Reconstruction the feedback regulation of amino acid metabolism to develop a non-auxotrophic L-threonine producing Corynebacterium glutamicum.

L-Threonine is an important feed additive with the third largest market size among the amino acids produced by microbial fermentation. The GRAS (generally regarded as safe) industrial workhorse Corynebacterium glutamicum is an attractive chassis for L-threonine production. However, the present L-threonine production in C. glutamicum cannot meet the requirement of industrialization due to the relatively low production level of L-threonine and the accumulation of large amounts of by-products (such as L-lysine, L-isoleucine, and glycine). Herein, to enhance the L-threonine biosynthesis in C. glutamicum, releasing the aspartate kinase (LysC) and homoserine dehydrogenase (Hom) from feedback inhibition by L-lysine and L-threonine, respectively, and overexpressing four flux-control genes were performed. Next, to reduce the formation of by-products L-lysine and L-isoleucine without the cause of an auxotrophic phenotype, the feedback regulation of dihydrodipicolinate synthase (DapA) and threonine dehydratase (IlvA) was strengthened by replacing the native enzymes with heterologous analogues with more sensitive feedback inhibition by L-lysine and L-isoleucine, respectively. The resulting strain maintained the capability of synthesizing enough amounts of L-lysine and L-isoleucine for cell biomass formation but exhibited almost no extracellular accumulation of these two amino acids. To further enhance L-threonine production and reduce the by-product glycine, L-threonine exporter and homoserine kinase were overexpressed. Finally, the rationally engineered non-auxotrophic strain ZcglT9 produced 67.63 g/L (17.2% higher) L-threonine with a productivity of 1.20 g/L/h (108.0% higher) in fed-batch fermentation, along with significantly reduced by-product accumulation, representing the record for L-threonine production in C. glutamicum. In this study, we developed a strategy of reconstructing the feedback regulation of amino acid metabolism and successfully applied this strategy to de novo construct a non-auxotrophic L-threonine producing C. glutamicum. The main end by-products including L-lysine, L-isoleucine, and glycine were almost eliminated in fed-batch fermentation of the engineered C. glutamicum strain. This strategy can also be used for engineering producing strains for other amino acids and derivatives.

Injectable and Conductive Nanomicelle Hydrogel with α-Tocopherol Encapsulation for Enhanced Myocardial Infarction Repair.

Substantial advancements have been achieved in the realm of cardiac tissue repair utilizing functional hydrogel materials. Additionally, drug-loaded hydrogels have emerged as a research hotspot for modulating adverse microenvironments and preventing left ventricular remodeling after myocardial infarction (MI), thereby fostering improved reparative outcomes. In this study, diacrylated Pluronic F127 micelles were used as macro-cross-linkers for the hydrogel, and the hydrophobic drug α-tocopherol (α-TOH) was loaded. Through the in situ synthesis of polydopamine (PDA) and the incorporation of conductive components, an injectable and highly compliant antioxidant/conductive composite FPDA hydrogel was constructed. The hydrogel exhibited exceptional stretchability, high toughness, good conductivity, cell affinity, and tissue adhesion. In a rabbit model, the material was surgically implanted onto the myocardial tissue, subsequent to the ligation of the left anterior descending coronary artery. Four weeks postimplantation, there was discernible functional recovery, manifesting as augmented fractional shortening and ejection fraction, alongside reduced infarcted areas. The findings of this investigation underscore the substantial utility of FPDA hydrogels given their proactive capacity to modulate the post-MI infarct microenvironment and thereby enhance the therapeutic outcomes of myocardial infarction.

Cardiac-specific overexpression of CREM-IbΔC-X via CRISPR/Cas9 in mice presents a new model of atrial cardiomyopathy with spontaneous atrial fibrillation.

