ITGAV Promotes the Progression of Head and Neck Squamous Cell Carcinoma.

Head and neck squamous cell carcinoma (HNSCC) refers to the malignancy of squamous cells in the head and neck region. Ranked as the seventh most common cancer worldwide, HNSCC has a very low survival rate, highlighting the importance of finding therapeutic targets for the disease. Integrins are cell surface receptors that play a crucial role in mediating cellular interactions with the extracellular matrix (ECM). Within this protein family, Integrin αV (ITGAV) has received attention for its important functional role in cancer progression. In this study, we first demonstrated the upregulation of ITGAV expression in HNSCC, with higher ITGAV expression levels correlating with significantly lower overall survival, based on TCGA (the Cancer Genome Atlas) and GEO datasets. Subsequent in vitro analyses revealed an overexpression of ITGAV in highly invasive HNSCC cell lines UM1 and UMSCC-5 in comparison to low invasive HNSCC cell lines UM2 and UMSCC-6. In addition, knockdown of ITGAV significantly inhibited the migration, invasion, viability, and colony formation of HNSCC cells. In addition, chromatin immunoprecipitation (ChIP) assays indicated that SOX11 bound to the promoter of ITGAV gene, and SOX11 knockdown resulted in decreased ITGAV expression in HNSCC cells. In conclusion, our studies suggest that ITGAV promotes the progression of HNSCC cells and may be regulated by SOX11 in HNSCC cells.

The efficacy of medial meniscal posterior Root tear Repair with or without high tibial osteotomy: a systematic review.

BACKGROUND: Medial meniscal posterior root tear (MMPRTs) is a common lesion of the knee joint, and repair surgery is a well-established treatment option. However, patients with obvious varus alignment are at an increased risk for MMPRT and can suffer from a greater degree of medial meniscus extrusion, which leads to the development of osteoarthritis following repair. The efficacy of high tibial osteotomy (HTO) as a means of correcting this malformation, and its potential benefits for MMPRT repair, remains unclear. PURPOSE: To explore whether HTO influenced the outcome of MMPRT repair in clinical scores and radiological findings. STUDY DESIGN: Systematic review. METHODS: According to the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analyses) guidelines, we searched PubMed, Embase, Web of Science, and the Cochrane Library databases for studies reporting the outcomes of MMPRT repair and extracted data about characteristics of patients, clinical functional scores and radiologic outcomes. One reviewer extracted the data and 2 reviewers assessed the risk of bias and performed a synthesis of the evidence. Articles were eligible if they reported the results of MMPRT repair with exact mechanical axis (registered in the International Prospective Register of Systematic Reviews, CRD42021292057). RESULTS: Fifteen studies with 625 cases of high methodological quality were identified. Eleven studies were assigned to the MMPRT repair group (M) with 478 cases performing MMPRT repair only, and others belonged to the MMPRT repair and HTO group (M and T) performing HTO and MMPRT repair. Most of the studies had significantly improved clinical outcome scores, especially in M groups. And the radiologic outcomes showed that the osteoarthritis deteriorated in both groups with similar degree in about 2-year follow-up. CONCLUSION: HTO is a useful supplement in treating MMPRT patients with severe osteoarthritis and the clinical and radiological outcomes were similar with MMPRT repair alone. Which would be better for patients' prognosis generally, performing MMPRT repair alone or a combination of HTO and MMPRT repair, was still controversial. We suggested taking K-L grade into account. Large-scale randomized control studies were called for in the future to help make better clinical decisions. LEVEL OF EVIDENCE: III.

Structures of the human Wilson disease copper transporter ATP7B.

The P-type ATPase ATP7B exports cytosolic copper and plays an essential role in the regulation of cellular copper homeostasis. Mutants of ATP7B cause Wilson disease (WD), an autosomal recessive disorder of copper metabolism. Here, we present cryoelectron microscopy (cryo-EM) structures of human ATP7B in the E1 state in the apo, the putative copper-bound, and the putative cisplatin-bound forms. In ATP7B, the N-terminal sixth metal-binding domain (MBD6) binds at the cytosolic copper entry site of the transmembrane domain (TMD), facilitating the delivery of copper from the MBD6 to the TMD. The sulfur-containing residues in the TMD of ATP7B mark the copper transport pathway. By comparing structures of the E1 state human ATP7B and E2-Pi state frog ATP7B, we propose the ATP-driving copper transport model of ATP7B. These structures not only advance our understanding of the mechanisms of ATP7B-mediated copper export but can also guide the development of therapeutics for the treatment of WD.

Clinicopathological Features of Kidney Injury Related to Immune Checkpoint Inhibitors: A Systematic Review.

