Incidence and Risk Factors for the Development of Axial Symptoms Following Posterior Single-Door Laminoplasty: A Retrospective Analysis.

OBJECTIVE: Posterior single-door laminoplasty is a widely practiced clinical procedure, but the occurrence of postoperative axial syndrome (AS) remains a significant concern. The aim of this study was to identify risk factors associated with AS and develop a risk prediction model. METHODS: Clinical data from 226 patients who underwent posterior single-door laminoplasty between June 2017 and June 2022 were collected. Through Logistic model analysis, the risk factors of AS are clarified and the intensity of each risk factor is explained in the form of forest plot. Subsequently, we constructed a predictive model and plotted receiver operating characteristic curves to assess the model's predictive value. RESULTS: In the end, 87 cases were diagnosed with AS, resulting in an incidence rate of 38.5%. Logistic regression analysis revealed that preoperative encroachment rate of anterior spinal canal (pre-op ERASC), intraoperative facet joints destruction, intraoperative open-door angle, postoperative loss of cervical curvature, and postoperative loss of cervical range of motion were independent risk factors for AS. Conversely, preoperative cervical curvature (pre-op CC) and postoperation early function training were protective factors against AS. The Youden index indicated that the cutoff values for pre-op ERASC and pre-op CC were 26.6°and 16.5, respectively. The risk prediction model for AS was constructed and a nomogram was plotted. The model has high clinical value. CONCLUSIONS: Pre-op ERASC, pre-op CC, intraoperative facet joints destruction, intraoperative open-door angle, postoperative loss of cervical curvature, postoperative loss of cervical range of motion, and postoperation early function training are independent influencing factors for AS occurrence. The risk model has good practicability.

The clinical effect of unilateral decompressive laminectomy plus fusion with unilateral biportal endoscopic technique for single level lumbar spinal stenosis.

PURPOSE: This study aimed to compare and analyze the effectiveness of unilateral biportal endoscopic (UBE) decompressive laminectomy plus fusion and microscope-assisted open decompressive laminectomy plus fusion. METHODS: A total of 143 patients with lumbar spinal stenosis were enrolled in this study between March 2020 and February 2021 with a minimum 2 years follow-up visit to our hospital. Sixty-five patients underwent the unilateral biportal endoscopic technique and were assigned to the UBE group, and the remaining 78 patients with microscope assistant were assigned to the Microscope group. The baseline characteristics, clinical outcomes, and radiological data were retrospectively collected and analyzed, as well as Clinical outcomes, radiological data and complications. RESULTS: There were no significant differences between the two groups in terms of baseline characteristics (P > 0.05). The UBE group was demonstrated to be significantly superior in CRP, drainage, blood loss, treatment cost and Hospital stay than the Microscope group (P < 0.05), whereas a significant longer operation time was observed (P < 0.05). The VAS-B, ODI, and JOA-L scores of the UBE group at 1 year follow-up were significantly greater than those of the Microscope group (P < 0.05). Regarding radiological data, there were no significant differences in the section area of the spinal canal and fusion grade between the two groups (P > 0.05). CONCLUSION: In view of the satisfactory clinical outcomes of patients and notable decompression at the stenosed segment, UBE is a feasible, minimally invasive technique for single level lumbar canal stenosis.

Loss of ZNRF3/RNF43 Unleashes EGFR in Cancer.

ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the most negatively correlated protein with ZNRF3/RNF43 mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data highlight ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptor, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.

Analysis of risk factors for axial symptoms after posterior cervical open-door laminoplasty.

