Consistent signatures in the human gut microbiome of old- and young-onset colorectal cancer.

The incidence of young-onset colorectal cancer (yCRC) has been increasing in recent decades, but little is known about the gut microbiome of these patients. Most studies have focused on old-onset CRC (oCRC), and it remains unclear whether CRC signatures derived from old patients are valid in young patients. To address this, we assembled the largest yCRC gut metagenomes to date from two independent cohorts and found that the CRC microbiome had limited association with age across adulthood. Differential analysis revealed that well-known CRC-associated taxa, such as Clostridium symbiosum, Peptostreptococcus stomatis, Parvimonas micra and Hungatella hathewayi were significantly enriched (false discovery rate <0.05) in both old- and young-onset patients. Similar strain-level patterns of Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were observed for oCRC and yCRC. Almost all oCRC-associated metagenomic pathways had directionally concordant changes in young patients. Importantly, CRC-associated virulence factors (fadA, bft) were enriched in both oCRC and yCRC compared to their respective controls. Moreover, the microbiome-based classification model had similar predication accuracy for CRC status in old- and young-onset patients, underscoring the consistency of microbial signatures across different age groups.

Long-Term Outcomes of dMMR/MSI-H Rectal Cancer Treated With Anti-PD-1-Based Immunotherapy as Curative-Intent Treatment.

BACKGROUND: Neoadjuvant anti-PD-1 therapy has shown encouraging efficacy in patients with deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) locally advanced rectal cancer (LARC), which suggests its potential as a curative-intent therapy and a promising treatment option for organ preservation. We aimed to investigate the long-term outcomes of patients with dMMR/MSI-H LARC who experienced clinical complete response (cCR) after anti-PD-1 therapy. METHODS: We retrospectively analyzed patients with dMMR/MSI-H LARC who achieved cCR and received nonoperative management following neoadjuvant anti-PD-1-based treatment from 4 Chinese medical centers. Patients were followed up for at least 1 year after they achieved cCR, their clinical data were collected, and survival outcomes were analyzed using the Kaplan-Meier method. RESULTS: A total of 24 patients who achieved cCR and received nonoperative management from March 2018 to May 2022 were included, with a median age of 51.0 years (range, 19.0-77.0 years). The median treatment course to reach cCR was 6.0 (range, 1.0-12.0). Fifteen patients (62.5%) continued their treatments after experiencing cCR, and the median treatment course was 17.0 (range, 3.0-36.0). No local regrowth or distant metastasis was observed in a median follow-up time of 29.1 months (range, 12.6-48.5 months) after cCR. The 3-year disease-free and overall survivals were both 100%. CONCLUSIONS: Patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR following anti-PD-1-based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate these findings.

Casticin ameliorates osteoarthritic cartilage damage in rats through PI3K/AKT/HIF-1α signaling.

Knee osteoarthritis (KOA) is a chronic, disabling knee joint lesion in which degeneration and defects in articular cartilage are the most important features. Casticin (CAS) is a flavonoid extracted from the Chinese herb Vitex species that has anti-inflammatory and antitumor effects. The aim of this study was to investigate the therapeutic and mechanistic effects of CAS on cartilage damage in KOA. A KOA rat model was established by anterior cruciate ligament transection (ACLT), and cartilage morphological changes were assessed by histological analysis and micro-CT scans. Subsequently, chondrocytes were treated with 10 ng/mL IL-1ß to establish an OA model. CCK-8 assays and EdU assays were performed to assess the viability of CAS-treated chondrocytes. Western blotting, flow cytometry and Hoechst 33342/PI Double Stain were used to detect chondrocyte apoptosis. Western blotting, qRT‒PCR and ELISA were used to detect changes in inflammatory mediators. In addition, cartilage matrix-related indices were detected by Western blotting, qRT‒PCR and immunofluorescence (IF) analysis. Immunohistochemistry (IHC) and Western blotting were performed to detect the expression of p-PI3K, p-AKT and HIF-1α in vivo and in vitro. Micro-CT, pathological sections and related scores showed that CAS improved the alterations in bony structures and reduced cartilage damage and osteophyte formation in the ACLT model. In vivo, CAS attenuated IL-1ß-induced cartilage matrix degradation, apoptosis and the inflammatory response. In addition, CAS inhibited the expression of the PI3K/AKT/HIF-1α signaling pathway in the ACLT animal model and IL-1ß cell model. CAS may ameliorate cartilage damage in OA by inhibiting the PI3K/AKT/HIF-1α signaling pathway, suggesting that CAS is a potential strategy for the treatment of OA.

