Fusobacterium nucleatum, a Gram‐negative oral anaerobe, is a significant contributor to colorectal cancer. Using an in vitro cancer progression model, we discover that F. nucleatum stimulates the ...growth of colorectal cancer cells without affecting the pre‐cancerous adenoma cells. Annexin A1, a previously unrecognized modulator of Wnt/β‐catenin signaling, is a key component through which F. nucleatum exerts its stimulatory effect. Annexin A1 is specifically expressed in proliferating colorectal cancer cells and involved in activation of Cyclin D1. Its expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age, and sex. The FadA adhesin from F. nucleatum up‐regulates Annexin A1 expression through E‐cadherin. A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the non‐cancerous cells. We therefore propose a “two‐hit” model in colorectal carcinogenesis, with somatic mutation(s) serving as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous. This model extends the “adenoma‐carcinoma” model and identifies microbes such as F. nucleatum as cancer “facilitators”.
Synopsis
Fusobacterium nucleatum specifically stimulates colorectal carcinoma cells by inducing the Wnt/β‐catenin modulator Annexin A1. This supports a model where driver mutations serve as the first, and microbial infection as the second “hit” to promote cancer progression.
Fusobacterium nucleatum stimulates colorectal cancer cells without affecting precancerous adenoma cells.
Annexin A1 is specifically expressed in colorectal cancer cells and is a predictor of poor prognosis.
The Fusobacterium nucleatum FadA adhesin up‐regulates Annexin A1 expression through E‐cadherin.
A positive feedback loop between FadA and Annexin A1 is specifically present in cancer cells.
Fusobacterium nucleatum specifically stimulates colorectal carcinoma cells by inducing the Wnt/β‐catenin modulator Annexin A1. This supports a model where driver mutations serve as the first, and microbial infection as the second “hit” to promote cancer progression.
A clinician's guide to double hit lymphomas Cheah, Chan Yoon; Oki, Yasuhiro; Westin, Jason R. ...
British journal of haematology,
March 2015, Volume:
168, Issue:
6
Journal Article
Peer reviewed
Open access
Summary
Double hit lymphomas (DHL) represent a subset of highly aggressive B‐cell malignancies characterized by the presence of recurrent cytogenetic rearrangements affecting MYC and either BCL2 ...and/or BCL6. Recent studies have expanded the concept to include MYC/BCL2 protein co‐expressing lymphomas. Around 5–10% of diffuse large B‐cell lymphomas are ‘double hit’ using the cytogenetic definition, whilst around 30–40% are MYC/BCL2 protein co‐expressing. In this review, we provide a comprehensive overview of this condition written with the practicing clinician in mind, covering the definition and classification, when DHL should be suspected and how to make the diagnosis, the prognostic factors and a detailed discussion of recent evidence regarding optimal therapy. In particular, we discuss choice of induction regimen, the role of central nervous system‐directed prophylaxis, stem cell transplantation and relapsing or refractory disease and provide our opinions based on the currently available evidence. Finally, we highlight some of the more exciting therapies currently in development for this highly aggressive disease.
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•TPPU_DSF easily calculates thermodynamic parameters from a single DSF measurement.•Compatible with common real time PCR instruments used for DSF measurements and high-throughput ...compound screening campaigns.•For the Web application no installation is required. It is compatible with all operating systems, it is free and open source and generates publication-ready figures and tables.•Data security. Data never leaves the user's computer, thus ensuring confidentiality.
Here we present TPPU_DSF (https://maciasnmr.net/tppu_dsf/). This is a free and open-source web application that opens, converts, fits, and calculates the thermodynamic parameters of protein unfolding from standard differential scanning fluorimetry (DSF) data in an automated manner. The software has several applications. In the context of screening compound libraries for protein binders, obtaining thermodynamic parameters provides a more robust approach to detecting hits than the changes in the melting temperature (Tm) alone, thereby helping to increase the number of positive hits in screening campaigns. Moreover, changes in ΔGuo indicate protein response to binding at lower compound concentrations than those in the Tm, thereby reducing the costs associated with the amounts of protein and compounds required for the assays. Also, by adding thermodynamic information to the Tm comparison, the software can contribute to the optimization of protein constructs and buffer conditions, a common practice before structural and functional projects.
•We describe two patients with autoimmune heparin-induced thrombocytopenia (HIT) successfully treated with early high-dose intravenous immunoglobulin (IVIg).•High-dose IVIg may be an effective ...strategy for patients with HIT refractory to alternative anticoagulants.•Early IVIg treatment should be considered for patients with autoimmune HIT and a severe hypercoagulable state.
High-dose intravenous immunoglobulin (IVIg) can be effective for patients with refractory autoimmune heparin-induced thrombocytopenia (HIT). We report two patients with autoimmune HIT (aHIT) successfully treated with early high-dose IVIg.
Case 1 was a 48-year-old male who had persisting HIT with recurrent ischemic stroke after mitral valve replacement. Case 2 was a 71-year-old male who had flush heparin HIT with cerebral venous thrombosis after total hip arthroplasty. High-dose IVIg was administered 6 and 4 days after starting argatroban due to non-improved thrombocytopenia and persistently high D-dimer values, respectively. Both patients achieved favorable functional recovery at discharge as well as improvements of thrombocytopenia and hypercoagulation.
Early high-dose IVIg may be effective for patients with aHIT and hypercoagulability.
