Left main and two vessels calcified coronary aneurysms presented as out of hospital cardiac arrest in young patient

Abstract A 37‐year‐old patient was admitted secondary to ventricular fibrillation induced out of hospital cardiac arrest. Coronary angiogram revealed left main, left anterior descending, and right coronary arteries aneurysms. The patient underwent bypass surgery with four grafts. Ejection fraction improved from 30% upon admission to 45% at 3 months of follow‐up

The Unusual Late-Onset Graves’ Disease following Hashimoto’s Related Hypothyroidism: A Case Report and Literature Review

Background. The shift of Graves’ disease (GD) to Hashimoto’s disease- (HD-) related hypothyroidism is well established. However, the opposite is rare. This is likely to the loss of critical thyroid mass available for stimulation by thyroid hormone receptor stimulating antibody, making this shift unusual. Herein, we report a young lady with a late shift from HD into GD and present a scoping literature review. Case presentation. We report a twenty-five-year-old lady with a sixteen-year-history of Hashimoto’s-related hypothyroidism stable on levothyroxine. While following in the clinic, she started developing thyrotoxic symptoms in the form of anxiety, weight loss, and palpitation. Physical examination was remarkable for mild exophthalmos. The thyroid function test confirmed hyperthyroidism. Levothyroxine-induced hyperthyroidism was initially suspected; however, the symptoms did not improve despite reducing and stopping levothyroxine. Subsequent workup confirmed the diagnosis of GD. Discussion and Conclusion. This case highlights a unique association that has significant diagnostic and management implications. This shift should be considered when hyperthyroidism persists despite reducing or stopping levothyroxine. The diagnosis is made utilizing antibody titers and radioiodine update scan. While the management depends on the disease’s stage and the treating physician preference, antithyroid agents can be used initially. Following up these patients is essential as the shift can be transient

Myxedema Psychosis: Neuropsychiatric Manifestations and Rhabdomyolysis Unmasking Hypothyroidism

Background. Hypothyroidism is a prevalent endocrine disorder, often presenting with a spectrum of symptoms reflecting a hypothyroid state. It is also generally linked to causing mood swings, psychomotor slowing, and fatigue; however, in rare instances, it may lead to or induce acute psychosis, a condition referred to as myxedema psychosis (MP). We report a case of myxedema psychosis and present a literature review discussing its presentation, diagnosis, management, and prognosis. Case Presentation. A 36-year-old lady presented with one-week history of persecutory and paranoid delusions, along with visual and auditory hallucinations. She had no prior history of psychiatric illnesses. She underwent total thyroidectomy three years before the current presentation due to papillary thyroid cancer. She was not on regular follow-up, nor any specific therapy. On examination, she was agitated and violent. There were no signs of myxedema, and the physical exam was unremarkable. The initial workup showed a mild elevation in serum creatinine. Additional investigations revealed a high thyroid-stimulating hormone (TSH) of 56.6 mIU/L, low free T4<0.5 pmol/L, elevated creatine kinase of 3601 U/L, and urine dipstick positive for blood, suggestive of myoglobinuria. MRI of the head was unremarkable. We diagnosed her as a case of myxedema psychosis and mild rhabdomyolysis. She was started on oral thyroxine 100 mcg/day, fluoxetine 20 mg daily, and as-needed haloperidol. She was closely followed and later transferred to the Psychiatry Hospital for further management. Within one week, her symptoms improved completely, and she was discharged off antipsychotics with additional scheduled follow-ups to monitor TFTs and observe for any recurrence. Discussion and Conclusion. Myxedema psychosis is a rare presentation of hypothyroidism—a common endocrine disorder. Scarce data are describing this entity; hence, there is currently a lack of awareness amongst clinicians regarding proper identification and management. Moreover, the atypical nature of presentations occasionally adds to a diagnostic dilemma. Thus, any patient with new-onset psychosis should be screened for hypothyroidism, and awareness of this entity must be emphasized amongst clinicians and guideline makers

Gastrointestinal cancer cells treatment with bevacizumab activates a VEGF autoregulatory mechanism involving telomerase catalytic subunit hTERT via PI3K-AKT, HIF-1α and VEGF receptors

