Ubiquitin-specific protease 22 controls melanoma metastasis and vulnerability to ferroptosis through targeting SIRT1/PTEN/PI3K signaling.

Metastasis is a major contributing factor that affects the prognosis of melanoma patients. Nevertheless, the underlying molecular mechanisms involved in melanoma metastasis are not yet entirely understood. Here, we identified ubiquitin-specific protease 22 (USP22) as a pro-oncogenic protein in melanoma through screening the survival profiles of 52 ubiquitin-specific proteases (USPs). USP22 demonstrates a strong association with poor clinical outcomes and is significantly overexpressed in melanoma. Ablation of USP22 expression remarkably attenuates melanoma migration, invasion, and epithelial-mesenchymal transition in vitro and suppresses melanoma metastasis in vivo. Mechanistically, USP22 controls melanoma metastasis through the SIRT1/PTEN/PI3K pathway. In addition, we conducted an United States Food and Drug Administration-approved drug library screening and identified topotecan as a clinically applicable USP22-targeting molecule by promoting proteasomal degradation of USP22. Finally, we found that both pharmacological and genetic silence of USP22 sensitize RSL3-induced ferroptosis through suppressing the PI3K/Akt/mTOR pathway and its downstream SCD, and ferroptosis inhibitor could partly rescued the decreased lung metastasis by topotecan in vivo. Overall, our findings reveal a prometastatic role of USP22 and identify topotecan as a potent USP22-targeting drug to limit melanoma metastasis.

Efficacy of a smartphone application assisting home-based rehabilitation and symptom management for patients with lung cancer undergoing video-assisted thoracoscopic lobectomy: a prospective, single-blinded, randomised control trial (POPPER study).

BACKGROUND: Video-assisted thoracoscopic (VATS) lobectomy can affect patients' pulmonary function and quality of life significantly. No optimal protocol combining patient-reported outcome-based symptom management and post-discharge rehabilitation programme has yet been established. This study aimed to assess the efficacy of a novel smartphone app designed for home-based symptom management and rehabilitation. METHODS: The app was developed based on three modules: a symptom reporting system with alerts, aerobic and respiratory training exercises, and educational material. Four core symptoms were selected based on a questionnaire survey of 201 patients and three rounds of Delphi voting by 30 experts. We screened 265 patients and randomly assigned 136 equally to the app group and usual care group. The primary outcome was pulmonary function recovery at 30 days postoperatively. Secondary outcomes included symptom burden and interference with daily living (both rated using the MD Anderson Symptom Inventory for Lung Cancer), aerobic exercise intensity, emergency department visits, app-related safety, and satisfaction with the app. FINDINGS: Of the 136 participants, 56.6% were women and their mean age was 61 years. The pulmonary function recovery ratio 1 month after surgery in the app group was significantly higher than that in the usual care group (79.32% vs. 75.73%; P=0.040). The app group also recorded significantly lower symptom burden and interference with daily living scores and higher aerobic exercise intensity after surgery than the usual care group. Thirty-two alerts were triggered in the app group. The highest pulmonary function recovery ratio and aerobic exercise intensity were recorded in those patients who triggered alerts in both groups. INTERPRETATION: Using a smartphone app is an effective approach to accelerate home-based rehabilitation after VATS lobectomy. The symptom alert mechanism of this app could optimise recovery outcomes, possibly driven by patients' increased self-awareness.

BRD4 inhibitor suppresses melanoma metastasis via the SPINK6/EGFR-EphA2 pathway.

BET inhibition or BRD4 depletion is a promising and attractive therapy for metastatic melanoma; however, the mechanism is still unclear. Here, we indicated that BET inhibition suppressed melanoma metastasis both in vitro and in vivo and identified a new mechanism by which BET inhibitors suppress melanoma metastasis by blocking the direct interaction of BRD4 and the SPINK6 enhancer. Moreover, we demonstrated that SPINK6 activated the EGFR/EphA2 complex in melanoma and the downstream ERK1/2 and AKT pathways. Thus, these results identified the SPINK6/EGFR-EphA2 axis as a new oncogenic pathway in melanoma metastasis and support the further development of BRD4 inhibitors for the treatment of metastatic melanoma in the clinic.