Atrial cardiomyopathy (ACM) forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. However, generating stable animal models that accurately replicate the entire progression of atrial lesions, particularly the onset of AF, presents significant challenges. In the present study, we found that the isoform of CRE-binding protein modulator (CREM-IbΔC-X), which is involved in the regulation of cardiac development and atrial rhythm, was highly expressed in atrial biopsies from patients with AF. Building upon this finding, we employed CRISPR/Cas9 technology to create a mouse model with cardiac-specific overexpression of CREM-IbΔC-X (referred to as CS-CREM mice). This animal model effectively illustrated the development of ACM through electrophysiological and structural remodelings over time. Proteomics and Chip-qPCR analysis of atrial samples revealed significant upregulation of cell-matrix adhesion and extracellular matrix structural components, alongside significant downregulation of genes related to atrial functions in the CS-CREM mice. Furthermore, the corresponding responses to anti-arrhythmia drugs, i.e., amiodarone and propafenone, suggested that CS-CREM mice could serve as an ideal in vivo model for drug testing. Our study introduced a novel ACM model with spontaneous AF by cardiac-specifically overexpressing CREM-IbΔC-X in mice, providing valuable insights into the mechanisms and therapeutic targets of ACM.

Development of a growth-coupled selection platform for directed evolution of heme biosynthetic enzymes in Corynebacterium glutamicum.

Heme is an important tetrapyrrole compound, and has been widely applied in food and medicine industries. Although microbial production of heme has been developed with metabolic engineering strategies during the past 20 years, the production levels are relatively low due to the multistep enzymatic processes and complicated regulatory mechanisms of microbes. Previous studies mainly adopted the strategies of strengthening precursor supply and product transportation to engineer microbes for improving heme biosynthesis. Few studies focused on the engineering and screening of efficient enzymes involved in heme biosynthesis. Herein, a growth-coupled, high-throughput selection platform based on the detoxification of Zinc-protoporphyrin IX (an analogue of heme) was developed and applied to directed evolution of coproporphyrin ferrochelatase, catalyzing the insertion of metal ions into porphyrin ring to generate heme or other tetrapyrrole compounds. A mutant with 3.03-fold increase in k cat/K M was selected. Finally, growth-coupled directed evolution of another three key enzymes involved in heme biosynthesis was tested by using this selection platform. The growth-coupled selection platform developed here can be a simple and effective strategy for directed evolution of the enzymes involved in the biosynthesis of heme or other tetrapyrrole compounds.

Practical Electrochemical Method to Enhance Needle Visibility during Ultrasound Imaging.

Ultrasound-guided needle interventions play a pivotal role in the diagnosis and treatment processes in clinical practice. However, existing echogenic needles face challenges in achieving a balance between effectiveness, ease of manufacturing, and inexpensiveness. In this study, we developed an echogenic needle that encompassed the aforementioned advantages through the use of the electrolysis technology. The overall contour of the needle after electrolysis was observed using bright-field microscopy, while scanning electron microscopy (SEM) was employed to examine the micro-variations on the needle's surface. Subsequently, we validated the enhanced visualization effects in vitro (pork) and in vivo (anesthetized rabbit's thigh) puncture phantoms. To ensure the safety of the needles after the puncture procedure, we conducted Vickers hardness tests, SEM detection, bright-field microscopy, and DAPI staining. The results demonstrated that the surface roughness of the needle increased with the duration of electrolysis. Taking into account the comprehensive safety tests, the needle, subjected to 40 s of electrolysis, demonstrated a safe and effective enhancement of ultrasound visualization.

[Advances of development and application amino acid biosensors].

Amino acids are the basic building blocks of protein that are very important to the nutrition and health of humans and animals, and widely used in feed, food, medicine and daily chemicals. At present, amino acids are mainly produced from renewable raw materials by microbial fermentation, forming one of the important pillar industries of biomanufacturing in China. Amino acid-producing strains are mostly developed through random mutagenesis- and metabolic engineering-enabled strain breeding combined with strain screening. One of the key limitations to further improvement of production level is the lack of efficient, rapid, and accurate strain screening methods. Therefore, the development of high-throughput screening methods for amino acid strains is very important for the mining of key functional elements and the creation and screening of hyper-producing strains. This paper reviews the design of amino acid biosensors and their applications in the high-throughput evolution and screening of functional elements and hyper-producing strains, and the dynamic regulation of metabolic pathways. The challenges of existing amino acid biosensors and strategies for biosensor optimization are discussed. Finally, the importance of developing biosensors for amino acid derivatives is prospected.