Heat Shock Protein 22 Attenuates Nerve Injury-induced Neuropathic Pain Via Improving Mitochondrial Biogenesis and Reducing Oxidative Stress Mediated By Spinal AMPK/PGC-1α Pathway in Male Rats.

Heat shock protein 22 (hsp22) plays a significant role in mitochondrial biogenesis and redox balance. Moreover, it's well accepted that the impairment of mitochondrial biogenesis and redox imbalance contributes to the progress of neuropathic pain. However, there is no available evidence indicating that hsp22 can ameliorate mechanical allodynia and thermal hyperalgesia, sustain mitochondrial biogenesis and redox balance in rats with neuropathic pain. In this study, pain behavioral test, western blotting, immunofluorescence staining, quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Dihydroethidium staining are applied to confirm the role of hsp22 in a male rat model of spared nerve injury (SNI). Our results indicate that hsp22 was significantly decreased in spinal neurons post SNI. Moreover, it was found that intrathecal injection (i.t.) with recombinant heat shock protein 22 protein (rhsp22) ameliorated mechanical allodynia and thermal hyperalgesia, facilitated nuclear respiratory factor 1 (NRF1)/ mitochondrial transcription factor A (TFAM)-dependent mitochondrial biogenesis, decreased the level of reactive oxygen species (ROS), and suppressed oxidative stress via activation of spinal adenosine 5'monophosphate-activated protein kinase (AMPK)/ peroxisome proliferative activated receptor γ coactivator 1α (PGC-1α) pathway in male rats with SNI. Furthermore, it was also demonstrated that AMPK antagonist (compound C, CC) or PGC-1α siRNA reversed the improved mechanical allodynia and thermal hyperalgesia, mitochondrial biogenesis, oxidative stress, and the decreased ROS induced by rhsp22 in male rats with SNI. These results revealed that hsp22 alleviated mechanical allodynia and thermal hyperalgesia, improved the impairment of NRF1/TFAM-dependent mitochondrial biogenesis, down-regulated the level of ROS, and mitigated oxidative stress through stimulating the spinal AMPK/PGC-1α pathway in male rats with SNI.

Matrix metalloproteinases as attractive therapeutic targets for chronic pain: A narrative review.

Chronic pain constitutes an abnormal pain state that detrimentally affects the quality of life, daily activities, occupational performance, and stability of mood. Despite the prevalence of chronic pain, effective drugs with potent abirritation and minimal side effects remain elusive. Substantial studies have revealed aberrant activation of the matrix metalloproteinases (MMPs) in multiple chronic pain models. Additionally, emerging evidence has demonstrated that the downregulation of MMPs can alleviate chronic pain in diverse animal models, underscoring the unique and crucial role of MMPs in different stages and types of chronic pain. This review delves into the mechanistic insights and roles of MMPs in modulating chronic pain. The aberrant activation of MMPs has been linked to neuropathic pain through mechanisms involving myelin abnormalities in peripheral nerve and spinal dorsal horn (SDH), hyperexcitability of dorsal root ganglion (DRG) neurons, activation of N-methyl-d-aspartate receptors (NMDAR) and Ca2+-dependent signals, glial cell activation, and proinflammatory cytokines release. Different MMPs also contribute significantly to inflammatory pain and cancer pain. Furthermore, we summarized the substantial therapeutic potential of MMP pharmacological inhibitors across different types of chronic pain. Overall, our findings underscore the promising therapeutic prospects of MMPs targeting for managing chronic pain.

