Effectiveness of immune checkpoint inhibitors in combination with tyrosine kinase inhibitors in patients with advanced or metastatic colorectal carcinoma with either mismatch repair proficient or metastatic microsatellite stable disease: A systematic review and meta­analysis.

Immune checkpoint inhibitors (ICIs) have limited efficacy in mismatch repair proficient (pMMR) or metastatic microsatellite stable (MSS) advanced or metastatic colorectal cancer (mCRC). ICIs, in conjunction with tyrosine kinase inhibitors (TKIs) possessing anti-angiogenic properties, serve as a potential strategy for circumventing the resistance exhibited by MSS or pMMR mCRC to immunotherapeutic interventions. The present study aimed to evaluate efficacy and safety of ICIs + TKIs and provide a reference for the treatment of CRC. The present systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, Cochrane, Web of Science and ClinicalTrials.gov databases were screened from January 1, 2003 to July 28, 2023. A total of 14 studies were included in qualitative and quantitative analyses, with a total of 819 patients enrolled. The Newcastle-Ottawa scale scores of the 14 cohort studies included were ≥7, indicating they were of a high quality. The objective response rate (ORR) of ICIs + TKIs was 14% [95% confidence interval (CI), 0.08-0.24; P=0.132] in patients with advanced or metastatic MSS/pMMR CRC. The disease control rate (DCR) was 65% (95% CI, 0.58-0.74; P<0.0001). The overall incidence of adverse events of varying severity linked to combination of ICIs and TKIs in patients with advanced or metastatic MSS/pMMR CRC was 64% (95% CI, 0.52-0.78; P<0.0001). The incidence of grade ≥3 adverse reactions was 24% (95% CI, 0.14-0.4; P<0.0001). The sensitivity analysis indicated that the exclusion of individual studies did not yield statistically significant variations in combined analysis results. Based on the examination of publication bias, ORR and DCR, Begg's and Egger's tests had P-values of 0.114 and 0.395, respectively. Overall publication bias overall was absent in the Begg's funnel plot, as there was no apparent asymmetry. Nonetheless, the P-values of the Egger's and Begg's tests for adverse reactions and adverse reactions grade ≥3 were P=0.008 and P=0.048, respectively. The asymmetry of the Begg's funnel plots was evident, suggesting the presence of potential publication bias regarding adverse event results. In conclusion, the combination of ICIs and TKIs demonstrates a favorable effectiveness and notable safety profile in the management of patients with advanced or metastatic MSS/pMMR CRC.

Comparison of enteral immunonutrition and enteral nutrition in patients undergoing gastric cancer surgery: a systematic review and meta-analysis of randomized, controlled trials.

OBJECTIVE: Enteral immunonutrition is a nutritional intervention that has been studied in postoperative patients with gastric cancer, but its effectiveness is controversial. This study aimed to investigate the effects of enteral immunonutrition and enteral nutrition on immune function in patients who undergo gastric cancer surgery. METHODS: We performed a systematic review and meta-analysis. A comprehensive search was conducted in PubMed, Embase, Cochrane, Web of Knowledge, and ClinicalTrials.gov from the inception of the review until 10 March 2023. Twelve studies were included for qualitative and quantitative analyses. RESULTS: We studied 1124 patients, including 565 patients in the enteral immunonutrition group and 559 in the enteral nutrition (controls) group. All included randomized, controlled trials were high quality. CD4+ levels, lymphocytes, transferrin concentrations, and systemic inflammatory response syndrome were not significantly different between the enteral immunonutrition and enteral nutrition groups. However, CD8+, immunoglobulins G and M, and proalbumin concentrations, CD4+/CD8+, and infectious complications were significantly higher in the enteral immunonutrition group than in the enteral nutrition group. A sensitivity analysis showed consistent results after excluding each study. Begg's test showed no publication bias. CONCLUSIONS: Enteral immunonutrition is an effective nutritional intervention that improves immune function in patients who have undergone gastric cancer surgery.

Zn(OTf)2-Promoted Isocyanide-Based Three-Component Reaction: Direct Access to 2-Oxazolines and ß-Amino Amides.

An efficient one-pot reaction of propargylamides, isocyanides, and water catalyzed by zinc was developed for the rapid construction of 2-oxazolines with a wide functional group tolerance. The methylene-3-oxazoline was proven to play a vitally important role to start the tandem cascade transformation through unfunctionalized alkynes with sequential nucleophilic addition approaches of isocyanide and water. Notably, with a slight alteration of the reaction temperature and the addition of one molecule of water, various ß-amino amide derivatives were synthesized in good to excellent yields.

