Lenvatinib Plus Pembrolizumab Versus Standard of Care for Previously Treated Metastatic Colorectal Cancer: Final Analysis of the Randomized, Open-Label, Phase III LEAP-017 Study.

PURPOSE: Treatment options are limited for patients with previously treated metastatic colorectal cancer (mCRC). In the LEAP-017 study, we evaluate whether lenvatinib in combination with pembrolizumab improves outcomes compared with standard of care (SOC) in previously treated mismatch repair proficient or not microsatellite instability high (pMMR or not MSI-H) mCRC. METHODS: In this international, multicenter, randomized, controlled, open-label, phase III study, eligible patients age 18 years and older with unresectable, pMMR or not MSI-H mCRC, that had progressed on or after, or could not tolerate, standard treatment, were randomly assigned 1:1 to lenvatinib 20 mg orally once daily plus pembrolizumab 400 mg intravenously once every 6 weeks or investigator's choice of regorafenib or trifluridine/tipiracil (SOC). Randomization was stratified by presence or absence of liver metastases. The primary end point was overall survival (OS). LEAP-017 is registered at ClinicalTrials.gov (NCT04776148), and has completed recruitment. RESULTS: Between April 8, 2021, and December 21, 2021, 480 patients were randomly assigned to lenvatinib plus pembrolizumab (n = 241) or SOC (n = 239). At final analysis (median follow-up of 18.6 months [IQR, 3.9]), median OS with lenvatinib plus pembrolizumab versus SOC was 9.8 versus 9.3 months (hazard ratio [HR], 0.83 [95% CI, 0.68 to 1.02]; P = .0379; prespecified threshold P = .0214). Grade ≥3 treatment-related adverse events occurred in 58.4% (lenvatinib plus pembrolizumab) versus 42.1% (SOC) of patients. Two participants died due to treatment-related adverse events, both in the lenvatinib plus pembrolizumab arm. CONCLUSION: In patients with pMMR or not MSI-H mCRC that had progressed on previous therapy, there was no statistically significant improvement in OS after lenvatinib plus pembrolizumab treatment versus SOC. No new safety signals were observed.

The survival outcome differs between left-sided colon and middle/low rectal cancer after colorectal hepatic metastasectomy.

INTRODUCTION: The clinical outcomes between left-sided colon cancer and middle/low rectal cancer appear to be different. We aimed to examine the impact of primary tumor location regarding the left-sided colon and middle/low rectum on the overall survival (OS) of colorectal hepatic metastasectomy. PATIENTS AND METHODS: Patients who underwent colorectal hepatic metastasectomy were retrospectively enrolled. Patients were classified into two groups according to primary tumor location (left-sided colon and middle/low rectum). Categorical variables were compared using the chi-square test or Fisher's exact test, and continuous variables were analyzed using Student'st-test. Survival was analyzed by the KaplanMeier method and log-rank test. The prognostic factors were analyzed by univariate and multivariate analyses using Cox proportional hazards regression models. RESULTS: Totally, 365 patients were enrolled. Patients with left-sided colon cancer had significantly better OS than those with middle/low rectal cancer (hazard ratio (HR) 0.725, P=0.018), with a median OS of 48 months and 38 months, respectively. In the subgroup analysis of RAS mutations, those with left-sided colon cancer had significantly prolonged OS compared to those with middle/low rectum cancer (HR 0.608, P=0.034), with a median OS of 49 months and 26 months, respectively. This observation was limited to patients with RAS mutations. CONCLUSION: According to our findings, middle/low rectal cancer had poorer survival outcome, and should not be categorized together with left-sided colon cancer in terms of OS following colorectal hepatic metastasectomy.

Effects of Levosimendan on Diaphragmatic Dysfunction in Patients with Sepsis.

OBJECTIVE: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. METHODS: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBT) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 µg/kg for 10 minutes, followed by a continuous infusion at 0.2 µg/kg/min. The control group received an equivalent dose of a placebo. The pre- and post-administration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). RESULTS: Forty-four patients were enrolled in the study. We found that post-administration of levosimendan, the patients' tidal volume (GCSMV) increased, while the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the pre-administration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively), and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the post-administration levels of DE, TFdi, and D-RSBI as compared to the pre-administration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). CONCLUSION: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

Interferon gamma induces higher neutrophil extracellular traps leading to tumor-killing activity in microsatellite stable colorectal cancer.

