Male breast cancer differs from female breast cancer in molecular features that affect prognoses and drug responses.

BACKGROUND: Male breast cancer (MBC) is a rare malignancy with a worse prognosis than female breast cancer (FBC). Current MBC treatment strategies are based on those for FBC. However, molecular differences between MBC and FBC with respect to prognosis and drug responses remain unclear. METHODS: After controlling for confounding factors with propensity score matching (PSM), differences between MBC and FBC were comprehensively analyzed using many types of data: survival, immune microenvironments, sex hormone responses, drug sensitivity, transcriptomes, genomes, epigenomes, and proteomes. RESULTS: Overall survival (OS) and cancer-specific survival (CSS) were both worse for MBC than for FBC. Differentially expressed mRNAs were enriched in numerous cancer-related functions and pathways, with SPAG16 and STOX1 being as the most important prognosis-related mRNAs for MBC. Competing endogenous RNA (ceRNA) and transcription factor (TF)-mRNA regulatory networks contain potential prognostic genes. Nine genes had higher mutation frequencies in MBC than in FBC. MBC shows a comparatively poor response to immunotherapy, with five proteins that promote breast cancer progression being highly expressed in MBC. MBC may be more responsive than FBC to estrogen. We detected six United States Food and Drug Administration (FDA)-approved therapeutic target genes as being differentially expressed between MBC and FBC. CONCLUSION: The poor prognosis of MBC compared to FBC is due to numerous molecular differences and resulting drug responses.

Diagnostic strategy of metagenomic next-generation sequencing for gram negative bacteria in respiratory infections.

OBJECTIVE: This study aims to identify the most effective diagnostic method for distinguishing pathogenic and non-pathogenic Gram-negative bacteria (GNB) in suspected pneumonia cases using metagenomic next-generation sequencing (mNGS) on bronchoalveolar lavage fluid (BALF) samples. METHODS: The effectiveness of mNGS was assessed on BALF samples collected from 583 patients, and the results were compared with those from microbiological culture and final clinical diagnosis. Three interpretational approaches were evaluated for diagnostic accuracy. RESULTS: mNGS outperformed culture significantly. Among the interpretational approaches, Clinical Interpretation (CI) demonstrated the best diagnostic performance with a sensitivity of 87.3%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 98.3%. CI's specificity was significantly higher than Simple Interpretation (SI) at 37.9%. Additionally, CI excluded some microorganisms identified as putative pathogens by SI, including Haemophilus parainfluenzae, Haemophilus parahaemolyticus, and Klebsiella aerogenes. CONCLUSION: Proper interpretation of mNGS data is crucial for accurately diagnosing respiratory infections caused by GNB. CI is recommended for this purpose.

Optimizing Cervical Target Volume in Patients with Nasopharyngeal Cancer Based On Nodal Drainage Distance.

PURPOSE: To determine the potential nodal drainage distances of nasopharyngeal carcinoma (NPC) by investigating spatial distribution of metastatic lymph nodes (LN). EXPERIMENTAL DESIGN: Patients with NPC harboring at least two ipsilateral metastatic LNs were enrolled. LN spreading distances were analyzed in nonrestricted direction, cranial-to-caudal direction, and between the two most caudal LNs. Euclidean distance (ED) and vertical distance (VD) between any two LNs were computed. The nearest-neighbor ED and VD covering 95% of LNs or patients (p95-ED and p95-VD) were considered drainage distances, and were further validated by independent internal and external cohorts with recurrent LNs. RESULTS: In all, 5,836 metastatic LNs in 948 patients were contoured. Corresponding to the three scenarios, per-LN level, the p95-EDs were 2.83, 3.28, and 3.55 cm, and p95-VDs were 2.17, 2.32, and 2.63 cm, respectively. Per-patient level, the p95-EDs were 3.25, 3.95, and 3.81 cm, and p95-VDs were 2.67, 2.81, and 2.73 cm, respectively. In internal validation, over 95% of recurred LNs occurred within ED of 2.91 cm and VD of 0.82 cm to the neighbor LN, and the corresponding distances in external validation were 2.77 and 0.67 cm, respectively. CONCLUSIONS: In NPC, the maximum LN drainage distance was 3.95 cm without considering the direction. Specifically, in cranial-to-caudal direction, the sufficient vertical drainage distance was 2.81 cm, indicating that a 3-cm extension from the most inferior node may be rational as caudal border of the prophylactic clinical target volume (CTV). These findings promote in-depth understanding of nodal spreading patterns, uncovering paramount evidence for individualized CTV.

