Psoas attenuation is associated with early postoperative complications in geriatric patients undergoing multilevel lumbar fusion surgery for degenerative lumbar spinal stenosis.

BACKGROUND: Morphometric analysis of the psoas major muscle has shown utility in predicting postoperative morbidity in various surgical fields, but its usefulness in predicting complications in elderly patients undergoing multilevel lumbar fusion surgery has not been studied. The study aimed to investigate if psoas major parameters are independent risk factors of early postoperative complication among elderly patients. METHODS: Patients who underwent multilevel lumbar fusion for degenerative lumbar spinal stenosis (DLSS) were included. The psoas major was measured at the lumbar 3/4 intervertebral disc level in three ways on computed tomography image: psoas muscle mass index, mean muscle attenuation, and morphologic change of the psoas major. Early complications were graded using the Clavien-Dindo classification system and the Comprehensive complication index (CCI). A CCI ≥ 26.2 indicated severe complications. Logistic regression was performed to identify independent risk factors. RESULTS: This retrospective study reviewed 108 patients (mean age 70.9 years, female to male ratio 1.8:1). Complications were observed in 72.2% of patients, with allogeneic blood transfusion being the most frequent (66.7%), followed by wound infection, acute heart failure (2.8% each). Severe complications occurred in 13.9% of patients. After multivariable regression analysis, those in the lowest psoas muscle attenuation tertile had higher odds of experiencing early postoperative complications (OR: 3.327, 95% CI 1.134-9.763, p = 0.029) and severe complications (OR: 6.964, 95% CI 1.928-25.160, p = 0.003). CONCLUSION: The psoas muscle attenuation can be used as a predictor of early postoperative complications in elderly patients undergoing multilevel lumbar fusion surgery for DLSS.

Cyclin-dependent kinase 12 deficiency reprogrammes cellular metabolism to alleviate ferroptosis potential and promote the progression of castration-resistant prostate cancer.

BACKGROUND: Cyclin-dependent kinase 12 (CDK12)-deficient prostate cancer defines a subtype of castration-resistant prostate cancer (CRPC) with a poor prognosis. Current therapy, including PARP inhibitors, shows minimal treatment efficacy for this subtype of CRPC, and the underlying mechanism remains elusive. METHODS: Based on bioinformatics analysis, we evaluated the relationship between CDK12 deficiency and prostate cancer patient's prognosis and treatment resistance. Furthermore, we used CRISPR-Cas9 technology and mass spectrometry-based metabolomic profiling to reveal the metabolic characteristics of CDK12-deficient CRPC. To elucidate the specific mechanisms of CDK12 deficiency-mediated CRPC metabolic reprogramming, we utilized cell RNA-seq profiling and other molecular biology techniques, including cellular reactive oxygen species probes, mitochondrial function assays, ChIP-qPCR and RNA stability analyses, to clarify the role of CDK12 in regulating mitochondrial function and its contribution to ferroptosis. Finally, through in vitro drug sensitivity testing and in vivo experiments in mice, we identified the therapeutic effects of the electron transport chain (ETC) inhibitor IACS-010759 on CDK12-deficient CRPC. RESULTS: CDK12-deficient prostate cancers reprogramme cellular energy metabolism to support their aggressive progression. In particular, CDK12 deficiency enhanced the mitochondrial respiratory chain for electronic transfer and ATP synthesis to create a ferroptosis potential in CRPC cells. However, CDK12 deficiency downregulated ACSL4 expression, which counteracts the lipid oxidation stress, leading to the escape of CRPC cells from ferroptosis. Furthermore, targeting the ETC substantially inhibited the proliferation of CDK12-deficient CRPC cells in vitro and in vivo, suggesting a potential new target for the therapy of CDK12-deficient prostate cancer. CONCLUSIONS: Our findings show that energy and lipid metabolism in CDK12-deficient CRPC work together to drive CRPC progression and provide a metabolic insight into the worse prognosis of CDK12-deficient prostate cancer patients. KEY POINTS: CDK12 deficiency promotes castration-resistant prostate cancer (CRPC) progression by reprogramming cellular metabolism. CDK12 deficiency in CRPC leads to a more active mitochondrial electron transport chain (ETC), ensuring efficient cell energy supply. CDK12 phosphorylates RNA Pol II to ensure the transcription of ACSL4 to regulate ferroptosis. Mitochondrial ETC inhibitors exhibit better selectivity for CDK12-deficient CRPC cells, offering a promising new therapeutic approach for this subtype of CRPC patients.

