Gut-derived metabolite 3-methylxanthine enhances cisplatin-induced apoptosis via dopamine receptor D1 in a mouse model of ovarian cancer.

Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both in vivo and in vitro. Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.

NAMPT­NAD+ is involved in the senescence­delaying effects of saffron in aging mice.

As the proportion of the elderly population grows rapidly, the senescence-delaying effects of Traditional Chinese Medicine is being investigated. The aim of the present study was to investigate the senescence-delaying effects of saffron in naturally aging mice. The active ingredients in an aqueous saffron extract were determined using high-performance liquid chromatography (HPLC). Mice were divided into saffron (8- and 16-months-old) and control groups (3-, 8-, and 16-months-old), and saffron extract was administered to the former groups for 8 weeks. The open field test and Barnes maze test were used to evaluate the locomotor activity, learning and memory function of the mice. The levels of inflammatory factors in the brain were determined by ELISA. In addition, the activities of acetylcholinesterase (AChE) and superoxide dismutase, and the contents of malondialdehyde and nicotinamide adenine dinucleotide (NAD+) were detected by enzyme immunoassay, and the content of NAMPT was detected by ELISA, western blotting and reverse transcription-quantitative PCR. The cellular distribution of NAMPT and synaptic density were evaluated by immunofluorescence, and the pathological morphologies of the liver, skin, kidneys were observed by hematoxylin and eosin staining. HPLC revealed that the crocin and picrocrocin contents of the saffron extract were 19.56±0.14 and 12.00±0.13%, respectively. Saffron exhibited the potential to improve the learning and memory function in aging mice as it increased synaptic density and decreased AChE activity. Also, saffron ameliorated the pathological changes associated with organ aging, manifested by increasing the number of hepatocytes and the thickness of the skin, and preventing the aging-induced ballooning and bleeding in the kidneys. Furthermore, saffron increased the contents of NAMPT and NAD+ in the brain and decreased the content of NAMPT in the serum. In addition, it changed the cellular distribution of NAMPT in aging mice, manifested as reduced NAMPT expression in microglia and astrocytes, and increased NAMPT expression in neurons. Saffron also decreased the contents of proinflammatory cytokines and oxidative stress factors in aging mice. Altogether, these findings indicate that saffron exerts senescence-delaying effects in naturally aging mice, which may be associated with the NAMPT-NAD+ pathway.

LSKANet: Long Strip Kernel Attention Network for Robotic Surgical Scene Segmentation.

Surgical scene segmentation is a critical task in Robotic-assisted surgery. However, the complexity of the surgical scene, which mainly includes local feature similarity (e.g., between different anatomical tissues), intraoperative complex artifacts, and indistinguishable boundaries, poses significant challenges to accurate segmentation. To tackle these problems, we propose the Long Strip Kernel Attention network (LSKANet), including two well-designed modules named Dual-block Large Kernel Attention module (DLKA) and Multiscale Affinity Feature Fusion module (MAFF), which can implement precise segmentation of surgical images. Specifically, by introducing strip convolutions with different topologies (cascaded and parallel) in two blocks and a large kernel design, DLKA can make full use of region- and strip-like surgical features and extract both visual and structural information to reduce the false segmentation caused by local feature similarity. In MAFF, affinity matrices calculated from multiscale feature maps are applied as feature fusion weights, which helps to address the interference of artifacts by suppressing the activations of irrelevant regions. Besides, the hybrid loss with Boundary Guided Head (BGH) is proposed to help the network segment indistinguishable boundaries effectively. We evaluate the proposed LSKANet on three datasets with different surgical scenes. The experimental results show that our method achieves new state-of-the-art results on all three datasets with improvements of 2.6%, 1.4%, and 3.4% mIoU, respectively. Furthermore, our method is compatible with different backbones and can significantly increase their segmentation accuracy. Code is available at https://github.com/YubinHan73/LSKANet.

Speculation on optimal numbers of examined lymph node for early-stage epithelial ovarian cancer from the perspective of stage migration.