Discovery of fused benzimidazole-imidazole autophagic flux inhibitors for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) with the absence of estrogen receptor (ER), progesterone receptor (PR) and HER2 ptotein, is the highly aggressive subtype of breast cancer that exhibits poor prognosis and high tumor recurrence. It is vital to develop effective agents regulating the core molecular pathway of TNBC. Through a medium throughput screening and iterative medicinal chemistry optimization, we identified compound 7h as an autophagic flux inhibitor, which showed potent activities against human TNBC (MDA-MB-231 and MDA-MB-468) cell lines with IC50 values of 8.3 µM, and 6.0 µM, respectively, which are comparable to the potency of 5-FU and Cisplatin, the first line therapies for TNBC. Extensive investigation of mechanisms of action indicated that 7h inhibits autophagic flux and sequential accumulation of p62, leading to DNA damage and disrepair in TNBC cells. Importantly, nuclear p62 accumulation induced by compound 7h results in the inhibition of RNF168-mediated chromatin ubiquitination and the degradation of HR-related proteins in regulating the DNA damage response (DDR) process. In in vivo studies, compound 7h completely suppressed tumor growth in the MDA-MB-231 xenograft model at a dose of 15 mg/kg/q.d. Our findings indicate that compound 7h is an autophagic flux inhibitor and induced the degradation of HR-related proteins. Compound 7h could be potentially developed as an anti-cancer therapeutics for TNBC.

Effect of hyperthermic intraperitoneal chemotherapy in combination with cytoreductive surgery on the prognosis of patients with colorectal cancer peritoneal metastasis: a systematic review and meta-analysis.

BACKGROUND: Peritoneal metastasis often occurs in patients with colorectal cancer peritoneal metastasis, and the prognosis is poor. A large body of evidence highlights the beneficial effects of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on survival, but to date, there is little consensus on the optimal treatment strategy for patients with colorectal cancer peritoneal metastasis. The purpose of this study is to evaluate the impact of CRS + HIPEC on survival and provide reference for the treatment of patients with colorectal cancer peritoneal metastasis. METHODS: This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The PubMed, Embase, Cochrane, Web of Knowledge, and ClinicalTrials.gov databases were screened from inception of the review to March 11, 2022. Ten studies were included in qualitative and quantitative analysis. RESULTS: A total of 3200 patients were enrolled in the study, including 788 patients in the CRS and HIPEC groups and 2412 patients in the control group, of which 3 were randomized controlled trials and 7 were cohort studies. The 3 randomized controlled studies were of high quality, and the quality scores of the 7 cohort studies were all 7 or above, indicating high quality. The results showed that the OS of CRS + HIPEC group was higher than that of control group (HR: 0.53, 95% CI: 0.38-0.73; P < 0.00001, I2 = 82.9%); the heterogeneity of the studies was large. The subgroup analysis showed that the OS of CRS and HIPEC group was higher than that of PC group (HR: 0.37, 95% CI: 0.30-0.47; P = 0.215, I2 = 31%) and higher than that in CRS group (HR: 0.73, 95% CI: 0.49-1.07; P = 0.163, I2 = 44.8%); the heterogeneity of the studies was low. In the OPEN group, the OS of THE CRS and HIPEC groups was higher than that in the control group (HR: 0.51, 95% CI: 0.38-0.70; P = 0.353, I2 = 3.9%); OPEN group showed lower heterogeneity. The OS of 60-100-min group was higher than that in the control group (HR: 0.65, 95% CI: 0.49-0.88; P = 0.172, I2 = 37.4%); the heterogeneity of the studies was low. Sensitivity analysis showed that there was no significant difference in the results of the combined analysis after each study was deleted. The results of publication bias showed that the P-value of Egger and Begg tests was 0.078 > 0.05, indicating that there is no publication bias. CONCLUSIONS: CRS + HIPEC can improve the survival rate of patients with colorectal cancer peritoneal metastasis.

High resolution multispectral spatial light modulators based on tunable Fabry-Perot nanocavities.

