Oxygen and Iron Availability Shapes Metabolic Adaptations of Cancer Cells.

The dynamic changes between glycolysis and oxidative phosphorylation (OXPHOS) for adenosine triphosphate (ATP) output, along with glucose, glutamine, and fatty acid utilization, etc., lead to the maintenance and selection of growth advantageous to tumor cell subgroups in an environment of iron starvation and hypoxia. Iron plays an important role in the three major biochemical reactions in nature: photosynthesis, nitrogen fixation, and oxidative respiration, which all require the participation of iron-sulfur proteins, such as ferredoxin, cytochrome b, and the complex I, II, III in the electron transport chain, respectively. Abnormal iron-sulfur cluster synthesis process or hypoxia will directly affect the function of mitochondrial electron transfer and mitochondrial OXPHOS. More research results have indicated that iron metabolism, oxygen availability and hypoxia-inducible factor mutually regulate the shift between glycolysis and OXPHOS. In this article, we make a perspective review to provide novel opinions of the regulation of glycolysis and OXPHOS in tumor cells.

Anus preservation in low rectal adenocarcinoma based on MMR/MSI status (APRAM): a study protocol for a randomised, controlled, open-label, multicentre phase III trial.

BACKGROUND: Anus preservation has been a challenge in the treatment of patients with low rectal adenocarcinoma (within 5 cm from the anal verge) because it is difficult to spare the anus with its functioning sphincter complex under the safe margin of tumour resection. Patients with dMMR/MSI-H can achieve a favourable complete response (CR) rate by using a single immune checkpoint inhibitor. For patients with pMMR/MSS/MSI-L, intensified neoadjuvant three-drug chemotherapy may be the preferred option for anal preservation. In addition, the watch and wait (W&W) strategy has been proven safe and feasible for patients with rectal cancer who achieve a clinical complete response (cCR). Therefore, we initiated this clinical trial to explore the optimal neoadjuvant treatment pattern for patients with low locally advanced rectal cancer (LARC) with different MMR/MSI statuses, aiming to achieve a higher cCR rate with the W&W strategy and ultimately provide more patients with a chance of anus preservation. METHODS: This is a randomised, controlled, open-label, multicentre phase III trial. Patients with clinical stage T2-4 and/or N + tumours located within 5 cm from the anal verge are considered eligible. Based on the results of pathological biopsy, the patients are divided into two groups: dMMR/MSI-H and pMMR/MSS. Patients in the dMMR/MSI-H group will be randomly allocated in a 1:1 ratio to either arm A (monoimmunotherapy) or arm B (short-course radiotherapy followed by monoimmunotherapy). Patients in the pMMR/MSS group will be initially treated with long-term pelvic radiation with concurrent capecitabine combined with irinotecan. Two weeks after the completion of chemoradiotherapy (CRT), the patients will be randomly allocated in a 1:1 ratio to arm C (XELIRI six cycle regime) or arm D (FOLFIRINOX nine cycle regime). The irinotecan dose will be adjusted according to the UGT1A1-genotype. After treatment, a comprehensive assessment will be performed to determine whether a cCR has been achieved. If achieved, the W&W strategy will be adopted; otherwise, total mesorectal excision (TME) will be performed. The primary endpoint is cCR with the maintenance of 12 months at least, determined using digital rectal examination, endoscopy, and rectal MRI or PET/CT as a supplementary method. DISCUSSION: APRAM will explore the best anus preservation model for low LARC, combining the strategies of consolidation chemotherapy, immunotherapy, and short-course radiotherapy, and aims to preserve the anus of more patients using W&W. Our study provides an accurate individual treatment mode based on the MMR/MSI status for patients with low LARC, and more patients will receive the opportunity for anus preservation under our therapeutic strategy, which would transform into long-term benefits. TRIAL REGISTRATION: Clinicaltrials.gov NCT05669092 (Registered 28th Nov 2022).

Accelerating the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies.

Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool can be used to produce materials for the toxicology (Tox) study, reducing time to the clinic by 4-5 months. During the coronavirus disease 2019 (COVID-19) pandemic, the anti-COVID drugs timeline from DNA transfection to the clinical stage was decreased to 6 months using a stable pool to generate a clinical drug substrate (DS) with limited stability, virus clearance, and Tox study package. However, a lean chemistry, manufacturing, and controls (CMC) package raises safety and comparability risks and may leave extra work in the late-stage development and commercialization phase. In addition, whether these accelerated COVID-19 drug development strategies can be applied to non-COVID projects and established as a standard practice in biologics development is uncertain. Here, we present a case study of a novel anti-tumor drug in which application of "fast-to-FIH" approaches in combination with BeiGene's de-risk strategy achieved successful delivery of a complete CMC package within 10 months. A comprehensive comparability study demonstrated that the DS generated from a stable pool and a single-cell-derived master cell bank were highly comparable with regards to process performance, product quality, and potency. This accomplishment can be a blueprint for non-COVID drug programs that approach the pace of drug development during the pandemic, with no adverse impact on the safety, quality, and late-stage development of biologics.

Circadian Clock REV-ERBs Agonist SR9009 Induces Synergistic Antitumor Activity in Multiple Myeloma by Suppressing Glucose-Regulated Protein 78-Dependent Autophagy and Lipogenesis.

Background: Proteasome inhibitors, such as bortezomib, have demonstrated efficacy in the therapeutic management of multiple myeloma (MM). However, it is important to note that these inhibitors also elicit endoplasmic reticulum stress, which subsequently triggers the unfolded protein response (UPR) and autophagy, which have been shown to facilitate the survival of tumor cells. The disruption of the circadian clock is considered a characteristic feature of cancer. However, how disrupted circadian clock intertwines with tumor metabolism and drug resistance is not clearly clarified. This work explores the antitumor effectiveness of bortezomib and the circadian clock agonist SR9009, elucidating their impact on glucose-regulated protein 78 (GRP78), the autophagy process, and lipogenesis. Methods: The antitumor effects of bortezomib and SR9009 were evaluated using human MM cell lines (RPMI8226 and U266) in vitro and in vivo nonobese diabetic/severe combined immunodeficient (NOD/SCID) murine xenograft MM model. The assessment of cell viability was conducted using the cell counting kit-8 (CCK8) method, whereas the measurement of cell proliferation was performed with the inclusion of EdU (5-ethynyl-2'-deoxyuridine). Apoptosis was assessed by flow cytometry. The cells were transduced using adenovirus-tf-LC3, which was labeled with dual fluorescence. Subsequently, confocal imaging was employed to observe and examine the autophagosomes. REV-ERBα knockdown leads to upregulation of ATG5 and BENC1 at the protein level with immunoblot. Changes in the expression levels of GRP78, LC3, stearoyl-CoA desaturase 1 (SCD1), and fatty acid synthase (FASN) were assessed through the utilization of quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Results: Our results showed that both bortezomib and circadian clock REV-ERBs agonist SR9009 decreased MM viability, proliferation rate and induced an apoptotic response in a dose-dependent manner in vitro. However, the two differ greatly in their mechanisms of action. Bortezomib upregulated GRP78 and autophagy LC3, while circadian clock agonist SR9009 inhibited GRP78 and autophagy LC3. Combined SR9009 with bortezomib induced synergistic cytotoxicity against MM cells. REV-ERBα knockdown lead to upregulation of ATG5, BENC1 and significant upregulation of FASN, and SCD1. Mechanically, SR9009 inhibited the core autophagy gene ATG5 and BECN1, and two essential enzymes for de novo lipogenesis FASN and SCD1. SR9009 had synergistic effect with bortezomib and slowed down murine xenograft models of human MM tumor growth in vivo. Conclusions: Taken together, these results demonstrated that the circadian clock component REV-ERBs agonist SR9009 could inhibit GRP78-induced autophagy and de novo lipogenesis processes and had a synergistic effect with proteasome inhibitors in both in vitro and in vivo models of MM. Our findings shed light on how a disrupted circadian clock interacts with metabolic mechanisms to shape proteasome inhibitor drug resistance and suggest that SR9009 may be able to overcome the inherent drug resistance of proteasome inhibitors.