BACKGROUND: Laminoplasty (LP), a procedure commonly used to treat cervical spondylotic myelopathy (CSM), often results in the development of axial symptoms (AS) postoperatively. This study aims to analyze the risk factors associated with the occurrence of AS after LP. METHODS: We collected and evaluated clinical data from 264 patients with CSM who underwent LP treatment at our institution from January 2018 to January 2022 through a single-center retrospective study. Of the patients, 153 were male and 111 were female, with an average age of 58.1 ± 6.7 years. All patients underwent C3-7 posterior laminoplasty. Based on the occurrence of postoperative axial symptoms, the patients were divided into an AS group and a non-AS group. General information, including age, gender, disease duration, Japanese Orthopaedic Association (JOA) score, postoperation early function training, and collar-wearing time, was recorded and compared between the two groups. Surgical-related data, such as operative segments, surgical time, intraoperative blood loss, intraoperative facet joint destruction, and destruction of the C7 spinous process muscle insertion, were also compared. Imaging data, including preoperative cervical curvature, cervical range of motion, preoperative encroachment rate of the anterior spinal canal, and angle of laminar opening, were collected. Univariate and multivariate logistic regression analyses were used to identify risk factors for the development of AS after LP, and receiver operator characteristic (ROC) curves were utilized to explore the optimal preoperative parameters. RESULTS: All 264 patients successfully underwent surgery and were followed up for an average of 19.5 ± 6.8 months. At the 6-month follow-up, 117 patients were diagnosed with AS, resulting in an incidence rate of 40.2%. The multivariate logistic regression analysis identified that preoperative encroachment rate of anterior spinal canal (Pre-op ERASC), intraoperative facet joints destruction (Intra-op FJD), intraoperative open-door angle (Intra-op OA), destroy the C7 spinous process muscle insertion (Destroy C7 SPMI), postoperative loss of cervical curvature (Post-op LCC), and postoperative loss of cervical range of motion (Post-op LCROM) were independent risk factors for AS. Conversely, preoperative cervical curvature (Pre-op CC) and postoperation early function training (Post-op EFT) were protective factors against AS. According to the ROC curve, the cutoff values for preoperative anterior spinal canal occupation rate and preoperative cervical curvature were 28.5% and 16.5°, respectively. When the preoperative anterior spinal canal occupation rate was greater than 28.5% or the preoperative cervical curvature was less than 16.5°, AS was more likely to occur after surgery. CONCLUSION: High preoperative anterior spinal canal occupation rate, facet joint damage during surgery, C7 spinous process muscle stop point damage, larger angle of laminar opening, and greater postoperative cervical curvature loss and cervical range of motion loss are associated with an increased risk of developing AS after cervical laminoplasty. Conversely, a larger preoperative cervical curvature and early postoperative functional exercises can help reduce the occurrence of AS.

Biomechanical evaluation of a novel atlas polyaxial transverse connecting screw system, an in vitro human cadaveric study.

PURPOSE: To introduce a novel transverse connecting screw system, and to evaluate the biomechanical stability of the novel screw system using human cadaveric specimens. METHODS: Six fresh-frozen cadaveric upper cervical spines were used in our study. Every specimen was tested under 5 conditions: intact group; unstable group; C1 to C2 screw rod system group; C1 to C2 + crosslink system group; atlas polyaxial transverse connecting screw (APTCS) system. RESULTS: Compared with the intact state, C1 to C2 screw rod system, C1 to C2 + CL system and APTCS showed statistically decrease range of motion in all directions except for the unstable group under posterior extension direction (P < .05). APTCS group has the least range of motion in all directions (P < .001). CONCLUSION: The APTCS system was able to restore stability to the atlantoaxial joint. APTCS system has the advantages of easy installation, convenient bone grafting, and strong biomechanical strength.

Cross-reactive antibody response to Monkeypox virus surface proteins in a small proportion of individuals with and without Chinese smallpox vaccination history.

BACKGROUND: After the eradication of smallpox in China in 1979, vaccination with the vaccinia virus (VACV) Tiantan strain for the general population was stopped in 1980. As the monkeypox virus (MPXV) is rapidly spreading in the world, we would like to investigate whether the individuals with historic VACV Tiantan strain vaccination, even after more than 40 years, could still provide ELISA reactivity and neutralizing protection; and whether the unvaccinated individuals have no antibody reactivity against MPXV at all. RESULTS: We established serologic ELISA to measure the serum anti-MPXV titer by using immunodominant MPXV surface proteins, A35R, B6R, A29L, and M1R. A small proportion of individuals (born before 1980) with historic VACV Tiantan strain vaccination exhibited serum ELISA cross-reactivity against these MPXV surface proteins. Consistently, these donors also showed ELISA seropositivity and serum neutralization against VACV Tiantan strain. However, surprisingly, some unvaccinated young adults (born after 1980) also showed potent serum ELISA activity against MPXV proteins, possibly due to their past infection by some self-limiting Orthopoxvirus (OPXV). CONCLUSIONS: We report the serum ELISA cross-reactivity against MPXV surface protein in a small proportion of individuals both with and without VACV Tiantan strain vaccination history. Combined with our serum neutralization assay against VACV and the recent literature about mice vaccinated with VACV Tiantan strain, our study confirmed the anti-MPXV cross-reactivity and cross-neutralization of smallpox vaccine using VACV Tiantan strain. Therefore, it is necessary to restart the smallpox vaccination program in high risk populations.

