Novel BRD4-p53 Inhibitor SDU-071 Suppresses Proliferation and Migration of MDA-MB-231 Triple-Negative Breast Cancer Cells.

A promising alternative for cancer treatment involves targeted inhibition of the epigenetic regulator bromodomain-containing protein 4 (BRD4); however, available BRD4 inhibitors are constrained by their potency, oral bioavailability, and cytotoxicity. Herein, to overcome the drawback of the translational BRD4 inhibitors, we describe a novel BRD4-p53 inhibitor, SDU-071, which suppresses BRD4 interaction with the p53 tumor suppressor and its biological activity in MDA-MB-231 triple-negative breast cancer (TNBC) cells in vitro and in vivo. This novel small-molecule BRD4-p53 inhibitor suppresses cell proliferation, migration, and invasion by downregulating the expression of BRD4-targeted genes, such as c-Myc and Mucin 5AC, and inducing cell cycle arrest and apoptosis, as demonstrated in cultured MDA-MB-231 TNBC cells. Its antitumor activity is illustrated in an orthotopic mouse xenograft mammary tumor model. Overall, our results show that SDU-071 is a viable option for potentially treating TNBC as a new BRD4-p53 inhibitor.

A Novel growth guidance system for early onset scoliosis: a preliminary in vitro study.

PURPOSE: The purpose of the study was to describe a novel growth guidance system, which can avoid metal debris and reduce the sliding friction forces, and test the durability and glidability of the system by in vitro test. METHOD: Two major modifications were made to the traditional Shilla system, including the use of ultra-high molecular weight polyethylene (UHMWPE) gaskets to avoid direct contact between the screw and rod, and polishing the surface of the sliding part of the rod. We tested the durability of the system by a fatigue test, which the samples were test on the MTS system for a 10 million cycle of a constant displacement. Pre and post-testing involved weighing the UHMWPE gaskets and observing the wear conditions. The sliding ability were measured by a sliding displacement test. The maximum sliding displacement of the system was measured after a 300 cycles of dynamic compressive loads in a sinusoidal waveform. RESULTS: After the fatigue test, all the UHMWPE gaskets samples showed some of the fretting on the edge of the inner sides, but its still isolated and avoided the friction between the screws and rods. There was no production of metallic fretting around the sliding screws and rods. The average wear mass of the UHMWPE gaskets was 0.002 ± 0.001 g, less than 1.7% of the original mass. In the sliding test, the novel growth guidance system demonstrated the best sliding ability, with an average maximum sliding distance(AMSD) of 35.75 ± 5.73 mm, significantly better than the group of the traditional Shilla technique(AMSD 3.65 ± 0.46 mm, P < 0.0001). CONCLUSION: In conclusion, we modified the Shilla technique and designed a novel growth guidance system by changing the friction interface of sliding screw and rod, which may significantly reduce the metallic debris and promote spine growth. The fatigue test and sliding dislocation test demonstrated the better durability and glidability of the system. An in vivo animal experiment should be performed to further verify the system.

microRNA-125b-1-3p mediates autophagy via the RRAGD/mTOR/ULK1 signaling pathway and mitigates atherosclerosis progression.

Atherosclerosis is characterised by lipid accumulation and formation of foam cells in arterial walls. Dysregulated autophagy is a crucial factor in atherosclerosis development. The significance of microRNA (miR)-125b-1-3p in cardiovascular disease is well-established; however, its precise role in regulating autophagy and impact on atherosclerosis in vascular smooth muscle cells (VSMCs) remain unclear. Here, we observed reduced autophagic activity and decreased miR-125b expression during atherosclerosis progression. miR-125b-1-3p overexpression significantly reduced atherosclerotic plaque development in mice; it also led to decreased lipid uptake and deposition in VSMCs, enhanced autophagy, and suppression of smooth muscle cell phenotypic changes in-vitro. An interaction between miR-125b-1-3p and the RRAGD/mTOR/ULK1 pathway was revealed, elucidating its role in promoting autophagy. Therefore, miR-125b-1-3p plays a pivotal role in enhancing autophagic processes, inhibiting foam cell formation in VSMCs and mitigating atherosclerosis progression, partly through RRAGD/mTOR/ULK1 signaling axis modulation. Thus, miR-125b-1-3p is a promising target for preventive and therapeutic strategies for atherosclerosis.