The crucial value of serum ferritin in assessing high-risk factors and prognosis for patients with endometrial carcinoma.

BACKGROUND: Endometrial carcinoma is a common malignant tumor in female reproductive system. At present, there is no effective and economic prognostic index. This study aimed to investigate the effect of serum ferritin levels on the prognosis of endometrial carcinoma. METHODS: Data of 367 patients who diagnosed with endometrial carcinoma at the First Affiliated Hospital of Chongqing Medical University between January 2012 and August 2018 was retrospectively analyzed. The prediction accuracy was evaluated by receiver operating characteristics curves and Youden's J statistics. Hosmer-lemeshow test was used to confirm the goodness of fit of the model. The prognostic value of serum ferritin on disease free survival (DFS) and overall survival (OS) of endometrial carcinoma was evaluated by univariate log-rank tests and multivariate cox regression models. RESULTS: Preoperative high serum ferritin was correlated with older age, high grade, specific histological subtypes and recurrence of endometrial carcinoma (P < 0.05). The DFS and OS of 198 patients with elevated serum ferritin levels were significantly lower than those with low serum ferritin levels (P = 0.001 and P = 0.002, respectively). In multivariate analysis, serum ferritin was an independent prognostic factor for DFS and OS in endometrial carcinoma (P = 0.012, P = 0.028). CONCLUSION: Through our research, we found that the high expression of serum ferritin level was not only related to low DFS and OS in patients with endometrial carcinoma, but also related to the high-risk factors of endometrial carcinoma recurrence. So serum ferritin levels may be used to predict the poor prognosis of patients with endometrial carcinoma.

The value of serum HE4 and CA125 levels for monitoring the recurrence and risk stratification of endometrial endometrioid carcinoma.

To evaluate the role of serum human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) levels for predicting and monitoring the recurrence of endometrial endometrioid carcinoma (EEC) and assessing preoperative risk stratification in EEC patients. A total of 434 EEC patients were selected for this retrospective study between May 2011 and August 2018. Serum HE4 and CA125 levels were analyzed before the initial treatment, at the first postoperative follow-up, and at recurrence or the last follow-up. Patients were risk stratified according to the European Society for Medical Oncology (ESMO), European Society for Radiotherapy & Oncology (ESTRO) and European Society of Gynaecological Oncology (ESGO) guideline. We compared the ability of these biomarkers for prediction and monitoring by performing receiver operating characteristic curve analysis and identified optimal cut-off values by determining the Youden index. Kaplan-Meier analyses were also performed to determine prognostic value. Preoperative serum HE4 was identified as a significant predictor for the recurrence of EEC (p = 0.014). Preoperative serum HE4 and CA125 levels were related to depth of myometrial invasion, lymph node status and FIGO stage. Serum HE4 and CA125 levels were both statistically significant markers for monitoring the recurrence of EEC (P = 0.000 for each biomarker). When combined, the two markers showed higher levels of sensitivity and specificity. The two biomarkers were also significant biomarkers for evaluating the risk stratification of patients undergoing lymphadenectomy (P = 0.000 for each biomarker). For premenopausal stage I patients, preoperative serum HE4 and CA125 levels were significant predictors of the need for ovarian preservation (P = 0.000 and P = 0.002, respectively). For premenopausal patients with stage I intramucosal differentiation, preoperative serum levels of HE4 were significant predictors for fertility preservation (P = 0.024). Preoperative serum HE4 level can be used to predict the recurrence of EEC. Postoperative serum HE4 and CA125 levels can be used to monitor the recurrence of EEC and are more sensitive when combined. Preoperative serum levels of CA125 and HE4 levels are of significant value for risk stratification in EEC patients.

Unraveling Colorectal Cancer and Pan-cancer Immune Heterogeneity and Synthetic Therapy Response Using Cuproptosis and Hypoxia Regulators by Multi-omic Analysis and Experimental Validation.