Many colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the CRC tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in CRC development. Tumor-associated neutrophils (TANs) found in tumor tissues exhibit an immunosuppressive phenotype and are associated with CRC patient prognosis. Neutrophil extracellular traps (NETs), DNA meshes containing cytotoxic enzymes released into the extracellular space, may be promising therapeutic targets in cancer. This study showed increased NETs in tumor tissues and peripheral neutrophils of high levels of microsatellite instability (MSI-H) CRC patients compared to microsatellite stable (MSS) CRC patients. IFNγ response genes were enriched in MSI-H CRC patients compared to MSS CRC patients. Co-culturing neutrophils with MSI-H CRC cell lines induced more NET formation and higher cellular apoptosis than MSS CRC cell lines. IFNγ treatment induced more NET formation and apoptosis in MSS CRC cell lines. Using subcutaneous or orthotopic CT-26 (MSS)-tumor-bearing mice models, IFNγ reduced tumor size and enhanced PD-1 antibody-induced tumor-killing activity, accompanied by upregulated NETs and cellular apoptosis. These findings suggest IFNγ could be a therapeutic strategy for MSS CRC.

Extraction, purification, structural characterization and pharmacological activities of polysaccharides from sea buckthorn (Hippophae rhamnoides L.): A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Sea buckthorn (Hippophae rhamnoides L.) is an edible fruit with a long history in China as a medicinal plant. The fruits of H. rhamnoides are rich in a variety of nutrients and pharmacological active compounds. As one of the most important active ingredients in sea buckthorn, polysaccharides have attracted the attention of researchers due to their antioxidant, anti-fatigue, and liver protective qualities. AIM OF THE REVIEW: This review summarizes recent studies on extraction, purification, structural characterization and pharmacological activities of polysaccharides from sea buckthorn. In addition, the relationship between the structure and the activities of sea buckthorn polysaccharides (SBPS) were discussed. This review would provide important research bases and up-to-date information for the future in-depth development and application of sea buckthorn polysaccharides in the field of pharmaceuticals and functional foods. MATERIALS AND METHODS: By inputting the search term "Sea buckthorn polysaccharides", relevant research information was obtained from databases such as Web of Science, Google Scholar, PubMed, China Knowledge Network (CNKI), China Master Theses Full-text Database, and China Doctoral Dissertations Full-text Database. RESULTS: The main extraction methods of SBPS include hot water extraction (HWE), ultrasonic assisted extraction (UAE), microwave-assisted extraction (MAE), flash extraction (FE), and ethanol extraction. More than 20 polysaccharides have been isolated from sea buckthorn fruits. The chemical structures of sea buckthorn polysaccharides obtained by different extraction, isolation, and purification methods are diverse. Polysaccharides from sea buckthorn display a variety of pharmacological properties, including antioxidant, anti-fatigue, liver protection, anti-obesity, regulation of intestinal flora, immunoregulation, anti-tumor, anti-inflammatory, and hypoglycemic activities. CONCLUSIONS: Sea buckthorn has a long medicinal history and characteristics of an ethnic medicine and food. Polysaccharides are one of the main active components of sea buckthorn, and they have received increasing attention from researchers. Sea buckthorn polysaccharides have remarkable pharmacological activities, health benefits, and broad application prospects. In addition, further exploration of the chemical structure of SBPS, in-depth study of their pharmacological activities, identification of their material basis, characterization of disease resistance mechanisms, and potential health functions are still directions of future research. With the accumulation of research on the extraction and purification processes, chemical structure, pharmacological effects, molecular mechanisms, and structure-activity relationships, sea buckthorn polysaccharides derived from natural resources will ultimately make significant contributions to human health.

UHPLC-MS/MS Method Development and Validation for the Genotoxic Impurities Trimethyl Phosphate and Triisopropyl Phosphate of Elagolix Sodium.

Elagolix sodium is a gonadotropin-releasing hormone (GnRH) receptor antagonist that inhibits endogenous GnRH signaling by competitively binding to GnRH receptors in the pituitary gland to treat moderate to severe pain associated with endometriosis. To keep the safety and quality of the drug, a fast quantitative method by reversed-phase ultrahigh-performance liquid chromatography coupled with tandem mass spectrometry has been developed and validated for the identification, assay and estimation of potential genotoxic impurities trimethyl phosphate and triisopropyl phosphate in commercial batches of this active pharmaceutical ingredient in accordance with International Conference on Harmonization guidelines Q2 and M7. The method was validated by assessing specificity, sensitivity, linearity, the limit of quantification and detection, accuracy, precision and robustness for above analytes at a very low concentration, whose quantification and detection limits reached to 24 and 4.8 pg/ml, respectively, and the total run time for a single injection was 6 min.

