Evaluation of the impact of repeated intravenous phage doses on mammalian host-phage interactions.

Phage therapy has shown great promise for the treatment of multidrug-resistant bacterial infections. However, the lack of a thorough and organized understanding of phage-body interactions has limited its clinical application. Here, we administered different purified phages (Salmonella phage SE_SZW1, Acinetobacter phage AB_SZ6, and Pseudomonas phage PA_LZ7) intravenously to healthy animals (rats and monkeys) to evaluate the phage-induced host responses and phage pharmacokinetics with different intravenous (IV) doses in healthy animals. The plasma and the organs were sampled after different IV doses to determine the phage biodistribution, phage-induced cytokines, and antibodies. The potential side effects of phages on animals were assessed. A non-compartment model revealed that the plasma phage titer gradually decreased over time following a single dose. Repeated doses resulted in a 2-3 Log10 decline of the plasma phage titer at 5 min compared to the first dose, regardless of the type of phage administered in rats. Host innate immune responses were activated including splenic enlargement following repeated doses. Phage-specific neutralization antibodies in animals receiving phages were detected. Similar results were obtained from monkeys. In conclusion, the mammalian bodies were well-tolerant to the administered phages. The animal responses to the phages and the phage biodistribution profiles could have a significant impact on the efficacy of phage therapy.IMPORTANCEPhage therapy has demonstrated potential in addressing multidrug-resistant bacterial infections. However, an insufficient understanding of phage-host interactions has impeded its broader clinical application. In our study, specific phages were administered intravenously (IV) to both rats and monkeys to elucidate phage-host interactions and evaluate phage pharmacokinetics (PK). Results revealed that with successive IV administrations, there was a decrease in plasma phage concentrations. Concurrently, these administrations elicited both innate and adaptive immune responses in the subjects. Notably, the observed immune responses and PK profiles exhibited variation contingent upon the phage type and the mammalian host. Despite these variations, the tested mammals exhibited a favorable tolerance to the IV-administered phages. This underscores the significance of comprehending these interactions for the optimization of phage therapy outcomes.

The effects of iron-based nanomaterials (Fe NMs) on plants under stressful environments: Machine learning-assisted meta-analysis.

Mitigating the adverse effects of stressful environments on crops and promoting plant recovery in contaminated sites are critical to agricultural development and environmental remediation. Iron-based nanomaterials (Fe NMs) can be used as environmentally friendly nano-fertilizer and as a means of ecological remediation. A meta-analysis was conducted on 58 independent studies from around the world to evaluate the effects of Fe NMs on plant development and antioxidant defense systems in stressful environments. The application of Fe NMs significantly enhanced plant biomass (mean = 25%, CI = 20%-30%), while promoting antioxidant enzyme activity (mean = 14%, CI = 10%-18%) and increasing antioxidant metabolite content (mean = 10%, CI = 6%-14%), reducing plant oxidative stress (mean = -15%, CI = -20%∼-10%), and alleviating the toxic effects of stressful environments. The observed response was dependent on a number of factors, which were ranked in terms of a Random Forest Importance Analysis. Plant species was the most significant factor, followed by Fe NM particle size, duration of application, dose level, and Fe NM type. The meta-analysis has demonstrated the potential of Fe NMs in achieving sustainable agriculture and the future development of phytoremediation.

Triggerable Prodrug Nanocoating Enables On-Demand Activation of Microbial and Small-Molecular Therapeutics for Combination Treatment.

The synergy of living microbial and small-molecular therapeutics has been widely explored for treating a variety of diseases, while current combination strategies often suffer from low bioavailability, heterogeneous spatiotemporal distribution, and premature drug release. Here, the use of a triggerable prodrug nanocoating is reported to enable the on-demand activation of microbial and small-molecular therapeutics for combination treatment. As a proof-of-concept study, a reactive oxygen species-responsive aromatic thioacetal linker is employed to prepare cationic chitosan-drug conjugates, which can form a nanocoating on the surface of living bacteria via electrostatic interaction. Following administration, the wrapped bacteria can be prevented from in vivo insults by the shielding effect of the nanocoating and be co-delivered with the conjugated drug in a spatiotemporally synchronous manner. Upon reaching the lesion site, the upgraded reactive oxygen species trigger in situ cleavage of the thioacetal linker, resulting in the release of the conjugated drug and a linker-derived therapeutic cinnamaldehyde. Meanwhile, a charge reversal achieved by the generation of negatively charged thiolated chitosan induces the dissociation of the nanocoating, leading to synchronous release of the living bacteria. The adequate activation of the combined therapeutics at the lesion site exhibits superior synergistic treatment efficacy, as demonstrated by an in vivo assessment using a mouse model of colitis. This work presents an appealing approach to combine living microbial and small-molecular therapeutics for advanced therapy of diseases.

