinical applications.

Global changes in chromatin accessibility and transcription following ATRX inactivation in human cancer cells.

α-Tthalassemia mental retardation X-linked (ATRX) is a chromatin remodeler frequently mutated in many cancers. Despite the binding pattern of ATRX in heterochromatin, ATRX-mediated epigenomic changes in cancer cells have not been profiled, especially for the heterochromatin regions. Here, we profiled genome-wide maps of chromatin accessibility in ATRX-intact and ATRX-null human cancer cells. We found extensive changes in chromatin accessibility in both repetitive DNA regions and non-repetitive regulatory regions following ATRX loss. These changes are highly correlated with changes in transcription, which lead to alterations in cancer-related signalling pathways, such as upregulation of the TGF-ß pathway and downregulation of the cadherin family of proteins. These findings indicate that ATRX deficiency induces epigenomic changes and promotes tumorigenesis through both genome instability and shifts in transcription.

Genome-Wide CRISPR-Cas9 Screen Reveals Selective Vulnerability of ATRX-Mutant Cancers to WEE1 Inhibition.

The tumor suppressor gene ATRX is frequently mutated in a variety of tumors including gliomas and liver cancers, which are highly unresponsive to current therapies. Here, we performed a genome-wide synthetic lethal screen, using CRISPR-Cas9 genome editing, to identify potential therapeutic targets specific for ATRX-mutated cancers. In isogenic hepatocellular carcinoma (HCC) cell lines engineered for ATRX loss, we identified 58 genes, including the checkpoint kinase WEE1, uniquely required for the cell growth of ATRX null cells. Treatment with the WEE1 inhibitor AZD1775 robustly inhibited the growth of several ATRX-deficient HCC cell lines in vitro, as well as xenografts in vivo. The increased sensitivity to the WEE1 inhibitor was caused by accumulated DNA damage-induced apoptosis. AZD1775 also selectively inhibited the proliferation of patient-derived primary cell lines from gliomas with naturally occurring ATRX mutations, indicating that the synthetic lethal relationship between WEE1 and ATRX could be exploited in a broader spectrum of human tumors. As WEE1 inhibitors have been investigated in several phase II clinical trials, our discovery provides the basis for an easily clinically testable therapeutic strategy specific for cancers deficient in ATRX. SIGNIFICANCE: ATRX-mutant cancer cells depend on WEE1, which provides a basis for therapeutically targeting WEE1 in ATRX-deficient cancers.See related commentary by Cole, p. 375.

Arthroscopy-assisted surgery: The management of posterolateral tibial plateau depression fracture accompanying ligament injury: A case series and review of the literature.

Tibial plateau fractures are multiple fracture patterns associated with soft-tissue injuries. Among which, the combined existence of posterolateral tibial plateau depression fracture with anterior cruciate ligament (ACL) rupture has been reported rarely. Meanwhile, surgical method for the treatment of depression fracture is fairly complex. The aim of this article is to show a case series of this unusual injury pattern and the therapy of posterolateral tibial plateau depression fracture accompanying ACL rupture. In our treatment, arthroscopy assisted reduction of depression fracture and ACL reconstruction reduces surgical trauma and leads to good functional recovery. We also review the current literature.