Introduction: In early-stage epithelial ovarian cancer (EOC), how to perform lymphadenectomy to avoid stage migration and achieve reliable targeted excision has not been explored in depth. This study comprehensively considered the stage migration and survival to determine appropriate numbers of examined lymph node (ELN) for early-stage EOC and high-grade serous ovarian cancer (HGSOC). Methods: From the Surveillance, Epidemiology, and End Results database, we obtained 10372 EOC cases with stage T1M0 and ELN ≥ 2, including 2849 HGSOC cases. Generalized linear models with multivariable adjustment were used to analyze associations between ELN numbers and lymph node stage migration, survival and positive lymph node (PLN). LOESS regression characterized dynamic trends of above associations followed by Chow test to determine structural breakpoints of ELN numbers. Survival curves were plotted using Kaplan-Meier method. Results: More ELNs were associated with more node-positive diseases, more PLNs and better prognosis. ELN structural breakpoints were different in subgroups of early-stage EOC, which for node stage migration or PLN were more than those for improving outcomes. The meaning of ELN structural breakpoint varied with its location and the morphology of LOESS curve. To avoid stage migration, the optimal ELN for early-stage EOC was 29 and the minimal ELN for HGSOC was 24. For better survival, appropriate ELN number were 13 and 8 respectively. More ELNs explained better prognosis only at a certain range. Discussion: Neither too many nor too few numbers of ELN were ideal for early-stage EOC and HGSOC. Excision with appropriate numbers of lymph node draining the affected ovary may be more reasonable than traditional sentinel lymph node resection and systematic lymphadenectomy.

Toxic footprint and materials profile of electronic components in printed circuit boards.

Waste printed circuit boards (WPCBs) contain valuable material resources and hazardous substances, thereby posing a challenge for sustainable resource recovery and environmental protection initiatives. Overcoming this challenge will require mapping the toxic footprint of WPCBs to specific materials and substances used in manufacturing electronic components (ECs). Therefore, this work collected 50 EC specimens from WPCBs in five ubiquitous consumer products, such as television, refrigerator, air conditioner, washing machine and computer. The work extracted and analyzed metal contents and used leachability assessments based on tests adopted by the regulatory policies from China and the United States. The work found that copper and iron are the most abundant constituents in ECs, with concentrations ranging 5.90-796.62 g/kg and 0-831.53 g/kg, respectively; whereas abundance of precious metal content is in the order of silver > gold > palladium > platinum, with silver concentration ranging 15-5290 mg/kg. The content of marginally-regulated toxic substance arsenic ranged 0-9700 mg/kg; whereas fully regulated toxic metals such as chromium, lead and mercury did not exceed the thresholds set by China and US standards. The work found new toxic threats from arsenic and selenium leached from 20 of 50 ECs exceeding regulatory standards. These results will aid manufacturers and recyclers in protecting workers' health and environmental quality from arsenic and selenium pollution, and should initiate discussion about regulating these toxic components as part of a comprehensive program to reduce the toxic footprint of electronic products.

Effect of modified no-touch laparoscopic radical hysterectomy on outcomes of early stage cervical cancer: A retrospective cohort study.

OBJECTIVES: We aimed to compare the prognosis of modified no-touch laparoscopic radical hysterectomy (MLRH) and laparoscopic radical hysterectomy (LRH) on survival in patients with early stage cervical cancer. MATERIALS AND METHODS: The clinicopathological data of patients with stage IB1 and IIA1 cervical cancer, who underwent radical surgery between 2014 and 2019, were retrospectively reviewed. The 5-year disease-free survival (DFS) and overall survival (OS) were compared between the MLRH and LRH groups using the Kaplan-Meier method. Independent prognostic factors for 5-year DFS and OS were identified using multivariate, forward, stepwise Cox proportional hazards regression models. RESULTS: A total of 223 patients with stage IB1 and IIA1 cervical cancer were included. Kaplan-Meier analysis revealed that the 5-year DFS and OS rates in the MLRH (n = 81) group were significantly higher than those in the LRH group (n = 142) (DFS, 94.5% vs. 78.8%, p = 0.007; OS, 96.7% vs. 87.6%, p = 0.033). No significant differences were identified between the two groups in terms of operative time, blood loss, transfusion requirement, and intraoperative or postoperative complications. MLRH was an independent prognostic factor associated with increased 5-year DFS (adjusted hazard ratio [HR], 0.202; 95% confidence interval [CI], 0.069-0.594; p = 0.004) and 5-year OS (adjusted HR, 0.163; 95% CI, 0.035-0.748; p = 0.020). CONCLUSION: The oncologic outcomes were superior with MLRH than with LRH in patients with stage IB1 and IIA1 cervical cancer. Contact of cervical tumor cells with the pelvic cavity likely explains the worse prognosis associated with LRH.

Early detection of a cesarean scar pregnancy with placenta increta by contrast-enhanced ultrasound in the first trimester: A case report and literature review.

Cesarean scar pregnancy (CSP) is a rare form of ectopic pregnancy, which is a long-term complication of cesarean section. Prompt and accurate diagnosis of CSP is important to decrease maternal mobility and mortality. However, it is difficult to make an early detection for CSP complicated with morbidly adherent placenta. Contrast-enhanced ultrasound with the advantage in blood flow imaging is low-cost, time-saving, safe and more accessible in clinical practice. Here, we report a case with early detection of CSP with placenta increta by contrast-enhanced ultrasound and its successful uterine-sparing surgical management.

