Extended Endoscopic Transsphenoidal Surgery with Total Cyst Wall Decollement for Suprasellar Cystic Craniopharyngioma: Case Report and Literature Review.

For most cystic craniopharyngiomas, intracapsular debulking is a good strategy to get a large operation space and protect vital structures. However, this surgical strategy may lead to the residual and recurrence of the tumor capsule wall. Therefore, there is an urgent need for a new surgical strategy without residual capsule walls for the removal of cystic craniopharyngiomas. We reviewed a 45-year-old male with vision loss and visual field defects, whose head MRI revealed a suprasellar cystic lesion. The patient underwent extended endoscopic transsphenoidal surgery. The surgical strategy of total cystic wall decollement was adopted, which was that the lesion surrounded by the capsule was completely separated from the surrounding tissue without destroying the capsule and maintaining the tension of the capsule. The lesion was totally resected and pathological findings confirmed the diagnosis of craniopharyngioma. After the operation, both the visual acuity and pituitary function were significantly improved. In addition, he suffered from transient diabetes insipidus, which was subsequently relieved. During the 33-month follow-up, there was no tumor recurrence. Compared with the traditional surgical strategy of intracapsular debulking, the surgical strategy of total cystic wall decollement has the advantages of less residual tumor capsules, low tumor recurrence rates, etc. Therefore, for specific cystic craniopharyngiomas, the surgical strategy of total cystic wall decollement may be an effective surgical strategy to reduce tumor recurrence.

Corosolic acid inhibits EMT in lung cancer cells by promoting YAP-mediated ferroptosis.

BACKGROUND: Corosolic acid (CA), a naturally occurring pentacyclic triterpenoid is renowned for its anticancer attributes. Previous studies have predominantly centered on the anticancer properties of CA in lung cancer, specifically its role in inducing apoptosis, however, investigations regarding its involvement in ferroptosis have been scarce. METHODS: The apoptotic and proliferative effects were evaluated by CCK8 and colony formation assay. Cell death and ROS generation were measured to assess the response of CA to iron death induction. Scratch and invasion assays were performed to verify the effect of CA on the invasive ability of lung cancer cells. Protein and mRNA expression were analyzed using Western blotting and qPCR. The CHX assay was carried out to detect protein half-life. Metabolite levels were measured with appropriate kits. Protein expression was detected through IF and IHC. A xenograft tumor model was established to investigate the inhibitory effect of CA on lung cancer in vivo. RESULTS: The current findings revealed that CA exerts its anticancer effect by inducing cell death, accompanied by the accumulation of lipid reactive oxygen species (ROS), hinting at the possible involvement of ferroptosis. Our experimental results further substantiated the significance of ferroptosis in the CA anticancer mechanism, as ferroptosis inhibitors were found to effectively rescue CA-induced cell death. Significantly, we demonstrated for the first time that CA could induce ferroptosis further by suppressing EMT in lung cancer cells. Additionally, CA could regulate GPX4 to induce ferroptosis, interestingly, CA downregulated GSH synthetase by inhibiting YAP rather than GPX4, thereby reducing GSH, inducing ferroptosis, and further suppressing EMT in lung cancer cells.We also discovered that GSS is a crucial downstream target of YAP in regulating GSH. Moreover, a xenograft mouse model indicated that CA could trigger ferroptosis in lung cancer cells by regulating YAP expression and GSH levels. CONCLUSION: CA inhibited lung cancer cell metastasis by inducing ferroptosis. Our data offer the first evidence that CA induces ferroptosis in lung cancer cells by regulating YAP/GSS to modulate GSH, thereby further suppressing EMT. These results imply the potential of CA as an inducer of ferroptosis to inhibit lung cancer metastasis.

Urine is better for rare earth elements bimonitoring in long-term exposed population: An exposure-response relationship study.

With the soaring use of rare earth elements (REEs) worldwidely in high-technology and clean energy industries, there were growing concerns for adverse health effect from the REEs exposure. However, there is a lack of biomonitoring research concerning both urine and blood in population with definite exposure. We performed a biomonitoring study that involved 103 REEs exposed males and 110 males as non-REEs exposed controls. We measured the levels of REEs in environment and urine and blood samples from participants, and explored the exposure-response relationship between REEs in environment and body fluids. The effects of exposure duration and smoking status on the internal exposure level of REEs were also investigated. The results showed environmental REEs level of exposure group was significantly higher than that of control group (range of geometric mean of exposure vs. control: 1.08-4.07 × 104 ng/m3 vs.