<div><p>Background</p><p>Targeting angiogenesis has been considered a promising treatment of choice for a large number of malignancies, including gastrointestinal cancers. Bevacizumab is an anti-vascular endothelial growth factor (anti-VEGF) being used for this purpose. However, treatment efficacy is largely questioned. Telomerase activity, responsible for cancer cell immortality, is detected in 85–95% of human cancers and is considered a potential regulator of VEGF. The aim of our study was to investigate the interrelationship between VEGF and hTERT in gastrointestinal cancers and to explore cell response to a combined inhibition of telomerase and VEGF.</p><p>Methods</p><p>AGS (gastric cancer), Caco-2 (colorectal cancer) and HepG2/C3A (hepatocellular carcinoma), were treated with telomerase inhibitors BIBR-1232 (10μM) and costunolide (10μM), with bevacizumab (Avastin® at 5 ng/ml or 100μg/ml) or with a combination of both types of inhibitors. VEGF and hTERT mRNA levels, and telomerase activity were detected by RT-PCR. VEGF levels were quantified by ELISA. Telomerase was knocked down using hTERT siRNA and hTERT was overexpressed in the telomerase negative cell line, Saos-2 (osteosarcoma), using constructs expressing either wild type hTERT (hTERT-WT) or dominant negative hTERT (hTERT-DN). Tube formation by HUVECs was assessed using ECMatrix™ (EMD Millipore).</p><p>Results</p><p>Our results showed that telomerase regulates VEGF expression and secretion through its catalytic subunit hTERT in AGS, Caco2, and HepG2/C3A, independent of its catalytic activity. Interestingly, VEGF inhibition with bevacizumab (100μg/ml) increased hTERT expression 42.3% in AGS, 94.1% in Caco2, and 52.5% in HepG2/C3A, and increased telomerase activity 30-fold in AGS, 10.3-fold in Caco2 and 8-fold in HepG2/C3A. A further investigation showed that VEGF upregulates hTERT expression in a mechanism that implicates the PI3K/AKT/mTOR pathway and HIF-1α. Moreover, bevacizumab treatment increased VEGFR1 and VEGFR2 expression in cancer cells and human umbilical vein endothelial cells (HUVECs) through hTERT. Thus, the combination of bevacizumab with telomerase inhibitors decreased VEGF expression and secretion by cancer cells, inhibited VEGFR1 and VEGFR2 upregulation, and reduced tube formation by HUVECs.</p><p>Conclusions</p><p>Taken together, our results suggest that bevacizumab treatment activates a VEGF autoregulatory mechanism involving hTERT and VEGF receptors and that an inhibition of this pathway could improve tumor cell response to anti-VEGF treatment.</p></div

Telomerase inhibition decreases alpha-fetoprotein expression and secretion by hepatocellular carcinoma cell lines: in vitro and in vivo study.

Alpha-fetoprotein (AFP) is a diagnostic marker for hepatocellular carcinoma (HCC). A direct relationship between poor prognosis and the concentration of serum AFP has been observed. Telomerase, an enzyme that stabilizes the telomere length, is expressed by 90% of HCC. The aim of this study was to investigate the effect of telomerase inhibition on AFP secretion and the involvement of the PI3K/Akt/mTOR signaling pathway. Proliferation and viability tests were performed using tetrazolium salt. Apoptosis was determined through the Annexin V assay using flow cytometry. The concentrations of AFP were measured using ELISA kits. The AFP mRNA expression was evaluated using RT-PCR, and cell migration was evaluated using a Boyden chamber assay. The in vivo effect of costunolide on AFP production was tested in NSG mice. Telomerase inhibition by costunolide and BIBR 1532 at 5 and 10 μM decreased AFP mRNA expression and protein secretion by HepG2/C3A cells. The same pattern was obtained with cells treated with hTERT siRNA. This treatment exhibited no apoptotic effect. The AFP mRNA expression and protein secretion by PLC/PRF/5 was decreased after treatment with BIBR1532 at 10 μM. In contrast, no effect was obtained for PLC/PRF/5 cells treated with costunolide at 5 or 10 μM. Inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP concentration. In contrast, the MAPK/ERK pathway appeared to not be involved in HepG2/C3A cells, whereas ERK inhibition decreased the AFP concentration in PLC/PRF/5 cells. Modulation of the AFP concentration was also obtained after the inhibition or activation of PKC. Costunolide (30 mg/kg) significantly decreased the AFP serum concentration of NSG mice bearing HepG2/C3A cells. Both the inhibition of telomerase and the inhibition of the PI3K/Akt/mTOR signaling pathway decreased the AFP production of HepG2/C3A and PLC/PRF/5 cells, suggesting a relationship between telomerase and AFP expression through the PI3K/Akt/mTOR pathway

Telomerase regulates VEGF secretion and expression independently of telomerase activity.

