Value-added utilization technologies for seaweed processing waste in a circular economy: Developing a sustainable modern seaweed industry.

The global seaweed industry annually consumes approximately 600,000 tons of dried algal biomass to produce algal hydrocolloids, yet only 15-30% of this biomass is utilized, with the remaining 70-85% discarded or released as scum or wastewater during the hydrocolloid extraction process. This residual biomass is often treated as waste and not considered for further commercial use, which contradicts the principles of sustainable development. In reality, the residual algal biomass could be employed to extract additional biochemical components, such as pigments, proteins, and cellulose, and these ingredients have important application prospects in the food sector. According to the biorefinery concept, recycling various products alongside the principal product enhances overall biomass utilization. Transitioning from traditional single-product processes to multi-product biorefineries, however, raises operating costs, presenting a significant challenge. Alternatively, developing value-added utilization technologies that target seaweed waste without altering existing processes is gaining traction among industry practitioners. Current advancements include methods such as separation and extraction of residual biomass, anaerobic digestion, thermochemical conversion, enzymatic treatment, functionalized modification of algal scum, and efficient utilization through metabolic engineering. These technologies hold promise for converting seaweed waste into alternative proteins, dietary supplements, and bioplastics for food packaging. Combining multiple technologies may offer the most effective strategy for future seaweed waste treatment. Nonetheless, most research on value-added waste utilization remains at the laboratory scale, necessitating further investigation at pilot and commercial scales.

Potential regulation and prognostic model of colorectal cancer with extracellular matrix genes.

Background: The tumor microenvironment (TME) of colorectal cancer (CRC) mainly comprises immune cells, stromal cells, tumor cells, as well as the extracellular matrix (ECM), which holds a pivotal position. The ECM affects cancer progression, but its regulatory roles and predictive potential in CRC are not fully understood. Methods: We analyzed transcriptomes from CRC tumors and paired normal tissues to study ECM features. Up-regulated ECM components were examined through functional enrichment analysis, and single-cell sequencing identified cell types producing collagen, regulators, and secreted factors. Transcription factor analysis and cell-cell interaction studies were conducted to identify potential regulators of ECM changes. Additionally, a prognostic model was developed using TCGA-CRC cohort data, focusing on up-regulated core ECM components. Results: Bulk RNA-seq analysis revealed a unique ECM pattern in tumors, with ECM abundance and composition significantly related to patient survival. Up-regulated ECM components were linked to various cancer-related pathways. Fibroblasts and non-fibroblasts interactions were crucial in forming the TME. Key potential regulators identified included ZNF469, PRRX2, TWIST1, and AEBP1. A prognostic model based on five ECM genes (THBS3, LAMB3, ESM1, SPRX, COL9A3) demonstrated strong associations with immune suppression and tumor angiogenesis. Conclusions: The ECM components were involved in various cell-cell interactions and correlated with tumor development and poor survival outcomes. The ECM prognostic model components could be potential targets for novel therapeutic interventions in colorectal cancer.

Intracorporeal versus Extracorporeal Anastomosis in Laparoscopic Right Hemicolectomy: An Updated Systematic Review and Meta-Analysis of Randomized Control Trials.

