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Acute myeloid leukemia (AML) is a serious, life-threatening, and hardly curable hematological malignancy that affects the myeloid cell progenies and challenges patients of all ages but mostly occurs in adults. Although several therapies are available including chemotherapy, allogeneic hematopoietic stem cell transplantation (alloHSCT), and receptor-antagonist drugs, the 5-year survival of patients is quietly disappointing, less than 30%. alloHSCT is the major curative approach for AML with promising results but the treatment has severe adverse effects such as graft-versus-host disease (GVHD). Therefore, as an alternative, more efficient and less harmful immunotherapy-based approaches such as the adoptive transferring T cell therapy are in development for the treatment of AML. As such, chimeric antigen receptor (CAR) T cells are engineered T cells which have been developed in recent years as a breakthrough in cancer therapy. Interestingly, CAR T cells are effective against both solid tumors and hematological cancers such as AML. Gradually, CAR T cell therapy found its way into cancer therapy and was widely used for the treatment of hematologic malignancies with successful results particularly with somewhat better results in hematological cancer in comparison to solid tumors. The AML is generally fatal, therapy-resistant, and sometimes refractory disease with a disappointing low survival rate and weak prognosis. The 5-year survival rate for AML is only about 30%. However, the survival rate seems to be age-dependent. Novel CAR T cell therapy is a light at the end of the tunnel. The CD19 is an important target antigen in AML and lymphoma and the CAR T cells are engineered to target the CD19. In addition, a lot of research goes on the discovery of novel target antigens with therapeutic efficacy and utilizable for generating CAR T cells against various types of cancers. In recent years, many pieces of research on screening and identification of novel AML antigen targets with the goal of generation of effective anti-cancer CAR T cells have led to new therapies with strong cytotoxicity against cancerous cells and impressive clinical outcomes. Also, more recently, an improved version of CAR T cells which were called modified or smartly reprogrammed CAR T cells has been designed with less unwelcome effects, less toxicity against normal cells, more safety, more specificity, longer persistence, and proliferation capability. The purpose of this review is to discuss and explain the most recent advances in CAR T cell-based therapies targeting AML antigens and review the results of preclinical and clinical trials. Moreover, we will criticize the clinical challenges, side effects, and the different strategies for CAR T cell therapy.

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Neurodegenerative diseases (NDs) including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.

Objectives Metastases are common in non-cirrhotic livers but are considered unlikely in the setting of cirrhosis. However, the degree of fibrosis in cirrhosis may vary; thus metastases may still access the liver vasculature and present as a mass in cirrhotic livers. This possibility may affect pathologists’ diagnostic algorithms when faced with a liver mass biopsy. Methods We hypothesized that metastases can occur in cirrhotic livers if fibrous remodeling is not severe or abnormal veno-arterial shunting exists to override an obstructed portal system. We searched departmental archives for cirrhotic livers with masses, categorizing fibrosis by Laennec staging: 4A = mild cirrhosis, 4B = moderate, 4 C = severe. Results Of 1453 cirrhotic livers with masses, 1429 were primary tumors and 24 were metastases (1.7 %). Of livers with metastases, most had 4A or 4B cirrhosis by Laennec staging (n = 17; 71 %). Eleven patients were evaluated by ultrasound Doppler; 2 of 5 with Laennec 4 C had reversal of portal vein flow, but all 4A & 4B patients had patent portal veins without reversed flow. Echocardiograms (13 patients) showed no ventricular or atrial septal defects or arteriovenous shunts. Conclusions Metastases are uncommon in cirrhotic livers, accounting for 1.7 % of masses. Most involved livers had mild or moderate cirrhosis (Laennec 4A/4B) and patent portal veins; however, as some Laennec 4 C cases also contained metastases, obstructed portal access may not be enough to deter metastatic access.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States with the incidence rate more than doubling in 20 years. HCC is unique since a noninvasive diagnosis can be achieved with imaging alone when specific clinical criteria and imaging characteristics are met, obviating the need for tissue sampling. However, HCC is a highly heterogeneous neoplasm. Atypical HCC subtypes vary significantly in their morphology, which can be attributed to specific histologic and molecular features, and can cause deviations from the classic imaging characteristics. The different morphologic subtypes of HCC frequently present a diagnostic challenge for radiologists and pathologists since their imaging and pathologic features can overlap with those of non-HCC malignancies. Identifying an atypical subtype can have important clinical implications. Liver transplant, albeit a scarce and limited resource, is the optimal treatment for conventional HCC, potentially curing both the tumor and the underlying pre-malignant condition. Some HCC subtypes as well as mimickers are associated with unacceptably high recurrence and poor outcome after transplant, and there remains limited data on the role and prognosis of liver transplantation for treatment of rare HCC subtypes. Other subtypes tend to recur later than classic HCC, potentially requiring a different follow-up scheme. This review will discuss the appearance of different HCC subtypes in relation to their histopathologic features. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 3.