Cuproptosis, a new type of programmed cell death (PCD), is closely related to cellular tricarboxylic acid cycle and cellular respiration, while hypoxia can modulate PCD. However, their combined contribution to tumor subtyping remains unexplored. Here, we applied a multi-omics approach to classify TCGA_COADREAD based on cuproptosis and hypoxia. The classification was validated in three colorectal cancer (CRC) cohorts and extended to a pan-cancer analysis. The results demonstrated that pan-cancers, including CRC, could be divided into three distinct subgroups (cuproptosis-hypoxia subtypes, CHSs): CHS1 had active metabolism and poor immune infiltration but low fibrosis; CHS3 had contrasting characteristics with CHS1; CHS2 was intermediate. CHS1 may respond well to cuproptosis inducers, and CHS3 may benefit from a combination of immunotherapy and anti-fibrosis/anti-hypoxia therapies. In CRC, the CHSs also showed a significant difference in prognosis and sensitivity to classic drugs. Organoid-based drug sensitivity assays validated the results of transcriptomics. Cell-based assays indicated that masitinib and simvastatin had specific effects on CHS1 and CHS3, respectively. A user-friendly website based on the classifier was developed (https://fan-app.shinyapps.io/chs_classifier/) for accessibility. Overall, the classifier based on cuproptosis and hypoxia was applicable to most pan-cancers and could aid in personalized cancer therapy.

Identification and characterization of an unexpected isomerization motif in CDRH2 that affects antibody activity.

Aspartic acid (Asp) isomerization is a spontaneous non-enzymatic post-translation modification causing a change in the structure of the protein backbone, which is commonly observed in therapeutic antibodies during manufacturing and storage. The Asps in Asp-Gly (DG), Asp-Ser (DS), and Asp-Thr (DT) motifs in the structurally flexible regions, such as complementarity-determining regions (CDRs) in antibodies, are often found to have high rate of isomerization, and they are considered "hot spots" in antibodies. In contrast, the Asp-His (DH) motif is usually considered a silent spot with low isomerization propensity. However, in monoclonal antibody mAb-a, the isomerization rate of an Asp residue, Asp55, in the aspartic acid-histidine-lysine (DHK) motif present in CDRH2 was found to be unexpectedly high. By determining the conformation of DHK motif in the crystal structure of mAb-a, we found that the Cgamma of the Asp side chain carbonyl group and the back bone amide nitrogen of successor His were in proximal contact, which facilitates the formation of succinimide intermediate, and the +2 Lys played an important role in stabilizing such conformation. The contributing roles of the His and Lys residues in DHK motif were also verified using a series of synthetic peptides. This study identified a novel Asp isomerization hot spot, DHK, and the structural-based molecular mechanism was revealed. When 20% Asp55 isomerization in this DHK motif occurred in mAb-a, antigen binding activity reduced to 54%, but the pharmacokinetics in rat was not affected significantly. Although Asp isomerization of DHK motif in CDR does not appear to have a negative impact on PK, DHK motifs in the CDRs of antibody therapeutics should be removed, considering the high propensity of isomerization and impact on antibody activity and stability.

Pathological characteristics and tumour immune microenvironment of lung malignancies with RET rearrangement.

BACKGROUND: For patients with lung malignancies with RET rearrangement, the efficacy of immune checkpoint inhibitors is limited. The characteristics of the tumour immune microenvironment (TIME) and molecular pathological features of these patients have not been well elucidated. We aimed to investigate their clinical outcomes and explore characteristics of TIME, using multiplex immunohistochemistry technology (mIHC). PATIENTS AND METHODS: The pathology and TIME characteristics of 29 patients with lung malignancies with RET rearrangement were retrospectively analysed, and their relationships with clinical efficacy and prognosis were investigated. Gene detection relied on high-throughput sequencing, and TIME detection was based on mIHC. RESULTS: Of 29 patients, 25(86%) had adenocarcinoma, and the acinar type accounted for the greatest percentage of patients, followed by the solid type, regardless of whether the disease was early or locally advanced and metastatic. In addition, we report a novel KIF5B-RET(k24:R8) rearrangement in pulmonary sarcoma. The density of CD8+ T cells in tumour stroma in early-stage patients was significantly higher than that in locally advanced and metastatic patients (P = 0.014). The proportion of M2 macrophages in tumour stroma was significantly higher than that in tumour parenchyma (P = 0.046). Although the difference was not statistically significant (P = 0.098), patients positive for M2 macrophage infiltration into the tumour parenchyma (≥5%) may have a better prognosis. Seven patients received immunotherapy and disease control rate was 85.7%. CONCLUSIONS: A novel KIF5B-RET rearrangement variant in pulmonary sarcoma shows similar TIME characteristics to lung cancer. amongst patients with lung malignancies with RET rearrangement, patients with M2 macrophage infiltration into the tumour parenchyma may have a better prognosis, but further studies with larger cohorts are needed.