Is it necessary to extend fusion to L4 when correcting pediatric L5-S1 spondylolisthesis?

OBJECTIVE: The objective of this study was to investigate whether extending fusion to L4 is imperative in the surgical treatment of pediatric L5-S1 spondylolisthesis. METHODS: This retrospective analysis encompassed 68 pediatric cases of dysplastic L5-S1 spondylolisthesis who underwent posterior lumbar interbody fusion surgery at two hospitals. Patients were categorized into two groups based on the upper instrumented vertebra (group L4 and group L5). Data were collected from medical records and radiological images obtained preoperatively and at last follow-up. Radiographic parameters including slip percentage (SP), lumbar lordosis (LL), sagittal vertical axis (SVA), pelvic incidence (PI), Spinal Deformity Study Group dysplastic lumbosacral angle (SDSG-LSA), pelvic tilt (PT), Dubousset's lumbosacral angle (Dub-LSA), sacral slope (SS), and severity index (SI) were measured. Surgery-related data and complication data were also collected. The incidence rates of complications were compared, including those of neurological deficit, adjacent-segment instability (ASI), and other complications. ASI was defined as progression of slippage > 3 mm or posterior opening > 5° in the adjacent segment. Clinical outcomes were assessed with the numeric rating scale (NRS) and the Oswestry Disability Index (ODI) scores. The follow-up period for all patients lasted a minimum of 2 years. RESULTS: Among all 68 patients, group L4 consisted of 15 patients and group L5 comprised 53 patients. The patients included in both groups had comparable baseline demographic characteristics and radiographic parameters. Postoperative SP and SDSG-LSA were significantly lower in group L5 (p < 0.05). No other postoperative radiographic differences were observed between groups. One patient in group L4 and 3 patients in group L5 experienced transient neurological deficits (p > 0.05). There were 13 cases of ASI in group L5 compared with none in group L4 (24.5% vs 0%, p > 0.05). Of the 13 patients with ASI, 4 underwent revision surgery due to L4-5 level instability and clinical symptoms. The remaining individuals exhibited no symptoms, and regular annual follow-up assessments are being conducted for all patients. The NRS and ODI scores at final follow-up did not exhibit any significant differences between the two groups. CONCLUSIONS: Fusion to L5 could achieve comparable satisfactory results to fixation to L4, albeit with increased likelihood of ASI. Extension of fusion to L4 may not be necessary for most patients with pediatric L5-S1 spondylolisthesis.

Accessing gold p-acid reactivity under electrochemical anode oxidation (EAO) through oxidation relay.

The gold π-acid activation under electrochemical conditions is achieved. While EAO allows easy access to gold(III) intermediates over alternative chemical oxidation under mild conditions, the reported examples so far are limited to coupling reactions due to the rapid AuIII reductive elimination. Using aryl hydrazine-HOTf salt as precursors, the π-activation reaction mode was realized through oxidation relay. Both alkene and alkyne di-functionalization were achieved with excellent functional group compatibility and regioselectivity, which extended the versatility and utility of electrochemical gold redox chemistry for future applications.

Macrophage RAGE deficiency prevents myocardial fibrosis by repressing autophagy-mediated macrophage alternative activation.