Introduction: Coronavirus disease 2019 (COVID-19) is declared as pandemic by the World Health Orgnazation (WHO) on March 2020. One of the heavily utilized measures during this pandemic is vitamin C (aka ascorbic acid). Unfortunately, vitamin C has been associated with glucose measurement interference and thus this study highlights the elevated levels of blood glucose correlated with the presence of vitamin C interference. Methodology: Thirty samples were selected randomly and the blood glucose were measured prior and post the addition of spiked standard concentrations of vitamin C. The interference of vitamin C with glucose readings in COVID-19 pandemic were evaluated and observed employing the Auto Chemistry Analyzer machine. Results: The addition of ascorbic acid (vitamin C) standards (spikes) into the isolated samples shows a correlated increment in the reading measures. Thereafter, the increments of Random Blood Sugar (RBS) readings after being spiked with the vitamin C standards shows a logarithmic correlation with good interesting R-squared (R2 = 0.9921). Conclusions: The authors find that the presence of vitamin C in blood actively and significantly alters the glucose level readings especially with the highly consumption of vitamin C during the COVID-19 pandemic.

Endometrial carcinomas (ECs) are the most common gynecologic cancers in the western world. The impact of androgen receptor (AR) on clinicopathologic parameters of EC is not well studied. The aim of our study is to assess the role of AR expression in ECs and correlate its expression with estrogen (ER) and progesterone (PR). A retrospective review of 261 EC was conducted. H&E slides were reviewed and clinicopathologic parameters were analyzed. Immunohistochemical stains for AR, ER, and PR were performed on a tissue microarray. The hormonal expression was evaluated and the data were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. Patients' age ranged from 31 to 91 (median=65 y). Type I EC included 202 endometrioid and 7 mucinous carcinoma, whereas type II included 34 serous, 16 carcinosarcoma, and 2 clear cell carcinoma. Although not significant, AR expression showed more frequent association with type I EC, early tumor stage (I-II), and low FIGO grade (1-2) EC. AR expression significantly correlated with absence of lymphovascular invasion (P=0.041) and decreased LN involvement (P=0.048). Patients with AR expression showed increased disease-free survival (208 vs. 165 mo, P=0.008) and late disease recurrence (P=0.009). AR expression had a positive significant correlation with PR (P

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.

Background: Undoubtedly, cancer is regarded as a major concern for researchers alongside the whole humanity for its high mortality rates. At this moment, there must be some researchers working hard to design, synthesize, and biologically investigate the effects of some potential candidates to fight back cancer. Materials and methods: In previous unpublished work, the authors successfully designed, synthesized, characterized a potential two spebrutinib analogues. Consequently, these analogues were evaluated with the employment of MCF-7, HCT116, and MDCK cell lines. Results: In respect to the spebrutinib standard, one of these analogues has superior activity against MCF-7 cell line (IC50; 10.744 µg/mL against 13.566 µg/mL for spebrutinib) and an enhanced toxicity profile on MDCK cell line (IC50; 8.653 mg/mL against 4.011 mg/mL for spebrutinib). Conclusion: The two compounds showed good activity against breast and colon cell lines and enhanced toxicity profile against normal kidney cell line in respect to spebrutinib standard.

Objective: Both ibuprofen and tranexamic acid were tried to treat colorectal carcinoma, however, combined drugs were not. Accordingly, with the aid of SciFinder®, online absence of the mutual prodrug (codrug) was affirmed. This persuade the authors to conduct this research. Methods: The ibuprofen-tranexamic acid codrug was synthesized and characterized with 83% yield. The purified white powder codrug was tested against HCT116 colorectal cancerous cell line and MDCK normal non-cancerous cell line. Results: The newly synthesized and characterized ibuprofen-tranexamic acid codrug has significant parameters. One of which it absolutely obeyes the Lipinski rule of five. Moreover, like the Lipinski rule of five, the number of rotatable bonds (7 rotatable bonds) and the topological polar surface area tPSA (66.4 A2) shows a very favourable oral absorption drug candidate. The IC50 of the mutual prodrug against HCT116 colorectal cells was 5.33 mg/ml, while the IC50 for the MDCK normal kidney cell line was 6.4 g/ml. Conclusion: The authors conclude that the newly synthesized ibuprofen-tranexamic acid codrug has fair anticancer activity against HCT116 colorectal cancer cell line with tolerated toxicity profile acquired with the MDCK normal kidney cell line.