An antihypertensive drug-AT1 inhibitor attenuated BRCA development promoted by chronic psychological stress via Ang II/PARP1/FN1 pathway.

Chronic psychological stress contributes to the occurrence of cancer and activates the renin-angiotensin system (RAS). However, the mechanisms by which RAS promotes the progression of breast cancer (BRCA) under chronic psychological stress are remain unknown. In this study, we observed elevated levels of Angiotensin II (Ang II) in both serum and BRCA tissue under chronic stress, leading to accelerated BRCA growth in a mouse model. An antihypertensive drug, candesartan (an AT1 inhibitor), effectively attenuated Ang II-induced cell proliferation and metastasis. Utilizing mass spectrometry and weighted gene co-expression network analysis (WGCNA), we identified fibronectin 1 (FN1) as the hub protein involved in chronic stress-Ang II/AT1 axis. Focal adhesion pathway was identified as a downstream signaling pathway activated during the progression of chronic stress. Depletion of FN1 significantly attenuated Ang II-induced proliferation and metastasis of BRCA cells. Poly (ADP-ribose) polymerase 1 (PARP1) was found to bind to the DNA promoter of FN1, leading to the transcription of FN1. Ang II upregulated PARP1 expression, resulting in increased FN1 levels. Recombinant FN1 partially restored the progress of BRCA malignancy induced by the Ang II/PARP1 pathway. In vivo, candesartan reversed the progressive effect of chronic psychological stress on BRCA. In clinical samples, Ang II levels in both serum and tumor tissues are higher in stressed patients compared to control patients. Serum Ang II levels were positively correlated with chronic stress indicators. In conclusion, our study demonstrated that chronic psychological stress accelerates the malignancy of BRCA, and the AT1 inhibitor candesartan counteracts these effects by suppressing the Ang II-AT1 axis and the downstream PARP1/FN1/focal adhesion pathway.

Long-Term Outcomes of Endoscopic Resection versus Open Surgery for Locally Advanced Sinonasal Malignancies in Combination with Radiotherapy.

Objective Our objective was to compare the long-term outcomes of endoscopic resection versus open surgery in combination with radiotherapy for locally advanced sinonasal malignancies (SNMs). Methods Data for continuous patients with sinonasal squamous cell carcinoma and adenocarcinoma who received surgery (endoscopic or open surgery) combined with radiotherapy in our center between January 1999 and December 2016 were retrospectively reviewed. A 1:1 matching with propensity scores was performed. Overall survival (OS), progression-free survival (PFS), and local recurrence rate (LRR) were evaluated. Results We identified 267 eligible patients, 90 of whom were included after matching: 45 patients in the endoscopy group and 45 in the open group. The median follow-up time was 87 months. In the endoscopic group, 84.4% of patients received intensity-modulated radiotherapy (IMRT), with a mean gross tumor volume (GTV) dose of 68.28 Gy; in the open surgery group, 64.4% of patients received IMRT, with a mean GTV dose of 64 Gy. The 5-year OS, PFS, and LRR were 69.9, 58.6, and 24.5% in the endoscopic group and 64.6, 54.4, and 31.8% in the open surgery group, respectively. Multivariable regression analysis revealed that the surgical approach was not associated with lower OS, PFS, or LRR. The overall postoperative complications were 13% in the endoscopic group, while 21.7% in the open group. Conclusion For patients with locally advanced SNMs, minimally invasive endoscopic resection, in combination with a higher radiation dose and new radiation techniques such as IMRT, yields survival outcomes similar to those of open surgery in combination with radiotherapy.