Spatial light modulators (SLMs) are the most relevant technology for dynamic wavefront manipulation. They find diverse applications ranging from novel displays to optical and quantum communications. Among commercial SLMs for phase modulation, Liquid Crystal on Silicon (LCoS) offers the smallest pixel size and, thus, the most precise phase mapping and largest field of view (FOV). Further pixel miniaturization, however, is not possible in these devices due to inter-pixel cross-talks, which follow from the high driving voltages needed to modulate the thick liquid crystal (LC) cells that are necessary for full phase control. Newly introduced metasurface-based SLMs provide means for pixel miniaturization by modulating the phase via resonance tuning. These devices, however, are intrinsically monochromatic, limiting their use in applications requiring multi-wavelength operation. Here, we introduce a novel design allowing small pixel and multi-spectral operation. Based on LC-tunable Fabry-Perot nanocavities engineered to support multiple resonances across the visible range (including red, green and blue wavelengths), our design provides continuous 2π phase modulation with high reflectance at each of the operating wavelengths. Experimentally, we realize a device with 96 pixels (~1 µm pitch) that can be individually addressed by electrical biases. Using it, we first demonstrate multi-spectral programmable beam steering with FOV~18° and absolute efficiencies exceeding 40%. Then, we reprogram the device to achieve multi-spectral lensing with tunable focal distance and efficiencies ~27%. Our design paves the way towards a new class of SLM for future applications in displays, optical computing and beyond.

Ki67 for evaluating the prognosis of gastrointestinal stromal tumors: A systematic review and meta-analysis.

Overexpression of Ki67 is observed in tumor cells, and it has been suggested to be a marker for cancer prognosis. However, the relationship between Ki67 expression and the risk of recurrence of gastrointestinal stromal tumors (GISTs) remains poorly defined. In the present study, a meta-analysis was used to examine the associations between Ki67 levels and GIST recurrence. Studies reporting GIST and Ki67 were found by searching Cochrane Library, PubMed and Embase until October 14, 2021. The Newcastle-Ottawa Scale (NOS) was used to verify the quality of the evidence. Totally, 1682 patient cases were included. The odds ratio (OR) estimates and 95% confidence interval (CI) for each publication were determined by a fixed-effects (Mantel-Haenszel) model. A total of 20 studies that fulfilled the inclusion criteria were finally included in the analysis. The average score of quality evaluation was 6.4 points according to NOS. It was found that Ki67 levels were significantly higher in the NIH L group compared with the NIH VL group (OR: 0.51; 95% CI: 0.26-0.99; P=0.04; P heterogeneity=0.44). There was also greater Ki67 overexpression in the NIH I group compared with the NIH L group (OR: 0.45, 95% CI: 0.31-0.65; P<0.0001; P heterogeneity=0.32), while Ki67 levels were greater in the NIH H group than in the NIH I group (OR: 0.20; 95% CI: 0.15-0.28; P<0.00001; P heterogeneity=0.56). In conclusion, Ki67 overexpression may be a useful marker of the risk of recurrent GIST transformation.

[Effects of Climate Warming on the Key Process and Index of Black Soil Carbon and Nitrogen Cycle During Freezing Period].

As an critical part of the global biogeochemical cycle, the winter soil carbon and nitrogen cycles are extremely sensitive to climate warming. Furthermore, the black soil in northeast China is fertile and rich in organic matter and is a vital production base of commodity grains in China. For as long as half a year, the black soil is in a freezing-thawing state. Climate warming will change the snow cover thickness and soil freezing degree on the surface of the black soil in the winter and affect the freezing-thawing cycle frequency and timing of the soil, thus exerting a profound influence on the fixation, transformation, and release of soil carbon and nitrogen during the freezing period and throughout the year. To better understand the effects of climate warming on the black soil carbon and nitrogen dynamics during the freezing period, an experiment was conducted with two warming levels (W1 and W2) using an infrared radiometer to simulate soil warming. The warming increased the surface soil temperature (0 cm soil temperature) by 1.54℃ (W1) and 4.10℃ (W2), respectively, and significantly increased the soil moisture content compared with the control (C) during the freezing period, most likely because of the melting snow. The snow cover thickness, soil freezing depth, soil organic carbon (SOC), and labile organic carbon (LC) content were reduced by both warming treatments. However, the effect of the temperature increase during the freezing period on the key processes and indicators of the nitrogen cycle in black soil was relatively more complicated. With the increase in temperature, the content of nitrate nitrogen (NO3--N) decreased significantly, and the content of total nitrogen (TN) and net nitrogen nitrification rate increased significantly, while the ammonium nitrogen (NH4+-N), total inorganic nitrogen (TIN) content, and the net nitrogen mineralization rate exhibited a significant increase first and then decreased. In summary, climate warming will bring a warmer and more humid environment to the black soil during the freezing period, and the resulting changes in the soil carbon and nitrogen content and transformation processes will have a profound impact on the structure, productivity of the plants and microbial communities, and carbon and nitrogen cycles in the subsequent growing season. The results provide a scientific basis for studying the carbon and nitrogen cycle mechanisms of the northeast black soil during the freezing period.