Risk Control Values and Remediation Goals for Benzo[a]pyrene in Contaminated Sites: Sectoral Characteristics, Temporal Trends, and Empirical Implications.

Benzo[a]pyrene (BaP) is a highly carcinogenic pollutant of global concern. There is a need for a comprehensive assessment of regulation decisions for BaP-contaminated site management. Herein, we present a quantitative evaluation of remediation decisions from 206 contaminated sites throughout China between 2011 and 2021 using the cumulative distribution function (CDF) and related statistical methodologies. Generally, remediation decisions seek to establish remediation goals (RGs) based on the risk control values (RCVs). Cumulative frequency distributions, followed non-normal S-curve, emerged multiple nonrandom clusters. These clusters are consistent with regulatory guidance values (RGVs), of national and local soil levels in China. Additionally, priority interventions for contaminated sites were determined by prioritizing RCVs and identifying differences across industrial sectors. Notably, we found that RCVs and RGs became more relaxed over time, effectively reducing conservation and unsustainable social and economic impacts. The joint probability curve was applied to model decision values, which afforded a generic empirically important RG of 0.57 mg/kg. Overall, these findings will help decision-makers and governments develop appropriate remediation strategies for BaP as a ubiquitous priority pollutant.

Soil contamination with cadmium and potential risk around various mines in China during 2000-2020.

Cadmium (Cd) pollution in mining areas is the most important challenge for soil environment management in China. Assessing the actual Cd pollution risk in various mining areas and identifying the core areas requiring supervision can provide a basis for government departments and industries to carry out detailed further investigations in key areas. In this study, we collated published data on metal mine circumjacent soil contaminated by Cd in China from 2002 to 2020 to conduct a comprehensive study on soil cadmium pollution and ecological and health risks in mining areas. The temporal and spatial variations of Cd concentrations and the pollution source were investigated. Results indicated that the Cd concentration in soil was strongly associated with the types of mining area. The Cd pollution in the circumjacent soil of lead-zinc and tungsten mines with high heavy metal pollution discharging coefficient was more serious than the soil around other mines. Identification of temporal and spatial variations for soil Cd in China indicated that the high Cd concentrations were found in the central, southern, and southwestern regions of China, and the distribution of mining activities in these regions are relatively concentrated. Meanwhile, a temporal turning point in the mean soil Cd concentration occurred in these regions in 2012, which indicated that the heavy metal control management policy implemented by the government was effective. The ecological risk of soil Cd pollution around mining areas was moderate to high. Health risk assessment showed that some regions adjacent mining areas had a high non-carcinogenic risk, notably, lead-zinc and tungsten mining areas were more serious. Supervision should focus on reducing ecological risks and protecting the safety of agricultural products rather than concentrating on health risks. The research results provide a reference for the priority management of contaminated soil in mining areas.

The role of brain barriers in the neurokinetics and pharmacodynamics of lithium.

Lithium (Li) is the most widely used mood stabilizer in treating patients with bipolar disorder. However, more than half of the patients do not or partially respond to Li therapy, despite serum Li concentrations in the serum therapeutic range. The exact mechanisms underlying the pharmacokinetic-pharmacodynamic (PK-PD) relationships of lithium are still poorly understood and alteration in the brain pharmacokinetics of lithium may be one of the mechanisms explaining the variability in the clinical response to Li. Brain barriers such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) play a crucial role in controlling blood-to-brain and brain-to-blood exchanges of various molecules including central nervous system (CNS) drugs. Recent in vivo studies by nuclear resonance spectroscopy revealed heterogenous brain distribution of Li in human that were not always correlated with serum concentrations, suggesting regional and variable transport mechanisms of Li through the brain barriers. Moreover, alteration in the functionality and integrity of brain barriers is reported in various CNS diseases, as a cause or a consequence and in this regard, Li by itself is known to modulate BBB properties such as the expression and activity of various transporters, metabolizing enzymes, and the specialized tight junction proteins on BBB. In this review, we will focus on recent knowledge into the role of the brain barriers as key-element in the Li neuropharmacokinetics which might improve the understanding of PK-PD of Li and its interindividual variability in drug response.