Engineering of the DNA replication and repair machinery to develop binary mutators for rapid genome evolution of Corynebacterium glutamicum.

Corynebacterium glutamicum is an important industrial workhorse for production of amino acids and chemicals. Although recently developed genome editing technologies have advanced the rational genetic engineering of C. glutamicum, continuous genome evolution based on genetic mutators is still unavailable. To address this issue, the DNA replication and repair machinery of C. glutamicum was targeted in this study. DnaQ, the homolog of ϵ subunit of DNA polymerase III responsible for proofreading in Escherichia coli, was proven irrelevant to DNA replication fidelity in C. glutamicum. However, the histidinol phosphatase (PHP) domain of DnaE1, the α subunit of DNA polymerase III, was characterized as the key proofreading element and certain variants with PHP mutations allowed elevated spontaneous mutagenesis. Repression of the NucS-mediated post-replicative mismatch repair pathway or overexpression of newly screened NucS variants also impaired the DNA replication fidelity. Simultaneous interference with the DNA replication and repair machinery generated a binary genetic mutator capable of increasing the mutation rate by up to 2352-fold. The mutators facilitated rapid evolutionary engineering of C. glutamicum to acquire stress tolerance and protein overproduction phenotypes. This study provides efficient tools for evolutionary engineering of C. glutamicum and could inspire the development of mutagenesis strategy for other microbial hosts.

Sulfur fertilization and water management ensure phytoremediation coupled with argo-production by mediating rhizosphere microbiota in the Oryza sativa L.-Sedum alfredii Hance rotation system.

Sulfur (S) fertilizers, water management and crop rotation are important agronomic practices, related to soil heavy metal bioavailability. However, the mechanisms of microbial interactions remain unclear. Herein, we investigated how S fertilizers (S0 and Na2SO4) and water management affected plant growth, soil cadmium (Cd) bioavailability, and rhizospheric bacterial communities in the Oryza sativa L. (rice)-Sedum alfredii Hance (S. alfredii) rotation system through 16S rRNA gene sequencing and ICP-MS analysis. During rice cultivation, continuous flooding (CF) was better than alternating wetting and drying (AWD). CF treatment decreased soil Cd bioavailability by the promotion of insoluble metal sulfide production and soil pH, thus lowering Cd accumulation in grains. S application recruited more S-reducing bacteria in the rhizosphere of rice, whilst Pseudomonas promoted metal sulfide production and rice growth. During S. alfredii cultivation, S fertilizer recruited S-oxidizing and metal-activating bacteria in the rhizosphere. Thiobacillus may oxidize metal sulfides and enhance Cd and S absorption into S. alfredii. Notably, S oxidation decreased soil pH and elevated Cd content, thereby promoting S. alfredii growth and Cd absorption. These findings showed rhizosphere bacteria were involved in Cd uptake and accumulation in the rice-S. alfredii rotation system, thus providing useful information for phytoremediation coupled with argo-production.

Sustainable and high-level microbial production of plant hemoglobin in Corynebacterium glutamicum.

BACKGROUND: Plant hemoglobin shows great potential as a food additive to circumvent the controversy of using animal materials. Microbial fermentation with engineered microorganisms is considered as a promising strategy for sustainable production of hemoglobin. As an endotoxin-free and GRAS (generally regarded as safe) bacterium, Corynebacterium glutamicum is an attractive host for hemoglobin biosynthesis. RESULTS: Herein, C. glutamicum was engineered to efficiently produce plant hemoglobin. Hemoglobin genes from different sources including soybean and maize were selected and subjected to codon optimization. Interestingly, some candidates optimized for the codon usage bias of Escherichia coli outperformed those for C. glutamicum regarding the heterologous expression in C. glutamicum. Then, saturated synonymous mutation of the N-terminal coding sequences of hemoglobin genes and fluorescence-based high-throughput screening produced variants with 1.66- to 3.45-fold increase in hemoglobin expression level. To avoid the use of toxic inducers, such as isopropyl-ß-D-thiogalactopyranoside, two native inducible expression systems based on food additives propionate and gluconate were developed. Promoter engineering improved the hemoglobin expression level by 2.2- to 12.2-fold. Combination of these strategies and plasmid copy number modification allowed intracellular production of hemoglobin up to approximately 20% of total protein. Transcriptome and proteome analyses of the hemoglobin-producing strain revealed the cellular response to excess hemoglobin accumulation. Several genes were identified as potential targets for further enhancing hemoglobin production. CONCLUSIONS: In this study, production of plant hemoglobin in C. glutamicum was systematically engineered by combining codon optimization, promoter engineering, plasmid copy number modification, and multi-omics-guided novel target discovery. This study offers useful design principles to genetically engineer C. glutamicum for the production of hemoglobin and other recombinant proteins.

