Nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision and exploring the technical advantages of robotic surgery.

Background: Total mesorectal excision (TME), represents a key technique in radical surgery for rectal cancer. This study aimed to construct a preoperative nomogram for predicting the surgical difficulty of laparoscopic total mesorectal excision (L-TME) and to investigate whether there were potential benefits of robotic TME (R-TME) for patients with technically challenging rectal cancer. Methods: Consecutive mid-low rectal cancer patients receiving total mesorectal excision were included. A preoperative nomogram to predict the surgical difficulty of L-TME was established and validated. Patients with technically challenging rectal cancer were screened by calculating the prediction score of the nomogram. Then patients with technically challenging rectal cancer who underwent different types of surgery, R-TME or L-TME, were analyzed for comparison. Results: A total of 533 consecutive patients with mid-low rectal cancer who underwent TME at a single tertiary medical center between January 2018 and January 2021 were retrospectively enrolled. Multivariable analysis demonstrated that mesorectal fat area, intertuberous distance, tumor size, and tumor height were independent risk factors for surgical difficulty. Subsequently, these variables were used to construct the nomogram model to predict the surgical difficulty of L-TME. The area under the receiver operating characteristic curve of the nomogram was 0.827 (95% CI 0.745 - 0.909) and 0.809 (95% CI 0.674- 0.944) in the training and validation cohort, respectively. For patients with technically challenging rectal cancer, R-TME was associated with a lower diverting ileostomy rate (p = 0.003), less estimated blood loss (p < 0.043), shorter procedure time (p = 0.009) and shorter postoperative hospital stay (p = 0.037). Conclusion: In this study, we established a preoperative nomogram to predict the surgical difficulty of L-TME. Furthermore, this study also indicated that R-TME has potential technical advantages for patients with technically challenging rectal cancer.

Nomogram for predicting prolonged postoperative ileus after laparoscopic low anterior resection for rectal cancer.

BACKGROUND: Prolonged postoperative ileus (PPOI) is a common complication after colorectal surgery that increases patient discomfort, hospital stay, and financial burden. However, predictive tools to assess the risk of PPOI in patients undergoing laparoscopic low anterior resection have not been developed. Thus, the purpose of this study was to develop a nomogram to predict PPOI after laparoscopic low anterior resection for rectal cancer. METHODS: A total of 548 consecutive patients who underwent laparoscopic low anterior resection for mid-low rectal cancer at a single tertiary medical center were retrospectively enrolled between January 2019 and January 2023. Univariate and multivariate logistic regression analysis was performed to analyze potential predictors of PPOI. The nomogram was constructed using the filtered variables and internally verified by bootstrap resampling. Model performance was evaluated by receiver operating characteristic curve and calibration curve, and the clinical usefulness was evaluated by the decision curve. RESULTS: Among 548 consecutive patients, 72 patients (13.1%) presented with PPOI. Multivariate logistic analysis showed that advantage age, hypoalbuminemia, high surgical difficulty, and postoperative use of opioid analgesic were independent prognostic factors for PPOI. These variables were used to construct the nomogram model to predict PPOI. Internal validation, conducted through bootstrap resampling, confirmed the great discrimination of the nomogram with an area under the curve of 0.738 (95%CI 0.736-0.741). CONCLUSIONS: We created a novel nomogram for predicting PPOI after laparoscopic low anterior resection. This nomogram can assist surgeons in identifying patients at a heightened risk of PPOI.

Biodegradable polyester-based nano drug delivery system in cancer chemotherapy: a review of recent progress (2021-2023).

Cancer presents a formidable threat to human health, with the majority of cases currently lacking a complete cure. Frequently, chemotherapy drugs are required to impede its progression. However, these drugs frequently suffer from drawbacks such as poor selectivity, limited water solubility, low bioavailability, and a propensity for causing organ toxicity. Consequently, a concerted effort has been made to seek improved drug delivery systems. Nano-drug delivery systems based on biodegradable polyesters have emerged as a subject of widespread interest in this pursuit. Extensive research has demonstrated their potential for offering high bioavailability, effective encapsulation, controlled release, and minimal toxicity. Notably, poly (ε-caprolactone) (PCL), poly (lactic-co-glycolic acid) (PLGA), and polylactic acid (PLA) have gained prominence as the most widely utilized options as carriers of the nano drug delivery system. This paper comprehensively reviews recent research on these materials as nano-carriers for delivering chemotherapeutic drugs, summarizing their latest advancements, acknowledging their limitations, and forecasting future research directions.

