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  • 1
    Online Resource
    Online Resource
    Genome analysis of Cephalotrichum gorgonifer and identification of the biosynthetic pathway for rasfonin, an inhibitor of KRAS dependent cancer
    Springer Science and Business Media LLC ; 2023
    In:  Fungal Biology and Biotechnology Vol. 10, No. 1 ( 2023-06-24)
    Details
    In: Fungal Biology and Biotechnology, Springer Science and Business Media LLC, Vol. 10, No. 1 ( 2023-06-24)
    Abstract: Fungi are important sources for bioactive compounds that find their applications in many important sectors like in the pharma-, food- or agricultural industries. In an environmental monitoring project for fungi involved in soil nitrogen cycling we also isolated Cephalotrichum gorgonifer (strain NG_p51). In the course of strain characterisation work we found that this strain is able to naturally produce high amounts of rasfonin, a polyketide inducing autophagy, apoptosis, necroptosis in human cell lines and showing anti-tumor activity in KRAS-dependent cancer cells. Results In order to elucidate the biosynthetic pathway of rasfonin, the strain was genome sequenced, annotated, submitted to transcriptome analysis and genetic transformation was established. Biosynthetic gene cluster (BGC) prediction revealed the existence of 22 BGCs of which the majority was not expressed under our experimental conditions. In silico prediction revealed two BGCs with a suite of enzymes possibly involved in rasfonin biosynthesis. Experimental verification by gene-knock out of the key enzyme genes showed that one of the predicted BGCs is indeed responsible for rasfonin biosynthesis. Conclusions This study identified a biosynthetic gene cluster containing a key-gene responsible for rasfonin production. Additionally, molecular tools were established for the non-model fungus Cephalotrichum gorgonifer which allows strain engineering and heterologous expression of the BGC for high rasfonin producing strains and the biosynthesis of rasfonin derivates for diverse applications.
    Type of Medium: Online Resource
    ISSN: 2054-3085
    URL: Article
    DOI: 10.1186/s40694-023-00158-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 2806612-1
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  • 2
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    Online Resource
    Limosilactobacillus fermentum Limits Candida glabrata Growth by Ergosterol Depletion
    American Society for Microbiology ; 2023
    In:  Microbiology Spectrum Vol. 11, No. 2 ( 2023-04-13)
    Details
    In: Microbiology Spectrum, American Society for Microbiology, Vol. 11, No. 2 ( 2023-04-13)
    Abstract: Candida glabrata is a human-associated opportunistic fungal pathogen. It shares its niche with Lactobacillus spp. in the gastrointestinal and vaginal tract. In fact, Lactobacillus species are thought to competitively prevent Candida overgrowth. We investigated the molecular aspects of this antifungal effect by analyzing the interaction of C. glabrata strains with Limosilactobacillus fermentum . From a collection of clinical C. glabrata isolates, we identified strains with different sensitivities to L. fermentum in coculture. We analyzed the variation of their expression pattern to isolate the specific response to L. fermentum . C. glabrata - L. fermentum coculture induced genes associated with ergosterol biosynthesis, weak acid stress, and drug/chemical stress. L. fermentum coculture depleted C. glabrata ergosterol. The reduction of ergosterol was dependent on the Lactobacillus species, even in coculture with different Candida species. We found a similar ergosterol-depleting effect with other lactobacillus strains ( Lactobacillus crispatus and Lactobacillus rhamosus ) on Candida albicans , Candida tropicalis , and Candida krusei . The addition of ergosterol improved C. glabrata growth in the coculture. Blocking ergosterol synthesis with fluconazole increased the susceptibility against L. fermentum , which was again mitigated by the addition of ergosterol. In accordance, a C. glabrata Δerg11 mutant, defective in ergosterol biosynthesis, was highly sensitive to L. fermentum . In conclusion, our analysis indicates an unexpected direct function of ergosterol for C. glabrata proliferation in coculture with L. fermentum . IMPORTANCE The yeast Candida glabrata , an opportunistic fungal pathogen, and the bacterium Limosilactobacillus fermentum both inhabit the human gastrointestinal and vaginal tract. Lactobacillus species, belonging to the healthy human microbiome, are thought to prevent C. glabrata infections. We investigated the antifungal effect of Limosilactobacillus fermentum on C. glabrata strains quantitively in vitro . The interaction between C. glabrata and L. fermentum evokes an upregulation of genes required for the synthesis of ergosterol, a sterol constituent of the fungal plasma membrane. We found a dramatic reduction of ergosterol in C. glabrata when it was exposed to L. fermentum . This effect extended to other Candida species and other Lactobacillus species. Furthermore, fungal growth was efficiently suppressed by a combination of L. fermentum and fluconazole, an antifungal drug which inhibits ergosterol synthesis. Thus, fungal ergosterol is a key metabolite for the suppression of C. glabrata by L. fermentum .