Facile synthesis and biological evaluation of tryptamine-piperazine-2,5-dione conjugates as anticancer agents.

A facile and efficient route to synthesize N-heterocyclic fused tryptamine-piperazine-2,5-dione conjugates was developed via a post-Ugi cascade reaction. The targeted compounds were prepared by means of a mild reaction and simple operation procedure, which could be applied to a broad scope of starting materials. Compound 6h was demonstrated to induce significant growth inhibition of AsPC-1 and SW1990 human pancreatic cancer cell lines (IC50 = 6 ± 0.85 µM). Our protocol allows for the construction of a structurally diverse compound library and paves a new avenue for the discovery of pancreatic cancer drug candidates.

Long-wave infrared magnetic mirror based on Mie resonators on conductive substrate.

Metal films are often used in optoelectronic devices as mirrors and/or electrical contacts. In many such devices, however, the π-phase shift of the electric field that occurs upon reflection from a perfect electric conductor (for which a metal mirror is a reasonable approximation) is undesirable. This is because it results in the total electric field being zero at the mirror surface, which is unfavorable if one wishes for example to enhance absorption by a material placed there. This has motivated the development of structures that reflect light with zero phase shift, as these lead to the electric field having an anti-node (rather than node) at the surface. These structures have been denoted by a variety of terms, including magnetic mirrors, magnetic conductors, and high impedance surfaces. In this work, we experimentally demonstrate a long-wave infrared device that we term a magnetic mirror. It comprises an array of amorphous silicon cuboids on a gold film. Our measurements demonstrate a phase shift of zero and a high reflectance (of ∼90%) at a wavelength of 8.4 µm. We present the results of a multipole analysis that provides insight into the physical mechanism. Lastly, we investigate the use of our structure in a photodetector application by performing simulations of the optical absorption by monolayer graphene placed on the cuboids.

A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells.

We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.

Phase-only transmissive spatial light modulator based on tunable dielectric metasurface.

Rapidly developing augmented reality, solid-state light detection and ranging (LIDAR), and holographic display technologies require spatial light modulators (SLMs) with high resolution and viewing angle to satisfy increasing customer demands. Performance of currently available SLMs is limited by their large pixel sizes on the order of several micrometers. Here, we propose a concept of tunable dielectric metasurfaces modulated by liquid crystal, which can provide abrupt phase change, thus enabling pixel-size miniaturization. We present a metasurface-based transmissive SLM, configured to generate active beam steering with >35% efficiency and a large beam deflection angle of 11°. The high resolution and steering angle obtained provide opportunities to develop the next generation of LIDAR and display technologies.

Synthesis of Pyridodiindoles with Anticancer Activity by a Three-Component Cascade Condensation.

A novel three-component cascade reaction was discovered and developed to synthesize pyridodiindoles with the assistance of microwave irradiation. A collection of pyridodiindoles was prepared by means of the mild reaction and simple operation procedure, which could be applicable to a broad scope of functional aldehydes. Screening demonstrated that compound 5g exhibited a good potency in HCT116 cell lines, and this work validated the feasibility of this novel reaction for generating promising bioactive compounds.

Benzimidazoisoquinoline derivatives inhibit glioblastoma cell proliferation through down-regulating Raf/MEK/ERK and PI3K/AKT pathways.

BACKGROUND: Recent studies showed that benzimidazoleisoquinolinone derivatives exhibit anticancer activity against human cancer cell lines. The aim of this study is to evaluate the anti-tumor effects and mechanisms of benzimidazoleisoquinolinones in isocitrate dehydrogenase-wildtype subtype of human glioblastoma (GBM) cells. METHODS: Human U87 and LN229 cell lines were used to perform the experiments. MTT was applied to screen the effective small molecular inhibitors suppressing growth of GBM cells. Colony formation and BrdU staining assays were performed to assess the inhibition effect of compound-1H on the proliferation of GBM cells. The cell cycle and apoptosis were measured by flow cytometry and western blot to analyze the changes of the relative protein expressions and their signal pathways. RESULTS: Compound-1H could suppress GBM cells in a time- and dose-dependent manner. Treatment of compound-1H could arrest cell cycle in S phase through up-regulating P21 and P53, and down-regulating cyclin A and E in a dose-dependent manner. Compound-1H also induced mitochondrial-dependent apoptosis by increasing Bax, cleaved caspase-3, cleaved caspase-9 and poly ADP-ribose polymerase expression, and decreasing Bcl-2 expression. Moreover, phosphorylated (p)-AKT and p-ERK levels relating to cell proliferation were dramatically decreased in U87 and LN229 cells. CONCLUSIONS: Our results suggest that it is the first time to report the compound-1H with benzimidazoleisoquinolinone core playing antitumor activity in human glioblastoma cells by inhibiting Raf/MEK/ERK and PI3K/AKT signaling pathways, and it could be as a lead compound for the further development of targeted glioblastoma cancer therapy.

Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells.

Colorectal cancer (CRC) is one of the most frequent, malignant gastrointestinal tumors, and strategies and effectiveness of current therapy are limited. A series of benzimidazole-isoquinolinone derivatives (BIDs) was synthesized and screened to identify novel scaffolds for CRC. Of the compounds evaluated, 7g exhibited the most promising anti-cancer properties. Employing two CRC cell lines, SW620 and HT29, 7g was found to suppress growth and proliferation of the cell lines at a concentration of ∼20 µM. Treatment followed an increase in G2/M cell cycle arrest, which was attributed to cyclin B1 and cyclin-dependent kinase 1 (CDK1) signaling deficiencies with simultaneous enhancement in p21 and p53 activity. In addition, mitochondrial-mediated apoptosis was induced in CRC cells. Interestingly, 7g decreased phosphorylated AKT, mTOR and 4E-BP1 levels, while promoting the expression/stability of PTEN. Since PTEN controls input into the PI3K/AKT/mTOR pathway, antiproliferative effects can be attributed to PTEN-mediated tumor suppression. Collectively, these results suggest that BIDs exert antitumor activity in CRC by impairing PI3K/AKT/mTOR signaling. Against a small kinase panel, 7g exhibited low affinity at 5 µM suggesting anticancer properties likely stem through a non-kinase mechanism. Because of the novelty of BIDs, the structure can serve as a lead scaffold to design new CRC therapies.

Functionalized Spiroindolines with Anticancer Activity through a Metal-Free Post-Ugi Diastereoselective One-Pot Cascade Reaction.

A post-Ugi diastereoselective one-pot cascade reaction requiring no metal catalyst was developed. The reaction scope was wide with mild conditions and good yields. A collection of spiroindolines was prepared by the protocol and screening tests in several difficult-to-inhibit cancer cell lines were conducted. The relationship of structure and anticancer activities was promising and in the Huh7 cell lines compound 16 j is more potent than Vinbalstine. The cyclization design strategy could be applicable to other multicomponent reactions (MCRs) for synthesizing bioactive and drug-like heterocycles.

New angular oxazole-fused coumarin derivatives: synthesis and biological activities.

Twelve angular oxazole-fused coumarin derivatives were designed, synthesised and characterised by 1H NMR, 13C NMR and HRMS. The structure of compound 4a was further confirmed by X-ray single-crystal diffraction. The bioassay experiment results indicated that compounds 4f and 4l have high antifungal activity on the mycelium growth of 4 plant disease fungi. Especially, compound 4l has a stronger antifungal activity compare to the commercial fungicide, Carbendazim. The herbicidal activity experiment showed that 4a and 4b can significantly inhibit the taproot and caulis development of Chenopodium album seedling and have better activities than the commercial herbicide, Acetochlor.

Synthesis of isoindolin-1-one derivatives via multicomponent reactions of methyl 2-formylbenzoate and intramolecular amidation.

Four series of heterocyclic compounds were obtained using Ugi-type multicomponent reactions (MCRs) with methyl 2-formylbenzoate as one of the starting materials. A facile and efficient one-pot procedure was suitable for all the MCRs under acidic conditions. This process provided access to four series of complex and potentially biologically active scaffolds.

An Efficient and Facile Method for the Synthesis of Benzimidazoisoquinoline Derivatives via a Multicomponent Reaction.

Two series of benzimidazoisoquinoline and fused benzimidazoisoquinoline-benzimidazole derivatives have been synthesized using an efficient one-pot procedure. This process involves an intramolecular nucleophilic substitution reaction and provides facile access to two series of complexes and potentially interesting biologically active scaffolds.

Facile microwave-assisted synthesis of benzimidazole scaffolds via Ugi-type three-component condensation (3CC) reactions.

Two series of fused benzimidazoles were synthesized via a facile, one-pot procedure under microwave irradiation. This procedure generated the desired products in high yields and could provide a useful synthetic platform with potential applications in medicinal chemistry.