An αIIbß3 Monoclonal Antibody Traps a Semi-Extended Conformation and Allosterically Inhibits Large Ligand Binding.

Monoclonal antibodies (mAbs) have provided valuable information on the structure and function of platelet αIIbß3. Protein disulfide isomerase (PDI) has been implicated in αIIbß3 activation and binds to thrombin-activated αIIbß3. Using human platelets as immunogen, we identified a new mAb (R21D10) that inhibits the binding of PDI to platelets activated with a thrombin receptor-activating peptide (T6). R21D10 also partially inhibits T6-induced fibrinogen and PAC-1 binding to platelets, as well as T6- and ADP-induced platelet aggregation. Mutual competition experiments show that R21D10 does not inhibit binding of mAbs 10E5 (anti-αIIb cap domain) or 7E3 (anti-ß3 ß-I domain) and immunoblot studies indicate that R21D10 binds to ß3. Dissociation of αIIbß3 by EDTA had minimal effect on R21D10 binding. Cryo-electron microscopy of the αIIbß3-R21D10 Fab complex reveals that R21D10 binds to the ß3 I-EGF1 domain and traps an intermediate conformation of αIIbß3 with semi-extended leg domains. Binding of R21D10 produces a major structural change in the ß3 I-EGF2 domain associated with a new interaction between the ß3 I-EGF2 and the αIIb thigh domains, which may prevent the swing-out motion of the ß3 hybrid domain required for high-affinity ligand binding and protect αIIbß3 from EDTA-induced dissociation. R21D10 partially reverses the ligand binding priming effect of eptifibatide, suggesting that it can convert the swung-out conformation into the semi-extended conformation. We conclude that R21D10 inhibits ligand binding to αIIbß3 via a unique allosteric mechanism, which may or may not be related to its inhibition of PDI binding.

A machine learning radiomics based on enhanced computed tomography to predict neoadjuvant immunotherapy for resectable esophageal squamous cell carcinoma.

Background: Patients with resectable esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant immunotherapy (NIT) display variable treatment responses. The purpose of this study is to establish and validate a radiomics based on enhanced computed tomography (CT) and combined with clinical data to predict the major pathological response to NIT in ESCC patients. Methods: This retrospective study included 82 ESCC patients who were randomly divided into the training group (n = 57) and the validation group (n = 25). Radiomic features were derived from the tumor region in enhanced CT images obtained before treatment. After feature reduction and screening, radiomics was established. Logistic regression analysis was conducted to select clinical variables. The predictive model integrating radiomics and clinical data was constructed and presented as a nomogram. Area under curve (AUC) was applied to evaluate the predictive ability of the models, and decision curve analysis (DCA) and calibration curves were performed to test the application of the models. Results: One clinical data (radiotherapy) and 10 radiomic features were identified and applied for the predictive model. The radiomics integrated with clinical data could achieve excellent predictive performance, with AUC values of 0.93 (95% CI 0.87-0.99) and 0.85 (95% CI 0.69-1.00) in the training group and the validation group, respectively. DCA and calibration curves demonstrated a good clinical feasibility and utility of this model. Conclusion: Enhanced CT image-based radiomics could predict the response of ESCC patients to NIT with high accuracy and robustness. The developed predictive model offers a valuable tool for assessing treatment efficacy prior to initiating therapy, thus providing individualized treatment regimens for patients.

Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide-Drug Conjugates for Targeted Cancer Therapy.

Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo. Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 µM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.

Constructing high axiality mononuclear dysprosium molecular magnets via a regulation-of-co-ligands strategy.

