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Fulltext A forgotten clinical sign making a comeback

Chiam KH, A Hing CT, Low LL

Med J Malaysia, 2014 Feb;69(1):40-1.
PMID: 24814630 MyJurnal

We report a case of Staphylococcus aureus infective endocarditis in a patient presenting with fever and rare cutaneous manifestations of Osler Nodes and Janeway Lesions. There had not been any distinct risk factors. His echocardiography subsequently revealed vegetation at the anterior mitral valve leaflet. As Staphylococcus aureus infective endocarditis is of utmost significance in morbidity and mortality, a sharp clinical acumen and follow up investigations is required alongside a prolonged course of antibiotics. Our patient was then started on intravenous cloxacillin for 28 days and gentamicin for 5 days to which he made good progress and recovery.
Atypical endoscopic finding of colocolic intussusception: case report and literature review

Chiam KH, Sannasey S, Rajaintharan S, Muthukaruppan R

Ann Transl Med, 2022 Dec;10(23):1290.
PMID: 36618802 DOI: 10.21037/atm-2022-61

BACKGROUND: Adult-onset colonic intussusception is a rarely encountered condition that leads to large intestinal obstruction with time. Patients often present with a variety of symptoms that are non-specific making it challenging to arrive at a definitive diagnosis. This is worrying as diagnostic delay could lead to a significant increase in morbidity and mortality. We wish to present and describe a case of an atypical endoscopic finding of colocolic intussusception secondary to ascending colon cancer.
CASE DESCRIPTION: Sixty-seven-year-old lady was referred for 1 month's duration of passing melenic stools with mucus followed by a week's complain of hematochezia. Clinical examination and other relevant blood results were unremarkable except for iron deficiency anemia. Initial colonoscopy revealed a large mass within the splenic flexure with inconclusive biopsies. A more detailed colonoscopy repeated the following day revealed a massive, black-to-yellowish lesion within the splenic flexure with no viable mucosa seen. Colonic bezoar was initially suspected, however various endoscopic retrieval methods proved futile. Switching to a slimmer diagnostic gastroscope, the colon was carefully negotiated until a large ulcer was found within the ascending colon, adjacent to the mass' origin. An emergency CT abdomen and subsequently extended right hemicolectomy performed revealed a colocolic intussusception with sealed perforation secondary to an ascending colonic mass acting as an intussusceptum. Histopathology evaluation confirmed an ascending colon adenocarcinoma (pT2N0M0) amidst a background of extensive ischemic changes.
CONCLUSIONS: Endoscopic descriptions of colonic intussusception are unusual given their rarity. Furthermore, these lesions can mimic a colonic bezoar as a result of fecal accretion and this can ultimately lead to false diagnostic and therapeutic decisions. In such instances, clarification with a CT scan before management decision can potentially avert unnecessary endoscopic intervention and complications.
Fulltext The role of cell-matrix adhesion and cell migration in breast tumor growth and progression

Chong LH, Yip AK, Farm HJ, Mahmoud LN, Zeng Y, Chiam KH

Front Cell Dev Biol, 2024;12:1339251.
PMID: 38374894 DOI: 10.3389/fcell.2024.1339251

During breast cancer progression, there is typically increased collagen deposition resulting in elevated extracellular matrix rigidity. This results in changes to cell-matrix adhesion and cell migration, impacting processes such as the epithelial-mesenchymal transition (EMT) and metastasis. We aim to investigate the roles of cell-matrix adhesion and cell migration on breast tumor growth and progression by studying the impacts of different types of extracellular matrices and their rigidities. We embedded MCF7 spheroids within three-dimensional (3D) collagen matrices and agarose matrices. MCF7 cells adhere to collagen but not agarose. Contrasting the results between these two matrices allows us to infer the role of cell-matrix adhesion. We found that MCF7 spheroids exhibited the fastest growth rate when embedded in a collagen matrix with a rigidity of 5.1 kPa (0.5 mg/mL collagen), whereas, for the agarose matrix, the rigidity for the fastest growth rate is 15 kPa (1.0% agarose) instead. This discrepancy is attributable to the presence of cell adhesion molecules in the collagen matrix, which initiates collagen matrix remodeling and facilitates cell migration from the tumor through the EMT. As breast tumors do not adhere to agarose matrices, it is suitable to simulate the cell-cell interactions during the early stage of breast tumor growth. We conducted further analysis to characterize the stresses exerted by the expanding spheroid on the agarose matrix. We identified two distinct MCF7 cell populations, namely, those that are non-dividing and those that are dividing, which exerted low and high expansion stresses on the agarose matrix, respectively. We confirmed this using Western blot which showed the upregulation of proliferating cell nuclear antigen, a proliferation marker, in spheroids grown in the 1.0% agarose (≈13 kPa). By treating the embedded MCF7 spheroids with an inhibitor or activator of myosin contractility, we showed that the optimum spheroids' growth can be increased or decreased, respectively. This finding suggests that tumor growth in the early stage, where cell-cell interaction is more prominent, is determined by actomyosin tension, which alters cell rounding pressure during cell division. However, when breast tumors begin generating collagen into the surrounding matrix, collagen remodeling triggers EMT to promote cell migration and invasion, ultimately leading to metastasis.
Fulltext Zyxin regulates embryonic stem cell fate by modulating mechanical and biochemical signaling interface

Zhang S, Chong LH, Woon JYX, Chua TX, Cheruba E, Yip AK, et al.

