On Demand Bioorthogonal Switching of an Antibody-Conjugated SPECT Probe to a Cytotoxic Payload: from Imaging to Therapy.

Antibody-drug conjugates (ADCs) for the treatment of cancer aim to achieve selective delivery of a cytotoxic payload to tumor cells while sparing normal tissue. In vivo, multiple tumor-dependent and -independent processes act on ADCs and their released payloads to impact tumor-versus-normal delivery, often resulting in a poor therapeutic window. An ADC with a labeled payload would make synchronous correlations between distribution and tissue-specific pharmacological effects possible, empowering preclinical and clinical efforts to improve tumor-selective delivery; however, few methods to label small molecules without destroying their pharmacological activity exist. Herein, we present a bioorthogonal switch approach that allows a radiolabel attached to an ADC payload to be removed tracelessly at will. We exemplify this approach with a potent DNA-damaging agent, the pyrrolobenzodiazepine (PBD) dimer, delivered as an antibody conjugate targeted to lung tumor cells. The radiometal chelating group, DOTA, was attached via a novel trans-cyclooctene (TCO)-caged self-immolative para-aminobenzyl (PAB) linker to the PBD, stably attenuating payload activity and allowing tracking of biodistribution in tumor-bearing mice via SPECT-CT imaging (live) or gamma counting (post-mortem). Following TCO-PAB-DOTA reaction with tetrazines optimized for extra- and intracellular reactivity, the label was removed to reveal the unmodified PBD dimer capable of inducing potent tumor cell killing in vitro and in mouse xenografts. The switchable antibody radio-drug conjugate (ArDC) we describe integrates, but decouples, the two functions of a theranostic given that it can serve as a diagnostic for payload delivery in the labeled state, but can be switched on demand to a therapeutic agent (an ADC).

Mapping of lymph node metastasis from esophageal squamous cell carcinoma after neoadjuvant treatment: a prospective analysis from a high-volume institution in China.

The study aimed to describe the prevalence of lymph node metastases per lymph node station for esophageal squamous cell carcinoma (ESCC) after neoadjuvant treatment. Clinicopathological variables of ESCC patients were retrieved from the prospective database of the Surgical Esophageal Cancer Patient Registry in West China Hospital, Sichuan University. A two-field lymphadenectomy was routinely performed, and an extensive three-field lymphadenectomy was performed if cervical lymph node metastasis was suspected. According to AJCC/UICC 8, lymph node stations were investigated separately. The number of patients with metastatic lymph nodes divided by those who underwent lymph node dissection at that station was used to define the percentage of patients with lymph node metastases. Data are also separately analyzed according to the pathological response of the primary tumor, neoadjuvant treatment regimens, pretreatment tumor length, and tumor location. Between January 2019 and March 2023, 623 patients who underwent neoadjuvant therapy followed by transthoracic esophagectomy were enrolled. Lymph node metastases were found in 212 patients (34.0%) and most frequently seen in lymph nodes along the right recurrent nerve (10.1%, 58/575), paracardial station (11.4%, 67/587), and lymph nodes along the left gastric artery (10.9%, 65/597). For patients with pretreatment tumor length of >4 cm and non-pathological complete response of the primary tumor, the metastatic rate of the right lower cervical paratracheal lymph nodes is 10.9% (10/92) and 10.6% (11/104), respectively. For patients with an upper thoracic tumor, metastatic lymph nodes were most frequently seen along the right recurrent nerve (14.2%, 8/56). For patients with a middle thoracic tumor, metastatic lymph nodes were most commonly seen in the right lower cervical paratracheal lymph nodes (10.3%, 8/78), paracardial lymph nodes (10.2%, 29/285), and lymph nodes along the left gastric artery (10.4%, 30/289). For patients with a lower thoracic tumor, metastatic lymph nodes were most frequently seen in the paracardial station (14.2%, 35/247) and lymph nodes along the left gastric artery (13.1%, 33/252). The study precisely determined the distribution of lymph node metastases in ESCC after neoadjuvant treatment, which may help to optimize the extent of lymphadenectomy in the surgical management of ESCC patients after neoadjuvant therapy.