Two lanthanide complexes with formulae [DyIII(LN5)(pentafluoro-PhO)3] (1) and [DyIII(LN5)(2,6-difluoro-PhO)2](BPh4) (2) (LN5 = 2,14-dimethyl-3,6,10,13,19-pentaazabicyclo[13.3.1]nonadecal (19),2,13,15,17-pentaene) were structurally and magnetically characterized. DyIII ions lie in the cavity of a five coordinate nitrogen macrocycle, and in combination with the introduction of multi-fluorinated monodentate phenoxyl coligands a high axiality coordination symmetry is built. Using the pentafluorophenol co-ligand, complex 1 with a D2d coordination environment, is obtained and displays moderate single-molecule magnets (SMMs) behavior. When difluorophenol co-ligands were used, a higher local axisymmetric pentagonal bipyramidal coordination geometry was observed in complex 2, which displays apparent slow magnetic relaxation behavior with a hysteresis temperature of up to 5 K. Further magnetic studies of diluted samples combined with ab initio calculations indicate that the high axiality plays a crucial role in suppressing quantum tunneling of magnetization (QTM) and consequently results in good slow magnetic relaxation behavior. Different fluoro-substituted phenoxyl co-ligands have phenoloxy oxygen atoms with different electrostatic potentials as well as a different number of phenoloxy coligands along the magnetic axis, resulting in different ligand field strengths and coordination symmetries.

Recent Advances in DNA Nanotechnology-Based Sensing Platforms for Rapid Virus Detection.

Several major viral pandemics in history have significantly impacted the public health of human beings. The COVID-19 pandemic has further underscored the critical need for early detection and screening of infected individuals. However, current detection techniques are confronted with deficiencies in sensitivity and accuracy, restricting the capability of detecting trace amounts of viruses in human bodies and in the environments.The advent of DNA nanotechnology has opened up a feasible solution for rapid and sensitive virus determination. By harnessing the designability and addressability of DNA nanostructures, a range of rapid virus sensing platforms have been proposed. This review overviewed the recent progress, application, and prospect of DNA nanotechnology-based rapid virus detection platforms. Furthermore, the challenges and developmental prospects in this field were discussed.

Development of dynamic nomogram for predicting cancer-specific survival in hepatoid adenocarcinoma: A comprehensive SEER-based population analysis.

Hepatoid adenocarcinoma (HAC) is a poorly differentiated extrahepatic tumor that can produce alpha-fetoprotein (AFP). The literature does not provide a comprehensive understanding of the prognostic factors for HAC. Therefore, we present a novel nomogram to predict the cancer-specific survival (CSS) of patients with HAC. We analyzed 265 cases of HAC from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2004 to 2015. Using a Cox proportional hazard regression model, we identified several risk factors and incorporated them into our predictive nomogram. The nomogram's predictive ability was assessed by utilizing the concordance index (C-index), calibration curve, and receiver operating characteristic (ROC). Results from a multivariate Cox regression showed that CSS was independently correlated with liver metastasis, surgery, and chemotherapy. Our nomogram had a C-index of 0.71 (95% CI 0.71-0.96). Furthermore, calibration curves demonstrated concordance between the predicted survival probability from the nomogram and the observed survival probability. The areas under the curve (AUC) for 6-month, 1-, and 3-year survival were 0.80, 0.82, and 0.88, respectively. Our study successfully formulated a prognostic nomogram that offers promising predictions for the 6-month, 1-, and 3-year CSS of patients with HAC. This nomogram holds potential for practical use in guiding treatment decisions and designing clinical trials.

LINK-A: unveiling its functional role and clinical significance in human tumors.

LINK-A, also recognized as LINC01139, has emerged as a key oncological lncRNA in cancer. LINK-A is upregulated in solid and liquid tumor samples, including breast cancer, ovarian cancer, glioma, non-small-cell lung cancer, and mantle cell lymphoma. Notably, LINK-A is involved in regulating critical cancer-related pathways, such as AKT and HIF1α signaling, and is implicated in a range of oncogenic activities, including cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), cell invasion and migration, and glycolysis reprogramming. LINK-A's differential expression and its correlation with clinical features enable it to be a promising biomarker for cancer diagnosis, prognosis, and the stratification of tumor progression. Additionally, LINK-A's contribution to the development of resistance to cancer therapies, including AKT inhibitors and immunotherapy, underscores its potential as a therapeutic target. This review provides a comprehensive overview of the available data on LINK-A, focusing on its molecular regulatory pathways and clinical significance. By exploring the multifaceted nature of LINK-A in cancer, the review aims to offer a valuable resource for future research directions, potentially guiding the development of novel therapeutic strategies targeting this lncRNA in cancer treatment.