(1) Background: Despite increasing recognition of immune checkpoint inhibitors (ICIs) and kidney immune-related adverse events (IRAEs), no large-sample studies have assessed the pathological characteristics and outcomes of biopsy-proven kidney IRAEs. (2) Methods: We comprehensively searched PubMed, Embase, Web of Science, and Cochrane for case reports, case series, and cohort studies for patients with biopsy-proven kidney IRAEs. All data were used to describe pathological characteristics and outcomes, and individual-level data from case reports and case series were pooled to analyze risk factors associated with different pathologies and prognoses. (3) Results: In total, 384 patients from 127 studies were enrolled. Most patients were treated with PD-1/PD-L1 inhibitors (76%), and 95% presented with acute kidney disease (AKD). Acute tubulointerstitial nephritis/acute interstitial nephritis (ATIN/AIN) was the most common pathologic type (72%). Most patients (89%) received steroid therapy, and 14% (42/292) required RRT. Among AKD patients, 17% (48/287) had no kidney recovery. Analyses of pooled individual-level data from 221 patients revealed that male sex, older age, and proton pump inhibitor (PPI) exposure were associated with ICI-associated ATIN/AIN. Patients with glomerular injury had an increased risk of tumor progression (OR 2.975; 95% CI, 1.176, 7.527; p = 0.021), and ATIN/AIN posed a decreased risk of death (OR 0.164; 95% CI, 0.057, 0.473; p = 0.001). (4) Conclusions: We provide the first systematic review of biopsy-proven ICI-kidney IRAEs of interest to clinicians. Oncologists and nephrologists should consider obtaining a kidney biopsy when clinically indicated.

Structural mechanisms of TRPV2 modulation by endogenous and exogenous ligands.

The transient receptor potential vanilloid 2 (TRPV2) ion channel is a polymodal receptor widely involved in many physiological and pathological processes. Despite many TRPV2 modulators being identified, whether and how TRPV2 is regulated by endogenous lipids remains elusive. Here, we report an endogenous cholesterol molecule inside the vanilloid binding pocket (VBP) of TRPV2, with a 'head down, tail up' configuration, resolved at 3.2 Å using cryo-EM. Cholesterol binding antagonizes ligand activation of TRPV2, which is removed from VBP by methyl-ß-cyclodextrin (MßCD) as resolved at 2.9 Å. We also observed that estradiol (E2) potentiated TRPV2 activation by 2-aminoethoxydiphenyl borate (2-APB), a classic tool compound for TRP channels. Our cryo-EM structures (resolved at 2.8-3.3 Å) further suggest how E2 disturbed cholesterol binding and how 2-APB bound within the VBP with E2 or without both E2 and endogenous cholesterol, respectively. Therefore, our study has established the structural basis for ligand recognition of the inhibitory endogenous cholesterol and excitatory exogenous 2-APB in TRPV2.

Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel.

Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel, is gated by intracellular adenosine diphosphate ribose (ADPR), Ca2+, warm temperature, and oxidative stress. It is critically involved in physiological and pathological processes ranging from inflammation to stroke to neurodegeneration. At present, the channel's gating and ion permeation mechanisms, such as the location and identity of the selectivity filter, remain ambiguous. Here, we report the cryo-electron microscopy (cryo-EM) structure of human TRPM2 in nanodisc in the ligand-free state. Cryo-EM map-guided computational modeling and patch-clamp recording further identify a quadruple-residue motif as the ion selectivity filter, which adopts a restrictive conformation in the closed state and acts as a gate, profoundly contrasting with its widely open conformation in the Nematostella vectensis TRPM2. Our study reveals the gating of human TRPM2 by the filter and demonstrates the feasibility of using cryo-EM in conjunction with computational modeling and functional studies to garner structural information for intrinsically dynamic but functionally important domains.

Safety and Efficacy of the Rechallenge of Immune Checkpoint Inhibitors After Immune-Related Adverse Events in Patients With Cancer: A Systemic Review and Meta-Analysis.

Introduction: Little evidence exists on the safety and efficacy of the rechallenge of immune checkpoint inhibitors (ICIs) after immune-related adverse events (irAEs) in patients with cancer. Methods: We searched PubMed, Web of Science, Embase, and Cochrane for articles on ICI rechallenge after irAEs for systemic review and meta-analysis. The outcomes included the incidence and associated factors for safety and objective response rate (ORR) and disease control rate (DCR) for efficacy. Results: A total of 789 ICI rechallenge cases from 18 cohort studies, 5 case series studies, and 54 case reports were included. The pooled incidence of all-grade and high-grade irAEs after rechallenge in patients with cancer was 34.2% and 11.7%, respectively. Compared with initial ICI treatment, rechallenge showed a higher incidence for all-grade irAEs (OR, 3.81; 95% CI, 2.15-6.74; p < 0.0001), but similar incidence for high-grade irAEs (p > 0.05). Types of initial irAEs (pneumonitis and global irAEs) and cancer (non-small cell lung cancer and multiple cancer) recapitulated these findings. Gastrointestinal irAEs and time interval between initial irAEs and ICI rechallenge were associated with higher recurrence of high-grade irAEs (p < 0.05), whereas initial anti-PD-1/PD-L1 antibodies were associated with a lower recurrence (p < 0.05). Anti-PD-1/PD-L1 antibodies rechallenge was associated with a lower all-grade irAE recurrence (p < 0.05). The pooled ORR and DCR after rechallenge were 43.1% and 71.9%, respectively, showing no significant difference compared with initial ICI treatment (p > 0.05). Conclusions: ICI rechallenge after irAEs showed lower safety and similar efficacy outcomes compared with initial ICI treatment. Systematic Review Registration: PROSPERO, identifier CRD42020191405.

