Interfacial Engineering of MoS2@CoS2 Heterostructure Electrocatalysts for Effective pH-Universal Hydrogen Evolution Reaction.

The practical utilization of the hydrogen evolution reaction (HER) necessitates the creation of electrocatalysts that are both efficient and abundant in earth elements, capable of operating effectively within a wide pH range. However, this objective continues to present itself as an arduous obstacle. In this research, we propose the incorporation of sulfur vacancies in a novel heterojunction formed by MoS2@CoS2, designed to exhibit remarkable catalytic performances. This efficacy is attributed to the advantageous combination of the low work function and space charge zone at the interface between MoS2 and CoS2 in the heterojunction. The MoS2@CoS2 heterojunction manifests outstanding hydrogen evolution activity over an extensive pH range. Remarkably, achieving a current density of 10 mA cm-2 in aqueous solutions 1.0 M KOH, 0.5 M H2SO4, and 1.0 M phosphate-buffered saline (PBS), respectively, requires only an overpotential of 48, 62, and 164 mV. The Tafel slopes for each case are 43, 32, and 62 mV dec-1, respectively. In this study, the synergistic effect of MoS2 and CoS2 is conducive to electron transfer, making the MoS2@CoS2 heterojunction show excellent electrocatalytic performance. The synergistic effects arising from the heterojunction and sulfur vacancy not only contribute to the observed catalytic prowess but also provide a valuable model and reference for the exploration of other efficient electrocatalysts. This research marks a significant stride toward overcoming the challenges associated with developing electrocatalysts for practical hydrogen evolution applications.

Elementary excitations of single-photon emitters in hexagonal boron nitride.

Single-photon emitters serve as building blocks for many emerging concepts in quantum photonics. The recent identification of bright, tunable and stable emitters in hexagonal boron nitride (hBN) has opened the door to quantum platforms operating across the infrared to ultraviolet spectrum. Although it is widely acknowledged that defects are responsible for single-photon emitters in hBN, crucial details regarding their origin, electronic levels and orbital involvement remain unknown. Here we employ a combination of resonant inelastic X-ray scattering and photoluminescence spectroscopy in defective hBN, unveiling an elementary excitation at 285 meV that gives rise to a plethora of harmonics correlated with single-photon emitters. We discuss the importance of N π* anti-bonding orbitals in shaping the electronic states of the emitters. The discovery of elementary excitations in hBN provides fundamental insights into quantum emission in low-dimensional materials, paving the way for future investigations in other platforms.

Epidemiological and clinicopathological features of KRAS, NRAS, BRAF mutations and MSI in Chinese patients with stage I-III colorectal cancer.

The selection of appropriate treatment modalities based on the presence or absence of mutations in KRAS, NRAS, BRAF, and the microsatellite instability (MSI) status has become a crucial consensus in colorectal cancer (CRC) therapy. However, the distribution pattern of these genetic mutations and the prevalence of MSI status in Chinese stage I-III CRCs remain unclear. We retrospectively analyzed clinicopathological features, mutations in the KRAS, NRAS, and BRAF genes, as well as MSI status of 411 patients with stage I-III CRC who underwent surgery from June 2020 to December 2022 in the First Affiliated Hospital of Nanjing Medical University. The mutation rates of KRAS, NRAS, and BRAF were 48.9%, 2.2%, and 3.2%, respectively, and the microsatellite instability-high rate was 9.5%. KRAS mutation was independently associated with mucinous adenocarcinoma. Multivariate analysis suggested that tumor location and mucinous adenocarcinoma were independently associated with BRAF mutation. Only T stage was associated with NRAS mutations in the univariate analysis. Multivariate analysis revealed that factors such as larger tumor size, tumor location, younger age, and poor differentiation were independently associated with microsatellite instability-high status. The results illustrate the mutation frequencies of KRAS, NRAS, BRAF genes and MSI status in stage I-III CRC from the eastern region of China. These findings further validate the associations between these genes status and various clinicopathological characteristics.

Allosteric SHP2 inhibition enhances regorafenib's effectiveness in colorectal cancer treatment.