Potential Underestimation of Left Ventricular Mechanical Dyssynchrony in Dyssynchrony and Outcomes Assessment.

Objective: Left ventricular (LV) mechanical dyssynchrony (LVMD) is fundamental to the progression of heart failure and ventricular remodeling. The status of LVMD in different patterns of bundle branch blocks (BBB) is unclear. In this study, we analyzed the relationship between LVMD and left ventricular systolic dysfunction using real-time three-dimensional echocardiography (RT-3DE). Methods: RT-3DE and conventional two-dimensional echocardiography were performed on 68 patients with left bundle branch block (LBBB group), 106 patients with right bundle branch block (RBBB group), and 103 patients without BBB (Normal group). The RT-3DE data sets provided time-volume analysis for global and segmental LV volumes. The LV systolic dyssynchrony index (LVSDI) was calculated using the standard deviation (SD) and maximal difference (Dif) of time to minimum segmental volume (tmsv) for LV segments adjusted by the R-R interval. LVMD was considered if the LVSDI (Tmsv-16-SD) was greater than or equal to 5%. Results: LVSDI is negatively and significantly correlated with left ventricular ejection fraction (LVEF), but not with BBB or QRS duration. The proportion of LVMD in the LBBB, RBBB, and Normal group was 30.88%, 28.30%, and 25.24%, respectively, and there was no significant difference. Conclusion: In dilated cardiomyopathy, LVMD is more closely related to LVEF reduction than QRS morphology and duration.

Anti-inflammatory monomeric sorbicillinoids from the marine-fish-derived fungus Trichoderma sp. G13.

Four new monomeric sorbicillinoids, trichillinoids A - D (1-4), along with two known dimeric sorbicillinoids (5 and 6), and five known monomeric sorbicillinoids (7-11), were obtained from the marine-fish-derived fungus Trichoderma sp. G13. They were structurally characterized on the basis of comprehensive spectroscopic investigations (NMR, HRESIMS, and ECD). Compounds 1-4 displayed moderate anti-inflammatory activities, according to inhibiting the production of NO in RAW264.7 cells activated with IC50 values ranging from 14 to 20 µM.

Engineering Substrate Promiscuity of Nucleoside Phosphorylase Via an Insertions-Deletions Strategy.

Nucleoside phosphorylases (NPs) are the key enzymes in the nucleoside metabolism pathway and are widely employed for the synthesis of nucleoside analogs, which are difficult to access via conventional synthetic methods. NPs are generally classified as purine nucleoside phosphorylase (PNP) and pyrimidine or uridine nucleoside phosphorylase (PyNP/UP), based on their substrate preference. Here, based on the evolutionary information on the NP-I family, we adopted an insertions-deletions (InDels) strategy to engineer the substrate promiscuity of nucleoside phosphorylase AmPNPΔS2V102 K, which exhibits both PNP and UP activities from a trimeric PNP (AmPNP) of Aneurinibacillus migulanus. Furthermore, the AmPNPΔS2V102 K exerted phosphorylation activities toward arabinose nucleoside, fluorosyl nucleoside, and dideoxyribose, thereby broadening the unnatural-ribose nucleoside substrate spectrum of AmPNP. Finally, six purine nucleoside analogues were successfully synthesized, using the engineered AmPNPΔS2V102 K instead of the traditional "two-enzymes PNP/UP" approach. These results provide deep insights into the catalytic mechanisms of the PNP and demonstrate the benefits of using the InDels strategy to achieve substrate promiscuity in an enzyme, as well as broadening the substrate spectrum of the enzyme.