Current research status of Raman spectroscopy in glioma detection.

Glioma is the most common primary tumor of the nervous system. Conventional diagnostic methods for glioma often involve time-consuming or reliance on externally introduced materials. Consequently, there is an urgent need for rapid and reliable diagnostic techniques. Raman spectroscopy has emerged as a promising tool, offering rapid, accurate, and label-free analysis with high sensitivity and specificity in biomedical applications. In this review, the fundamental principles of Raman spectroscopy have been introduced, and then the progress of applying Raman spectroscopy in biomedical studies has been summarized, including the identification and typing of glioma. The challenges encountered in the clinical application of Raman spectroscopy for glioma have been discussed, and the prospects have also been envisioned.

A stented elephant trunk procedure with retrograde cerebral perfusion for a rare type of pseudoaneurysm with an aberrant right subclavian artery.

BACKGROUND: Aberrant right subclavian artery (ARSA) is a rare congenital vascular anomaly that increases the risk of aortic dissection (AD). Although several treatment options for cases of AD with ARSA have been proposed, such as traditional surgery, thoracic endovascular aortic repair, and a hybrid procedure, a consensus regarding the optimal treatment strategy has not yet been established. And there are no reported cases of pseudoaneurysm combined with ARSA. CASE PRESENTATION: A 44-year-old male was admitted with a 7-days history of chest pain. A physical examination was almost normal. Computed tomography angiography (CTA) showed an ARSA arose from the distal aortic arch and pseudoaneurysm located distal to the origin of the ARSA. The stented elephant trunk (SET) procedure with retrograde cerebral perfusion (RCP) was performed under moderate hypothermic circulatory arrest. The postoperative CTA demonstrated a well-perfused ARSA, left subclavian artery (LSA), left common carotid artery (LCCA), and right common carotid artery (RCCA), and occluded pseudoaneurysm with no endoleaks. He was discharged on postoperative day 9 and was doing well during his 6-months follow-up. CONCLUSIONS: With a smaller incision, a simple cannulation method, shorter surgical and circulatory arrest times, fewer blood transfusion requirements, and effective brain protection, the SET procedure with RCP can be a safe and feasible treatment option for complicated aortic arch anomalies with ARSA.

Follicle-stimulating hormone promotes atrial fibrosis in menopausal women with atrial fibrillation.

BACKGROUND: Postmenopausal women with atrial fibrillation (AF) exhibit a higher level of atrial fibrosis and a higher recurrence rate after ablation compared with men. However, the underlying mechanism remains unclear. OBJECTIVE: The purpost of this study was to investigate the mechanism through which menopause promotes atrial fibrosis. METHODS: In a prospective cohort of women with AF, regression analyses were conducted to assess the relationship between low-voltage area (LVA) and sex hormone levels. CREM-IbΔC-X mice, a spontaneous AF model, underwent bilateral ovariectomy (OVX). Electrocardiograms, echocardiograms, and Masson staining were performed. Follicle-stimulating hormone (FSH) stimulation was applied in male mice for 3 months. OVX was also applied in an angiotensin II (Ang II)-induced pressure overload mouse model, after programmed electrical stimulation and structural analyses. Bulk RNA sequencing (RNA-seq) was performed to elucidate potential mechanisms. RESULTS: Women demonstrated a significantly higher LVA burden than men (P < .001). A positive correlation was observed between LVA burden and FSH level (P = .002). Mice in the OVX group exhibited a significantly higher incidence of AF (P = .040) and atrial fibrosis (P = .021) compared with the Sham group, which could be attenuated by adeno-associated virus encoding small interfering RNA against Fshr. In male CREM-IbΔC-X mice, FSH stimulation promoted the occurrence of AF (P = .035) and atrial fibrosis (P = .002). In Ang II-induced female mice, OVX prompted atrial fibrosis, increased AF inducibility, and shortened atrial effective refractory period, which could be attenuated with knockdown of Fshr. RNA-seq indicated mitochondrial dysfunction. CONCLUSION: Postmenopausal women exhibited a higher LVA burden than men, which was positively correlated with FSH level. FSH promoted atrial fibrosis through oxidative stress.