Pre-validation of a Calu-3 epithelium cytotoxicity assay for predicting acute inhalation toxicity of chemicals.

Although in vivo inhalation toxicity tests have been widely conducted, the testing of many chemicals is limited for economic and ethical reasons. Therefore, we previously developed an in vitro acute inhalation toxicity test method. The goal of the present pre-validation study was to evaluate the transferability, reproducibility, and predictive capacity of this method. After confirming the transferability of the Calu-3 epithelium cytotoxicity assay, reproducibility was evaluated using 20 test substances at three independent institutions. Cytotoxicity data were analyzed using statistical methods, including the intra-class correlation coefficient and Bland-Altman plots for within- and between-laboratory reproducibility. The assay for the 20 test substances showed excellent agreement within and between laboratories. To evaluate the predictive capacity, 77 test substances were analyzed for acute inhalation toxicity. Accuracy was measured using a cutoff of 40%, and the relevance was analyzed as a receiver-operating characteristic (ROC) curve. An accuracy of 72.73% was obtained, and the area under the ROC curve was 0.77, indicating moderate performance. In this study, we found that the in vitro acute inhalation toxicity test method demonstrated good reliability and relevance for predicting the acute toxicity of inhalable chemicals. Hence, this assay has potential as an alternative test for screening acutely toxic inhalants.

Successful Laparoscopic Management of Type I Cesarean Scar Pregnancy A Case Series.

OBJECTIVE: To explore the efficacy of laparoscopic surgery without auxiliary treatment for type II cesarean scar pregnancy (CSP-II). STUDY DESIGN: This was a case series of 7 patients with CSP-II who underwent laparoscopic surgery without auxiliary treatment between April 2014 and April 2015. All cases were diagnosed by ultrasound, confirmed by laparoscopy, and managed by laparoscopic resection of scar and gestational tissue and wound repair. RESULTS: All 7 patients had successful surgeries without complication. Uterine scar and gestational tissues were resected, while also preserving the uterus. The operation time was 70.1 ± 16.3 min and blood loss was 65.7 ± 32.1 mL. Serum ß-hCG levels 24 hours after surgery declined by 84.8 ± 9.4%. Serum ß-hCG levels went back to <5 IU/L in all 7 patients by 14.4 ± 4.3 days after surgery. The time interval between surgery and first menstruation was 35.3 ± 4.5 days. CONCLUSION: These results suggest the possibility that skilled surgeons could use laparoscopy without auxiliary pretreatment to remove gestational tissues and uterine scar defect and to repair the wound in patients with CSP-II.

Functional exercise in combination with auricular plaster therapy is more conducive to rehabilitation of menopausal women patients with anxiety disorder.

OBJECTIVE: Observe the effect of functional exercise in combination with auricular plaster therapy on menopausal women patients with anxiety disorder. METHOD: Select 45 menopausal women patients with anxiety disorder and then adopt random digital table to divide them into a functional exercise group, an auricular plaster therapy group and a combination group. Each group consists of 15 patients. The patients in the functional exercise group do yoga exercise twice a day; those in the auricular plaster therapy group are provided with the auricular plaster therapy twice a day; those in the combination group do yoga exercise and then they are provided with the auricular plaster therapy twice a day. Before the treatment and after 12 weeks' treatment, respectively detect and compare the selected patients in the three groups in respect HAMA score, physical function score and mental function score; And the cured patients are followed up for 3 months to compare recurrence rate of each group. RESULTS: After 12 weeks' treatment, HAMA score, physical function score and mental function score of the combination group are obviously better than those of another two groups (P<0.05); Of the cure rate and the recurrence rate within 3 months, the cure rate of the combination group is higher and the recurrence rate is low. CONCLUSION: Through the functional rehabilitation exercise in combination with the auricular plaster, the combined curative effect is obviously better than that of single treatment and the clinical recurrence rate is significantly lower than that of single treatment. It shows that the combined treatment method presents obvious synergistic effect and the synergistic treatment is more beneficial to improve the curative effect.

Twelve-year experience with laparoscopic radical hysterectomy and pelvic lymphadenectomy in cervical cancer.