Difference Between Medical and Nonmedical Students on Knowledge, Practice, and Attitude Towards the Human Papillomavirus Vaccine in China: a Cross-Sectional Study.

HPV vaccine can prevent HPV infection effectively. The college student's vaccination status is unclear in mainland China. We assessed the knowledge, practice, and attitude towards HPV vaccine and compared the differences between medical and nonmedical students. It was a cross-sectional study using self-administered anonymous questionnaires. Nine-hundred sixty full-time college students were recruited randomly at Peking University in China. The medical students had higher level of knowledge of HPV and its vaccine than the nonmedical students (p < 0.001). The vaccinated female students were 9.0%. The high-grade clinical students had a higher uptake rate than the nonmedical students (19.5 vs 8.6%, p < 0.05). Awareness of HPV (p < 0.01), awareness of the vaccine (p < 0.001), and vaccinated family members or friends (p < 0.001) were related to the nonmedical students' vaccination. Vaccinated family members or friends were significant predictor for students' vaccination status (p < 0.001). Medical students knew more about HPV and its vaccine than nonmedical students. Female students' vaccinated rate was low, and the high-grade clinical students had a higher uptake rate than the nonmedical students.

Efficacy and safety of different fractions in stereotactic body radiotherapy for spinal metastases: A systematic review.

BACKGROUND: In the treatment of spinal metastases, stereotactic body radiotherapy (SBRT) delivers precise, high-dose radiation to the target region while sparing the spinal cord. A range of doses and fractions had been reported; however, the optimal prescribed scheme remains unclear. METHODS: Two reviewers performed independent literature searches of the PubMed, EMBASE, Cochrane Database, and Web of Science databases. Articles were divided into one to five fractions groups. The Methodological Index for Non-randomized Studies (MINORS) was used to assess the quality of studies. Local control (LC) and overall survival (OS) were presented for the included studies and a pooled value was calculated by the weighted average. RESULTS: The 38 included studies comprised 3,754 patients with 4,731 lesions. The average 1-year LCs for the one to five fractions were 92.7%, 84.6%, 86.8%, 82.6%, and 80.6%, respectively. The average 1-year OS for the one to five fractions were 53.0%, 70.4%, 60.1%, 48%, and 80%, respectively. The 24 Gy/single fraction scheme had a higher 1-year LC (98.1%) than those of 24 Gy/two fractions (85.4%), 27 Gy/three fractions (84.9%), and 24 Gy/three fractions (89.0%). The incidence of vertebral compression fracture was 10.3%, with 10.7% in the single-fraction group and 10.1% in the multi-fraction group. The incidence of radiation-induced myelopathy was 0.19%; three and two patients were treated with single-fraction and multi-fraction SBRT, respectively. The incidence of radiculopathy was 0.30% and all but one patient were treated with multi-fraction SBRT. CONCLUSIONS: SBRT provided satisfactory efficacy and acceptable safety for spinal metastases. Single-fraction SBRT demonstrated a higher local control rate than those of the other factions, especially the 24 Gy dose. The risk of vertebral compression fracture (VCF) was slightly higher in single-fraction SBRT and more patients developed radiculopathy after multi-fraction SBRT.

Src Inhibits the Hippo Tumor Suppressor Pathway through Tyrosine Phosphorylation of Lats1.

The Hippo pathway regulates cell proliferation, apoptosis, and stem cell self-renewal, and its inactivation in animal models causes organ enlargement followed by tumorigenesis. Hippo pathway deregulation occurs in many human cancers, but the underlying mechanisms are not fully understood. Here, we report tyrosine phosphorylation of the Hippo pathway tumor suppressor LATS1 as a mechanism underlying its regulation by cell adhesion. A tyrosine kinase library screen identified Src as the kinase to directly phosphorylate LATS1 on multiple residues, causing attenuated Mob kinase activator binding and structural alteration of the substrate-binding pocket in the kinase domain. Cell matrix adhesion activated the Hippo pathway effector transcription coactivator YAP partially through Src-mediated phosphorylation and inhibition of LATS1. Aberrant Src activation abolished the tumor suppressor activity of LATS1 and induced tumorigenesis in a YAP-dependent manner. Protein levels of Src in human breast cancer tissues correlated with accumulation of active YAP dephosphorylated on the LATS1 target site. These findings reveal tyrosine phosphorylation of LATS1 by Src as a novel mechanism of Hippo pathway regulation by cell adhesion and suggest Src activation as an underlying reason for YAP deregulation in tumorigenesis. Cancer Res; 77(18); 4868-80. ©2017 AACR.