Myocardial fibrosis (MF) is the characteristic pathological feature of various cardiovascular diseases that lead to heart failure (HF) or even fatal outcomes. Alternatively, activated macrophages are involved in the development of fibrosis and tissue remodeling. Although the receptor for advanced glycation end products (RAGE) is involved in MF, its potential role in regulating macrophage function in cardiac fibrosis has not been fully investigated. We aimed to determine the role of macrophage RAGE in transverse aortic constriction (TAC)-induced MF. In this study, we found that RAGE expression was markedly increased in the infiltrated alternatively activated macrophages within mice hearts after TAC. RAGE knockout mice showed less infiltration of alternatively activated macrophages and attenuated cardiac hypertrophy and fibrosis compared to the wild-type mice. Our data suggest that mice with macrophage-specific genetic deletion of RAGE were protected from interstitial fibrosis and cardiac dysfunction when subjected to pressure overload, which led to a decreased proportion of alternatively activated macrophages in heart tissues. Our in vitro experiments demonstrated that RAGE deficiency inhibited the differentiation into alternatively activated macrophages by suppressing autophagy activation. In the co-culture system, in vitro polarization of RAW264.7 macrophages toward an alternatively activated phenotype stimulated the expression of α-smooth muscle actin and collagen in cardiac fibroblasts. However, the knockdown of RAGE and inhibition of autophagy in macrophages showed reduced fibroblast-to-myofibroblast transition (FMT). Collectively, our results suggest that RAGE plays an important role in the recruitment and activation of alternatively activated macrophages by regulating autophagy, which contributes to MF. Thus, blockage of RAGE signaling may be an attractive therapeutic target for the treatment of hypertensive heart disease.

Risk factors for intensive care unit admission following correction surgery for adult spinal deformity.

OBJECTIVE: The literature currently available on the characteristics of patients who require intensive care unit (ICU) admission after correction surgery for adult spinal deformity is lacking; this study aimed to identify risk factors for postoperative ICU admission following correction surgery for adult spinal deformity. METHODS: A retrospective review of patients who underwent primary posterior-based spinal fusion from 2015 to 2023 was performed. According to the ward they returned to, patients were further divided into an ICU group and a non-ICU group. Univariate and multivariate analyses were performed to evaluate preoperative and perioperative parameters to identify independent risk factors for postoperative ICU admission in adult spinal deformity patients. RESULTS: A total of 274 patients were included, including 115 males (41.97%) and 159 females (58.03%). The mean age of the patients was 32.00 ± 11.16 years (19-77 years). Following adjusted analysis, the preoperative and perioperative factors that were independently associated with ICU admission were age, body mass index ≥ 28 kg/m2, neuromuscular spinal deformity, respiratory disease, grade III-IV American Society of Anesthesiologists (ASA) classification, a scoliosis Cobb angle ≥ 90°, a kyphosis Cobb angle ≥ 90°, and ≥ 12 fused segments. Compared with the non-ICU group, the ICU group had a higher incidence of complications, a longer hospital stay, and higher medical costs (P < 0.05). CONCLUSION: This study identified independent risk factors associated with postoperative ICU admission in adult spinal deformity patients; and explored relative measures to decrease or avoid the risk of postoperative ICU admission. Surgeons could use these data to develop and plan appropriate perioperative care processes in advance and provide consultation for family members before surgery.

Accessing Gold π-Acid Reactivity under Electrochemical Anode Oxidation (EAO) through Oxidation Relay.

The gold π-acid activation under electrochemical condition is achieved for the first time. While EAO allowing easy access to gold(III) intermediates over alternative chemical oxidation under mild conditions, the reported examples so far limited to coupling reactions due to the rapid AuIII reductive elimination. Using aryl hydrazine-HOTf salt as precursors, the π-activation reaction mode was realized through oxidation relay. Both alkene and alkyne di-functionalization were achieved with excellent functional group compatibility and regioselectivity, which extended the versatility and utility of electrochemical gold redox chemistry for future applications to come.

Asymmetric Hydrative Aldol Reaction (HAR) via Vinyl-Gold Promoted Intermolecular Ynamide Addition to Aldehydes.

Herein, we reported an intermolecular asymmetric hydrative aldol reaction through vinyl-gold intermediate under ambient conditions. This tandem alkyne hydration and sequential nucleophilic addition afforded a "base-free" approach to ß-hydroxy amides with high efficiency (up to 95 % yields, >50 examples). Vinyl gold intermediate was applied as reactive nucleophile and Fe(acac)3 was used as the critical co-catalyst to prevent undesired protodeauration, allowing this transformation to proceed under mild conditions with good functional group tolerance and excellent stereoselectivity (>20 : 1 d.r. and up to 99 % ee).