Overcoming Endosomal Escape Barriers in Gene Drug Delivery Using De Novo Designed pH-Responsive Peptides.

A major challenge in using nanocarriers for intracellular drug delivery is their restricted capacity to escape from endosomes into the cytosol. Here, we significantly enhance the drug delivery efficiency by accurately predicting and regulating the transition pH (pH0) of peptides to modulate their endosomal escape capability. Moreover, by inverting the chirality of the peptide carriers, we could further enhance their ability to deliver nucleic acid drugs as well as antitumor drugs. The resulting peptide carriers exhibit versatility in transfecting various cell types with a high efficiency of up to 90% by using siRNA, pDNA, and mRNA. In vivo antitumor experiments demonstrate a tumor growth inhibition of 83.4% using the peptide. This research offers a potent method for the rapid development of peptide vectors with exceptional transfection efficiencies for diverse pathophysiological indications.

Predictors of achieving minimal clinically important difference in functional status for elderly patients with degenerative lumbar spinal stenosis undergoing lumbar decompression and fusion surgery.

OBJECTIVE: To identify the predictors for the achievement of minimal clinically important difference (MCID) in functional status among elderly patients with degenerative lumbar spinal stenosis (DLSS) undergoing lumbar decompression and fusion surgery. METHODS: Patients who underwent lumbar surgery for DLSS and had a minimum of 1-year follow-up were included. The MCID achievement threshold for the Oswestry Disability Index (ODI) was set at 12.8. General patient information and the morphology of lumbar paraspinal muscles were evaluated using comparative analysis to identify influencing factors. Multiple regression models were employed to identify predictors associated with MCID achievement. A receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cut-off values for predicting functional recovery. RESULTS: A total of 126 patients (46 males, 80 females; mean age 73.0 ± 5.9 years) were included. The overall rate of MCID achievement was 74.6%. Patients who achieved MCID had significantly higher psoas major muscle attenuation (43.55 vs. 39.23, p < 0.001) and preoperative ODI (51.5 vs. 41.6, p < 0.001). Logistic regression showed that elevated psoas major muscle attenuation (p = 0.001) and high preoperative ODI scores (p = 0.001) were independent MCID predictors. The optimal cut-off values for predicting MCID achievement were found to be 40.46 Hounsfield Units for psoas major muscle attenuation and 48.14% for preoperative ODI. CONCLUSION: Preoperative psoas major muscle attenuation and preoperative ODI were reliable predictors of achieving MCID in geriatric patients undergoing lumbar decompression and fusion surgery. These findings offer valuable insights for predicting surgical outcomes and guiding clinical decision-making in elderly patients.

YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer.

Ferroptosis is a regulated cell death process initiated by iron-dependent phospholipid peroxidation and is mainly suppressed by GPX4-dependent and FSP1-dependent surveillance mechanisms. However, how the ferroptosis surveillance system is regulated during cancer development remains largely unknown. Here, we report that the YTHDC1-mediated m6A epigenetic regulation of FSP1 alleviates the FSP1-dependent ferroptosis suppression that partially contributes to the tumor suppressive role of YTHDC1 in lung cancer progression. YTHDC1 knockdown promoted the lung tumor progression and upregulated FSP1 protein level that resulted in ferroptosis resistance of lung cancer cells. Silencing FSP1 abrogated YTHDC1 knockdown-induced proliferation increase and ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruited the alternative polyadenylation regulator CSTF3 to generate a less stable shorter 3'-UTR contained FSP1 mRNA, whereas YTHDC1 downregulation generated the longer 3'-UTR contained FSP1 mRNA that is stabilized by RNA binding protein HuR and thus led to the enhanced FSP1 protein level. Therefore, our findings identify YTHDC1 as a tumor progression suppressor in lung cancer and a ferroptosis regulator through modulating the FSP1 mRNA stability and thus suggest a ferroptosis-related therapeutic option for YTHDC1high lung cancer.