ZIKV induces P62-mediated autophagic degradation of TRAF6 through TRAF6-NS1 interaction.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) is crucial in flavivirus infections, modulating the host immune response through interactions with viral proteins. Despite its importance, the relationship between TRAF6 and Zika virus (ZIKV) remains poorly understood. Our prior proteomics analysis revealed reduced TRAF6 protein levels in ZIKV-infected human trophoblast cells compared to non-infected controls. Subsequent studies in cell models and murine tissues confirmed a significant reduction in both TRAF6 mRNA and protein levels post-ZIKV infection. Further investigations unveiled that ZIKV induces P62-mediated degradation of TRAF6, with NS1 identified as the primary contributor. Co-localization and interaction studies demonstrated that NS1 promotes the association of P62, a key autophagy mediator, with TRAF6. Notably, our findings revealed TRAF6 enhances ZIKV infection, NS1 ubiquitination, NS1 expression, and the production of inflammatory cytokines and chemokines. These insights highlight the intricate TRAF6-ZIKV relationship, offering potential for drug targeting NS1-TRAF6 interactions to manage ZIKV infections effectively.

Outcomes of Traditional Dual Growing Rods With Apical Control Techniques for the Treatment of Early-Onset Scoliosis: Comparison With Patients Treated With Traditional Dual Growing Rods Only With a Minimum 2-Year Follow-up After Graduation.

BACKGROUND AND OBJECTIVES: Correction with traditional dual growing rods (TDGR) might not be sufficient for severe and rigid spinal deformity. TDGR combines with apical control techniques (ACT) could theoretically improve curve correction and decrease the incidence of mechanical complications. However, long-term results for TDGR with ACT are limited. The aim of this study was to retrospectively review and compare the outcomes of patients who graduated from TDGR with or without ACT. METHODS: Patients who were treated by TDGR with or without ACT with a minimum 2-year follow-up after graduation were enrolled. According to the intervention for the apex, patients were further divided into the TDGR group, the TDGR + apical control pedicle screws group (without apical fusion), and the TDGR + hybrid technique group. Clinical outcomes, radiological parameters, pulmonary function, and complications were compared among the 3 groups. RESULTS: A total of 76 patients (51 patients in the TDGR group, 10 patients in the apical control pedicle screws group, and 15 patients in the hybrid technique group) were enrolled. Compared with TDGR, TDGR + ACT achieved better main curve correction, better control of apical vertebral translation and rotation, and lower incidence of complications and revision surgery (P < .05) while maintaining development of the spine and chest. Although the difference was not significant, patients in the TDGR + ACT group had better pulmonary function at the last follow-up (P > .05). The percentage of patients receiving final fusion in the TDGR + ACT group was significantly lower than that in the TDGR group (P < .05). CONCLUSION: Compared with TDGR, TDGR + ACT can achieve better curve correction and apical control and comparable clinical outcomes while maintaining the growth of the spine and chest. Patients may derive more benefits from treatment with TDGR + ACT, including a lower incidence of mechanical complications and revision surgery, better pulmonary function, and the avoidance of final fusion.

Predicting the Time to Relapse Following Withdrawal from Different Biologics in Patients with Psoriasis who Responded to Therapy: A 12-Year Multicenter Cohort Study.