INTRODUCTION: Laparoscopic right hemicolectomy has become the standard surgical procedure for the treatment of right colon disease; however, the choice of anastomosis remains controversial. This study aimed to compare the safety and efficacy of intracorporeal anastomosis and extracorporeal anastomosis in laparoscopic right hemicolectomy. METHODS: A systematic literature search was performed in PubMed, Embase, Web of Science, and Cochrane Library. Randomized controlled trials that compared intracorporeal anastomosis with extracorporeal anastomosis in patients with laparoscopic right hemicolectomy until June 4, 2023, are selected. The primary outcomes measured were incidence of anastomotic leakage within 30 days post-operation. Statistical analyses were performed using Review Manager (version 5.4.1). RESULTS: Seven RCTs, including 720 patients, were eligible for the meta-analysis. The incidence of anastomotic leakage showed no significant difference between the intracorporeal anastomosis group and the extracorporeal anastomosis group (RR 0.93, 95% CI: 0.49, 1.76, p = 0.83, and I2 = 0%). However, the intracorporeal anastomosis group had significantly lower rates of postoperative ileus (RR 0.67, 95% CI: 0.45-0.99, p = 0.04, I2 = 46%) and surgical site infections (RR 0.34, 95% CI: 0.16-0.74, p = 0.007, I2 = 0%) compared to the extracorporeal anastomosis group. Additionally, patients in the intracorporeal anastomosis group experienced earlier postoperative passage of gas and stool (WMD -0.39, 95% CI: -0.60, -0.19, p = 0.0002, and I2 = 67%; WMD -0.53, 95% CI: -0.85, -0.21, p = 0.001, and I2 = 75%), as well as shorter hospital stays (WMD -0.46, 95% CI: -0.74, -0.18, p = 0.001, and I2 = 34%). CONCLUSION: In laparoscopic right hemicolectomy, intracorporeal anastomosis does not increase the incidence of anastomotic leakage within 30 days post-operation compared to extracorporeal anastomosis. In addition, intracorporeal anastomosis resulted in faster recovery of bowel function. This suggests that intracorporeal anastomosis is safe and effective.

Gut microbiome model predicts response to neoadjuvant immunotherapy plus chemoradiotherapy in rectal cancer.

BACKGROUND: Accurate evaluation of the response to preoperative treatment enables the provision of a more appropriate personalized therapeutic schedule for locally advanced rectal cancer (LARC), which remains an enormous challenge, especially neoadjuvant immunotherapy plus chemoradiotherapy (nICRT). METHODS: This prospective, multicenter cohort study enrolled patients with LARC from 6 centers who received nICRT. The dynamic variation in the gut microbiome during nICRT was evaluated. A species-level gut microbiome prediction (SPEED) model was developed and validated to predict the pathological complete response (pCR) to nICRT. FINDINGS: A total of 50 patients were enrolled, 75 fecal samples were collected from 33 patients at different time points, and the pCR rate reached 42.4% (14/33). Lactobacillus and Eubacterium were observed to increase after nICRT. Additionally, significant differences in the gut microbiome were observed between responders and non-responders at baseline. Significantly higher abundances of Lachnospiraceae bacterium and Blautia wexlerae were found in responders, while Bacteroides, Prevotella, and Porphyromonas were found in non-responders. The SPEED model showcased a superior predictive performance with areas under the curve of 98.80% (95% confidence interval [CI]: 95.67%-100%) in the training cohort and 77.78% (95% CI: 65.42%-88.29%) in the validation cohort. CONCLUSIONS: Programmed death 1 (PD-1) blockade plus concurrent long-course CRT showed a favorable pCR rate and is well tolerated in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) patients with LARC. The SPEED model can be used to predict the pCR to nICRT based on the baseline gut microbiome with high robustness and accuracy, thereby assisting clinical physicians in providing individualized management for patients with LARC. FUNDING: This research was funded by the China National Natural Science Foundation (82202884).

Perfusion outcomes with near-infrared indocyanine green imaging system in laparoscopic total mesorectal excision for mid-rectal or low-rectal cancer (POSTER): a study protocol.