Percutaneous Endoscopic Lumbar Discectomy for Calcified Lumbar Disc Herniation: A Retrospective Cohort Study, Systematic Review and Meta-Analysis.

BACKGROUND: Calcified lumbar disc herniation (CLDH) is a subtype characterized by calcification, leading to increased surgical complexity. Percutaneous endoscopic lumbar discectomy (PELD) is a minimally invasive technique, but its effectiveness and complications in CLDH patients remain to be fully evaluated. OBJECTIVE: To assess the effectiveness and complications of PELD in treating CLDH patients. STUDY DESIGN: A retrospective cohort study combined with a systematic review and meta-analysis. SETTING: Department of Pain Medicine, an affiliated hospital of a university. METHODS: Data from patients who underwent PELD in our department between March 2020 and May 2021 were collected. Forty CLDH patients were included in the study group, and equally matched cases with uncalcified lumbar disc herniation (UCLDH) served as controls. A systematic search was conducted on October 5, 2022, using EMBASE, PubMed, Cochrane Library, the China Biology Medicine disk, the China National Knowledge Infrastructure, and the Wanfang databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A random-effects model was used to calculate pooled results. RESULTS: Eighty patients were included in the retrospective cohort, and 41 studies were included in the meta-analysis. Both the retrospective cohort and meta-analysis consistently showed a significant decrease in visual analog scale (VAS) and Oswestry Disability Index (ODI) scores in the CLDH group after the operation. In the retrospective cohort, the excellent or good rate according to the MacNab classification was 85%, with no reported complications. The meta-analysis revealed a pooled excellent or good rate of 91.8% and a low complication rate of 2.9%. Combining the findings from our retrospective cohort and meta-analysis, we observed that the CLDH group had longer operation times and slightly higher postoperative ODI scores compared to the UCLDH group. LIMITATIONS: Small sample size and lack of long-term follow-up in the retrospective cohort, as well as limited inclusion of comparative studies in the meta-analysis. CONCLUSION: PELD is an effective and safe treatment option for CLDH patients. In comparison to UCLDH patients, CLDH patients may experience longer operation times and slightly slower functional recovery than those with UCLDH.

A novel, highly sensitive, one-tube nested quantitative real-time PCR for Brucella in human blood samples.

IMPORTANCE: This study developed a highly sensitive and efficient method for the detection of brucellosis by introducing a one-tube nested quantitative real-time PCR (qPCR) approach, representing a remarkable advance in the field. The method demonstrated an impressive analytical sensitivity of 100 fg/µL, surpassing conventional qPCR and enabling the detection of even low levels of Brucella DNA. In addition, the study's comprehensive evaluation of 250 clinical samples revealed a specificity of 100% and a sensitivity of 98.6%, underscoring its reliability and accuracy. Most importantly, the new method significantly improved the detection rate of low-burden samples, reducing cycle threshold values by an average of 6.4. These results underscore the immense potential of this approach to facilitate rapid and accurate brucellosis diagnosis, which is critical for effective disease management and control.

Clinical Characteristics and Long-Term Outcomes following Surgery Combined with Adjuvant Radiotherapy for Patients with Frontal Sinus Malignancies.