Topical Dihydroartemisinin Improves Wound Healing in Diabetic Mice.

Impaired skin wound healing is a common complication of diabetes mellitus. Angiogenesis is a critical step in wound healing because it allows oxygen and nutrients to reach the injured area, thereby promoting wound cell proliferation, re-epithelialisation, and collagen regeneration. However, the neovascularisation ability of patients with diabetes often decreases. Therefore, finding ways to improve diabetic angiogenesis is important for treating diabetic wounds that do not heal. To the best of our knowledge, it is unclear whether dihydroartemisinin (DHA) affects diabetic wounds. This study sought to determine how topical DHA affects the healing of diabetic wounds and how it is related to markers of angiogenesis. We topically applied DHA to full-thickness cutaneous lesions in a streptozotocin (STZ)-induced diabetic mouse model. Under a fluorescence microscope, the pathological morphology of the wound skin was observed, together with the positive expression of platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF). Western blotting was used to determine the CD31 and VEGF protein expression levels. The mRNA expression was determined using qualitative real-time polymerase chain reaction (qRT-PCR). We found that DHA can improve the expression of CD31 and VEGF, and accelerate wound healing in diabetic mice. We believe that DHA promotes angiogenesis, which is associated with increased VEGF signalling in vivo. Therefore, DHA can effectively accelerate the process of diabetic wound healing by promoting angiogenesis, implying that DHA may be used as a topical drug for the treatment of diabetic wounds.

Correlation of psoas major muscle morphology with function and clinical symptoms in patients with symptomatic multilevel lumbar spinal stenosis.

OBJECTIVE: This study was performed to quantify the morphological characteristics of the psoas major muscle in patients with symptomatic multilevel degenerative lumbar spinal stenosis (SMLSS) and assess the correlations of these morphological characteristics with function and clinical symptoms. METHODS: One hundred fourteen patients diagnosed with SMLSS (≥ 3 segments) were included. The patients' presenting symptoms were assessed with the Oswestry Disability Index (ODI), and visual analogue scale (VAS) scores were recorded. The morphology of the psoas major was evaluated at the L3/4 intervertebral disc level in three ways: by measuring (i) the psoas muscle mass index (PMI); (ii) the mean muscle attenuation (Hounsfield units, HU); and (iii) the morphologic change of the psoas major (mean ratios of the short axis to the long axis of the bilateral psoas major). RESULTS: Men had a higher PMI than women (p = 0.001). Patients with severe disability had a significantly lower PMI (p = 0.002) and muscle attenuation (p = 0.001). The PMI and muscle attenuation were significantly higher in the patients with no or mild back pain (both p < 0.001). In the univariable and multivariable analyses, a greater HU value was associated with a higher functional status as assessed by the ODI (p = 0.002), and a higher PMI was associated with less severe back pain as measured by the VAS score (p < 0.001). CONCLUSION: This study showed that muscle attenuation of psoas major positively correlated with the functional status and PMI negatively correlated with low back pain severity in patients diagnosed with SMLSS. Future prospective studies are needed to evaluate whether improvement in such muscle parameters through physiotherapy programs can alleviate the clinical symptoms and improve the functional status of patients with SMLSS.

A potassium-chloride co-transporter promotes tumor progression and castration resistance of prostate cancer through m6A reader YTHDC1.

SLC12A5, a neuron-specific potassium-chloride co-transporter, has been reported to promote tumor progression, however, the underlying mechanism remains unclear. Here we report that SLC12A5 functions as an oncogene to promote tumor progression and castration resistance of prostate cancer through the N6-methyladenosine (m6A) reader YTHDC1 and the transcription factor HOXB13. We have shown that the level of SLC12A5 was increased in prostate cancer, in comparison to its normal counterparts, and further elevated in castration-resistant prostate cancer (CRPC). The enhanced expression of SLC12A5 mRNA was associated with neuroendocrine prostate cancer (NEPC) progression and poor survival in prostate cancer. Furthermore, we demonstrated that SLC12A5 promoted the castration resistance development of prostate cancer in addition to the cell proliferation and migration. Interestingly, SLC12A5 was detected in the cell nucleus and formed a complex with nuclear m6A reader YTHDC1, which in turn upregulated HOXB13 to promote the prostate cancer progression. Therefore, our findings reveal a mechanism that how the potassium-chloride cotransporter SLC12A5 promotes the tumor progression and provide a therapeutic opportunity for prostate cancer to apply the neurological disorder drug SLC12A5 inhibitors.

