Catecholamine levels with use of electronic and combustible cigarettes.

INTRODUCTION: Smoking elevates catecholamines that increase the risk for cardiovascular disease. Sparse evidence exists about the effects of e-cigarettes and catecholamines. Higher levels of catecholamines could trigger the increased heart rate, blood pressure, and decreased vascular function reported with the use of e-cigarettes. We investigated the difference in urinary catecholamines and their metabolites before and after the use of an e-cigarette containing nicotine or cigarettes compared to no tobacco use. METHODS: In our observational cohort exposure study, healthy adults aged 21-45 years who were currently using e-cigarettes, cigarettes, or had never used tobacco, participated in an acute exposure visit using their most common tobacco product. Urine was collected before, 1, and 2 hours after a 3-second puff every 30 seconds for 10 minutes on an e-cigarette or straw or use of 1 cigarette. Urinary catecholamines and their metabolites were measured by ultra-high-performance liquid chromatography. Participants (n=323) were grouped by the product used at the visit. We compared levels of creatinine normalized log-transformed urinary catecholamines and their metabolites across groups using Dunn's test following a Kruskal-Wallis test in unadjusted and demographically adjusted models. RESULTS: Prior to use, individuals who used cigarettes (n=70) had lower urinary metabolites from epinephrine, serotonin, and norepinephrine. No differences were seen in those who used e-cigarettes (n=171) and those who did not use tobacco (n=82). In fully adjusted models, 1 h after the use of a combustible or e-cigarette, log-transformed urinary metabolites from norepinephrine (ß=1.22; 95% CI: 0.39-2.05, p=0.004 and ß=1.06; 95% CI: 0.39-1.74, p=0.002), dopamine (ß=0.37; 95% CI: 0.24-0.5, p<0.001 and ß=0.15; 95% CI: 0.05-0.26, p<0.001), and epinephrine (ß=1.89; 95% CI: 0.51-3.27, p=0.008 and ß=1.49; 95% CI: 0.38-2.61, p=0.009) were elevated. In fully adjusted models, combustible cigarette use was associated with elevated urinary norepinephrine (ß=0.46; 95% CI: 0.13-0.81, p=0.007) and dopamine (ß=0.19; 95% CI: 0.06-0.31, p=0.003) 1 h after use. CONCLUSIONS: We found that the use of both e-cigarettes and cigarettes was associated with elevated urinary catecholamines or their metabolites. Catecholamines could be useful as a biomarker of harm for tobacco use and considered by tobacco regulatory scientists in future research.

Effects and Action Mode of Oleic Acid and Azone on Release and Penetration Process of Levothyroxine Sodium Patches.

In recent years, there has been a significant increase in the prevalence of thyroid diseases, particularly hypothyroidism. In this study, we investigated the impact and mechanisms of Chemical permeation enhancement(CPE) on transdermal permeation of levothyroxine sodium (L-T4) patches.We found that the combination of oleic acid (OA) and Azone (NZ) yielded the best transdermal permeation effect for L-T4.Subsequently, we also investigated the relevant propermeability mechanism.The results demonstrate that the combined application of OA and NZ significantly enhances the transdermal permeation of L-T4 compared to individual applications,it is attributed to two mechanisms: firstly, OA improves drug release by increasing the flowability of the pressure-sensitive adhesive (PSA) matrix; secondly, both OA and NZ act on the stratum corneum, especially facilitating L-T4 permeation through the hair follicle pathway. No skin irritation or cytotoxicity is observed with these final patches, which exhibit a remarkable therapeutic effect on hypothyroidism. this study contributes to the development of transdermal formulations of L-T4.

Illness uncertainty, resilience, and perceived social support among patients with moyamoya disease: a cross-sectional study.

