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BackgroundThe five-year recurrence rate of hepatocellular carcinoma (HCC) remains as high as 70%. A complete clinical response has not been observed without surgical resection. Here, we report a rare case of clinical complete response and long-term survival in a patient with massive HCC receiving treatment with immunotherapy, anti-angiogenic therapy, and radiotherapy.Case descriptionA 38-year-old woman presented to our hospital for abdominal pain that persisted for 3 months. She was diagnosed as Barcelona Clinic Liver Cancer(BCLC) stage A, with a Cancer of the Liver Italian Program (CLIP) score of 3, American Joint Committee on Cancer (AJCC) Tumor-Node-Metastasis (TNM) staging systems stage IB. She refused surgical resection and trans-arterial chemoembolization and accepted a non-invasive systematic treatment strategy involving immunotherapy, anti-angiogenic therapy, and radiotherapy. Her tumor burden decreased, and she experienced partial response before radiotherapy. Following radiotherapy, she experienced a complete clinical response and has been alive for more than 36 months after her initial presentation. She is currently alive.ConclusionA non-invasive systematic treatment strategy is a potential radical treatment option for patients with massive HCC.

Abstract Background Numerous common oncogenic driver events have been confirmed in non-small cell lung cancer (NSCLC). Although targeted therapy has revolutionized NSCLC treatment, some patients still do not respond. NCAPG, also known as non-SMC condensin I complex subunit G, was positively associated with proliferation and migration in several tumor types. Methods We used transcriptional sequencing and TCGA database analysis to identify NCAPG as a new therapeutic target for NSCLC. The oncogenic roles of NCAPG in NSCLC tumor growth and metastasis were detected in vitro and in vivo. Ncapg +/+ or Ncapg +/− mice with urethane treatment were analyzed for oncogenesis of NSCLC. Results We investigated NCAPG as a new oncogenic driver which promoted NSCLC tumorigenesis and progression. We used transcriptome sequencing and the Cancer Genome Atlas (TCGA) database analysis to screen and found that NCAPG was negatively correlated with NSCLC survival. Using immunohistochemistry, we demonstrated that NCAPG overexpression was an independent risk factor for NSCLC survival. Functionally, NCAPG knockdown inhibited proliferation, migration, and invasion of NSCLC cells in vitro and in vivo. We exposed wildtype or Ncapg +/− mice to urethane and discovered that urethane-induced lung tumors were reduced in Ncapg +/− mice. Mechanistically, the function of NCAPG in promoting initiation and progression of NSCLC was closely related to LGALS1, which was also upregulated in NSCLC and might interact directly with NCAPG. Conclusions This study indicates that NCAPG is one of the essential factors for NSCLC oncogenesis and progression, providing a new target for prognosis prediction and treatment of NSCLC.

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type–containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1–induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1– sarcolemma membrane–associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.

Half the population of China live in coastal zones where 70% of large cities are also located. Intensive human activities pose significant environmental and ecological hazards to these cities that are already vulnerable to natural hazards and climate change. The sustainable development of coastal cities is thus both a national and international issue. Rongcheng is a typical coastal city in east China. It is a national marine ranch demonstration area that is subjected to multi-stressors from human activities and climate change. The dominant economic sectors include aquaculture and fisheries, agriculture, shipping and tourism. A multitude of resulting pressures come mainly from intensified human activities, such as intensive aquaculture, overfishing, industrial pollutants, agricultural runoff, land reclamation and port expansion. In addition, Rongcheng is also facing exogenic pressures from extreme climate events such as intensified storms, storm surges, droughts and sea ice. A growing awareness of these problems brought together a trans-disciplinary group from local government, research institutions, local practitioners and coastal representatives to jointly explore and co-design adaptive coastal management options. In this transdisciplinary study, a social-ecological analysis based on a combination of the Systems Approach Framework and the Drivers-Pressures-States-Impacts-Responses framework was used to analyze and formulate an adaptive management plan for the sustainability of Rongcheng. More than 40 stakeholders including government, companies, civil society and institutions participated in the study through questionnaires and on-site meetings. A statistical analysis of the results identified urgent issues impeding the sustainable development of Rongcheng. The issues identified were poorly regulated aquaculture, loss of shoreline, and the decline of seagrass and cultural heritage. The study identified management options and measures, some of which were adopted by the local government in a co-designed management plan. The measures included upgrading of aquaculture industry, habitat conservation and restoration, and the development of cultural tourism. Another outcome was the increased knowledge exchange between stakeholders to inform management, policy, and decision making, as well as raised awareness of vulnerability to natural hazards and climate change. The success of this case study provides a reference for the adaptive management of other coastal cities and their sustainable development in a changing climate.