The Spatiotemporal Expression of SOCS3 in the Brainstem and Spinal Cord of Amyotrophic Lateral Sclerosis Mice.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of motor neurons from the brain and spinal cord. The excessive neuroinflammation is thought to be a common determinant of ALS. Suppressor of cytokine signaling-3 (SOCS3) is pathologically upregulated after injury/diseases to negatively regulate a broad range of cytokines/chemokines that mediate inflammation; however, the role that SOCS3 plays in ALS pathogenesis has not been explored. Here, we found that SOCS3 protein levels were significantly increased in the brainstem of the superoxide dismutase 1 (SOD1)-G93A ALS mice, which is negatively related to a progressive decline in motor function from the pre-symptomatic to the early symptomatic stage. Moreover, SOCS3 levels in both cervical and lumbar spinal cords of ALS mice were also significantly upregulated at the pre-symptomatic stage and became exacerbated at the early symptomatic stage. Concomitantly, astrocytes and microglia/macrophages were progressively increased and reactivated over time. In contrast, neurons were simultaneously lost in the brainstem and spinal cord examined over the course of disease progression. Collectively, SOCS3 was first found to be upregulated during ALS progression to directly relate to both increased astrogliosis and increased neuronal loss, indicating that SOCS3 could be explored to be as a potential therapeutic target of ALS.

Impact of Postoperative Bracing Following Spinal Fusion for Degenerative Lumbar Conditions: An Updated Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: There is a lack of consensus on the use of postoperative bracing for lumbar degenerative conditions. Spine surgeons typically determine whether to apply postoperative braces based primarily on clinical experience rather than robust, evidence-based medical data. Thus, the present study sought to assess the impact of postoperative bracing on clinical outcomes, complications, and fusion rates following lumbar fusion surgery in patients with degenerative spinal conditions. METHODS: Only randomized controlled studies published between January 1990 and 20 October 2023 were included in this meta-analysis. The primary outcome measures consisted of pre- and postoperative assessments of the Oswestry Disability Index (ODI) and visual analog scale (VAS) scores. Improvements in VAS and ODI scores were analyzed in the early postoperative period (1 month after operation) and at final follow-up, respectively. The analysis also encompassed fusion rates and complications. RESULTS: Five studies with 362 patients were included in the present meta-analysis. In the early postoperative period, the brace group showed a relatively better improvement in ODI scores compared with the no-brace group (19.47 vs 18.18), although this difference was not statistically significant (P = 0.34). Similarly, during the late postoperative period, the brace group demonstrated a slightly greater improvement in VAS scores in comparison to the no-brace group (4.05 vs 3.84), but this difference did not reach statistical significance (P = 0.30). The complication rate was relatively lower in the brace group compared with the no-brace group (14.9% vs 17.4%), although there was no statistical difference between the 2 groups (P = 0.83). Importantly, there were no substantial differences in fusion rates between patients with or without braces. CONCLUSION: The present meta-analysis revealed that the implementation of a brace following lumbar fusion surgery did not yield substantial differences in terms of postoperative pain relief, functional recovery, complication rates, or fusion rates when compared with cases where no brace was employed. CLINICAL RELEVANCE: This meta-analysis provides valuable insights into the clinical impact of postoperative bracing following lumbar fusion surgery for degenerative spinal conditions.

A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22.

The CUL3-RING E3 ubiquitin ligases (CRL3s) play an essential role in response to extracellular nutrition and stress stimuli. The ubiquitin ligase function of CRL3s is activated through dimerization. However, how and why such a dimeric assembly is required for its ligase activity remains elusive. Here, we report the cryo-EM structure of the dimeric CRL3KLHL22 complex and reveal a conserved N-terminal motif in CUL3 that contributes to the dimerization assembly and the E3 ligase activity of CRL3KLHL22. We show that deletion of the CUL3 N-terminal motif impairs dimeric assembly and the E3 ligase activity of both CRL3KLHL22 and several other CRL3s. In addition, we found that the dynamics of dimeric assembly of CRL3KLHL22 generates a variable ubiquitination zone, potentially facilitating substrate recognition and ubiquitination. These findings demonstrate that a CUL3 N-terminal motif participates in the assembly process and provide insights into the assembly and activation of CRL3s.

