Ring domains are essential for GATOR2-dependent mTORC1 activation.

The GATOR2-GATOR1 signaling axis is essential for amino-acid-dependent mTORC1 activation. However, the molecular function of the GATOR2 complex remains unknown. Here, we report that disruption of the Ring domains of Mios, WDR24, or WDR59 completely impedes amino-acid-mediated mTORC1 activation. Mechanistically, via interacting with Ring domains of WDR59 and WDR24, the Ring domain of Mios acts as a hub to maintain GATOR2 integrity, disruption of which leads to self-ubiquitination of WDR24. Physiologically, leucine stimulation dissociates Sestrin2 from the Ring domain of WDR24 and confers its availability to UBE2D3 and subsequent ubiquitination of NPRL2, contributing to GATOR2-mediated GATOR1 inactivation. As such, WDR24 ablation or Ring deletion prevents mTORC1 activation, leading to severe growth defects and embryonic lethality at E10.5 in mice. Hence, our findings demonstrate that Ring domains are essential for GATOR2 to transmit amino acid availability to mTORC1 and further reveal the essentiality of nutrient sensing during embryonic development.

Energy status dictates PD-L1 protein abundance and anti-tumor immunity to enable checkpoint blockade.

Aberrant energy status contributes to multiple metabolic diseases, including obesity, diabetes, and cancer, but the underlying mechanism remains elusive. Here, we report that ketogenic-diet-induced changes in energy status enhance the efficacy of anti-CTLA-4 immunotherapy by decreasing PD-L1 protein levels and increasing expression of type-I interferon (IFN) and antigen presentation genes. Mechanistically, energy deprivation activates AMP-activated protein kinase (AMPK), which in turn, phosphorylates PD-L1 on Ser283, thereby disrupting its interaction with CMTM4 and subsequently triggering PD-L1 degradation. In addition, AMPK phosphorylates EZH2, which disrupts PRC2 function, leading to enhanced IFNs and antigen presentation gene expression. Through these mechanisms, AMPK agonists or ketogenic diets enhance the efficacy of anti-CTLA-4 immunotherapy and improve the overall survival rate in syngeneic mouse tumor models. Our findings reveal a pivotal role for AMPK in regulating the immune response to immune-checkpoint blockade and advocate for combining ketogenic diets or AMPK agonists with anti-CTLA4 immunotherapy to combat cancer.

Surgical efficacy and survival prediction of patients with unspecified malignant bone tumors.

BACKGROUND: The surgical efficacy and prognostic outcomes of patients with unspecific malignant bone tumors (UMBTs) remain unclear. The study is to address: 1) What are the clinicopathological features and prognostic determinants for patients with UMBTs? 2) Can a nomogram be developed for clinicians to predict the short and long-term outcomes for individuals with UMBTs? 3) Does surgery improve outcomes for UMBT patients who received radiotherapy or chemotherapy after balancing the confounding bias? METHODS: 400 UMBT patients were filtrated from the Surveillance, Epidemiology, and End Results database to assess the clinicopathological features, treatments, and factors affecting prognosis. The optimal cutoff values of continuous variables were identified by the x-tile software. Kaplan-Meier method and multivariate Cox proportional hazard modeling were performed to evaluate the independent prognostic factors. Nomogram was further developed by using R software with rms package. The surgical efficacy was further assessed for patients receiving radiotherapy or chemotherapy after performing propensity score matching. RESULTS: The enrolled cohort included 195 (48.8%) female and 205 (51.2%) male patients. The 2- and 5-year cancer-specific survival (CSS) and overall survival (OS) rate were 58.2 ± 3.0%, 46.8 ± 3.2%, and 46.5 ± 2.6%, 34.4 ± 2.5%, respectively. Nomogram was finally developed for CSS and OS according to the identified independent factors: age, tumor extent, primary tumor surgery, tumor size, and pathology grade. For UMBT patients who received radiotherapy or chemotherapy, surgical intervention was associated with better CSS (pr = 0.003, pc = 0.002) and OS (pr = 0.035, pc = 0.002), respectively. CONCLUSIONS: Nomogram was developed for individual UMBT patient to predict short and long-term CSS and OS rate, and more external patient cohorts are warranted for validation. Surgery improves outcomes for UMBT patients who received either radiotherapy or chemotherapy.

Distribution and predictive value of initial presenting symptoms in spinal metastases from primary cancer patients.