Cadmium inhibits powdery mildew colonization and reconstructs microbial community in leaves of the hyperaccumulator plant Sedum alfredii.

Understanding the influence of the heavy metal cadmium (Cd) on the phyllosphere microbiome of hyperaccumulator plants is crucial for enhancing phytoremediation. The characteristics of the phyllosphere of Sedum alfredii Hance, a hyperaccumulator plant, were investigated using 16S rRNA and internal transcribed spacer amplicon sequencing of powdery mildew-infected leaves treated or untreated with Cd. The results showed that the colonization of powdery mildew caused severe chlorosis and necrosis in S. alfredii leaves, and the relative abundance of Leotiomycetes in infected leaves increased dramatically and significantly decreased phyllosphere microbiome diversity. However, S. alfredii preferentially accumulated higher concentrations of Cd in the leaves of infected plants than in uninfected plants by powdery mildew, which in turn significantly inhibited powdery mildew colonization in leaves; the relative abundance of the fungal class Leotiomycetes in infected leaves decreased, and alpha and beta diversities of the phyllosphere microbiome significantly increased with Cd treatment in the infected plants. In addition, the inter-kingdom networks in the microbiota of the infected leaves treated with Cd presented many nodes and edges, and the highest inter-kingdom modularity compared to the untreated infected leaves, indicating a highly connected microbial community. These results suggest that Cd significantly inhibits powdery mildew colonization by altering the composition of the phyllosphere microbiome in S. alfredii leaves, paving the way for efficient heavy metal phytoremediation and providing a new perspective on defense strategies against heavy metals.

Survival and complications after neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy for locally advanced gastric cancer: a systematic review and meta-analysis.

Background: There is increasing evidence that neoadjuvant chemoradiotherapy is superior to neoadjuvant chemotherapy for patients with locally advanced gastric cancer. However, a number of studies have come to the opposite conclusion. Therefore, our meta-analysis is to evaluate the efficacy and safety of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy in the treatment of locally advanced gastric cancer. Methods: We searched Wanfang Database, China National Knowledge Network database, VIP database, China Biomedical Literature Database, PubMed, Embase and Cochrane Library. The searched terms included'Stomach Neoplasms', 'Neoadjuvant Therapy' and 'Chemoradiotherapy'. The retrieval time was from the establishment of the corresponding database to September 2022, and our meta-analysis was performed using RevMan (version 5.3) and Stata (version 17) software. Results: A total of 17 literatures were included, which involved 7 randomized controlled trials and 10 retrospective studies, with a total of 6831 patients. The results of meta-analysis showed that compared with NACT group, the complete response rate(RR=1.95, 95%CI 1.39-2.73, p=0.0001), the partial response rate(RR=1.44, 95%CI 1.22-1.71, p=0.0001), the objective response rate(RR=1.37, 95%CI 1.27-1.54, p=0.00001), the pathologic complete response rate(RR=3.39, 95%CI 2.17-5.30, p=0.00001), the R0 resection rate(RR=1.18, 95%CI 1.09-1.29, p=0.0001) and 3-year overall survival rate(HR=0.89, 95%CI 0.82-0.96, p=0.002) of neoadjuvant chemoradiotherapy group were significantly improved. The results of subgroup analyses of gastric cancer subgroup and gastroesophageal junction cancer subgroup were consistent with the overall results. Meanwhile, the stable disease(RR=0.59, 95%CI:0.44-0.81, P=0.0010) of neoadjuvant chemoradiotherapy group was lower than that of neoadjuvant chemotherapy group, and there were no statistical significance in the progressive disease rate(RR=0.57, 95%CI:0.31-1.03, P=0.06), five-year overall survival rate(HR=1.03, 95%CI:0.99-1.07, P=0.839), postoperative complications and adverse reactions between the neoadjuvant chemoradiotherapy group and neoadjuvant chemotherapy group. Conclusion: Compared with neoadjuvant chemotherapy, neoadjuvant chemoradiotherapy might bring more survival benefits without significantly increasing adverse reactions. neoadjuvant chemoradiotherapy may be a recommended treatment for patients with locally advanced gastric cancer. Systematic Review Registration: https://inplasy.com/inplasy-2022-12-0068/, identifier INPLASY202212068.