H2AFX might be a prognostic biomarker for hepatocellular carcinoma.

BACKGROUND: H2AFX can play a central role in DNA repair, replication, transcription regulation, and chromosomal stability. However, there is little research to explore the expression of H2AFX in cancers. Moreover, the correlation between the expression of H2AFX and tumor immunity, which affects the prognosis of hepatocellular carcinoma (HCC), is not clear. This article aimed to observe the correlation between H2AFX and tumor tissue infiltration biomarkers in HCC and its prognostic potential in HCC. METHOD: Oncomine and TIMER database were used to assess the expression level of H2AFX mRNA, and GEPIA and Kaplan-Meier databases were used to evaluate its prognostic potential. The TIMER database analyzed the relationship between h2afx expression level and tumor immune cell infiltration markers in liver cancer tissues. RESULTS: The results showed that H2AFX was overexpressed in tumor tissues than normal tissues in HCC via analysis, and its expression level was correlated with the survival rate of HCC. Moreover, the expression level of H2AFX was related to various immune biomarkers. These results show that overexpression of H2AFX would reflect the poor prognosis of HCC, and these would also reflect that the gene H2AFX can affect the infiltration of HCC immune cells and then play a role in regulating tumor immunity. CONCLUSION: Our study showed that the gene H2AFX might be a potential poor prognostic biomarker in HCC and might be involved in the infiltration of HCC immune cells.

Androgen Metabolism and Response in Prostate Cancer Anti-Androgen Therapy Resistance.

All aspects of prostate cancer evolution are closely related to androgen levels and the status of the androgen receptor (AR). Almost all treatments target androgen metabolism pathways and AR, from castration-sensitive prostate cancer (CSPC) to castration-resistant prostate cancer (CRPC). Alterations in androgen metabolism and its response are one of the main reasons for prostate cancer drug resistance. In this review, we will introduce androgen metabolism, including how the androgen was synthesized, consumed, and responded to in healthy people and prostate cancer patients, and discuss how these alterations in androgen metabolism contribute to the resistance to anti-androgen therapy.

Characteristics of catechin loading rice porous starch/chitosan functional microsphere and its adsorption towards Pb2.

In this paper, we explore the adsorption potential of catechin (CT) loaded composite microspheres and provide a new micron scale carrier of functional factor. Chitosan (CS) modified rice porous starch (RPS/CS) was used as a CT adsorption carrier to prepare bioactive CT-loaded composite microspheres (CT@RPS/CS). The adsorption kinetics, storage characteristics, and biological activity maintenance of CT@RPS/CS were studied in an aqueous solution, and the sustained-release characteristics of CT@RPS/CS were studied in vitro during simulated gastrointestinal digestion. An aqueous solution further studied the removal characteristics of adsorbed heavy metal ion Pb2+. RPS/CS can significantly improve the ability to adsorb CT. RPS/CS can also significantly improve CT's storage stability, antioxidant stress, and slow-release characteristics, and the sustained release effect in gastric and intestinal juice. CT@RPS/CS can be removed Pb2+ by adsorbing in the solution, and their adsorption was physical adsorption and chemisorption, but the primary interaction is chemisorption. CT@RPS/CS can be used as a micron carrier of new food functional factors, which has potential space for improving and expanding the functional characteristics of its loaded functional factors and the endowing of new functions.

Which sagittal evaluation system can effectively predict mechanical complications in the treatment of elderly patients with adult degenerative scoliosis? Roussouly classification or Global Alignment and Proportion (GAP) Score.