The risk of developing second primary malignancies among colorectal cancer patients.

BACKGROUND: The increasing number of young colorectal cancer (CRC) survivors has led to ongoing concerns about the risk of secondary primary malignancies (SPMs). Here, we intended to comprehensively explore the pooled standardized incidence rates (SIRs) for total and site-specific SPMs in CRC survivors with different restriction to lag period. METHODS: Pubmed, Embase, Cochrane Library, and Web of science databases were searched to identify any studies reporting the SIRs of SPM following CRC until August 2021. Total and site-specific SIRs with different restriction to lag period were pooled using fixed/random effect models. RESULTS: A total of 42 full-text publications with more than 1, 524, 236 CRC survivors and 166, 210 SPM patients were included in the meta-analysis. Pooled data showed an increased SIRs for all SPMs in CRC survivors with different restriction to lag period (no restriction to lag period, SIR = 1.15, 95% CI = [1.08-1.23]; 1-year lag, 1.16 [1.10-1.23]; 5-year lag, 1.18 [1.09-1.28]; 10-year lag, 1.24 [1.11-1.39]). The conclusions were consistent for neoplasms of colorectum, corpus uteri, and small intestine with different restriction to lag period. However, limited evidence was presented for associations between CRC survivors and SPM for prostate, breast (female), ovarian, stomach, urinary bladder, kidney, thyroid, bone and soft tissue. CONCLUSION: CRC survivors are associated with an increased risk of SPMs, especially neoplasms of colorectum, corpus uteri, and small intestine. Further studies should explore the risks for these neoplasms in CRC survivors, thus providing the reference for future follow-up care.

Melanoma survivors are at increased risk for second primary keratinocyte carcinoma.

BACKGROUND: Recent large cohorts have reported that melanoma survivors are at risk of developing second keratinocyte carcinoma (KC). However, the detailed proportion and risk are still unknown. We aimed to comprehensively analyze the risk of developing keratinocyte carcinoma after primary melanoma. METHODS: We conducted systematic literature research in PubMed, Embase, Web of Science, and Cochrane Library published prior to September 13, 2021. Proportion and standardized incidence ratios (SIR) with its corresponding 95% confidence interval (CI) were pooled for assessing the risk. RESULTS: A total of 15 studies encompassing 168,286 patients were included in our analysis. The pooled proportions of melanoma survivors that developed a subsequent basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and KC were 4.11% (95% CI, 1.32-6.90), 2.54% (95% CI, 1.78-3.31), and 5.45% (95% CI, 3.06-7.84), respectively. The risks of developing a second BCC, SCC, and KC in melanoma survivors were 5.3-fold (SIR 5.30; 95% CI, 4.87-5.77), 2.6-fold (SIR 2.58; 95% CI, 1.33-5.04), and 6.2-fold (SIR 6.17; 95% CI, 3.66-10.39) increased in comparison with the general population. Both fixed effects and random effects models were applied in conducting meta-analysis and reached a consistent conclusion. CONCLUSIONS: Our results indicated melanoma survivors are at elevated risk of experiencing second primary BCC and SCC, which suggested the significance of surveillance for second primary KC and efforts for prevention in patients with a history of melanoma.

Bromodomain and extra-terminal inhibitors emerge as potential therapeutic avenues for gastrointestinal cancers.

