Targeting the Cdc2-like kinase 2 for overcoming platinum resistance in ovarian cancer.

Platinum resistance represents a major barrier to the survival of patients with ovarian cancer (OC). Cdc2-like kinase 2 (CLK2) is a major protein kinase associated with oncogenic phenotype and development in some solid tumors. However, the exact role and underlying mechanism of CLK2 in the progression of OC is currently unknown. Using microarray gene expression profiling and immunostaining on OC tissues, we found that CLK2 was upregulated in OC tissues and was associated with a short platinum-free interval in patients. Functional assays showed that CLK2 protected OC cells from platinum-induced apoptosis and allowed tumor xenografts to be more resistant to platinum. Mechanistically, CLK2 phosphorylated breast cancer gene 1 (BRCA1) at serine 1423 (Ser1423) to enhance DNA damage repair, resulting in platinum resistance in OC cells. Meanwhile, in OC cells treated with platinum, p38 stabilized CLK2 protein through phosphorylating at threonine 343 of CLK2. Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Toxic effects of combined exposure to homoyessotoxin and nitrite on the survival, antioxidative responses, and apoptosis of the abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) and nitrite (NO2-N), released during harmful dinoflagellate cell lysis adversely affect abalones. However, their toxicity mechanisms in shellfish remain unclear. This study investigated the economic abalone species Haliotis discus hannai exposed to varying concentrations of homo-YTX (0, 2, 5, and 10 µg L-1) and NO2-N (0, 3, and 6 mg L-1) on the basis of their 12 h LC50 values (5.05 µg L-1 and 4.25 mg L-1, respectively) and the environmentally relevant dissolved concentrations during severe dinoflagellate blooms, including mixtures. The test abalones were exposed to homo-YTX and NO2-N for 12 h. The mortality rate (D), reactive oxygen species (ROS) levels, antioxidant defense capabilities, and expression levels of antioxidant-related, Hsp-related, and apoptosis-related genes in abalone gills were assessed. Results showed that the combined exposure to homo-YTX and NO2-N increased the D and ROS levels and upregulated B-cell lymphoma-2 (BCL2)-associated X (BAX) and caspase3 (CASP3) expression levels while reducing glutathione peroxidase (GPx) activity and GPx, CuZnSOD, and BCL2 expression levels. High concentrations of homo-YTX (10 µg L-1) and NO2-N (6 mg L-1) solutions and the combinations of these toxicants inhibited the activities of superoxide dismutase (SOD) and catalase (CAT) and downregulated the expression levels of MnSOD, CAT, Hsp70, and Hsp90. The ROS levels were negatively correlated with the activities of SOD, CAT, and GPx and the expression levels of MnSOD, CuZnSOD, CAT, GPx, Hsp70, Hsp90, and BCL2. These results suggest that homo-YTX, in conjunction with NO2-N, induces oxidative stress, disrupts antioxidant defense systems, and triggers caspase-dependent apoptosis in the gills of abalone. ROS-mediated antioxidative and heat-shock responses and apoptosis emerge as potential toxicity mechanisms affecting the survival of H. discus hannai due to homo-YTX and NO2-N exposure.

Chemotherapy alone versus chemotherapy plus 125I brachytherapy for the second-line treatment of locally recurrent cervical cancer after/with radical treatment: A propensity score analysis.

Rationale and objectives: The primary aim of this study was to conduct a retrospective comparative analysis of the survival outcomes in patients with recurrent cervical cancer (CC). Specifically, we aimed to compare the efficacy of chemotherapy alone versus the combined approach of chemotherapy and 125I brachytherapy subsequent to the failure of initial chemotherapy treatment. Materials and methods: Patients diagnosed with recurrent CC subsequent to the failure of initial chemotherapy from January 2007 to December 2016 were enrolled from 2 hospitals. These patients were then divided into two groups: Group A, which underwent second-line chemotherapy alone, and Group B, which received both second-line chemotherapy and 125I brachytherapy. The assessment of overall survival (OS) and progression-free survival (PFS) was carried out through propensity score matching (PSM) (1:1), Kaplan-Meier curves, log-rank tests, and Cox proportional hazard regression for survival analysis. Results: A matched cohort comprising 88 patients each in Group A and Group B was included in the study. In Group A, the 1-, 2-, and 3-year cumulative PFS rates were 40.9 %, 15.9 %, and 5.7 % respectively, while in Group B, these rates were significantly higher at 79.5 %, 48.9 %, and 25.0 % (P = 0.003). Similarly, the 1-, 2-, and 3-year cumulative OS rates among Group A were 67.0 %, 27.3 %, and 5.7 % compared to 89.8 %, 63.6 %, and 30.7 % among Group B, suggesting a difference with statistical significance (P < 0.001) between the two groups. Moreover, the incidence of complications was similar between groups (P = 0.698). Conclusions: Our findings suggest that the combined approach of chemotherapy and 125I brachytherapy yields superior therapeutic effects but similar complication rates compared to chemotherapy alone in patients experiencing local recurrence of CC following failed initial chemotherapy.