Taenionemasinensis sp. n., the first endemic species of Taenionema Banks, 1905 (Plecoptera, Taeniopterygidae) from China.

Background: The taeniopterygid genus Taenionema Banks, 1905 currently contains 14 species distributed in the Nearctic and the eastern Palearctic Regions. Taenionemajaponicum (Okamoto, 1922) is the only species known from the Eastern Hemisphere, specifically in Japan, Korea, Mongolia, Russia and north-eastern China. The authors recently described the larvae of an undetermined Taenionema species, which was supposed to represent a second Palaearctic species. New information: This paper reports the first endemic species of Taenionema Banks, 1905, Taenionemasinensis sp. n. from China, which also represents the second species of Taenionema from the Eastern Hemisphere. Description and illustrations based on male and female adults are provided. The new species is easily distinguished from all congeners by the bilobed abdominal sternum 9 of the male adult. The female adult is characterised by the posteriorly truncate postgenital plate. The male larva is distinguished by the emarginate subgenital plate and hook-shaped paraprocts.

Membrane engineering of Escherichia coli based on "Building bridges" and "Digging tunnels" to improve electro-fermentation of succinate.

Succinate is the end product of anaerobic metabolism of Escherichia coli, and its over-production needs abundant reducing force. Electro-fermentation (EF) is a novel biotechnology to steer and control fermentative processes by supplying extra electrons. However, E.coli is a non-electroactive strain which needs the support of electron shuttle in EF. Here, membrane engineering strategies of "Building bridges" via screening direct electron transport pathway and "Digging tunnels" via screening membrane porins were developed to improve the transmembrane transport of electron during the cathodic electro-fermentation (CEF). As a result, the total electron quantity during electro-fermentation was increased from 1.21 mmol to 7.90 mmol, and succinate yield was increased by 23.3% when these strategies simultaneously were applied to the succinate candidate E. coli Suc260. Hence, this study provides a reference mode for designing and constructing non-electroactive bacteria for electro-fermentation of reductive metabolites.

Gold-Catalyzed Amine Cascade Addition to Diyne-Ene: Enantioselective Synthesis of 1,2-Dihydropyridines.

With the well-documented chemical and biological applications, piperidine and pyridine are among the most important N-heterocycles, and a new synthetic strategy, especially one with an alternative bond-forming design, is of general interest. Using the gold-catalyzed intermolecular condensation of amine and diyne-ene, we report herein the first example of enantioselective 1,2-dihydropyridine synthesis through a formal [3+2+1] fashion (up to 95 % yield, up to 99 % e.e.).

Ten-year trends in surgical management of 1207 congenital scoliosis.

PURPOSE: To report and analyze development trends in the surgical treatment of congenital scoliosis (CS) in a large CS cohort over a 10-year period. METHODS: We retrospectively searched and extracted medical records of CS inpatients receiving posterior instrumented fusion surgery at our institute from January 2010 to December 2019. We analyzed information on demographics and surgical information, including the surgical approach, number of fused segments, use of osteotomy and titanium cage implantation, length of stay, intraoperative blood loss, and rates of complications and readmission. RESULTS: 1207 CS inpatients were included. In the past decade, the proportion of patients younger than 5 years increased from 15.5 to 26.9%. The average number of fused segments decreased from 9.24 to 7.48, and the proportion of patients treated with short-segment fusion increased from 13.4 to 30.3%. The proportion of patients treated with osteotomy and titanium cage implantation increased from 55.65% and 12.03% to 76.5% and 40.22%. The average length of stay and blood loss decreased from 16.5 days and 816.1 ml to 13.5 days and 501.7 ml. The complication and readmission rates also decreased during these ten years. CONCLUSION: During this ten-year period, the surgical treatment of CS at our institute showed trends toward a younger age at fusion, lower number of fused segments, higher rate of osteotomy and titanium cage implantation, reduced blood loss, shorter length of stay and lower rate complications and readmission. These results suggest performing osteotomy combined with titanium cage implantation at an earlier age can achieve fewer fused segments and complications.