Gastrointestinal (GI) cancers, including colorectal cancer, pancreatic cancer, liver cancer and gastric cancer, are severe social burdens due to high incidence and mortality rates. Bromodomain and extra-terminal (BET) proteins are epigenetic readers consisting of four conserved members (BRD2, BRD3, BRD4 and BRDT). BET family perform pivotal roles in tumorigenesis through transcriptional regulation, thereby emerging as potential therapeutic targets. BET inhibitors, disrupting the interaction between BET proteins and acetylated lysines, have been reported to suppress tumor initiation and progression in most of GI cancers. In this review, we will demonstrate how BET proteins participate in the GI cancers progression and highlight the therapeutic potential of targeting BET proteins for GI cancers treatment.

Prognostic and therapeutic significance of a novel ferroptosis related signature in colorectal cancer patients.

Increasing studies have highlighted the importance of ferroptosis in colorectal cancer (CRC). However, how to use ferroptosis-related genes (FRGs) to predict the prognosis and guide the treatment of CRC remains unknown. To build a prognostic prediction model using the GEO and TCGA databases and explored a therapeutic strategy for CRC patients based on FRGs. A total of 60 FRGs were identified and three of them including ACACA, GSS, and NFS1 were associated with the prognosis of CRC. Using Lasso regression analysis, an FRGs signature was constructed and validated as an independent prognostic predictor. Then we developed a nomogram based on the FRGs signature and clinical prognostic factors to predict the prognosis of CRC patients, which was better than the traditional TNM staging system. Single-sample gene set enrichment analysis (ssGSEA) was further performed for the functional analysis and suggested that JAK-STAT signaling, Ras signaling pathway, MAPK signaling pathway, and PI3K-Akt signaling pathway were significantly enriched in CRC patients with higher FRGs risk score. Interestingly, CRC cells with higher FRGs risk score were more sensitive to RSL3. Knocking down GSS and NFS1 increased the FRGs risk score and the sensitivity of CRC cells to RSL3. For the clinic use, we screened 75 FDA-approved cancer drugs and found that Fludarabine phosphate could decrease the expression of GSS and NFS1 most. Fludarabine phosphate, in combination with RSL3, showed a strong synergistic effect on CRC cells. Together, this study identified a potent prognostic model and provided an alternative individualized treatment for CRC patients.

Pretreatment neutrophil-to-lymphocyte ratio predicts the benefit of gastric cancer patients with systemic therapy.

Pretreatment neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with the prognosis of inoperable gastric cancer patients with systemic therapy. However, no consensus on the association has been reached. In this study, we mainly evaluated whether pretreatment NLR predicted the benefit of inoperable gastric cancer patients with systemic therapy, including chemotherapy, targeted therapy and immunotherapy. PubMed, Embase and Cochrane Library databases were systematically searched from inception up to September 16th, 2020. A total of 36 studies including 8614 patients were involved in the meta-analysis. Pooled data revealed that high pretreatment NLR was significantly associated with poor outcomes of OS (HR = 1.78, 95% CI = [1.59, 1.99]) and PFS (HR = 1.63, 95% CI = [1.39, 1.91]) in gastric cancer. Subgroup analyses stratified by country, study type, case load, analysis of HR, cutoff of pretreatment NLR, or treatment types arrived at the same conclusion. Pooled data based on different effect models and sensitivity analyses did not change the conclusion. Overall, high pretreatment NLR predicts the poor prognosis of inoperable gastric cancer patients with systemic therapy. Measurement of pretreatment NLR will assist clinicians with patient counseling and clinical treatment guiding accordingly.

Clinical Significance of Plasma D-Dimer in COVID-19 Mortality.