Metabarcoding revealed a high diversity of Amphidomataceae (Dinophyceae) and the seasonal distribution of their toxigenic species in the Taiwan Strait.

The dinophyte family Amphidomataceae includes the genera Azadinium and Amphidoma. Four of these species are known to produce azaspiracids, which are lipophilic phycotoxins accumulating in shellfish. The diversity and biogeography of Amphidomataceae is far from yet resolved. Here we performed a time series sampling of both water and sediments in the Taiwan Strait from Nov. 2018 to April 2021. Metabarcoding was performed to unveil the diversity of Amphidomataceae targeting internal transcribed spacer (ITS1) region and partial large subunit ribosomal DNA (LSU rDNA D1-D3), followed by quantitative PCR (qPCR) with modified primers for Az. poporum ribotypes. The diversity of Amphidomataceae was revealed from the water samples with the aid of ITS1 and LSU based molecular phylogeny. The LSU based approach detected only a few species. In contrast, ITS1 based dataset showed eight new Azadinium clades and several ZOTUs (zero-radius operational taxonomic units) grouping together with Am. languida. Moreover, eleven known Azadinium species including three ribotypes of Az. poporum and Az. dexteroporum, and two ribotypes of Az. spinosum, were detected. The latter two species have not been reported in China before. Among these toxigenic species, Az. poporum was relevantly abundant whereas others were rare. The maximum of 209 cells L -1 of Az. poporum ribotype A was estimated using qPCR nearby Quanzhou in Nov. 2018 and 172 cells L 1 of Az. poporum ribotype B was detected far off coast in Apr. 2021. Metabarcoding on sediment samples revealed Az. poporum ribotypes B and C, but strains obtained with sediment incubation experiments yielded only ribotype B. Using qPCR about 0.2 cysts g -1 of Az. poporum ribotype B were quantified in May 2019 but cysts of Az. poporum ribotype C were not detected. Our results suggest that metabarcoding targeting ITS1 region is powerful to uncover the diversity of harmful dinophytes. Our results also highlight the rich diversity of Amphidomataceae and risk potential of azaspiracids in the Taiwan Strait and surrounding waters.

Tislelizumab for cervical cancer: A retrospective study and analysis of correlative blood biomarkers.

Background: Tislelizumab is an anti-programmed cell death 1 (PD-1) monoclonal antibody engineered to minimize binding to Fcγ receptors. It has been used to treat several solid tumors. However, its efficacy and toxicity, and the predictive and prognostic value of baseline hematological parameters in patients with recurrent or metastatic cervical cancer (R/M CC) receiving tislelizumab remain unclear. Methods: We reviewed 115 patients treated for R/M CC with tislelizumab from March 2020 to June 2022 in our institute. The antitumor activity of tislelizumab was assessed using RECIST v1.1. Associations between the baseline hematological parameters and efficacy of tislelizumab in these patients were analyzed. Results: With a median follow-up of 11.3 months (range, 2.2-28.7), the overall response rate was 39.1% (95% CI, 30.1-48.2) and the disease control rate was 77.4% (95% CI, 69.6-85.2). The median progression-free survival (PFS) was 19.6 months (95% CI, 10.7 to not reached). The median overall survival (OS) was not reached. Treatment-related adverse events (TRAEs) of any grade occurred in 81.7% of the patients and only 7.0% of the patients experienced grade 3 or 4 TRAEs. Univariate and multivariate regression analyses showed that the level of pretreatment serum C-reactive protein (CRP) was an independent risk factor for the response (complete or partial response) to tislelizumab and the PFS of R/M CC patients treated with tislelizumab (P = 0.0001 and P = 0.002, respectively). R/M CC patients with elevated baseline CRP levels had a short PFS (P = 0.0005). Additionally, the CRP-to-albumin ratio (CAR) was an independent risk factor for the PFS and OS of R/M CC patients treated with tislelizumab (P = 0.001 and P = 0.031, respectively). R/M CC patients with an elevated baseline CAR had short PFS and OS (P < 0.0001 and P = 0.0323, respectively). Conclusions: Tislelizumab showed promising antitumor activity and tolerable toxicity in patients with R/M CC. The baseline serum CRP levels and CAR showed potential for predicting the efficacy of tislelizumab and the prognosis of R/M CC patients receiving tislelizumab.

