Spotlight on ideal target antigens and resistance in antibody-drug conjugates: Strategies for competitive advancement.

Antibody-drug conjugates (ADCs) represent a novel and promising approach in targeted therapy, uniting the specificity of antibodies that recognize specific antigens with payloads, all connected by the stable linker. These conjugates combine the best targeted and cytotoxic therapies, offering the killing effect of precisely targeting specific antigens and the potent cell-killing power of small molecule drugs. The targeted approach minimizes the off-target toxicities associated with the payloads and broadens the therapeutic window, enhancing the efficacy and safety profile of cancer treatments. Within precision oncology, ADCs have garnered significant attention as a cutting-edge research area and have been approved to treat a range of malignant tumors. Correspondingly, the issue of resistance to ADCs has gradually come to the fore. Any dysfunction in the steps leading to the ADCs' action within tumor cells can lead to the development of resistance. A deeper understanding of resistance mechanisms may be crucial for developing novel ADCs and exploring combination therapy strategies, which could further enhance the clinical efficacy of ADCs in cancer treatment. This review outlines the brief historical development and mechanism of ADCs and discusses the impact of their key components on the activity of ADCs. Furthermore, it provides a detailed account of the application of ADCs with various target antigens in cancer therapy, the categorization of potential resistance mechanisms, and the current state of combination therapies. Looking forward, breakthroughs in overcoming technical barriers, selecting differentiated target antigens, and enhancing resistance management and combination therapy strategies will broaden the therapeutic indications for ADCs. These progresses are anticipated to advance cancer treatment and yield benefits for patients.

Adjuvant treatment strategy evolution and risk stratification for hormone receptor-positive, human epidermal growth factor receptor-2 negative early breast cancer in China.

BACKGROUND: Patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2 negative (HER2-) early breast cancer (EBC) with high-risk clinicopathological features face an increased risk of recurrence. This study explored the evolving treatment landscape and clinical outcomes in patients with EBC using a nationwide database. PATIENTS AND METHODS: The study cohort comprised HR+/HER2-, stages 1-3, patients with EBC who underwent surgery and received adjuvant endocrine therapy (AET) from January 2013 to March 2021. High-risk patients were defined by ≥4 positive axillary lymph nodes, or 1-3 positive lymph node(s) with at least one high-risk feature (histologic grade 3, tumor size ≥5 cm, or Ki-67 ≥20%). A low-risk cohort included patients not meeting the criteria. Survival analysis was conducted with a cutoff of September 2021. RESULTS: The study included 4088 eligible patients (1310 high-risk patients and 2778 low-risk patients). High-risk patients were more likely to receive adjuvant chemotherapy and radiotherapy compared to low-risk patients. From 2013 to 2021, an increasing proportion of patients received aromatase inhibitors and ovarian function suppression as part of their AET. The 2-, 5-, and 7-year invasive disease-free survival for high-risk cohort were 90.67%, 75.26%, and 57.10%, respectively, these rates were notably higher for low-risk cohort at 97.14%, 89.85%, and 84.83%. High-risk patients demonstrated a higher risk of recurrence or death compared with low-risk patients (hazard ratio, 2.38; 95% CI, 1.82-3.12). CONCLUSION: In the setting of standard or even intensive AET, patients with EBC with high-risk features still present high recurrence risk, highlighting the urgent need for innovative adjuvant treatment strategies.

Neoadjuvant inetetamab and pertuzumab with taxanes and carboplatin (TCbIP) In locally advanced HER2-positive breast cancer: a prospective cohort study with propensity-matched analysis.