Iron oxide nanoparticles inhibit tumor growth by ferroptosis in diffuse large B-cell lymphoma.

Since the approval by the Food and Drug Administration (FDA), ferumoxytol and other iron oxide nanoparticles (IONs) have been widely used as iron supplements for patients with iron deficiency. Meanwhile, IONs have also been used as contrast agents in magnetic resonance imaging and as drug carriers. Importantly, IONs have demonstrated a significant inhibitory effect on the growth of tumors, including hematopoietic and lymphoid tumors, such as leukemia. In this study, we further demonstrated the effect of IONs on inhibiting the growth of diffuse large B-cell lymphoma (DLBCL) cells by enhancing ferroptosis-mediated cell death. IONs treatment caused an accumulation of intracellular ferrous iron and the onset of lipid peroxidation in DLBCL cells as well as the suppressed expression of anti-ferroptosis protein Glutathione Peroxidase 4 (GPX4), thereby leading to increased ferroptosis. Mechanistically, IONs increased cellular lipid peroxidation through the generation of ROS via the Fenton reaction and regulating the iron metabolism-related proteins, such as ferroportin (FPN) and transferrin receptor (TFR), which elevated the intracellular labile iron pool (LIP). Hence, our findings suggest the potential therapeutic effect of IONs on the treatment of patients with DLBCL.

Medial Epicanthoplasty With the Classic and Modified Skin Redraping Method: A Retrospective Case Control Study.

ABSTRACT: The skin redraping method for medial epicanthoplasty is characterized by some shortcomings which warrants modification. In this study, clinical data of 193 patients who underwent medial epichanthoplasty by the modified skin redraping technique or the classic skin redraping technique were reviewed retrospectively. The patients underwent operation between May 2018 and June 2020 and were followed up for not less than 6 months. Interepicanthal distance, interpupillary distance, patient satisfaction, and postoperative complications were evaluated. In terms of interepicanthal distance/inter-pupillary distance ratio (P > 0.05) and satisfaction score (P = 0.759), the modified skin redraping technique and the classic skin redraping technique were similar. In the classic skin redraping group, there were 3 cases of visible scarring in the lower eyelid, corresponding to significantly more cases than in the modified skin redraping group (n = 0, P < 0.001). There were more out-fold cases in the modified skin redraping group (76/90) than in the classic skin redraping group (17/88) (P < 0.001). Utilizing the modified skin redraping medial epicanthoplasty can prevent medial hooding of the upper eyelid, reduce the probability of visible scarring, and produce more out-fold with concurrent double eyelidplasty compared with classic skin redraping epicanthoplasty. Level of evidence: IV.

[Correlation between Peripheral Blood Intermediate Monocytes Increased and the Disease Progression of Patients with Diffuse Large BCell Lymphoma].

AbstractObjective: To explore the distribution characteristics and clinical significance of peripheral blood monocyte subgroups in patients with diffuse large Bcell lymphoma(DLBCL). METHODS: The percentage of peripheral blood monocyte subsets of 82 DLBCL patients (including 32 newly diagnosis, 29 remission and 21 relapse) and 30 healthy controls were detected by flow cytometry, and the correlation with the clinical characteristics and its diagnostic value of DLBCL were analyzed. RESULTS: The proportion of intermediate monocytes in patients with newly diagnosed DLBCL group was higher than that in healthy controls (t=5.888, P<0.01). The proportion in relapsed group was higher than those in newly diagnosed DLBCL group（t=2.106，P=0.04） and remission group （t=6.882， P＜0.01）, and the proportion of intermediate monocytes in newly diagnosed DLBCL group was higher than that in Remission group (t=3.969, P<0.01). With the increase of International Prognostic Index (IPI) score, the percentage of intermediate monocytes in patients with DLBCL increased (r=0.37). Furthermore, when the proportion of intermediate monocytes was 10.91% as the cutoff value, the sensitivity and specificity of the whole sample were 90.60% and 9100%, respectively. CONCLUSION: The disease progression is related to the increased intermediate monocytes, which can be used as a potential diagnostic index for DLBCL.