The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic ...screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road to clinical candidates and novel drug targets. Whereas this process is usually straightforward for target screening hits, phenotypic screening hits act through a variety of mostly unknown mechanisms within a large and poorly understood biological space. Our analysis suggests successful hit triage and validation is enabled by three types of biological knowledge—known mechanisms, disease biology, and safety—while structure-based hit triage may be counterproductive.
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Phenotypic and target screening have important differences. Vincent et al. conduct an analysis of the hit triage process for phenotypic screens, which suggests successful hit validation and prioritization is best enabled by three types of biological knowledge—known mechanisms, disease biology, and safety—while structure-based hit triage may be counterproductive.
Double-Hit and Triple-Hit Follicular Lymphoma Ziemba, Jessica B; Wolf, Zena; Weinstock, Matthew ...
American journal of clinical pathology,
04/2020, Volume:
153, Issue:
5
Journal Article
Peer reviewed
Open access
Abstract
Objectives
To better characterize the clinicopathologic presentation and outcomes of follicular lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit and triple-hit follicular ...lymphoma), we present three cases from our institution and perform a literature review of 37 published cases.
Methods
Cases were identified using institutional SoftPath software and the MEDLINE database via the PubMed search engine. Clinical and pathologic data were collected with subsequent stratification by histologic grade and treatment for comparison.
Results
Similar to classic follicular lymphoma, patients presented most often with low-grade (1-2) but high-stage (III-IV) disease with absence of B symptoms; however, overall survival was worse than that of traditional follicular lymphoma. In a small sample size, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) achieved better outcomes than a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Specific pathologic features that might prompt testing for MYC rearrangement include elevated proliferation index out of proportion to cytology and aggressive features such as angioinvasion.
Conclusions
Double-hit and triple-hit follicular lymphoma may be better classified as a distinct entity from classical follicular lymphoma with a worse prognosis. Aggressive therapy with a treatment regimen used for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements might be beneficial, but more evidence is needed to justify aggressive treatment as standard of care.
Background: High-grade B-cell lymphoma (HGBL) with rearrangements of MYC and BCL2 and/or BCL6, called double and triple-hit lymphomas (DTH-HGBL), are lymphoid malignancies with inferior outcomes when ...treated with standard chemotherapy. The identification of DTH-HGBL cases is challenging, considering their variable clinical, morphologic, and immunohistochemical features.
Materials and Methods: Retrospective revision of medical data of patients diagnosed with DTH-HGBL confirmed by FISH, between January 2010 and January 2020, in three Tertiary Portuguese Hospitals (Coimbra Hospital and University Center, Portuguese Oncology Institute – Coimbra and Portuguese Oncology Institute – Porto). Pathological features, morphology, and immunohistochemical profile were evaluated by at least two experienced pathologists in hematopoietic and lymphoid neoplasms.
Results: The cohort included 24 patients: 33.3% triple-hit, 58.3%, MYC/BCL2 double-hit and 8.3% MYC/BCL6 double-hit. There was no gender predominance, with a median age of 62.5±14.3y, 33.3% were diagnosed as nodal disease, and 66.7% as extranodal. Morphologic features of DLBCL were present in 50% of cases, morphological features of both DLBCL and Burkitt lymphoma (DLBCL/BL) in 45.8% and 4.2% of blastoid morphology. Immunohistochemical evaluation, regarding the Hans algorithm, revealed a Germinal center (GC)/GC-like subtype in 83.3% of cases and a non-GC/non-GC-like subtype in 16.7%. MYC was positive in 42.9% and the median proliferative index was 80±12.4%.
Conclusion: DTH-HGBL has a very broad range of features. We consider that a cost-effective approach would be to perform cytogenetic analysis in DLBCL and DLBCL/BL cases with GC/GC-like subtype. MYC and BCL2 immunohistochemistry can be useful to identify patients who may benefit from more aggressive therapies, but not as tools for case selection for FISH.
Adverse outcome pathways (AOPs) are a recent toxicological construct that connects, in a formalized, transparent and quality-controlled way, mechanistic information to apical endpoints for regulatory ...purposes. AOP links a molecular initiating event (MIE) to the adverse outcome (AO) via key events (KE), in a way specified by key event relationships (KER). Although this approach to formalize mechanistic toxicological information only started in 2010, over 200 AOPs have already been established. At this stage, new requirements arise, such as the need for harmonization and re-assessment, for continuous updating, as well as for alerting about pitfalls, misuses and limits of applicability. In this review, the history of the AOP concept and its most prominent strengths are discussed, including the advantages of a formalized approach, the systematic collection of weight of evidence, the linkage of mechanisms to apical end points, the examination of the plausibility of epidemiological data, the identification of critical knowledge gaps and the design of mechanistic test methods. To prepare the ground for a broadened and appropriate use of AOPs, some widespread misconceptions are explained. Moreover, potential weaknesses and shortcomings of the current AOP rule set are addressed (1) to facilitate the discussion on its further evolution and (2) to better define appropriate vs. less suitable application areas. Exemplary toxicological studies are presented to discuss the linearity assumptions of AOP, the management of event modifiers and compensatory mechanisms, and whether a separation of toxicodynamics from toxicokinetics including metabolism is possible in the framework of pathway plasticity. Suggestions on how to compromise between different needs of AOP stakeholders have been added. A clear definition of open questions and limitations is provided to encourage further progress in the field.
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