PURPOSE: Primary cancer patients may have some symptoms and develop spinal metastases in their disease progression. This study was to report the distribution and predictive value of specific initial presenting symptoms in patients with spine metastatic disease. METHODS: The clinical information about patients with primary cancers was retrospectively collected and analyzed at their initial diagnosis from January 2008 to December 2017. The distribution and specific value of initial presenting symptoms were analyzed in predicting spinal metastases. RESULTS: A total of 14,603 cancer patients were finally included, of whom 1665 (11.4%) cases were confirmed with spinal metastases. 41.55% (6067/14,603) patients had initial presenting symptoms, while 92.19% (1535/1665) patients with spinal metastases presented at least one initial presenting symptoms. Among 6269 patients with symptoms, 1535 (24.49%) were diagnosed with spinal metastases. Factors including primary tumor type, local pain, night-aggravating pain, limb numbness, limb weakness, unstable gait, claudication, loss of sphincter control, and weight loss are associated with the distribution of spinal metastases. The pooled sensitivity, specificity, positive predictive value, and negative predictive value were 90.9% (89.4-92.2%), 64.9% (64.0-65.7%), 24.99% (23.91-26.11%), and 98.23% (97.92-98.50%), respectively. Positive likelihood ratio of "night-aggravating pain" was 33.25 (12.65-87.36) and 17.26 (12.25-24.32) in patients < 45 and 45-64 years old, respectively. CONCLUSIONS: The distribution of spinal metastases is associated with primary tumor type and initial presenting symptoms. The predictive value of initial presenting symptoms differs in age groups, but resembles in cancer types. The presence of night-aggravating pain had relative high value in predicting metastases in cancer patients under 65 years old.

EWS-FLI1-mediated tenascin-C expression promotes tumour progression by targeting MALAT1 through integrin α5ß1-mediated YAP activation in Ewing sarcoma.

BACKGROUND: The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear. METHODS: TNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored. RESULTS: TNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5ß1 signalling might be correlated with YAP dephosphorylation and nuclear translocation. CONCLUSIONS: TNC may promote ES tumour progression by targeting MALAT1 through integrin α5ß1-mediated YAP activation.

Symptomatic aneurysmal bone cysts of the spine: clinical features, surgical outcomes, and prognostic factors.

PURPOSE: The aim of the study was to report the long-term outcomes and analyze the potential prognostic factors that may contribute to symptomatic patients with aneurysmal bone cyst (ABC) of the spine undergoing surgical treatments. METHODS: A retrospective analysis of consecutive patients with ABCs of the spine was performed. The clinical features were reviewed, and the disease-free survival (DFS) and overall survival (OS) rates were estimated using the Kaplan-Meier method. Factors with p values ≤ 0.05 were subjected to multivariate analysis by Cox proportional hazards model to identify the independent prognostic contributors. p values < 0.05 were considered statistically significant. RESULTS: A total of 42 patients with ABCs of the spine were included in the study. All patients received surgical treatments. The mean follow-up period was 41.3 months (median 39.5, range 24-64). Local recurrence was detected in eight patients after surgery in our center, whereas death occurred in three patients. The estimated 5-year DFS and OS rate was 54.1% and 76.8%, respectively. The statistical analyses indicated that both en bloc resection and primary/secondary tumor status were independent prognostic factors for DFS. CONCLUSIONS: Secondary ABC status may be associated with worse prognosis, and en bloc resection remains the treatment of choice for ABCs with neurologic deficits or spinal instability of the spine, which is correlated with better prognosis for local tumor control. These slides can be retrieved under Electronic Supplementary Material.

[Advanced progress in classic genomic and non-genomic regulating mechanism mediated by retinoic acids in anti-cancer treatments].

Retinoic acid, an active metabolite of vitamin A, exerts multiple effects on regulating embryonic development and inducing differentiation, proliferation, apoptosis as well as resistance in various cancer cells. Apart from the classic genomic action (binding to the nuclear receptors to regulate the expression of its downstream target genes), retinoic acids also play important roles in anti-cancer effect through non-genomic pathways (via extranuclear and non-transcriptional effects).

Treatment and outcomes of 28 patients with spinal metastasis from gynecological cancer.