Objective: The present study aims to investigate the levels of illness uncertainty in patients with moyamoya disease and to determine the association of socio-demographic characteristics, perceived social support and resilience with illness uncertainty in patients with moyamoya disease. Method: A cross-sectional survey using convenience sampling was conducted in two hospitals in China from August to December 2023. A socio-demographic characteristics questionnaire, the Chinese versions of Mishel's Unsurety in Disease Scale (MUIS), the Chinese version of Connor-Davidson Resilience Scale (CD-RISC), and the Chinese version of Multidimensional Scale of Perceived Social Support (MSPSS) were used to perform this research. The collected data were analyzed using SPSS 24.0 statistical software. The t-test, one-way analysis of variance (ANOVA), pearson correlation analysis and hierarchical regression analysis were used to identify associated factors. Result: A total of 263 patients with moyamoya disease were recruited in this survey. The score of illness uncertainty was at a moderate level of (100.03 ± 18.59). The present study identified a negative correlation between illness uncertainty with resilience perceived social support. Hierarchical regression analysis showed that gender, occupation, education level, resilience and perceived social support were the related factors of illness uncertainty. Conclusion: Patients with moyamoya disease experienced moderate disease uncertainty on average, which was related to gender, occupation, education level, resilience and perceived social support. Future research is needed to better explore the complex relationships between illness uncertainty, resilience, and perceived social support with different types of moyamoya disease using longitudinal research.

Synthetic approaches and clinical application of representative small-molecule inhibitors of phosphodiesterase.

Phosphodiesterases (PDEs) constitute a family of enzymes that play a pivotal role in the regulation of intracellular levels of cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Dysregulation of PDE activity has been implicated in diverse pathological conditions encompassing cardiovascular disorders, pulmonary diseases, and neurological disorders. Small-molecule inhibitors targeting PDEs have emerged as promising therapeutic agents for the treatment of these ailments, some of which have been approved for their clinical use. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation PDE inhibitors. The objective of this review is to provide an overview of the synthesis and clinical application of representative approved small-molecule PDE inhibitors, with the aim of offering guidance for further advancements in the development of novel PDE inhibitors.

[Testis-sparing microsurgery for benign testis tumor: A report of 16 cases].

OBJECTIVE: To investigate the safety and clinical effect of testis-sparing microsurgery (TSMS) in the treatment of benign testis tumor (BTT). METHODS: We retrospectively analyzed the clinical data on 16 cases of BTT treated in the Department of Andrology of the Affiliated Hospital of Qingdao University from October 2020 to February 2023. The median age of the patients was 23 years. All the tumors were unilateral, 7 in the left and 9 in the right side, with a median diameter of 1.85 cm (1.0－3.5 cm). The patients all underwent color Doppler flow imaging (CDFI), MRI, semen analysis and examination of serum T, alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG) and lactate dehydrogenase (LDH), followed by TSMS. The boundaries between the tumors and normal testis tissue were accurately identified under the microscope, and the tumors and the adjacent normal testis tissue 2 mm from their margins were excised completely. Bipolar coagulation forceps were used for wound hemostasis to maximally preserve the normal testis tissue. The resected specimens were subjected to fast frozen pathology intraoperatively, and the patients were followed up for 14－40 months by regular scrotal CDFI, MRI and examinations of serum T and semen parameters. RESULTS: The levels of serum T, AFP, HCG and LDH and semen parameters were all within the normal range preoperatively. TSMS were successfully completed in all the cases, and all were pathologically confirmed as BTT according to the latest edition of WHO Classification of Tumors: Urinary and Male Genital Tumors. CDFI showed normal blood supply within the testis tissue at 1 month after surgery. No signs of intra-testicular tumor residue, recurrence or metastasis, nor significant changes in the levels of serum T, AFP, HCG or LDH or semen parameters were observed during the follow-up as compared with the baseline. Natural conception was achieved in 2 cases at 16 and 18 months respectively after surgery. CONCLUSION: BTT can be differentially diagnosed by CDFI and MRI before surgery and confirmed by histopathology. TSMS can achieve complete excision of the tumor, maximal sparing of the normal testis tissue and thereby effective preservation of male fertility.

Childhood Family Stress and Women's Health: Parasympathetic Activity as a Risk and Resiliency Factor.

Childhood family stress (CFS) exacerbates risk for physical health problems across the lifespan. Health risks associated with CFS are particularly relevant for women who tend to endorse more CFS than men. Importantly, some evidence suggests that individuals may vary in their susceptibility to CFS. Parasympathetic activity, which helps to regulate automatic bodily activity (e.g., breathing, digestion), has been proposed to represent a marker of plasticity to environmental exposure. However, no research to date has tested whether parasympathetic activity may modulate the impact of early adversity on health. We examined whether parasympathetic activity would moderate the link between CFS and health complaints in a sample of 68 undergraduate women (Mean age = 19.44). Participants self-reported CFS and health complaints. Parasympathetic activity was indexed using high-frequency heart rate variability (HF-HRV) and was evaluated by measuring changes in HF-HRV in response to and following a laboratory-based stress induction. Multiple regression analyses indicated that CFS was significantly associated with more health complaints. Further, HF-HRV in response to stress and during recovery relative to baseline significantly moderated relationship between CFS and health complaints. Specifically, more CFS was significantly associated with more health complaints among women who showed mean or greater decreases in HF-HRV in response to stress. Additionally, lower levels of CFS were associated with fewer health complaints among women who showed mean or greater HF-HRV during recovery relative to baseline. Findings highlight the importance of parasympathetic activity in modulating stress-health links.