OBJECTIVES: This study aims to evaluate the morbidity, oncological outcome, and prognostic factors of cervical cancer patients treated with laparoscopic radical hysterectomy and pelvic lymphadenectomy (LRH). METHODS: Patients with cervical cancer undergoing LRH at the First People's Hospital of Foshan between August 1998 and March 2010 were enrolled in this study. The medical records were reviewed. RESULTS: A total of 240 patients were identified. According to FIGO stage, the number of patients with stage Ia2, Ib1, Ib2, IIa, and IIb was 2, 163, 34, 35, and 6, respectively. The conversion rate was 1.25%. Intraoperative and postoperative complications occurred in 7.08% and 9.16% patients, respectively. Other medical problems included 74 cases (30%) of bladder dysfunction. Excluding the lost cases, the median follow-up of 221 cases was 35 months, and 5-year survival rate for Ia2, Ib1, Ib2, IIa was 100%, 82%, 66%, 60%, respectively. Univariate analysis showed factors impacting the survival rate were FIGO stage>Ib1, non-squamous histologic type, deep cervical stromal invasion, and lymph node metastasis (P=0.027, 0.023, 0.007, 0.000). The Cox-proportional hazards regression analysis indicated that only lymph node metastasis (OR=3.827, P=0.000) was independent of poor prognostic factor. The 5-year survival rates in Ib1 were 88% with negative lymph nodes and 59% with positive lymph nodes (P=0.000). CONCLUSIONS: Our data demonstrate that LRH can be performed in stage Ia2-Ib1 or less advanced node negative cervical cancer patients without compromising survival. The feasibility of LRH for more advanced patients needs further investigations.

Complications of laparoscopic radical hysterectomy and pelvic lymphadenectomy--experience of 117 patients.

OBJECTIVE: To describe the combined surgical technique of laparoscopic radical hysterectomy and pelvic lymphadenectomy (LRH + LPL) for cervical cancers and summarize our experiences in prevention and treatment of complications, so as to provide strategies to prevent and appropriately manage the complications that may occur during these procedures. METHODS: A retrospective study was conducted on LRH + LPL in 117 cases of cervical cancer with International Federation of Gynecology and Obstetrics stages Ib (n = 96) and II a (n = 21) from August 1998 to December 2006. The intraoperative and postoperative complications were analyzed. RESULTS: The overall conversion rate was 1.7% (2/117). Four patients had vessel injuries, 3 of which were treated laparoscopically. One patient had a common iliac vein laceration that could not be controlled laparoscopically after failing to deal with the injured branch of common iliac vein. Cystotomy occurred in 5 patients. One case of stage IIa with a bladder laceration longer than 3 cm was converted to laparotomy during the early stages of the learning curve. The remaining 4 were managed laparoscopically. Postoperative complications occurred in 38.5% (n = 45) of the patients, including 38 patients with urinary retention who exhibited complete resolution within 6 months by intermittent training and catheterization, 4 with lymphocyst who underwent conservation treatment, 1 with ureteral fistula that was treated by cystoscopic placement of double-J ureteral stents, 1 with mild adynamic bowel obstruction who received conservative management, and 1 with vesicovaginal fistula that was closed by conservative treatment. CONCLUSIONS: With the continuous skilled laparoscopic technology, mastering the tips of prevention, and treatment of complications, LRH + LPL will be widely performed in the future.

A comparison of laparoscopic radical hysterectomy and pelvic lymphadenectomy and laparotomy in the treatment of Ib-IIa cervical cancer.

OBJECTIVE: To compare the feasibility, morbidity, and survival outcome of the laparoscopic radical hysterectomy and pelvic lymphadenectomy (LRH+LPL) with abdominal radical hysterectomy and pelvic lymphadenectomy (ARH+APL) for FIGO stage Ib-IIa cervical carcinoma. METHODS: The consecutive cases with FIGO Ib-IIa cervical cancer from August 1998 to December 2005 were documented, including 90 patients underwent LRH+LPL, and 35 patients underwent ARH+APL as control group. The clinic data of perioperative periods and survival were compared between groups. RESULTS: In laparoscopy group the operating time increased significantly (262.99+/-67.6 min vs. 217.2+/-71.56 min, P=0.001), and the recovery time of bowel decreased significantly (1.96+/-0.62 days vs. 2.40+/-1.06 days, P=0.025). No significant difference was found between groups when the blood loss during operation (369.78+/-249.94 ml vs. 455.14+/-338.05 ml, P=0.125), numbers of the pelvic lymph nodes resected (21.28+/-8.39 vs. 18.77+/-9.47, P=0.151), recovery time of bladder function and postoperative hospital stays were compared. All laparoscopic procedures were completed successfully except 2 cases converted to laparotomy. The median follow-up was 26 months (range 5 to 84 months). Ten and five cases lost to follow-up in laparoscopy and laparotomy group, respectively. Excluding the lost cases, the recurrence rate (13.75% vs. 12%, P>0.05) and the mortality rate (10% vs. 8%, P>0.05) between groups was similar. CONCLUSION: Our data demonstrated that cervical cancer could be treated successfully with LRH+LPL with similar efficacy and recurrence rates to ARH+APL. LRH+LPL is a safe and effective alternative to conventional abdominal surgery for stage Ib-IIa cervical cancer, and should be used if the surgeon is sufficiently trained. Its clinical value should be confirmed by multicenter randomized clinic trials.