Human spinal GABA neurons survive and mature in the injured nonhuman primate spinal cord.

Spinal cord injury (SCI) leads to permanent neural dysfunction without effective therapies. We previously showed that human pluripotent stem cell (hPSC)-derived spinal GABA neurons can alleviate spasticity and promote locomotion in rats after SCI, but whether this strategy can be translated into the clinic remains elusive. Here, a nonhuman primate (NHP) model of SCI was established in rhesus macaques (Macaca mulatta) in which the T10 spinal cord was hemisected, resulting in neural conduction failure and neural dysfunction, including locomotion deficits, pain, and spasms. Grafted human spinal GABA neurons survived for up to 7.5 months in the injured monkey spinal cord and retained their intrinsic properties, becoming mature and growing axons and forming synapses. Importantly, they are functionally alive, as evidenced by designer receptors exclusively activated by designer drug (DREADD) activation. These findings represent a significant step toward the clinical translation of human spinal neuron transplantation for treating SCI.

Deciphering chloramphenicol biotransformation mechanisms and microbial interactions via integrated multi-omics and cultivation-dependent approaches.

BACKGROUND: As a widely used broad-spectrum antibiotic, chloramphenicol is prone to be released into environments, thus resulting in the disturbance of ecosystem stability as well as the emergence of antibiotic resistance genes. Microbes play a vital role in the decomposition of chloramphenicol in the environment, and the biotransformation processes are especially dependent on synergistic interactions and metabolite exchanges among microbes. Herein, the comprehensive chloramphenicol biotransformation pathway, key metabolic enzymes, and interspecies interactions in an activated sludge-enriched consortium were elucidated using integrated multi-omics and cultivation-based approaches. RESULTS: The initial biotransformation steps were the oxidization at the C1-OH and C3-OH groups, the isomerization at C2, and the acetylation at C3-OH of chloramphenicol. Among them, the isomerization is an entirely new biotransformation pathway of chloramphenicol discovered for the first time. Furthermore, we identified a novel glucose-methanol-choline oxidoreductase responsible for the oxidization of the C3-OH group in Sphingomonas sp. and Caballeronia sp. Moreover, the subsequent biotransformation steps, corresponding catalyzing enzymes, and the microbial players responsible for each step were deciphered. Synergistic interactions between Sphingomonas sp. and Caballeronia sp. or Cupriavidus sp. significantly promoted chloramphenicol mineralization, and the substrate exchange interaction network occurred actively among key microbes. CONCLUSION: This study provides desirable strain and enzyme resources for enhanced bioremediation of chloramphenicol-contaminated hotspot sites such as pharmaceutical wastewater and livestock and poultry wastewater. The in-depth understanding of the chloramphenicol biotransformation mechanisms and microbial interactions will not only guide the bioremediation of organic pollutants but also provide valuable knowledge for environmental microbiology and biotechnological exploitation. Video Abstract.

Deciphering a novel chloramphenicols resistance mechanism: Oxidative inactivation of the propanediol pharmacophore.

Expanding knowledge about new types of antibiotic resistance genes is of great significance in dealing with the global antibiotic resistance crisis. Herein, a novel oxidoreductase capO was discovered to be responsible for oxidative inactivation of chloramphenicol and thiamphenicol. The antibiotic resistance mechanism was comprehensively deciphered using multi-omics and multiscale computational approaches. A 66,383 bp DNA fragment carrying capO was shared among four chloramphenicol-resistant strains, and the co-occurrence of capO with a mobile genetic element cluster revealed its potential mobility among different taxa. Metagenomic analysis of 772 datasets indicated that chloramphenicol was the crucial driving factor for the development and accumulation of capO in activated sludge bioreactors treating antibiotic production wastewater. Therefore, we should pay sufficient attention to its possible prevalence and transfer to pathogens, especially in some hotspot environments contaminated with high concentrations of chloramphenicols. This finding significantly expands our knowledge boundary about chloramphenicols resistance mechanisms.

Nimodipine Promotes Functional Recovery After Spinal Cord Injury in Rats.