Gabapentin alleviates peripheral nerve sensitization induced by inflammatory arthritis via ionotropic glutamate receptor NR2B subunit.

Inflammatory arthritis leads to peripheral nerve sensitization, but the therapeutic effect is often unsatisfactory. Our preliminary studies have found that in mice with inflammatory arthritis, the use of ionotropic glutamate receptor antagonists can produce a good analgesic effect without altering foot swelling, suggesting that pain relief may be related to the improvement of neuropathic pain. However, the underlying mechanisms remain unclear. To further investigate the effects of neuropathic pain medications on inflammatory arthritis and the impact of the ionotropic glutamate receptor NR2B subunit (NR2B) on inflammatory arthritis, this study employed gabapentin (GBP) treatment on the inflammatory arthritis mouse model (the adjuvant induced arthritis, AIA), and we found a significant reduction in pain. Further studies revealed that in AIA, the expression levels of NR2B, TRPV1, pain-related molecules (substance P, PGE2), inflammatory cytokines (IL-1, IL-6, TNF-α, and GM-CSF) and Ca2+ were elevated in the foot and dorsal root ganglia (DRG). GBP treatment was able to influence the downregulation of the expression levels of NR2B, TRPV1, pain-related molecules, inflammatory cytokines and Ca2+. Mechanistic studies have shown that GBP treatment affects the downregulation of NR2B, and the downregulation of NR2B expression leads to the downregulation of TRPV1, pain-related molecules and inflammatory cytokines, thereby alleviating pain. These results suggest that in peripheral sensitization caused by AIA, GBP can play a role in improving pain, and NR2B may be a key target of peripheral nerve sensitization induced by inflammatory arthritis. GBP provides a theoretical basis for the clinical treatment of inflammatory arthritis.

Immunoinflammatory features and cognitive function in treatment-resistant schizophrenia: unraveling distinct patterns in clozapine-resistant patients.

Patients with treatment-resistant schizophrenia (TRS), particularly those resistant to clozapine (CTRS), pose a clinical challenge due to limited response to standard antipsychotic treatments. Inflammatory factors like tumor necrosis factor-alpha (TNF-α), interleukin 2 (IL-2), and interleukin 6 (IL-6) are implicated in schizophrenia's pathophysiology. Our study examines cognitive function, psychopathological symptoms and inflammatory factors in TRS patients, focusing on differences between CTRS and non-CTRS individuals, as well as healthy controls. A cohort of 115 TRS patients and 84 healthy controls were recruited, assessing IL-2, IL-6 and TNF-α. The Positive and Negative Syndrome Scale (PANSS) was applied to assess psychopathological symptoms, while the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was applied to assess cognitive functioning. CTRS patients showed lower visuospatial constructional score (p = 0.015), higher PANSS scores, higher levels of IL-2 and reduced TNF-α than non-CTRS patients (p < 0.05). Notably, IL-2 was independently associated with psychopathology symptoms in CTRS patients (Beta = 0.268, t = 2.075, p = 0.042), while IL-6 was associated with psychopathology symptoms in non-CTRS patients (Beta = - 0.327, t = - 2.109, p = 0.042). Sex-specific analysis in CTRS patients revealed IL-2 associations with PANSS total and positive symptoms in females, and TNF-α associations with PANSS positive symptoms in males. Furthermore, IL-2, IL-6, and TNF-α displayed potential diagnostic value in TRS patients and CTRS patients (p < 0.05). Clozapine­resistant symptoms represent an independent endophenotype in schizophrenia with distinctive immunoinflammatory characteristics, potentially influenced by sex.

Evaluation of ST6Gal1 expression and clinicopathological significance in human glioma.