The aim of this study was to provide some useful information concerning clinical characteristics, surgical treatment, potential contributing factor and prognostic factors for patients with gynecological cancer (GC) spinal metastasis. We reviewed 28 patients with GC spinal metastasis in our spine tumor center between July 2008 and July 2015. Surgeries were performed on 22 of them. Univariate and multivariate analyses were conducted to identify potential prognostic factors affecting spinal metastasis-free survival (SMFS) and overall survival. The operative patients responded favorably according to decrease of VAS score and increase of Frankel grade after surgery. The 1- and 2-year survival rates in all patients were 60.7 and 41.0%, respectively. Univariate analysis suggested that age at diagnosis with GC was the potential contributing factor for spinal metastasis, while Frankel grade, ECOG-PS, visceral metastasis and chemotherapy were the potential prognostic factors affecting survival. Multivariate analysis indicated that the independent prognostic factors came from visceral metastasis and chemotherapy. Surgery played an important role in improving patients' quality of life. Patients over 50 years old had a shorter SMFS after diagnosed with GC. Visceral metastasis was an adverse prognostic factor for patients with GC spinal metastasis, while chemotherapy was a favorable one.

Surgical management and outcome of synovial sarcoma in the spine.

BACKGROUND: Synovial sarcoma (SS) is a soft tissue sarcoma that rarely occurs in the spine, and a minimal number of cases have been reported in the literature. Spinal SS is challenging in diagnosis and treatment and has a poor prognosis. The aim of this study was to summarize and analyse the clinical features and outcomes of patients with spinal SS. METHODS: A total of 16 cases of patients with spinal SS admitted to our institution were reviewed retrospectively. General information, radiological findings and treatment strategies were collected. These patients were followed up regarding their continuing treatment, local or distant recurrence and survival. RESULTS: Spinal SS patients in this series ranged in age from 12 to 68 years (median, 33). Four en bloc resections and 12 piecemeal resections were performed. Improved Frankel (P = 0.002), visual analogue scale (P = 0.002) and Karnofsky Performance Status (P = 0.002) scores were seen postoperatively. The mean follow-up period was 35.9 ± 23.5 (median 31.5, range 4-87) months, with four local recurrences and three distant metastases detected. Eight patients (50.0%) died of disease by the last follow-up. The 1-, 3- and 5-year overall survival rates were 87.5%, 61.4% and 40.9%, respectively. Preoperative chemotherapy was used in three patients to facilitate surgical resection, and adjuvant chemotherapy and radiotherapy were used in six patients. CONCLUSIONS: Spinal SS has a relatively high risk of local recurrence and distant metastasis. Surgical intervention can improve the neurological function and relieve pain in these patients. En bloc excision is an effective treatment strategy to improve survival and prevent local recurrence. Management of spinal SS should be under the instruction of a multidisciplinary team.

Single-stage multi-level construct design incorporating ribs and chest wall reconstruction after en bloc resection of spinal tumour.

PURPOSE: Multi-level reconstruction incorporating the chest wall and ribs is technically demanding after multi-segmental total en bloc spondylectomy (TES) of thoracic spinal tumours. Few surgical techniques are reported for effective reconstruction. A novel and straightforward technical reconstruction through posterior-lateral approach was presented to solve the extensive chest wall defect and prevent occurrences of severe respiratory dysfunctions after performing TES. The preliminary outcomes of surgery were reviewed. METHODS: Multi-level TES was performed for five patients with primary or recurrent thoracic spinal malignancies through posterior-lateral approach. The involved ribs and chest wall were removed to achieve tumour-free margin. Then titanium mesh with allograft bone and pedicle screw-rod system were adopted for the circumferential spinal reconstruction routinely. Titanium rods were modified accordingly to attach to the screw-rod system proximally, and the distal end of rods was dynamically inserted into the ribs. RESULTS: The mean surgery time was 6.7 hours (range 5-8), with the average blood loss of 3260 ml (range 2300-4500). No severe neurological complications were reported while three patients had complaints of slight numbness of chest skin (no. 1, 3, and 5). No severe respiratory complications occurred during peri-operative period. No implant failure and no local recurrence or distant metastases were observed with an average follow-up of 12.5 months. CONCLUSIONS: The single-stage reconstructions incorporating spine and chest wall are straightforward and easy to perform. The preliminary outcomes of co-reconstructions are promising and favourable. More studies and longer follow-up are required to validate this technique.

Tyrosine kinase inhibitor sunitinib therapy is effective in the treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival.

Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy.

HIF-1α activates hypoxia-induced PFKFB4 expression in human bladder cancer cells.