Formation mechanism and environmental drivers of Alexandrium catenella bloom events in the coastal waters of Qinhuangdao, China.

In the last 5 years, paralytic shellfish toxins (PSTs) have been recurrently detected in mollusks farmed in the mussel culture area of Qinhuangdao city, along with the occurrence of toxic outbreaks linked to dinoflagellate species of the Alexandrium genus. To understand the formation mechanism and variation of these events, continuous and comprehensive PSTs monitoring was carried out between 2017 and 2020. Through the analysis of both phytoplankton and cysts via light microscopy and quantitative polymerase chain reaction, it was shown that Alexandrium catenella was responsible for the production of PSTs, which consisted mainly of gonyautoxins 1,4 (GTX1/4, 87%) and GTX2/3 (13%). During bloom events in 2019, mussels accumulated the highest PSTs value (929 µg STX di-HCl eq·kg-1) in conjunction with the peak of cell abundances, and toxin profiles were consistent with high distributions of GTX1/4, GTX2/3, and Neosaxitoxin. Toxin metabolites vary in different substances and mainly transferred to a stable proportion of α-epimer: ß-epimers 3:1. The environmental drivers of Alexandrium blooms included the continuous rise of water temperature (>4 °C) and calm weather with low wind speed and no significant precipitation. By comparing toxin profiles and method sensitivity, it was found that dissolved toxins in seawater are more useful for early warning. These results have important implications for the effective monitoring and management of paralytic shellfish poisoning outbreaks.

Changes in physiological activities are responsible for homoyessotoxin-induced toxicity in abalone Haliotis discus hannai.

Homoyessotoxin (homo-YTX) is a lipid-soluble toxin produced by toxic dinoflagellates. It is widely distributed in marine ecosystems worldwide, and it poses a threat to the survival of aquatic animals. The tissues of the abalone Haliotis discus hannai are easily damaged by homo-YTX during harmful algal blooms. In this study, H. discus hannai was exposed to homo-YTX (0, 2, 5, and 10 µg L-1) to evaluate the rates of survival (S) and death (D) and the antioxidative, metabolic, and digestive physiological responses in the gills and digestive gland of abalone. Homo-YTX decreased S and the activities of Na+/K+-adenosine triphosphatase, Ca2+/Mg2+-adenosine triphosphatase, superoxide dismutase, catalase, alkaline phosphatase, xanthine oxidase, lactate dehydrogenase, amylase, protease, and lipase. Meanwhile, D, the reactive oxygen species level, and the malondialdehyde content increased with increasing concentrations of homo-YTX. In addition, homo-YTX induced oxidative stress, enhanced the lipid peroxidation reaction, reduced the energy supply, and inhibited the metabolic and digestive physiological activities in the gills and digestive gland of abalone. Oxidative stress-mediated insufficient energy supply and physiological activity reduction caused the death of abalone.

Unraveling the Gonyaulax baltica Species Complex: Cyst-theca Relationship of Impagidinium variaseptum, Spiniferites pseudodelicatus sp. nov. and S. ristingensis (Gonyaulacaceae, Dinophyceae), With Descriptions of Gonyaulax bohaiensis sp. nov, G. amoyensis sp. nov. and G. portimonensis sp. nov.