Systems metabolic engineering of Escherichia coli for hyper-production of 5­aminolevulinic acid.

BACKGROUND: 5-Aminolevulinic acid (5-ALA) is a promising biostimulant, feed nutrient, and photodynamic drug with wide applications in modern agriculture and therapy. Although microbial production of 5-ALA has been improved realized by using metabolic engineering strategies during the past few years, there is still a gap between the present production level and the requirement of industrialization. RESULTS: In this study, pathway, protein, and cellular engineering strategies were systematically employed to construct an industrially competitive 5-ALA producing Escherichia coli. Pathways involved in precursor supply and product degradation were regulated by gene overexpression and synthetic sRNA-based repression to channel metabolic flux to 5-ALA biosynthesis. 5-ALA synthase was rationally engineered to release the inhibition of heme and improve the catalytic activity. 5-ALA transport and antioxidant defense systems were targeted to enhance cellular tolerance to intra- and extra-cellular 5-ALA. The final engineered strain produced 30.7 g/L of 5-ALA in bioreactors with a productivity of 1.02 g/L/h and a yield of 0.532 mol/mol glucose, represent a new record of 5-ALA bioproduction. CONCLUSIONS: An industrially competitive 5-ALA producing E. coli strain was constructed with the metabolic engineering strategies at multiple layers (protein, pathway, and cellular engineering), and the strategies here can be useful for developing industrial-strength strains for biomanufacturing.

Directed evolution of linker helix as an efficient strategy for engineering LysR-type transcriptional regulators as whole-cell biosensors.

Whole-cell biosensors based on transcriptional regulators are powerful tools for rapid measurement, high-throughput screening, dynamic metabolic regulation, etc. To optimize the biosensing performance of transcriptional regulator, its effector-binding domain is commonly engineered. However, this strategy is encumbered by the limitation of diversifying such a large domain and the risk of affecting effector specificity. Molecular dynamics simulation of effector binding of LysG (an LysR-type transcriptional regulator, LTTR) suggests the crucial role of the short linker helix (LH) connecting effector- and DNA-binding domains in protein conformational change. Directed evolution of LH efficiently produced LysG variants with extended operational range and unaltered effector specificity. The whole-cell biosensor based on the best LysGE58V variant outperformed the wild-type LysG in enzyme high-throughput screening and dynamic regulation of l-lysine biosynthetic pathway. LH mutations are suggested to affect DNA binding and facilitate transcriptional activation upon effector binding. LH engineering was also successfully applied to optimize another LTTR BenM for biosensing. Since LTTRs represent the largest family of prokaryotic transcriptional regulators with highly conserved structures, LH engineering is an efficient and universal strategy for development and optimization of whole-cell biosensors.

Characteristics of bacterial communities in rhizosphere and bulk soil in Fe-deficient citrus growing in coastal saline-alkali land.

