The safety, feasibility and oncological outcomes of laparoscopic completion total gastrectomy for remnant gastric cancer: a prospective study with 3-year follow-up (FUGES-004 study).

BACKGROUND: The efficacy of laparoscopic completion total gastrectomy (LCTG) for remnant gastric cancer (RGC) remains controversial. METHODS: The primary outcome was postoperative morbidity within 30 days after surgery. Secondary outcomes included 3-year disease-free survival (DFS), 3-year overall survival (OS), and recurrence. Inverse probability treatment weighted (IPTW) was used to balance the baseline between LCTG and OCTG. RESULTS: Final analysis included 46 patients with RGC who underwent LCTG at the FJMUUH between June 2016 and June 2020. The historical control group comprised of 160 patients who underwent open completion total gastrectomy (OCTG) in the six tertiary teaching hospitals from CRGC-01 study. After IPTW, no significant difference was observed between the LCTG and OCTG groups in terms of incidence (LCTG vs. OCTG: 28.0% vs. 35.0%, P=0.379) or severity of complications within 30 days after surgery. Compared with OCTG, LCTG resulted in better short-term outcomes and faster postoperative recovery. However, the textbook outcome rate was comparable between the two groups (45.9% vs. 32.8%, P=0.107). Additionally, the 3-year DFS and 3-year OS of LCTG were comparable to those of OCTG (DFS: log-rank P=0.173; OS: log-rank P=0.319). No significant differences in recurrence type, mean recurrence time, or 3-year cumulative hazard of recurrence were observed between the two groups (all P>0.05). Subgroup analyses and concurrent comparisons demonstrated similar trends. CONCLUSIONS: This prospective study suggested that LCTG was non-inferior to OCTG in both short- and long-term outcomes. In experienced centers, LCTG may be considered as a viable treatment option for RGC.

Conditional survival analysis and real-time prognosis prediction in stage III T3-T4 colon cancer patients after surgical resection: a SEER database analysis.

BACKGROUND: Conditional survival (CS) takes into consideration the duration of survival post-surgery and can provide valuable additional insights. The aim of this study was to investigate the risk factors associated with reduced one-year postoperative conditional survival in patients diagnosed with stage III T3-T4 colon cancer and real-time prognosis prediction. Furthermore, we aim to develop pertinent nomograms and predictive models. METHODS: Clinical data and survival outcomes of patients diagnosed with stage III T3-T4 colon cancer were obtained from the Surveillance, Epidemiology, and End Results (SEER) database, covering the period from 2010 to 2019. Patients were divided into training and validation cohorts at a ratio of 7:3. The training set consisted of a total of 11,386 patients for conditional overall survival (cOS) and 11,800 patients for conditional cancer-specific survival (cCSS), while the validation set comprised 4876 patients for cOS and 5055 patients for cCSS. Univariate and multivariate Cox regression analyses were employed to identify independent risk factors influencing one-year postoperative cOS and cCSS. Subsequently, predictive nomograms for cOS and cCSS at 2-year, 3-year, 4-year, and 5-year intervals were constructed based on the identified prognostic factors. The performance of these nomograms was rigorously assessed through metrics including the concordance index (C-index), calibration curves, and the area under curve (AUC) derived from the receiver operating characteristic (ROC) analysis. Clinical utility was further evaluated using decision curve analysis (DCA). RESULTS: A total of 18,190 patients diagnosed with stage III T3-T4 colon cancer were included in this study. Independent risk factors for one-year postoperative cOS and cCSS included age, pT stage, pN stage, pretreatment carcinoembryonic antigen (CEA) levels, receipt of chemotherapy, perineural invasion (PNI), presence of tumor deposits, the number of harvested lymph nodes, and marital status. Sex and tumor site were significantly associated with one-year postoperative cOS, while radiation therapy was notably associated with one-year postoperative cCSS. In the training cohort, the developed nomogram demonstrated a C-index of 0.701 (95% CI, 0.711-0.691) for predicting one-year postoperative cOS and 0.701 (95% CI, 0.713-0.689) for one-year postoperative cCSS. Following validation, the C-index remained robust at 0.707 (95% CI, 0.721-0.693) for one-year postoperative cOS and 0.700 (95% CI, 0.716-0.684) for one-year postoperative cCSS. ROC and calibration curves provided evidence of the model's stability and reliability. Furthermore, DCA underscored the nomogram's superior clinical utility. CONCLUSIONS: Our study developed nomograms and predictive models for postoperative stage III survival in T3-T4 colon cancer with the aim of accurately estimating conditional survival. Survival bias in our analyses may lead to overestimation of survival outcomes, which may limit the applicability of our findings.