The taxonomy of the extant dinoflagellate genus Gonyaulax is challenging since its thecate morphology is rather conservative. In contrast, cysts of Gonyaulax are varied in morphology and have been related with the fossil-based genera Spiniferites and Impagidinium. To better understand the systematics of Gonyaulax species, we performed germination experiments on cysts that can be identified as S. ristingensis, an unidentified Spiniferites with petaloid processes here described as Spiniferites pseudodelicatus sp. nov. and Impagidinium variaseptum from Chinese and Portuguese waters. Despite marked differences in cyst morphology, motile cells of S. pseudodelicatus and I. variaseptum are indistinguishable from Gonyaulax baltica. Motile cells hatched from S. ristingensis are morphologically similar to G. baltica as well but differ in the presence of one pronounced antapical spine. Three new species, Gonyaulax amoyensis (cyst equivalent S. pseudodelicatus), Gonyaulax bohaiensis (cyst equivalent I. variaseptum), and Gonyaulax portimonensis (cyst equivalent S. ristingensis), were erected. In addition, a new ribotype (B) of G. baltica was reported from South Korea and a bloom of G. baltica ribotype B is reported from New Zealand. Molecular phylogeny based on LSU and SSU rRNA gene sequences revealed that Gonyaulax species with minute or short antapical spines formed a well-resolved clade, whereas species with two pronounced antapical spines or lack of antapical spines formed the sister clade. Six strains of four above species were examined for yessotoxin production by liquid chromatography coupled with tandem mass spectrometry, and very low concentrations of yessotoxin were detected for one G. bohaiensis strain.

The 100 most cited articles in lateral epicondylitis research: A bibliometric analysis.

Introduction: Lateral epicondylitis is a significant clinical problem in orthopaedics. There have been numerous articles written about this. Bibliometric analysis is critical for determining a field's most influential study. We attempt to identify and analyze the top 100 citations in lateral epicondylitis research. Materials and methods: On December 31, 2021, an electronic search was conducted in the Web of Science Core Collection and the Scopus search engine with no restrictions on publication years, language, or study design. We reviewed each article's title and abstract until the top 100 were documented and evaluated in various ways. Results: Between 1979 and 2015, the 100 most cited articles were published in 49 journals. The total number of citations ranged from 75 to 508 (mean ± SD, 145.5 ± 90.9), with citation densities ranging from 2.2 to 37.6 citations per year (mean ± SD, 8.7 ± 6.5). The United States is the most productive country, and the 2000s witnessed a surge in lateral epicondylitis research. The year of publication had a moderately positive correlation with citation density. Conclusion: Our findings offer readers a fresh perspective on historical development hotspot areas of lateral epicondylitis research. Disease progression, diagnosis, and management have always been topics of discussion in articles. PRP-based biological therapy has emerged as a promising area for future research.

Morpho-molecular description of a new HAB species, Pseudocochlodinium profundisulcus gen. et sp. nov., and its LSU rRNA gene based genetic diversity and geographical distribution.

Harmful algal blooms (HABs) caused by an unknown dinoflagellate species have frequently occurred in the Pearl River Estuary, China Since 2006. These blooms were associated with severe water discoloration and economic losses, ranging from several km2 to 300 km2 with the maximum recorded cell density being 2.77 × 107 cells⋅L-1. This unknown dinoflagellate species was initially identified as Cochlodinium geminatum and subsequently reclassified as Polykrikos geminatus. However, after reviewing the original descriptions for Cochlodinium geminatum sensu Schütt (1895) and the genus Polykrikos, we considered this species is incongruent with their original descriptions. Further morphological examinations and particularly phylogenetic analyses based on the SSU and partial LSU rRNA genes of isolates and resting cysts from China and Japan prompted us to consider it a new species of a new genus. This new species was proposed to be Pseudocochlodinium profundisulcus gen. et sp. nov., based on its open comma-shaped apical structure complex (ASC), cingulum encircling the cell less than one and a half turns, a deep sulcus with a torsion of a half turn, either single cell or cell chain consisting of two cells with the same number of nuclei and zooids, the resting cyst bearing lobed ornaments, and the evolutionary distances from Polykrikos (and others) on the phylogenetic trees constructed using the concatenated SSU and partial LSU rRNA gene sequences. Metabarcoding investigation of surface sediment samples collected in China revealed that the species to be widely present along the entire Chinese coast with the highest abundance in the South China Sea. Further re-analysis of the Tara Oceans metabarcoding dataset targeting the SSU rRNA gene V9 domain suggested a global distribution of this new genus. Phylogenetic analyses on 46 OTUs (average length: ∼552 bases) of its LSU rRNA gene sequences (mainly D1-D2 domains) obtained from surface sediment samples revealed intraspecific genetic diversity of this species. Interestingly, based on the different distributions and the abundance of these OTUs along the coast of China, this species appeared to have expanded its distribution from the South China Sea to the northern Yellow Sea, or preferred a warm water habitat. We consider that the present work improves the taxonomy and provides important insights into the biogeography of Pseudocochlodinium profundisulcus.⋅.