Interleukin-17: A Putative Novel Pharmacological Target for Pathological Pain.

Pathological pain imposes a huge burden on the economy and the lives of patients. At present, drugs used for the treatment of pathological pain have only modest efficacy and are also plagued by adverse effects and risk for misuse and abuse. Therefore, understanding the mechanisms of pathological pain is essential for the development of novel analgesics. Several lines of evidence indicate that interleukin-17 (IL-17) is upregulated in rodent models of pathological pain in the periphery and central nervous system. Besides, the administration of IL-17 antibody alleviated pathological pain. Moreover, IL-17 administration led to mechanical allodynia which was alleviated by the IL-17 antibody. In this review, we summarized and discussed the therapeutic potential of targeting IL-17 for pathological pain. The upregulation of IL-17 promoted the development of pathological pain by promoting neuroinflammation, enhancing the excitability of dorsal root ganglion neurons, and promoting the communication of glial cells and neurons in the spinal cord. In general, the existing research shows that IL-17 is an attractive therapeutic target for pathologic pain, but the underlying mechanisms still need to be investigated.

Epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China: a hospital-based retrospective study.

Traumatic spinal cord injury is potentially catastrophic and can lead to permanent disability or even death. China has the largest population of patients with traumatic spinal cord injury. Previous studies of traumatic spinal cord injury in China have mostly been regional in scope; national-level studies have been rare. To the best of our knowledge, no national-level study of treatment status and economic burden has been performed. This retrospective study aimed to examine the epidemiological and clinical features, treatment status, and economic burden of traumatic spinal cord injury in China at the national level. We included 13,465 traumatic spinal cord injury patients who were injured between January 2013 and December 2018 and treated in 30 hospitals in 11 provinces/municipalities representing all geographical divisions of China. Patient epidemiological and clinical features, treatment status, and total and daily costs were recorded. Trends in the percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department and cost of care were assessed by annual percentage change using the Joinpoint Regression Program. The percentage of traumatic spinal cord injuries among all hospitalized patients and among patients hospitalized in the orthopedic department did not significantly change overall (annual percentage change, -0.5% and 2.1%, respectively). A total of 10,053 (74.7%) patients underwent surgery. Only 2.8% of patients who underwent surgery did so within 24 hours of injury. A total of 2005 (14.9%) patients were treated with high-dose (≥ 500 mg) methylprednisolone sodium succinate/methylprednisolone (MPSS/MP); 615 (4.6%) received it within 8 hours. The total cost for acute traumatic spinal cord injury decreased over the study period (-4.7%), while daily cost did not significantly change (1.0% increase). Our findings indicate that public health initiatives should aim at improving hospitals' ability to complete early surgery within 24 hours, which is associated with improved sensorimotor recovery, increasing the awareness rate of clinical guidelines related to high-dose MPSS/MP to reduce the use of the treatment with insufficient evidence.

Involvement of the heat shock response (HSR) regulatory pathway in cadmium-elicited cerebral damage.