High power optical frequency comb with 10-19 frequency instability.

Optical frequency combs with more than 10 W have paved the way for extreme ultraviolet combs generation by interaction with inert gases, leading to extreme nonlinear spectroscopy and the ultraviolet nuclear clock. Recently, the demand for an ultra-long-distance time and frequency space transfer via optical dual-comb proposes a new challenge for high power frequency comb in respect of power scaling and optical frequency stability. Here we present a frequency comb based on fiber chirped pulse amplification (CPA), which can offer more than 20 W output power. We further characterize the amplifier branch noise contribution by comparing two methods of locking to an optical reference and measure the out-of-loop frequency instability by heterodyning two identical high-power combs. Thanks to the low noise CPA, reasonable locking method, and optical path-controlled amplifiers, the out-of-loop beat note between two combs demonstrates the unprecedented frequency stability of 4.35 × 10-17 at 1s and 6.54 × 10-19 at 1000 s.

Mixed-Valence CuI /CuIII Metal-Organic Frameworks with Non-innocent Ligand for Multielectron Transfer.

We report two novel three-dimensional copper-benzoquinoid metal-organic frameworks (MOFs), [Cu4 L3 ]n and [Cu4 L3 ⋅ Cu(iq)3 ]n (LH4 =1,4-dicyano-2,3,5,6-tetrahydroxybenzene, iq=isoquinoline). Spectroscopic techniques and computational studies reveal the unprecedented mixed valency in MOFs, formal Cu(I)/Cu(III). This is the first time that formally Cu(III) species are witnessed in metal-organic extended solids. The coordination between the mixed-valence metal and redox-non-innocent ligand L, which promotes through-bond charge transfer between Cu metal sites, allows better metal-ligand orbital overlap of the d-π conjugation, leading to strong long-range delocalization and semiconducting behavior. Our findings highlight the significance of the unique mixed valency between formal Cu(I) and highly-covalent Cu(III), non-innocent ligand, and pore environments of these bench stable Cu(III)-containing frameworks on multielectron transfer and electrochemical properties.

Impact of Cochlear Dose on Hearing Preservation Following Stereotactic Radiosurgery in Treatment of Vestibular Schwannomas: A Multi-Center Study.

OBJECTIVE: Stereotactic radiosurgery (SRS) is a well-established treatment for vestibular schwannomas (VS). Hearing loss remains a main morbidity of VS and its treatments, including SRS. The effects of radiation parameters of SRS on hearing remain unknown. The goal of this study is to determine the effect of tumor volume, patient demographics, pretreatment hearing status, cochlear radiation dose, total tumor radiation dose, fractionation, and other radiotherapy parameters on hearing deterioration. METHODS: Multicenter retrospective analysis of 611 patients who underwent SRS for VS from 1990-2020 and had pre- and post-treatment audiograms. RESULTS: Pure tone averages (PTAs) increased and word recognition scores (WRSs) decreased in treated ears at 12-60 months while remaining stable in untreated ears. Higher baseline PTA, higher tumor radiation dose, higher maximum cochlear dose, and usage of single fraction resulted in higher post radiation PTA; WRS was only predicted by baseline WRS and age. Higher baseline PTA, single fraction treatment, higher tumor radiation dose, and higher maximum cochlear dose resulted in a faster deterioration in PTA. Below a maximum cochlear dose of 3 Gy, there were no statistically significant changes in PTA or WRS. CONCLUSIONS: Decline of hearing at one year in VS patients after SRS is directly related to maximum cochlear dose, single versus 3-fraction treatment, total tumor radiation dose, and baseline hearing level. The maximum safe cochlear dose for hearingtbrowd preservation at one year is 3 Gy, and the use of 3 fractions instead of one fraction was better at preserving hearing.

Surgical strategy for colorectal cancer with synchronous liver and extrahepatic metastases: A scoring system and decision tree model.