Abstract Background Nucleus pulposus (NP) deterioration plays a significant role in the development of intervertebral disc degeneration (IVDD) and low back pain (LBP). This paper aims to identify potential genes within degenerated NP tissue and elucidate the pathogenesis of IVDD through bioinformatics analysis. Methods We conducted a transcriptomic analysis of patient's degenerative NP tissue employing advanced bioinformatics techniques and machine learning algorithms. Utilizing hdWGCNA, we successfully acquired WGCNA single-cell sequencing data and pinpointed crucial genes implicated in IVDD. Subsequently, we employed the Monocle3 package to perform pseudotime sequence analysis, enabling the identification of genes associated with the differentiation and developmental processes of NP tissue. Following this, normalized and logarithmically transformed the bulk sequencing data. Subsequently, we conducted preliminary screening using single-factor logistic regression on the genes derived from single-cell sequencing. Next, we applied two machine learning techniques, namely, SVM–RFE and random forest, to discern pivotal pathogenic genes. Finally, we used validation sets to verify trends and qualitativeness and performed in vitro and in vivo validation analyses of normal and degenerative NP tissues. Results 909 genes associated with IVDD were identified through hdWGCNA, while pseudotime sequence analysis uncovered 1964 genes related to differentiation and developmental processes. The two had 208 genes in common. Subsequently, we conducted an initial screening of single-cell genes by integrating the bulk database with single logistic regression. Next, we utilized machine learning techniques to identify the IVDD genes CDH, DPH5, and SELENOF. PCR analysis confirmed that the expression of CDH and DPH5 in degraded nucleus pulposus cells (NPCs) was decreased by 31% and 28% in vivo, and 36% and 29% in vitro, respectively, while SELENOF showed the opposite trend. Furthermore, IVDD was validated through imaging and histological staining. Conclusion As pathogenic genes in IVDD, our findings indicate that CTH, DPH5, and SELENOF are important players and might be promising therapeutic targets for IVDD treatment.

Abstract Background Intervertebral disc degeneration disease (IVDD) is a major cause of disability and reduced work productivity worldwide. Annulus fibrosus degeneration is a key contributor to IVDD, yet its mechanisms remain poorly understood. Autophagy, a vital process for cellular homeostasis, involves the lysosomal degradation of cytoplasmic proteins and organelles. This study aimed to investigate the role of autophagy in IVDD using a hydrogen peroxide (H2O2)-induced model of rat annulus fibrosus cells (AFCs). Methods AFCs were exposed to H2O2 to model oxidative stress-induced degeneration. Protein expression levels of collagen I, collagen II, MMP3, and MMP13 were quantified. GEO database analysis identified alterations in miR-2355-5p expression, and its regulatory role on the mTOR pathway and autophagy was assessed. Statistical tests were used to evaluate changes in protein expression and pathway activation. Results H2O2 exposure reduced collagen I and collagen II expression to approximately 50% of baseline levels, while MMP3 and MMP13 expression increased twofold. Activation of autophagy restored collagen I and II expression and decreased MMP3 and MMP13 levels. GEO analysis revealed significant alterations in miR-2355-5p expression, confirming its role in regulating the mTOR pathway and autophagy. Conclusions Autophagy, mediated by the miR-2355-5p/mTOR pathway, plays a protective role in AFCs degeneration. These findings suggest a potential therapeutic target for mitigating IVDD progression.