Objectives Primary frontal sinus malignancies (FSMs) are the rarest sinonasal cancers. This study aimed to determine clinicopathologic characteristics of primary FSMs and provide long-term survival outcomes. Design This study is a retrospective review. Setting The study was conducted at a tertiary medical center. Participants Patients who participated in this study were diagnosed with primary FSMs. Main Outcome Measures Median survival time is the primary outcome measure of this study. Results In this series, the median age was 48 years (30-53 years) and all patients were male. There were five cases with squamous cell carcinoma and one with osteosarcoma. All cases presented with locally advanced disease without regional lymphatic metastasis, including five cases of stage III and one case of stage II. The two most common pathways of tumor invasion were as follows: local tumor broke posteriorly through bone wall and invaded dura mater, followed by frontal lobe; local tumor infiltrated downward through the floor of frontal sinus into ethmoid sinus, thereafter invaded laterally orbit and orbital contents. All patients received surgery followed by postoperative radiotherapy at the total doses of 50 to 75.95 Gy. Among them, only one patient underwent R0 resection, the rest of patients underwent R1/R2 resection. With a median survival time of 56 months (32-76 months), two patients receiving R1/R2 resection developed treatment failure and died within 5 years, including one case with local recurrence and one with local recurrence, thereafter distant metastasis. Conclusion The majority of FSMs presented with peripherally invasive progression lesions which led to a high ratio of R1/R2 resection. Surgery combined with postoperative radiotherapy might result in satisfactory efficacy.

Failure Patterns Within Different Histological Types in Sinonasal Malignancies: Making the Complex Simple.

OBJECTIVE: To analyze the failure patterns in patients with different histological subtypes of sinonasal malignancies (SNMs). STUDY DESIGN: Retrospectively gathered data. SETTING: Academic university hospital. METHODS: Patients with SNMs treated at a tertiary referral center between January 1999 and January 2019 were included. We assessed the failure patterns within different histological subtypes. RESULTS: The study included 897 patients. The median follow-up time was 100 months. Adenoid cystic carcinoma (ACC) had a moderate risk of developing local recurrence (LR) and distant metastasis (DM). Compared with ACC, squamous cell carcinoma (SCC), adenocarcinoma (AC), soft tissue sarcoma (STS), and mucosal melanoma (MM) were classified as a high LR risk group. For DM, neuroendocrine carcinoma (NEC), STS, and MM were in the high-risk group. CONCLUSIONS: ACC had intermediate local and distant failure risks, while SCC, AC, STS, and MM were at high LR risks. NEC, STS, and MM were at high DM risk.

Urinary SPP1 has potential as a non-invasive diagnostic marker for focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a type of chronic glomerular nephropathy showing characteristic glomerular sclerosis, diagnosed by kidney biopsy. However, it is difficult and expensive to monitor disease progression with repeated renal biopsy in clinical practice, and thus here we explored the feasibility of urine biomarkers as non-invasive diagnostic tools. We downloaded scRNA-seq datasets of 20 urine cell samples and 3 kidney tissues and obtained two gene lists encoding extracellular proteins for bioinformatic analysis; in addition, we identified key EP-Genes by immunohistochemical staining and performed bulk RNA sequencing with 12 urine samples. We report that urine cells and kidney cells were correlated. A total of 64 EP-Genes were acquired by intersecting genes of distal tubular cluster with extracellular proteins. Function enrichment analysis showed that EP-Genes might be involved in the immune response and extracellular components. Six key EP-Genes were identified and correlated with renal function. IMC showed that key EP-Genes were located mainly in tubules. Cross verification and examination of a urine RNAseq dataset showed that SPP1 had diagnostic potential for FSGS. The presence of urine SPP1 was primarily associated with macrophage infiltration in kidney, and the pathogenesis of FSGS may be related to innate immunity. Urinary cells seemed to be strongly similar to kidney cells. In summary, SPP1 levels reflect renal function and may have potential as a biomarker for non-invasive diagnosis of FSGS.

The metastasis patterns and their prognostic features in patients with de novo metastatic breast cancer of different ages.