A new earwig species of the genus Liparura Burr, 1907 (Dermaptera: Forficulidae) from China.

A new earwig species of the genus Liparura Burr, 1907 of the family Forficulidae, namely L. chongqingensis sp. nov., is described from Chongqing, southwestern China. The new species is characterized by the male forceps basally approached to each other, and each with a small tooth protruding dorsad. A key to the species of Liparura is provided.

Clinical outcomes of the traditional dual growing rod technique combined with apical pedicle screws in the treatment of early-onset scoliosis: preliminary results from a single center.

OBJECTIVE: Limited control of an apical deformity is a major disadvantage in the traditional dual growing rod (TDGR) technique. Previous literature has reported the results of apical pedicle screw placement (APS) as an apical control technique in patients with early-onset scoliosis (EOS). However, the clinical outcomes, indications, and complications of the TDGR technique combined with APSs have not been well described. The purpose of this study was to evaluate the preliminary clinical outcomes of the TDGR technique combined with APSs in EOS patients. METHODS: Clinical data of 12 patients with EOS who were treated with the TDGR technique combined with APSs at the index surgery at the authors' center from January 2010 to January 2020, with a minimum 2-year follow-up, were retrospectively reviewed. Indications for the use of APSs included 1) no vertebral segmentation failure, fused ribs, or multiple hemivertebrae at the apex; 2) at least 2 normal discs around the apex; and 3) proper development of apical pedicles on the convex side. Etiology, age at index surgery, number of lengthening procedures, follow-up duration, and complications were recorded. Radiographic measurements included Cobb angle, apical vertebral translation (AVT), apical vertebral rotation (AVR), thoracic kyphosis, lumbar lordosis, spine height, and space available for the lung (SAL). RESULTS: The mean follow-up period was 4.0 ± 1.4 years, with a mean of 4.8 lengthening procedures per patient. The mean Cobb angle improved from 61.7° ± 10.4° to 19.9° ± 9.0° after the index surgery (19.6° ± 9.4° at the latest follow-up). The mean postindex AVT decreased to 16.8 ± 8.9 mm from a preindex AVT of 56.3 ± 9.7 mm and further improved to 13.6 ± 10.0 mm at the latest follow-up. The mean annual increases in T1-12 and T1-S1 height were 9.0 ± 4.7 mm and 13.9 ± 6.5 mm, respectively. The SAL improved from 0.91 to 1.04 at the latest follow-up. AVR improved significantly after the index surgery (p = 0.013), while minor deterioration was observed after repeat lengthening procedures. Five complications (2 implant related and 3 alignment related) occurred in 4 patients. CONCLUSIONS: For EOS patients with good flexibility (without segmentation failure or multiple hemivertebrae at the apex), the TDGR technique combined with APSs can improve primary curve correction, maintain good correction results, and allow continuous spine growth, which may reduce the risks of complications during lengthening treatment. More multicenter prospective studies with larger samples are needed to further validate the findings of this study.

Nuanxinkang prevents the development of myocardial infarction-induced chronic heart failure by promoting PINK1/Parkin-mediated mitophagy.