Exploration of resting cysts (stages) and their relevance for possibly HABs-causing species in China.

The studies on the species diversity, distribution, environmental implications, and molecular basis of resting cysts (stages) of dinoflagellates and a few species of other groups conducted in China during the last three decades are reviewed. The major achievements are summarized as the following five aspects: 1) The continual efforts in detecting the species diversity of resting cysts (spores) in dinoflagellates and other classes using either morphological or molecular approaches, or both, in the four seas of China, which led to identifications of 106 species of dinoflagellate resting cysts and 4 species of resting stages from other groups of microalgae, with a total of 64 species of dinoflagellate cysts and the resting stage of the brown tide-causing Aureococcus anophagefferens being unequivocally identified via molecular approaches from the sediments of Chinese coastal waters; 2) The well-known toxic and HABs-causing dinoflagellates Karenia mikimotoi, Karlodinium veneficum, Akashiwo sanguinea and the pelagophyte A. anophagefferens were proven to be resting cyst (stage) producers via laboratory studies on their life cycles and field detections of resting cysts (resting stage cells). And, via germination experiment and subsequent characterization of vegetative cells, numerous dinoflagellate species that had never been described or found to form cysts were discovered and characterized; 3) The distributions of the resting cysts of Alexandrium catenella, A. pacificum, Gymnodinium catenatum, K. mikimotoi, K. veneficum and Azadinium poporum and the resting stage cells of A. anophagefferens were morphologically and molecularly mapped in all four seas of China, with A. anophagefferens proven to have been present in the Bohai Sea for at least 1,500 years; 4) Obtaining important insights into the 'indicator' values of the dinoflagellate cyst assemblages in sediment cores for tracking eutrophication, environmental pollution and other anthropological influences in coastal waters; 5) Studies on the cyst-pertinent processes and genetic basis (transcriptomics together with physiological and chemical measurements) of resting cyst dormancy not only revealed the regulating patterns of some environmental factors in cyst formation and germination, but also identified many characteristically active or inactive metabolic pathways, differentially expressed genes, and the possibly vital regulating function of the phytohormone abscisic acid and a group of molecular chaperones in resting cysts. We also identified seven issues and three themes that should be addressed and explored by Chinese scientists working in the area in the future.

Is Routine Gastroscopy/Colonoscopy Reasonable in Patients With Suspected Ovarian Cancer: A Retrospective Study.

OBJECTIVE: To evaluate the value of routine preoperative gastroscopy/colonoscopy in patients with suspected ovarian cancer for differential diagnosis and judgment of bowel resection. METHODS: All women diagnosed with suspected ovarian cancer who underwent gastroscopy/colonoscopy before surgery in our center were retrospectively identified. Gastroscopy/colonoscopy results and clinical pathology, imaging, and surgical findings were analyzed. RESULTS: 389 patients were included. Among them, 40 (including 13 gastric and 9 colonic malignancy) were ovarian metastasis. Compared with imaging, gastrointestinal endoscopy showed no statistical advantage in the specificity and sensitivity (99.4% vs. 99.7%, P=1.0; 55.0% vs. 45.2%, P=0.057; respectively). All patients with gastric/colonic cancer metastasize except for one had indicative imaging or tumor marker abnormalities. Three patients with colonic cancer metastases underwent optimal surgery and alive with no recurrence, the other 19 patients experienced palliative chemotherapy. There is no significant difference in the sensitivity of colonoscopy and imaging in predicting intestinal incision (61.5% vs. 43.8%, P=0.804), whereas the latter had higher specificity (87.8% vs. 74.3%, P=0.001). CONCLUSIONS: For patients with suspected ovarian cancer, the incidence of gastrointestinal metastases is low, routine gastroscopy/colonoscopy before treatment is less efficient. Gastroscopy/colonoscopy has limited power to predict the need for gastrointestinal resection before ovarian cancer surgery.