Barrett's esophagus (BE) is a predisposing factor of esophageal adenocarcinoma/gastroesophageal junction adenocarcinoma (ECA/GEJ Aca). BE patients are stratified and subsequently monitored according to the risk of malignant progression by the combination of endoscopy and biopsy. This study is to evaluate the maspin expression patterns as early diagnostic markers of malignancy in BE patients. Immunohistochemistry (IHC) staining was performed on 62 archival core biopsies from 35 patients, including BE without dysplasia (intestinal metaplasia, IM), BE with low grade dysplasia, BE with high grade dysplasia, carcinoma in situ, and well to poorly differentiated ECA/GEJ Aca (PD-ECA/GEJ Aca). The intensity and the subcellular distribution of immunoreactivity were evaluated microscopically. Statistical analysis was performed using the χ2 and Fisher exact tests. The level of epithelial-specific tumor suppressor maspin protein inversely correlated with the progression from IM to PD-ECA/GEJ Aca. Lesions of each pathological grade could be divided into subtypes that exhibited distinct maspin subcellular distribution patterns, including nuclear only (Nuc), combined nuclear and cytoplasmic (Nuc+Cyt), cytoplasmic only (Cyt) and overall negligible (Neg). The Cyt subtype, which was minor in both IM and dysplasia (approximately 10%), was predominant in ECA/GEJ Aca as early as well-differentiated lesions (more than 50%: p = 0.0092). In comparison, nuclear staining of the tumor suppressor TP53 was heterogeneous in dysplasia, and did not correlate with the differentiation grades of ECA/GEJ Aca. The Cyt subtype of maspin expression pattern in core biopsies of BE patients may serve as a molecular marker for early diagnosis of ECA/GEJ Aca. This work was supported by the NIH grant P30CA022453 (to the Karmanos Cancer Institute with Sheng, S. as a program leader), the Ruth Sager Memorial Fund (to Sheng, S.), the Karmanos Cancer Institute Pilot Project Grant 25S5Z (to Sheng, S.), and the Karmanos Cancer Institute Prostate Cancer Research Pilot Project Grant (to Sheng, S.).

Background: Recently, in silico or computer-aided drug design has emerged as a cornerstone on the harbor of modern drug discovery. One of the approaches to treat cancer is the inhibition of tyrosine kinase, which is considered as a key enzyme in the survival of the cancerous cells. Spebrutinib, as a member of the tyrosine kinase inhibitors, has few unwanted side effects due to its off-target bindings. In this work, the GOLD program was employed to predict the bindings and thus the inhibitory activity toward the tyrosine kinase. Methodology: After the design and docking processes, the chemical synthesis of three spebrutinib analogues was achieved. Results: The percent yields of the chemical syntheses were ranged from 81% to 89%. These analogues were characterized utilizing; FT-IR, DSC, CHN, and 1H NMR. In conclusion, these new spebrutinib analogues were successfully designed, synthesized, and characterized. However, these analogues are potential anticancer agents and biological activity against cancerous and toxicity pattern against normal cells are crucial to affirm the present findings.

T regulatory (Treg) cells represent a unique subset of T lymphocytes. Although they represent a small fraction of circulating T cells ( ABBREVIATIONS:DC – dendritic cell, GI – gastrointestinal, IBD – inflammatory bowel disease, IL-2 - interleukin 2, IPEX - immunodysregulation, polyendocrinopathy, and enteropathy X-linked, iTreg - induced T regulatory cells, nTreg - naturally occurring T regulatory cells, PBMC – peripheral blood mononuclear cells, SCFA – short chain fatty acids, Th - T helper, TGF-β - transforming growth factor, Tr1 - type 1 regulatory cells, Treg – T regulatory cells.

Enterotoxigenic Escherichia coli (ETEC) produces both heat-labile (LT) and heat-stable (ST) enterotoxins and is a major cause of diarrhea in infants in developing countries and in travelers to those regions. In addition to inducing fluid secretion, LT is a powerful mucosal adjuvant capable of promoting immune responses to coadministered antigens. In this study, we examined purified A subunit to further understand the toxicity and adjuvanticity of LT. Purified A subunit was enzymatically active but sensitive to proteolytic degradation and unable to bind gangliosides, and even in the presence of admixed B subunit, it displayed low cyclic AMP (cAMP) induction and no enterotoxicity. Thus, the AB5 structure plays a key role in protecting the A subunit from proteolytic degradation and in delivering the enzymatic signals required for secretion. In contrast, the A subunit alone was capable of activating dendritic cells and enhanced immune responses to multiple antigens following intranasal immunization; therefore, unlike toxicity, LT adjuvanticity is not dependent on the AB5 holotoxin structure or the presence of the B subunit. However, immune responses were maximal when signals were received from both subunits either in an AB5 structure or with A and B admixed. Furthermore, the quality of the immune response (i.e., IgG1/IgG2 balance and mucosal IgA and IL-17 secretion) was determined by the presence of an A subunit, revealing for the first time induction of Th17 responses with the A subunit alone. These results have important implications for understanding ETEC pathogenesis, unraveling immunologic responses induced by LT-based adjuvants, and developing new mucosal vaccines.