Risk factors analysis and risk prediction model construction of non-specific low back pain: an ambidirectional cohort study.

PURPOSE: Non-specific low back pain (NLBP) is a common clinical condition that affects approximately 60-80% of adults worldwide. However, there is currently a lack of scientific prediction and evaluation systems in clinical practice. The purpose of this study was to analyze the risk factors of NLBP and construct a risk prediction model. METHODS: We collected baseline data from 707 patients who met the inclusion criteria and were treated at the Sixth Hospital of Ningbo from December 2020 to December 2022. Logistic regression and LASSO regression were used to screen independent risk factors that influence the onset of NLBP and to construct a risk prediction model. The sensitivity and specificity of the model were evaluated by tenfold cross-validation, and internal validation was performed in the validation set. RESULTS: Age, gender, BMI, education level, marital status, exercise frequency, history of low back pain, labor intensity, working posture, exposure to vibration sources, and psychological status were found to be significantly associated with the onset of NLBP. Using these 11 predictive factors, a nomogram was constructed, and the area under the ROC curve of the training set was 0.835 (95% CI 0.756-0.914), with a sensitivity of 0.771 and a specificity of 0.800. The area under the ROC curve of the validation set was 0.762 (95% CI 0.665-0.858), with a sensitivity of 0.800 and a specificity of 0.600, indicating that the predictive value of the model for the diagnosis of NLBP was high. In addition, the calibration curve showed a high degree of consistency between the predicted and actual survival probabilities. CONCLUSION: We have developed a preliminary predictive model for NLBP and constructed a nomogram to predict the onset of NLBP. The model demonstrated good performance and may be useful for the prevention and treatment of NLBP in clinical practice.

Efficient cancer modeling through CRISPR-Cas9/HDR-based somatic precision gene editing in mice.

CRISPR-Cas9 has been used successfully to introduce indels in somatic cells of rodents; however, precise editing of single nucleotides has been hampered by limitations of flexibility and efficiency. Here, we report technological modifications to the CRISPR-Cas9 vector system that now allows homology-directed repair-mediated precise editing of any proto-oncogene in murine somatic tissues to generate tumor models with high flexibility and efficiency. Somatic editing of either Kras or Pik3ca in both normal and hyperplastic mammary glands led to swift tumorigenesis. The resulting tumors shared some histological, transcriptome, and proteome features with tumors induced by lentivirus-mediated expression of the respective oncogenes, but they also exhibited some distinct characteristics, particularly showing less intertumor variation, thus potentially offering more consistent models for cancer studies and therapeutic development. Therefore, this technological advance fills a critical gap between the power of CRISPR technology and high-fidelity mouse models for studying human tumor evolution and preclinical drug testing.

Analysis of risk factors for contralateral symptomatic foraminal stenosis after unilateral transforaminal lumbar interbody fusion.