BACKGROUND: For patients with psoriasis, discontinuation of biologics following remission has become more common in daily practice. OBJECTIVE: We aimed to identify predictors and construct a predictive model for time to relapse following withdrawal from biologics. METHODS: This 12-year, multicenter, observational cohort study was performed in six dermatology centers between February 2011 and February 2024. We identified biological treatment episodes in patients with moderate-to-severe psoriasis and included only treatment episodes in which a clinical response (≥ 50% reduction in Psoriasis Area and Severity Index score [PASI 50] from baseline) was achieved and the patient withdrew from biological therapy with a well-controlled status (PASI < 10 and ≥ 50% improvement in PASI from baseline). The primary outcome was time to relapse, which was defined as the period from the last biologic administration to relapse. An extended multivariate Cox proportional hazards analysis (Prentice-Williams-Peterson Gap time model) was used to predict relapse and generate a predictive model. RESULTS: This study screened 1613 biological treatment episodes, and 991 treatment episodes were enrolled. The time to relapse decreased significantly as the number of previous withdrawals from biological treatment increased (p < 0.001). Similarly, the time to relapse decreased significantly as the number of previous biologics used increased (p < 0.001). The maximum PASI improvement during biological treatment decreased and the PASI score at withdrawal of biological treatment increased in parallel as the number of prior withdrawals from biologics increased. The time to relapse following withdrawal was longest for interleukin (IL)-23 inhibitors (IL-23i), followed by the IL-12/23i, IL-17 inhibitors (IL-17i), and tumor necrosis factor-α inhibitors. After adjustment, multivariate Cox regression identified the following significant predictors of relapse following withdrawal: the mechanisms of action of biologics (hazard ratio [HR] for IL-17i vs IL-12/23i, 1.59; HR for IL-23i vs IL-12/23i, 0.60), number of previous withdrawals from biological treatment (HR 1.23; 95% confidence interval [CI] 1.13‒1.33), time to achieve PASI 50 (HR 1.01; 95% CI 1.00‒1.02), maximum PASI improvement on biologics (HR 0.98; 95% CI 0.98‒0.99), and PASI at the end of therapy (HR 1.03; 95% CI 1.01‒1.05). The model had good predictive and discriminative ability. CONCLUSIONS: These results have the potential to help physicians and patients make individualized treatment decisions; information on the risk of relapse of psoriasis at specific timepoints following the withdrawal of biologics is particularly valuable for patients considering discontinuation of biologics or as-needed biologic therapy. However, the benefit and risk of repeated withdrawals of biologics should be carefully weighed, as the treatment efficacy and duration of remission decline as the number of withdrawals increases.

Primary aldosteronism with postoperative elevation of aldosterone treated effectively by finerenone: A case report.

The authors report a case of primary aldosteronism (PA) with postoperative elevation of aldosterone treated effectively by finerenone. The patient was a hypertensive man with a 30-year history of hypertension and sustained an acute myocardial infarction 5 years ago. Bilateral adrenal nodules with hyperplasia were detected and PA was confirmed. His blood potassium, direct renin concentration, and aldosterone level returned to normal after surgery of right adrenalectomy. However, 1 year after surgery, he experienced a decrease in blood potassium and an increase in aldosterone. A saline infusion test revealed an aldosterone level of 124.47 pg/mL. The patient consented to treatment with finerenone. His aldosterone and potassium levels and blood pressure have been controlled well during follow-up. This case highlights the need to screen for secondary hypertension as early as possible. Finerenone may be effective for patients with PA who are not candidates for surgery and those not relieved after surgery.

[Baroreflex failure syndrome after the resection of complex paragangliomas of head and neck: a case report].

Protection of cranial nerves is one of the major challenges in the resection of paragangliomas of head and neck, especially in complex paragangliomas. We report a case of bilateral jugular tumor with unilateral carotid body tumor. Baroreflex failure syndrome（BFS） occurred after staged resection of bilateral lesions. There is still a lack of effective treatment for this complication. More prudent and reasonable treatment strategy is important to reduce the incidence of BFS.

Comparison of the Long-term Survival Outcome of Surgery versus Stereotactic Body Radiation Therapy as Initial Local Treatment for Pulmonary Oligometastases from Colorectal Cancer: A Propensity Score Analysis.

PURPOSE: Optimal local treatment for pulmonary oligometastases from colorectal cancer (CRC) remains unclear. We aimed to compare the long-term survival outcomes between surgery and stereotactic body radiation therapy (SBRT) as the initial local treatment for CRC pulmonary oligometastases. MATERIALS AND METHODS: We retrospectively reviewed 335 consecutive patients who initially underwent surgery or SBRT for CRC pulmonary metastases from 2011 to 2022, and 251 patients (173 surgery and 78 SBRT) were ultimately included. Freedom from intrathoracic progression (FFIP), progression-free survival (PFS), and overall survival (OS) were compared using stabilized inverse probability of treatment weighting (sIPTW) analysis. In addition, patterns of intrathoracic progression and subsequent treatment were analyzed. RESULTS: Median follow-up was 61.6 months for surgery and 54.4 months for SBRT. After sIPTW adjustment, significant differences emerged in both FFIP and PFS between surgery and SBRT (FFIP: hazard ratio [HR] = 0.50, 95% confidence interval [CI], 0.31-0.79; PFS: HR = 0.56, 95% CI, 0.36-0.87). The 3- and 5-year FFIP rates were 58.6% and 54.8%, respectively, after surgery, and 34.6% and 31.3%, respectively, after SBRT (P = .006). The 3- and 5-year PFS rates were 49.4% and 45.2%, respectively, after surgery, and 28.8% and 26.1%, respectively, after SBRT (P = .010). However, OS was not significantly affected by treatment approach (HR = 0.93, 95% CI, 0.49-1.76). The 3- and 5-year OS rates were 85.9% and 73.1%, respectively, after surgery, and 78.9% and 68.7%, respectively, after SBRT (P = .849). Recurrence at the treated site was more prevalent after SBRT than after surgery (33.3% vs 16.9%), whereas new intrathoracic tumors occurred more frequently after surgery than after SBRT (71.8% vs 43.1%). Both groups chose radiation therapy as the primary local salvage treatment. CONCLUSIONS: Notwithstanding the significant differences in FFIP and PFS between surgery and SBRT, the long-term survival of patients with CRC pulmonary oligometastases did not depend on the initial choice of the local treatment approach.