Abstract Intervertebral disc degeneration (IVDD) is the primary factor contributing to low back pain (LBP). Unlike elderly patients, many young IVDD patients usually have a history of trauma or long-term abnormal stress, which may lead to local inflammatory reaction causing by immune cells, and ultimately accelerates degeneration. Research has shown the significance of M1-type macrophages in IVDD; nevertheless, the precise mechanism and the route by which it influences the function of nucleus pulposus cell (NPC) remain unknown. Utilizing a rat acupuncture IVDD model and an NPC degeneration model induced by lipopolysaccharide (LPS), we investigated the function of M1 macrophage-derived exosomes (M1-Exos) in IVDD both in vivo and in vitro in this study. We found that M1-Exos enhanced LPS-induced NPC senescence, increased the number of SA-β-gal-positive cells, blocked the cell cycle, and promoted the activation of P21 and P53. M1-Exos derived from supernatant pretreated with the exosome inhibitor GW4869 reversed this result in vivo and in vitro. RNA-seq showed that Lipocalin2 (LCN2) was enriched in M1-Exos and targeted the NF-κB pathway. The quantity of SA-β-gal-positive cells was significantly reduced with the inhibition of LCN2, and the expression of P21 and P53 in NPCs was decreased. The same results were obtained in the acupuncture-induced IVDD model. In addition, inhibition of LCN2 promotes the expression of type II collagen (Col-2) and inhibits the expression of matrix metalloproteinase 13 (MMP13), thereby restoring the equilibrium of metabolism inside the extracellular matrix (ECM) in vitro and in vivo. In addition, the NF-κB pathway is crucial for regulating M1-Exo-mediated NPC senescence. After the addition of M1-Exos to LPS-treated NPCs, p-p65 activity was significantly activated, while si-LCN2 treatment significantly inhibited p-p65 activity. Therefore, this paper demonstrates that M1 macrophage-derived exosomes have the ability to deliver LCN2, which activates the NF-κB signaling pathway, and exacerbates IVDD by accelerating NPC senescence. This may shed new light on the mechanism of IVDD and bring a fresh approach to IVDD therapy. Graphical Abstract

Abstract Objective Although spinal endoscopic techniques have shown great advantages in the treatment of single-segment lumbar disk herniation (LDH), the therapeutic advantages for double-segment LDH are controversial. To compare the outcomes of percutaneous endoscopic interlaminar discectomy (PEID) versus conventional open lumbar discectomy (COLD) for the treatment of L4/5 and L5/S1 double-segmental LDH. Methods From January 2016 to September 2021, we included 50 patients with double-segmental LDH who underwent PEID (n = 25) or COLD (n = 25). The clinical outcomes between the two groups were evaluated using the visual analog scale (VAS), the Oswestry disability index (ODI), and the modified MacNab criteria. Moreover, the incision length, operation time, intraoperative fluoroscopy time, postoperative bedtime, hospital stays, and complications were also recorded and compared after surgery. Results In both groups, the VAS and ODI scores at different timepoints postoperatively were significantly improved compared with those preoperatively (P

Nucleus pulposus, annulus fibrosus, and cartilage endplate constitute an avascular intervertebral disc (IVD), which is crucial for spinal and intervertebral joint mobility. As one of the most widespread health issues worldwide, intervertebral disc degeneration (IVDD) is recognized as a key contributor to back and neck discomfort. A number of degenerative disorders have a strong correlation with ferroptosis, a recently identified novel regulated cell death (RCD) characterized by an iron-dependent mechanism and a buildup of lipid reactive oxygen species (ROS). There is growing interest in the part ferroptosis plays in IVDD pathophysiology. Inhibiting ferroptosis has been shown to control IVDD development. Several studies have demonstrated that in TBHP-induced oxidative stress models, changes in ferroptosis marker protein levels and increased lipid peroxidation lead to the degeneration of intervertebral disc cells, which subsequently aggravates IVDD. Similarly, IVDD is significantly relieved with the use of ferroptosis inhibitors. The purpose of this review was threefold: 1) to discuss the occurrence of ferroptosis in IVDD; 2) to understand the mechanism of ferroptosis and its role in IVDD pathophysiology; and 3) to investigate the feasibility and prospect of ferroptosis in IVDD treatment.