Cannabidiol Increases Proliferation, Migration, Tubulogenesis, and Integrity of Human Brain Endothelial Cells through TRPV2 Activation.

The effect of cannabidiol (CBD), a high-affinity agonist of the transient receptor potential vanilloid-2 (TRPV2) channel, has been poorly investigated in human brain microvessel endothelial cells (BMEC) forming the blood-brain barrier (BBB). TRPV2 expression and its role on Ca2+ cellular dynamics, trans-endothelial electrical resistance (TEER), cell viability and growth, migration, and tubulogenesis were evaluated in human primary cultures of BMEC (hPBMEC) or in the human cerebral microvessel endothelial hCMEC/D3 cell line. Abundant TRPV2 expression was measured in hCMEC/D3 and hPBMEC by qRT-PCR, Western blotting, nontargeted proteomics, and cellular immunofluorescence studies. Intracellular Ca2+ levels were increased by heat and CBD and blocked by the nonspecific TRP antagonist ruthenium red (RR) and the selective TRPV2 inhibitor tranilast (TNL) or by silencing cells with TRPV2 siRNA. CBD dose-dependently induced the hCMEC/D3 cell number (EC50 0.3 ± 0.1 µM), and this effect was fully abolished by TNL or TRPV2 siRNA. A wound healing assay showed that CBD induced cell migration, which was also inhibited by TNL or TRPV2 siRNA. Tubulogenesis of hCMEC/D3 cells in 3D matrigel cultures was significantly increased by 41 and 73% after a 7 or 24 h CBD treatment, respectively, and abolished by TNL. CBD also increased the TEER of hPBMEC monolayers cultured in transwell, and this was blocked by TNL. Our results show that CBD, at extracellular concentrations close to those observed in plasma of patients treated by CBD, induces proliferation, migration, tubulogenesis, and TEER increase in human brain endothelial cells, suggesting CBD might be a potent target for modulating the human BBB.

Water incubation-induced fluctuating release of heavy metals in two smelter-contaminated soils.

The soil moisture regime can affect the release of heavy metals in soil. In the previous studies, slightly polluted soils or artificially contaminated soil samples were considered to investigate the effect of soil moisture. We used highly smelter-contaminated and aged soils to study the release of typical heavy metals (Cu, Zn, Cd and Pb) induced by water incubation in batch experiments with characterization via speciation and X-ray diffraction analyses (XRD). The results show that the leachable concentrations of the heavy metals increased slightly in the first 30 days, decreased drastically between 30 and 90 days, and immobilized relatively constant thereafter. The fluctuation was ascribed to the changes of soil Eh and pH, the reductive dissolution of crystalline iron oxides, the formation of new amorphous iron oxides, the absorption of dissolved organic matter and the precipitation of metal sulfide. Speciation analysis indicated that a proportion of the soil heavy metals was transformed from an exchangeable fraction to a less labile fraction after water incubation. And the presence of a lead iron oxide phase and the peak increasing of zinc sulfide were observed via XRD analyses. Finally, water incubation restrained the release of heavy metals after 180 days of incubation, and reduced the leachability of Cu, Zn, Cd and Pb by as much as 1.61%-7.21% for soil A and 0.43%-3.36% for soil B, respectively. The study findings have implications for the formulation of risk control and management strategies for heavy metals in smelter-contaminated soils.

Sodium Transporters Are Involved in Lithium Influx in Brain Endothelial Cells.