INTRODUCTION: Anastomotic leakage (AL) is defined as the failure of complete healing or disruption of the anastomosis subsequent to rectal cancer surgery, resulting in the extravasation of intestinal contents into the intra-abdominal or pelvic cavity. It is a serious complication of rectal cancer surgery, accounting for a considerable increase in morbidity and mortality. The use of fluorescence imaging technology in surgery allows surgeons to better evaluate blood perfusion. However, the conclusions of some existing studies are not consistent, so a consensus on whether the near-infrared indocyanine green (NIR-ICG) imaging system can reduce the incidence of AL is needed. METHODS: This POSTER trial is designed as a multicentre, prospective, randomised controlled clinical study adhering to the "population, interventions, comparisons, outcomes (PICO)" principles. It is scheduled to take place from August 2019 to December 2024 across eight esteemed hospitals in China. The target population consists of patients diagnosed with rectal cancer through pathological confirmation, with tumours located≤10 cm from the anal verge, eligible for laparoscopic surgery. Enrolled patients will be randomly assigned to either the intervention group or the control group. The intervention group will receive intravenous injections of ICG twice, with intraoperative assessment of anastomotic blood flow using the near-infrared NIR-ICG system during total mesorectal excision (TME) surgery. Conversely, the control group will undergo conventional TME surgery without the use of the NIR-ICG system. A 30-day follow-up period postoperation will be conducted to monitor and evaluate occurrences of AL. The primary endpoint of this study is the incidence of AL within 30 days postsurgery in both groups. The primary outcome investigators will be blinded to the application of ICG angiography. Based on prior literature, we hypothesise an AL rate of 10.3% in the control group and 3% in the experimental group for this study. With a planned ratio of 2:1 between the number of cases in the experimental and control groups, and an expected 20% lost-to-follow-up rate, the initial estimated sample size for this study is 712, comprising 474 in the experimental group and 238 in the control group. ETHICS AND DISSEMINATION: This study has been approved by Ethics committee of Beijing Friendship Hospital, Capital Medical University (approval number: 2019-P2-055-02). The results will be disseminated in major international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04012645.

Efficacy and safety of PD-1 blockade plus long-course chemoradiotherapy in locally advanced rectal cancer (NECTAR): a multi-center phase 2 study.

Adding PD-1 blockade in the neoadjuvant regimens for locally advanced rectal cancer (LARC) patients with microsatellite stable (MSS) / mismatch repair-proficient (pMMR) tumors is an attractive, but debatable strategy. This phase 2, multicenter, prospective, single-arm study enrolled patients from 6 centers from June 2021 to November 2022. Locally advanced rectal cancer (LARC, cT3-4aN0M0 and cT1-4aN1-2M0) patients aged ≥18 years with the distance from distal border of tumor to anal verge ≤10 cm (identified by Magnetic Resonance Imaging) were qualified for inclusion. The patients received long-course radiotherapy (50 Gy/25 fractions, 2 Gy/fraction, 5 days/week) and three 21-day cycles capecitabine (850-1000 mg/m2, bid, po, day1-14) and three 21-day cycles tislelizumab (200 mg, iv.gtt, day8) as neoadjuvant. Total mesorectal excision (TME) was 6-12 weeks after the end of radiotherapy to achieve radical resection. A total of 50 patients were enrolled in this study. The pathological complete response rate was 40.0% [20/50, 95% confidence interval (CI): 27.61-53.82%], while 15 (30.0%, 95% CI: 19.1-43.75%), 9 (18.0%, 95% CI: 9.77-30.8%), 2 (4.0%, 95% CI: 1.10-13.46%) patients respectively achieved grade 1, 2, and 3 tumor regression. Treatment-related adverse events (TRAEs) occurred in 28 (56.0%) LARC patients, including 26(52.0%) with grade I-II and 2 (4.0%) with grade III (1 with grade 3 immune-related colitis and 1 with grade 3 rash). PD-1 blockade plus long-course chemoradiotherapy (CRT) showed promising therapeutic effects according to pathological complete response rate and is well-tolerated in LARC patients. A larger randomized controlled study is desired to further validate the above findings.

Exploring causal correlations between circulating levels of cytokines and colorectal cancer risk: A Mendelian randomization analysis.