Well-defined diatomic catalysis for photosynthesis of C2H4 from CO2.

Owing to the specific electronic-redistribution and spatial proximity, diatomic catalysts (DACs) have been identified as principal interest for efficient photoconversion of CO2 into C2H4. However, the predominant bottom-up strategy for DACs synthesis has critically constrained the development of highly ordered DACs due to the random distribution of heteronuclear atoms, which hinders the optimization of catalytic performance and the exploration of actual reaction mechanism. Here, an up-bottom ion-cutting architecture is proposed to fabricate the well-defined DACs, and the superior spatial proximity of CuAu diatomics (DAs) decorated TiO2 (CuAu-DAs-TiO2) is successfully constructed due to the compact heteroatomic spacing (2-3 Å). Owing to the profoundly low C-C coupling energy barrier of CuAu-DAs-TiO2, a considerable C2H4 production with superior sustainability is achieved. Our discovery inspires a novel up-bottom strategy for the fabrication of well-defined DACs to motivate optimization of catalytic performance and distinct deduction of heteroatom synergistically catalytic mechanism.

Comparing the short-term clinical outcomes and therapeutic effects of different colectomies in patients with refractory slow-transit constipation in eastern countries: a network meta-analysis.

Surgical treatment has been widely used in patients with refractory slow transit constipation (RSTC). The aim of this network meta-analysis (NMA) was to compare the effects of different colectomies on short-term postoperative complications and quality of life in patients with RSTC. Electronic literature searches were performed in the PubMed, Web of Science, EMBASE, WANFANG DATA, and Cochrane Central Register of controlled trials databases and were searched up to December 2022. Selected to compare the short-term clinical outcomes and quality of life of the treatment of RSTC. A random-effects Bayesian NMA was conducted to assess and rank the effectiveness of different surgical modalities. This study included a total of six non-randomized controlled trials involving 336 subjects. It was found that subtotal colectomy with cecorectal anastomosis (CRA) demonstrated superior effectiveness in several aspects, including reduced hospital stay (MD 0.06; 95% CI [0.02, 1.96]), shorter operative time (MD 4.75; 95% CI [0.28, 14.07]), lower constipation index (MD 0.61; 95% CI [0.04, 1.71]), improved quality of life (MD 4.42; 95% CI [0.48, 4.42]). Additionally, in terms of short-term clinical outcomes, subtotal colectomy with ileosigmoidal anastomosis (SC-ISA) procedure ranked the highest in reducing small bowel obstruction (OR 0.24; 95% CI [0.02, 0.49]), alleviating abdominal pain (OR 0.53; 95% CI [0.05, 1.14]), minimizing abdominal distension (OR 0.33; 95% CI [0.02, 0.65]), and reducing incision infection rates (OR 0.17; 95% CI [0.01, 0.33]). Furthermore, SC-ISA ranked as the best approach in terms of patient satisfaction (OR 0.66; 95% CI [0.02, 1.46]). Based on our research findings, we recommend that CRA be considered as the preferred treatment approach for patients diagnosed with RSTC.

Infrared light dual excitation of Ni-phytate-sensitized ZnIn2S4 with sulfur vacancies for enhanced NIR-driven photocatalysis.