Non-anatomic repair of medial meniscus posterior root tears to the posterior capsule provided favourable outcomes in middle-aged and older patients.

PURPOSE: To describe a non-anatomic arthroscopic all-inside repair technique for middle-aged and older patients with medial meniscus posterior root tears (MMPRTs) and to evaluate the short- to mid-term clinical and radiologic results. The hypothesis was that this procedure would yield good clinical outcome results and structural healing in middle- and older-aged patients. METHODS: This was a retrospective study evaluating patients who had undergone MMPRT repair by suturing the meniscal root directly to the capsule, rather than by the transtibial technique, between 2013 and 2016. This all-inside repair technique was performed for patients with type II MMPRTs who were over 40 years old. Exclusion criteria included tibial osteotomy due to malalignment, concomitant multiple-ligament injuries and follow-up time less than 2 years. The Lysholm score, Tegner activity score and International Knee Documentation Committee (IKDC) score were evaluated preoperatively and at the final follow-up. Medial meniscal extrusion, the International Cartilage Repair Society (ICRS) grades of the medial compartment, and the healing status of the medial meniscus root were assessed on magnetic resonance imaging preoperatively and at the final follow-up. RESULTS: Twenty-nine patients (mean age 61.7 ± 7.9) were included; the mean follow-up duration was 46.2 ± 7.9 months. The mean Lysholm score significantly improved from 33.7 ± 20.9 preoperatively to 81.7 ± 19.9 at the final follow-up (p < 0.001), the median Tegner activity score improved from 1.0 (range 1-4) to 3.0 (range 2-4, p < 0.001), and the mean IKDC score improved from 20.1 ± 16.4 to 69.6 ± 16.2 (p < 0.001). On MRI, 9 (31%) cases had complete healing; 17 (59%) had partial healing; and 3 (10%) had failed healing (ICCs ≥ 0.92). Mean meniscal extrusion significantly increased from 2.3 ± 1.7 mm preoperatively to 3.5 ± 1.5 mm postoperatively (p < 0.001, ICCs ≥ 0.92). CONCLUSION: Non-anatomic arthroscopic all-inside repair of MMPRTs to the posterior capsule yielded good to excellent clinical results and a high rate of healing in the medial meniscus root on MRI in middle-aged and older patients at short- to mid-term follow-up, despite increased meniscal extrusion. This method is an alternative to the transtibial pullout repair technique for treating MMPRTs in middle- and older-aged patients. LEVEL OF EVIDENCE: Level IV.

Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis.

Osteoporosis, an aging-associated bone metabolic disease, is affecting millions of people worldwide. The deregulated process of osteoblastic differentiation has been linked with the progression of osteoporosis. Trelagliptin is a long-acting inhibitor of DPP-4 used for the management of type 2 diabetes mellitus. However, it is unknown whether Trelagliptin possesses a beneficial effect in osteoblastic differentiation. Interestingly, we found that treatment with Trelagliptin enhanced differentiation and promoted the mineralization of MC3T3-E1 cells. Firstly, Trelagliptin increased the activity of alkaline phosphatase (ALP) and promoted osteoblastic calcium deposition. Additionally, treatment with Trelagliptin upregulated ALP, osteocalcin (OCN), osteopontin (OPN), and bone morphogenetic protein-2 (BMP-2). Notably, Trelagliptin increased RUNX2, a major regulator of osteoblastic differentiation. Mechanistically, Trelagliptin upregulated the levels of p-AMPKα. Blockage of AMPK with compound C abolished the effects of Trelagliptin in RUNX2 and osteoblastic differentiation, suggesting the involvement of AMPK. Our findings suggest that Trelagliptin might possess a potential for the treatment of osteoporosis.

Downregulation of NUDT21 contributes to cervical cancer progression through alternative polyadenylation.