Comparative outcomes of obese and non-obese patients with lumbar disc herniation receiving full endoscopic transforaminal discectomy: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the impact of full endoscopic transforaminal discectomy (FETD) on clinical outcomes and complications in both obese and non-obese patients presenting with lumbar disc herniation (LDH). METHODS: A systematic search of relevant literature was conducted across various primary databases until November 18, 2023. Operative time and hospitalization were evaluated. Clinical outcomes included preoperative and postoperative assessments of the Oswestry Disability Index (ODI) and visual analogue scale (VAS) scores, conducted to delineate improvements at 3 months postoperatively and during the final follow-up, respectively. Complications were also documented. RESULTS: Four retrospective studies meeting inclusion criteria provided a collective cohort of 258 patients. Obese patients undergoing FETD experienced significantly longer operative times compared to non-obese counterparts (P = 0.0003). Conversely, no statistically significant differences (P > 0.05) were observed in hospitalization duration, improvement of VAS for back and leg pain scores at 3 months postoperatively and final follow-up, improvement of ODI at 3 months postoperatively and final follow-up. Furthermore, the overall rate of postoperative complications was higher in the obese group (P = 0.02). The obese group demonstrated a total incidence of complications of 17.17%, notably higher than the lower rate of 9.43% observed in the non-obese group. CONCLUSION: The utilization of FETD for managing LDH in individuals with obesity is associated with prolonged operative times and a higher total complication rate compared to their non-obese counterparts. Nevertheless, it remains a safe and effective surgical intervention for treating herniated lumbar discs in the context of obesity.

Tunable Phonon Polariton Hybridization in a van der Waals Hetero-Bicrystal.

Phonon polaritons, the hybrid quasiparticles resulting from the coupling of photons and lattice vibrations, have gained significant attention in the field of layered van der Waals heterostructures. Particular interest has been paid to hetero-bicrystals composed of molybdenum oxide (MoO3) and hexagonal boron nitride (hBN), which feature polariton dispersion tailorable via avoided polariton mode crossings. In this work, we systematically study the polariton eigenmodes in MoO3-hBN hetero-bicrystals self-assembled on ultrasmooth gold using synchrotron infrared nanospectroscopy. We experimentally demonstrate that the spectral gap in bicrystal dispersion and corresponding regimes of negative refraction can be tuned by material layer thickness, and we quantitatively match these results with a simple analytic model. We also investigate polaritonic cavity modes and polariton propagation along "forbidden" directions in our microscale bicrystals, which arise from the finite in-plane dimension of the synthesized MoO3 micro-ribbons. Our findings shed light on the unique dispersion properties of polaritons in van der Waals heterostructures and pave the way for applications leveraging deeply sub-wavelength mid-infrared light matter interactions. This article is protected by copyright. All rights reserved.

A von-Neumann-like photonic processor and its application in studying quantum signature of chaos.

Photonic quantum computation plays an important role and offers unique advantages. Two decades after the milestone work of Knill-Laflamme-Milburn, various architectures of photonic processors have been proposed, and quantum advantage over classical computers has also been demonstrated. It is now the opportune time to apply this technology to real-world applications. However, at current technology level, this aim is restricted by either programmability in bulk optics or loss in integrated optics for the existing architectures of processors, for which the resource cost is also a problem. Here we present a von-Neumann-like architecture based on temporal-mode encoding and looped structure on table, which is capable of multimode-universal programmability, resource-efficiency, phase-stability and software-scalability. In order to illustrate these merits, we execute two different programs with varying resource requirements on the same processor, to investigate quantum signature of chaos from two aspects: the signature behaviors exhibited in phase space (13 modes), and the Fermi golden rule which has not been experimentally studied in quantitative way before (26 modes). The maximal program contains an optical interferometer network with 1694 freely-adjustable phases. Considering current state-of-the-art, our architecture stands as the most promising candidate for real-world applications.

Resource-Efficient Direct Characterization of General Density Matrix.

Sequential weak measurements allow for the direct extraction of individual density-matrix elements, rather than relying on global reconstruction of the entire density matrix, which opens a new avenue for the characterization of quantum systems. Nevertheless, extending the sequential scheme to multiqudit quantum systems is challenging due to the requirement of multiple coupling processes for each qudit and the lack of appropriate precision evaluation. To address these issues, we propose a resource-efficient scheme (RES) that directly characterizes the density matrix of general multiqudit systems while optimizing measurements and establishing a feasible estimation analysis. In the RES, an efficient observable of the quantum system is constructed such that a single meter state coupled to each qudit is sufficient to extract the corresponding density-matrix element. An appropriate model based on the statistical distribution of errors is utilized to evaluate the precision and feasibility of the scheme. We have experimentally applied the RES to the direct characterization of general single-photon qutrit states and two-photon entangled states. The results show that the RES outperforms sequential schemes in terms of efficiency and precision in both weak- and strong-coupling scenarios. This Letter sheds new light on the practical characterization of large-scale quantum systems and the investigation of their nonclassical properties.