Near-infrared (NIR) light accounts for about half of the solar spectrum, and the effective utilization of low-energy NIR light is an important but challenging task in the field of photocatalysis. Molecular semiconductor photocatalytic systems (MSPSs) are highly tunable, available and stable, and are considered to be one of the most promising ways to achieve efficient NIR hydrogen production. Here, we demonstrate efficient dual-excitation in MSPS consisting of ZnIn2S4-x (ZIS1-x) with sulfur vacancies and phytic acid nickel (PA-Ni), which differs from other NIR-responsive photosensitized systems. The system achieves a hydrogen evolution reaction (HER) of 119.85 µmol h-1 g-1 at λ > 800 nm illumination, which is an excellent performance among all reported NIR catalysts and even outperforms the noble metal catalysts when compared to the reported literature. The superior activity is attributed to the unique charge dynamics and higher carrier concentration of the system. This work demonstrates the potential of dual-excitation systems for efficient utilization of low-energy NIR light.

Association of hemicolectomy with survival in stage II colorectal cancer: a retrospective cohort study.

To compare the oncological survival outcomes of partial colectomy (PC) and hemicolectomy (HC) in patients with stage II colon cancer. A total of 18,795 patients with stage II colon cancer who underwent hemicolectomy (n = 12,022) or partial colectomy (n = 6773) from 2010 to 2019 were included in the the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific survival (CSS) were compared between the two groups, and the threshold of harvested lymph nodes was determined. The results showed that age, gender, race, tumor site, scope of regional lymph nodes, postoperative chemotherapy, postoperative radiotherapy, harvested lymph nodes, and tumor size were significantly different between the PC and HC groups (all P < 0.05). The OS rate was slightly lower in hemicolectomy patients than in partial colectomy patients (69.9% vs. 74.5%, respectively, P < 0.001), but CSS was similar between the two groups (87.9% vs. 88.1%, respectively, P = 0.32). After propensity score matching (PSM) was performed, the OS and CSS rates in the two groups were significantly different (CSS 84.3% vs. 88.0%, P < 0.001; OS 62.2% vs. 72.5%, P < 0.001). The survminer R package determined that the optimum threshold for the harvested lymph node count in stage II colon cancer patients was 16. CSS was significantly different between patients with ≥ 12 lymph nodes harvested and patients with ≥ 16 lymph nodes harvested (P = 0.043). Univariate and multivariate Cox regression and survival analyses of stage II colon cancer patients showed that the survival benefit of stage II colon cancer patients receiving partial colectomy was superior to that of patients receiving hemicolectomy. Partial colectomy has significant oncological benefits over hemicolectomy in the treatment of stage II colon cancer patients, even in the case of pT4b or tumor deposits. Removal of 16 lymph nodes during colectomy for stage II colon cancer correlated with improved survival, and this threshold was more effective than the standard threshold of 12 lymph nodes in distinguishing between patients with good and poor prognoses.

Flame doping of indium ions into TiO2 nanorod arrays for enhanced photochemical water oxidation.

Indium (In) ions were diffused into a TiO2 (In-TiO2) photoelectrode via a facile and efficient flame doping method resulting in improved photo-induced carrier separation. The dopant concentration was systematically investigated, and a volcano-type relationship between the dopant concentration and photoelectrochemical (PEC) performance was observed. The optimum incident photon-to-current efficiency and photocurrent density of In-TiO2 were 38.6% and 0.70 mA cm-2 at 1.23 V, respectively, 2.1 and 11.2 times the values of pristine TiO2, respectively. In doping resulted in improved charge separation and lower surface adsorption energies for reactant molecules, as evidenced by experimental and computational methods.

Comparison of the short-term and long-term outcomes of three different types of inferior mesenteric artery ligation in left colonic and rectal cancers: a network meta-analysis.