Spinal cord injury (SCI) is a devastating condition that results in severe motor, sensory, and autonomic dysfunction. The L-/T-type calcium channel blocker nimodipine (NMD) exerts a protective effect on neuronal injury; however, the protective effects of long-term administration of NMD in subjects with SCI remain unknown. Thus, the aim of this study was to evaluate the role of long-term treatment with NMD on a clinically relevant SCI model. Female rats with SCI induced by 25 mm contusion were subcutaneously injected with vehicle or 10 mg/kg NMD daily for six consecutive weeks. We monitored the motor score, hind limb grip strength, pain-related behaviors, and bladder function in this study to assess the efficacy of NMD in rats with SCI. Rats treated with NMD showed improvements in locomotion, pain-related behaviors, and spasticity-like symptoms, but not in open-field spontaneous activity, hind limb grip strength or bladder function. SCI lesion areas and perilesional neuronal numbers, gliosis and calcitonin gene-related peptide (CGRP+) fiber sprouting in the lumbar spinal cord and the expression of K+-Cl- cotransporter 2 (KCC2) on lumbar motor neurons were also observed to further explore the possible protective mechanisms of NMD. NMD-treated rats showed greater tissue preservation with reduced lesion areas and increased perilesional neuronal sparing. NMD-treated rats also showed improvements in gliosis, CGRP+ fiber sprouting in the lumbar spinal cord, and KCC2 expression in lumbar motor neurons. Together, these results indicate that long-term treatment with NMD improves functional recovery after SCI, which may provide a potential therapeutic strategy for the treatment of SCI.

Polyacrylamide Hydrogel Composite E-skin Fully Mimicking Human Skin.

Transparent e-skin that can fully mimic human skin with J-shaped mechanical-behavior and tactile sensing attributes have not yet been reported. In this work, the skin-like hydrogel composite with J-shaped mechanical behavior and highly transparent, tactile, soft but strong, flexible, and stretchable attributes is developed as structural strain sensing element for e-skin. Piezo-resistive polyacrylamide (PAAm) hydrogel is used as supporting matrix to endow high transparency, softness, flexibility, stretch-ability and strain sensing capability desired for e-skin. Ultrahigh molecular weight polyethylene (UHMWPE) fiber with a wavy configuration is designed as reinforcement filler to provide the tunable strain-limiting effect. As a result, the as-prepared UHMWPE fiber/PAAm composite e-skin presents unique "J-shape" stress-strain behavior akin to human skin. And the PAAm composite can switch from supersoft to highly stiff in the designed strain range up to 100% with a prominent tensile strength of 48.3 MPa, which enables it to have the high stretch-ability and excellent load-bearing ability, simultaneously. Moreover, finite element model is developed to clarify the stress distribution and damage evolution for the UHMWPE fiber/PAAm composite during the tensile process. The PAAm composite exhibits not only an excellent strain sensing performance with a long-term reliability up to 5000 loading-unloading cycles but also an extraordinary softness and mechanical strength with a low initial modulus of 6.7 kPa, which is matchable with soft human epidermis. Finally, the e-skin is used for demonstrations in monitoring various human activities and protecting structural integrity in designed strain ranges. The strategy for reinforcing piezo-resistive hydrogel with wavy-shaped UHMWPE fibers proposed here is promising for the development of transparent, flexible, soft but strong e-skin with a tunable strain-limiting effect akin to human skin.

Human spinal GABA neurons alleviate spasticity and improve locomotion in rats with spinal cord injury.

Spinal cord injury (SCI) often results in spasticity. There is currently no effective therapy for spasticity. Here, we describe a method to efficiently differentiate human pluripotent stem cells from spinal GABA neurons. After transplantation into the injured rat spinal cord, the DREADD (designer receptors exclusively activated by designer drug)-expressing spinal progenitors differentiate into GABA neurons, mitigating spasticity-like response of the rat hindlimbs and locomotion deficits in 3 months. Administering clozapine-N-oxide, which activates the grafted GABA neurons, further alleviates spasticity-like response, suggesting an integration of grafted GABA neurons into the local neural circuit. These results highlight the therapeutic potential of the spinal GABA neurons for SCI.

PAX6D instructs neural retinal specification from human embryonic stem cell-derived neuroectoderm.