Structural insights into the ubiquitylation strategy of the oligomeric CRL2FEM1B E3 ubiquitin ligase.

Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2FEM1B in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2FEM1B is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2FEM1B. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2FEM1B according to substrates with different scales.

Increased resected lymph node stations improved survival of esophageal squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery have been recommended as the standard treatments for locally advanced esophageal squamous cell carcinoma (ESCC). In addition, nodal metastases decreased in frequency and changed in distribution after neoadjuvant therapy. This study aimed to examine the optimal strategy for lymph node dissection (LND) in patients with ESCC who underwent nCRT. METHODS: The hazard ratios (HRs) for overall survival (OS) and disease-free survival (DFS) were calculated using the Cox proportional hazard model. To determine the minimal number of LNDs (n-LNS) or least station of LNDs (e-LNS), the Chow test was used. RESULTS: In total, 333 patients were included. The estimated cut-off values for e-LNS and n-LNS were 9 and 15, respectively. A higher number of e-LNS was significantly associated with improved OS (HR: 0.90; 95% CI 0.84-0.97, P = 0.0075) and DFS (HR: 0.012; 95% CI: 0.84-0.98, P = 0.0074). The e-LNS was a significant prognostic factor in multivariate analyses. The local recurrence rate of 23.1% in high e-LNS is much lower than the results of low e-LNS (13.3%). Comparable morbidity was found in both the e-LNS and n-LND subgroups. CONCLUSION: This cohort study revealed an association between the extent of LND and overall survival, suggesting the therapeutic value of extended lymphadenectomy during esophagectomy. Therefore, more lymph node stations being sampled leads to higher survival rates among patients who receive nCRT, and standard lymphadenectomy of at least 9 stations is strongly recommended.

Caltrop-like Small-Molecule Antidotes That Neutralize Unfractionated Heparin and Low-Molecular-Weight Heparin In Vivo.

Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) are widely applied for surgical procedures and extracorporeal therapies, which, however, suffer bleeding risk. Protamine, the only clinically approved antidote, can completely neutralize UFH, but only partially neutralizes LMWHs, and also has a number of safety drawbacks. Here, we show that caltrop-like multicationic small molecules can completely neutralize both UFH and LMWHs. In vitro and ex vivo assays with plasma and whole blood and in vivo assays with mice and rats support that the lead compound is not only superior to protamine by displaying higher neutralization activity and broader therapeutic windows but also biocompatible. The effective neutralization dose and the maximum tolerated dose of the lead compound are determined to be 0.4 and 25 mg/kg in mice, respectively, suggesting good promise for further preclinical studies.

Impact of deep muscle invasion on nodal status and survival in patients with pT2 esophageal squamous cancer.

BACKGROUND: Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status and survival outcomes. METHODS: We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model. RESULTS: A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.46-6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio [HR]: 1.37, 95% CI: 1.05-1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05-2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19-1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08-1.94; p = 0.035). CONCLUSIONS: We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.

Vitamin D receptor induces oxidative stress to promote esophageal squamous cell carcinoma proliferation via the p53 signaling pathway.