PURPOSE: To analyze the risk factors of contralateral symptomatic foraminal stenosis (FS) after unilateral transforaminal lumbar interbody fusion (TLIF) and to guide and standardize the operation process of unilateral TLIF to reduce the occurrence of contralateral symptomatic FS. METHODS: A retrospective study was undertaken on 487 patients with lumbar degeneration who underwent unilateral TLIF in the Department of Spinal Surgery of Ningbo Sixth Hospital between January 2017 and January 2021, comprising 269 males and 218 females, with a mean age of 57.1 years (range, 48-77 years). Cases of intraoperative improper operations, such as screw deviation, postoperative hematoma, and contralateral disc herniation, were excluded, and cases of nerve root symptoms caused by contralateral FS were analyzed. Post-surgery, 23 patients with nerve root symptoms caused by contralateral FS were categorized as group A, and 60 patients without nerve root symptoms were randomly selected as group B during the same period. The general data (gender, age, body mass index (BMI), bone mineral density (BMD), and diagnosis) and imaging parameters before and after operation (including contralateral foramen area (CFA), lumbar lordosis angle (LL), segmental lordosis angle (SL), disc height (DH), foramen height (FH), foramen width (FW), fusion cage position, and the difference between postoperative and preoperative) were compared between the two groups. Univariate analysis was performed, and multivariate analysis was undertaken through logistics analysis to determine the independent risk factors. Additionally, the clinical outcomes of the two groups were compared immediately before surgery and one year after surgery, using the visual analogue scale (VAS) score and the Japanese Orthopaedic Association (JOA) score for evaluation. RESULTS: The patients in this study were followed up for a period of 19-25 (22.8atien months. Among them, 23 cases (4.72% incidence) were diagnosed with contralaterally symptomatic FS after the surgery. Univariate analysis indicated significant differences between the two groups in CFA, SL, FW, and cage coronal position. Logistic regression analysis identified preoperative contralateral foramen area (OR = 1.176, 95% CI (1.012, 1.367)), small segmental lordosis angle (OR = 2.225, 95% CI (1.124, 4.406)), small intervertebral foramen width (OR = 2.706, 95% CI (1.028, 7.118)), and cage coronal position not crossing the midline (OR = 1.567, 95% CI (1.142, 2.149)) as independent risk factors for contralateral symptomatic FS after unilateral TLIF. However, there was no statistically significant difference in the pain VAS score between the two groups one year after the operation. In contrast, there was a significant difference in the JOA score between the two groups. CONCLUSION: The identified risk factors for contralateral symptomatic FS after TLIF include preoperative contralateral intervertebral foramen stenosis, a small segmental lordosis angle, a small intervertebral foramen width, and the coronal position of the cage not crossing the midline. For patients with these risk factors, it is recommended to carefully lock the screw rod during the recovery of lumbar lordosis and ensure that the coronal position of the fusion cage is implanted beyond the midline. If necessary, preventive decompression should also be considered. However, this study did not quantify the imaging data for each risk factor, and further research is needed to improve our understanding of the topic.

Fortuitous somatic mutations during antibody evolution endow broad neutralization against SARS-CoV-2 Omicron variants.

Striking antibody evasion by emerging circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identify a clonally related antibody family from a convalescent individual. One of the members, XG005, exhibits potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members show significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface reveals how crucial somatic mutations endow XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality exhibits a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provide a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

Effect of preoperative contralateral foramen stenosis on contralateral root symptoms after unilateral transforaminal lumbar interbody fusion: a ambispective cohort study.

PURPOSE: To evaluate the correlation between the degree of preoperative contralateral foraminal stenosis(CFS) and the incidence of contralateral root symptoms after unilateral transforaminal lumbar interbody fusion(TLIF) and to evaluate the appropriate candidate of preventive decompression according to the degree of preoperative contralateral foraminal stenosis. METHODS: An ambispective cohort study was conducted to investigate the incidence of contralateral root symptoms after unilateral transforaminal lumbar interbody fusion (TLIF) and the effectiveness of preventive decompression. A total of 411 patients were included in the study, all of whom met the inclusion and exclusion criteria and underwent surgery at the Department of Spinal Surgery, Ningbo Sixth Hospital, between January 2017 and February 2021. The study was divided into two groups: retrospective cohort study A and prospective cohort study B. The 187 patients included in study A from January 2017 to January 2019 did not receive preventive decompression. They were divided into four groups based on the degree of preoperative contralateral intervertebral foramen stenosis: no stenosis group A1, mild stenosis group A2, moderate stenosis group A3, and severe stenosis group A4. A Spearman rank correlation analysis was used to evaluate the correlation between the preoperative contralateral foramen stenosis degree and the incidence of contralateral root symptoms after unilateral TLIF. From February 2019 to February 2021, 224 patients were included in the prospective cohort group B. The decision to perform preventive decompression during the operation was based on the degree of preoperative contralateral foramen stenosis. Severe intervertebral foramen stenosis was treated with preventive decompression as group B1, while the rest were not treated with preventive decompression as group B2. The baseline data, surgical-related indicators, the incidence of contralateral root symptoms, clinical efficacy, imaging results, and other complications were compared between group A4 and group B1. RESULTS: All 411 patients completed the operation and were followed up for an average of 13.5 ± 2.8 months. In the retrospective study, there was no significant difference in baseline data among the four groups (P > 0.05). The incidence of postoperative contralateral root symptoms increased gradually, and a weak positive correlation was found between the degree of preoperative intervertebral foramen stenosis and the incidence of postoperative root symptoms (rs = 0.304, P < 0.001). In the prospective study, there was no significant difference in baseline data between the two groups. The operation time and blood loss in group A4 were less than those in group B1 (P < 0.05). The incidence of contralateral root symptoms in group A4 was higher than that in group B1 (P = 0.003). However, there was no significant difference in leg VAS score and ODI index between the two groups at 3 months after the operation (P > 0.05). There was no significant difference in cage position, intervertebral fusion rate, and lumbar stability between the two groups (P > 0.05). No incisional infection occurred after the operation. No pedicle screw loosening, displacement, fracture, or interbody fusion cage displacement occurred during follow-up. CONCLUSION: This study found a weak positive correlation between the degree of preoperative contralateral foramen stenosis and the incidence of contralateral root symptoms after unilateral TLIF. Intraoperative preventive decompression of the contralateral side may prolong the operation time and increase intraoperative blood loss to some extent. However, when the contralateral intervertebral foramen stenosis reaches the severe level, it is recommended to perform preventive decompression during the operation. This approach can reduce the incidence of postoperative contralateral root symptoms while ensuring clinical efficacy.