PURPOSE: The prognostic outcomes of metastasis patterns in patients with de novo metastatic breast cancer (dnMBC) of different ages are unknown. Our study used a large-scale data to investigate the metastasis patterns and prognostic features in dnMBC of different ages. METHODS: Total 24,698 women with dnMBC in the Surveillance, Epidemiology and End Results database (2010-2018) were divided into three groups by age. Chi-squared test was used to compare metastasis patterns and logistic regression was performed to investigate the risk of age and specific organ metastases. Kaplan-Meier survival curves were used to compare the overall survival. RESULTS: In three groups, young group had the largest proportion of liver metastases (35.2% vs. 28.2% vs. 21.1%, p < 0.001), and elderly group had the largest proportion of lung metastases (22.6% vs. 30.0% vs. 35.0%, p < 0.001) and the lowest proportion of bone metastases (65.7% vs. 67.6% vs. 64.4%, p < 0.001). In young group, patients with liver metastases had better prognosis than patients with lung metastases (MST: 34 months vs. 29 months, p = 0.041), but in middle-aged and elderly groups, the prognosis of lung metastases was better than that of liver metastases (MST in middle-aged group: 24 months vs. 20 months, p = 0.002; MST in elderly group: 12 months vs. 6 months, p < 0.001). CONCLUSION: DnMBC patients at different age have distinct metastasis patterns and prognostic features. The findings lend support to consideration of tailored management and surveillance strategies for different age patients.

[Clinical characteristics and efficacy of oropharyngeal carcinoma with secondary primary tumor].

Objective:To analysis the clinical features and prognosis in oropharyngeal carcinoma with secondary primary tumor. Methods:A retrospective analysis was performed on 468 pathologically confirmed oropharyngeal cancer as the primary tumor patients with p16 status, excluded distant metastasis, and admitted to the Chinese Academy of Medical Sciences from January 2010 to December 2020. The clinical features and prognosis of the secondary primary tumor were analyzed. Results:Among 468 patients with oropharyngeal cancer treated at initial diagnosed, 222 cases were P16-negative. With a median follow-up time of 64.3 months, 66 cases developed second primary cancer, with an incidence of 29.3%, among which 63.6%（42/66） were synchronous and 36.4%（24/66） were heterochronous, esophagus was the most commonly involved site. The 5-year OS of p16-negative oropharyngeal carcinoma with synchronous second primary cancer, without second primary cancer and with heterogeneous second primary cancer were 26.3% and 57.3% and 73.2%（P=0.001）; The second primary cancer accounted for 11.2%（12/107） of the deaths in the whole group, among them, the heterochronous second primary accounted for 75.0%（9/12）. There were 246 patients with p16 positive, with a median follow-up time of 52.4 months, 20 patients developed second primary cancer（8.1%）. Among them, 65.0%（13/20） were synchronous and 35.0%（7/20） were heterochronous. Esophagus was the most commonly involved site. The 4-year OS of p16-positive with synchronous, heterochronous and non-second primary cancer group were 51.9%, 80.7% and 83.3%. Secondary primary cancer accounted for 3.8%（2/52） of all deaths in p16 positvie group. Conclusion:The incidence of second primary cancer of p16 positive and negative oropharyngeal carcinoma were different. The esophagus was the most commonly involved site regardless of p16 status. Regardless of p16 status, the survival of patients with synchronous second primary cancer was worse than those without second primary cancer. For p16-negative oropharyngeal carcinoma, the prognosis was better in patients with heterogeneous second primary cancer, the second primary cancer is one of the main causes of death.

[Comparison of different laryngeal preservation strategies based on chemoradiotherapy in locally advanced hypopharyngeal carcinoma].