BACKGROUND: Inetetamab is the first domestically developed innovative anti-HER2 monoclonal antibody in China, proven effective and safe in HER2-positive advanced breast cancer. However, its efficacy and safety in neoadjuvant treatment of HER2-positive locally advanced breast cancer (LABC) remain to be validated. METHODS: This prospective cohort study aimed to evaluate the efficacy and safety of inetetamab combined with pertuzumab, taxanes, and carboplatin (TCbIP) in neoadjuvant therapy for HER2-positive LABC, comparing it to data from patients treated with the TCbHP regimen (trastuzumab combined with pertuzumab, taxanes, and carboplatin) using propensity score matching (PSM). The primary endpoint was total pathological complete response (tpCR). Adverse events (AEs), objective response rate (ORR), and near-pCR were key secondary endpoints. RESULTS: Forty-four patients with clinical stage IIA-IIIC HER2-positive LABC were prospectively enrolled and treated with the TCbIP regimen. The tpCR rate among 28 patients who completed surgery was 60.7%, comparable to and slightly higher than the TCbHP group in PSM (60.7% vs. 53.6%, P = 0.510). The ORR was 96.4%, and the DCR reached 100.0%. The most common ≥ grade 3 AE was neutropenia (21.4% vs. 11.9%, P = 0.350). No significant reduction in left ventricular ejection fraction was observed, and no patient withdrew from treatment due to AEs. CONCLUSION: Neoadjuvant therapy with TCbIP showed good efficacy and safety in patients with HER2-positive LABC and might be another promising option for neoadjuvant treatment. TRIAL REGISTRATION: NCT05749016 (registration date: Nov 01, 2021).

Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer.

Cysteinyl aspartate specific proteinase (caspase)-6 belongs to the caspase family and plays a vital role in mediating cell death. Under certain conditions, three pathways of programmed cell death (PCD), including apoptosis, necroptosis and pyroptosis (PANoptosis), transform one way into another, with enormous therapeutic potential. Initially, scholars reported that caspase-6 is a caspase executor that mediates apoptosis. With the ceaseless exploration of the PCD types, studies have demonstrated that caspase-6 mediates pyroptosis by regulating gasdermin D and mediates necroptosis by regulating mixed lineage kinase domain-like. By regulating PANoptosis, caspase-6 plays a crucial role in tumorigenesis in humans and mediates anti-tumour immunity. Therefore, a comprehensive understanding of caspase-6 function in cancer via PANoptosis is important for the prevention and therapy of tumours. This article summarized the function of caspase-6 in PANoptosis and its impact on cancer development, providing targets and strategies for tumour treatment.

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status.

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that plays a carcinogenic role in breast cancer (BC) through gene amplification, mutation, or overexpression. Traditional methods of HER2 detection were divided into positive (immunohistochemistry (IHC) 3+/fluorescence in situ hybridization (FISH) amplification) and negative (IHC 2+/FISH-, IHC 1+, IHC 0) according to the dichotomy method. Anti-HER2-targeted therapies, such as trastuzumab and pertuzumab, have significantly improved the prognosis of HER2-positive patients. However, up to 75% to 85% of patients remain HER2-negative. In recent years, with the rapid development of molecular biology, gene detection technology, targeted therapy, and immunotherapy, researchers have actively explored the clinicopathological characteristics, molecular biological characteristics, treatment methods, and HER2 detection methods of HER2-low/zero breast cancer. With the clinical efficacy of new anti-HER2 targeted drugs, accurate classification of breast cancer is very important for the treatment choice. Therefore, the following review summarizes the necessity of developing HER2 detection methods, and the clinicopathological and drug treatment characteristics of patients with HER2-low/zero, to light the dawn of the treatment of breast cancer patients with HER2-low/zero expression.

New era of medical education: asynchronous and synchronous online teaching during and after COVID-19.

COVID-19 struck the world suddenly and unexpectedly. Since traditional education requires face-to-face communication, to avoid further spreading of the virus a majority part of that education has moved online. Our study attempts to compare the differences between online medical education with a unique course design and traditional face-to-face education. We conducted a retrospective analysis of a total of 4,098 medical students between 2019 and 2020, including two groups of students who received online education and classroom education for the same subjects, respectively. Freshmen enrolled in September 2018 received traditional classroom physiology and pharmacology education in the spring semester of 2019. Because of the impact of the COVID-19 pandemic, freshmen who were enrolled in September 2019 received online physiology and pharmacology education in the spring semester of 2020. The final marks of the two groups of students were recorded and compared. Data on students participating in online discussions, learning, homework, and watching instructional videos were also recorded. There was no significant difference in the final academic performance between the two groups [average mark: 55.93 (online education) vs. 56.27 (classroom education), P = 0.488]. Further analysis showed that student participation rates in online discussions, online learning, and online viewing of instructional videos were closely correlated with final grades in online courses (P < 0.01). In conclusion, our results suggest that the pedagogical effects of online education during COVID-19 were promising, and we provide a well-designed medical online course to inspire further improvements in online education.NEW & NOTEWORTHY The COVID-19 pandemic has led to a massive temporary conversion of offline education to online education worldwide. Previous studies have noted that more students believed they had better learning experience in face-to-face learning. However, with our method of online teaching, we still showed a relatively similar performance result compared with offline education.