Colorectal cancer has the highest mortality rate of all digestive system diseases. Considering the debate about cytokines and biases that exist in traditional observational study designs, we performed a two-sample Mendelian randomization (MR) analysis to explore the association of circulating cytokines with CRC risk. In this study, we used cytokine genetic variants from a recently published genome-wide association study (GWAS) including 14,824 European-ancestry participants. Summary-level data for colorectal cancer were obtained from genome-wide association analyses of the FinnGen consortium. In addition, we conducted independent supplementary analyses using genetic variation data of colorectal cancer and cytokines from a large public GWAS in 2021. Among 91 circulating factors, we only found IL-12B to be significantly associated with CRC risk (odds ratio [OR]: 1.19; 95% confidence interval [CI]: 1.00-1.42; p = .046). We used 2021 data for analysis and found that higher Interleukin-12p70 levels (IL-12p70) were revealed to have a significant positive association with CRC risk (OR: 1.27; 95% CI: 1.13-1.43; p < 1.22 × 10-3). Moreover, CRC was suggestively correlated with an elevated level of vascular endothelial growth factor (VEGF) (OR: 1.17; 95% CI: 1.02-1.35; p = .026), macrophage colony-stimulating factor (M-CSF) (OR: 0.85; 95% CI: 0.76-0.96; p = .005), IL-13 (OR: 1.15; 95% CI: 1.02-1.30; p = .028), IL-10 (OR: 1.23; 95% CI: 1.01-1.49; p = .037), and IL-7 (OR: 1.19; 95% CI: 1.02-1.39; p = .024). Our MR studies support that one cytokine IL-12 is significantly associated with CRC risk and that five cytokines VEGF, M-CSF, IL-13, IL-10, and IL-7 are associated with CRC risk.

Panax notoginseng saponins stimulates the differentiation and neurite development of C17.2 neural stem cells against OGD/R injuries via mTOR signaling.

Ischemic stroke remains a major disease worldwide, and most stroke patients often suffer from serious sequelae. Endogenous neurogenesis matters in the repair and regeneration of impaired neural cells after stroke. We have previously reported in vivo that PNS could strengthen the proliferation and differentiation of neural stem cells (NSCs), modulate synaptic plasticity and protect against ischemic brain injuries in cerebral ischemia rats, which could be attributed to mTOR signaling activation. Next, to obtain further insights into the function mechanism of PNS, we evaluated the direct influence of PNS on the survival, differentiation and synaptic development of C17.2 NSCs in vitro. The oxygen glucose deprivation/reperfusion (OGD/R) model was established to mimic ischemic brain injuries. We found that after OGD/R injuries, PNS improved the survival of C17.2 cells. Moreover, PNS enhanced the differentiation of C17.2 cells into neurons and astrocytes, and further promoted synaptic plasticity by significantly increasing the expressions of synapse-related proteins BDNF, SYP and PSD95. Meanwhile, PNS markedly activated the Akt/mTOR/p70S6K pathway. Notably, the mTOR inhibitor rapamycin pretreatment could reverse these desirable results. In conclusion, PNS possessed neural differentiation-inducing properties in mouse C17.2 NSCs after OGD/R injuries, and Akt/mTOR/p70S6K signaling pathway was proved to be involved in the differentiation and synaptic development of C17.2 cells induced by PNS treatment under the in vitro ischemic condition. Our findings offer new insights into the mechanisms that PNS regulate neural plasticity and repair triggered by NSCs, and highlight the potential of mTOR signaling as a therapeutic target for neural restoration after ischemic stroke.

Colorimetric assay for α-amanitin based on inhibition of carbon dots/AuNPs nanoenzyme activity.

Accidental ingestion of poisonous mushrooms leading to poisoning is a global issue. The most important and lethal toxin causing mushroom poisoning is α-amanitin, with a lethal dose of about 0.1 mg kg-1. Rapid detection of wild mushrooms before consumption or rapid identification of toxins after poisoning can effectively reduce the occurrence of fatalities. This study established a method for detecting α-amanitin using carbon dots/AuNPs nanoenzymes (D-Glu-CDs/AuNPs) with robust peroxidase-like activity. This nanoenzyme was prepared employing glucose carbon dots and sodium citrate as reducing and stabilizing agents, respectively. It could oxidize the substrate TMB (tetramethylbenzidine) to produce blue o-TMB. When α-amanitin specifically bound to the active site of the nanoenzyme, a resultant decrease was observed in catalytic activity and the absorbance value at 652 nm. The regression equation Y = -0.06083x + 0.9643, with an R2 value of 0.996, was obtained. The limit of detection was determined to be 48.03 ng mL-1, and the recoveries in urine ranged from 91.2% to 97.6%. This method enabled the visualization of α-amanitin, and the whole detection process was completed within 20 min. The approach holds promise for the quantitative and qualitative determination of α-amanitin in urine samples.