To perform a network meta-analysis of the literature to assess the short-term and long-term outcomes of three operations for left colon and rectal cancer. Electronic literature searches were performed in the PubMed, Web of Science, EMBASE, and Cochrane Central Register of Controlled Trials databases up to August 2022. A Bayesian network meta-analysis using R software, ADDIS, and Review Manager 5.4 was conducted to compare outcomes of high ligation of the inferior mesenteric artery(IMA),low ligation of the IMA with D2 dissection (LLD2), and low ligation of the IMA with D3 dissection (LLD3). Sensitivity analysis was applied to investigate the influence of each primary study on the final result of the meta-analysis. Asymmetry of data was estimated by using Egger's tests. Publication bias corrected by trimming and filling method. A total of 44 studies, 5 randomized clinical trials (RCTs) and 39 non-RCTs, were included in this meta-analysis. HL was associated with a higher risk of anastomotic leakage (HL vs. LLD2, OR = 1.35, 95% CI 1.13-3.25, P = 0.001; HL vs. LLD3, OR = 1.65, 95% CI 1.35-2.01, P < 0.001), and required a longer postoperative hospital stay (HL vs. LLD3, SMD = 0.28, 95%CI 0.09-0.48, P = 0.01).However HL showed an advantage in terms of operation time(HL vs. LLD3, SMD = - 0.13, 95%CI - 0.26 to 0.01, P = 0.04). LLD3 is most likely to rank best in terms of short-term and long-term outcomes after surgery for left colon and rectal cancer. Caution should be taken in the risk of anastomotic leakage when treating colorectal cancer with LLD2. HL, LLD2 and LLD3 provide similar overall survival rates for left colon and rectal cancer.

Visible-light-driven photoreforming of poly(ethylene terephthalate) plastics via carbon nitride porous microtubes.

It is highly desirable but challenging to realize efficient photoreforming of plastic waste over metal-free semiconductors. Here, we synthesized metal-free carbon nitride porous microtube (CNxPM) photocatalysts by carrying out a pyrolysis of the supramolecular assembly formed by the self-assembly of L-arginine (L-Arg) and melamine, the modification of L-Arg rationally engineering the microstructure and electronic structure of the CNxPM system for efficient visible-light-driven photoreforming of poly(ethylene terephthalate) (PET) to hydrogen (H2) and high-value chemicals. In particular, the amount of formate converted from PET substrate under visible light was highest in metal-free semiconductors without any co-catalyst reported so far, presenting the first example of visible-light-driven photoreforming of PET over a completely metal-free single-component semiconductor without any co-catalyst.

Nitrogen-doped graphene quantum dots embedding CuCo-LDH hierarchical hollow structure for boosted charge storage capability in supercapacitor.

The nanostructure optimization of layered double hydroxide (LDH) can effectively alleviate fragile agglomerated problems. Herein, nitrogen-doped graphene quantum dots (NGQDs) embedded in CuCo-LDH hierarchical hollow structure is synthesized by hydrothermal and impregnation methods. The electrochemical results show that the ordered multi-component structure could effectively inhibit the aggregation and layer stacking. At the same time, the hierarchical structure establishes new electron and ion transfer channels, greatly reducing the resistance of interlayer transport and accelerating the diffusion rate of electrolyte ions. Besides, NGQDs have both good electrical conductivity and abundant active sites, which can further improve the electron transmission rate and effectively strengthen the energy storage capacity of the material. Therefore, the large specific capacity of 1009 F g-1 can be displayed at 1 A g-1. The energy density of the assembled carbon cloth (CC)@CuCo-LDH/NGQDs//activated carbon (AC) device can reach 58.6 Wh kg-1 at 850 W kg-1. Above test results indicate that CC@CuCo-LDH/NGQDs//AC devices exhibit stable multi-component hierarchical structure and excellent electrical conductivity, which provides an effective strategy for enhancing the electrochemical characteristics of asymmetric supercapacitors.

Photochemical and electrochemical co-regulation of the BiVO4 photoanode for water splitting.