Density Functional Theory and Machine Learning-Based Quantitative Structure-Activity Relationship Models Enabling Prediction of Contaminant Degradation Performance with Heterogeneous Peroxymonosulfate Treatments.

Heterogeneous peroxymonosulfate (PMS) treatment is recognized as an effective advanced oxidation process (AOP) for the treatment of organic contaminants. Quantitative structure-activity relationship (QSAR) models have been applied to predict the oxidation reaction rates of contaminants in homogeneous PMS treatment systems but are seldom applied in heterogeneous treatment systems. Herein, we established QSAR models updated with density functional theory (DFT) and machine learning approaches to predict the degradation performance for a series of contaminants in heterogeneous PMS systems. We imported the characteristics of organic molecules calculated using constrained DFT as input descriptors and predicted the apparent degradation rate constants of contaminants as the output. The genetic algorithm and deep neural networks were used to improve the predictive accuracy. The qualitative and quantitative results from the QSAR model for the degradation of contaminants can be used to select the most appropriate treatment system. A strategy for selection of the optimum catalyst for PMS treatment of specific contaminants was also established according to the QSAR models. This work not only increases our understanding of contaminant degradation in PMS treatment systems but also highlights a novel QSAR model to predict the degradation performance in complicated heterogeneous AOPs.

Advances in Plant Epigenome Editing Research and Its Application in Plants.

Plant epistatic regulation is the DNA methylation, non-coding RNA regulation, and histone modification of gene sequences without altering the genome sequence, thus regulating gene expression patterns and the growth process of plants to produce heritable changes. Epistatic regulation in plants can regulate plant responses to different environmental stresses, regulate fruit growth and development, etc. Genome editing can effectively improve plant genetic efficiency by targeting the design and efficient editing of genome-specific loci with specific nucleases, such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALEN), and clustered regularly interspaced short palindromic repeats/CRISPR-associated 9 (CRISPR/Cas9). As research progresses, the CRISPR/Cas9 system has been widely used in crop breeding, gene expression, and epistatic modification due to its high editing efficiency and rapid translation of results. In this review, we summarize the recent progress of CRISPR/Cas9 in epigenome editing and look forward to the future development direction of this system in plant epigenetic modification to provide a reference for the application of CRISPR/Cas9 in genome editing.

Characterization of cross-reactive monoclonal antibodies against SARS-CoV-1 and SARS-CoV-2: Implication for rational design and development of pan-sarbecovirus vaccines and neutralizing antibodies.