Risk factors for anastomotic leak and postoperative morbidity after right hemicolectomy for colon cancer: results from a prospective, multi-centre, snapshot study in China.

BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50 ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50 ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.

A Specific Mini-Intrabody Mediates Lysosome Degradation of Mutant Huntingtin.

Accumulation of misfolded proteins leads to many neurodegenerative diseases that can be treated by lowering or removing mutant proteins. Huntington's disease (HD) is characterized by the intracellular accumulation of mutant huntingtin (mHTT) that can be soluble and aggregated in the central nervous system and causes neuronal damage and death. Here, an intracellular antibody (intrabody) fragment is generated that can specifically bind mHTT and link to the lysosome for degradation. It is found that delivery of this peptide by either brain injection or intravenous administration can efficiently clear the soluble and aggregated mHTT by activating the lysosomal degradation pathway, resulting in amelioration of gliosis and dyskinesia in HD knock-in (KI-140Q) mice. These findings suggest that the small intrabody peptide linked to lysosomes can effectively lower mutant proteins and provide a new approach for treating neurodegenerative diseases that are caused by the accumulation of mutant proteins.

Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing.

Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.

Long-course chemoradiation plus concurrent/sequential PD-1 blockade as neoadjuvant treatment for MMR-status-unscreened locally advanced rectal cancer: protocol of a multicentre, phase 2, randomised controlled trial (the POLAR-STAR trial).

INTRODUCTION: Recent preclinical studies have discovered unique synergism between radiotherapy and immune checkpoint inhibitors, which has already brought significant survival benefit in lung cancer. In locally advanced rectal cancer (LARC), neoadjuvant radiotherapy plus immune checkpoint inhibitors have also achieved surprisingly high pathological complete response (pCR) rates even in proficient mismatch-repair patients. As existing researches are all phase 2, single-cohort trials, we aim to conduct a randomised, controlled trial to further clarify the efficacy and safety of this novel combination therapy. METHODS AND ANALYSIS: Eligible patients with LARC are randomised to three arms (two experiment arms, one control arm). Patients in all arms receive long-course radiotherapy plus concurrent capecitabine as neoadjuvant therapy, as well as radical surgery. Distinguishingly, patients in arm 1 also receive anti-PD-1 (Programmed Death 1) treatment starting at Day 8 of radiation (concurrent plan), and patients in arm 2 receive anti-PD-1 treatment starting 2 weeks after completion of radiation (sequential plan). Tislelizumab (anti-PD-1) is scheduled to be administered at 200 mg each time for three consecutive times, with 3-week intervals. Randomisation is stratified by different participating centres, with a block size of 6. The primary endpoint is pCR rate, and secondary endpoints include neoadjuvant-treatment-related adverse event rate, as well as disease-free and overall survival rates at 2, 3 and 5 years postoperation. Data will be analysed with an intention-to-treat approach. ETHICS AND DISSEMINATION: This protocol has been approved by the institutional ethical committee of Beijing Friendship Hospital (the primary centre) with an identifying serial number of 2022-P2-050-01. Before publication to peer-reviewed journals, data of this research will be stored in a specially developed clinical trial database. TRIAL REGISTRATION NUMBER: NCT05245474.

Development and Validation of a Post-Radiotherapy Prediction Model for Bowel Dysfunction After Rectal Cancer Resection.