A novel pretreatment strategy that can regulate the amount of oxygen vacancies (Ovac) across the wormlike-BiVO4 photoanode by photochemical and electrochemical co-processing. Upon decorating NiFeOx as an oxygen evolution cocatalyst for promoting the surface oxidation kinetics, a record-high photocurrent density of 6.42 mA cm-2 is obtained at 1.23 vs. RHE (100 mW cm-2).

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Exosome miR-3184-5p inhibits gastric cancer growth by targeting XBP1 to regulate the AKT, STAT3, and IRE1 signalling pathways.

MicroRNAs can regulate the transcription of protein-coding genes associated with the development and progression of cancer. In this study, we explored the potential diagnostic function of exosome miR-3184-5p in gastric cancer. This exosome was isolated from the blood samples of 150 patients with gastric cancer and 60 healthy participants. The mean particle size and concentration of serum exosome in the patients with gastric cancer were 104.6 nm (93.97-115.84) and 6.21e+009 particles/ml (5.15e+009-7.12e+009), respectively. miR-3184-5p expression was substantially downregulated in the patients with gastric cancer compared with that in the healthy participants. The gastric cancer cell line HGC-27 was cultured and transfected with the mimic and an inhibitor to overexpress and inhibit miR-3184-5p expression. miR-3184-5p strongly suppressed cell proliferation, migration, and invasion but induced cell apoptosis. Luciferase reporter assay revealed that XBP1 was the target of miR-3184-5p. miR-3184-5p substantially downregulated the expression of CD44, cyclin D1, MMP2, p65, p-AKT, and p-STAT3 but upregulated that of GRP78, IRE1, p-JNK, and CHOP. Moreover, miR-3184-5p cleaved caspase-12 and inhibited BCL-2 expression. These results suggested that the downregulation of miR-3184-5p in patients with gastric cancer might regulate the AKT, STAT3, and IRE1 pathways to promote the vitality of gastric cancer cells.

Brominated and Sulfur-Containing Angucyclines Derived from a Single Pathway: Identification of Nocardiopsistins D-F.

One novel brominated nocardiopsistin D (1) and two new sulfur-containing nocardiopsistins E-F (2-3) were identified from Nocardiopsis sp. HB-J378. The biosynthetic gene cluster ncd featuring a brominase was identified. Compounds 1-3 exhibited significant anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activities with minimum inhibitory concentrations (MICs) of 0.098, 3.125, and 0.195 µg/mL, respectively. The single bromination in 1 drastically enhanced the anti-MRSA activity by 128-fold without altering cell toxicity and acquired new activities against the bacterial pathogens vancomycin-resistant S. aureus (VRSA), Enterococcus faecium, and Bacillus cereus.

Short-term Outcomes of Laparoscopy-Assisted vs Open Surgery for Patients With Low Rectal Cancer: The LASRE Randomized Clinical Trial.