Caspase-8: A key protein of cross-talk signal way in "PANoptosis" in cancer.

Cysteinyl aspartate specific proteinase (Caspase)-8 has long been considered a promoter of apoptosis and part of the mechanism by which cytotoxic drugs kill cancer cells. With the continuous exploration of the types of programmed cell death, an increasing number of studies have confirmed that caspase-8 plays an important role in cancer. Recently, scholars have proposed the term "PANoptosis," which mainly includes three programmed cell death modes, namely pyroptosis, apoptosis and necroptosis. In addition to mediating endogenous apoptotic pathways, caspase-8 can also participate in the cleavage of gasdermin (GSDM) family proteins to induce pyroptosis. Furthermore, the expression of enzymatically inactive caspase-8 (C362S) can cause embryonic lethality and inflammatory tissue destruction in mice by inducing necroptosis and pyroptosis. Therefore, the activation and deletion of caspase-8 enzyme activity, as well as the knockout of the coding gene, are closely related to "PANoptosis." In addition, caspase-8 can also improve the tumor microenvironment and enhance tumor antiimmunity. Studies have shown that caspase-8 is also associated with tumor growth and invasion, angiogenesis and metastasis, therapeutic resistance and poor clinical outcomes. Therefore, it is very important to measure the cancer-promoting and anticancer effects of caspase-8 and find a balance, and to study its role in the effect of "PANoptosis" in depth. This article reviews the role of caspase-8 in "PANoptosis" in cancer to provide new strategies and targets for cancer.

Pyroptosis, a new bridge to tumor immunity.

Pyroptosis refers to the process of gasdermin (GSDM)-mediated programmed cell death (PCD). Our understanding of pyroptosis has expanded beyond cells and is known to involve extracellular responses. Recently, there has been an increasing interest in pyroptosis due to its emerging role in activating the immune system. In the meantime, pyroptosis-mediated therapies, which use the immune response to kill cancer cells, have also achieved notable success in a clinical setting. In this review, we discuss that the immune response induced by pyroptosis activation is a double-edged sword that affects all stages of tumorigenesis. On the one hand, the activation of inflammasome-mediated pyroptosis and the release of pyroptosis-produced cytokines alter the immune microenvironment and promote the development of tumors by evading immune surveillance. On the other hand, pyroptosis-produced cytokines can also collect immune cells and ignite the immune system to improve the efficiency of tumor immunotherapies. Pyroptosis is also related to some immune checkpoints, especially programmed death-1 (PD-1) or programmed death- ligand 1 (PD-L1). In this review, we mainly focus on our current understanding of the interplay between the immune system and tumors that process through pyroptosis, and debate their use as potential therapeutic targets.

The influence of photodynamic therapy on the Warburg effect in esophageal cancer cells.

To investigate whether the Warburg effect is a key modulator on the resistance mechanism of photodynamic therapy (PDT). Glycolysis was examined by the test of lactate product and glucose uptake at different post-PDT time points. Cell viability was detected by the CCK-8 assay and cell proliferation was detected by colony formation assay. The expression of glycolysis and related proteins were examined by western blotting. Target gene was silenced by RNAi. In the present study, we assessed the effect of PDT on cancer cell glycolysis. Our team has demonstrated that pyruvate kinase M2 (PKM2), a key speed-limiting enzyme of glycolysis, was significantly overexpressed in patients with esophageal cancer. Our results in the present study showed that PKM2 was downregulated, and lactate product and glucose uptake were inhibited in cells exposed to 5-aminolevulinic acid (5-ALA)-mediated PDT at 4 h after treatment. However, at 24 h after PDT, we observed a substantial increase in PKM2 expression, lactate product, and glucose uptake. Moreover, silencing of PKM2 gene abrogated the upregulatory effect of PDT on glycolysis at late post-PDT period. 2-Deoxy-D-glucose (2-DG) is a recognized chemical inhibitor of glycolysis. The combined treatment of 2-DG and PDT significantly inhibited tumor growth in vitro at 24 h. These results demonstrate that PDT drives the Warburg effect in a time-dependent manner, and PKM2 plays an important role in this progress, which indicated that PKM2 may be a potential molecular target to increase the sensitivity of esophageal cancer cells to PDT.

ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-ß1 pathway.

BACKGROUND: Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-ß1 and the possible mechanisms mediating the effects. METHODS: The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor ß1 (TGF-ß1) signal pathway were measured by real-time RT-PCR and western blot. RESULTS: The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-ß1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. CONCLUSIONS: ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-ß1 in HK-2 cells.

[Effect of grain-bean package, grain-bean package dietary fiber and single whole grain dietary fiber on dyslipidemia rats].

OBJECTIVE: To observe and compare the effects of grain-bean package, dietary fiber (DF) extracted from grain-bean package, and DF from grain corn on the blood lipids and fatty acid synthase (FAS) activity in high-fat, high-cholesterol feeding induced dyslipidemia rats, and observe its effects on regulation of sterol regulatory element protein-1c (SREBP-1c) mRNA expression in rat liver. METHODS: Consolidation 50 SD rats of clean grade feeding adaptation for one week, randomly assigned into normal control group, hyperlipidemia model group, grain-bean package group, grain-bean package DF group and grain corn group. Feed with corresponding diets for 8 weeks, and measure the total cholesterol (TC), triglyceridaemia (TG), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG), FAS, SREBP-1c mRNA of all groups. RESULT: Compared with control group, TC, TG, FBG levels of hyperlipidemia model group were significantly increased (P < 0.05). Compared with model group, TC, TG, FBG levels of grain-bean package group, grain-bean package DF group were significantly decreased, HDL-C levels significantly increased, and activity of FAS, regulation of SREBP-1c were significantly decreased (P < 0.05). CONCLUSION: The Grain-bean package dietary fiber can improve blood lipids levels of dyslipidemia rats, and decrease FAS activity and SREBP-1c mRNA expression.

Efficient chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle as "in situ" vaccine integrated tumor ICD and immunoagonist.

INTRODUCTION: Immunotherapy has unprecedentedly opened up a series of neoteric tactics for cancer treatment. As a burgeoning approach, chemo-immunotherapy has innovatively expanded the accomplishments of conventional chemotherapeutic agents for cancer governing. OBJECTIVES: An efficacious chemo-immunotherapy leveraging minimalist electrostatic complex nanoparticle (NP) integrated tumor immunogenic cell death (ICD) and immunoagonist was developed as a watertight "in situ" vaccine for cancer therapy through convenient intratumoral administration with minimized systemic toxicity. METHODS: Chemical-modified pH-sensitive cis-aconityl-doxorubicin (CAD) and immunoadjuvant unmethylated cytosine-phosphate-guanine (CpG) were co-packaged by polycationic polyethylenimine (PEI) though electrostatic-interaction to construct PEI/CpG/CAD NP. By intratumoral injection, this positively charged NP could be detained at tumor site and endocytosed by tumor cells effortlessly. Then, doxorubicin was released through cis-aconityl cleavage induced by endosomal-acidity and further triggered tumor ICD, the moribund tumor cells could release damage-associated molecular patterns (DAMPs) to recruit dendritic cells (DCs). Meanwhile, the entire tumor debris derived into diversified antigens and cooperated with immunostimulatory CpG to excite DC maturation and activated comprehensive antitumor immunity. RESULTS: Prominent tumor suppression was achieved in aggressive mouse melanoma tumor model, which verified the feasibility and effectiveness of this minimalist CAD/CpG-codelivered NP. CONCLUSION: This study has provided a convenient and promising paradigm for potent cancer chemo-immunotherapy.

[Effect of compound whole grain-soybean on oxidative stress].

OBJECTIVE: To observe the in vitro oxidation resistance of compound whole grain and the effect on improving the disorder of lipid metabolism and the oxidative stress in rats. METHODS: Make extracting of compound whole grain, rice, flour and black rice, method use chemical colorimetry to detect total antioxidant capacity, hydroxyl radical (*OH) and superoxide anion (O2-*). Forty-four male SD rats were divided into four groups in random: negative control group, model control group, white rice-flour group and compound whole grain. All 4 groups were fed for 8 weeks with different experimental diets. Weight, total cholesterol (TC), triglyceride (TG ), high density lipoprotein cholesterol (HDL-C) were detected in serum. Malondialdehyde (MDA), total antioxidant capacity (T-AOC), super oxygen dehydrogenizes (SOD), glutathione peroxidase (GSH-Px) were detected in serum and liver. RESULTS: The T-AOC, the ability of body cleaning hydroxyl radical and superoxide anion were enhanced,quite with the black rice. In all 3 treatment groups, compound whole grain group had higher HDL-C, T-AOC, SOD, GSH-Px, while TC, TG, MDA were lower. Compared with negative control groups, there is no significant difference. CONCLUSION: Compound whole grain can have good effect on oxidative stress. This effect is the important mechanism of lipid metabolism disorders.