BACKGROUND & AIMS: The benefit of radiotherapy for rectal cancer is based largely on a balance between a decrease in local recurrence and an increase in bowel dysfunction. Predicting postoperative disability is helpful for recovery plans and early intervention. We aimed to develop and validate a risk model to improve the prediction of major bowel dysfunction after restorative rectal cancer resection with neoadjuvant radiotherapy using perioperative features. METHODS: Eligible patients more than 1 year after restorative resection following radiotherapy were invited to complete the low anterior resection syndrome (LARS) score at 3 national hospitals in China. Clinical characteristics and imaging parameters were assessed with machine learning algorithms. The post-radiotherapy LARS prediction model (PORTLARS) was constructed by means of logistic regression on the basis of key factors with proportional weighs. The accuracy of the model for major LARS prediction was internally and externally validated. RESULTS: A total of 868 patients reported a mean LARS score of 28.4 after an average time of 4.7 years since surgery. Key predictors for major LARS included the length of distal rectum, anastomotic leakage, proximal colon of neorectum, and pathologic nodal stage. PORTLARS had a favorable area under the curve for predicting major LARS in the internal dataset (0.835; 95% CI, 0.800-0.870, n = 521) and external dataset (0.884; 95% CI, 0.848-0.921, n = 347). The model achieved both sensitivity and specificity >0.83 in the external validation. In addition, PORTLARS outperformed the preoperative LARS score for prediction of major events. CONCLUSIONS: PORTLARS could predict major bowel dysfunction after rectal cancer resection following radiotherapy with high accuracy and robustness. It may serve as a useful tool to identify patients who need additional support for long-term dysfunction in the early stage. CLINICALTRIALS: gov, number NCT05129215.

Research on the recycling and disposal of Chinese pesticide packaging waste based on evolutionary game theory.

This study aims to determine the optimal strategy and driving factors of the critical nodes of pesticide packaging waste recycling by constructing the recycling process of "village collection-town transport-county management." Counties, towns, and villages are the central nodes of collection, coordination, and communication in the recycling process. Their strategy selection and influencing factor analysis are related to the development of recycling. The county processing center, township transit center, and village recycling center were selected to construct a game model, and strategy and parameter assumptions were made to obtain the optimal strategy combination. The results showed that strict supervision, professional transportation and strict implementation are the best strategies for counties, towns and villages, respectively. Simulation analysis confirmed that factors such as cost, reward restricted the strategy selection of each subject. The higher the supervision, transport, and input costs, the lower the enthusiasm of counties, towns, and villages to participate in recycling, respectively. Reasonable control of reward could help each participant choose a stable strategy. The study provided the idea of a pilot before promotion for the government and emphasized the importance of controlling incentive policies and relative costs to improve the recycling process of pesticide packaging waste.

Modified Podophyllotoxin Phenoxyacetamide Phenylacetate Derivatives: Tubulin/AKT1 Dual-Targeting and Potential Anticancer Agents for Human NSCLC.

Cancer is a major disease threatening human health worldwide, among which non-small-cell lung cancer (NSCLC) is the most deadly. Clinically, almost all anticancer drugs eventually fail to consistently benefit patients due to serious drug resistance. AKT is a key effector of the PI3K/AKT/mTOR pathway, which is closely related to the occurrence, development, and drug resistance of tumors. Herein, we first designed and synthesized 20 kinds of novel hybrid molecules targeting both tubulin and AKT based on a podophyllotoxin (PPT) skeleton through computer-aided drug design. By CCK8 assay, we screened the compound D1-1 (IC50 = 0.10 µM) with the strongest inhibitory activity against H1975 cells, and its activity was 100 times higher than PPT (IC50 = 12.56 µM) and 300 times higher than gefitinib (IC50 = 32.15 µM). Affinity analysis results showed that D1-1 not only retained the tubulin targeting of PPT but also showed strong AKT targeting. Subsequent pharmacological experiments showed that D1-1 significantly inhibited the proliferation and metastasis of H1975 cells and slightly induced their apoptosis by inhibiting both tubulin polymerization and the AKT pathway activation. Collectively, these data demonstrate that the novel hybrid molecule D1-1 may be an excellent lead compound for the treatment of human NSCLC as a dual inhibitor of tubulin and AKT.