BACKGROUND: To achieve the proper sagittal alignment, previous studies have developed different assessment systems for adult degenerative scoliosis (ADS) which could help the spine surgeon in making treatment strategies. The purpose of our study is to evaluate whether Roussouly classification or global alignment and proportion (GAP) score is more appropriate in the prediction of mechanical complications after surgical treatment of ADS. METHODS: ADS patients who received long segmental fusion in the treatment during the period from December 2016 to December 2018 were evaluated in this study. Basic information and radiologic measurements were collected for analysis. Patients were divided into two groups according to occurrence or absence of mechanical complications for comparison. Mechanical complications included proximal junctional kyphosis (PJK), proximal junctional failure (PJF). GAP categories divided GAP score into proportioned spinopelvic position, moderately disproportioned position, and severely disproportioned position according to the cut-off values. The correlation between evaluation systems and mechanical complications was analyzed through a logistic regression model via stepwise backward elimination based on the Wald statistics. Receiver operator characteristic (ROC) curve was used to determine the predictability of the evaluation systems in the occurrence of mechanical complications and calculate their cut-off value. Area under the curve (AUC) was used to evaluate the validity of the thresholds. RESULTS: A total of 80 patients were included in this study. There were 41 patients in mechanical complication group and 39 patients in no mechanical complication group. GAP score (P = 0.008) and GAP categories (P = 0.007) were positively correlated with mechanical complications; Roussouly score was negatively correlated with mechanical complications (P = 0.034); GAP score was positively correlated with PJK (P = 0.021); Roussouly score was negatively correlated with implant-related complications (P = 0.018); GAP categories were correlated with implant loosening (P = 0.023). Results of ROC showed that GAP score was more effective in predicting PJK (AUC = 0.863) and PJF (AUC = 0.724) than Roussouly score; GAP categories (AUC = 0.561) was more effective than GAP score (AUC = 0.555) in predicting implant-related complications. CONCLUSIONS: Roussouly classification could only be a rough estimate of optimal spinopelvic alignment. Quantitative parameters in GAP score made it more effective in predicting mechanical complications, PJK and PJF than Roussouly classification.

Circulating Tumor Cells (CTCs): A Unique Model of Cancer Metastases and Non-invasive Biomarkers of Therapeutic Response.

Late-stage cancer metastasis remains incurable in the clinic and is the major cause death in patients. Circulating tumor cells (CTCs) are thought to be metastatic precursors shed from the primary tumor or metastatic deposits and circulate in the blood. The molecular network regulating CTC survival, extravasation, and colonization in distant metastatic sites is poorly defined, largely due to challenges in isolating rare CTCs. Recent advances in CTC isolation and ex vivo culture techniques facilitates single-cell omics and the development of related animal models to study CTC-mediated metastatic progression. With these powerful tools, CTCs can potentially be used as non-invasive biomarkers predicting therapeutic response. These studies may open a new avenue for CTC-specific drug discoveries. In this short review, we aim to summarize recent progress in the characterization of CTCs and their clinical relevance in various cancers, setting the stage for realizing personalized therapies against metastases.

Oral microbiota in the oral-genitourinary axis: identifying periodontitis as a potential risk of genitourinary cancers.

Periodontitis has been proposed as a novel risk factor of genitourinary cancers: although periodontitis and genitourinary cancers are two totally distinct types of disorders, epidemiological and clinical studies, have established associations between them. Dysbiosis of oral microbiota has already been established as a major factor contributing to periodontitis. Recent emerging epidemiological evidence and the detection of oral microbiota in genitourinary organs indicate the presence of an oral-genitourinary axis and oral microbiota may be involved in the pathogenesis of genitourinary cancers. Therefore, oral microbiota provides the bridge between periodontitis and genitourinary cancers. We have carried out this narrative review which summarizes epidemiological studies exploring the association between periodontitis and genitourinary cancers. We have also highlighted the current evidence demonstrating the capacity of oral microbiota to regulate almost all hallmarks of cancer, and proposed the potential mechanisms of oral microbiota in the development of genitourinary cancers.

ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer.