Objective:This study aimed to evaluate the clinical features and treatment outcomes of the value of response-adapted treatment following radiotherapy and induction chemotherapy follwing subsequent comprehensive therapy in patients with resectable locally advanced hypopharyngeal carcinoma. Methods:This cohort study was conducted from September 2010 to September 2020 in our hospital, 231 patients pathologically confirmed stage Ⅲ and ⅣB resectable locally advanced hypopharyngeal carcinoma included. For the IC-directed ART strategy, IC is used to select good candidates to receive radical RT or CCRT, and others undergo surgery. He response-adapted strategy was determined based on the primary tumor response, which was evaluated at a dose of 50 Gy. If the response reached complete response or partial response（more than 80% tumor regression）, patients received radical RT or CCRT; otherwise, they received surgery, if possible, at 4 to 6 weeks after RT. The end points of the study were OS（overall survival）, progression free survival（PFS）, locoregional recurrence-free survival（LRRFS） and LDFS. Results:In IC-directed group, 75.0%（57/76） patients reached PR after 2 cycles of induction chemotherapy. While in RT-directed group, 70.3%（109/155） patients reached large PR at dose of 50 Gy. The median interquartile range follow-up period of the whole cohort was 63.8 months. The 5-year OS, PFS, LRRFS and SFL of the whole cohort were 47.9%、39.6%、44.3% and 36.2%, respectively. In evaluations based on the different treatment strategies, the 5-year OS and SFL were 51.3% versus 37.0%（HR 0.67; 95%CI 0.43-1.05; P=0.07） and 27.8% versus 39.8%（HR 0.68; 95%CI 0.46-0.99; P=0.04） between IC-directed and RT-directed groups. In additional, surgery complications did not significantly differ between these two groups. Conclusion:In this cohort study, the response-adapted strategy based on an early RT response facilitated better treatment tailoring, and higher laryngeal preservation compared with IC-directed strategies. This approach could provide a feasible laryngeal preservation strategy in patients with resectable locally advanced hypopharyngeal carcinoma.

Feasibility of omitting contralateral neck irradiation in patients with node-negative sinonasal squamous cell carcinoma crossing the midline.

BACKGROUND: Identifying the lymph node target volume in patients with node-negative sinonasal squamous cell carcinoma (SNSCC) crossing the midline poses a challenge. This study aims to address this. METHODS: We retrospectively reviewed clinically N0 patients with tumors crossing the midline who received elective neck irradiation (ENI) from two centers between 1999 and 2019. The main endpoint was regional relapse-free survival (RRFS). RESULTS: We included 104 patients: 64 received bilateral ENI, and 40 received ipsilateral-only ENI (median follow-up time was 89.99 and 95.01 months, respectively). At 5 years, the RRFS rates were comparable (57.68% vs. 55.83%, p = 0.372), as were the contralateral RRFS (57.68% vs. 61.62%, p = 0.541). Five-year OS, LRFS, and DMFS showed no significant difference between two groups. CONCLUSIONS: Our findings provide preliminary evidence suggesting the potential for avoiding contralateral ENI in SNSCC patients with midline crossing tumors who undergo ipsilateral ENI, covering at least level II. Validation through future prospective studies is necessary.

Apatinib plus etoposide in pretreated patients with advanced triple-negative breast cancer: a phase II trial.

BACKGROUND: Treatment options for pretreated triple-negative breast cancer (TNBC) are limited. This study aimed to evaluate the efficacy and safety of apatinib, an antiangiogenic agent, in combination of etoposide for pretreated patients with advanced TNBC. METHODS: In this single-arm phase II trial, patients with advanced TNBC who failed to at least one line of chemotherapy were enrolled. Eligible patients received oral apatinib 500 mg on day 1 to 21, plus oral etoposide 50 mg on day 1 to 14 of a 3-week cycle until disease progression or intolerable toxicities. Etoposide was administered up to six cycles. The primary endpoint was progression-free survival (PFS). RESULTS: From September 2018 to September 2021, 40 patients with advanced TNBC were enrolled. All patients received previous chemotherapy in the advanced setting, with the median previous lines of 2 (1-5). At the cut-off date on January 10, 2022, the median follow-up was 26.8 (1.6-52.0) months. The median PFS was 6.0 (95% confidence interval [CI]: 3.8-8.2) months, and the median overall survival was 24.5 (95%CI: 10.2-38.8) months. The objective response rate and disease control rate was 10.0% and 62.5%, respectively. The most common adverse events (AEs) were hypertension (65.0%), nausea (47.5%) and vomiting (42.5%). Four patients developed grade 3 AE, including two with hypertension and two with proteinuria. CONCLUSIONS: Apatinib combined with oral etoposide was feasible in pretreated advanced TNBC, and was easy to administer. CLINICAL TRIAL REGISTRATION: Chictr.org.cn, (registration number: ChiCTR1800018497, registration date: 20/09/2018).