Glioma is the most common brain tumor, accounting for a large majority of cancer-related deaths. ß-galactoside α2, 6 sialyltranferase 1 (ST6Gal1), the primary enzyme responsible for the conjugation of α2, 6 sialic acids to protein and lipid targets, is strongly associated with the occurrence and development of several brain tumor types. Still, the expression, targets, and functions of ST6Gal1 in glioma patients remain undetermined. As sialylation of the Ig-like cell adhesion family molecules have prominent roles in the latter's regulation in other biological contexts, we screened for members that have potential to be regulated by ST6Gal1 in silico and examined co-expressed protein modules using data derived from the Cancer Genome Atlas (TCGA) database, and we identified neural cell adhesion molecule (NCAM1) as a major ST6Gal1-interacting target. Bioinformatic binding analysis confirmed the interaction of ST6Gal1 and NCAM1. Immunohistochemistry was then used to evaluate post-operative samples from 156 patients with gliomas. ST6Gal1 and NCAM1 were co-expressed in gliomas, and their expression correlated significantly (p = 0.002) by univariate analysis. Our study also found that the expression levels of both ST6Gal1 and NCAM1 corresponded negatively with glioma grade, isocitrate dehydrogenase (IDH) mutation, and proliferation index (Ki67). Consistently, Kaplan-Meier survival curves showed that lower ST6Gal1 and NCAM1 protein levels are linked to unfavorable outcomes in glioma patients (p = 0.018 and p < 0.001, respectively). Our data indicate that ST6Gal1 may participate in the inhibition of oncogenesis and malignant progression via interacting with and targeting NCAM1 in glioma, thus presenting a novel strategy for intervention.

Synthetic routes and clinical application of new drugs approved by EMA during 2023.

In 2023, the European Medicines Agency (EMA) granted approval to 77 new molecular entities (NMEs), consisting of 45 new chemical entities (NCEs) and 32 new biological entities (NBEs). These pharmacological agents encompass a broad spectrum of therapeutic domains, including oncology, cardiology, dermatology, diagnostic medicine, endocrinology, gastroenterology and hepatology, metabolic disorders, and neurology. Among the 77 approved pharmaceuticals, three received accelerated review status, and 17 (22 %) were granted orphan drug designation for the treatment of rare diseases. This review provides an overview of the clinical applications and synthetic routes of 42 newly approved NCEs by the EMA in 2023. The objective is to offer a comprehensive understanding of the synthetic approaches used in the development of these drug molecules, thereby inspiring the creation of novel, efficient, and applicable synthetic methodologies.

Olanzapine Induces Adipogenesis and Glucose Uptake by Activating Glycolysis and Synergizing with the PI3K-AKT Pathway.

BACKGROUND: Administration of olanzapine (OLA) is closely associated with obesity and glycolipid abnormalities in patients with schizophrenia (SCZ), although the exact molecular mecha- nisms remain elusive. OBJECTIVE: We conducted comprehensive animal and molecular experiments to elucidate the mecha- nisms underlying OLA-induced weight gain. METHODS: We investigated the mechanisms of OLA-induced adipogenesis and lipid storage by em- ploying a real-time ATP production rate assay, glucose uptake test, and reactive oxygen species (ROS) detection in 3T3-L1 cells and AMSCs. Rodent models were treated with OLA using various interven- tion durations, dietary patterns (normal diets/western diets), and drug doses. We assessed body weight, epididymal and liver fat levels, and metabolic markers in both male and female mice. RESULTS: OLA accelerates adipogenesis by directly activating glycolysis and its downstream PI3K sig- naling pathway in differentiated adipocytes. OLA promotes glucose uptake in differentiated 3T3-L1 preadipocytes. In mouse models with normal glycolipid metabolism, OLA administration failed to in- crease food intake and weight gain despite elevated GAPDH expression, a marker related to glycolysis and PI3K-AKT. This supports the notion that glycolysis plays a significant role in OLA-induced met- abolic dysfunction. CONCLUSION: OLA induces glycolysis and activates the downstream PI3K-AKT signaling pathway, thereby promoting adipogenesis.

Causal relationship of inflammatory cytokines and serum metabolites in cerebral small vessel disease: a two-step Mendelian randomization study.