It is not clear whether D-dimer can be an independent predictor of coronavirus disease 2019 (COVID-19) mortality, and the cut-off of D-dimer for clinical use remains to be determined. Therefore, a comprehensive analysis is still necessary to illuminate the clinical significance of plasma D-dimer in COVID-19 mortality. We searched PubMed, Embase, Cochrane Library, and Scopus databases until November 2020. STATA software was used for all the statistical analyses. The identifier of systematic review registration was PROSPERO CRD42020220927. A total of 66 studies involving 40,614 COVID-19 patients were included in our meta-analysis. Pooled data showed that patients in high D-dimer group had poor prognosis than those in low D-dimer group [OR = 4.52, 95% CI = (3.61, 5.67), P < 0.001; HR = 2.81, 95% CI = (1.85, 4.27), P < 0.001]. Sensitivity analysis, pooled data based on different effect models and the Duval and Tweedie trim-and-fill method did not change the conclusions. Subgroup analyses stratified by different countries, cutoffs, sample size, study design, and analysis of OR/HR still keep consistent conclusions. D-dimer was identified as an independent predictor for COVID-19 mortality. A series of values including 0.5 µg/ml, 1 µg/ml, and 2 µg/ml could be determined as cutoff of D-dimer for clinic use. Measurement and monitoring of D-dimer might assist clinicians to take immediate medical actions and predict the prognosis of COVID-19.

3D Phage-based biomolecular filter for effective high throughput capture of Salmonella Typhimurium in liquid streams.

Foodborne illnesses caused by pathogens on fresh produce remain one of the most critical food safety problems the world faces. The recalls of pasta salad in 2018 and pre-cut melons in 2019 imply current methods in identifying the source of pathogens and outbreak prevention are inappropriate and time consuming. In this article, a new technology, called the 3D phage-based biomolecular filter, was developed to simultaneously capture and concentrate foodborne pathogens from large volumes of liquid streams (food liquid or wash water streams). The 3D phage-based filter consisted of phage-immobilized magnetoelastic (ME) filter elements, a filter pipe system, and a uniform magnetic field to fix and align the ME filter elements in the 3D filter column. The closely packed ME filter elements display a 3D layered structure which allows for enhanced surface interaction of the immobilized bacteriophage with specific pathogens in the passing liquid streams. As a result, a pathogen capture rate of more than 90% was achieved at a high flow rate of 3 mm/s with 20,000 ME filter elements. The capability of the 3D phage-based filter to capture pathogens in liquid streams at different filter element packing densities was further validated by experiments, finite element analysis and theoretical calculations. The capture rate increases significantly with larger numbers of ME filter elements placed in the testing pipe, and the turbulence flow induced by the 3D stacking of ME filter elements can further improve the capture efficiency. This technology enables rapid capture and analysis of large volume of water in processing fresh fruit and vegetables for the presence of small quantities of pathogens, which will ultimately benefit producers, the food industry, and society with improved food safety and production efficiency.

The effect of gene therapy on postoperative recurrence of small hepatocellular carcinoma (less than 5cm).

To observe the curative effect of surgery combined with gene therapy on small hepatocellular carcinoma. Seventy-seven patients with small hepatocellular carcinoma (diameter < 5 cm) underwent surgical resection. The tumor located at the edge of the liver was treated by local excision or irregular hepatectomy. The tumor in the center of the liver was resected by hepatic lobectomy in order to ensure at least a 2-cm safety margin. Fifty-four patients underwent gene therapy (gene group) one or two times before operation, whereas 23 patients underwent surgery alone (control group) selected by themselves. The injectable gene was made of ADV-TK (adenovirus containing thymidine kinase suicide gene, with a concentration of 5 × 1012/ml). The prognosis of patients was analyzed by imaging twice a year. In the gene group, the 1-, 3-, and 5-year survival rates were 91.4, 63.6, and 52.1%. In the control group, the survival rates were 84.3, 54.4, and 32.6%, respectively. There was a significant difference in the overall survival rates between two groups. Factors associated with overall survival in univariate analysis included bilirubin, prothrombin activity, cirrhosis, and gene therapy (P < 0.05). In the multivariate analysis, it included cirrhosis, gene therapy, and bilirubin. The gene therapy hepatocellular carcinoma patients with a diameter < 5 cm could significantly reduce recurrence after operation. It was worthy of being popularized.

A novel and safe approach: middle cranial approach for laparoscopic right hemicolon cancer surgery with complete mesocolic excision.