Emergence of various circulating SARS-CoV-2 variants of concern (VOCs) promotes the identification of pan-sarbecovirus vaccines and broadly neutralizing antibodies (bNAbs). Here, to characterize monoclonal antibodies cross-reactive against both SARS-CoV-1 and SARS-CoV-2 and to search the criterion for bNAbs against all emerging SARS-CoV-2, we isolated several SARS-CoV-1-cross-reactive monoclonal antibodies (mAbs) from a wildtype SARS-CoV-2 convalescent donor. These antibodies showed broad binding capacity and cross-neutralizing potency against various SARS-CoV-2 VOCs, including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta), but failed to efficiently neutralize Omicron variant and its sublineages. Structural analysis revealed how Omicron sublineages, but not other VOCs, efficiently evade an antibody family cross-reactive against SARS-CoV-1 through their escape mutations. Further evaluation of a series of SARS-CoV-1/2-cross-reactive bNAbs showed a negative correlation between the neutralizing activities against SARS-CoV-1 and SARS-CoV-2 Omicron variant. Together, these results suggest the necessity of using cross-neutralization against SARS-CoV-1 and SARS-CoV-2 Omicron as criteria for rational design and development of potent pan-sarbecovirus vaccines and bNAbs.

Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models.

Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer. PREVENTION RELEVANCE: PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.

Fortuitous Somatic Mutations during Antibody Evolution Endow Broad Neutralization against SARS-CoV-2 Omicron Variants.

Striking antibody evasion by emerging circulating SARS-CoV-2 variants drives the identification of broadly neutralizing antibodies (bNAbs). However, how a bNAb acquires increased neutralization breadth during antibody evolution is still elusive. Here, we identified a clonally-related antibody family from a convalescent individual. One of the members, XG005, exhibited potent and broad neutralizing activities against SARS-CoV-2 variants, while the other members showed significant reductions in neutralization breadth and potency, especially against the Omicron sublineages. Structural analysis visualizing the XG005-Omicron spike binding interface revealed how crucial somatic mutations endowed XG005 with greater neutralization potency and breadth. A single administration of XG005 with extended half-life, reduced antibody-dependent enhancement (ADE) effect, and increased antibody product quality, exhibited a high therapeutic efficacy in BA.2- and BA.5-challenged mice. Our results provided a natural example to show the importance of somatic hypermutation during antibody evolution for SARS-CoV-2 neutralization breadth and potency.

STAT5 confers lactogenic properties in breast tumorigenesis and restricts metastatic potential.

Signal transducer and activator of transcription 5 (STAT5) promotes cell survival and instigates breast tumor formation, and in the normal breast it also drives alveolar differentiation and lactogenesis. However, whether STAT5 drives a differentiated phenotype in breast tumorigenesis and therefore impacts cancer spread and metastasis is unclear. We found in two genetically engineered mouse models of breast cancer that constitutively activated Stat5a (Stat5aca) caused precancerous mammary epithelial cells to become lactogenic and evolve into tumors with diminished potential to metastasize. We also showed that STAT5aca reduced the migratory and invasive ability of human breast cancer cell lines in vitro. Furthermore, we demonstrated that STAT5aca overexpression in human breast cancer cells lowered their metastatic burden in xenografted mice. Moreover, RPPA, Western blotting, and studies of ChIPseq data identified several EMT drivers regulated by STAT5. In addition, bioinformatic studies detected a correlation between STAT5 activity and better prognosis of breast cancer patients. Together, we conclude that STAT5 activation during mammary tumorigenesis specifies a tumor phenotype of lactogenic differentiation, suppresses EMT, and diminishes potential for subsequent metastasis.

Posterior temporary fixation of C1-C2 screw-rod system for unstable C1 burst fracture.