Colorectal cancer (CRC) is the third most common cancer globally. Regorafenib, a multi-target kinase inhibitor, has been approved for treating metastatic colorectal cancer patients who have undergone at least two prior standard anti-cancer therapies. However, regorafenib efficacy as a single agent remains suboptimal. A promising target at the crossroads of multiple signaling pathways is the Src homology 2 domain-containing protein tyrosine phosphatase (SHP2). However, a combination approach using SHP2 inhibitors (SHP099) and anti-angiogenic drugs (Regorafenib) has not been reported in current research. In this study, we conducted in vitro experiments combining SHP099 and regorafenib and established an MC-38 colon cancer allograft mouse model. Our results revealed that co-treatment with SHP099 and regorafenib significantly inhibited cell viability and altered the biological characteristics of tumor cells compared with treatment alone in vitro. Furthermore, the combination strategy demonstrated superior therapeutic efficacy compared to monotherapy with either drug. This was evidenced by reduced tumor size, decreased proliferation, increased apoptosis, normalized tumor microvasculature, and improved antitumor immune response in vivo. These findings suggest that the combination of an SHP2 inhibitor and regorafenib is a promising therapeutic approach for patients with colorectal cancer.

Evaluating AI in medicine: a comparative analysis of expert and ChatGPT responses to colorectal cancer questions.

Colorectal cancer (CRC) is a global health challenge, and patient education plays a crucial role in its early detection and treatment. Despite progress in AI technology, as exemplified by transformer-like models such as ChatGPT, there remains a lack of in-depth understanding of their efficacy for medical purposes. We aimed to assess the proficiency of ChatGPT in the field of popular science, specifically in answering questions related to CRC diagnosis and treatment, using the book "Colorectal Cancer: Your Questions Answered" as a reference. In general, 131 valid questions from the book were manually input into ChatGPT. Responses were evaluated by clinical physicians in the relevant fields based on comprehensiveness and accuracy of information, and scores were standardized for comparison. Not surprisingly, ChatGPT showed high reproducibility in its responses, with high uniformity in comprehensiveness, accuracy, and final scores. However, the mean scores of ChatGPT's responses were significantly lower than the benchmarks, indicating it has not reached an expert level of competence in CRC. While it could provide accurate information, it lacked in comprehensiveness. Notably, ChatGPT performed well in domains of radiation therapy, interventional therapy, stoma care, venous care, and pain control, almost rivaling the benchmarks, but fell short in basic information, surgery, and internal medicine domains. While ChatGPT demonstrated promise in specific domains, its general efficiency in providing CRC information falls short of expert standards, indicating the need for further advancements and improvements in AI technology for patient education in healthcare.

Exosomes secreted by Fusobacterium nucleatum-infected colon cancer cells transmit resistance to oxaliplatin and 5-FU by delivering hsa_circ_0004085.

BACKGROUND: A large number of Fusobacterium nucleatum (Fn) are present in colorectal cancer (CRC) tissues of patients who relapse after chemotherapy, and Fn has been reported to promote oxaliplatin and 5-FU chemoresistance in CRC. Pathogens such as bacteria and parasites stimulate exosome production in tumor cells, and the regulatory mechanism of exosomal circRNA in the transmission of oxaliplatin and 5-FU chemotherapy resistance in Fn-infected CRC remains unclear. METHODS: Hsa_circ_0004085 was screened by second-generation sequencing of CRC tissues. The correlation between hsa_circ_0004085 and patient clinical response to oxaliplatin/5-FU was analyzed. Exosome tracing experiments and live imaging systems were used to test the effect of Fn infection in CRC on the distribution of hsa_circ_0004085. Colony formation, ER tracking analysis and immunofluorescence were carried out to verify the regulatory effect of exosomes produced by Fn-infected CRC cells on chemotherapeutic resistance and ER stress. RNA pulldown, LC-MS/MS analysis and RIP were used to explore the regulatory mechanism of downstream target genes by hsa_circ_0004085. RESULTS: First, we screened out hsa_circ_0004085 with abnormally high expression in CRC clinical samples infected with Fn and found that patients with high expression of hsa_circ_0004085 in plasma had a poor clinical response to oxaliplatin/5-FU. Subsequently, the circular structure of hsa_circ_0004085 was identified. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes produced by Fn-infected CRC cells transferred hsa_circ_0004085 between cells and delivered oxaliplatin/5-FU resistance to recipient cells by relieving ER stress. Hsa_circ_0004085 enhanced the stability of GRP78 mRNA by binding to RRBP1 and promoted the nuclear translocation of ATF6p50 to relieve ER stress. CONCLUSIONS: Plasma levels of hsa_circ_0004085 are increased in colon cancer patients with intracellular Fn and are associated with a poor response to oxaliplatin/5-FU. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes secreted by Fn-infected CRC cells deliver hsa_circ_0004085 between cells. Hsa_circ_0004085 relieves ER stress in recipient cells by regulating GRP78 and ATF6p50, thereby delivering resistance to oxaliplatin and 5-FU.