Analysis of latrine fecal odor release pattern and the deodorization with composited microbial agent.

As an important source of malodor, the odor gases emitted from public toilet significantly interfered the air quality of living surroundings, resulting in environmental problem which received little attention before. Thus, this paper explored the odor release pattern of latrine feces and deodorization effect with composited microbial agent in Chengdu, China. The odor release rules were investigated in sealed installations with a working volume of 9 L for 20 days. The odor units (OU), ammonia (NH3), hydrogen sulfide (H2S) and total volatile organic compounds (TVOC) were selected to assess the release of malodorous gases under different temperature and humidity, while the highest malodor release was observed under 45℃, with OU and TVOC concentration was 643.91 ± 2.49 and 7767.33 ± 33.50 mg/m3, respectively. Microbes with deodorization ability were screened and mixed into an agent, which composited of Bacillus amyloliquefaciens, Lactobacillus plantarum, Enterococcus faecalis and Pichia fermentans. The addition of microbial deodorant could significantly suppress the release of malodor gas during a 20-day trial, and the removal efficiency of NH3, H2S, TVOC and OU was 81.50 %, 38.31 %, 64.38 %, and 76.86 %, respectively. The analysis of microbial community structure showed that temperature was the main environmental factor driving the microbial variations in latrine feces, while Firmicutes, Actinobacteria, Proteobacteria and Bacteroidetes were the main bacteria phyla involved in the formation and emission of malodorous gases. However, after adding the deodorant, the abundance of Bacteroidetes, Proteobacteria and Actinobacteria were decreased, while the abundance of Firmicutes was increased. Furthermore, P. fermentans successfully colonized in fecal substrates and became the dominant fungus after deodorization. These results expanded the understanding of the odor release from latrine feces, and the composited microbial deodorant provided a valuable basis to the management of odor pollution.

LINC01134: a pivotal oncogene with promising predictive maker and therapeutic target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) represents a leading and fatal malignancy within the gastrointestinal tract. Recent advancements highlight the pivotal role of long non-coding RNAs (lncRNAs) in diverse biological pathways and pathologies, particularly in tumorigenesis. LINC01134, a particular lncRNA, has attracted considerable attention due to its oncogenic potential in hepatoma. Current research underscores LINC01134's potential in augmenting the onset and progression of HCC, with notable implications in drug resistance. This review comprehensively explores the molecular functions and regulatory mechanisms of LINC01134 in HCC, offering a fresh perspective for therapeutic interventions. By delving into LINC01134's multifaceted roles, we aim to foster novel strategies in HCC management.

Biological roles of SLC16A1-AS1 lncRNA and its clinical impacts in tumors.

Recent studies have increasingly highlighted the aberrant expression of SLC16A1-AS1 in a variety of tumor types, where it functions as either an oncogene or a tumor suppressor in the pathogenesis of different cancers. The expression levels of SLC16A1-AS1 have been found to significantly correlate with clinical features and the prognosis of cancer patients. Furthermore, SLC16A1-AS1 modulates a range of cellular functions, including proliferation, migration, and invasion, through its interactions with diverse molecules and signaling pathways. This review examines the latest evidence regarding the role of SLC16A1-AS1 in the progression of various tumors and explores its potential clinical applications as a novel prognostic and diagnostic biomarker. Our comprehensive review aims to deepen the understanding of SLC16A1-AS1's multifaceted role in oncology, underscoring its potential as a significant biomarker and therapeutic target.

Riemerella anatipestifer UvrC is required for iron utilization, biofilm formation and virulence.