Commun Biol, 2023 Jan 18;6(1):62.
PMID: 36653484 DOI: 10.1038/s42003-023-04421-0

Biochemical signaling and mechano-transduction are both critical in regulating stem cell fate. How crosstalk between mechanical and biochemical cues influences embryonic development, however, is not extensively investigated. Using a comparative study of focal adhesion constituents between mouse embryonic stem cell (mESC) and their differentiated counterparts, we find while zyxin is lowly expressed in mESCs, its levels increase dramatically during early differentiation. Interestingly, overexpression of zyxin in mESCs suppresses Oct4 and Nanog. Using an integrative biochemical and biophysical approach, we demonstrate involvement of zyxin in regulating pluripotency through actin stress fibres and focal adhesions which are known to modulate cellular traction stress and facilitate substrate rigidity-sensing. YAP signaling is identified as an important biochemical effector of zyxin-induced mechanotransduction. These results provide insights into the role of zyxin in the integration of mechanical and biochemical cues for the regulation of embryonic stem cell fate.
Fulltext Zyxin Is Involved in Fibroblast Rigidity Sensing and Durotaxis

Yip AK, Zhang S, Chong LH, Cheruba E, Woon JYX, Chua TX, et al.

Front Cell Dev Biol, 2021;9:735298.
PMID: 34869319 DOI: 10.3389/fcell.2021.735298

Focal adhesions (FAs) are specialized structures that enable cells to sense their extracellular matrix rigidity and transmit these signals to the interior of the cells, bringing about actin cytoskeleton reorganization, FA maturation, and cell migration. It is known that cells migrate towards regions of higher substrate rigidity, a phenomenon known as durotaxis. However, the underlying molecular mechanism of durotaxis and how different proteins in the FA are involved remain unclear. Zyxin is a component of the FA that has been implicated in connecting the actin cytoskeleton to the FA. We have found that knocking down zyxin impaired NIH3T3 fibroblast's ability to sense and respond to changes in extracellular matrix in terms of their FA sizes, cell traction stress magnitudes and F-actin organization. Cell migration speed of zyxin knockdown fibroblasts was also independent of the underlying substrate rigidity, unlike wild type fibroblasts which migrated fastest at an intermediate substrate rigidity of 14 kPa. Wild type fibroblasts exhibited durotaxis by migrating toward regions of increasing substrate rigidity on polyacrylamide gels with substrate rigidity gradient, while zyxin knockdown fibroblasts did not exhibit durotaxis. Therefore, we propose zyxin as an essential protein that is required for rigidity sensing and durotaxis through modulating FA sizes, cell traction stress and F-actin organization.
Narrow-band imaging for scar (NBI-SCAR) classification: from conception to multicenter validation

Zorron Cheng Tao Pu L, Chiam KH, Yamamura T, Nakamura M, Berzin TM, Mir FF, et al.

Gastrointest Endosc, 2020 May;91(5):1146-1154.e5.
PMID: 31494134 DOI: 10.1016/j.gie.2019.08.036

BACKGROUND AND AIMS: Surveillance post-endoscopic resection (ER) currently warrants biopsy samples from the resection site scar in most cases, although clinical practice is variable. A classification with standard criteria for scars has not yet been established. We aimed to create and validate a novel classification for post-ER scars by using specific criteria based on advanced imaging.
METHODS: Key endoscopic features for scars with and without recurrence were (1) dark brown color, elongated/branched pit pattern, and dense capillary pattern and (2) whitish, pale appearance, round/slightly large pits, and irregular sparse vessels. Scars were first assessed with high-definition white-light endoscopy (HD-WLE) followed by interrogation with narrow-band imaging (NBI). Scars with at least 2 concordant characteristics were diagnosed with "high confidence" for NBI for scar (NBI-SCAR) classification. The final endoscopic predictions were correlated with histopathology. The primary outcome was the difference in sensitivity between NBI-SCAR and HD-WLE predictions. Secondary outcomes included the validation of our findings in 6 different endoscopy settings (Australia, United States, Japan, Brazil, Singapore, and Malaysia). The validation took place in 2 sessions separated by 2 to 3 weeks, each with 10 one-minute videos of post-ER scars on underwater NBI with dual focus. Inter-rater and intrarater reliability were calculated with Fleiss' free-marginal kappa and Bennett et al. S score, respectively.
RESULTS: One hundred scars from 82 patients were included. Ninety-five scars were accurately predicted with high confidence by NBI-SCAR in the exploratory phase. NBI-SCAR sensitivity was significantly higher compared with HD-WLE (100% vs 73.7%, P < .05). In the validation phase, similar results were found for endoscopists who routinely perform colonoscopies and use NBI (sensitivity of 96.4%). The inter-rater and intrarater reliability throughout all centers were, respectively, substantial (κ = .61) and moderate (average S = .52) for this subset.
CONCLUSIONS: NBI-SCAR has a high sensitivity and negative predictive value for excluding recurrence for endoscopists experienced in colonoscopy and NBI. In this setting, this approach may help to accurately evaluate or resect scars and potentially mitigate the burden of unnecessary biopsy samples.