Prostate cancer (PCa) exhibits an elevated level of de novo lipogenesis that provides both energy and basic metabolites for its malignant development. Long-chain polyunsaturated fatty acids (PUFAs) are elongated and desaturated from palmitate but their effects on PCa progression remain largely unknown. Here, we showed that PUFAs were significantly upregulated by androgen deprivation therapy (ADT) and elevated in neuroendocrine (NE)-like PCa cells. The key enzyme of PUFA elongation, ELOVL5, was overexpressed in NE-like PCa cells as well. Furthermore, we demonstrated that knocking down ELOVL5 in enzalutamide resistant NE-like PCa cells diminished the neuroendocrine phenotypes and enzalutamide resistance, while overexpressing ELOVL5 augmented the enzalutamide resistance of PCa cells in vitro and in vivo. Mechanistically, ELOVL5-mediated PUFA elongation enhanced the lipid raft-associated AKT-mTOR signaling activation and therefore contributes to the enzalutamide resistance. These findings suggest that ELOLV5-mediated PUFA elongation may be a potential novel target for the treatment of enzalutamide resistant NE-like PCa.

Identification of microRNAs and their target genes related to needle discoloration of evergreen tree Chinese cedar (Cryptomeria fortunei) in cold winters.

MAIN CONCLUSION: Comparative analysis of miRNAs and their gene targets between the evergreen and yellowish-brown Cryptomeria fortunei phenotypes in cold winters suggests a possible role of miRNA-regulated pathways in needle color. Cryptomeria fortunei (Chinese cedar) is a conifer tree of considerable economic, ornamental and ecological importance. Despite the evergreen nature of C. fortunei, most needles turn yellowish- or reddish-brown in winter. The roles of microRNAs (miRNAs) in regulating pigment biosynthesis in color-leafed plants have been widely investigated. However, whether or not an miRNA-mediated staged discoloration mechanism exists in evergreen C. fortunei is currently unknown. In this study, we deciphered the microRNAs landscape in overwintering C. fortunei needles using high-throughput sequencing. A total of 517 known and 212 novel miRNA mature/star sequences, including 233 differentially expressed miRNAs, were identified. Based on integrated transcriptome and miRNA analysis, 2702 target unigenes of the miRNAs were predicted and these targets were significantly enriched in pigment-related biosynthesis pathways. A miRNA-target pigment biosynthesis regulatory network was then constructed, and its module miRNA (ath-miR858b, aly-miR858-3p, cme-miR828 and novel33_mature)-MYBs (v-myb avian myeloblastosis viral oncogene homolog) appeared to be a key factor regulating needle discoloration in C. fortunei. These miRNA-MYBs were further confirmed by degradome sequencing. Overall, these findings provide new insight into the posttranscriptional regulatory mechanism of leaf/needle discoloration in gymnosperms and may contribute to the miRNA-mediated genetic improvement of evergreen C. fortunei needles.

A glutaminase isoform switch drives therapeutic resistance and disease progression of prostate cancer.

Cellular metabolism in cancer is significantly altered to support the uncontrolled tumor growth. How metabolic alterations contribute to hormonal therapy resistance and disease progression in prostate cancer (PCa) remains poorly understood. Here we report a glutaminase isoform switch mechanism that mediates the initial therapeutic effect but eventual failure of hormonal therapy of PCa. Androgen deprivation therapy inhibits the expression of kidney-type glutaminase (KGA), a splicing isoform of glutaminase 1 (GLS1) up-regulated by androgen receptor (AR), to achieve therapeutic effect by suppressing glutaminolysis. Eventually the tumor cells switch to the expression of glutaminase C (GAC), an androgen-independent GLS1 isoform with more potent enzymatic activity, under the androgen-deprived condition. This switch leads to increased glutamine utilization, hyperproliferation, and aggressive behavior of tumor cells. Pharmacological inhibition or RNA interference of GAC shows better treatment effect for castration-resistant PCa than for hormone-sensitive PCa in vitro and in vivo. In summary, we have identified a metabolic function of AR action in PCa and discovered that the GLS1 isoform switch is one of the key mechanisms in therapeutic resistance and disease progression.

Novel Gene Signatures Predictive of Patient Recurrence-Free Survival and Castration Resistance in Prostate Cancer.