PFKFB4 is reported to regulate glycolysis by synthesizing fructose-2, 6-bisphosphate (F2,6BP) and has proved to be associated with most malignancies. However, the underlying mechanism for increased PFKFB4 expression in bladder cancer remains unclear. The present study demonstrated that PFKFB4 was overexpressed in bladder cancer tissues. In addition, the expression of PFKFB4 elevated in bladder cancer cells in the hypoxic condition, while in nomoxic condition, the expression of PFKFB4 still very low. Furthermore, we identified the hypoxia-responsive elements (HRE)-D from five putative HREs in the promoter region of PFKFB4 and demonstrated that the HRE-D was transactivated by the HIF-1α in bladder cancer cells. By using the Double-immunofluorescence co-localization assay, we revealed that the HIF-1α expression was associated with PFKFB4 expression in human bladder cancer specimens. Altogether, our study for the first time identified the pivotal role of HIF-1α in the connection between PFKFB4 and hypoxia in bladder cancer, which may prove to be a potential target for the treatment of bladder cancer.

The role of LOXL2 in tumor progression, immune response and cellular senescence: a comprehensive analysis.

LOXL2, an enzyme belonging to the LOX family, facilitates the cross-linking of extracellular matrix (ECM) elements. However, the roles of the LOXL2 gene in mechanisms of oncogenesis and tumor development have not been clearly defined. In this pan-cancer study, we examined the notable disparity in LOXL2 expression at the mRNA and protein levels among various cancer types and elucidated its interconnected roles in tumor progression, mutational profile, immune response, and cellular senescence. Apart from investigating the hyperexpression of LOXL2 being related to poorer prognosis in different types of tumors, this study also unveiled noteworthy connections between LOXL2 and genetic mutations, infiltration of tumor immune cells, and genes in immune checkpoint pathways. Further analysis revealed the participation of LOXL2 in multiple pathways related to cancer extracellular matrix remodeling and cellular senescence. Moreover, our investigation uncovered that the knockdown and inhibition of LOXL2 significantly attenuated the proliferation and migration of PC-9 and HCC-LM3 cells. The knock-down and inhibition of LOXL2 enhanced cellular senescence in lung and liver cancer cells, as confirmed by SA-ß-Gal staining and quantitative RT-PCR analyses. This comprehensive analysis offers valuable insights on the functions of LOXL2 in different types of cancer and its role in regulating the senescence of cancer cells.

Measurement properties of health-related quality of life measures for people living with metastatic disease of the spine: a systematic review.

PURPOSE: Patients with spinal metastases (SM) suffer from a significant quality of life (QoL) deterioration. The measurement of QoL has garnered significant attention. In this study, the authors aimed to investigate the frequency of QoL measurement, systematically appraise the measurement properties of identified instruments, and facilitate the effective selection of an appropriate QoL instrument for patients with SM. METHODS: This systematic review adhered to the newly revised Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement guidelines. The methodological quality of the studies was assessed using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. Measurement property results were assessed using the adapted criteria. Each measurement property was allocated a separate rating (excellent, good, fair, or poor). 'Best evidence synthesis' was performed using COSMIN outcomes and the quality of findings. RESULT: Two hundred and nine publications were included, and 18 instruments were identified. ECOG, EuroQol-5D, SF-36, SOSGOQ, and EORTC-QLQ-C30 were the top five instruments used for patients with SM in published literature. The measurement properties evaluated included internal consistency (four instruments), reliability (three instruments), validity (five instruments), validity (nine measures), floor and ceiling effects (four instruments), responsiveness (four instruments), and interpretability (three measures). Based on the limited evidence, the Brief Pain Inventory (BPI) had the best methodological quality. CONCLUSIONS: Owing to the limitations of BPI in assessment domains, we cannot fully support the use of BPI. For the lack of high-quality research, it is challenging to nominate a single appropriate measure. Additional studies are needed to explore the evidence before a confirmatory decision is made.

Mechanical Behavior of Anchor Bolts for Shallow Super-Large-Span Tunnels in Weak Rock Mass.