Nudix Hydrolase 21 (NUDT21), an alternative polyadenylation (APA)-regulatory protein, exhibits tumor-suppressive effects. However, its role in cervical cancer (CxCa) remains unknown. In the present study, we found that NUDT21 expression was reduced in CxCa tissues and cells, and NUDT21 levels were highly associated with the clinical prognosis of patients with CxCa. Knockdown of NUDT21 promoted CxCa cell proliferation, migration, and invasion in vitro, as well as tumorigenesis and lung metastasis in vivo. Overexpression of NUDT21 produces the opposite effects. Moreover, we performed polyadenylation site sequencing (PAS-Seq) and identified 457 transcripts with lengthened 3' untranslated regions (3' UTRs) upon NUDT21 overexpression. In particular, NUDT21 modulated the expression of several genes involved in fatty acid metabolism and the Wnt and NF-κB signaling pathways in CxCa development. Taken together, our study demonstrated that the APA regulatory effect of NUDT21 is an important mechanism for CxCa suppression.

Long-term outcomes of individualized management after sentinel lymph-node biopsy for vulvar cancer.

BACKGROUND: The management for patients with vulvar cancer after sentinel lymph-node biopsy (SLNB) remains controversial. The aim of this study was to investigate the long-term outcomes of individualized management after SLNB for early stage vulvar cancer. METHODS: The medical records of patients with vulvar cancer treated by surgery involving SLNB between 2004 and 2019 were retrospectively reviewed. During this period, the inguinofemoral lymphadenectomy (IL) were performed with individualized strategy, while the postoperative intensity-modulated radiotherapy was planned with a consistent policy. RESULTS: We identified 138 patients with at least one sentinel node detected, of whom 64 underwent further IL while 74 had SLNB only. Nodal metastases (pN+) were confirmed in 22 patients with IL and 16 without. Radiotherapy was scheduled with the dose of 60-70 Gy for all pN+ patients and finally completed in 15 with IL and 15 without. The median follow-up time was 56 months (6-156 months). Recurrence was observed in 24 patients, of whom 10 were pN- at primary treatment. The 3-year overall survival (OS) was 97.2, 95.2, 68.3, and 71.8%; 3-year disease-free survival (DFS) was 94.5, 91.4, 60.2, and 59.2%, respectively, for patients with pN- and IL, pN- and SLNB, pN+ and IL, and pN+ and SLNB. Neither OS nor DFS showed significant difference between SLNB and IL in pN- (P = 0.564 for OS, P = 0.423 for DFS), or pN + patients (P = 0.920 for OS, P = 0.862 for DFS). CONCLUSIONS: With appropriate adjuvant radiotherapy, SLNB alone provided similar long-term survival compared with IL for both patients with and without sentinel node metastasis.

Pretreatment C-Reactive Protein/Albumin Ratio is Associated With Poor Survival in Patients With 2018 FIGO Stage IB-IIA HPV-Positive Cervical Cancer.

