Anoikis resistance--protagonists of breast cancer cells survive and metastasize after ECM detachment.

Breast cancer exhibits the highest global incidence among all tumor types. Regardless of the type of breast cancer, metastasis is a crucial cause of poor prognosis. Anoikis, a form of apoptosis initiated by cell detachment from the native environment, is an outside-in process commencing with the disruption of cytosolic connectors such as integrin-ECM and cadherin-cell. This disruption subsequently leads to intracellular cytoskeletal and signaling pathway alterations, ultimately activating caspases and initiating programmed cell death. Development of an anoikis-resistant phenotype is a critical initial step in tumor metastasis. Breast cancer employs a series of stromal alterations to suppress anoikis in cancer cells. Comprehensive investigation of anoikis resistance mechanisms can inform strategies for preventing and regressing metastatic breast cancer. The present review first outlines the physiological mechanisms of anoikis, elucidating the alterations in signaling pathways, cytoskeleton, and protein targets that transpire from the outside in upon adhesion loss in normal breast cells. The specific anoikis resistance mechanisms induced by pathological changes in various spatial structures during breast cancer development are also discussed. Additionally, the genetic loci of targets altered in the development of anoikis resistance in breast cancer, are summarized. Finally, the micro-RNAs and targeted drugs reported in the literature concerning anoikis are compiled, with keratocin being the most functionally comprehensive. Video Abstract.

Identification of critical genes associated with radiotherapy resistance in cervical cancer by bioinformatics.

Background: Cervical cancer (CC) is one of the common malignant tumors in women, Currently, 30% of patients with intermediate to advanced squamous cervical cancer are still uncontrolled or recurrent after standard radical simultaneous radiotherapy; therefore, the search for critical genes affecting the sensitivity of radiotherapy may lead to new strategies for treatment. Methods: Firstly, differentially expressed genes (DEGs) between radiotherapy-sensitivity and radiotherapy-resistance were identified by GEO2R from the gene expression omnibus (GEO) website, and prognosis-related genes for cervical cancer were obtained from the HPA database. Subsequently, the DAVID database analyzed gene ontology (GO). Meanwhile, the protein-protein interaction network was constructed by STRING; By online analysis of DEGs, prognostic genes, and CCDB data that are associated with cervical cancer formation through the OncoLnc database, we aim to search for the key DEGs associated with CC, Finally, the key gene(s) was further validated by immunohistochemistry. Result: 298 differentially expressed genes, 712 genes associated with prognosis, and 509 genes related to cervical cancer formation were found. The results of gene function analysis showed that DEGs were mainly significant in functional pathways such as variable shear and energy metabolism. By further verification, two genes, ASPH and NKAPP1 were identified through validation as genes that affect both sensitivities to radiotherapy and survival finally. Then, immunohistochemical results showed that the ASPH gene was highly expressed in the radiotherapy-resistant group and had lower Overall survival (OS) and Progression-free survival (PFS). Conclusion: This study aims to better understand the characteristics of cervical cancer radiation therapy resistance-related genes through bioinformatics and provide further research ideas for finding new mechanisms and potential therapeutic targets related to cervical cancer radiation therapy.

Successful Treatment of a Patient With Brain Metastasis From Ovarian Cancer With BRCA Wild Type Using Niraparib: A Case Report and Review of the Literature.

Background: Brain metastases from ovarian cancer are extremely rare and have a very poor prognosis. A multimodal approach (surgery combined with radiotherapy and chemotherapy) yields the best results in reducing neurological symptoms and prolonging survival. Unfortunately, not every patient receives a complete multimodal treatment due to their individual factors. Poly(ADP-ribose) polymerase (PARP) inhibitors have emerged as a maintenance treatment option for recurrent ovarian cancer. Using PARPi may prolong the overall survival in patients with brain metastases and recurrent ovarian cancer. Case Presentation: We report a case of a female patient with advanced ovarian cancer without any germline or somatic BRCA mutation. After 21 months, after reduction surgery and adjuvant chemotherapy, she was diagnosed with brain metastasis. Due to her physical fitness and economic situation, she did not receive any radiotherapy or chemotherapy but only received surgical debulking of the brain metastasis and niraparib maintenance treatment. Up to now, she has achieved a good treatment response, and the PFS is 29 months. Conclusion: Based on the response of our patient, PARP inhibitors as a single agent can probably be considered in patients with brain metastasis from ovarian cancer without BRCA mutation who cannot tolerate radiotherapy and chemotherapy.

Efficacy of apatinib in advanced hepatocellular carcinoma with lung metastasis: a retrospective, multicenter study.