Structural phase purification of bulk HfO2:Y through pressure cycling.

We combine synchrotron-based infrared absorption and Raman scattering spectroscopies with diamond anvil cell techniques and first-principles calculations to explore the properties of hafnia under compression. We find that pressure drives HfO[Formula: see text]:7%Y from the mixed monoclinic ([Formula: see text]) [Formula: see text] antipolar orthorhombic ([Formula: see text]) phase to pure antipolar orthorhombic ([Formula: see text]) phase at approximately 6.3 GPa. This transformation is irreversible, meaning that upon release, the material is kinetically trapped in the [Formula: see text] metastable state at 300 K. Compression also drives polar orthorhombic ([Formula: see text]) hafnia into the tetragonal ([Formula: see text]) phase, although the latter is not metastable upon release. These results are unified by an analysis of the energy landscape. The fact that pressure allows us to stabilize targeted metastable structures with less Y stabilizer is important to preserving the flat phonon band physics of pure HfO[Formula: see text].

Network analysis of frailty indicators in hospitalized elderly patients: unveiling the role of depression and hemoglobin as core factors.

BACKGROUND: Frailty is a significant concern among hospitalized older adults, influenced by multiple factors. Understanding the complex interactions between these variables can be facilitated through a network perspective. AIM: This study aimed to identify the core factor and physiological indicator of frailty in hospitalized elderly patients and visualize their interactions within the network structure. METHODS: Frailty was assessed using the Tilburg Frailty Indicators, with a score of 5 or higher indicating frailty. Additional variables related to sociodemographic, physical and clinical, psychological and cognitive aspects, as well as physiological indicators, were extracted from electronic health records. A partial correlation network analysis was conducted using an adaptive LASSO algorithm, based on univariate correlation and logistic regression, to examine the network structure and identify influential nodes. RESULTS: The average age of participants was 70.74 ± 7.52 years, with 24.27% classified as frail. Frailty was associated with 38 of 145 initially included variables (P < 0.05). The network analysis revealed depression as the most central node, followed by drugs used, sleep disorders, loneliness, masticatory obstacles, drinking, and number of teeth missing. Hemoglobin emerged as the most central biochemical indicator in the network, based on network center index analysis (Strength = 4.858, Betweenness = 223, Closeness = 0.034). CONCLUSIONS: Frailty in hospitalized older adults is influenced by various social, physical, and psychological factors, with depression as the core factor of utmost importance. Changes in hemoglobin levels could serve as an essential indicator. This innovative network approach provides insights into the multidimensional structure and relationships in real-world settings.

Local Electrochemical Corrosion of 6061 Aluminum Alloy with Nano-SiO2/MAO Composite Coating.

To improve the corrosion resistance of 6061 Al in electric vehicle battery packs, a composite coating of nano-SiO2/Micro-Arc oxidation (MAO) ceramic structure was prepared on its surface. Electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization curves (PDP) were used to evaluate the corrosion resistance of the specimens after 7 days immersion in a 3.5% NaCl solution. The corrosion resistance of the prefabricated coatings was measured via local electrochemical impedance spectroscopy (LEIS). Confocal microscopy, scanning electron microscopy (SEM), and X-ray diffraction (XRD) were used to characterize the microstructure and phase composition of the specimens. An energy dispersive spectrometer (EDS) was used to detect the elemental composition of the surface of the specimen. The results showed that the specimen with nano-SiO2/MAO composite coating had the least amount of micropores and superior corrosion resistance. The global electrochemical impedance of nano-SiO2/MAO composite coating was 1.1 times higher than that of the MAO coating and 8.4 times higher than that of the 6061 Al. When the coating was defective, the local electrochemical impedance of the nano-SiO2/MAO composite coating was still two times higher than that of the MAO coating. In the presence of scratches, the nano-SiO2/MAO composite coating still showed high corrosion resistance. The collapse corrosion mechanism of the nano-SiO2/MAO composite coating was proposed.

Clinical evaluation of a multitarget fecal immunochemical test-sDNA test for colorectal cancer screening in a high-risk population: a prospective, multicenter clinical study.