BACKGROUND: The role of hepatectomy in a specific group of patients with synchronous colorectal cancer with liver metastases (SCRLM) and synchronous extrahepatic disease (SEHD) is still unclear. The aim of this study was to evaluate the efficacy of liver surgery and define the selection criteria for surgical candidates in patients with SCRLM + SEHD. METHODS: Between July 2007 and October 2018, 475 patients with colorectal cancer with liver metastases (CRLM) who underwent liver resection were retrospectively reviewed. Sixty-five patients with SCRLM + SEHD were identified and included in the study. Clinical pathological data of these patients were analyzed to evaluate the influence on survival. Important prognostic factors were identified by univariate and multivariate analyses. The risk score system and decision tree analysis were generated according to the important prognostic factors for better patient selection. RESULTS: The 5-year survival rate of patients with SCRLM + SEHD was 21.9%. The most important prognostic factors were SCRLM number of more than five, site of SEHD other than the lung only, inability to achieve SCRLM + SEHD R0 resection, and BRAF mutation of cancer cells. The proposed risk score system and decision tree model easily discriminated between patients with different survival rates and identified the profile of suitable surgical patients. CONCLUSION: Liver surgery should not be a contraindication for patients with SCRLM + SEHD. Patients with complete SCRLM + SEHD R0 resection, SCRLM number less than or equal to five, SEHD confined to the lung only, and wild-type BRAF could have favorable survival outcomes. The proposed scoring system and decision tree model may be beneficial to patient selection in clinical use.

Isotope-coded derivatization with designed Girard-type reagent as charged isobaric mass tags for non-targeted profiling and discovery of natural aldehydes by liquid chromatography-tandem mass spectrometry.

Aldehyde-containing metabolites are reactive electrophiles that have attracted extensive attention due to their widespread occurrence in organisms and natural foods. Herein we described a newly-designed Girard's reagent, 1-(4-hydrazinyl-4-oxobutyl)pyridin-1-ium bromide (HBP), as charged tandem mass (MS/MS) tags to facilitate selective capture, sensitive detection and semi-targeted discovery of aldehyde metabolites via hydrazone formation. After HBP labeling, the detection signals of the test aldehydes were increased by 21-2856 times, with the limits of detection were 2.5-7 nM. Upon isotope-coded derivatization with a pair of labeling reagents, HBP-d0 and its deuterium-labeled counterpart HBP-d5, the aldehyde analytes were converted to hydrazone derivatives, which generated characteristic neutral fragments of 79 Da and 84 Da, respectively. The isobaric HBP-d0/HBP-d5 labeling based LC-MS/MS method was validated by relative quantification of human urinary aldehydes (slope=0.999, R2 > 0.99, RSDs ≤ 8.5%) and discrimination analysis between diabetic and control samples. The unique isotopic doubles (Δm/z = 5 Da) by dual neutral loss scanning (dNLS) provided a generic reactivity-based screening strategy that allowed non-targeted profiling and identification of endogenous aldehydes even amidst noisy data. The LC-dNLS-MS/MS screening of cinnamon extracts led to finding 61 possible natural aldehydes and guided discovery of 10 previously undetected congeners in this medicinal plant.

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability.

BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.

Interface Wetting Driven by Laplace Pressure on Multiscale Topographies and Its Application to Performance Enhancement of Metal-Composite Hybrid Structure.

Surface topography reconstruction is extensively used to address the issue of weak bonding at the polymer-metal interface of metal-composite hybrid structure, while enhancement from this approach is seriously impaired by insufficient interface wetting. In this study, the wetting behavior of polymer on aluminum surfaces with multiscale topographies was theoretically and experimentally investigated to realize stable and complete wetting. Geometric dimensions of multiscale surface topographies have a notable impact on interfacial forces at the three-phase contact line of polymer/air/aluminum, and a competition exists between Laplace pressure and bubble pressure in dominating the wetting behavior. Laplace pressure facilitates the degassing of trapped air bubbles in grooves, bringing more robust interfacial wettability to grooves than dimples and grids. Conversely, dimples with excessive dimensions generate interfacial pores, and this intrinsic mechanism is theoretically unraveled. Moreover, different degrees of interface wetting cause variations in bonding strength of polymer-aluminum interface, which changes from ∼18% improvement to ∼17% reduction compared to original strength. Finally, groove topography perfectly achieved complete wetting between polymer and aluminum and consequently improved flexure performance by over 11% for the aluminum-carbon fiber hybrid side impact bar, which verifies the importance of complete wetting at a part scale. This study deepens the understanding of wetting behavior and clarifies the intrinsic correlation between interfacial bonding performance and surface topography.