Sulfiredoxin 1 ameliorates doxorubicin-induced cardiotoxicity by suppressing oxidative stress and inflammation via the Sirt1/NLRP3 pathway.

BACKGROUND: Doxorubicin (DOX) is limited in clinical use due to its cardiotoxic side effects. Oxidative stress and inflammation are pivotal mechanisms underlying doxorubicin-induced cardiotoxicity (DIC). Sulfiredoxin 1 (Srxn1) plays a central role in antioxidant effects. However, the role of Srxn1 in DIC has not yet been fully elucidated. This study aims to explore the effects and underlying mechanisms of Srxn1 on DIC. METHODS: We overexpressed Srxn1 in the myocardium using an adeno-associated virus 9 (AAV9) system, delivered through tail vein injection. C57BL/6 mice received intraperitoneal injections of DOX (4 mg/kg) weekly for four consecutive weeks to establish a mouse model of DIC. We used echocardiography, histopathological, and molecular techniques to elucidate the effects and mechanisms. RESULTS: Our findings demonstrate that overexpression of Srxn1 significantly enhanced cardiac function and mitigated myocardial injury in mice exposed to DOX. Overexpressing Srxn1 attenuated oxidative stress and inflammation induced by DOX. Furthermore, Srxn1 overexpression led to upregulation of sirtuin 1 (Sirt1) expression and inhibited the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome. Notably, the protective effects of Srxn1 were significantly abrogated by the Sirt1 inhibitor EX527. CONCLUSION: The protective effects of Srxn1 against DOX-induced cardiac oxidative stress and inflammation operate by targeting the Sirt1/NLRP3 signaling pathway to alleviate DIC. Srxn1 could be a potential candidate for the treatment of DOX-induced myocardial injury.

Precise Identification of Glioblastoma Micro-Infiltration at Cellular Resolution by Raman Spectroscopy.

Precise identification of glioblastoma (GBM) microinfiltration, which is essential for achieving complete resection, remains an enormous challenge in clinical practice. Here, the study demonstrates that Raman spectroscopy effectively identifies GBM microinfiltration with cellular resolution in clinical specimens. The spectral differences between infiltrative lesions and normal brain tissues are attributed to phospholipids, nucleic acids, amino acids, and unsaturated fatty acids. These biochemical metabolites identified by Raman spectroscopy are further confirmed by spatial metabolomics. Based on differential spectra, Raman imaging resolves important morphological information relevant to GBM lesions in a label-free manner. The area under the receiver operating characteristic curve (AUC) for Raman spectroscopy combined with machine learning in detecting infiltrative lesions exceeds 95%. Most importantly, the cancer cell threshold identified by Raman spectroscopy is as low as 3 human GBM cells per 0.01 mm2. Raman spectroscopy enables the detection of previously undetectable diffusely infiltrative cancer cells, which holds potential value in guiding complete tumor resection in GBM patients.

First copy number variant in trans with single nucleotide variant in CCN6 causing progressive pseudorheumatoid dysplasia revealed by genome sequencing and deep phenotyping in monozygotic twins.