Variability in drug response to lithium (Li+) is poorly understood and significant, as only 40% of patients with bipolar disorder highly respond to Li+. Li+ can be transported by sodium (Na+) transporters in kidney tubules or red blood cells, but its transport has not been investigated at the blood-brain barrier (BBB). Inhibition and/or transcriptomic strategies for Na+ transporters such as NHE (SLC9), NBC (SLC4), and NKCC (SLC12) were used to assess their role on Li+ transport in human brain endothelial cells. Na+-free buffer was also used to examine Na+/Li+ countertransport (NLCT) activity. The BBB permeability of Li+ evaluated in the rat was 2% that of diazepam, a high passive diffusion lipophilic compound. Gene expression of several Na+ transporters was determined in hCMEC/D3 cells, human hematopoietic stem-cell-derived BBB models (HBLEC), and human primary brain microvascular endothelial cells (hPBMECs) and showed the following rank order with close expression profile: NHE1 > NKCC1 > NHE5 > NBCn1, while NHE2-4, NBCn2, and NBCe1-2 were barely detected. Li+ influx in hCMEC/D3 cells was increased in Na+-free buffer by 3.3-fold, while depletion of chloride or bicarbonate had no effect. DMA (NHE inhibitor), DIDS (anionic carriers inhibitor), and bumetanide (NKCC inhibitor) decreased Li+ uptake significantly in hCMEC/D3 by 52, 51, and 47%, respectively, while S0859 (NBC inhibitor) increased Li+ influx 2.3-fold. Zoniporide (NHE1 inhibitor) and siRNA against NHE1 had no effect on Li+ influx in hCMEC/D3 cells. Our study shows that NHE1 and/or NHE5, NBCn1, and NKCC1 may play a significant role in the transport of Li+ through the plasma membrane of brain endothelial cells.

The effect of morbid obesity on morphine glucuronidation.

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4-61.9)kg/m2), 7-15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4-46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of -26% (range -74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers.

The objective of our work was to study the association between the jejunal expression levels of P-gp, MRP2, MRP3, UGT2B7, CYP3A4, the ABCB1 c.3435C > T polymorphism, and several obesity-associated biomarkers, as well as oral morphine and glucuronides pharmacokinetics in a population of morbidly obese subjects. The pharmacokinetics of oral morphine (30 mg) and its glucuronides was performed in obese patients candidate to bariatric surgery. A fragment of jejunal mucosa was preserved during surgery. Subjects were genotyped for the ABCB1 single nucleotide polymorphism (SNP) c.3435C > T. The subjects were 6 males and 23 females, with a mean body mass index of 44.8 (35.4-61.9) kg/m(2). The metabolic ratios AUC0-inf M3G/morphine and AUC0-inf M6G/morphine were highly correlated (rs = 0.8, p < 0.0001) and were 73.2 ± 24.6 (34.7-137.7) and 10.9 ± 4.1 (3.8-20.6). The pharmacokinetic parameters of morphine and its glucuronides were not associated with the jejunal contents of P-gp, CYP3A4, MRP2, and MRP3. The jejunal content of UGT2B7 was positively associated with morphine AUC0-inf (rs = 0.4, p = 0.03). Adiponectin was inversely correlated with morphine Cmax (rs = -0.44, p = 0.03). None of the factors studied was associated with morphine metabolic ratios. The interindividual variability in the jejunal content of drug transporters and metabolizing enzymes, the ABCB1 gene polymorphism, and the low-grade inflammation did not explain the variability in morphine and glucuronide exposure. High morphine metabolic ratio argued for an increased morphine glucuronidation in morbidly obese patients.

Distinct clinical characteristics in stage III rectal cancer among different age groups and treatment outcomes after neoadjuvant chemoradiotherapy.