BACKGROUND: Mastering right hemicolectomy techniques using laparoscopy in colorectal cancer surgery is very difficult. Although the long-term prognosis of laparoscopic right hemicolectomy (LRH) and complete mesocolic excision is unquestionable, different surgeons have their own opinions on routes of conducting LRH. OBJECTIVES: LRH surgery is very complex due to the upper abdominal anatomical structure and vascular variation. Therefore, it has been considered the most difficult of all colorectal cancer surgeries. Our innovative middle cranial approach (MCA) was developed to avoid unnecessary injuries and minimize the operative time, thereby reducing the patient's hospital stay and improving their short-term prognosis. METHODS: We compared 90 colon cancer patients who underwent the MCA between January 2016 and January 2017 with 82 patients who underwent the conventional central approach conducted by the same group of physicians (with Dr Cui as the surgeon) from 2011 to 2015. A short-term statistical analysis was performed. RESULTS: A total of 90 patients were included: 43 men and 47 women. Twenty-three patients underwent abdominal surgery (including stomach, rectum, and sigmoid colon surgery; appendectomy; and uterine attachment surgery). The median age of these patients was 62.6 (28-85) years; the median BMI was 22.9 (14.7-33.3) kg/m2; the mean bleeding volume was 53.9 (10-100) ml; the mean tumour diameter was 5.7 (0.8-9) cm, and the average number of lymph nodes detected was 19.2 (7-49). CONCLUSIONS: Our study showed that radical resection of right-sided colon cancer using the MCA was safe and feasible for the treatment of colorectal cancer patients.

Detection of Salmonella Typhimurium on Spinach Using Phage-Based Magnetoelastic Biosensors.

Phage-based magnetoelastic (ME) biosensors have been studied as an in-situ, real-time, wireless, direct detection method of foodborne pathogens in recent years. This paper investigates an ME biosensor method for the detection of Salmonella Typhimurium on fresh spinach leaves. A procedure to obtain a concentrated suspension of Salmonella from contaminated spinach leaves is described that is based on methods outlined in the U.S. FDA Bacteriological Analytical Manual for the detection of Salmonella on leafy green vegetables. The effects of an alternative pre-enrichment broth (LB broth vs. lactose broth), incubation time on the detection performance and negative control were investigated. In addition, different blocking agents (BSA, Casein, and Superblock) were evaluated to minimize the effect of nonspecific binding. None of the blocking agents was found to be superior to the others, or even better than none. Unblocked ME biosensors were placed directly in a concentrated suspension and allowed to bind with Salmonella cells for 30 min before measuring the resonant frequency using a surface-scanning coil detector. It was found that 7 h incubation at 37 °C in LB broth was necessary to detect an initial spike of 100 cfu/25 g S. Typhimurium on spinach leaves with a confidence level of difference greater than 95% (p < 0.05). Thus, the ME biosensor method, on both partly and fully detection, was demonstrated to be a robust and competitive method for foodborne pathogens on fresh products.

Polymorphism of DNA methyltransferase 3B -149C/T and cancer risk: a meta-analysis.

Published data on the association between DNA methyltransferase (DNMT) 3B -149C/T polymorphism and cancer risk remain inconclusive. To derive a more precise estimation for this association, we performed a meta-analysis of 5,903 cancer cases and 8,132 controls from 22 published case-control studies. We used odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the strength of the association. Our meta-analysis suggested that DNMT3B -149C/T polymorphism was associated with the risk of head and neck cancer under heterozygote comparison (OR 0.73, 95 % CI 0.59-0.90) and dominant model (OR 1.75, 95 % CI 0.62-0.92), although no evidence of association between DNMT3B -149C/T polymorphism and cancer risk was observed as we compared in the pooled analyses (homozygote comparison: OR 0.96, 95 % CI 0.86-1.09; heterozygote comparison: OR 1.07, 95 % CI 0.86-0.32; dominant model: OR 1.03, 95 % CI 0.85-1.25; recessive model: OR 0.93, 95 % CI 0.8-1.08). More studies are needed to detect DNMT3B -149C/T polymorphism and its association with cancer in different ethnic populations incorporated with environment exposures in the susceptibility of different kinds of cancer.