Colorectal cancer (CRC) is a major malignancy threatening the health of people in China and screening could be effective for preventing the occurrence and reducing the mortality of CRC. We conducted a multicenter, prospective clinical study which recruited 4,245 high-risk CRC individuals defined as having positive risk-adapted scores or fecal immunochemical test (FIT) results, to evaluate the clinical performance of the multitarget fecal immunochemical and stool DNA (FIT-sDNA) test for CRC screening. Each participant was asked to provide a stool sample prior to bowel preparation, and FIT-sDNA test and FIT were performed independently of colonoscopy. We found that 186 (4.4%) were confirmed to have CRC, and 375 (8.8%) had advanced precancerous neoplasia among the high CRC risk individuals. The sensitivity of detecting CRC for FIT-sDNA test was 91.9% (95% CI, 86.8-95.3), compared with 62.4% (95% CI, 54.9-69.3) for FIT (P < 0.001). The sensitivity for detecting advanced precancerous neoplasia was 63.5% (95% CI, 58.3-68.3) for FIT-sDNA test, compared with 30.9% (95% CI, 26.3-35.6) for FIT (P < 0.001). Multitarget FIT-sDNA test detected more colorectal advanced neoplasia than FIT. Overall, these findings indicated that in areas with limited colonoscopy resources, FIT-sDNA test could be a promising further risk triaging modality to select patients for colonoscopy in CRC screening.

Single-cell analyses reveal cannabidiol rewires tumor microenvironment via inhibiting alternative activation of macrophage and synergizes with anti-PD-1 in colon cancer.

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy. Cannabidiol (CBD) is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects, including neuroprotective, antiemetic, anti-inflammatory, and antineoplastic activities. This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) technologies. Here, we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment (TME). Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity. Furthermore, CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages, thereby preventing tumor progression. Mechanistically, CBD altered the metabolic pattern of macrophages and related anti-tumor signaling pathways. We found that CBD inhibited the alternative activation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes. Furthermore, CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1 (PD-1) immunotherapy in xenografted mice. Taken together, we provide new insights into the anti-tumor effects of CBD.

A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway.

Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.

Erratum: Author correction to "DNA damage repair promotion in colonic epithelial cells by andrographolide downregulated cGAS‒STING pathway activation and contributed to the relief of CPT-11-induced intestinal mucositis" [Acta Pharmaceutica Sinica B 12 (2022) 262-273].

[This corrects the article DOI: 10.1016/j.apsb.2021.03.043.].

Efficacy and safety of Xian-Lian-Jie-Du optimization decoction as an adjuvant treatment for prevention of recurrence in patients with stage IIIB/IIIC colon cancer: study protocol for a multicentre, randomized controlled trial.

INTRODUCTION: Colon cancer remains one of the most prevalent cancers worldwide. Unfortunately, there are no recognized and effective therapeutic strategies to prevent tumor recurrence after radical resection and chemotherapy, and the disease-free survival (DFS) in patients with stage IIIB or IIIC disease remains unsatisfactory. Xian-Lian-Jie-Du optimization decoction (XLJDOD) is a Chinese herbal medicine (CHM) empirical prescription, which has been validated experimentally and clinically that could inhibit the progression of colorectal cancer and ameliorate the symptoms. The purpose of this study is to evaluate the efficacy and safety of XLJDOD in prevention of recurrence of colon cancer. METHODS: This study is a multi-center, double-blind, randomized, placebo-controlled trial conducted at 13 hospitals of China. Following the completion of surgery and adjuvant 5- fluorouracil-based chemotherapy, a total of 730 subjects with stage IIIB or IIIC colon cancer will be randomized in a 1:1 ratio to an intervention group (n = 365; XLJDOD compound granule) and a control group (n = 365; Placebo). Patients will receive 6-month treatments and be followed up with 3 monthly assessments for 2 years. The primary outcome is 2-year DFS rate and the secondary outcomes are 1, 2-year relapse rate (RR), overall survival (OS) and quality of life (QoL). Safety outcomes such as adverse events will be also assessed. A small number of subgroup analysis will be carried out to explore the heterogeneity of effects of XLJDOD. DISCUSSION: The outcomes from this randomized controlled trial will provide objective evidences to evaluate XLJDOD's role as an adjuvant treatment in colon cancer. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , identifier: NCT05709249. Registered on 31 Jan 2023.