The heat shock response (HSR) is a cellular protective mechanism that is characterized by the induction of heat shock transcription factors (HSFs) and heat shock proteins (HSPs) in response to diverse cellular and environmental stressors, including cadmium (Cd). However, little is known about the relationship between the damaging effects of Cd and the HSR pathway in the chicken cerebrum following Cd exposure. To explore whether Cd exposure elicits cerebral damage and triggers the HSR pathway, chicks were exposed to Cd in the daily diet at different concentrations (35, 70, or 140 mg/kg feed) for 90 days, while a control group was fed the standard diet without Cd. Histopathological examination of cerebral tissue from Cd-exposed chickens showed neuronal damage, as evidenced by swelling and degeneration of neurons, loss of neurons, and capillary damage. Cd exposure significantly increased mRNA expression of HSF1, HSF2, and HSF3, and mRNA and protein expression of three major stress-inducible HSPs (HSP60, HSP70, and HSP90). Moreover, Cd exposure differentially modulated mRNA expression of small HSP (sHSPs), most notably reducing expression of HSP27 (HSPB1). Furthermore, Cd exposure increased TUNEL-positive neuronal apoptotic cells and up-regulated protein expression of caspase-1, caspase-8, caspase-3, and p53, leading to apoptosis. Taken together, these data demonstrate that activation of the HSR and apoptotic pathways by Cd exposure is involved in Cd-elicited cerebral damage in the chicken. Synopsis for the graphical abstract Cadmium (Cd)-induced neuronal damage triggers the heat shock response (HSR) by activating heat shock transcription factors (HSFs) and subsequent induction of major heat shock proteins (notably, HSP60, HSP70, and HSP90). Moreover, Cd exposure activates caspase-1, caspase-8, caspase-3, and p53 protein, thereby resulting in neuronal apoptosis in the chicken brain.

Astragaloside IV relieves IL-1ß-induced human nucleus pulposus cells degeneration through modulating PI3K/Akt signaling pathway.

BACKGROUND: Intervertebral disc degeneration (IDD) is a multifactorial disease that is associated with nucleus pulposus (NP) apoptosis and extracellular matrix (ECM) degeneration and inflammation. Astragaloside IV (AS IV) has antioxidant, free radical scavenging, anti-inflammatory and anti-apoptosis effects. This study was to investigate whether AS IV could inhibit IL-1ß-mediated apoptosis of HNP cells and its possible signal transduction pathway. METHODS: Human nucleus pulposus cells (HNPCs) were stimulated with AS IV or LY294002 (PI3K inhibitor), followed by exposure to IL-1ß for 24 hours. CCK8, TUNEL analysis and flow cytometry, ELISA and Western blotting were used to analyze the effects of AS IV on cell proliferation, apoptosis, inflammation, ECM and PI3K/Akt pathway signaling path-related proteins in IL-1ß-induced HNPCs. RESULTS: Compared with IL-1ß-induced HNPCs, AS IV could improve the proliferation activity and the expressions of Collagen II, Aggrecan and Bcl-2 proteins, inhibit the apoptosis rate, inflammation and Bax and cleaved caspase-3 protein expression, and increase the activity of PI3K/Akt pathway. LY294002 attenuated the protective effect of AS IV against IL-1ß-induced HNPCs degeneration. CONCLUSION: AS IV can inhibit IL-1ß-induced HNPCs apoptosis inflammation and ECM degeneration by activating PI3K/Akt signaling pathway, which can be an effective drug to reduce disc degeneration.

Efficacy of PD-1 inhibitors for colorectal cancer and polyps in Lynch syndrome patients.