BACKGROUND: Mitochondrial dysfunction is an important pathological feature of chronic heart failure (CHF). Regulation of mitophagy can effectively maintain mitochondrial homeostasis and energy metabolism, thereby inhibiting the development of CHF. Nuanxinkang (NXK), a Chinese herbal compound preparation, has significant cardioprotective effects on CHF; however, its underlying mechanism on mitophagy has not been completely clarified. This research intended to investigate the mechanism of NXK in treating myocardial infarction (MI)-induced CHF. METHODS: The left anterior descending coronary artery (LAD) ligation surgery was performed to establish an MI-induced CHF model in male C57BL/6 mice. From 1 day after surgery, mice were given NXK (0.41, 0.82 or 1.65 g/kg/d), Perindopril (PDPL, 0.607 mg/kg/d), or an equivalent amount of sterile water by gavage for 28 continuous days. Then, mice were examined for cardiac function, myocardial fibrosis, cardiomyocyte apoptosis, mitochondrial structure and mitophagy levels of cardiomyocytes, etc. In addition, a hypoxic injury model was created using HL-1 cardiomyocytes from wild-type (WT) mice. HL-1 cells were pretreated with or without NXK-containing serum. Mitochondrial function and mitophagy levels were examined in HL-1 cells. RESULTS: In MI-induced CHF mice, cardiac dysfunction, severe cardiac remodeling, elevated levels of oxidative stress, reduced ATP levels, and inhibition of PINK1/Parkin-mediated mitophagy were observed. High-dose NXK treatment (1.65 g/kg/d) significantly improved myocardial energy metabolism, inhibited cardiac remodeling, improved cardiac function, and restored cardiac PINK1/Parkin-mediated mitophagy levels to some extent in MI mice. In vitro, elevated levels of mitochondrial reactive oxygen species (ROS) with impaired mitochondrial membrane potential (ΔΨm) were observed in hypoxic HL-1 cells. While NXK treatment significantly protected cardiomyocytes from hypoxia-induced mitochondrial dysfunction, which is consistent with the in vivo results. Further studies showed that NXK could increase PINK1/Parkin-mediated mitophagy levels in cardiomyocytes, which could be blocked by the mitophagy inhibitor Mdivi-1. CONCLUSION: In conclusion, NXK could prevent cardiac mitochondrial dysfunction and improve cardiac function against MI-induced CHF by promoting Pink1/Parkin-mediated mitophagy, which represents a very prospective strategy for the treatment of CHF.

Plantamajoside attenuates cardiac fibrosis via inhibiting AGEs activated-RAGE/autophagy/EndMT pathway.

Advanced glycation end products (AGEs) have been identified to transduce fibrogenic signals via inducing the activation of their receptor (RAGE)-mediated pathway. Recently, disrupting AGE-RAGE interaction has become a promising therapeutic strategy for chronic heart failure (CHF). Endothelial-to-mesenchymal transition (EndMT) is close to the cardiac fibrosis pathological process. Our previous studies have demonstrated that knockout RAGE suppressed the autophagy-mediated EndMT, and thus alleviated cardiac fibrosis. Plantamajoside (PMS) is the major bioactive compound of Plantago Asiatica, and its activity of anti-fibrosis has been documented in many reports. However, its effect on CHF and the underlying mechanism remains elusive. Thus, we tried to elucidate the protective role of PMS in CHF from the viewpoint of the AGEs/RAGE/autophagy/EndMT axis. Herein, PMS was found to attenuate cardiac fibrosis and dysfunction, suppress EndMT, reduce autophagy levels and serum levels of AGEs, yet did not affect the expression of RAGE in CHF mice. Mechanically, PMS possibly binds to the V-domain of RAGE, which is similar to the interaction between AGEs and RAGE. Importantly, this competitive binding disturbed AGEs-induced the RAGE-autophagy-EndMT pathway in vitro. Collectively, our results indicated that PMS might exert an anti-cardiac fibrosis effect by specifically binding RAGE to suppress the AGEs-activated RAGE/autophagy/EndMT pathway.

Drug vector representation and potential efficacy prediction based on graph representation learning and transcriptome data: Acacetin from traditional Chinese Medicine model.