UvrC is a subunit of excinuclease ABC, which mediates nucleotide excision repair (NER) in bacteria. Our previous studies showed that transposon Tn4531 insertion in the UvrC encoding gene Riean_1413 results in reduced biofilm formation by Riemerella anatipestifer strain CH3 and attenuates virulence of strain YZb1. In this study, whether R. anatipestifer UvrC has some biological functions other than NER was investigated. Firstly, the uvrC of R. anatipestifer strain Yb2 was in-frame deleted by homologous recombination, generating deletion mutant ΔuvrC, and its complemented strain cΔuvrC was constructed based on Escherichia coli - R. anatipestifer shuttle plasmid pRES. Compared to the wild-type (WT) R. anatipestifer strain Yb2, uvrC deleted mutant ΔuvrC significantly reduced biofilm formation, tolerance to H2O2- and HOCl-induced oxidative stress, iron utilization, and adhesion to and invasion of duck embryonic hepatocytes, but not its growth curve and proteolytic activity. In addition, animal experiments showed that the LD50 value of ΔuvrC in ducklings was about 13-fold higher than that of the WT, and the bacterial loads in ΔuvrC infected ducklings were significantly lower than those in Yb2-infected ducklings, indicating uvrC deletion in R. anatipestifer attenuated virulence. Taken together, the results of this study indicate that R. anatipestifer UvrC is required for iron utilization, biofilm formation, oxidative stress tolerance and virulence of strain Yb2, demonstrating multiple functions of UvrC.RESEARCH HIGHLIGHTSDeletion of uvrC in R. anatipestfer Yb2 significantly reduced its biofilm formation.uvrC deletion led to reduced tolerance to H2O2- and HOCl-induced oxidative stress.The iron utilization of uvrC deleted mutant was significantly reduced.The uvrC deletion in R. anatipestifer Yb2 attenuated its virulence.

LncRNA-MUF: A Novel Oncogenic Star with Potential as a Biological Marker and Therapeutic Target for Gastrointestinal Malignancies.

Gastrointestinal (GI) cancers pose a significant global health challenge, characterized by a high incidence and poor prognosis. The delayed detection and occurrence of metastasis contribute to the overall low survival rates associated with these cancers. Therefore, there is an urgent need to identify novel molecular targets for effective GI cancer treatment. Recent research has shed light on the potential of long non-coding RNAs (lncRNAs) as promising targets in cancer therapy, given their strong association with carcinogenesis and profound impact on tumor development. Among these lncRNAs, lncRNA-MUF, also known as LINC00941, has emerged as a key player in oncogenic regulation, specifically implicated in the progression of various GI cancers, including esophageal, gastric, colorectal, hepatic, and pancreatic cancer. This review aims to provide an updated and focused analysis of the regulatory roles of LINC00941 in the initiation and progression of GI cancer. Our objective is to unravel the underlying molecular mechanisms through which LINC00941 influences GI cancer phenotypes both in vivo and in vitro, with a special emphasis on the key molecules and signaling pathways involved. Additionally, LINC00941 has demonstrated clinical significance in terms of clinical pathology, prognosis, and diagnosis in GI tumors, further reinforcing its potential as a novel therapeutic target.

Tibetan medicine Ruyi Zhenbao Pill ameliorates neuropathic pain by inhibiting the CXCL10-CXCR3 pathway in spinal cord of spinal nerve ligation model.