Cytoplasmic YAP1-mediated ESCRT-III assembly promotes autophagic cell death and is ubiquitinated by NEDD4L in breast cancer.

BACKGROUND: Nuclear Yes1-associated transcriptional regulator (YAP1) promotes tumor progression. However, the function of cytoplasmic YAP1 in breast cancer cells and its impact on the survival of breast cancer patients remain unclear. Our research aimed to explore the biological function of cytoplasmic YAP1 in breast cancer cells and the possibility of cytoplasmic YAP1 as a predictive marker of breast cancer survival. METHODS: We constructed cell mutant models, including NLS-YAP15SA (nuclear localized), YAP1S94A (incapable of binding to the TEA domain transcription factor family) and YAP1S127D (cytoplasmic localized), and used Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) incorporation assays, and Western blotting (WB) analysis to detect cell proliferation and apoptosis. The specific mechanism of cytoplasmic YAP1-mediated endosomal sorting complexes required for transport III (ESCRT-III) assembly was studied by co-immunoprecipitation, immunofluorescence staining, and WB analysis. Epigallocatechin gallate (EGCG) was used to simulate YAP1 retention in the cytoplasm in in vitro and in vivo experiments to study the function of cytoplasmic YAP1. YAP1 binding to NEDD4-like E3 ubiquitin protein ligase (NEDD4L) was identified using mass spectrometry and was verified in vitro. Breast tissue microarrays were used to analyze the relationship between cytoplasmic YAP1 expression and the survival of breast cancer patients. RESULTS: YAP1 was mainly expressed in the cytoplasm in breast cancer cells. Cytoplasmic YAP1 promoted autophagic death of breast cancer cells. Cytoplasmic YAP1 bound to the ESCRT-III complex subunits charged multivesicular body protein 2B (CHMP2B) and vacuolar protein sorting 4 homolog B (VPS4B), promoting assembly of CHMP2B-VPS4B and activating autophagosome formation. EGCG retained YAP1 in the cytoplasm, promoting the assembly of CHMP2B-VPS4B to promote autophagic death of breast cancer cells. YAP1 bound to NEDD4L, and NEDD4L mediated ubiquitination and degradation of YAP1. Breast tissue microarrays revealed that high levels of cytoplasmic YAP1 were beneficial to the survival of breast cancer patients. CONCLUSIONS: Cytoplasmic YAP1 mediated autophagic death of breast cancer cells by promoting assembly of the ESCRT-III complex; furthermore, we established a new breast cancer survival prediction model based on cytoplasmic YAP1 expression.

17⍺-Estradiol Protects against HIV-1 Tat-Induced Endolysosome Dysfunction and Dendritic Impairments in Neurons.

HIV-1 Tat continues to play an important role in the development of HIV-associated neurocognitive disorders (HAND), which persist in 15-55% of people living with HIV even with virological control. In the brain, Tat is present on neurons, where Tat exerts direct neuronal damaging effects by, at least in part, disrupting endolysosome functions, a pathological feature present in HAND. In this study, we determined the protective effects of 17α-estradiol (17αE2), the predominant form of estrogen in the brain, against Tat-induced endolysosome dysfunction and dendritic impairment in primary cultured hippocampal neurons. We demonstrated that pre-treatment with 17αE2 protected against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Estrogen receptor alpha (ERα) knockdown impairs the ability of 17αE2 to protect against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Furthermore, over-expressing an ERα mutant that fails to localize on endolysosomes impairs 17αE2's protective effects against Tat-induced endolysosome dysfunction and reduction in dendritic spine density. Our findings demonstrate that 17αE2 protects against Tat-induced neuronal injury via a novel ERα-mediated and endolysosome-dependent pathway, and such a finding might lead to the development of novel adjunct therapeutics against HAND.