Importance: The efficacy of laparoscopic vs open surgery for patients with low rectal cancer has not been established. Objective: To compare the short-term efficacy of laparoscopic surgery vs open surgery for treatment of low rectal cancer. Design, Setting, and Participants: This multicenter, noninferiority randomized clinical trial was conducted in 22 tertiary hospitals across China. Patients scheduled for curative-intent resection of low rectal cancer were randomized at a 2:1 ratio to undergo laparoscopic or open surgery. Between November 2013 and June 2018, 1070 patients were randomized to laparoscopic (n = 712) or open (n = 358) surgery. The planned follow-up was 5 years. Data analysis was performed from April 2021 to March 2022. Interventions: Eligible patients were randomized to receive either laparoscopic or open surgery. Main Outcomes and Measures: The short-term outcomes included pathologic outcomes, surgical outcomes, postoperative recovery, and 30-day postoperative complications and mortality. Results: A total of 1039 patients (685 in laparoscopic and 354 in open surgery) were included in the modified intention-to-treat analysis (median [range] age, 57 [20-75] years; 620 men [59.7%]; clinical TNM stage II/III disease in 659 patients). The rate of complete mesorectal excision was 85.3% (521 of 685) in the laparoscopic group vs 85.8% (266 of 354) in the open group (difference, -0.5%; 95% CI, -5.1% to 4.5%; P = .78). The rate of negative circumferential and distal resection margins was 98.2% (673 of 685) vs 99.7% (353 of 354) (difference, -1.5%; 95% CI, -2.8% to 0.0%; P = .09) and 99.4% (681 of 685) vs 100% (354 of 354) (difference, -0.6%; 95% CI, -1.5% to 0.5%; P = .36), respectively. The median number of retrieved lymph nodes was 13.0 vs 12.0 (difference, 1.0; 95% CI, 0.1-1.9; P = .39). The laparoscopic group had a higher rate of sphincter preservation (491 of 685 [71.7%] vs 230 of 354 [65.0%]; difference, 6.7%; 95% CI, 0.8%-12.8%; P = .03) and shorter duration of hospitalization (8.0 vs 9.0 days; difference, -1.0; 95% CI, -1.7 to -0.3; P = .008). There was no significant difference in postoperative complications rate between the 2 groups (89 of 685 [13.0%] vs 61 of 354 [17.2%]; difference, -4.2%; 95% CI, -9.1% to -0.3%; P = .07). No patient died within 30 days. Conclusions and Relevance: In this randomized clinical trial of patients with low rectal cancer, laparoscopic surgery performed by experienced surgeons was shown to provide pathologic outcomes comparable to open surgery, with a higher sphincter preservation rate and favorable postoperative recovery. Trial Registration: ClinicalTrials.gov Identifier: NCT01899547.

Uncovering Lasonolide A Biosynthesis Using Genome-Resolved Metagenomics.

Invertebrates, particularly sponges, have been a dominant source of new marine natural products. For example, lasonolide A (LSA) is a potential anticancer molecule isolated from the marine sponge Forcepia sp., with nanomolar growth inhibitory activity and a unique cytotoxicity profile against the National Cancer Institute 60-cell-line screen. Here, we identified the putative biosynthetic pathway for LSA. Genomic binning of the Forcepia sponge metagenome revealed a Gram-negative bacterium belonging to the phylum Verrucomicrobia as the candidate producer of LSA. Phylogenetic analysis showed that this bacterium, here named "Candidatus Thermopylae lasonolidus," only has 88.78% 16S rRNA identity with the closest relative, Pedosphaera parvula Ellin514, indicating that it represents a new genus. The lasonolide A (las) biosynthetic gene cluster (BGC) was identified as a trans-acyltransferase (AT) polyketide synthase (PKS) pathway. Compared with its host genome, the las BGC exhibits a significantly different GC content and pentanucleotide frequency, suggesting a potential horizontal acquisition of the gene cluster. Furthermore, three copies of the putative las pathway were identified in the candidate producer genome. Differences between the three las repeats were observed, including the presence of three insertions, two single-nucleotide polymorphisms, and the absence of a stand-alone acyl carrier protein in one of the repeats. Even though the verrucomicrobial producer shows signs of genome reduction, its genome size is still fairly large (about 5 Mbp), and, compared to its closest free-living relative, it contains most of the primary metabolic pathways, suggesting that it is in the early stages of reduction. IMPORTANCE While sponges are valuable sources of bioactive natural products, a majority of these compounds are produced in small quantities by uncultured symbionts, hampering the study and clinical development of these unique compounds. Lasonolide A (LSA), isolated from marine sponge Forcepia sp., is a cytotoxic molecule active at nanomolar concentrations, which causes premature chromosome condensation, blebbing, cell contraction, and loss of cell adhesion, indicating a novel mechanism of action and making it a potential anticancer drug lead. However, its limited supply hampers progression to clinical trials. We investigated the microbiome of Forcepia sp. using culture-independent DNA sequencing, identified genes likely responsible for LSA synthesis in an uncultured bacterium, and assembled the symbiont's genome. These insights provide future opportunities for heterologous expression and cultivation efforts that may minimize LSA's supply problem.