BACKGROUND: Programmed death-1 (PD-1) inhibitor is effective for colorectal cancer (CRC) with deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H). We aimed to explore its effects on CRCs and colonic polyps in Lynch syndrome (LS) patients. METHODS: LS patients with CRC who had evaluable tumours and received at least 2 cycles of PD-1 inhibitors were retrospectively included. PD-1 inhibitors were given as a monotherapy or in combination with other therapies, including anticytotoxic T-lymphocyte-associated antigen-4 treatment, radiotherapy, chemotherapy, and targeted therapy. Correlations of treatment responses with clinicopathological characteristics and genomic profiles were analysed. RESULTS: A total of 75 LS patients were included, with a median age of 39 years. The median duration of follow-up was 27 months (range, 3-71). The objective response rate (ORR) was 70.7%, including 28.0% (n = 21) complete responses and 42.7% (n = 32) partial responses. Four of five cases of LS CRCs displaying proficient MMR (pMMR) or microsatellite stable (MSS) were not responsive. Mucinous/signet-ring cell differentiation was associated with a lower ORR (P = 0.013). The 3-year overall survival and progression-free survival were 91.2% and 82.2%, respectively. A polyp was detected in 26 patients during surveillance. Seven adenomas disappeared after treatment, and they were all larger than 7 mm. CONCLUSION: PD-1 inhibitors are highly effective for dMMR and MSI-H LS CRCs, but not for pMMR or MSS LS CRCs or mucinous/signet-ring cell CRC. Large LS adenomas may also be eliminated by anti-PD-1 treatment. DATA AVAILABILITY STATEMENT: Due to the privacy of patients, the related data cannot be available for public access but can be obtained from Pei-Rong Ding (dingpr@sysucc.org.cn) upon reasonable request. The key raw data have been uploaded to the Research Data Deposit public platform (www.researchdata.org.cn).

L-carnitine alleviates synovitis in knee osteoarthritis by regulating lipid accumulation and mitochondrial function through the AMPK-ACC-CPT1 signaling pathway.

BACKGROUND: Knee osteoarthritis (KOA) is a disability-associated condition that is rapidly growing with the increase in obesity rates worldwide. There is a pressing need for precise management and timely intervention in the development of KOA. L-carnitine has been frequently recommended as a supplement to increase physical activity in obese individuals due to its role in fatty acid metabolism, immune disorders, and in maintaining the mitochondrial acetyl-CoA/CoA ratio. In this study, we aimed to investigate the anti-inflammatory effects of L-carnitine on KOA and delineate a potential molecular mechanism. METHODS: Lipopolysaccharide-stimulated primary rat fibroblast-like synoviocytes (FLS) were treated with an AMP-activated protein kinase (AMPK) inhibitor or siRNA and carnitine palmitoyltransferase 1 (CPT1) siRNA to examine the synovial protective effects of L-carnitine. An anterior cruciate ligament transection model of rats was treated with an AMPK agonist (metformin) and CPT1 inhibitor (etomoxir) to define the therapeutic effects of L-carnitine. RESULTS: L-carnitine displayed a protective effect against synovitis of KOA in vitro and in vivo experiments. Specifically, L-carnitine treatment can reduce synovitis by inhibiting AMPK-ACC-CPT1 pathway activation and showed an increase in fatty acid ß-oxidation, a lower lipid accumulation, and a noticeable improvement in mitochondrial function. CONCLUSIONS: Our data suggested that L-carnitine can mitigate synovitis in FLS and synovial tissue, and the underlying mechanism may be related to improving mitochondrial function and reducing lipid accumulation via the AMPK-ACC-CPT1 signaling pathway. Therefore, L-carnitine may be a potential treatment strategy for KOA.

Resveratrol protects against cadmium-induced cerebrum toxicity through modifications of the cytochrome P450 enzyme system in microsomes.

BACKGROUND: Cadmium (Cd), known as a vital contaminant in the environment, penetrates the blood-brain barrier and accumulates in the cerebrum. Acute toxicosis of Cd, which leads to lethal cerebral edema, intracellular accumulation and cellular dysfunction, remains to be illuminated with regard to the exact molecular mechanism of cerebral toxicity. Resveratrol (RES), present in the edible portions of numerous plants, is a simply acquirable and correspondingly less toxic natural compound with neuroprotective potential, which provides some theoretical bases for antagonizing Cd-induced cerebral toxicity. RESULTS: This work was executed to research the protective effects of RES against Cd-induced toxicity in chicken cerebrum. Markedly, these lesions were increased in the Cd group, which also exhibited a thinner cortex, reduced granule cells, vacuolar degeneration, and an enlarged medullary space in the cerebrum. Furthermore, Cd induced CYP450 enzyme metabolism disorders by disrupting the nuclear xenobiotic receptor response (NXRs), enabling the cerebrum to reduce the ability to metabolize exogenous substances, eventually leading to Cd accumulation. Meanwhile, accumulated Cd promoted oxidative damage and synergistically promoted the damage to neurons and glial cells. CONCLUSION: RES initiated NXRs (especially for aromatic receptor and pregnancy alkane X receptor), decreasing the expression of CYP450 genes, changing the content of CYP450, maintaining CYP450 enzyme normal activities, and exerting antagonistic action against the Cd-induced abnormal response of nuclear receptors. These results suggest that the cerebrum toxicity caused by Cd was reduced by pretreatment with RES. © 2023 Society of Chemical Industry.