CC chemokine receptor 2 (CCR2) expression promotes diffuse large B-Cell lymphoma survival and invasion.

In recent years, CC chemokine receptor 2 (CCR2) has been found to be involved in tumor growth, angiogenesis, epithelial mesenchymal transition, metastasis, and immune escape. CCR2 overexpression was first identified as a poor prognostic predictor in diffuse large B-cell lymphoma (DLBCL) in our published article, but the mechanisms involved remain unknown. In this work, we collected data from another 138 patients with DLBCL data and verified the CCR2 expression level and its relationship to clinicopathological characteristics. Furthermore, we explored the possible mechanisms via in vitro and in vivo experiments. We showed that CCR2 overexpression was an independent prognostic marker and predicted shorter overall survival (OS) and progression-free survival (PFS) in patients with DLBCL. Blockade of CCR2 expression with a CCR2 antagonist inhibited tumor cell proliferation, migration, and anti-apoptosis ability in vitro by affecting the PI3K/Akt signaling pathway and the p38 MAPK signaling pathway. Furthermore, administration of a CCR2 antagonist decreased tumor growth and dissemination of DLBCL cells and increased survival time in the xenograft model. Our study demonstrates that CCR2 expression plays an important role in the development of DLBCL by stimulating cell proliferation, migration, and anti-apoptosis. Therefore, the inhibition of CCR2 may be a potential target for anticancer therapy in DLBCL.

The Preeminent Value of the Apparent Diffusion Coefficient in Assessing High-Risk Factors and Prognosis for Stage I Endometrial Carcinoma Patients.

OBJECTIVES: To evaluate the role of the apparent diffusion coefficient (ADC) value in the individualized management of stage I endometrial carcinoma (EC). METHODS: A retrospective analysis was performed on 180 patients with stage I EC who underwent 1.5-T magnetic resonance imaging. The mean ADC (mADC), minimum ADC (minADC), and maximum ADC (maxADC) values of each group were measured and compared. We analyzed the relationship between ADC values and stage I EC prognosis by Kaplan-Meier method and Cox proportional hazards analysis. RESULTS: Patients with lower ADC values were more likely to be characterized by higher grades, specific histological subtypes and deeper myometrial invasion. The mADC, minADC and maxADC values (×10-3 mm2/s) were 1.045, 0.809 and 1.339, respectively, in grade 1/2 endometrioid carcinoma with superficial myometrial invasion, which significantly differed from those in grade 3 or nonendometrioid carcinoma or with deep myometrial invasion (0.929, 0.714 and 1.215) (P=<0.001, <0.001 and <0.001). ADC values could be used to predict these clinicopathological factors. Furthermore, the group with higher ADC values showed better disease-free survival and overall survival. CONCLUSIONS: The present study indicated that ADC values were associated with the high-risk factors for stage I EC and to assess whether fertility-sparing, ovarian preservation or omission of lymphadenectomy represent viable treatment options. Moreover, this information may be applied to predict prognosis. Thus, ADC values could contribute to managing individualized therapeutic schedules to improve quality of life.

Serum HE4 and CA125 combined to predict and monitor recurrence of type II endometrial carcinoma.