Based on the Xiabeishan No.2 tunnel project of the Hang-Shao-Tai high-speed railway in China, the mechanical behavior of the anchor bolts for shallow super-large-span (SSLS) tunnels in weak rock mass is comprehensively investigated through laboratory tests, numerical simulation, and field tests. Firstly, an eight-month field test is conducted in the Xiabeishan No.2 tunnel, and it is discovered that the blasting vibration created by the construction of the middle pilot tunnel caused serious damage to the temporary support, seriously affecting the development of the bolt axial force and causing great construction risks. Then, the refined finite difference model of the SSLS tunnels is formulated, and a series of field and laboratory tests are conducted to acquire the calculation parameters. By comparing the monitored and simulated bolt axial force, the reliability of the numerical model is verified. Subsequently, the influence of the rock condition, construction scheme and bolt length on the mechanical behavior of anchor bolts is discussed. It is revealed that the rock grade significantly affects the bearing characteristics of anchor bolts. The construction scheme can greatly affect the magnitude and development mode of the bolt axial force, but the final distribution characteristics of the bolt axial force do not change regardless of the construction sequence. The axial force of the anchor bolts grows rapidly with the bolt length when the bolt length is within 18 m; meanwhile, when the bolt length exceeds 18 m, increasing the bolt length has a limited effect on the improvement in the bolt support performance. Finally, some optimization measures are proposed according to the monitoring data and simulation results.

Surgical Treatments and Long-Term Outcomes for Pediatric Patients With Lumbar Spinal Tumors.

STUDY DESIGN: Retrospective case‒control study. OBJECTIVES: This study aimed to report the effects of surgical intervention on spinal stability recovery and to assess the long-term outcomes of children and adolescents with lumbar tumors. METHODS: From January 2016 to June 2021, 42 pediatric patients with lumbar tumors were selected and separated into different groups based on the surgical method used (total en bloc resection (TER) group, n = 21; piecemeal resection (PR) group, n = 21; titanium mesh (TM) group n = 23; artificial vertebrae (AV) group n = 19). The clinicopathological characteristics, treatments and related outcomes were described in detail and compared between groups, with P value ≤.05 indicating statistically significant differences. RESULTS: The average follow-up duration was 24.89 months, and the mean age was 14.89 ± 2.41 years. There were no significant differences in the mean operation time, average blood loss, complication rate, or length of hospital stay between the groups. The ODI, VAS and JOA scores at the final follow-up (FF) were elevated after surgery in all groups. The FF local angular drift (LOD) and lumbar angular drift (LUD) were greater in the TM group than in the AV group (P = .03, P = .001). CONCLUSIONS: After surgery, pediatric patients with lumbar tumors can obtain satisfactory spinal stability, effective relief of pain symptoms and substantial improvements in neurological function. There was no significant difference in the invasiveness, safety or timeliness between the 2 surgical methods, so TER is recommended due to its low postoperative recurrence rate and good local control. Spinal fusion in the AV group resulted in better spinal stability.

Prognostic factors of sarcomas occurring in bone and joint: A SEER based study.

To clarify the epidemiology, treatment, and prognosis of sarcomas occurring in the bones and joints. The surveillance, epidemiology, and end results (SEER) 18 registries, comprising sarcoma diagnoses made between 2008 and 2014, were queried for sarcomas arising in bones or joints. Kaplan-Meier analysis, multivariate logistic regression analysis, Cox proportional hazards model, and nomograms were used to identify prognostic factors. 2794 patients aged from 1 to 99 (55.8% male) with microscopically confirmed diagnosed as sarcomas (including osteosarcoma, chondrosarcoma, Ewing sarcoma, and soft tissue sarcomas) which primary site limited to bone and joint were identified. Eight independent factors, including age, race, sex, tumor site, histology, pathology grade, tumor size, and total number of malignant tumors (TNOMT), were associated with tumor metastasis. Nine independent prognostic factors, including age (>=60 year, hazard ratio [HR] = 4.145, 95% confidence interval [CI], P < .001), sex (female, HR = 0.814, 95%CI, P = .007), tumor site (spine, HR = 2.527, 95%CI, P < .001), histology, pathology grade (undifferentiated, HR = 5.816, 95%CI, P < .001), tumor size (>=20 cm, HR = 3.043, 95%CI, P < .001), tumor extent (distant, HR = 4.145, 95%CI, P < .001), surgery (no performed, HR = 2.436, 95%CI, P < .001), and TNOMT (1, HR = 0.679, 95%CI, P < .001, were identified and incorporated to construct a nomogram for 2- and 5-year overall survival (OS). The calibration curve for the probability of survival showed good agreement between prediction by the nomogram and actual observation. The C-index of the nomogram for survival prediction was 0.814. Patients who received chemotherapy had a significantly decreased risk of death only for Ewing sarcoma, poorly differentiated tumors, undifferentiated tumors, and distant tumor invasion (P < .05). However, radiotherapy did not show significant differences in OS. This study presents population-based estimates of prognosis for patients with bone sarcomas and demonstrates the impact of age, race, sex, tumor site, histology, pathology grade, tumor size, tumor extent, surgery, radiotherapy, chemotherapy, and the TNOMT on OS. Moreover, the nomogram resulted in a more accurate prognostic prediction. However, in our study, radiotherapy showed no survival benefit, perhaps because detailed data on treatment factors were unavailable and which may have influenced the results.