Biallelic pathogenic variants in CCN6 cause progressive pseudorheumatoid dysplasia (PPD), a rare skeletal dysplasia. The predominant features include noninflammatory progressive joint stiffness and enlargement, which are not unique to this condition. Nearly 100% of the reported variants are single nucleotide variants or small indels, and missing of a second variant has been reported. Genome sequencing (GS) covers various types of variants and deep phenotyping (DP) provides detailed and precise information facilitating genetic data interpretation. The combination of GS and DP improves diagnostic yield, especially in rare and undiagnosed diseases. We identified a novel compound heterozygote involving a disease-causing copy number variant (g.112057664_112064205del) in trans with a single nucleotide variant (c.624dup(p.Cys209MetfsTer21)) in CCN6 in a pair of monozygotic twins, through the methods of GS and DP. The twins had received three nondiagnostic results before. The g.112057664_112064205del variant was missed by all the tests, and the recorded phenotypes were inaccurate or even misleading. The twins were diagnosed with PPD, ending a 13-year diagnostic odyssey. There may be other patients with PPD experiencing underdiagnosis and misdiagnosis due to inadequate genetic testing or phenotyping methods. This case highlights the critical role of GS and DP in facilitating an accurate and timely diagnosis.

Efficacy and Safety of Multikinase Inhibitors for Patients With Refractory Thyroid Cancer: Systematic Review and Network Meta-Analysis.

CONTEXT: Multikinase inhibitors (MKIs) improve the treatment of refractory thyroid cancer, including radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) and advanced medullary thyroid carcinoma (aMTC). OBJECTIVE: This study aims to compare the efficacy of MKIs in improving survival outcomes and safety. DATA SOURCES: Comprehensive database searches of MEDLINE via PubMed, EMBASE, and Cochrane were performed from inception to December 2023. STUDY SELECTION: Three independent authors selected these studies. Randomized controlled trials that compared the use of a MKI to other MKIs or placebo were included. DATA EXTRACTION AND SYNTHESIS: This review followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Risk of bias was analyzed using the Cochrane risk of bias 2 tool. Bayesian network meta-analysis was performed. Treatments were grouped into common nodes based on the type of MKI. MAIN OUTCOMES AND MEASURES: Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included objective response rate, disease control rate, clinical benefit rate, and adverse events. RESULTS: Cabozantinib 60 mg/day (CAB60) was associated with the highest prolonged PFS in RAIR-DTC patients, followed by lentivatinib 18 or 24 mg/day (LEN18 or LEN24), and apatinib. PFS was also improved in aMTC patients who received CAB 140 mg/day (CAB140), CAB60, or anlotinib. A significantly greater improvement on the performance of OS was seen in CAB60, LEN24, anlotinib, and sorafenib in RAIR-DTC patients, but in aMTC patients there were lack of statistical differences. Compared with the low-dose MKIs, high-dose MKIs such as CAB, LEN, and vandetanib increased the incidence of adverse events. CONCLUSION: CAB60, LEN, and apatinib are promising topical MKIs with statistically significant primary outcomes in RAIR-DTC patients, while CAB and anlotinib are effective in prolonging PFS in aMTC patients.

Novel PLCZ1 compound heterozygous mutations indicate gene dosage effect involved in total fertilisation failure after ICSI.

In brief: PLCZ1 mutations are related to total fertilisation failure (TFF) after intracytoplasmic sperm injection (ICSI), characterised by abnormal oocyte oscillations. The novel PLCZ1 compound heterozygous mutations reported by this study were associated with TFF after ICSI, with one of the mutations indicating a gene dosage effect. Abstract: Oocyte activation failure is thought to be one of the main factors for total fertilisation failure (TFF) after intracytoplasmic sperm injection (ICSI), which could be induced by abnormal calcium oscillations. Phospholipase C zeta (PLCZ), a sperm factor, is associated with Ca2+ oscillations in mammalian oocytes. To date, some mutations in PLCZ1 (the gene that encodes PLCZ) have been linked to TFF, as demonstrated by the observed reduction in protein levels or activity to induce Ca2+ oscillations. In this study, normozoospermic males whose sperms exhibited TFF after ICSI and their families were recruited. First, mutations in the PLCZ1 sequence were identified by whole exome sequencing and validated using Sanger sequencing. Then, the locations of PLCZ1/PLCZ and the transcript and protein levels in the sperm of the patients were studied. Subsequently, in vitro function analysis and in silico analysis were performed to investigate the function-structure correlation of mutations identified in PLCZ1 using western blotting, immunofluorescence, RT-qPCR, and molecular simulation. Ca2+ oscillations were detected after cRNA microinjection into MII mouse oocytes to investigate calcium oscillations induced by abnormal PLCZ. Five variants with compound heterozygosity were identified, consisting of five new mutations and three previously reported mutations distributed across the main domains of PLCZ, except the EF hands domain. The transcript and protein levels decreased to varying degrees among all detected mutations in PLCZ1 when transfected in HEK293T cells. Among these, mutations in M138V and R391* of PLCZ were unable to trigger typical Ca2+ oscillations. In case 5, aberrant localisation of PLCZ in the sperm head and an increased expression of PLCZ in the sperm were observed. In conclusion, this study enhances the potential for genetic diagnosis of TFF in clinics and elucidates the possible relationship between the function and structure of PLCZ in novel mutations.