China special issue on gastrointestinal tumors-Improved survival after multidisciplinary team decision for patients with advanced gastrointestinal cancer: A multicenter, noninterventional, controlled study.

Formal multidisciplinary team (MDT) discussions in clinical practice require time and space but have unclear survival benefits for advanced gastrointestinal cancer patients. Our study aimed to investigate the long-term survival of patients with advanced gastrointestinal cancer after MDT decision. From June 2017 to June 2019, continuous MDT discussions on advanced gastrointestinal cancer were conducted in 13 medical centers in China. MDT decisions and actual treatment received by patients were prospectively recorded. The primary endpoint was the difference in overall survival (OS) between patients in the MDT decision implementation and nonimplementation groups. The secondary endpoints included the implementation rate of MDT decisions and subgroup survival analysis. A total of 461 MDT decisions of 455 patients were included in our study. The implementation rate of MDT decisions was 85.7%. Previous treatment had an impact on MDT decision-making. The OS was 24.0 months and 17.0 months in the implementation and nonimplementation groups, respectively. The implementation of MDT decisions significantly reduced the risk of death in multivariate analyses (hazard ratio = 0.518; 95% confidence interval: 0.304-0.884, P = .016). Subgroup analysis showed a significant difference in survival of patients with colorectal cancer, but not in survival of patients with gastric cancer. The rate of secondary MDT discussion was only 5.6% among patients who the MDT decisions were discontinued due to changes in their condition. MDT discussion can prolong the OS of patients with advanced gastrointestinal cancer, especially those with colorectal cancer. Timely scheduling of the subsequent MDT discussion is necessary when the disease condition changes.

Erosion-Corrosion Behavior of Friction Stud Welded Joints of X65 Pipelines in Simulated Seawater under Different Flow Rates.

In order to study the complex erosion-corrosion mechanism of friction stud welded joints in seawater, experiments were carried out in the mixed solution of 3 wt% sea sand and 3.5% NaCl at flow rates of 0 m/s, 0.2 m/s, 0.4 m/s, and 0.6 m/s. The effects of corrosion and erosion-corrosion at different flow rates on materials were compared. The corrosion resistance of X65 friction stud welded joint was studied by electrochemical impedance spectroscopy (EIS) and potentiodynamic polarization (PDP) curves. The corrosion morphology was observed by a scanning electron microscope (SEM), and the corrosion products were analyzed by energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD). The results showed that the corrosion current density decreased first and then increased with the increase in the simulated seawater flow rate, which indicated that the corrosion resistance of the friction stud welded joint increased first and then decreased. The corrosion products are FeOOH (α-FeOOH and γ-FeOOH), and Fe3O4. According to the experimental results, the erosion-corrosion mechanism of friction stud welded joints in seawater environment was predicted.

Polymorphisms of Placental Iodothyronine Deiodinase Genes in a Rural Area of Northern China with High Prevalence of Neural Tube Defects.

INTRODUCTION: We have reported that high total homocysteine and the coexistence of inadequate thyroid hormones in maternal serum increase the risk of fetal neural tube defects (NTDs). Placental iodothyronine deiodinases (DIOs: DIO1, DIO2, and DIO3) play a role in regulating the conversions between different forms of maternal thyroid hormones. This study hypothesized that single nucleotide polymorphisms (SNPs) in placental DIOs genes could be related to NTDs. METHODS: We performed a case-control study from 2007 to 2009 that included pregnant women from Lüliang, Shanxi Province, China. Nine distinct SNPs in DIOs genes were analyzed, and placental samples were obtained from 83 pregnant women with NTD fetuses and 90 pregnant women with normal fetuses. The nine SNPs were analyzed using the Cochran-Armitage test and the Fisher's exact test. RESULTS: There were no statistically significant differences between case and control in the nine SNPs of DIOs (p > 0.05). CONCLUSIONS: The results of this study suggested that SNPs of DIO genes in the placenta among pregnant women have no statistically significant difference between the two groups, suggesting that other factors might be involved in metabolism of maternal thyroid hormone provided to fetuses, such as epigenetic modification of methylation and homocysteinylation and genomic imprinting in the placenta. Further functional studies on placenta samples are necessary.

Neoadjuvant sintilimab and chemotherapy in patients with potentially resectable esophageal squamous cell carcinoma (KEEP-G 03): an open-label, single-arm, phase 2 trial.