Background: Esophageal squamous cell carcinoma (ESCC) is a common pathological esophageal cancer with poor prognosis. Vitamin D deficiency reportedly occurs in ESCC patients, and this is related to single nucleotide polymorphism of vitamin D receptor (VDR). Objective: We investigated the effect of VDR on ESCC proliferation, invasion, and metastasis and its potential mechanism. Methods: ESCC and normal tissues were collected from 20 ESCC patients. The ESCC tissue microarray contained 116 pairs of ESCC and normal tissues and 73 single ESCC tissues. VDR expression and its clinicopathological role were determined by real-time quantitative polymerase chain reaction, Western blot, and immunohistochemistry staining. sh-VDR and VDR overexpression were used to validate the effect of VDR on ESCC cell phenotype, and tandem mass tag-based quantitative proteomics and bioinformatics methods identified differential VDR-related proteins. The downstream pathway and regulatory effect were analyzed using ingenuity pathway analysis (IPA). Differentially expressed proteins were verified through parallel reaction monitoring and Western blot. In vivo imaging visualized subcutaneous tumor growth following tail vein injection of VDR-deficient ESCC cells. Results: High VDR expression was observed in ESCC tissues and cells. Gender, T stage, and TNM stage were related to VDR expression, which was the independent prognostic factor related to ESCC. VDR downregulation repressed ESCC cell proliferation, invasion, and migration in vitro and subcutaneous tumor growth and lung metastases in vivo. The cell phenotype changes were reversed upon VDR upregulation, and differential proteins were mainly enriched in the p53 signaling pathway. TP53 cooperated with ABCG2, APOE, FTH1, GCLM, GPX1, HMOX1, JUN, PRDX5, and SOD2 and may activate apoptosis and inhibit oxidative stress, cell metastasis, and proliferation. TP53 was upregulated after VDR knockdown, and TP53 downregulation reversed VDR knockdown-induced cell phenotype changes. Conclusions: VDR may inhibit p53 signaling pathway activation and induce ESCC proliferation, invasion, and metastasis by activating oxidative stress.

Macrocycles and Acyclic Cucurbit[n]urils as Pseudo[2]catenane Partners for Long-Acting Neuromuscular Blocks and Rapid Reversal In Vivo.

Long-acting neuromuscular blocks followed by rapid reversal may provide prolonged surgeries with improved conditions by omitting repetitive or continuous administration of the neuromuscular blocking agent (NMBA), eliminating residual neuromuscular block and minimizing postoperative recovery, which, however, is not clinically available. Here, we demonstrate that imidazolium-based macrocycles (IMCs) and acyclic cucurbit[n]urils (ACBs) can form such partners by functioning as long-acting NMBAs and rapid reversal agents through a pseudo[2]catenation mechanism based on stable complexation with Ka values of over 109 M-1. In vivo experiments with rats reveal that, at the dose of 2- and 3-fold ED90, one IMC attains a duration of action corresponding to 158 or 442 min for human adults, covering most of prolonged surgeries. The block can be reversed by one ACB with recovery time significantly shorter than that achieved by sugammadex for reversing the block of rocuronium, the clinically most widely used intermediate-acting NMBA.

Impact of Skeletal Muscle Loss and Sarcopenia on Outcomes of Locally Advanced Esophageal Cancer during Neoadjuvant Chemoradiation.

BACKGROUND: The impact of changes in skeletal muscle and sarcopenia on outcomes during neoadjuvant chemoradiotherapy (NACR) for patients with esophageal cancer remains controversial. PATIENTS AND METHODS: We retrospectively analyzed the data of patients with locally advanced esophageal squamous cell cancer who received NACR followed by esophagectomy between June 2013 and December 2021. The images at third lumbar vertebra were analyzed to measure the cross-sectional area and calculate skeletal muscle index (SMI) before and after NACR. SMI less than 52.4 cm2/m2 for men and less than 38.5 cm2/m2 for women were defined as sarcopenia. The nonlinearity of the effect of percent changes in SMI (ΔSMI%) to survival outcomes was assessed by restricted cubic splines. RESULTS: Overall, data of 367 patients were analyzed. The survival outcomes between sarcopenia and non-sarcopenia groups had no significant differences before NACR. However, patients in post-NACR sarcopenia group showed poor overall survival (OS) benefit (P = 0.016) and poor disease-free survival (DFS) (P = 0.043). Severe postoperative complication rates were 11.9% in post-NACR sarcopenia group and 5.0% in post-NACR non-sarcopenia group (P = 0.019). There was a significant non-linear relationship between ΔSMI% and survival outcomes (P < 0.05 for non-linear). On the multivariable analysis of OS, ΔSMI% > 12% was the independent prognostic factor (HR 1.76, 95% CI 1.03-2.99, P = 0.039) and significant difference was also found on DFS analysis (P = 0.025). CONCLUSIONS: Patients with post-neoadjuvant chemoradiotherapy sarcopenia have worse survival and adverse short-term outcomes. Moreover, greater loss in SMI is associated with increased risks of death and disease progression during neoadjuvant chemoradiotherapy, with maximum impact noted with SMI loss greater than 12%.