Aims: Citruses often occur with imbalance in iron nutrition in coastal saline-alkali lands, which severely limits the yield and quality of the fruit. In the rhizosphere, the salt content plays a crucial role in reducing uptake of iron, as well as the activity and abundance of bacteria. However, few studies have explored how salt content affects the effectiveness of iron and the community structure of bacteria across different vertical spatial scales. Methods: We investigated the citrus rhizosphere (0-30 cm) and bulk (0-60 cm) soil microenvironments of the coastal saline soil were analyzed using the 16S rRNA amplicon and inductively coupled plasma-optical emission spectroscopy. Results: We found that the nutrient-related elements in the rhizosphere and bulk soil decreased with increasing soil depth, while the salinity-related elements showed the opposite trend. The nutrient-related element content in the rhizosphere was higher than that in the bulk, whereas the salinity-alkaline-related element content was lower than that in the bulk. The structure and diversity of bacterial communities are affected by the rhizosphere and soil depth. In the bulk, there are enriched bacteria such as WB1-A12, Nitrospiraceae and Anaerolineae that are tolerant to salt-alkali stress. In the rhizosphere, bacteria that promote plant nutrient absorption and secretion of iron carriers, such as Pseudomonas, Streptomyces, and Duganella, are prominent. Conclusions: The soil depth and rhizosphere affect soil nutrients and saline alkali-related factors. Changes in soil depth and rhizosphere determine the structure and diversity of bacterial communities. Rhizosphere enhances iron absorption promoting bacteria to alleviate iron deficiency stress in saline-alkali soils. Our results indicate that citrus roots maybe can resist the stress of iron deficiency in saline-alkali soils by enhancing iron absorption promoting bacteria.

Engineering allosteric inhibition of homoserine dehydrogenase by semi-rational saturation mutagenesis screening.

Allosteric regulation by pathway products plays a vital role in amino acid metabolism. Homoserine dehydrogenase (HSD), the key enzyme for the biosynthesis of various aspartate family amino acids, is subject to feedback inhibition by l-threonine and l-isoleucine. The desensitized mutants with the potential for amino acid production remain limited. Herein, a semi-rational approach was proposed to relieve the feedback inhibition. HSD from Corynebacterium glutamicum (CgHSD) was first characterized as a homotetramer, and nine conservative sites at the tetramer interface were selected for saturation mutagenesis by structural simulations and sequence analysis. Then, we established a high-throughput screening (HTS) method based on resistance to l-threonine analog and successfully acquired two dominant mutants (I397V and A384D). Compared with the best-ever reported desensitized mutant G378E, both new mutants qualified the engineered strains with higher production of CgHSD-dependent amino acids. The mutant and wild-type enzymes were purified and assessed in the presence or absence of inhibitors. Both purified mutants maintained >90% activity with 10 mM l-threonine or 25 mM l-isoleucine. Moreover, they showed >50% higher specific activities than G378E without inhibitors. This work provides two competitive alternatives for constructing cell factories of CgHSD-related amino acids and derivatives. Moreover, the proposed approach can be applied to engineering other allosteric enzymes in the amino acid synthesis pathway.

Biofortification Technology for the Remediation of Cadmium-Contaminated Farmland by the Hyperaccumulator Sedum alfredii under Crop Rotation and Relay Cropping Mode.

Soil cadmium (Cd) extraction for hyperaccumulators is one of the most important technologies for the remediation of Cd-contaminated farmland soil. However, a phytoremediation model using a single hyperaccumulator cannot guarantee normal agricultural production in contaminated areas. To solve this problem, a combination of efficient remediation and safe production has been developed. Based on two-period field experiments, this study explored the effect of biofortification on soil Cd remediation using the fruit tree Sedum alfredii Hance and oil sunflower crop rotation and relay cropping mode. BioA and BioB treatments could markedly improve the efficiency of Cd extraction and remediation, and the maximum increase in Cd accumulation was 243.29%. When BioB treatment was combined with papaya-S. alfredii and oil sunflower crop rotation and relay cropping mode, the highest soil Cd removal rate in the two periods was 40.84%, whereas the Cd concentration of papaya fruit was lower than safety production standards (0.05 mg/kg). These results demonstrate that biofortification measures can significantly improve the Cd extraction effect of S. alfredii crop rotation and relay cropping restoration modes, which has guiding significance for Cd pollution remediation and safe production in farmland.

Nimotuzumab combined with chemoradiotherapy for the treatment of cervical cancer: A meta-analysis of randomized controlled trials.