Comparison of Half-Effective Concentration of Propofol in Patients with Parkinson's Disease and Non-Parkinson's Disease.

Objective: This study aimed to compare the half-effective concentration (EC50) of propofol required for the bispectral index (BIS) 50 in patients with Parkinson's disease (PD) and non-PD (NPD) during induction by the Dixon's improved sequential method. Methods: This prospective study recruited 20 patients with PD undergoing deep brain stimulation and 20 patients with NPD accompanied by meningioma or glioma undergoing intracranial surgery from March 2018 to March 2019. The patients were induced by propofol via target-controlled infusion. The target effect-site concentration of propofol was determined by the Dixon's improved sequential method. The results of the pilot experiment showed that the target effect-site concentration for the first patient with PD and NPD was 3.5 µg/mL and 2.8 µg/mL, respectively. BIS values were recorded after achieving a constant effect-site concentration of propofol. The increment or decrement of the target effect-site concentration of the next patient was 0.1 µg/mL. Results: Demographic data, general physical condition, and hemodynamic values were similar between the PD and the NPD groups. The target effect-site concentration of propofol induction doses was significantly higher in the PD group than in the NPD group. The EC50 of propofol required for BIS 50 was 3.213 µg/mL [95% confidence interval (CI), 3.085-3.287 µg/mL] in the PD group and 2.77 µg/mL (95% CI, 2.568-2.977 µg/mL) in the NPD group. Conclusion: The EC50 of propofol required for BIS 50 was higher in patients with PD than in patients with NPD.

Psychosocial Factors Associated With Physical Activity Among Low-Income Overweight or Obese Mothers with Young Children.

PURPOSE: Investigate the associations between psychosocial factors and physical activity. DESIGN: Secondary data analysis utilizing baseline data of a large-scale community-based randomized controlled lifestyle behavior intervention. SETTING: The Special Supplemental Program for Women, Infants, and Children in Michigan, USA. SUBJECTS: Low-income overweight or obese mothers with young children (N = 740, 65% response rate). MEASURES: Survey data were collected via phone interview. Predictors included self-efficacy, autonomous motivation, emotional coping, and social support. Self-reported leisure physical activity was the outcome variable. Covariates were age, race, smoking, employment, education, body mass index, and postpartum status. ANALYSIS: A multiple linear regression model was applied. RESULTS: Self-efficacy (ß = .32, 95% CI = .11, .52, P = .003) and autonomous motivation (ß = .10, 95% CI = .03, .17, P = .005) were positively associated with physical activity. However, emotional coping and social support were not associated with physical activity. CONCLUSION: Future research should examine the longitudinal association of key psychosocial factors with physical activity.