[Research of the whole grain-soybean compound package to regulate the cholesterol metabolism by SREBP-2, LDLR and visfatin].

OBJECTIVE: To discuss the possible mechanism of the whole grain-soybean compound package on dyslipidaemia rats. METHODS: 44 SD rats were randomly divided into four groups: the hyperlipidaemic group, the rice-flour group, the whole grain-soybean compound package group and the negative control group by lipid profiles, fed with corresponding feed for eight weeks. Serum total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) were measured before and after the test. At the end of the experiment, blood samples were taken from the femoral artery, the rat organs were collected and weighted. Serum Visfatin levels and SREBP-2 mRNA and LDLR mRNA in the liver were measured. RESULTS: Compared with the hyperlipidaemic group and rice-flour group, the body weight, serum TC, TG and LDL-C of whole grain-soybean compound package group were significantly decreased (P < 0.05), HDL-C was significantly increased (P < 0.05). Visfatin levels were significantly decreased (P < 0.05). Gene expressions of SREBP-2 and LDLR were significantly increased (P < 0.05). Gene expression of Visfatin in whole grain-soybean compound package group was significantly lower than that in hyperlipidaemia group and rice-flour group (P < 0.05). CONCLUSION: Whole grain-soybean compound package can improve the serum lipid profiles and Visfatin of rats fed with a high fat diet. The possible mechanism is that the whole grain-soybean compound package can activate the expression of SREBP-2, LDLR and Visfatin. And then enhance the expressing activity of regulate the cholesterol metabolism by SREBP-2, LDLR and Visfatin. Ultimately, to reduce the level of rats' cholesterol, and then ameliorate the dyslipidaemia of rats.

Botulinum toxin in the treatment of sialorrhea in severe neurological patients with tracheotomy.

OBJECTIVE: To observe the clinical effect of botulinum toxin type A (BTA) injection into the salivary glands of the severe neurological patients with tracheotomy METHODS: Seven patients with severe neurological disorders after tracheotomy and obvious drooling symptoms were enrolled. BTA was injected into bilateral parotid glands and submandibular glands under the guidance of ultrasound. Unstimulated salivary flow rate (uSFR) and Drooling Severity and Frequency Scale (DSFS) were used to evaluate drooling before injection, 1 week, and 4 weeks after injection. We compared the extubation time, time of changing from balloon cannula to metal cannula, hospitalization time and incidence of recurrent pulmonary infection between these patients and other patients accepted conventional curation. RESULTS: (1) The drooling severity scale (DSFS-S), the drooling frequency scale (DSFS-F), the drooling frequency and severity scale total score (DSFS-T) were significantly lower at 4 weeks after BTA injection compared to prior-treatment (p < .001). (2) uSFR of 1 week and 4 weeks were both statistically decreased than the untreated condition (p < .001). (3) Compared with the conventional group, the time of changing from balloon cannula to metal cannula was shortened obviously (p < .05) and incidence of recurrent pulmonary infection was clearly decreased (p < .05) after BTA treatment CONCLUSION: Ultrasound-guided BTA injection into salivary glands can effectively reduce saliva secretion. We also found that the time of changing cannula was shortened obviously and the incidence of recurrent pneumonia infection was reduced. BTA injection of salivary glands to cure drooling could advance to the clinical therapy in severe neurological patients after tracheotomy.

Improved survival in patients with isolated liver metastasis at initial diagnosis with surgery at primary and metastatic sites: A population-based study in patients with breast cancer.