Abstract Objective To evaluate the safety and efficacy of cervical pedicle screw (CPS) placement with O‐arm navigation in the treatment of lower cervical fracture‐dislocation. Methods A retrospective clinical study was performed involving 42 consecutive patients with lower cervical spine fracture‐dislocation who underwent CPS fixation surgery with O‐arm navigation (CPS group) or received conventional lateral mass screw (LMS) fixation surgery (LMS group) between August 2015 and August 2019. Accuracy of CPS position was evaluated by postoperative CT. The clinical parameters including preoperative and final follow‐up Japanese Orthopaedic Association (JOA) score and American Spinal Injury Association (ASIA) Impairment Scale, preoperative Sub‐axial Injury Classification (SLIC) score, number of fixation segments, operation time, intraoperative blood loss, injury mechanism, injury location, surgical complications were also assessed between the two groups. Results In LMS group, the preoperative SLIC score was 7.5 ± 0.9, ASIA score improvement was 0.8 ± 0.5, JOA score improvement was 3.0 ± 1.8, mean operation time was 204 ± 89 min, intraoperative blood loss was 311 ± 127 ml. In CPS group, the preoperative SLIC score was 7.3 ± 1.2, ASIA score improvement was 0.9 ± 0.5, JOA score improvement was 3.2 ± 2.4, mean operation time is 241 ± 85 min, intraoperative blood loss is about 327 ± 120 ml. There was no significant difference in terms of above clinical parameters between the two groups (P > 0.05), the fixation segments in CPS group (3.5 ± 1.1) were less than that in LMS group (4.2 ± 0.7) (P = 0.037). The accuracy of CPS insertion was evaluated based on postoperative CT. Of all the 118 CPSs, 83 (70.3%) were defined as Grade 0; 27 (22.9%) as Grade 1; eight (6.8%) as Grade 2; and none as Grade 3. CPS malposition rate in this study was 6.8%. In this study, there was no direct intraoperative or postoperative complication caused by CPS or LMS insertion. All the operations were successfully completed in two groups. One of the patients in LMS group presented cerebrospinal fluid leak caused by bone fragment broken of the dural sac, which led to delayed incision healing. CPS group and LMS group both had two patients who suffered pulmonary infection after surgery. A total of 78.6% of the patients showed evidence of neurologic recovery. Satisfactory reduction was achieved in all cases and maintained throughout the follow‐up duration. Conclusion In the treatment of lower cervical spine fracture‐dislocation, cervical pedicle screw insertion with O‐arm navigation is a safe and effective method for posterior fixation.

Abstract Objective To retrospectively analyze the short and long-term efficacies of O-arm-navigated percutaneous short segment pedicle screw fixation, with or without screwing of the fractured vertebra. Methods A total of 42 patients who underwent O-arm-navigated percutaneous short segment pedicle screw fixation for the treatment of thoracolumbar fractures from February 2015 to December 2018 were selected for analysis. The patients were divided into two groups according to the surgical intervention they received: Group A received percutaneous short segment pedicle screw fixation with screwing of the fractured vertebra and Group B received percutaneous short segment pedicle screw fixation without screwing of the fractured vertebra. Radiographic analysis included Cobb angles and percentage of anterior vertebral height (AVH%). Clinical functional outcomes were assessed using the visual analog scale (VAS) for back pain and the oswestry disability index (ODI) scores. Results No significant differences were observed in the operation time and intraoperative blood loss between the two groups (P > 0.05). The length of incision was statistically significantly different between the two groups (P 0.05). However, the Cobb angle and AVH% were both significantly larger in Group A than Group B at the final follow-up (P 0.05). Conclusion In the short term, both minimally invasive treatments were safe and effective in treating thoracolumbar fracture. Although there was significant difference between the two groups in Cobb angle and vertebral body height at the last follow-up, the difference was small. Therefore, these specific parameters will be an important outcome measure in further investigations.

ObjectiveThis study aims to investigate the clinical outcome of single and double incision for double-level percutaneous interlaminar lumbar discectomyMethodsA retrospective analysis was performed involving patients with L4/5 and L5/S1 double-level lumbar disc herniation who received percutaneous interlaminar lumbar discectomy (PEID) in our hospital from January 2017 to December 2020. These enrolled patients were divided into single- and double-incision groups, with 25 patients in each group. We compared the incision length, operation time, fluoroscopy times, and length of hospital stay between the two groups. Meanwhile, the postoperative visual analogue scale (VAS), Oswestry Disability Index (ODI), Japanese Orthopedic Association score (JOA), and modified MacNab standard were used to evaluate the outcomes of the patients within the two groups.ResultsIt showed that the single-incision group performed better than double-incision group in incision length, operation time, and fluoroscopy times (P 0.05). At the last follow-up, the excellent and good rates of MacNab efficacy in the two groups were 92% and 88%, respectively, but no significant difference was observed between the two groups (P > 0.05).ConclusionBoth the single- and double-incision approaches are effective and safe for managing L4/5 and L5/S1 double-level LDH. Single-incision PEID for treating L4/5 and L5/S1 double-segment lumbar disc herniation has advantages of less trauma, fewer intraoperative fluoroscopy times, and shorter operation time, as compared to double-incision PEID. However, the operation of double-segment LDH through a single laminar incision is difficult, the learning curve is steep, and professional skill is highly required. Importantly, the surgical indications should be strictly grasped.