Targeting NF-kappaB in Waldenstrom macroglobulinemia

The nuclear factor-B (NF-B) path-way has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-B pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-B activity. We demonstrated that perifosine and bortezomib both targeted NF-B through its recruitment to the promoter of its target gene IB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-B pathway.      

Prostaglandin E2 mediates phosphorylation and down-regulation of the tuberous sclerosis-2 tumor suppressor (tuberin) in human endometrial adenocarcinoma cells via the Akt signaling pathway

Prostaglandin (PG) E2 promotes tumor growth via interaction with its G protein-coupled receptors and activation of intracellular signaling. Tuberous sclerosis 2 (tuberin) is a tumor suppressor, which negatively regulates cell growth. Its phosphorylation results in its inactivation and targeted down- regulation, thus lifting the growth inhibition effects. This study investigated the expression and localization of tuberin in neoplastic and normal endometrium and the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Quantitative RT-PCR and Western blot analysis demonstrated reduced expression of tuberin in neoplastic tissue, compared with normal endometrial tissue. Tuberin expression was localized by immunohistochemistry to the glandular epithelial compartment in neoplastic and normal endometrium. We investigated the effect of PGE2 on phosphorylation of tuberin via the Akt pathway. Treatment of neoplastic and normal endometrium with 100 nm PGE2 enhanced phosphorylated tuberin immunoreactivity in the glandular epithelium. PGE2 also phosphorylated Akt and tuberin in Ishikawa endometrial adenocarcinoma cells, leading to a reduction in expression of total tuberin protein. Cotreatment of cells with wortmannin or LY294002 inhibited the PGE2-induced phosphorylation of Akt and tuberin. These data suggest that PGE2 signaling may promote endometrial tumorigenesis by inactivation of tuberin after its phosphorylation via the Akt signaling pathway.     

Nurses’ stories from Beirut: The 2020 explosive disaster on top of a pandemic and economic crises

The World Health Organization designated last year as the International Year of the Nurse and the Midwife. And as we know worldwide, 2020 became an unforgettable year as nurses and midwives everywhere confronted the COVID‐19 pandemic. To be a nurse in 2020 was challenging and heroic, but being a nurse in 2020 in Beirut, Lebanon was so extraordinarily charged with adversity. The country witnessed in a one‐year series of tragedies of epic dimensions – laying a heavy toll on front‐line nurses. We present our stories as eight Lebanese nurses, giving voice to our incredible experiences and our ongoing resilience in the face of these adversities. We served in the emergency department of a Beirut city hospital after a catastrophic explosion occurred in the capital on the 4th of August 2020. We reported for duty during a disaster of immense magnitude and are now coping with the aftermath of trauma. As nurses, we have faced many traumas in our country that has experienced through war and terrorism for decades. Arising from this disaster and challenges of the pandemic, we give policy recommendations that deserve urgent attention in Lebanon and underscore the need for disaster preparation, funding, education and importantly mental health care for nurses and other health professionals with help and support of the international community.     

Proteomic analysis of mantle-cell lymphoma by protein microarray

Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19(+) purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.     

Ciliated Hepatic Foregut Cyst: An Increasingly Diagnosed Condition

Ciliated hepatic foregut cyst is a rare foregut cystic developmental malformation. It presents as a solitary cystic lesion in segment four of the liver. Histologically, it consists of four distinct layers; namely, the inner ciliate columnar epithelium, subepithelial connective tissue, smooth muscle layer, and an outer fibrous layer. Usually asymptomatic and detected incidentally, other modes of presentation can include portal hypertension, obstructive jaundice, and development of malignancy. We present a case of a young asymptomatic woman with a complex cyst in segment four of the liver, who underwent a laparoscopic resection, focusing our discussion on the review of the literature and the diagnostic dilemma encountered in these rare cases.     

Two-decade-long trends (1975-1997) in the incidence,hospitalization, and long-term death rates associated with complete heart block complicating acute myocardial infarction: a community-wide perspective

Background The purpose of this community-wide study was to describe a >2-decade-long experience (1975-97) in the incidence and death rates associated with complete heart block (CHB) in patients with acute myocardial infarction (AMI). Limited population-based data exist describing recent, and changes with time therein, incidence and case-fatality rates associated with CHB complicating AMI. Methods We conducted an observational study of 9082 metropolitan Worcester, Mass, residents (1990 census = 437,000) hospitalized with validated AMI in all greater Worcester hospitals during 11 1-year periods between 1975 and 1997. Results Overall, CHB developed in 5.0% of patients with AMI. The incidence rates of CHB declined in the periods studied (6.0% in 1975/78 vs 3.1% in 1997). Declines in the occurrence of CHB were noted in patients with anterior or inferior/posterior MI. These trends remained after adjustment for other factors that might affect the risk of CHB. Patients in whom CHB developed experienced significantly higher hospital death rates than patients in whom CHB did not develop (46.8% vs 14.6%). However, improving trends in the hospital survival rate of patients with CHB were observed between 1975/78 (47.4% surviving) and 1997 (61.3% surviving). Patients in whom CHB developed during hospitalization were not at increased risk for dying after hospital discharge. Conclusions Our findings indicate that the incidence of CHB complicating AMI has declined with time. The hospital prognosis of patients in whom CHB developed has improved, but these patients remain at an increased risk of hospital mortality. The long-term prognosis of patients with inferior MI and CHB is similar to that of patients in whom CHB did not develop. Patients with anterior MI and CHB may be at an increased risk of long-term mortality. (Am Heart J 2003;145:500-7.)     

Use of three‐dimensional power doppler sonography in the diagnosis of uterine arteriovenous malformation and follow‐up after uterine artery embolization: Case report and brief review of literature

Arteriovenous malformations (AVM) of the uterus can cause life‐threatening hemorrhage. Unexplained, heavy vaginal bleeding in a reproductive age woman should raise suspicion for an AVM. Here a 37‐year‐old woman had increasingly severe vaginal bleeding for 15 days. Serum β‐hCG was elevated. Two‐dimensional transvaginal ultrasound suggested retained products of conception. Before dilation and curettage (D&C), color Doppler and three‐dimensional (3D) power Doppler demonstrated findings indicative of uterine AVM. A bilateral uterine artery embolization was performed without complications. Three months after uterine artery embolization, 3D power Doppler ultrasonography found complete resolution of the AVM. This case illustrates the importance of assessing both gray‐scale and 3D power Doppler, and the ability of postprocedure Doppler to assess resolution. © 2014 Wiley Periodicals, Inc. J Clin Ultrasound 43:327–334, 2015