Identification of three small nucleolar RNAs (snoRNAs) as potential prognostic markers in diffuse large B-cell lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a non-Hodgkin lymphoma with high mortality rates. Small nucleolar RNAs (snoRNAs) are tumor-specific biological markers, but there are few studies on the role of snoRNAs in DLBCL. MATERIALS AND METHODS: Survival-related snoRNAs were selected to construct a specific snoRNA-based signature via computational analyses (Cox regression and independent prognostic analyses) to predict the prognosis of DLBCL patients. To assist in clinical applications, a nomogram was built by combining the risk model and other independent prognostic factors. Pathway analysis, gene ontology analysis, transcription factor enrichment, protein-protein interactions, and single nucleotide variant analysis were used to explore the potential biological mechanisms of co-expressed genes. RESULTS: Twelve prognosis-correlated snoRNAs were selected from the DLBCL patient cohort of microarray profiles, and a three-snoRNA signature consisting of SNORD1A, SNORA60, and SNORA66 was constructed. DLBCL patients could be divided into high-risk and low-risk cohorts using the risk model, and the high-risk group and activated B cell-like (ABC) type DLBCL were linked with disappointing survival. In addition, SNORD1A co-expressed genes were inseparably linked to the biological functions of the ribosome and mitochondria. Potential transcriptional regulatory networks have also been identified. MYC and RPL10A were the most mutated SNORD1A co-expressed genes in DLBCL. CONCLUSION: Put together, our findings explored the potential biological effects of snoRNAs in DLBCL, and provided a new predictor for DLBCL prediction.

Neoadjuvant Immunotherapy Leads to Major Response and Low Recurrence in Localized Mismatch Repair-Deficient Colorectal Cancer.

BACKGROUND: Our study aimed to evaluate the efficacy and feasibility of neoadjuvant anti-PD-1 treatment for localized mismatch repair-deficient (dMMR) colorectal cancer (CRC). PATIENTS AND METHODS: The study cohort included patients with localized dMMR CRC who received PD-1 inhibitors as neoadjuvant therapy from 3 medical centers in Southern China. Main eligibility criteria included age between 18 and 75 years, ECOG performance status of 0 or 1, and receipt of ≥2 doses of PD-1 inhibitors. RESULTS: A total of 73 patients were included. Most of the tumors were locally advanced, including 19 (26.0%) T4a and 29 (39.7%) T4b. Most patients (79.5%) received PD-1 inhibitor monotherapy. Objective response per radiologic assessment was achieved in 62 (84.9%) patients, including 17 (23.3%) with complete response (CR) and 45 (61.6%) with partial response, with a median time to response of 9.6 weeks. Patients with T4a/4b disease had a similar response rate as those with T2-3 disease (84.0% vs 85.4%; P=.999). As of writing, a total of 50 patients have undergone surgery. Pathologic CR was achieved in most (57.1%) patients and remained high (59.5%) even among the 38 patients with T4a/4b disease. The 17 patients with CR did not undergo surgery and adopted a watch-and-wait strategy. After a median follow-up of 17.2 months (range, 3.4-45.1 months), the overall median recurrence-free and overall survivals were not reached. Among patients undergoing surgery or achieving CR, the 2-year tumor-specific disease-free and overall survival rates were both 100%. During neoadjuvant treatment, grade 3-4 adverse events occurred in 8 patients; 4 required acute intervention. Severe postoperative complications were recorded in 4 patients, 3 of whom required a second surgery. CONCLUSIONS: Neoadjuvant therapy with PD-1 blockade is highly effective for localized dMMR CRC, with an acceptable safety profile and low recurrence rate. This treatment holds promise for becoming the new standard of care for localized dMMR CRCs.

Novel therapeutic strategy in the treatment of ossification of the ligamentum flavum associated with dural ossification.