BACKGROUND: The aim of this study was to investigate epidemiological characteristics, risk factors, optimal treatment options, and survival outcomes of breast cancer patients with isolated liver metastasis (BCILM). METHODS: Patients with breast cancer (BC) were selected from Incidence-Surveillance, Epidemiology, and End Results (SEER) Research Plus Data, 17 registries between 2010 and 2019. The Kaplan-Meier method and log-rank test were used to compare survival rates between patients who received or did not receive surgery for the primary and liver metastatic sites. Univariate and multivariate analyses were conducted using Cox regression analysis. RESULTS: This study included 17 743 stage IV BC patients, with 3604 (20.3%) patients experiencing liver metastasis at initial diagnosis. Of 3604 liver metastasis patients, 951 were diagnosed with BCILM. The median survival time of patients with BCILM who underwent surgery at the primary site (52.0 months) or distant sites (85.0 months) was significantly longer than that of patients who did not undergo surgery at the primary site (23.0 months) or distant sites (32.0 months). Univariate analysis indicated that age, race, histological grade, molecular subtype, T stage, N stage, surgery of the primary site, surgery to other regional/distant sites, radiotherapy, and chemotherapy were prognostic factors affecting the overall survival (OS) and cancer-specific survival (CSS) of patients with BCILM (p < 0.05). Multivariate analysis suggested that age, race, molecular subtype, T stage, surgery of the primary site, radiotherapy, and chemotherapy were independent prognostic factors. In the BCILM cohort, HR+ /HER2+ patients exhibited the best OS and CSS, followed by HR- /HER2+ , HR+ /HER2- , and HR- /HER2- patients (p < 0.0001; p < 0.0001). CONCLUSION: Surgery at the primary and metastatic sites was associated with better survival in patients with BCILM. HER2+ patients with BCILM had a significantly better prognosis than HER2- patients.

SERS combined with the difference in bacterial extracellular electron transfer ability to distinguish Shewanella.

Shewanella plays an important role in geochemical cycle, biological corrosion, bioremediation and bioenergy. The development of methods for identifying Shewanella can provide technical support for its rapid screening, in-depth research into its extracellular respiratory mechanism and its application in ecological environment remediation. As a tool for microbial classification, identification and detection, Surface-enhanced Raman scattering (SERS) has high feasibility and application potential. In this work, bio-synthesized silver nanoparticles (AgNPs) were used as SERS substrates to effectively distinguish different types of Shewanella bacteria based on the difference in bacterial extracellular electron transfer (EET) ability. AgNPs were combined with the analyzed bacteria to prepare "Bacteria-AgNPs" SERS samples, which can strongly enhance the Raman signal of the target bacteria and reliably obtain spatial information of different molecular functional groups of each bacteria. Our developed approach can effectively distinguish between non-metal reducing and metal-reducing bacteria, and can further distinguish the three subspecies of Shewanella (Shewanella oneidensis MR-1, Shewanella decolorationis S12, and Shewanella putrefaciens SP200) at the genus and species level. The Raman signal enhancement is presumably caused by the excitation of local surface plasma (LSP) and the enhancement of surrounding electric field. Therefore, our developed method can achieve interspecific and intraspecies discrimination of bacteria. The proposed method can be extended to distinguish other metal-reducing bacteria, and the novel SERS active substrates can be developed for practical applications.

A phase II study of a doublet metronomic chemotherapy regimen consisting of oral vinorelbine and capecitabine in Chinese women with HER2-negative metastatic breast cancer.

BACKGROUND: This single-arm prospective phase II trial was performed to assess the efficacy and safety of the dual oral metronomic vinorelbine and capecitabine (mNC) regimen in women with HER2-negative metastatic breast cancer (MBC) in China. METHODS: The mNC regimen was administered to the enrolled cases, including oral vinorelbine (VNR) 40 mg three times weekly (on days 1, 3 and 5 every week) and capecitabine (CAP) 500 mg three times a day, until disease progression or intolerable toxicity. The primary endpoint was the 1-year progression-free survival (PFS) rate. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), clinical benefit rate (CBR) and treatment-related adverse events (TRAEs). Stratified factors included treatment lines and hormone receptor (HR) status. RESULTS: Between June 2018 and March 2023, 29 patients were enrolled into the study. The median follow-up time was 25.4 months (range, 2.0-53.8). In the entire group, the 1-year PFS rate was 54.1%. ORR, DCR and CBR were 31.0%, 96.6% and 62.1%, respectively. The mPFS was 12.5 months (range, 1.1-28.1). Subgroup analysis revealed that ORRs were 29.4% and 33.3% in first- and ≥second-line chemotherapy, respectively. ORRs were 29.2% (7/24) and 40.0% (2/5) for HR-positive MBC and metastatic triple-negative breast cancer (mTNBC), respectively. Grade 3/4 TRAEs were neutropenia (10.3%) and nausea/vomiting (6.9%). CONCLUSIONS: The dual oral mNC regimen showed very good safety features and improved compliance without loss of efficacy in both first- and second-line treatments. The regimen also reached an excellent ORR in the mTNBC subgroup.