ETHNOPHARMACOLOGICAL RELEVANCE: Ruyi Zhenbao Pill (RYZBP) is a traditional Tibetan medicine that has been used for over 300 years in China to treat neurological diseases, specifically neuropathic pain (NP). However, its characteristics and mechanism of action in treating NP remains unclear. AIM OF THE STUDY: Based on animal experiments and transcriptomics to evaluate the characteristics and mechanism of RYZBP in treating NP. METHODS: Mice were divided into six groups using random assignment: sham-operation group, spinal nerve ligation (SNL) group, RYZBP low (0.65 g kg-1), medium (1.30 g kg-1), high (2.60 g kg-1) doses groups, and positive drug pregabalin (PGB, 0.05 g kg-1) group. Mice received intragastrical administered for 14 consecutive days. SNL and intrathecal injection models were employed. The analgesic effects were assessed using the Von Frey test, Acetone test, and Hot Plate test. L5 spinal dorsal horns were collected for transcriptomics on day 15. The potential signaling pathways and Hub genes of RYZBP to ameliorate NP were obtained through transcriptomics and network pharmacology. Molecular docking was utilized to evaluate the binding ability of candidate active ingredients with the Hub genes. Finally, western blot (WB) and immunofluorescence (IF) were used to validate the predicted targets. RESULTS: RYZBP demonstrated a dose-dependent alleviation of mechanical allodynia, cold and heat stimulus-induced pain in SNL mice. Transcriptomics analysis identified 24 differentially expressed genes, and pathway enrichment analysis revealed that the CXCL10-CXCR3 signal axis may be the primary biological pathway through which RYZBP relieve NP. Molecular docking test indicated that the active ingredient in RYZBP exhibit a strong affinity for the target protein CXCL10. WB and IF tests showed that RYZBP can significantly inhibit CXCL10 and CXCR3 and its downstream molecules expression in the spinal dorsal horn of SNL mice. Additionally, intrathecal injection of rmCXCL10 worsened pain hypersensitivity, while RYZBP was able to suppress the pain hypersensitivity response induced by rmCXCL10 and reduce the expression levels of CXCL10 and CXCR3 and its downstream molecules. CONCLUSION: RYZBP had a significant analgesic effect on NP model, and this effect may be related to inhibiting the CXCL10-CXCR3 pathway in the spinal dorsal horn.

Discovery and Mechanistic Understanding of a Lipase from Rhizorhabdus dicambivorans for Efficient Ester Aminolysis in Aromatic Amines.

The formation of amide bonds via aminolysis of esters by lipases generates a diverse range of amide frameworks in biosynthetic chemistry. Few lipases have satisfactory activity towards bulky aromatic amines despite numerous attempts to improve the efficiency of this transformation. Here, we report the discovery of a new intracellular lipase (Ndbn) with a broad substrate scope. Ndbn turns over a range of esters and aromatic amines in the presence of water (2 %; v/v), producing a high yield of multiple valuable amides. Remarkably, a higher conversion rate was observed for the synthesis of amides from substrates with aromatic amine rather than aliphatic amines. Molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) studies showcase the mechanism for the preference for aromatic amines, including a more suitable orientation, shorter catalytic distances in the active site pocket and a lower reaction barrier for aromatic than for aliphatic amines. This unique lipase is thus a promising biocatalyst for the efficient synthesis of aromatic amides.

Design, synthesis and bioactivity evaluation of novel fusion peptides and their CPT conjugates inducing effective anti-tumor responses on HER2 positive tumors.

Human epidermal growth factor receptor 2 (HER2) represents an ideal target for antibody drug development, abnormal expression of the HER2 gene is associated with multiple tumor types. Pertuzumab, as the first monoclonal antibody inhibitor of HER2 dimerization, has been FDA-approved for HER2-positive patients. In order to enhance the activity of HER2-targeted peptide-drug conjugates (PDCs) developed based on pertuzumab, a novel class of conjugates 1-9 was designed and synthesized by fusing the N-terminal peptide sequence of the second mitochondria-derived activator of caspases (SMAC) with P1, followed by conjugation with CPT molecules. Compound 4 exhibited excellent in vitro anti-tumor activity across the three HER2-positive cell lines, comparable to the activity of CPT. Apoptosis induction assays indicated that the synergistic effect of the SMAC sequence enhanced the pro-apoptotic activity of the conjugate. Western Blot analysis and Caspase activity studies validated the mechanism through which SMAC peptides, in synergy with CPT, enhance the activity of PDCs. In vivo studies demonstrated that compound 4 possesses superior anti-tumor activity compared to CPT and can effectively mitigate potential renal toxicity associated with free SMAC peptides. In conclusion, conjugate 4 exhibited excellent anti-tumor activity both in vitro and in vivo, offering potential for further development as a novel peptide-conjugated drug.