Whether an unstable C1 burst fracture should be treated surgically or conservatively is controversial. The purpose of this study is to evaluate the effectiveness and motion-preserving function of temporary fixation of C1-C2 screw-rod system for the reduction and fixation of unstable C1 burst fracture. We retrospectively reviewed 10 patients who were treated with posterior C1-C2 temporary fixation without fusion. We assessed age at surgery, gender, pre- and postoperative visual analog scale (VAS), Neck Disability Index (NDI), atlanto-dens interval (ADI), lateral mass distance (LMD), and rotation function of C1-C2 complex. Six males and 4 females were included in our study. The average follow-up duration was 14.1 ± 1.37 months. The left-to-right ROMs of C1-C2 rotation was 9.6° ± 1.42°. The preoperative cervical VAS was 8.30 ± 0.48; the postoperative cervical VAS of C1-C2 fusion was 2.90 ± 0.57. The preoperative VAS for removal was 2.0 ± 0.00, and the postoperative VAS for removal was 2.3 ± 0.48. The preoperative cervical NDI was 81.40% ± 2.07%, the postoperative cervical NDI of C1-C2 fusion was 18.10% ± 1.52%. The preoperative NDI for removal was 15.9% ± 1.20%. The postoperative NDI for removal was 14.5% ± 1.08%. The preoperative ADI was 4.43 ± 0.34 mm, and postoperative ADI was 1.94 ± 0.72 mm. The preoperative LMD was 6.36 ± 0.58 mm, and postoperative LMD was 1.64 ± 0.31 mm. Posterior temporary C1-C2 fixation can achieve a good fusion and satisfied reduction of C1 fracture, relieve the pain, improve the cervical function outcome, but may reduce the rotational range of motion of C1-C2. Posterior C1-C2 temporary fixation without fusion was not suitable for C1 burst fracture. We recommend permanent C1-C2 fixation and fusion for C1 burst fracture if surgery is necessary.

Targeting the Pro-survival Protein BCL-2 to Prevent Breast Cancer.

Current chemopreventive strategies require 3-5 years of continuous treatment and have the concerns of significant side effects; therefore, new chemopreventive agents that require shorter and safer treatments are urgently needed. In this study, we developed a new murine model of breast cancer that mimics human breast cancer initiation and is ideal for testing the efficacy of chemopreventive therapeutics. In this model, introduction of lentivirus carrying a PIK3CA gene mutant commonly found in breast cancers infects a small number of the mammary cells, leading to atypia first and then to ductal carcinomas that are positive for both estrogen receptor and progesterone receptor. Venetoclax is a BH3 mimetic that blocks the anti-apoptotic protein BCL-2 and has efficacy in treating breast cancer. We found that venetoclax treatment of atypia-bearing mice delayed the progression to tumors, improved overall survival, and reduced pulmonary metastasis. Therefore, prophylactic treatment to inhibit the pro-survival protein BCL-2 may provide an alternative to the currently available regimens in breast cancer prevention. PREVENTION RELEVANCE: This study demonstrates that prophylactic treatment with the BCL2-specific antagonist venetoclax prevents breast cancer initiated by a mutated and activated PIK3CA, the most common breast oncogene.

Reliability and repeatability of a modified thoracolumbar spine injury classification scoring system.

Purpose: On the basis of the Thoracolumbar Injury Classification and Severity Score (TLICS), an modified TLICS classification system was presented, its reliability and repeatability were assessed, and the factors influencing classification consistency were examined. Methods: Five spinal surgeons were chosen at random. The clinical data of 120 patients with thoracolumbar fractures admitted to the Department of Spine Surgery, Ningbo Sixth Hospital from December 2019 to June 2021 were categorized using the modified TLICS system. After 6 weeks, disrupt the order of data again. Using unweighted Cohen's kappa coefficients, the consistency of the modified TLICS system was assessed in five aspects: neurofunctional status, disc injury status, fracture morphology, posterior ligament complex (PLC) integrity, and treatment plan. Results: In terms of reliability, the average kappa values for the subclasses of the modified TLICS system (neurofunctional status and disc injury status) were 0.920 and 0.815, respectively, reaching the category of complete confidence. Fracture morphology and treatment plan had average kappa values of 0.670 and 0.660, respectively, which were basically reliable. The average kappa value of PLC integrity was 0.453, which belonged to the category of moderate confidence. The average kappa coefficients of each subcategory (neurological status, disc injury status) had excellent consistency, and the kappa values were 0.936 and 0.879, respectively, which belonged to the completely credible category. The kappa values of fracture morphology and treatment plan repeatability were 0.772 and 0.749, respectively, reaching the basic credibility category. PLC integrity repeatability kappa value is low, 0.561, to moderate credibility category. Conclusion: The modified TLICS system is intuitive and straightforward to understand. The examination of thoracolumbar fracture injuries is more exhaustive and precise, with excellent reliability and repeatability. The examination of neurological status and disc injury status is quite reliable and consistent. The consistency of fracture morphology is slightly poor, which is basically credible; the PLC integrity consistency is poor, reaching a reliability level of moderate, which may be associated with the subjectivity of clinical evaluation of PLC.