Synergistically enhanced cancer immunotherapy by combining protamine-based nanovaccine with PD-L1 gene silence nanoparticle.

Tumor vaccine has brought a new dawn for cancer immunotherapy, but disillusionary therapeutic outcomes have been achieved due to the inefficient in vivo vaccine delivery. Moreover, tumor cells customarily resort to various wily tricks to circumvent the recognition and sweeping of the immune system, the immune escape effect has badly aggravated the difficulty of cancer management. With respect to the foregoing, in this study, a promising combinational strategy which cooperated nanovaccine with immune escape inhibition was developed for synergistically enhancing the oncotherapy efficiency. On the one hand, natural polycationic macromolecule protamine (PRT) was utilized as the carrier to construct an antigen and adjuvant co-packaged nanovaccine for facilitating the ingestion in antigen-presenting cells, amplifying antigen cross-presentation and optimizing in vivo delivery. On the other hand, PD-L1 silence gene was selected and hitchhiked in a pH-responsive nanoparticle developed in our previous study. The therapeutic gene could be successfully delivered into the tumors to down-regulate PD-L1 expression and cripple tumor immune escape. The combination of nanovaccine with PD-L1 gene silence nanoparticle could synchronously stimulate antitumor immune responses and reduce immune escape, synergistically enhance the therapeutic efficiency. This study will furnish the prospective tactics for the research of cancer immunotherapy.

Eribulin combined with antiangiogenic agents in women with HER2-negative metastatic breast cancer: a retrospective multicenter study.

Background: The relative lack of specifically targeted agents for HER2-negative metastatic breast cancer (MBC) makes the need for new agents or combination therapies to maximize clinical benefit while reducing toxicity critical. Objectives: To retrospectively analyze the efficacy and safety of eribulin combined with antiangiogenic drugs in the treatment of Chinese women with HER2-negative MBC. Methods: A total of 85 consecutive MBC patients with HER2-negative who were treated with eribulin + antiangiogenic agents between October 2020 and April 2023 in four institutions were retrospectively included in this study. Patients received eribulin 1.4 mg/m2 (day 1 and 8) plus bevacizumab 7.5 mg/kg (day 1, 64 patients) or anlotinib 10 mg daily (day 1-14, 16 patients) or apatinib 250 mg daily (5 patients) on a 21-day cycle until progression or unacceptable toxicity. The primary end-point was progression-free survival (PFS), according to Response Evaluation Criteria in Solid tumors (RECIST) 1.1. Secondary end-points included toxicities, objective response rate (ORR), disease control rate (DCR), and overall survival (OS). Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study included 85 HER2-negative MBC patients, with 41 patients (48.2%) in the first to second line group and 44 patients (51.8%) in the greater than or equal to third line group. The median age was 54.0 years. Thirty patients in the first to second line group and 14 patients in the greater than or equal to third line group had triple-negative breast cancer (TNBC). The ORR and DCR were 34.1% (29/85) and 75.3% (64/85). The median PFS (mPFS) of total population was 6.0 months (95% CI: 4.3-7.7), and median OS (mOS) was immature. The mPFS was 7.7 and 4.3 months in the first to second and greater than or equal to third line treatment (p = 0.003), respectively. TNBC patients in first to second line therapy showed a significantly longer PFS (6.5 months versus 2.0 months, p = 0.021) compared to greater than or equal to third line. The incidences of cardiovascular toxicity were 29.4% in grades 1-2 and no grades 3-4. Hematologic toxicity (leukopenia and neutropenia) was the most common grade ⩾3 AEs, and AEs were more common in patients in greater than or equal to third line. Conclusion: The results suggest that eribulin combined with antiangiogenic therapy has a meaningful clinical activity and an acceptable safety profile in HER2-negative MBC.