PURPOSE: To investigate the imaging characteristics of thoracic ossification of ligamentum flavum (OLF) combined with dural ossification (DO) and the clinical efficacy of zoning laminectomy. METHOD: The clinical data of 48 patients with thoracic OLF combined with DO who underwent zoning laminectomy between June 2016 and May 2020 were retrospectively analyzed. The modified Japanese Orthopedic Association (mJOA) score was used to evaluate neurological function before and after surgery, and the clinical efficacy was evaluated according to the improvement rate. RESULTS: The symptoms of all patients significantly improved after the operation, and the average follow-up time was 27.8 (10-47) months. In addition, the average mJOA score had increased from 5.0 (2-8) preoperatively to 8.7 (6-11) postoperatively (t = 18.880, P < 0.05). The average improvement rate was 62.6% (25-100%), with 16 patients graded as excellent, 21 as good, and 11 as fair. Cerebrospinal fluid leakage occurred in 12 cases (25.0%), and all of them healed well after treatment. No postoperative aggravation of neurological dysfunction, wound infection or hematoma occurred. At the last follow-up, there was no recurrence of symptoms and kyphosis. CONCLUSION: The Zoning laminectomy described here is both safe and effective.

The effect of off-hours hip surgery on patients' outcomes: a RECORD-compliant retrospective, propensity score-matched cohort study.

BACKGROUND: Off-hours working may have negative impacts on the performance of clinicians, leading to possible adverse outcomes of patients. We aimed to explore the impact of off-hours hip surgery on early postoperative outcomes. METHODS: All patients who underwent hip surgery between January 2015, and December 2020 in our hospital were evaluated in this retrospective cohort study. We measured in-hospital mortality, some postoperative complications, and some intraoperative prognostic indicators. Propensity score matching (PSM) was used to adjust for confounding baseline factors. RESULTS: We identified 143 patients in the original cohort. After PSM, 266 patients in the on-hours group were matched with 105 similar patients in the off-hours group. Compared with the on-hours group, the off-hours group had more general anesthesia (81.0% vs. 62.4%; RR, 1.30; 95% CI, 1.14 to 1.48; P=0.001), higher amount of intraoperative CRBC (0 U [0-2] vs. 0 U [0-0]; P=0.032) and FFP transfusion (0 mL [0-150] vs. 0 mL [0-0]; P=0.005), higher dosage of intraoperative sufentanil (24.5±14.5 µg vs. 20.7±13.9 µg; P=0.020), higher incidence of postoperative renal dysfunction (13.3% vs. 6.4%; RR, 2.09; 95% CI, 1.07 to 4.08; P=0.029), hypotension (2.9% vs. 0%; P=0.022), and hypoxemia (3.8% vs. 0.4%; RR, 10.13; 95% CI, 1.15 to 89.61; P=0.024), and higher in-hospital mortality (2.9% vs. 0%; P=0.022). CONCLUSIONS: Off-hours hip surgery was associated with adverse early postoperative prognosis, suggesting that more attention should be paid to off-hours hip surgery.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Nano-Selenium Antagonized Cadmium-Induced Liver Fibrosis in Chicken.

Cadmium is a global ecological toxic pollutant; in animals, hepatotoxic fibrosis is caused by bioaccumulation of Cd through food chains. We determined the path of nano-Se antagonism in Cd-induced hepatocyte pyroptosis by targeting the APJ-AMPK-PGC1α pathway, using an in vivo model of hepatotoxicity. All 1-day-old chicks were treated with Cd (140 mg/kg BW/day) and/or nano-Se (0.3 or 0.6 mg/kg BW/day) for 90 days. The result showed that Cd (1.55 ± 0.148) activated NLRP3 inflammasome 49.903% as compared to the Con group (1.034 ± 0.008) to release the inflammasome as a result of hepatocyte pyroptosis (2.824 ± 0.057). Compared with the Con group (1.010 ± 0.021), Kupffer cells were 219.109% more to activate astrocytes through the APJ-AMPK-PGC1α pathway, resulting in 185.149% more hepatic fibrosis. However, the fibrosis degree of the H-Se + Cd group (1.252 ± 0.056) was 56.5278% (p < 0.001) lower than that of the Cd group (2.880 ± 0.124). Therefore, this study established that pyroptotic hepatocytes and Kupffer cells could be targeted for nano-Se antagonizing Cd toxicity, which reveals a potential new approach targeting astrocytes for the treatment of liver fibrosis triggered by Cd pollution.