Linearly-polarized short-pulse AOM Q-switched 978 nm photonic crystal fiber laser.

A linearly-polarized, high peak power, short-pulse, Q-switching Yb-doped large-mode-area photonic crystal fiber (PCF) oscillator with three-level system operation is demonstrated. By optimizing cavity parameters and adopting linear polarization component, the laser can easily obtain linearly-polarized output over 2 W at 978 nm with polarization extinction ratio (PER) up to 43 dB without any additional wavelength filter. Less than 50 ns stable output pulses are achieved within repetition range of 10 kHz-200 kHz and short pulse of 9 ns pulse duration, 130 kW peak power at 10 kHz can be reached. The characteristics and the key issues of the laser, such as interpulse ASE, spectrum ASE around 1030 nm, are with detailed discussion in the paper.

Lentivirus-mediated RNA interference targeting the ObR gene in human breast cancer MCF-7 cells in a nude mouse xenograft model.

BACKGROUND: There is a significant association between obesity and breast cancer, which is possibly due to the expression of leptin. Therefore, it is important to clarify the role of leptin/ObR (leptin receptor) signaling during the progression of human breast cancer. METHODS: Nude mice with xenografts of MCF-7 human breast cancer cells were administered recombinant human leptin subcutaneous via injection around the tumor site. Mice in the experimental group were intratumorally injected with ObR-RNAi-lentivirus, while negative control group mice were injected with the same dose of negative-lentivirus. Tumor size was blindly measured every other day, and mRNA and protein expression levels of ObR, estrogen receptor a (ERa), and vascular endothelial growth factor (VEGF) for each group were determined. RESULTS: Knockdown of ObR-treated xenografted nude mice with a high leptin microenvironment was successfully established. Local injection of ObR-RNAi-lentivirus significantly suppressed the established tumor growth in nude mice. ObR level was significantly lower in the experimental group than in the negative control group, while the amounts of ERa and VEGF expression were significantly lower in the leptin group than in the control group (P < 0.01 for all). CONCLUSIONS: Inhibition of leptin/ObR signaling is essential to breast cancer proliferation and possible crosstalk between ObR and ERa, and VEGF, and may lead to novel therapeutic treatments aiming at targeting ObR in breast cancers.

Clinical significance of PHPT1 protein expression in lung cancer.

BACKGROUND: In our previous studies, we found the expression of 14-kD phosphohistidine phosphatase (PHPT1) was associated with lung cancer cells migration and invasion, and PHPT1 mRNA expression level in lung cancer tissues clinically correlated with lymph node metastasis. In the present study, we aimed to further investigate the expression of PHPT1 protein in lung cancer. METHODS: Expression of PHPT1 protein in tissue samples from 146 lung cancers and 30 normal tissues adjacent to lung cancers was assessed using immunohistochemical method. Fisher's exact test was used to analyze expression patterns of PHPT1 protein in these tissue types. Meanwhile, we studied the correlation between expression of PHPT1 protein and clinicopathological features in lung cancer. RESULTS: Significantly higher expression levels of PHPT1 protein were found in lung cancer samples (53.42%) than in normal tissues adjacent to lung cancer (23.33%) (P = 0.003). Fisher's exact test showed that lung cancer stage positively correlated with expression of PHPT1 protein (P = 0.02), and lung cancer samples with lymph node metastasis showed higher PHPT1 protein expression (P = 0.016) than the samples without lymph node metastasis. CONCLUSIONS: The results of this study agree with findings from our previous study of PHPT1 mRNA expression in lung cancer tissues, and strongly suggest that PHPT1 protein is closely associated with the carcinogenesis and metastasis of lung cancer. Thus, therapy targeting PHPT1 (inhibition or silencing) could be potentially benefited for lung cancer patients.