BACKGROUND AND PURPOSE: The aim was to investigate the causal relationships of inflammatory cytokines and serum metabolites in cerebral small vessel disease (CSVD). METHODS: Bidirectional Mendelian randomization was first conducted to screen inflammatory cytokines and serum metabolites that were associated with imaging features of CSVD, including white matter hyperintensities, recent small subcortical infarcts, cortical cerebral microinfarcts, cerebral microbleeds, lacunes and enlarged perivascular spaces. Sensitivity analyses were performed to evaluate the robustness and pleiotropy of these results. Subsequently, inflammatory cytokines and serum metabolites that were associated with CSVD were subjected to functional enrichment. Finally, mediation analysis was employed to investigate whether inflammatory cytokines or serum metabolites acted as an intermediary for the other in their causal relationship with CSVD. RESULTS: Of the inflammatory cytokines, five were risk factors (e.g., tumour-necrosis-factor-related apoptosis-inducing ligand) and five (e.g., fibroblast growth factor 19) were protective factors for CSVD. Eleven serum metabolites that increased CSVD risk and 13 metabolites that decreased CSVD risk were also identified. The majority of these markers of CSVD susceptibility were lipid metabolites. Natural killer cell receptor sub-type 2B4 was determined to act as a mediating factor of an unidentified metabolite for the enlargement of perivascular spaces. CONCLUSION: Several inflammatory cytokines and serum metabolites had causal relationships with imaging features of CSVD. A natural killer cell receptor mediated in part the promotional effect of a metabolite on perivascular space enlargement.

Association between UCP2 gene 3'UTR I/D and A55V polymorphisms and neural tube defects susceptibility: systematic review, meta-analysis, and trial sequential analysis.

Aim: Our study aimed to assess the association between UCP2 gene 3' untranslated region insertion/deletion (3'UTR I/D) and A55V (alanine/valine) polymorphisms and neural tube defects (NTDs) susceptibility. Materials and methods: According to pre-determined inclusion and exclusion criteria, the article search was conducted to search articles published before October 2023. Two authors independently screened the included articles and extracted their basic characteristics. After quality evaluation, the meta-analysis and trial sequential analysis (TSA) were conducted using RevMan 5.4, Stata/MP 17, and TSA 0.9.5.10 Beta. Subgroup analysis was conducted based on country and case group composition. Sensitivity analysis was conducted using a one-by-one exclusion method. Begg's and Egger's tests were used to evaluate publication bias. Results: A total of seven articles were included. Overall meta-analysis revealed significant heterogeneity among the included studies for 3'UTR I/D polymorphism of the UCP2 gene. Significant statistical data indicated that those with the DD genotype and D allele had higher chances of NTD compared to those with the II genotype and the I allele, respectively. The combined result of II vs. ID was not statistically significant. A55V variation showed no statistical significance in the risk of NTD, despite the absence of significant heterogeneity across the included studies. Most of the heterogeneity was resolved after subgrouping, and a higher risk of the ID genotype was found than the II genotype for Chinese people. Genotyping NTD patients or their mothers was not a factor affecting the heterogeneity. Sensitivity analysis and publication bias analysis suggested that positive findings supported our results. Conclusion: The UCP2 gene 3'UTR I/D polymorphism increased the likelihood of developing NTDs in the Chinese population, with the D allele being the risk factor, which contributed to the understanding of the genetic basis of NTDs. TSA indicated that more high-quality original studies were needed in the future for further validation.

Synthetic approaches and application of representative clinically approved fluorine-enriched anti-cancer medications.

Fluorine possesses distinctive chemical characteristics, such as its strong electron-withdrawing ability and small atomic size, which render it an invaluable asset in the design and optimization of pharmaceuticals. The utilization of fluorine-enriched medications for combating cancer has emerged as a prominent approach in medicinal chemistry and drug discovery, offering improved clinical outcomes and enhanced pharmacological properties. This comprehensive review explores the synthetic approaches and clinical applications of approved 22 representative fluorinated anti-cancer drugs from 2019 to present, shedding light on their historical development, brand names, drug target activity, mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity. Additionally, the review provides an extensive analysis of the representative synthetic techniques employed. Overall, this review emphasizes the significance of incorporating fluorine chemistry into anti-cancer drug research while highlighting promising future prospects for exploring compounds enriched with fluorine in the battle against cancer.

Variations in soil microbial communities in different saline soils under typical Populus spp. vegetation in alpine region of the Qaidam Basin, NW China.