MOF-based nanozyme grafted with cooperative Pt(IV) prodrug for synergistic anticancer therapy.

Manipulating Fenton chemistry in tumor microenvironment (TME) for the generation of reactive oxygen species is an effective strategy for chemodynamic therapy. However, this is usually restricted by limited intracellular content of H2O2 and insufficient acidic environment at the tumor site. Herein, a ferric metal-organic framework (MOF) is covalently grafted with a prodrug of cisplatin (Pt(IV) prodrug) and loaded with a biocatalyst glucose oxidase (GOx) to afford a nanozyme MOF-Pt(IV)@GOx for cascade reactions. In this system, the attached Pt(IV) prodrug on MOF plays a significant role in the cooperative enhancement of GOx loading and chemotherapy. The high concentration of glutathione in TME reduces Fe(III) to Fe(II) for Fenton reaction, and converts Pt(IV) prodrug to cisplatin for DNA targeting and H2O2 production. Meanwhile, glucose oxidation catalyzed by GOx not only consumes glucose for starvation therapy, but also promotes the intracellular acidity and H2O2 supply in TME, which are in favor of Fenton reaction. Both in vitro and in vivo studies demonstrate that MOF-Pt(IV)@GOx enables remarkable anticancer efficacy due to the synergistic trimodal therapy consisting of ferroptosis, starvation therapy, and chemotherapy.

High energy widely tunable narrow-linewidth Ti:sapphire laser using combined-cavity configuration.

A high-energy narrow-linewidth Ti:sapphire laser with widely tunable wavelength was investigated. The Littman cavity was seeded by an extended prism cavity, and they were coupled together by sharing a partial reflection mirror. The widely wavelength tunability of the prism cavity and the linewidth compression of Littman cavity were incorporated together, which resulted in a significantly increased tunable wavelength range from 720 nm to 884 nm with linewidth of less than 100 MHz. The coupling effect and the synchronization between the two cavities in temporal and spectral domain were discussed. The narrow-linewidth laser centered at 786 nm was further amplified to 36 mJ and frequency-doubled to 393 nm with pulse energy of 18.8 mJ while maintaining the narrow linewidth at a repetition rate of 10 Hz. This widely tunable narrow-linewidth laser is a promising light source for high-resolution fluorescence spectroscopy.

Clopidogrel delays and can reverse diabetic nephropathy pathogenesis in type 2 diabetic db/db mice.

BACKGROUND: Diabetic nephropathy (DN) is the principal cause of end-stage renal disease. Previous studies have shown that clopidogrel can prevent the early progression of renal injury. AIM: To elucidate whether clopidogrel is beneficial against DN by using a db/db mouse model. METHODS: db/db mice with a higher urinary albumin/creatinine ratio (ACR) relative to age- and sex-matched wild-type control mice were randomly allocated to clopidogrel and vehicle treatment groups. Clopidogrel was administered at doses of 5, 10, and 20 mg/kg by gavage for 12 wk. Body mass, blood glucose level, and urinary creatinine and albumin concentrations in each group were measured before and after the intervention. Renal fibrosis was evaluated using periodic acid-Schiff and Masson's trichrome staining. The renal protein expression of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and F4/80 was assessed using immunohistochemistry. Urinary TNF-α, monocyte chemoattractant protein-1 (MCP-1), and IL-6 levels were analyzed using enzyme-linked immunosorbent assay; TNF-α and IL-1ß mRNA expression was measured using real-time quantitative polymerase chain reaction. The protein expression of fibronectin (FN) and collagen I was assessed using immunohistochemistry. RESULTS: Clopidogrel treatment did not affect the body mass or blood glucose level of the db/db mice; however, it increased bleeding time and reduced urinary ACR in a dose-dependent manner. Immunohistochemical staining revealed an amelioration of renal fibrosis, significantly lower deposition of FN and collagen I, and significantly lower expression of the proinflammatory cytokines TNF-α and IL-1ß and lower levels of urinary TNF-α and MCP-1 in the clopidogrel-treated db/db mice (P < 0.05). Furthermore, clopidogrel significantly reduced macrophage infiltration into the glomeruli of the db/db mice. CONCLUSION: Clopidogrel significantly reduced renal collagen deposition and fibrosis and prevented renal dysfunction in db/db mice, most likely through inhibition of renal macrophage infiltration and the associated inflammation.