There is no recognized serum biomarker to predict the recurrence of endometrial carcinoma (EC). We aimed to explore serum human epididymis protein 4 (HE4) and cancer antigen 125 (CA125) as the biomarkers to predict and monitor recurrence of type II EC. 191 patients diagnosed with type II EC were involved for this retrospective study. Comparing recurrent with non-recurrent patients, HE4 levels resulted a statistically significant difference at primary diagnosis and recurrence, respectively (P = 0.002 and P = < 0.001), while CA125 levels resulted statistically significant (P = < 0.001) at recurrence. According to receiver operating characteristic curve analysis, the areas under the curve were significant for HE4 levels at primary diagnosis and recurrence predicting recurrence. Furthermore, CA125 levels at recurrence were significant. And the combination of both markers showed the higher sensitivity and specificity than single one. Patients with higher HE4 levels were associated with worse disease-free survival and overall survival, the opposite was true for patients with lower HE4 levels. The preoperative HE4 levels could be used to evaluate the risk factors of type II EC. Which suggested that HE4 levels might associated with the prognosis of type II EC. And combination of HE4 and CA125 could be applied to monitor recurrence during follow-up.

Diagnostic Value of Preoperative CA125, LDH and HE4 for Leiomyosarcoma of the Female Reproductive System.

PURPOSE: Leiomyosarcoma (LMS) is a rare and extremely aggressive malignancy that is derived from or shows evidence of differentiation toward smooth muscle. If LMS occurs in the female reproductive system, preoperative diagnosis can be difficult, as LMS is easily mistaken for a uterine leiomyoma, especially a degenerated uterine fibroid (DUF). Thus, we assessed the diagnostic value of the preoperative serum concentrations of cancer antigen 125 (CA125), lactate dehydrogenase (LDH) and human epididymis protein 4 (HE4) for differentiating LMS from DUF. PATIENTS AND METHODS: We enrolled patients with LMS or DUF who were receiving treatment in The First Affiliated Hospital of Chongqing Medical University between 2009 and 2020. If the preoperative serum concentrations of CA125, LDH and HE4 of our study participants had been tested, these data were analyzed. The preoperative serum concentrations of CA125, LDH and HE4 in participants with LMS (n = 37) were compared with those of participants with pathologically diagnosed DUF (n = 102), who served as the control group. RESULTS: The preoperative serum concentrations of CA125, LDH and HE4 of participants with LMS of the female reproductive system were significantly higher than those of participants with DUF (P = 0.009, P < 0.001, P = 0.001, respectively). The cut-off preoperative serum concentrations of CA125, LDH and HE4 were 30.85 U/mL, 186.50 U/L and 50.50 pmol/L, respectively. When these three parameters were used for an analysis of their combined diagnostic utility, the area under the curve (AUC) was 0.892, the sensitivity was 68.4% and the specificity was 95.1% (P < 0.001). CONCLUSION: A combined analysis of the preoperative serum concentrations of CA125, LDH and HE4 could be a promising method for diagnostically differentiating LMS of the female reproductive system from DUF.

Magnitudes and environmental drivers of greenhouse gas emissions from natural wetlands in China based on unbiased data.

Whether natural wetlands serve as the source or sink of greenhouse gases (GHGs) remains uncertain. Wetlands in China are diverse in type and abundant in quantity and differ greatly in spatial distribution, environmental conditions, and GHG fluxes. However, few studies focused on the differences in GHG emissions from different types of natural wetlands. Here, we adopted strict data collection criteria to create comprehensive and detailed datasets of fluxes of carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) from the marsh, coastal, lake, and river wetlands in China, and relevant environmental variables. Our study synthesized 265 field observations on GHGs that lasted at least one year (covering both the growing season and non-growing season) from 109 studies, among which CO2 measurements using the opaque chamber method were not included for eliminating the influence of absence of photosynthesis on net CO2 accounting. We found that CH4 contributed the largest warming effect among the three types of GHGs, and coastal and river wetlands respectively acted as the mitigators and motivators of global warming among the four types of wetlands. Correlation and regression analyses suggested that geographic location, soil moisture and organic carbon, and contents of nitrogen, phosphorus, and dissolved oxygen jointly drove wetland GHG fluxes. The comprehensive global warming potential of Chinese natural wetlands was estimated as 427 Tg CO2-equivalents year-1, which might result from increased wetland drainage, reclamation, and external nutrient inputs. This study highlights the incorporation of the full year-round GHG monitoring data without using opaque chambers to measure CO2 flux when extrapolating net GHG emissions and gives implications for natural wetland management and global warming mitigation strategies.