Genome-Scale Multimodal Analysis of Cell-Free DNA Whole-Methylome Sequencing for Noninvasive Esophageal Cancer Detection.

PURPOSE: Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection. MATERIALS AND METHODS: Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model. RESULTS: ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates. CONCLUSION: This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

Safety and Efficiency of Anlotinib in Patients with Recurrent Grade 4 Glioma: A Single-Center Retrospective Analysis.

PURPOSE: Anlotinib is a multi-target TKI which has been used in different advanced tumors. However, its efficiency and safety in patients with glioblastoma are still not well discussed. This retrospective study aimed to discover the safety and efficiency of anlotinib in recurrent grade 4 glioma. METHODS: The clinical data of patients with recurrent grade 4 glioma treated with anlotinib in our center were collected and analyzed. The progression-free survival (PFS), overall survival (OS), and OS after recurrence were calculated by Kaplan-Meier method and compared by log-rank test. Sub-group analysis was used to find possible variables that affect survival. RESULTS: From October 2017 to December 2020, seventeen patients with recurrent grade 4 glioma treated with anlotinib were enrolled. The median age was 50 with 13 males. The median KPS was 70. All patients received standard STUPP mode treatment before recurrence. The median PFS was 7 months [95% confidence interval (CI) 5.3-8.6]. The median OS after first diagnosis was 17 months (95% CI 15.7-18.3). The median OS after recurrence was 10 months (95% CI 7.6-12.4). The objective response rate was 33.33% (5/15), and the disease control rate was 60% (9/15). The existence of target genes was identified as a variable affecting the survival after recurrence. The median OS after recurrence in patients with target genes was 12 months (95% CI 6.9-17.1), whereas for patients without targets, the median OS was 4 months (95% CI 1.9-6.1) and for patients with an unknown status, the median OS was 10 months (95% CI 8.4-11.6) (P = 0.013). CONCLUSION: For recurrent grade 4 glioma, anlotinib can be considered as a supplement to the standard STUPP treatment, especially for the patient with anlotinib target genes.

Spiritual needs of women with breast cancer: A structural equation model.

PURPOSE: The purpose of this study was to develop a structural equation model (SEM) to explore the factors influencing the spiritual needs of breast cancer patients. METHODS: A cross-sectional study was conducted in the breast surgery department of a tertiary hospital in China from September 2020 to December 2020; convenience sampling and questionnaires were used to facilitate sampling and data collection. A total of 220 female breast cancer patients were included in the study. The data were analysed using multiple linear regression and structural equation modelling. RESULTS: Compared with patients with other diseases, patients with breast cancer have greater spiritual needs (76.16 ± 13.19). Multivariate analysis revealed that religious beliefs, education level, social support, and resilience are important factors affecting the mental health of women with cancer (p < 0.05). The structural equation model fit well (RMSEA = 0.056, χ2p = 0.002). Social support directly affected spiritual needs (ß = 0.607, p < 0.001) and indirectly affected spiritual needs through resilience (ß = 0.353, p < 0.001). Resilience directly affected spiritual needs (ß = 0.386, p < 0.05). Education level indirectly affected spiritual needs through social support (ß = 0.307, p < 0.001). CONCLUSION: This study provides a theoretical basis for intervention measures to improve the spiritual needs of female breast cancer patients. Paying more attention to social support and resilience may help solve the problem of meeting the high spiritual needs of breast cancer patients. Further research is needed to develop interventions.