    Type of Medium: Online Resource
    ISSN: 2165-0497
    URL: Article
    DOI: 10.1128/spectrum.03326-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2023
    detail.hit.zdb_id: 2807133-5
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  • 3
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    Online Resource
    Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy
    American Medical Association (AMA) ; 2022
    In:  JAMA Network Open Vol. 5, No. 11 ( 2022-11-21), p. e2243119-
    Details
    In: JAMA Network Open, American Medical Association (AMA), Vol. 5, No. 11 ( 2022-11-21), p. e2243119-
    Abstract: Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. Objective To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. Design, Setting, and Participants This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. Exposures Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. Main Outcomes and Measures The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. Results A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR] , 1.07; 95% CI, 1.01-1.13; P  = .03), aggressive biology (OR, 1.32; 95% CI, 1.15-1.53; P   & amp;lt; .001), and stenotic lesions (OR, 1.15; 95% CI, 1.01-1.31; P  = .03). Conclusions and Relevance This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    URL: Article
    DOI: 10.1001/jamanetworkopen.2022.43119
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    detail.hit.zdb_id: 2931249-8
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  • 4
    Online Resource
    Online Resource
    Effect of centre volume on pathological outcomes and postoperative complications after surgery for colorectal cancer: results of a multicentre national study
    Oxford University Press (OUP) ; 2023
    In:  British Journal of Surgery ( 2023-11-14)
    Details
    In: British Journal of Surgery, Oxford University Press (OUP), ( 2023-11-14)
    Abstract: The association between volume, complications and pathological outcomes is still under debate regarding colorectal cancer surgery. The aim of the study was to assess the association between centre volume and severe complications, mortality, less-than-radical oncologic surgery, and indications for neoadjuvant therapy. Methods Retrospective analysis of 16,883 colorectal cancer cases from 80 centres (2018–2021). Outcomes: 30-day mortality; Clavien-Dindo grade & gt;2 complications; removal of ≥ 12 lymph nodes; non-radical resection; neoadjuvant therapy. Quartiles of hospital volumes were classified as LOW, MEDIUM, HIGH, and VERY HIGH. Independent predictors, both overall and for rectal cancer, were evaluated using logistic regression including age, gender, AJCC stage and cancer site. Results LOW-volume centres reported a higher rate of severe postoperative complications (OR 1.50, 95% c.i. 1.15–1.096, P = 0.003). The rate of ≥ 12 lymph nodes removed in LOW-volume (OR 0.68, 95% c.i. 0.56–0.85, P & lt; 0.001) and MEDIUM-volume (OR 0.72, 95% c.i. 0.62–0.83, P & lt; 0.001) centres was lower than in VERY HIGH-volume centres. Of the 4676 rectal cancer patients, the rate of ≥ 12 lymph nodes removed was lower in LOW-volume than in VERY HIGH-volume centres (OR 0.57, 95% c.i. 0.41–0.80, P = 0.001). A lower rate of neoadjuvant chemoradiation was associated with HIGH (OR 0.66, 95% c.i. 0.56–0.77, P & lt; 0.001), MEDIUM (OR 0.75, 95% c.i. 0.60–0.92, P = 0.006), and LOW (OR 0.70, 95% c.i. 0.52–0.94, P = 0.019) volume centres (vs. VERY HIGH). Conclusion Colorectal cancer surgery in low-volume centres is at higher risk of suboptimal management, poor postoperative outcomes, and less-than-adequate oncologic resections. Centralisation of rectal cancer cases should be taken into consideration to optimise the outcomes.
    Type of Medium: Online Resource
    ISSN: 0007-1323 , 1365-2168
    URL: Article
    DOI: 10.1093/bjs/znad373
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2006309-X
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