PAX6 is essential for neural retina (NR) and forebrain development but how PAX6 instructs NR versus forebrain specification remains unknown. We found that the paired-less PAX6, PAX6D, is expressed in NR cells during human eye development and along human embryonic stem cell (hESC) specification to retinal cells. hESCs deficient for PAX6D failed to enter NR specification. Induced expression of PAX6D but not PAX6A in a PAX6-null background restored the NR specification capacity. ChIP-Seq, confirmed by functional assays, revealed a set of retinal genes and non-retinal neural genes that are potential targets of PAX6D, including WNT8B. Inhibition of WNTs or knocking down of WNT8B restored the NR specification capacity of neuroepithelia with PAX6D knockout, whereas activation of WNTs blocked NR specification even when PAX6D was induced. Thus, PAX6D specifies neuroepithelia to NR cells via the regulation of WNT8B.

Development and Validation of a Multiparameterized Artificial Neural Network for Prostate Cancer Risk Prediction and Stratification.

PURPOSE: To develop and validate a multiparameterized artificial neural network (ANN) on the basis of personal health information for prostate cancer risk prediction and stratification. METHODS: The 1997 to 2015 National Health Interview Survey adult survey data were used to train and validate a multiparameterized ANN, with parameters including age, body mass index, diabetes status, smoking status, emphysema, asthma, race, ethnicity, hypertension, heart disease, exercise habits, and history of stroke. We developed a training set of patients ≥ 45 years of age with a first primary prostate cancer diagnosed within 4 years of the survey. After training, the sensitivity and specificity were obtained as functions of the cutoff values of the continuous output of the ANN. We also evaluated the ANN with the 2016 data set for cancer risk stratification. RESULTS: We identified 1,672 patients with prostate cancer and 100,033 respondents without cancer in the 1997 to 2015 data sets. The training set had a sensitivity of 21.5% (95% CI, 19.2% to 23.9%), specificity of 91% (95% CI, 90.8% to 91.2%), area under the curve of 0.73 (95% CI, 0.71 to 0.75), and positive predictive value of 28.5% (95% CI, 25.5% to 31.5%). The validation set had a sensitivity of 23.2% (95% CI, 19.5% to 26.9%), specificity of 89.4% (95% CI, 89% to 89.7%), area under the curve of 0.72 (95% CI, 0.70 to 0.75), and positive predictive value of 26.5% (95% CI, 22.4% to 30.6%). For the 2016 data set, the ANN classified all 13,031 patients into low-, medium-, and high-risk subgroups and identified 5% of the cancer population as high risk. CONCLUSION: A multiparameterized ANN that is based on personal health information could be used for prostate cancer risk prediction with high specificity and low sensitivity. The ANN can further stratify the population into three subgroups that may be helpful in refining prescreening estimates of cancer risk.

The Ubiquitin E3 Ligase TRAF6 Exacerbates Ischemic Stroke by Ubiquitinating and Activating Rac1.

Stroke is one of the leading causes of morbidity and mortality worldwide. Inflammation, oxidative stress, apoptosis, and excitotoxicity contribute to neuronal death during ischemic stroke; however, the mechanisms underlying these complicated pathophysiological processes remain to be fully elucidated. Here, we found that the expression of tumor necrosis factor receptor-associated factor 6 (TRAF6) was markedly increased after cerebral ischemia/reperfusion (I/R) in mice. TRAF6 ablation in male mice decreased the infarct volume and neurological deficit scores and decreased proinflammatory signaling, oxidative stress, and neuronal death after cerebral I/R, whereas transgenic overexpression of TRAF6 in male mice exhibited the opposite effects. Mechanistically, we demonstrated that TRAF6 induced Rac1 activation and consequently promoted I/R injury by directly binding and ubiquitinating Rac1. Either functionally mutating the TRAF6 ubiquitination site on Rac1 or inactivating Rac1 with a specific inhibitor reversed the deleterious effects of TRAF6 overexpression during I/R injury. In conclusion, our study demonstrated that TRAF6 is a key promoter of ischemic signaling cascades and neuronal death after cerebral I/R injury. Therefore, the TRAF6/Rac1 pathway might be a promising target to attenuate cerebral I/R injury.SIGNIFICANCE STATEMENT Stroke is one of the most severe and devastating neurological diseases globally. The complicated pathophysiological processes restrict the translation of potential therapeutic targets into medicine. Further elucidating the molecular mechanisms underlying cerebral ischemia/reperfusion injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study revealed that ischemia-induced tumor necrosis factor receptor-associated factor 6 (TRAF6) upregulation binds and ubiquitinates Rac1 directly, which promotes neuron death through neuroinflammation and neuro-oxidative signals. Therefore, precisely targeting the TRAF6-Rac1 axis may provide a novel therapeutic strategy for stroke recovery.