Salinization is a severe threat to agriculture and the environment in many areas, and the same in Qaidam Basin, Qinghai Province, Northwestern China. Microorganisms have an important influence on regulating the biochemical cycles of ecosystems; however, systematic research exploring microbial diversity and interactions with saline-soil ecosystems' environmental variables remains scarce. Thus, 16 S rRNA high-throughput sequencing was performed in this paper to characterize microbial diversity under different levels of salinized soils: non-salinized (NS, 2.25 g/L), moderately salinized (MS, 6.14 g/L) and highly salinized (HS, 9.82 g/L). The alpha diversity results showed that the HS soil was significantly different from the NS and MS soils. An analysis of similarity (ANOSIM) and a principal co-ordinates analysis (PCoA) indicated that NS and MS clustered closely while HS separated from the other two. Significant differences in microbial composition were observed at the taxonomic level. Proteobacteria (42.29-79.23 %) were the most abundant phyla in the studied soils. Gammaproteobacteria (52.49 and 66.61 %) had higher abundance in the MS and HS soils at the class level; Methylophaga and Pseudomonas were the predominant bacteria in the HS soil; and Azotobacter and Methylobacillus were abundant in the MS soil. Most genera belonging to Proteobacteria and Actinobacteria were detected via a linear discriminate analysis (LDA) effect size (LEfSe) analysis, which indicated that microbes with the ability to degrade organic matter and accomplish nutrient cycling can be well-adapted to salt conditions. Further analyses (redundancy analysis and Mantel test) showed that the microbial communities were mainly related to the soil salinity, electrical conductivity (EC1:5), total phosphorus (TP) and ammonia nitrogen (NH4+-N). Overall, the findings of the study can provide insights for better understanding the dominant indigenous microbes and their roles in biochemical cycles in different saline soils in the Qaidam Basin, Qinghai Province, China. The researches related to microbial community under typical poplar species should further clarify the mechanism of plant-microbial interaction and benefit for microbial utilization in salt soil remediation.

Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy.

This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.

Point/Counterpoint #2: Current Clinical Considerations With Nonoperative Management of Rectal Cancer.

ABSTRACT: Locally advanced rectal cancer has historically been treated with multimodal therapy consisting of radiation therapy, chemotherapy, and total mesorectal excision. However, recent prospective trials and registry studies have demonstrated similar disease outcomes with nonoperative management for patients who experience an excellent clinical response to radiation and chemotherapy. This article reviews data regarding nonoperative management for rectal cancer, and highlights current challenges and limitations in a point-counterpoint format, in the context of two clinical cases.

Carbon monoxide polyhemoglobin improves the therapeutic effect and relieves inflammation in the colon tissue of haemorrhagic shock/resuscitation rats.

OBJECTIVE: The objective of this study was to test the therapeutic effect of carbon monoxide polyhemoglobin (polyCOHb) in haemorrhagic shock/resuscitation and its underlying mechanisms. METHODS: 48 rats were divided into two experimental parts, and 36 rats in the first experiment and 12 rats in the second experiment. In the first experimental part, 36 animals were randomly assigned to the following groups: hydroxyethyl starch group (HES group, n = 12), polyhemoglobin group (polyHb group, n = 12), and carbon monoxide polyhemoglobin group (polyCOHb group, n = 12). In the second experimental part, 12 animals were randomly assigned to the following groups: polyHb group (n = 6), and polyCOHb group (n = 6). Then the anaesthetised rats were haemorrhaged by withdrawing 50% of the animal's blood volume (BV), and resuscitated to the same volume of the animal's withdrawing BV with HES, polyHb, polyCOHb. In the first experimental part, the 72h survival rates of each groups animals were measured. In the second experimental part, the rats' mean arterial pressure (MAP), heart rate (HR), blood gas levels and other indicators were dynamically monitored in baseline, haemorrhagic shock (HS), at 0point resuscitation (RS 0h) and after 1 h resuscitation (RS 1h). The concentrations of malondialdehyde (MDA), superoxide dismutase (SOD), tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured by ELISA kits in both groups of rats at RS 1h. Changes in pathological sections were examined by haematoxylin-eosin (HE) staining. Nuclear factor erythroid 2-related factor 2 (Nrf2) and haem oxygenase-1 (HO-1) levels were detected by immunohistochemical analysis, while myeloperoxidase (MPO) levels were detected by immunofluorescence. DHE staining was used to determine reactive oxygen species (ROS) levels. RESULTS: The 72h survival rates of the polyHb and polyCOHb groups were 50.00% (6/12) and 58.33% (7/12) respectively, which were significantly higher than that of the 8.33% (1/12) in the HES group (p < 0.05). At RS 0h and RS 1h, the HbCO content of rats in the polyCOHb group (1.90 ± 0.21, 0.80 ± 0.21) g/L were higher than those in the polyHb group (0.40 ± 0.09, 0.50 ± 0.12)g/L (p < 0.05); At RS 1h, the MDA (41.47 ± 3.89 vs 34.17 ± 3.87 nmol/ml) in the plasma, Nrf2 and HO-1 content in the colon of rats in the polyCOHb group were lower than the polyHb group. And the SOD in the plasma (605.01 ± 24.46 vs 678.64 ± 36.37) U/mg and colon (115.72 ± 21.17 vs 156.70 ± 21.34) U/mg and the MPO content in the colon in the polyCOHb group were higher than the polyHb group (p < 0.05). CONCLUSIONS: In these haemorrhagic shock/resuscitation models, both polyCOHb and polyHb show similar therapeutic effects, and polyCOHb has more effective effects in maintaining MAP, correcting acidosis, reducing inflammatory responses than that in polyHb.