Risk factor for the development of surgical site infection following ileostomy reversal: a single-center report.

PURPOSE: Postoperative surgical site infection (SSI) is not uncommon in patients with ileostomy reversal. The appropriate index to predict the postoperative SSI in these individuals remains unclear. The aim of this study is to evaluate the risk factor for SSI after ileostomy reversal. METHODS: A consecutive cohort of 201 patients who underwent elective ileostomy reversal between January 2015 and January 2020 were retrospectively analyzed. Patients were divided into two groups: SSI group and non-SSI group. Univariate and multivariate analyses were conducted to identify risk factors for postoperative SSI. RESULTS: Postoperative SSI occurred in 37 (18.4%) patients. Compared with the non-SSI group, patients in SSI group had higher incidence of nutrition risk (56.77% vs 39.02%, P = 0.049), higher C-reactive protein (CRP) level (10.81 ± 16.49 vs 4.86 ± 4.14 mg/L, P < 0.001), and longer postoperative hospital stay (13.08 ± 3.71 vs 7.47 ± 2.38 days, P < 0.001). By analyzing the receiver-operating characteristic (ROC) curve, CRP have the value in predicting the occurrence of SSI. The areas under the ROC curves of CRP for SSI was 0.671 (95% confidence interval 0.568-0.774, P = 0.001) with an optimal diagnostic cut-off value of 8.0 mg/L. By the univariate and multivariate analyses, preoperative C-reactive protein (CRP) ≥ 8 mg/L(P < 0.001) and conventional linear closure method (P = 0.004) were independent risk factors for postoperative SSI. CONCLUSIONS: Preoperative CRP levels can be served as a predictive index for postoperative SSI after stoma reversal. Purse-string closure technique is the treatment of choice to minimize stoma site SSI in patients with stoma reversal.

Effects of Docetaxel plus Degarelix on Quality of Life and Vascular Endothelial Growth Factor in Patients with Prostate Cancer.

Objective: To investigate the effects of docetaxel plus degarelix on quality of life and vascular endothelial growth factor in patients with prostate cancer. Methods: Between 2018 and 2020, 38 patients with castration-resistant prostate cancer (CRPC) treated in our institution were assessed for eligibility and recruited. They were assigned at a ratio of 1 : 1 to receive either docetaxel plus degarelix (observation group) or degarelix (control group). Outcome measures included treatment efficacy, inflammatory factors level, vascular endothelial growth factor (VEGF) level, and quality of life of patients. Results: Docetaxel plus degarelix was associated with a significantly higher treatment efficacy (94.74%, including 9 (47.37%) cases of complete response (CR), 6 (31.58%) cases of partial response (PR), 4 (21.05%) cases of stable disease (SD), and 1 (5.36%) case of progressive disease (PD)) versus degarelix alone (63.16%, including 4 (21.05%) cases of CR, 5 (26.32%) cases of PR, 3 (15.79%) cases of SD, and 7 (36.84%) cases of PD) (P < 0.05). Before treatment, the two groups showed comparable levels of C-reaction protein (CRP), interleukin- (IL-) 6, and IL-10 (P > 0.05). Docetaxel plus degarelix resulted in significantly reduced levels of CRP and IL-6 and a significantly higher IL-10 level (28.84 ± 5.42, 25.31 ± 5.74, and 53.32 ± 11.02) versus degarelix alone (35.17 ± 6.31, 31.54 ± 8.17, and 42.76 ± 11.25) (P < 0.05). There were no significant differences in the urinary function, intestinal function, and hormone function scores between the two groups before treatment (P > 0.05). The patients receiving docetaxel plus degarelix had higher urinary function, intestinal function, and hormone function scores (38.87 ± 4.46, 86.51 ± 8.14, and 76.65 ± 7.15) versus monotherapy of degarelix (29.84 ± 3.58, 78.51 ± 7.31, and 66.78 ± 6.56) (P < 0.05). The two groups had similar pretreatment VEGF levels (P > 0.05). Docetaxel plus degarelix resulted in significantly lower VEGF levels (119.17 ± 21.38) versus degarelix (124.36 ± 23.14) at 6 months after treatment (P < 0.05). Conclusion: Docetaxel plus degarelix can enhance the therapeutic efficacy of patients with prostate cancer, mitigate inflammatory response, inhibit the VEGF expression of cancer cells, and improve the patients' quality of life. Further clinical trials are, however, required prior to general use in clinical practice.