PURPOSE: Lung is the most common extrahepatic metastatic site for patients with advanced hepatocellular carcinoma (HCC) and has a worse prognosis than intrahepatic metastasis. Apatinib is a receptor tyrosine kinase inhibitor that is promising for HCC treatment. We investigated whether apatinib is particularly effective for advanced HCC with lung metastasis. METHODS: Sixty-one study patients with advanced HCC treated with apatinib seen at three different institutions between 2015 and 2018 were identified by retrospective review. Forty-one had lung metastasis (13 multi-organ metastasis and 28 lung metastasis only). Twenty had non-lung metastasis. Treatment consisted of oral apatinib 500 mg once daily. Response was assessed by imaging. The primary endpoint was metastasis-specific (m) progression-free survival (mPFS), for which only progression of metastatic lesions was assessed. RESULTS: Median PFS was 3.37 months (range, 0.6-16.1) for all 61 patients. Objective response (OR) was achieved in 7/61 (11.6%) patients. For the 41 patients with lung metastasis, the median mPFS was 5 months (range, 0.9-21.9), with a mOR rate (mORR) of 22.0% (9/41). The mPFS of the 28 patients with only lung metastasis was better (hazard ratio/HR=0.316; 95% confidence interval/CI=0.144-0.696; log-rank p<0.001) than for the 20 with non-lung metastasis; comparison of the mORR showed similar results (21.4 vs. 5%; p=0.019). For the 13 patients with multi-organ metastasis, the mORR of lung lesions was marginally higher than that of other metastatic lesions (23.1 vs. 0%; p=0.096). CONCLUSIONS: Apatinib showed promising therapeutic effects on advanced HCC with lung metastasis, highlighting a population that could benefit preferentially from this treatment.

Combination of TMB and CNA Stratifies Prognostic and Predictive Responses to Immunotherapy Across Metastatic Cancer.

PURPOSE: Although tumor mutation burden (TMB) has been well known to predict the response to immune checkpoint inhibitors (ICI), lack of randomized clinical trial data has restricted its clinical application. This study aimed to explore the significance and feasibility of biomarker combination based on TMB and copy-number alteration (CNA) for the prognosis of each tumor and prediction for ICI therapy in metastatic pan-cancer milieu. EXPERIMENTAL DESIGN: Non-ICI-treated MSK pan-cancer cohort was used for prognosis analysis. Three independent immunotherapy cohorts, including non-small cell lung cancer (n = 240), skin cutaneous melanoma (n = 174), and mixed cancer (Dana-Farber, n = 98) patients from previous studies, were analyzed for efficacy of ICI therapy. RESULTS: TMB and CNA showed optimized combination for the prognosis of most metastatic cancer types, and patients with TMBlowCNAlow showed better survival. In the predictive analysis, both TMB and CNA were independent predictive factors for ICI therapy. Remarkably, when TMB and CNA were jointly analyzed, those with TMBhighCNAlow showed favorable responses to ICI therapy. Meanwhile, TMBhighCNAlow as a new biomarker showed better prediction for ICI efficacy compared with either TMB-high or CNA-low alone. Furthermore, analysis of the non-ICI-treated MSK pan-cancer cohort supported that the joint stratification of TMB and CNA can be used to categorize tumors into distinct sensitivity to ICI therapy across pan-tumors. CONCLUSIONS: The combination of TMB and CNA can jointly stratify multiple metastatic tumors into groups with different prognosis and heterogeneous clinical responses to ICI treatment. Patients with TMBhighCNAlow cancer can be an optimal subgroup for ICI therapy.

Ultrasound extraction optimization, structural features, and antioxidant activity of polysaccharides from Tricholoma matsutake.

An ultrasonic-assisted technique was employed to extract crude polysaccharide from Tricholoma matsutake fruiting bodies. Single-factor tests and orthogonal experimental design (L9(33)) were used to obtain the optimal extraction conditions. Results showed that the optimal parameters were as follows: ultrasonic temperature, 40 °C; ultrasonic time, 50 min; water to raw material ratio, 25 ml/g; ultrasonic frequency, 45 kHz; and ultrasonic power, 100 W. Three novel T. matsutake polysaccharide (TMP) fractions (TMP30, TMP60, and TMP80) were isolated and purified from TMP by stepwise alcohol precipitation. Their preliminary structural features were determined by high-performance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD) and Fourier transform infrared spectrophotometer (FT-IR) analyses. Furthermore, their in vitro antioxidant activity was investigated in terms of a reducing power assay and the scavenging rates of 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl radicals. The order of the various fractions based on their antioxidant activity was TMP80>TMP>TMP60>TMP30. These findings suggested that novel polysaccharide fractions from T. matsutake, especially TMP80, could be promising active macromolecules for biomedical use.

Enzymatic single-step preparation and antioxidant activity of hetero-chitooligosaccharides using non-pretreated housefly larvae powder.