Objectives: The present study aimed to identify the predictive value of inflammatory indexes stratified according to human papillomavirus (HPV) infection status in women with FIGO 2018 stage IB∼IIA cervical cancer. We also explored the influences of HPV infection status on the survival of cervical cancer patients. Methods: We collected data for 583 women with stage IB∼IIA cervical cancer in Sun Yat-sen University Cancer Center between 2009 and 2017. The t-test, chi-squared (χ2) test and Fisher's exact test were applied to compare the differences of inflammatory indexes and clinicopathological features between HPV-positive and HPV-negative groups. Univariate and multivariate analyses were used to identify clinicopathological factors that were associated with the prognosis of cervical cancer patients. Results: There were no differences in overall survival (OS) and progression-free survival (PFS) between HPV-positive and HPV-negative groups. In HPV-positive group, the maximum tumor size, neoadjuvant chemotherapy and the body mass index (BMI) correlated significantly with C-reactive protein/albumin ratio (CAR). The maximum tumor size and the prognostic nutritional index (PNI) correlated significantly with the platelet-lymphocyte ratio (PLR). The maximum tumor size, neoadjuvant chemotherapy and PLR correlated significantly with PNI. Univariate and multivariate analyses showed that the depth of tumor invasion (HR: 3.651, 95% CI: 1.464-9.103, p = 0.005; HR: 2.478, 95% CI: 1.218-5.043, p = 0.012) and CAR (HR: 5.201, 95% CI: 2.080-13.004, p < 0.0001; HR: 2.769, 95% CI: 1.406-5.455, p = 0.003) were independent predictors of poor OS and PFS. PNI was an independent protective factor of OS (HR: 0.341, 95% CI: 0.156-0.745, p = 0.007). PLR was an independent factor of PFS (HR: 1.991, 95% CI: 1.018-3.894, p = 0.044). In HPV-negative group, BMI correlated significantly with CAR. Only depth of invasion (HR: 9.192, 95% CI: 1.016-83.173, p = 0.048) was the independent predictor of poor OS, and no inflammation indexes were independent predictors of prognosis. Conclusion: In patients with HPV-positive cervical cancer, depth of invasion, PNI and CAR are independent factors of OS, and depth of invasion, PLR and CAR are independent factors for PFS. For patients with HPV-negative disease, no inflammation indexes had predictive value for prognosis. The predictive value of inflammation indexes on prognosis is more significant in patients with HPV-positive cervical cancer. Stratification of HPV infection status promotes a more precise clinical application of inflammation indexes, thus improving their accuracy and feasibility.

Proposal for modified inguinofemoral lymphadenectomy derived from investigation of anatomic distribution of sentinel and metastatic nodes in vulvar cancer.

OBJECTIVE: We aimed to develop a less invasive inguinofemoral lymphadenectomy (IFL) approach for vulvar cancer based on the investigation of the anatomic distribution of sentinel and metastatic nodes. METHODS: Patients with vulvar cancer treated by surgery between 1995 and 2019 were retrospectively reviewed. A seven-field method was adopted to assign the anatomic locations for lymph nodes removed via IFL or sentinel node biopsy. Only patients with nodal metastasis or sentinel nodes were included. RESULTS: A total of 102 patients with eligible data were analyzed. Nodal metastasis was confirmed in 118 groins undergoing IFL; sentinel node detection succeeded in 46 groins. The medial-inguinal field had the highest rate of nodal metastasis involvement (59.3%, 70/118) and sentinel nodes present (73.9%, 34/46). The inferior-femoral field was involved only in one groin with quadruple-field metastases. The lateral-inguinal field was not involved in any groin. Neither the lateral-inguinal nor the inferior-femoral field presented sentinel nodes. CONCLUSION: The lateral-inguinal and inferior-femoral fields of the groins have a low risk of developing nodal metastasis. Therefore, a modified IFL preserving these fields can be established to reduce surgical morbidity without sacrificing its therapeutic effect.

Clear Cell Adenocarcinoma of Uterine Cervix: A Single Institution Retrospective Experience.

PURPOSE: The purpose of the study is to summarize the clinical characteristics and identify the prognosis of clear cell adenocarcinoma of the uterine cervix (CCAUC) in patients without a history of diethylstilbestrol (DES) exposure. METHODS: Forty-two patients with CCAUC, treated initially at Sun Yat-sen University Cancer Center between 1985 and 2017, were studied. RESULTS: Of all the CCAUC patients, the median age was 47 years old, and the median tumor size was 3 cm. Thirty-four early stage patients (IB = 28, IIA = 6) underwent radical surgery. Eight advanced stage patients (IIB = 8) received concurrent chemoradiotherapy (n = 4) or radical surgery (n = 4). Survival analysis showed that patients with early stage (IB-IIA) had a significantly better 5-year progression-free survival (PFS) and overall survival (OS) than those with advanced stage (IIB) (p < 0.05). The patients with negative pelvic lymph node (PLN) had a significantly better 5-year PFS and OS than those with positive PLN (p < 0.05). Radiotherapy (RT) did not affect PFS or OS in early stage patients with intermediate risk factors (p > 0.05). Adjuvant chemotherapy (CT) did not affect PFS or OS in early stage patients without risk factors (p > 0.05). CONCLUSION: The FIGO stage and pelvic node status were important prognostic factors for both PFS and OS. For treatment modality, we recommended that radical surgery alone was used in early stage patients without high risk factors. Ovarian preservation in early stage patients involved some risk.