The high mortality rate associated with Gastric Cancer (GC) indicates the urgent need for actionable therapeutic targets. The nuclear exporter protein exportin 1 (XPO1/CRM1) is the exclusive exporter of many tumor suppressor proteins (TPSs) and growth regulators. XPO1 is often over-expressed in different malignancies leading to aberrant cytoplasmic localization of TSPs and subsequent inactivation. A detailed analysis on the correlation of XPO1 with inflammation-metaplasia-dysplasia-carcinoma sequence progression was performed using immunohistochemistry in 70 GC cases: (a) 10 cases from normal gastric mucosa, (b) 10 cases of stomach with intestinal metaplasia with and without inflammation, (c) 10 cases of mucosa with low-grade dysplasia (d) 10 cases of mucosa with high-grade dysplasia, (e) 10 cases of gastric adenocarcinoma and (f) 20 cases of metastatic gastric carcinoma. A correlation between XPO1 expression, the pathological and clinical features of the disease as well as survival were analyzed. Gastric cancer cell lines were exposed to the Selective Inhibitors of Nuclear Export (SINE) compounds (selinexor, KPT-8602, KPT-185, or the natural agent, leptomycin B (LMB), then analyzed using cytotoxicity and molecular assays. In addition, the activity of selinexor was evaluated in a sub-cutaneous xenograft of gastric cancer cell line NCI-N87. XPO1 served as a prognostic marker for poor outcome as positive staining of XPO1 in GC correlated with aggressive behavior of the disease. Targeting XPO1 using SINE compounds or LMB resulted in inhibition of GC cellular growth (IC50 Citation Format: Irfana Muqbil, Zaid Mahdi, Rahman Choudhary, Erkan Baloglu, William Senapedis, Yosef Landesman, Sharon Shacham, Michael Kauffman, Steve Kim, Rafic Beydoun, Richard N. Berri, Anthony Shields, Ramzi M. Mohammad, Asfar S. Azmi. Nuclear exporter protein XPO1 a novel prognostic and therapeutic target in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2491.

Burkholderia pseudomallei is a Gram-negative, facultative intracellular bacillus and the etiologic agent of melioidosis, a severe disease in Southeast Asia and Northern Australia. Like other multidrug-resistant pathogens, the inherent antibiotic resistance of B. pseudomallei impedes treatment and highlights the need for alternative therapeutic strategies that can circumvent antimicrobial resistance mechanisms. In this work, we demonstrate that host prostaglandin E2 (PGE2) production plays a regulatory role in the pathogenesis of B. pseudomallei. PGE2 promotes B. pseudomallei intracellular survival within macrophages and bacterial virulence in a mouse model of pneumonic melioidosis. PGE2-mediated immunosuppression of macrophage bactericidal effector functions is associated with increased arginase 2 (Arg2) expression and decreased nitric oxide (NO) production. Treatment with a commercially-available COX-2 inhibitor suppresses the growth of B. pseudomallei in macrophages and affords significant protection against rapidly lethal pneumonic melioidosis when administered post-exposure to B. pseudomallei-infected mice. COX-2 inhibition may represent a novel immunotherapeutic strategy to control infection with B. pseudomallei and other intracellular pathogens., Author Summary Burkholderia pseudomallei is the etiologic agent of melioidosis, a severe disease endemic in Southeast Asia and Northern Australia. B. pseudomallei is also classified as a Tier 1 select agent due to the threat of malicious use of the organism. Treatment of melioidosis is complicated by the inherent multidrug resistance of B. pseudomallei, leading to high case fatality rates or disease relapse. New therapeutic strategies are urgently needed to improve patient survival and to protect against a deliberate release of B. pseudomallei. Immunotherapeutics that can enhance the host immune response and delay disease progression represent a significant area of research interest. A number of immunomodulatory agents delivered locally to the lung prior to B. pseudomallei infection have afforded significant protection against pulmonary disease in animal models of melioidosis; however, their protective capacity significantly wanes upon post-exposure administration. In this work, we identify the PGE2 pathway as an immunotherapeutic target in pulmonary melioidosis and show that post-exposure COX-2 inhibition provides significant protection against lethal B. pseudomallei lung infection in mice. Further research examining FDA-approved COX-2 inhibitors as post-exposure prophylaxis for B. pseudomallei is warranted, as this may represent a safe, affordable, and efficacious immunotherapeutic strategy.