A novel chitinolytic enzyme-producing bacterium Chitiniphilus sp. LZ32 was isolated. Non-pretreated Housefly larvae powder (HLP) was used as an adsorbent to purify chitinolytic enzymes. The optimal conditions for hydrolysis of HLP by purifying enzymes chitinolytic enzymes were investigated. HPLC and MALDI-TOF analyses indicated that HLP enzymatic hydrolyzates mainly contain N-acetylglucosamine (GlcNAc) and hetero-chitooligosaccharides (COS) composed of GlcN and GlcNAc. The hetero-chitooligosaccharides (COS) had a degree of polymerization (DP) in the 2-6 range. The maximum production of COS was 158.3µg/mL after 72h of incubation. Maximum pentamer (51.2µg/mL) and hexamer concentrations (36.1µg/mL) were achieved at hydrolysis times of 72 and 84h, respectively. Antioxidant activities of purified COS products (PCOS) from different hydrolysis times were investigated in vitro. PCOS produced by hydrolysis times of 72h (PCOS-72) exhibited the strongest hydroxyl-scavenging ability and reducing power. These results indicate the potential of Chitiniphilus sp. LZ32 for COS production using HLP.

Chemical modification of an acidic polysaccharide (TAPA1) from Tremella aurantialba and potential biological activities.

TAPA1 was previously isolated from Tremella aurantialba fruiting bodies. In this paper, an acetylated derivative (TAPA1-ac) and a deactylated derivative (TAPA1-deac) of TAPA1 were prepared, and their characterization and immunostimulating activities were reported. Acetylation and deacetylation were found to occur actually by FT-IR and NMR spectra, together with calculational results. The degree of substitution (DS) of acetyl groups in TAPA1-ac was 0.23 and the content was 5.82%, which was higher than those of TAPA1 (0.03% and 0.70%, respectively) and TAPA1-deac (all were zero). Compared with TAPA1, TAPA1-ac showed significant immunostimulation effects on mouse spleen lymphocytes (MSLs) proliferation and nitric oxide (NO) production by macrophages RAW264.7, whereas TAPA1-deac showed markedly lower effects. These findings seemed to suggest that immunostimulating activities, including MSLs stimulation activity and NO production potency, might relate to the DS and content of acetyl groups, indicating that acetylation of TAPA1 was an effective way of enhancing immuno-stimulating activities.

Chemical analysis and antioxidant activity of polysaccharides extracted from Inonotus obliquus sclerotia.

Three water-soluble polysaccharide fractions (IOP40, IOP60 and IOP80) were isolated by using different concentrations of alcohol precipitation from Inonotus obliquus sclerotia. Their physicochemical properties, including total sugar content, protein content, monosaccharide composition and percentage were analyzed. And their in vitro antioxidant capacities were investigated in terms of reducing power assay and scavenging of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals, hydroxyl radicals, superoxide anion radicals and hydrogen peroxide (H2O2). In general, three polysaccharide fractions exhibited increasing antioxidant activity with increasing concentration at the ranges of tested dosage. The orders of reducing power, DPPH-scavenging capacity, H2O2-scavenging capacity, and hydroxyl-scavenging activity were all IOP60>IOP40>IOP80. These findings demonstrated that three polysaccharide fractions extracted from I. obliquus, especially IOP60, could be employed as natural ingredients in functional food and pharmaceutical industry to alleviate the oxidative stress.

Purification, chemical modification and immunostimulating activity of polysaccharides from Tremella aurantialba fruit bodies.

Ultrafiltration and a series of chromatographic steps were used to isolate and purify polysaccharides from Tremella aurantialba fruit bodies. Three crude fractions (TAP50w, TAP10-50w, and TAP1-10w), five semi-purified fractions (TAPA-TAPE), and one purified fraction (TAPA1) were obtained. A sulfated derivative of TAPA1 (TAPA1-s) was prepared by chemical modification. The immunostimulating activity of the polysaccharide fractions in vitro was determined using the mouse spleen lymphocyte proliferation assay. Of the three crude fractions tested, cell proliferation rates were increased most by TAP50w. Furthermore, TAPA1-s was markedly more stimulatory than TAPA1, indicating that sulfonation was an effective way to enhance the immunostimulating activity of polysaccharide.

Structural elucidation and immuno-stimulating activity of an acidic heteropolysaccharide (TAPA1) from Tremella aurantialba.

A novel acidic heteropolysaccharide (TAPA1) was purified from hot water extracts of Tremella aurantialba fruiting bodies by DEAE-Sepharose Fast Flow and Sephacryl S-500 High-Resolution Chromatography. The heteropolysaccharide had a molecular weight of ca. 1.35x10(6)Da, and a carbohydrate content estimated to be approximately 98.7% by the phenol-sulfuric acid method. It was composed mainly of d-mannose, d-xylose, and d-glucuronic acid in the ratio of ca. 5:4:1, along with trace amounts of d-galacturonic acid and d-glucose. Monosaccharide compositional analysis and GC-MS of methylated derivatives, combined with (1)H and (13)C NMR spectroscopies (including COSY, TOCSY, NOESY, HSQC, and HMBC spectra), revealed TAPA1 to consist of an alpha-(1-->3)-linked mannopyranosyl backbone, partially substituted at position 4 with xylose side chains, and at position 2 with side chains composed of either xylose, mannose, and glucuronic acid or of xylose and mannose. Bioactivity testing showed that TAPA1 stimulated the proliferation of mouse spleen lymphocytes in vitro.