Molecular actions of exosomes and their theragnostics in colorectal cancer: current findings and limitations.

Extracellular vesicles (EVs) are cell-released, membranous structures essential for intercellular communication. The biochemical compositions and physiological impacts of exosomes, lipid-bound, endosomal origin EVs, have been focused on, especially on the tumor-host interactions in a defined tumor microenvironment (TME). Despite recent progress in targeted therapy and cancer immunotherapy in colorectal cancer (CRC), cancer patients still suffer from distal metastasis and tumor relapse, suggesting unmet needs for biomarkers directing therapeutic interventions and predicting treatment responsiveness. As exosomes are indispensable for intercellular communication and high exosome abundance makes them feasible biomarker molecules, this review discusses exosome heterogeneity and how exosomes orchestrate the interplay among tumor cells, cancer stem cells (CSCs) and host cells, including stromal cells, endothelial cells and immunocytes, in the CRC TME. This review also discusses mechanisms for loading exosomal contents and potential exosomal DNA, RNA and protein biomarkers for early CRC detection. Finally, we summarize the diagnostic and therapeutic exosomes in clinical trials. We envision that detecting and targeting cancer-specific exosomes could provide therapeutic advances in developing personalized cancer medicine.

Role of Azole Drugs in Promoting Fungal Cell Autophagy Revealed by an NIR Fluorescence-Based Theranostic Probe.

Autophagy, a widespread degradation system in eukaryotes, plays an important role in maintaining the homeostasis of the cellular environment and the recycling of substances. Optical probes for the tracking of autophagy can be used as an effective tool not only to visualize the autophagy process but also to study autophagy-targeted drugs. Various molecule probes for autophagy of cancer cells emerge but are very limited for that of fungal cells, resulting in the lack of research on antifungal drugs targeting autophagy. To address this issue, we report an azole NIR fluorescence-based theranostic probe AF-1 with antifungal activity that is sensitive to autophagy-associated pH. The unique design of this probe lies in the introduction of both the pH-sensitive fluorophore with a detection range matching the pH range of the autophagy process and the conserved core structural fragment of azole drugs, providing a strategy to investigate the relationship between antifungal drug action and autophagy. As such, AF-1 exhibited excellent spectral properties and was found to target and induce the autophagy of the fungal cell membrane while maintaining moderate antifungal activity. Of note, using this theranostic probe as both a dye and drug, the autophagy process of fungi was visualized in a ratiometric manner, revealing the role of azole antifungal drugs in promoting autophagy to induce fungal cell apoptosis.

A Long-Term and Large-Scale Real-World Study in Taiwan: Efficacy of Target Therapy in Stage IV Colorectal Cancer.

This study expands the understanding of the role of target therapy in improving survival of patients with mCRC based on real-world study results. These data represent potential survival outcomes of Taiwanese patients with mCRC in clinical practice. CRC is the most commonly diagnosed cancer and the third leading cause of cancer-related death in Taiwan. The aim of this study was to evaluate the efficacy of target therapy in combination with chemotherapy for mCRC in Taiwan. This was a real-world, retrospective, observational study in patients diagnosed with mCRC (N=1583). A total of 792 patients received chemotherapy plus target therapy (anti-EGFR therapy, n=180; anti-VEGF therapy, n=612) and 791 patients who received chemotherapy alone. Overall survival (OS) and progression-free survival (PFS) were examined. For RAS wild-type patients, the median OS (mOS) was 34.3 months in the EGFR L (left-sided colon) group, 27.3 months in the VEGF L group, 18.4 months in VEGF R (right-sided colon) group, and 13.8 months in EGFR R group (P<0.001). Median PFS (mPFS) was 9.8 months in the EGFR L group, 8.9 months in the VEGF L group, 6.8 months in VEGF R group, and 5.8 months in EGFR R group. In patients with a RAS mutation, mOS was 25.4 months in the VEGF L group and 19.4 months in the VEGF R group (P=0.167). Judicious treatment allocation in Taiwanese patients with mCRC can result in an mOS of 34.3 months using cetuximab plus chemotherapy for left-sided tumors. An mOS of 48.5 months can be achieved using cetuximab plus chemotherapy in the neoadjuvant setting in mCRC patients with left-sided tumors. This study expands our understanding of the role of target therapy in improving survival of mCRC patients based on real-world study results.