Bioinspired Self-Assembly of Metalloporphyrins and Polyelectrolytes into Hierarchical Supramolecular Nanostructures for Enhanced Photocatalytic H2 Production in Water.

Polypeptides, as natural polyelectrolytes, are assembled into tailored proteins to integrate chromophores and catalytic sites for photosynthesis. Mimicking nature to create the water-soluble nanoassemblies from synthetic polyelectrolytes and photocatalytic molecular species for artificial photosynthesis is still rare. Here, we report the enhancement of the full-spectrum solar-light-driven H2 production within a supramolecular system built by the co-assembly of anionic metalloporphyrins with cationic polyelectrolytes in water. This supramolecular photocatalytic system achieves a H2 production rate of 793 and 685 µmol h-1 g-1 over 24 h with a combination of Mg or Zn porphyrin as photosensitizers and Cu porphyrin as a catalyst, which is more than 23 times higher than that of free molecular controls. With a photosensitizer to catalyst ratio of 10000 : 1, the highest H2 production rate of >51,700 µmol h-1 g-1 with a turnover number (TON) of >1,290 per molecular catalyst was achieved over 24 h irradiation. The hierarchical self-assembly not only enhances photostability through forming ordered stackings of the metalloporphyrins but also facilitates both energy and electron transfer from antenna molecules to catalysts, and therefore promotes the photocatalysis. This study provides structural and mechanistic insights into the self-assembly enhanced photostability and catalytic performance of supramolecular photocatalytic systems.

Prehospital ultrasound scanning for abdominal free fluid detection in trauma patients: a systematic review and meta-analysis.

INTRODUCTION: Focused assessment with sonography for trauma helps detect abdominal free fluid. Prehospital ultrasound scanning is also important because the early diagnosis of hemoperitoneum may reduce the time to definitive treatment in the hospital. This study investigated whether prehospital ultrasound scanning can help detect abdominal free fluid. MATERIALS AND METHODS: In this systematic review, relevant databases were searched for studies investigating prehospital ultrasound examinations for abdominal free fluid in trauma patients. The prehospital ultrasound results were compared with computed tomography, surgery, or hospital ultrasound examination data. The pooled sensitivity and specificity values were analyzed using forest plots. The overall predictive power was calculated by the summary receiver operating characteristic curve. The quality of the included studies was assessed using the quality assessment of diagnostic accuracy studies tool. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was performed to assess the certainty of evidence. RESULT: This meta-analysis comprised six studies that included 1356 patients. The pooled sensitivity and specificity values were 0.596 (95% confidence interval [CI] = 0.345-0.822) and 0.970 (95% CI = 0.953-0.983), respectively. The pooled area under the summary receiver operating characteristic curve was 0.998. The quality assessment tool showed favorable results. In the GRADE analysis, the quality of evidence was very low for sensitivity and high for specificity when prehospital ultrasound was used for hemoperitoneum diagnosis. CONCLUSION: The specificity of abdominal free fluid detection using prehospital ultrasound examinations in trauma patients was very high.

The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results.

Approved antibody-drug conjugates (ADCs) for HER2-positive breast cancer include trastuzumab emtansine and trastuzumab deruxtecan. To develop a differentiated HER2 ADC, we chose an antibody that does not compete with trastuzumab or pertuzumab for binding, conjugated to a reduced potency PBD (pyrrolobenzodiazepine) dimer payload. PBDs are potent cytotoxic agents that alkylate and cross-link DNA. In our study, the PBD dimer is modified to alkylate, but not cross-link DNA. This HER2 ADC, DHES0815A, demonstrates in vivo efficacy in models of HER2-positive and HER2-low cancers and is well-tolerated in cynomolgus monkey safety studies. Mechanisms of action include induction of DNA damage and apoptosis, activity in non-dividing cells, and bystander activity. A dose-escalation study (ClinicalTrials.gov: NCT03451162) in patients with HER2-positive metastatic breast cancer, with the primary objective of evaluating the safety and tolerability of DHES0815A and secondary objectives of characterizing the pharmacokinetics, objective response rate, duration of response, and formation of anti-DHES0815A antibodies, is reported herein. Despite early signs of anti-tumor activity, patients at higher doses develop persistent, non-resolvable dermal, ocular, and pulmonary toxicities, which led to early termination of the phase 1 trial.