Background: There is a rapidly increasing incidence of early-onset colorectal cancer (EO-CRC) which threatens the survival of young people, while aging also represents a challenging clinical problem. Objectives: We aimed to investigate the differences in the clinical characteristics and prognosis in stage III rectal cancer (RC), to help optimize treatment strategies. Design and methods: This study included 757 patients with stage III RC, all of whom received neoadjuvant chemoradiotherapy and total mesorectal excision. The whole cohort was categorized as very early onset (VEO, ⩽30 years old), early onset (EO, >30 years old, ⩽50 years old), intermediate onset (IO, >50 years, ⩽70 years), or late onset (LO, >70 years old). Results: There were more female VEO patients than males, more mucinous adenocarcinoma, signet-ring cell carcinoma, pre-treatment cT4 stage, and higher pre-treatment serum carbohydrate antigen 19-9 compared with the other three groups. VEO patients had the worst survival with the highest RC-related mortality (34.5%), recurrence (13.8%), and metastasis (51.7%). LO patients had the highest non-RC-related mortality rate (16.6%). The Cox regression model showed VEO was a negative independent prognostic factor for disease-free survival [DFS, hazard ratio (HR): 2.830, 95% confidence interval (CI): 1.633-4.904, p < 0.001], distant metastasis-free survival (DMFS, HR: 2.969, 95% CI: 1.720-5.127, p < 0.001), overall survival (OS, HR: 2.164, 95% CI: 1.102-4.249, p = 0.025), and cancer-specific survival (CSS, HR: 2.321, 95% CI: 1.145-4.705, p = 0.020). LO was a negative independent factor on DFS (HR: 1.800, 95% CI: 1.113-2.911, p = 0.017), DMFS (HR: 1.903, 95% CI: 1.150-3.149, p = 0.012), OS (HR: 2.856, 95% CI: 1.745-4.583, p < 0.001), and CSS (HR: 2.248, 95% CI: 1.282-3.942, p = 0.005). VEO patients had better survival in the total neoadjuvant therapy-like (TNT-like) pattern on DFS (p = 0.039). IO patients receiving TNT-like patterns had better survival on DFS, OS, and CSS (p = 0.006, p = 0.018, p = 0.006, respectively). Conclusion: In stage III RC, VEO patients exhibited unique clinicopathological characteristics, with VEO a negative independent prognostic factor for DFS, DMFS, OS, and CSS. VEO and IO patients may benefit from a TNT-like treatment pattern.

Reinforcement of the intestinal mucosal barrier via mucus-penetrating PEGylated bacteria.

The breakdown of the gut's mucosal barrier that prevents the infiltration of microorganisms, inflammatory cytokines and toxins into bodily tissues can lead to inflammatory bowel disease and to metabolic and autoimmune diseases. Here we show that the intestinal mucosal barrier can be reinforced via the oral administration of commensal bacteria coated with poly(ethylene glycol) (PEG) to facilitate their penetration into mucus. In mice with intestinal homoeostatic imbalance, mucus-penetrating PEGylated bacteria preferentially localized in mucus at the lower gastrointestinal tract, inhibited the invasion of pathogenic bacteria, maintained homoeostasis of the gut microbiota, stimulated the secretion of mucus and the expression of tight junctions, and prevented the mice from developing colitis and diabetes. Orally delivered PEGylated bacteria may help prevent and treat gastrointestinal disorders.

Characteristic study of biological CaCO3-supported nanoscale zero-valent iron: stability and migration performance.

nZVI has attracted much attention in the remediation of contaminated soil and groundwater, but the application is limited due to its aggregation, poor stability, and weak migration performance. The biological CaCO3 was used as the carrier material to support nZVI and solved the nZVI agglomeration, which had the advantages of biological carbon fixation and green environmental protection. Meanwhile, the distribution of nZVI was characterised by SEM-EDS and TEM carefully. Subsequently, the dispersion stability of bare nZVI and CaCO3@nZVI composite was studied by the settlement experiment and Zeta potential. Sand column and elution experiments were conducted to study the migration performance of different materials in porous media, and the adhesion coefficient and maximum migration distances of different materials in sand columns were explored. SEM-EDS and TEM results showed that nZVI could be uniformly distributed on the surface of biological CaCO3. Compared with bare nZVI, CaCO3@nZVI composite suspension had better stability and higher absolute value of Zeta potential. The migration performance of nZVI was poor, while CaCO3@nZVI composite could penetrate the sand column and have good migration performance. What's more, the elution rates of bare nZVI and CaCO3@nZVI composite in quartz sand columns were 5.8% and 51.6%, and the maximum migration distances were 0.193 and 0.885 m, respectively. In summary, this paper studies the stability and migration performance of bare nZVI and CaCO3@nZVI composite, providing the experimental and theoretical support for the application of CaCO3@nZVI composite, which is conducive to promoting the development of green remediation functional materials.

Assessing the thermal efficiency and emission reduction potential of alcohol-based fuel curing equipment in tobacco-curing.