PRMT1 orchestrates with SAMTOR to govern mTORC1 methionine sensing via Arg-methylation of NPRL2.

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling.

Thyroid function and associated mood changes after COVID-19 vaccines in patients with Hashimoto thyroiditis.

Context: Severe acute respiratory syndrome-coronavirus 2 (COVID-19) vaccines may incur changes in thyroid functions followed by mood changes, and patients with Hashimoto thyroiditis (HT) were suggested to bear a higher risk. Objectives: We primarily aim to find whether COVID-19 vaccination could induce potential subsequent thyroid function and mood changes. The secondary aim was to find inflammatory biomarkers associated with risk. Methods: The retrospective, multi-center study recruited patients with HT receiving COVID-19-inactivated vaccines. C-reactive proteins (CRPs), thyroid-stimulating hormones (TSHs), and mood changes were studied before and after vaccination during a follow-up of a 6-month period. Independent association was investigated between incidence of mood state, thyroid functions, and inflammatory markers. Propensity score-matched comparisons between the vaccine and control groups were carried out to investigate the difference. Results: Final analysis included 2,765 patients with HT in the vaccine group and 1,288 patients in the control group. In the matched analysis, TSH increase and mood change incidence were both significantly higher in the vaccine group (11.9% versus 6.1% for TSH increase and 12.7% versus 8.4% for mood change incidence). An increase in CRP was associated with mood change (p< 0.01 by the Kaplan-Meier method) and severity (r = 0.75) after vaccination. Baseline CRP, TSH, and antibodies of thyroid peroxidase (anti-TPO) were found to predict incidence of mood changes. Conclusion: COVID-19 vaccination seemed to induce increased levels and incidence of TSH surge followed by mood changes in patients with HT. Higher levels of pre-vaccine serum TSH, CRP, and anti-TPO values were associated with higher incidence in the early post-vaccine phase.

A Novel Defined Hypoxia-Related Gene Signature for Prognostic Prediction of Patients With Ewing Sarcoma.

The therapeutic strategy of Ewing sarcoma (EWS) remains largely unchanged over the past few decades. Hypoxia is reported to have an impact on tumor cell progression and is regarded as a novel potential therapeutic target in tumor treatment. This study aimed at developing a prognostic gene signature based on hypoxia-related genes (HRGs). EWS patients from GSE17674 in the GEO database were analyzed as a training cohort, and differently expressed HRGs between tumor and normal samples were identified. The univariate Cox regression, Least Absolute Shrinkage and Selection Operator (LASSO) and multivariate Cox regression analyses were used in this study. A total of 57 EWS patients from the International Cancer Genome Consortium (ICGC) database were set as the validation cohort. A total of 506 differently expressed HRGs between tumor and normal tissues were identified, among which 52 were associated with the prognoses of EWS patients. Based on 52 HRGs, EWS patients were divided into two molecular subgroups with different survival statuses. In addition, a prognostic signature based on 4 HRGs (WSB1, RXYLT1, GLCE and RORA) was constructed, dividing EWS patients into low- and high-risk groups. The 2-, 3- and 5-years area under the receiver operator characteristic curve of this signature was 0.913, 0.97 and 0.985, respectively. It was found that the survival rates of patients in the high-risk group were significantly lower than those in the low-risk group (p < 0.001). The risk level based on the risk score could serve as an independent clinical factor for predicting the survival probabilities of EWS patients. Additionally, antigen-presenting cell (APC) related pathways and T cell co-inhibition were differently activated in two risk groups, which may result in different prognoses. CTLA4 may be an effective immune checkpoint inhibitor to treat EWS patients. All results were verified in the validation cohort. This study constructed 4-HRGs as a novel prognostic marker for predicting survival in EWS patients.