Unlocking the Potential of Ultra-High Dose Fractionated Radiation for Effective Treatment of Glioblastoma in Mice.

Background: Current radiotherapy regimens for glioblastoma (GBM) have limited efficacy and fails to eradicate tumors. Regenerative medicine brings hope for repairing damaged tissue, opening opportunities for elevating the maximum acceptable radiation dose. In this study, we explored the effect of ultra-high dose fractionated radiation on tumor responses and brain injury in immunocompetent mice which can better mimic the tumor-host interactions observed in patients. We also evaluated the role of the hypoxia-inducible factor-1 alpha under radiation as potential target for combating radiation-induced brain injury. Methods: Naïve and Hif-1α+/- heterozygous mice received a fractionated daily dose of 20 Gy for three or five consecutive days. Magnetic resonance imaging (MRI) and histology were performed to assess brain injury post-radiation. The 2×105 human GBM1 luciferase-expressing cells were transplanted with tolerance induction protocol. Fractionated radiotherapy was performed during the exponential phase of tumor growth. Bioluminescence imaging, MRI, and immunohistochemistry staining were performed to evaluate tumor growth dynamics and radiotherapy responses. Additionally, animal lifespan was recorded. Results: Fractionated radiation of 5×20 Gy induced severe brain damage, starting 3 weeks after radiation. All animals from this group died within 12 weeks. In contrast, later onset and less severe brain injury were observed starting 12 weeks after radiation of 3×20 Gy. It resulted in complete GBM eradication and survival of all treated animals. Furthermore, Hif-1α+/- mice exhibited more severe vascular damage after fractionated radiation of 3×20 Gy. Conclusion: Ultra-high dose fractionated 3×20 Gy radiation has the potential to fully eradicate GBM cells at the cost of only mild brain injury. The Hif-1α gene is a promising target for ameliorating vascular impairment post-radiation, encouraging the implementation of neurorestorative strategies.

Ocr-mediated suppression of BrxX unveils a phage counter-defense mechanism.

The burgeoning crisis of antibiotic resistance has directed attention to bacteriophages as natural antibacterial agents capable of circumventing bacterial defenses. Central to this are the bacterial defense mechanisms, such as the BREX system, which utilizes the methyltransferase BrxX to protect against phage infection. This study presents the first in vitro characterization of BrxX from Escherichia coli, revealing its substrate-specific recognition and catalytic activity. We demonstrate that BrxX exhibits nonspecific DNA binding but selectively methylates adenine within specific motifs. Kinetic analysis indicates a potential regulation of BrxX by the concentration of its co-substrate, S-adenosylmethionine, and suggests a role for other BREX components in modulating BrxX activity. Furthermore, we elucidate the molecular mechanism by which the T7 phage protein Ocr (Overcoming classical restriction) inhibits BrxX. Despite low sequence homology between BrxX from different bacterial species, Ocr effectively suppresses BrxX's enzymatic activity through high-affinity binding. Cryo-electron microscopy and biophysical analyses reveal that Ocr, a DNA mimic, forms a stable complex with BrxX, highlighting a conserved interaction interface across diverse BrxX variants. Our findings provide insights into the strategic counteraction by phages against bacterial defense systems and offer a foundational understanding of the complex interplay between phages and their bacterial hosts, with implications for the development of phage therapy to combat antibiotic resistance.