Relationship between ascites volume and clinical outcomes in epithelial ovarian cancer.

OBJECTIVE: Ascites is a tumor microenvironment, ascites and massive ascites-induce compression could promote the progression of epithelial ovarian cancer (EOC); however, the impact of ascites volume on clinical outcomes has not been studied extensively. We aimed to investigate the association between ascites volume and clinical outcomes especially platinum resistance in EOC. METHODS: We retrospectively evaluated a total of 546 EOC patients with respect to the amount of ascites, clinicopathologic factors, and survival. Using the threshold of 1500 ml to classify patients into small- and large-volume ascites groups, we analyzed the correlation between ascites volume and clinicopathological factors, including platinum-free interval (PFI), and prognosis. RESULTS: Patients with large volume ascites were more likely to present with later stage disease, primary platinum-resistant (PPR) cancer, and suboptimal cytoreduction. Prolonged PFI was associated with decreased ascites volume. The large-volume ascites group showed worse progression-free survival (PFS) and overall survival (OS). An increase in ascites volume was associated with an increased risk of disease recurrence (hazard ratio [HR] = 1.115, 95% confidence interval [CI]: 1.035-1.200) and death (HR = 1.213, 95% CI: 1.090-1.350). CONCLUSIONS: Ascites was an independent predictor of PFS and OS in EOC patients. A large volume of ascites predicated a shortened PFI, an increased incidence of PPR and suboptimal cytoreduction. Thus, the volume of ascites is a simply available clinical parameter, which could be used to evaluate the prognosis and platinum resistance of EOC patients early, it contributes to formulate individualized treatment plan and improve the outcome of EOC patients.

Homogeneous Reforming of Aqueous Ethylene Glycol to Glycolic Acid and Pure Hydrogen Catalyzed by Pincer-Ruthenium Complexes Capable of Metal-Ligand Cooperation.

Glycolic acid is a useful and important α-hydroxy acid that has broad applications. Herein, the homogeneous ruthenium catalyzed reforming of aqueous ethylene glycol to generate glycolic acid as well as pure hydrogen gas, without concomitant CO2 emission, is reported. This approach provides a clean and sustainable direction to glycolic acid and hydrogen, based on inexpensive, readily available, and renewable ethylene glycol using 0.5 mol % of catalyst. In-depth mechanistic experimental and computational studies highlight key aspects of the PNNH-ligand framework involved in this transformation.

Prognostic Value of Ki-67 Index in Patients With Endometrial Stromal Sarcoma.

OBJECTIVE: The Ki-67 index is used to evaluate cell proliferation activity, which is related to tumor progression, metastasis, and prognosis. We aimed to explore the prognostic value of Ki-67 index in endometrial stromal sarcoma and to explore the optimal cut-off value of Ki-67 index for predicting recurrent endometrial stromal sarcoma. METHODS: A total of 82 patients with endometrial stromal sarcoma who were treated in our hospital were collected. Clinicopathological data of these patients were retrospectively analyzed. Ki-67 index was detected by the immunohistochemical method. Receiver operating characteristic curve and the Youden index were performed to determine the optimal cut-off value of Ki-67 index for predicting recurrent endometrial stromal sarcoma. The Cox regression was performed to analyze risk factors affecting prognosis of endometrial stromal sarcoma. The Kaplan-Meier method and Log-rank test were performed to analyze the survival of patients. RESULTS: The optimal cut-off value of Ki-67 index for predicting recurrent endometrial stromal sarcoma was 35%. The results of univariate analysis showed that high Ki-67 index (≥35%) was statistically significantly bound up with shorter progress free survival and overall survival. The results of multivariate analysis showed that Ki-67 index (P = 0.001) and ovarian preservation (P = 0.040) were independent prognostic factors of progress free survival. CONCLUSIONS: A Ki-67 index cut-off of 35% was optimal for predicting recurrent endometrial stromal sarcoma. Ki-67 index may be a useful prognostic marker in endometrial stromal sarcoma.