Epidemiology, site-specific characteristics and survival of carcinosarcoma: a retrospective study based on SEER database.

OBJECTIVES: Carcinosarcoma (CS) is a rare and biphasic malignancy characterised by a highly invasive biological nature and poor prognosis. This study explored the epidemiology, site-specific characteristics and survival outcome of CS. DESIGN: We conducted a retrospective study in the Surveillance, Epidemiology and End Results (SEER) database (1975-2018) for primary CS. SETTING AND PARTICIPANTS: SEER database includes publicly available information from regional and state cancer registries in the US centres. A total of 5042 CS patients were identified. We selected the top five anatomic CS (uterus, double adnexa, lung, bladder and breast) patients for further analysis. PRIMARY OUTCOME MEASURES: Incidence was estimated by geographical region, age, sex, race, stage and primary site. Trends were calculated using joinpoint regression. The cancer-specific survival (CSS) rate and initial treatment were summarised. RESULTS: Nearly 80% of CS occurred in the uterus and double adnexa, followed by lung, bladder and breast. The elderly and black population presented the highest age-adjusted rate of CS. The rates of distant metastasis in CS progressively increased from 1989 to 2018. Atlanta was the area with the highest incidence at 0.7 per 100 000. Pulmonary and bladder CS more frequently occurred in men and were diagnosed with regional stage. Distant metastasis was mostly found in ovary/fallopian tube CS. Radiotherapy was more commonly applied in uterine CS, while adnexa CS cases were more likely to receive chemotherapy. Multiple treatments were more used in breast CS. Pulmonary CS seemed to suffer worse CSS (median: 9.92 months), for which radiotherapy might not provide survival benefits (HR 0.60, 95% CI 0.42 to 0.86). Compared with the common histological types in each site, CS had the shortest survival. CONCLUSIONS: CS has unique clinical features in each primary site. Substantial prognosis variances exist based on tumour locations. The aggressive course is the common feature in CS at all sites.

Efficacy and safety analysis of a HER2-targeting antibody-drug conjugate combined with immune checkpoint inhibitors in solid tumors: a real-world study.

BACKGROUND: Disitamab Vedotin is a novel antibody-drug conjugate (ADC) drug targeting HER2, which has shown a potential synergistic effect between Disitamab Vedotin and immune checkpoint inhibitors (ICIs). Therefore, we plan to conduct a retrospective real-world study to evaluate the efficacy and safety of Disitamab Vedotin monotherapy or combined with ICIs in the treatment of advanced or metastatic solid tumors. METHODS: This retrospective study involved patients with locally advanced or metastatic solid tumors who were treated with Disitamab Vedotin monotherapy or combined with ICIs at West China Hospital of Sichuan University from July 2019 to June 2023. The observation items included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). RESULTS: This study included 49 patients, out of which 34 patients were treated with Disitamab Vedotin plus ICIs and 15 patients received Disitamab Vedotin alone. In all patients, the median PFS was 10 months. The 6-month and 1-year OS rates were 91.1% and 82.3%, respectively. Eighteen (36.7%) patients achieved a partial response, and sixteen (32.7%) patients had stable disease. The combination therapy of Disitamab Vedotin plus ICIs showed a higher ORR (44.1% vs. 20.0%) and a longer median PFS (14 vs. 8 months) compared to Disitamab Vedotin alone. The median PFS for patients expressed with HER2 2+/3+ was 10 months and was not reached for patients expressed with HER2 0/1+. Grade 3-4 TRAEs occurred in 14.7% of patients who received the combination treatment and in 26.7% of patients who received Disitamab Vedotin alone. CONCLUSIONS: Our study showed that Disitamab-Vedotin-based treatment, alone or in combination with ICIs, exerted considerable prognosis and good tolerance in patients with locally advanced or metastatic solid tumors, regardless of the HER2 expression levels. Whether combination therapy with ICIs provides greater therapeutic benefits compared to monotherapy needs to be further explored through randomized controlled trials.