Molecular signatures predictive of recurrence-free survival (RFS) and castration resistance are critical for treatment decision-making in prostate cancer (PCa), but the robustness of current signatures is limited. Here, we applied the Robust Rank Aggregation (RRA) method to PCa transcriptome profiles and identified 287 genes differentially expressed between localized castration-resistant PCa (CRPC) and hormone-sensitive PCa (HSPC). Least absolute shrinkage and selection operator (LASSO) and stepwise Cox regression analyses of the 287 genes developed a 6-gene signature predictive of RFS in PCa. This signature included NPEPL1, VWF, LMO7, ALDH2, NUAK1, and TPT1, and was named CRPC-derived prognosis signature (CRPCPS). Interestingly, three of these 6 genes constituted another signature capable of distinguishing CRPC from HSPC. The CRPCPS predicted RFS in 5/9 cohorts in the multivariate analysis and remained valid in patients stratified by tumor stage, Gleason score, and lymph node status. The signature also predicted overall survival and metastasis-free survival. The signature's robustness was demonstrated by the C-index (0.55-0.74) and the calibration plot in all nine cohorts and the 3-, 5-, and 8-year area under the receiver operating characteristic curve (0.67-0.77) in three cohorts. The nomogram analyses demonstrated CRPCPS' clinical applicability. The CRPCPS thus appears useful for RFS prediction in PCa.

N-cadherin inhibitor creates a microenvironment that protect TILs from immune checkpoints and Treg cells.

BACKGROUND: Few patients with prostate cancer benefit from current immunotherapies. Therefore, we aimed to explore new strategies to change this paradigm. METHODS: Human tissues, cell lines and in vivo experiments were used to determine whether and how N-cadherin impacts the production of programmed death ligand-1 (PD-L1) and indole amine 2,3-dioxygenase (IDO-1) and whether N-cadherin can increase the production of effector (e)Treg cells. Then, we used PC3-bearing humanized non-obese diabetic/severe combined immunodeficiency IL2Rγnull (hNSG) mice with an intravenous injection of human CD34+ hematopoietic stem cells into the tail vein to evaluate whether the N-cadherin antagonist N-Ac-CHAVC-NH2 (designated ADH-1) could improve the therapeutic effect of tumor-infiltrating lymphocyte (TIL)-related treatment. RESULTS: N-cadherin dramatically upregulated the expression of PD-L1 and IDO-1 through IFN-γ (interferongamma) signaling and increasing the production of free fatty acids that could promote the generation of eTreg cells. In preclinical experiments, immune reconstitution mediated by TILs slowed tumor growth and extended the survival time; however, this effect disappeared after immune system suppression by PD-L1, IDO-1 and eTreg cells. Furthermore, ADH-1 effectively reduced immunosuppression and enhanced TIL-related therapy. CONCLUSIONS: These data show that the N-cadherin antagonist ADH-1 promotes TIL antitumor responses. This important hurdle must be overcome for tumors to respond to immunotherapy.

Retrospective study on effectiveness of Activ L total disc replacement.

BACKGROUND: The effectiveness of lumbar total disc replacement (TDR) with different prostheses for sagittal alignment has been reported previously. However, there are only few reports on Activ L TDR and no specific evidence regarding whether sagittal alignment affects the clinical outcomes. METHODS: Eighty-seven patients who underwent mono- or bi-segmental lumbar TDR with Activ L were studied. The films of the upright anteroposterior and lateral spine in neutral, flexion, and extension positions were obtained before surgery and at 1 month and 1 and 3 years after surgery. The radiographic parameters such as lumbar lordosis (LL), index level lordosis (IL), pelvic incidence (PI), pelvic tilt (PT), segmental lordosis (SL), and sacral slope (SS) were measured based on the lateral upright radiographs. Clinical outcomes were evaluated using the Oswestry Disability Index (ODI) and visual analog scale (VAS) pre- and post-operatively. RESULTS: Eighty-seven patients with complete radiographic data were available for a 3-year follow-up period. Of these, 66 received a single-level TDR, and 21 received a 2-level TDR. At 1 month, the mean LL was similar to the pre-operative data and then was significantly increased to 45.1° at 3 years. On average, the IL tended to significantly increase, while the mean SL at L-5 was increased from 16.5° pre-operatively to 21.0° at 3 years. The mean SL at L1-2, L2-3, L3-4, and L5-S1; PI; PT; and SS showed no obvious difference after 3 years. In contrast, VAS and ODI scores showed significant improvement after surgery. CONCLUSIONS: Activ L TDR showed a favorable effect on sagittal alignment, enhancing the IL while preserving the LL and SS. However, satisfactory clinical results for over a 3-year follow-up were not affected by sagittal alignment.