ETHNOPHARMACOLOGICAL RELEVANCE: Acacetin is widely distributed in traditional Chinese medicine and traditional herbs, with strong biological activity. Perhaps there are many potential effects that have not been explored. In the field of drug discovery, Mainstream methods focus on chemical structure. Traditional medicine cannot adapt to the mainstream prediction methods due to its complex composition. AIM OF THE STUDY: Our aim is that provide a prediction method more suitable for traditional medicine by graph representation learning and transcriptome data. And use this method to predict acacetin. MATERIALS AND METHODS: Our method mainly consists of two parts. The first part is to use the method of graph representation learning to vectorize drugs as a database. The original data of this part comes from transcriptome data on Gene Expression Omnibus. The method of graph representation learning is an unsupervised learning. If there is no prior knowledge as the label data, the training effect cannot be analyzed. Therefore, we define a standard score to evaluate our results through the idea of Jaccard index. The second part is to put the target drug into our database. The potential similarity between drugs was evaluated by the Euclidean distance between vectors, and the potential efficacy of the target drug is predicted by combining the chemical-disease relationship data in the Comparative Toxicogenomics Database. The target drug in this paper uses acacetin. We compared the predicted results with existing reports, and we also experimentally verified the efficacy of improving insulin resistance in the predicted results. RESULTS: The prediction results are relatively consistent with the existing reports, which demonstrated that our method has a certain degree of predictive performance. And for the efficacy of improving insulin resistance in the predicted result, we verified it through experiments. CONCLUSIONS: We propose a method to predict the potential efficacy of drugs based on transcriptome data, using Graph representation learning, which is very suitable for traditional medicine. Through this method, we predicted the efficacy of acacetin, and the results are relatively consistent with the current reports. This provides a new idea for unsupervised learning to apply medical information.

Lowest Instrumented Vertebra at L3 Versus L4 in Posterior Fusion for Moderate Lenke 5C Type Adolescent Idiopathic Scoliosis: A Case-Match Radiological Study.

OBJECTIVE: To compare the radiological outcomes in Lenke 5C type patients whose lowest instrumented vertebra (LIV) was L3 or L4 in a case-match study. METHODS: We conducted a retrospective case-match study and included 82 patients in the study. Radiological results before surgery, after surgery, and at last follow-up were recorded and analyzed in the L3 and L4 groups. RESULTS: After matching the age, Risser's sign, sex, and main Cobb, 41 pairs of patients were enrolled in our study. The total fusion segments in the L3 group (median [interquartile range]: 5.0 [6.0-5.0]) were shorter than those in the L4 group (6.0 [6.5-6.0]). The main curve was significantly corrected after surgery in both groups, and was comparable at the last followup between groups. In addition, according to the results of Fisher precision probability test, there was no significant difference of coronal or sagittal imbalance between the 2 groups at the 2-year follow-up. CONCLUSION: The correction in coronal and sagittal planes in L3 group and L4 group remains similar. On account of more motion segments, L3 could be an ideal choice as LIV in moderate Lenke 5C type AIS. Long-term follow-up is needed to evaluate the effect of larger compensatory lumbar-sacral curve when stopping at L3.

Self-assembly of X-shaped antibody to combine the activity of IgG and IgA for enhanced tumor killing.

Rationale: IgA can induce activation of neutrophils which are the most abundant cell type in blood, but the development of IgA as therapeutic has been confounded by its short half-life and a weak ability to recruit NK cells as effector cells. Therefore, we generated an X-shaped antibody (X-body) based on the principle of molecular self-assembly that combines the activities of both IgG and IgA, which can effectively recruit and activate NK cells, macrophages, and neutrophils to kill tumor cells. Methods: X-body was generated by using a self-assembly strategy. The affinity of the X-body with the antigen and Fc receptors was tested by surface plasmon resonance. The shape of X-body was examined using negative staining transmission electron microscopy. The tumor cell killing activity of X-body was assessed in vitro and in multiple syngeneic mouse models. To explore the mechanism of X-body, tumor-infiltrating immune cells were analyzed by single-cell RNA-seq and flow cytometry. The dependence of neutrophil, macrophage, and NK cells for the X-body efficacy was confirmed by in vivo depletion of immune cell subsets. Results: The X-body versions of rituximab and trastuzumab combined the full spectrum activity of IgG and IgA and recruited NK cells, macrophages, and neutrophils as effector cells for eradication of tumor cells. Treatment with anti-hCD20 and anti-hHER2 X-bodies leads to a greater reduction in tumor burden in tumor-bearing mice compared with the IgA or IgG counterpart, and no obvious adverse effect is observed upon X-body treatment. Moreover, the X-body has a serum half-life and drug stability comparable to IgG. Conclusions: The X-body, as a myeloid-cell-centered therapeutic strategy, holds promise for the development of more effective cancer-targeting therapies than the current state of the art.