BACKGROUND: The standard neoadjuvant treatments in patients with esophageal squamous cell carcinoma (ESCC) still have either poor safety or efficacy. Better therapies are needed in China. METHODS: This was an open-label, single-arm, phase 2 trial. Patients with potentially resectable ESCC (cT1b-3, Nany, M0 or T4a, N0-1, or M0) received preoperative intravenous sintilimab plus triplet chemotherapy (liposomal paclitaxel, cisplatin, and S-1) every 3 weeks for two cycles. The primary endpoints were safety and surgical feasibility; the secondary endpoint was major pathological response (MPR) rate. Genomic biomarkers (genetic mutations, tumor mutational burden (TMB), circulating tumor DNA status and immune microenvironment) in baseline tumor samples were investigated. RESULTS: All 30 patients completed two cycles of neoadjuvant treatment and underwent surgical resection. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 36.7% (11/30) of patients. The most frequent TRAEs were decreased white cell count (76.7%), anemia (76.7%), and decreased neutrophil count (73.3%). All TRAEs were hematological toxicities; none caused ≥30 days surgical delay. The MPR and pathological complete response (pCR) rates were 50.0% (15/30; 95% CI 33.2 to 66.9) and 20.0% (6/30; 95% CI 9.5 to 37.3), respectively. Patients with higher TMB and more clonal mutations were more likely to respond. ERBB2 alterations and ctDNA high-releaser status have a negative correlation with neoadjuvant ICI response. No significant difference was observed between therapeutic response and tumor immune microenvironment. CONCLUSIONS: Neoadjuvant sintilimab plus platinum-based triplet chemotherapy appeared safe and feasible, did not delay surgery and induced a pCR rate of 20.0% in patients with potentially resectable ESCC. TRIAL REGISTRATION NUMBER: NCT03946969.

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis.

Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.

Pembrolizumab in Chinese patients with advanced melanoma: 3-year follow-up of the KEYNOTE-151 study.

Survival is generally poor for Chinese patients with advanced melanoma because of high rates of acral and mucosal melanoma and limited therapeutic options. The first analysis of the phase 1b KEYNOTE-151 study showed second-line pembrolizumab was well tolerated and had clinically meaningful antitumor activity in Chinese patients with advanced melanoma. Three-year follow-up is presented. Eligible patients were of Chinese descent and had unresectable stage III/IV melanoma that progressed after first-line therapy. Patients received pembrolizumab 2 mg/kg every 3 weeks for ≤35 cycles. Primary end points were safety and objective response rate (ORR). Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Response was assessed per RECIST v1.1 by blinded independent central review. Subgroup analyses were conducted by melanoma subtype and BRAF and PD-L1 status (acral melanoma only). 103 patients were enrolled; median follow-up duration (time from first dose to data cutoff [July 13, 2020]) was 44.6 months (IQR, 39.1-46.2). Any-grade treatment-related adverse events (TRAEs) occurred in 85.4% of patients, and grade 3/4 TRAEs in 12.6%. No grade 5 TRAEs occurred. Three patients discontinued pembrolizumab because of TRAEs (immune-mediated hepatitis, pneumonia, and arthritis). Immune-mediated AEs and infusion reactions occurred in 34.0% (grade 3/4, 2.9%). ORR was 17.6% (95% CI, 10.8-26.4; 1 complete response/17 partial responses), and median DOR was 13.8 months (range, 2.7-37.4+). Median PFS was 2.8 months (95% CI, 2.7-3.5) and 36-month PFS rate was 5.0%. Median OS was 13.2 months (95% CI, 10.4-16.5) and 36-month OS rate was 22.3%. Median OS for patients with known melanoma subtype was 14.8 months for acral, 13.5 months for nonacral cutaneous, and 7.4 months for mucosal melanoma. Among the acral subgroup, median OS was 22.8 months for PD-L1-positive disease, 8.4 months for PD-L1-negative disease, 18.5 months for BRAF wild-type disease, and 5.8 months for BRAF-mutant disease. Over 3 years' follow-up, second-line pembrolizumab continued to show manageable safety, clinically meaningful antitumor activity, and durable responses in Chinese patients with advanced melanoma. Subgroup analysis suggested particular benefit in PD-L1-positive and BRAF wild-type acral melanoma, although small subgroup sizes preclude definitive conclusions. Clinical trial registration: https://clinicaltrials.gov, identifier NCT02821000.