Sinonasal mucosal melanoma: Is there a need for elective neck irradiation?

BACKGROUND AND PURPOSE: Sinonasal mucosal melanoma (SNMM) is a rare malignant neoplasm. The regional failure pattern and effectiveness of elective neck irradiation (ENI) were not well defined. Here, we would assess the value of ENI for clinical node negative (cN0) SNMM patients. MATERIALS AND METHODS: A total of 107 SNMM patients treated at our institution over a period of 30 years was retrospectively analyzed. RESULTS: Five patients had lymph node metastases at diagnosis. Among the 102 cN0 patients analyzed, 37 patients had received ENI, and 65 patients had not. ENI significantly reduced the regional recurrence rate from 23.1% (15/65) to 2.7% (1/37). Ipsilateral levels Ib and II were the most common locations of regional relapse. Multivariate analysis also showed that ENI was the only independent favorable predictor for the achievement of regional control (HR: 9.120; 95% CI: 1.204-69.109; P = 0.032). CONCLUSION: This is the largest cohort of SNMM patients from a single institution analyzed for the assessment of the value of ENI on regional control and survival. ENI significantly reduced the regional relapse rate in our study. Ipsilateral levels Ib and II might be considerable when deliver elective neck irradiation, more evidence is needed in the future.

Comparing the bioequivalence and safety of liraglutide in healthy Chinese subjects: an open, single-dose, randomized, repeated, two-sequence, two-cycle phase I clinical trial.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is an endogenous incretin hormone. Liraglutide, a GLP-1 receptor agonist, can lower blood sugar by increasing insulin production and inhibiting the production of glucagon. This study researched the bioequivalence and safety of the test and reference drugs in healthy Chinese subjects. RESEARCH DESIGN AND METHODS: Subjects (N = 28) were randomly divided into group A and group B at a ratio of 1:1 for a two-cycle cross-over study. There was single dose per cycle with subcutaneous injection of the test and reference drugs, respectively. The washout was set at 14 days. Plasma drug concentrations were detected by specific liquid chromatography and tandem mass spectrometry (LC-MS/MS) assays. Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for the test and reference drugs were 107.11%, 106.56%, 106.09%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both had good safety in this study. CONCLUSION: The study shows that the two drugs had similar bioequivalence and safety. CLINICAL TRIAL REGISTRATION: DCTR: CTR20190914; ClinicalTrials.gov: NCT05029076.

Persistent response of furmonertinib plus anlotinib in a lung adenocarcinoma patient with an EGFR exon 20 insertion mutation: A case report.

Insertions in exon 20 represent the third most common type of EGFR mutation following in-frame deletions in exon 19 and the point mutation L858R in exon 21. They are generally associated with primary resistance to EGFR-TKIs. Although mobocertinib and amivantamab were approved for adult patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations, the efficacy of these two agents was rather moderate. Therefore, other more potent targeted agents are urgently needed. Here, we report a patient with advanced lung adenocarcinoma harboring an EGFR exon 20 insertion mutation (NM_005228: exon 20: c.2316_2321dup: p.773_774dup). After experiencing platinum-based chemotherapy, this patient received a combination of furmonertinib and anlotinib and achieved lasting stable disease (SD). The treatment was well tolerated, and only mild hand-foot syndrome was reported from the patient. To the best of our knowledge, this case firstly reported the encouraging efficacy of combined furmonertinib and anlotinib in an advanced lung adenocarcinoma patient with an EGFR exon 20 insertion mutation who was previously treated with platinum-based chemotherapy. In addition, we summarize the recent literature on therapies against NSCLC with EGFR exon 20 insertion mutations. This case might provide an alternative approach for clinical oncologists.