Management and prediction of immune-related adverse events for PD1/PDL-1 immunotherapy in colorectal cancer.

Programmed cell death protein (PD-1) is an important immunosuppressive molecule, which can inhibit interaction between PD-1 and its ligand PD-L1, further enhancing the T cell response and anti-tumor activity, which is called immune checkpoint blockade. Immunotherapy, represented by immune checkpoint inhibitors, has opened up a new era of tumor treatment and is gradually being applied to colorectal cancer recently. Immunotherapy was reported could achieve a high objective response rate (ORR) for colorectal cancer with high microsatellite instability (MSI), thus opening up a new era of colorectal cancer immunotherapy. Along with the increasing use of PD1 drugs in colorectal cancer, we should pay more attention to the adverse effects of these immune drugs while seeing the hope. Immune-related adverse events (irAEs) caused by immune activation and immune homeostasis during anti-PD-1/PD-L1 therapy can affect multi-organ and even be fatal in serious cases. Therefore, understanding irAEs is essential for their early detection and appropriate management. In this article, we review the irAEs that occur during the treatment of colorectal cancer patients with PD-1/PD-L1 drugs, analyze the current controversies and challenges, and point out future directions that should be explored, including exploring efficacy predictive markers and optimizing the paradigm of individualized immunotherapy.

Deep neural network training method based on vectorgraphs for designing of metamaterial broadband polarization converters.

In this work, we proposed a method of extracting feature parameters for deep neural network prediction based on the vectorgraph storage format, which can be applied to the design of electromagnetic metamaterials with sandwich structures. Compared to current methods of manually extracting feature parameters, this method can automatically and precisely extract the feature parameters of arbitrary two-dimensional surface patterns of the sandwich structure. The position and size of surface patterns can be freely defined, and the surface patterns can be easily scaled, rotated, translated, or transformed in other ways. Compared to the pixel graph feature extraction method, this method can adapt to very complex surface pattern design in a more efficient way. And the response band can be easily shifted by scaling the designed surface pattern. To illustrate and verify the method, a 7-layer deep neural network was built to design a metamaterial broadband polarization converter. Prototype samples were fabricated and tested to verify the accuracy of the prediction results. In general, the method is potentially applicable to the design of different kinds of sandwich-structure metamaterials, with different functions and in different frequency bands.

Interim result of phase II, prospective, single-arm trial of long-course chemoradiotherapy combined with concurrent tislelizumab in locally advanced rectal cancer.

Background: Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced rectal cancer, with modest benefits on tumor regression and survival. Since chemoradiotherapy combined with immune checkpoint inhibitors has been reported to have synergic effects. This study aims to explore the safety and efficacy of long-course chemoradiotherapy combined with concurrent tislelizumab as a neoadjuvant treatment regimen for patients with locally advanced rectal cancer. Methods: This manuscript reported the interim result of a prospective, multicenter, single-arm, phase II trial. Patients with mid-to-low locally advanced rectal cancer with clinical stages of cT3-4a N0M0 or cT1-4a N1-2M0 were included. The patients received long-course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles of capecitabine (1000 mg/m2, bid, day1-14) plus concurrent three 21-day cycles of tislelizumab (200 mg, day8), followed by a radical surgery 6-8 weeks after radiotherapy. The primary endpoint was the pathological complete response rate. (Clinical trial number: NCT04911517). Results: A total of 26 patients completed the treatment protocol between April 2021 and June 2022. All patients completed chemoradiotherapy, 24 patients received three cycles of tislelizumab, and 2 patients received two cycles. The pathological complete remission (ypT0N0) was achieved in 50% (13/26) of the patients with all proficient mismatch repair tumors. The immune-related adverse event occurred in 19.2% (5/26) of patients. Patients with no CEA elevation or age less than 50 were more likely to benefit from this treatment regimen. Conclusion: Long-course chemoradiotherapy combined with concurrent tislelizumab in patients with locally advanced low rectal cancer had favorable safety and efficacy, and does not increase the complication rate of surgery. Further study is needed to confirm these results.