Objectives: To assess the clinical efficacy and toxicity of nimotuzumab in combination with chemoradiotherapy or chemoradiotherapy alone in the treatment of cervical cancer. Methods: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, China Biomedical Medicine, Wanfang, and VIP databases were systematically searched for relevant literature. Ultimately, six randomised controlled trials (n=393) were included in our meta-analysis. Results: A total of 393 patients were included, of which 197 were in the nimotuzumab combined with chemoradiotherapy group and 196 were in the chemoradiotherapy group. The results of our meta-analysis showed that the complete remission rate (risk ratio [RR] = 1.34, 95% confidence interval [CI]: 1.08-1.65, P = 0.007), objective response rate (RR = 1.30, 95% CI: 1.16-1.44, P < 0.05), and three-year survival rate (RR = 1.27, 95% CI: 1.06-1.51, P = 0.008) in the nimotuzumab combined with chemoradiotherapy group were significantly improved compared with the chemoradiotherapy group. This difference was not statistically significant when comparing the incidence of adverse reactions (such as leukocytopenia, gastrointestinal reaction, radiocystitis, and radioproctitis) between the two groups. Conclusions: Nimotuzumab in combination with chemoradiotherapy has some advantages over chemoradiotherapy alone in the treatment of cervical cancer and does not increase toxicity. Therefore, nimotuzumab has the potential to be an effective treatment for cervical cancer; however, further evidence from large-scale randomised controlled trials is needed.

Neoadjuvant chemoradiotherapy for resectable gastric cancer: A meta-analysis.

Objectives: To evaluate the clinical curative effects and toxicity of neoadjuvant chemoradiotherapy for resectable gastric cancer compared to those of neoadjuvant chemotherapy. Methods: A systematic review and meta-analysis of the randomized controlled trials (RCTs) of neoadjuvant chemoradiotherapy versus neoadjuvant chemotherapy were performed in patients with resectable gastric cancer. Results: Seven RCTs were included (601 patients; 302 in the neoadjuvant chemoradiotherapy group and 299 in the neoadjuvant chemotherapy group). The neoadjuvant chemoradiotherapy group had an increased number of patients with a complete response [odds ratio (OR) = 3.79, 95% confidence interval (CI): 1.68-8.54, p = 0.001] and improved objective response rate (OR = 2.78, 95% CI: 1.69-4.57, p < 0.0001), 1-year (OR = 3.51, 95% CI: 1.40-8.81, p = 0.007) and 3-year (OR = 2.14, 95% CI: 1.30-3.50, p = 0.003) survival rates, R0 resection rate (OR = 2.21, 95% CI: 1.39-3.50, p = 0.0008), and complete pathologic response (OR = 4.39, 95% CI: 1.59-12.14, p = 0.004). Regarding the incidence of adverse effects after neoadjuvant therapy, only the occurrence rate of gastrointestinal reaction in the neoadjuvant chemoradiotherapy group was higher than that in the neoadjuvant chemotherapy group (OR = 1.76, 95% CI: 1.09-2.85, p = 0.02), and there was no significant difference in other adverse effects. There was no difference in the incidence of postoperative complications between the two groups. Conclusion: Neoadjuvant chemoradiotherapy for resectable gastric cancer has several advantages in terms of efficacy and safety compared to neoadjuvant chemotherapy. Therefore, neoadjuvant chemoradiotherapy has great potential as an effective therapy for resectable gastric cancers. Systematic Review Registration: https://inplasy.com/inplasy-2022-3-0164, registration number INPLASY202230164.

Crystal structure of 5-Aminolevulinate synthase HemA from Rhodopseudomonas palustris presents multiple conformations.

5-ALA is the precursor of all tetrapyrroles. 5-Aminolevulinate synthase (ALAS) catalyzes the production of 5-aminolevulinic acid (5-ALA) from glycine and succinyl-CoA. HemA from Rhodopseudomonas palustris (Rp-HemA) was reported to be a highly active ALAS. To understand the catalytic mechanism of Rp-HemA, the 2.05 Å resolution crystal structure of Rp-HemA was solved. Open, half close and close conformations were observed in the substrate-free structures. Structure comparison and sequence alignment suggest the newly observed half close conformation may also be conserved in ALAS family. The pre-existed close and half close conformations in Rp-HemA may play a key role for its high activity.