Ex Vivo Organoid Model of Adenovirus-Cre Mediated Gene Deletions in Mouse Urothelial Cells.

Bladder cancer is an understudied area, particularly in genetically engineered mouse models (GEMMs). Inbred GEMMs with tissue-specific Cre and loxP sites have been the gold standards for conditional or inducible gene targeting. To provide faster and more efficient experimental models, an ex vivo organoid culture system is developed using adenovirus Cre and normal urothelial cells carrying multiple loxP alleles of the tumor suppressors Trp53, Pten, and Rb1. Normal urothelial cells are enzymatically disassociated from four bladders of triple floxed mice (Trp53f/f: Ptenf/f: Rb1f/f). The urothelial cells are transduced ex vivo with adenovirus-Cre driven by a CMV promoter (Ad5CMVCre). The transduced bladder organoids are cultured, propagated, and characterized in vitro and in vivo. PCR is used to confirm gene deletions in Trp53, Pten, and Rb1. Immunofluorescence (IF) staining of organoids demonstrates positive expression of urothelial lineage markers (CK5 and p63). The organoids are injected subcutaneously into host mice for tumor expansion and serial passages. The immunohistochemistry (IHC) of xenografts exhibits positive expression of CK7, CK5, and p63 and negative expression of CK8 and Uroplakin 3. In summary, adenovirus-mediated gene deletion from mouse urothelial cells engineered with loxP sites is an efficient method to rapidly test the tumorigenic potential of defined genetic alterations.

Single-Cell Analyses of a Novel Mouse Urothelial Carcinoma Model Reveal a Role of Tumor-Associated Macrophages in Response to Anti-PD-1 Therapy.

Approximately 80% of patients with advanced bladder cancer do not respond to immune checkpoint inhibitor (ICI) immunotherapy. Therefore, there is an urgent unmet need to develop clinically relevant preclinical models so that factors governing immunotherapy responses can be studied in immunocompetent mice. We developed a line of mouse triple knockout (TKO: Trp53, Pten, Rb1) urothelial carcinoma organoids transplanted into immunocompetent mice. These bladder tumors recapitulate the molecular phenotypes and heterogeneous immunotherapy responses observed in human bladder cancers. The TKO organoids were characterized in vivo and in vitro and compared to the widely used MB49 murine bladder cancer model. RNAseq analysis of the TKO tumors demonstrated a basal subtype. The TKO xenografts demonstrated the expression of urothelial markers (CK5, CK7, GATA3, and p63), whereas MB49 subcutaneous xenografts did not express urothelial markers. Anti-PD-1 immunotherapy resulted in a mixed pattern of treatment responses for individual tumors. Eight immune cell types were identified (basophils, B cells, dendritic cells, macrophages, monocytes, neutrophils, NK cells, and T cells) in ICI-treated xenografts. Responder xenografts displayed significantly increased immune cell infiltration (15.3%, 742 immune cells/4861 total cells) compared to the non-responder tumors (10.1%, 452 immune cells/4459 total cells, Fisher Exact Test p < 0.0001). Specifically, there were more T cells (1.0% vs. 0.4%, p = 0.002) and macrophages (8.6% vs. 6.4%, p = 0.0002) in responder xenografts than in non-responder xenografts. In conclusion, we have developed a novel preclinical model that exhibits a mixed pattern of response to anti-PD-1 immunotherapy. The higher percentage of macrophage tumor infiltration in responders suggests a potential role for the innate immune microenvironment in regulating ICI treatment responses.