<p>(A, B) VEGF secretion was assessed by ELISA following a 48-h treatment with telomerase inhibitors BIBR-1532 (10 <i>μ</i>M) and costunolide (10 <i>μ</i>M), and after 72 h of hTERT knockdown with siRNA. (C, D) Total RNAs were isolated from the cells treated in (A), and VEGF expression was analyzed by real-time PCR with GAPDH as the internal control. (E, F, G) Saos-2 cells were transiently transfected with an empty vector, hTERT-WT, and hTERT-DN. hTERT (E) and VEGF expression (F) were quantified by real-time PCR. Secreted VEGF was quantified by ELISA (G). Results were expressed as the mean ±SD from a minimum of three experiments.</p

Telomerase regulates VEGF, VEGFR1, and VEGFR2 expression.

<p>AGS (A), Caco2 (B), and HepG2/C3A (C) cells were treated with control siRNA or hTERT siRNA with or without bevacizumab, and VEGF secretion was evaluated by ELISA. (D, E) Cells were treated with BIBR-1532, costunolide, or transiently transfected with hTERT siRNA for 72h. VEGFR1 (D) and VEGFR2 (E) transcript amounts were quantified with real-time PCR. (F, G) Saos-2 cells were transiently transfected with an empty vector, hTERT-WT or hTERT-DN. VEGFR1 (F) and VEGFR2 (G) were then quantified with real-time PCR. Results were expressed as the mean ± SD from three experiments.</p

Bevacizumab increases VEGFR1 and VEGFR2 expression.

<p>(A, B) Telomerase inhibitors were combined to bevacizumab (100 <i>μ</i>g/ml) and then VEGFR1 (A) and VEGFR2 (B) were quantified by real-time PCR. (C, D) Cells were transiently transfected with either control siRNA or hTERT siRNA and treated with bevacizumab (100 <i>μ</i>g/ml). VEGFR1 (C) and VEGFR2 (D) were quantified by real-time qPCR. (E, F) HUVECs were cultured in the presence of telomerase inhibitors for 48 h and hTERT siRNA for 72 h. The expression of VEGFR1 (E) and VEGFR2 (F) were quantified by real-time PCR. Results were expressed as the mean ± SD from three experiments.</p

Telomerase regulates tube formation by HUVECs.

<p>HUVECs previously treated with BIBR-1532 (10 μM), costunolide (10 μM), bevacizumab (5 ng/ml or 100 μg/ml), or hTERT siRNA were cultured on an extracellular matrix (ECM) in the presence or absence of recombinant VEGF165 (50 ng/ml). Angiogenesis began after 4 hours, and tube formation was then visualized after 6 hours, using an inverted microscope (100X).</p

Telomerase inhibition decreases the proliferation and tube formation of HUVECs.

<p>(A) HUVECs were treated with BIBR-1532 and costunolide. VEGFR2 protein levels were quantified by ELISA using the cell protein extracts. (B, C) HUVECs were transiently transfected with either a control siRNA or hTERT siRNA for 72 h. VEGFR1 and VEGFR2 expression was then assessed by real-time PCR. (D) HUVECs treated with BIBR-1532 and costunolide were collected and counted using trypan blue. (E) HUVECs were cultured in a 96-well plate and treated with telomerase inhibitors. Tetrazolium salt was added to each well and changes in absorbance following formazan formation was detected at 450 nm. (F, G) HUVECs were cultured on an ECM in the presence of recombinant VEGF₁₆₅ (50 ng/ml), telomerase inhibitors and bevacizumab. Capillary-like structures were quantified in the presence (F) and absence (G) of recombinant VEGF₁₆₅.Values are represented as the mean ± SE of 10 randomly chosen fields.</p