So far, coal, petroleum, and natural gas are still the most widely used fuels, and the emissions of SO2, NOX and particulate matter produced from their combustion have a serious influence on the air. Therefore, it is necessary to develop a clean fuel. In this study, the bulk curing barns were equipped with different fuel equipment, Barn A used traditional coal heating equipment; Barn B used biomass briquettes fuel (BBF) integrated heating equipment; Barn C equipped with alcohol-based fuel (ABF) heating equipment. The temperature of the outer surface of the heating equipment, the exhaust gas of the chimney, and the curing heat efficiency and energy consumption were analyzed. Compared with the barn BBF and barn coal, the barn ABF can meet the flue-cured tobacco curing highest temperature requirements of 68 °C, the accuracy of the target dry bulb temperature (DBT) curve during the curing of flue-cured tobacco was 93.4%. At the same time, during ABF combustion, the emissions of CO2 and CO were 40.82% and 0.19%, respectively. However, no emissions of NOX, SO2, and H2S were detected in the chimney exhaust. Compared with the barn BBF and barn coal, the thermal efficiency of barn ABF heating equipment in the barn was increased by 44.78% and 86.28%, respectively. Additionally, the coast per kilogram of dry tobacco was reduced by 19.44% and 45.28%, respectively. Therefore, compared to barn coal and barn BBF, the barn ABF can control temperature changes more accurately, and shows an obvious advantage in environmental protection and heat utilization efficiency.

Source-oriented probabilistic health risk assessment of soil potentially toxic elements in a typical mining city.

Identifying potential sources of soil potentially toxic elements (PTEs) and developing source-oriented health risk assessments in typical mining cities are key for pollution prevention and risk management. To this end, a case study was conducted to explore the pollution characteristics, potential sources, and human health risks of PTEs in Daye City, China. Indices, including the pollution factor (PF), pollution load index (PLI), and geo-accumulation index (Igeo), were applied to assess PTE pollution. Cd had the highest value among the detected PTEs, and 82.93% of the sampling sites had moderate pollution levels, with the highest mean Igeo value for Cd (2.30). Four potential sources were determined. Cr and Ni originated mainly from natural sources. Zn (91.5%) was exclusively and then Cd (33.1%) was moderately derived from industrial activities. The mixed source of various mineral exploitation smelting, and coal-fired traffic emissions leaded to the accumulation of As, Cd, and Pb. Cu was associated with Cu-related mining and smelting activities. The probabilistic health risk assessment indicated that the non-carcinogenic risks for populations were negligible. Overall, this work provides scientific information for environmental managers to manage soil PTE pollution through the effective management of anthropogenic sources with limited resources and costs.

Total neoadjuvant treatment and PD-1/PD-L1 checkpoint inhibitor in locally advanced rectal cancer.

For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.

Design and synthesis of diverse Cd2+/Zn2+/Cu2+ coordination polymers tuned by dicarboxylate and auxiliary 1,4-bis(pyridin-4-ylmethyl)piperazine ligands with luminescence and Hirshfeld surface analyses.

Four new coordination polymers, including 1D, 2D and 3D structures, were synthesized via a hydrothermal method using Cd2+/Zn2+/Cu2+ metal salts as nodes. These polymers were formed through self-assembly of four different dicarboxylic acid ligands, namely adamantane-1,3-dicarboxylic acid (H2adc), glutaric acid (H2glu), 5-hydroxyisophthalic acid (H2hip) and fumaric acid (H2fum), in conjunction with the auxiliary ligand [1,4-bis(pyridin-4-ylmethyl)piperazine (bpmp). The corresponding formulae are [Cd3(adc)2(bpmp)Cl2(H2O)2]n (1), {[Cd2(glu)2(bpmp)2(H2O)2]·8H2O·2CH3OH}n (2), [Zn(hip)(bpmp)(H2O)]n (3) and [Cu(fum)(bpmp)(H2O)2]n (4). Single-crystal X-ray diffraction studies revealed that the Cd2+ centers in complex 1 all adopt a six-coordinate mode but two distinct {CdO2N2Cl2} and {CuO5Cl} units. The 3D network of complex 1 can be simplified to a binodal (4.6)-connected underlying net with the point symbol (3·42·5·62)4(32·62·72·88·10). Each Cd2+ cation in complex 2 adopts a seven-coordinate {CdO5N2} center, forming an asymmetric pentagonal bipyramidal coordination. Its stacking structure is formed by the interaction of hydrogen bonds between 2D supramolecular layers, with the adjacent layers exhibiting mirror symmetry. Each Zn2+ ion in complex 3 displays a {ZnO3N} four-coordinate unit. Its stacking structure is formed by one-dimensional [Zn(hip)(bpmp)(H2O)]n chains connected through hydrogen bonds. On the other hand, complex 4 features a Jahn-Teller distorted {CuO4N2} octahedral coordination. Subsequently, the thermal stability of these complexes was investigated. The solid-state fluorescence spectroscopy was employed to analyze complexes 1, 2 and 3. Additionally, a Hirshfeld surface analysis was performed on complex 3.

Total neoadjuvant treatment to increase the clinical complete response rate for distal locally advanced rectal cancer (TESS): A study protocol of a prospective, open-label, multicenter, single-arm, phase 2 trial.

BACKGROUND: Standard treatment of locally advanced rectal cancer (LARC) was neoadjuvant chemoradiotherapy (CRT), followed by total mesorectal excision (TME). Total neoadjuvant treatment (TNT), a new concept, attempts to deliver both systemic chemotherapy and neoadjuvant CRT prior to surgery. Patients treated with neoadjuvant chemotherapy were more likely to show higher tumor regression. The objective of this trial was to increase complete clinical rate (cCR) for LARC patients by optimizing tumor response, using TNT regimen as compared to conventional chemoradiotherapy. TESS, a prospective, open-label, multicenter, single-arm, phase 2 study, is underway. METHODS: Main inclusion criteria include cT3-4aNany or cT1-4aN+ rectal adenocarcinoma aged 18-70y; Eastern Cooperative Oncology Group (ECOG) performance 0-1; location ≤5 cm from anal verge. Ninety-eight patients will receive 2 cycles of neoadjuvant chemotherapy Capeox (capecitabine + oxaliplatin) before, during, and after radiotherapy 50Gy/25 fractions, before TME (or other treatment decisions, such as Watch and Wait strategy) and adjuvant chemotherapy capecitabine 2 cycles. Primary endpoint is the cCR rate. Secondary endpoints include ratio of sphincter preservation strategy; pathological complete response rate and tumor regression grade distribution; local recurrence or metastasis; disease-free survival; locoregional recurrence-free survival; acute toxicity; surgical complications; long-term anal function; late toxicity; adverse effect, ECOG standard score, and quality of life. Adverse events are graded per Common Terminology Criteria for Adverse Events V5.0. Acute toxicity will be monitored during antitumor treatment, and late toxicity will be monitored for 3 years from the end of the first course of antitumor treatment. DISCUSSION: The TESS trial aims to explore a new TNT strategy, which is expected to increase the rate of cCR and sphincter preservation rate. This study will provide new options and evidence for a new sandwich TNT strategy in patients with distal LARC.

[Responses of Cd Accumulation in Rice and Spectral Characteristics of Soil Dissolved Organic Matter Regulated by Soil Amendments].

Studying the chemical composition and characteristic differences of soil dissolved organic matter (DOM) is significant for understanding the mechanism of Cd immobilization by soil amendments. Soil amendments have been widely applied to contaminated farmlands to reduce the accumulation of heavy metals in crops, but the spectral characteristics of DOM in soils under amendment regulation have rarely been studied. Typical Cd-contaminated paddy soil from South China was collected, three categories of amendments (organic-based, inorganic-based, and lime-based, a total of 11 types) were applied, rice planting pot trials were done, and the effects of different amendments on soil DOM were investigated. The spectral characteristics of rhizosphere soil DOM under the regulation of different amendments were comparatively analyzed using UV-Vis spectroscopy, 3D fluorescence spectroscopy, and parallel factor analysis (PARAFAC). The results showed that the lime-based amendments increased the soil pH and promoted the dissolution of organic matter from the soil solid phase, resulting in a significant increase in soil DOM content. Compared with that of the control, organic-based amendments increased the relative molecular weight and recent autochthonous origin contribution of soil DOM, inorganic-based amendments increased the aromatic content and hydrophobic components of soil DOM, and lime-based amendments increased the chromogenic components and the degree of humification of soil DOM. Four fluorescence components, C1 (255/465), C2 (325/400), C3 (275/390), and C4 (240/460), were identified using PARAFAC and verified with the OpenFluor database, all of which were humic-like. Two types of spectra corroborated with each other, indicating that soil DOM dominated by humus-like matter originated from terrestrial source input. The correlation analysis showed that the fluorescent component C4 of soil DOM could be used to predict Cd accumulation in brown rice in the red limestone soil-rice system. These results will provide a reference for the selection of the appropriate soil amendments.